Antonio Hardan, M.D.

All Publications

• Psychometric evaluation of the Autism Symptom Dimensions Questionnaire. Developmental medicine and child neurology Frazier, T. W., Dimitropoulos, A., Abbeduto, L., Armstrong-Brine, M., Kralovic, S., Shih, A., Hardan, A. Y., Youngstrom, E. A., Uljarević, M. 2024

  Abstract

  To replicate and extend previous psychometric findings for the Autism Symptom Dimensions Questionnaire (ASDQ).Using a cross-sectional design in two samples, including a total of 3366 children and adolescents (aged 2-17 years; 1399 with autism spectrum disorder) and a small case series, factor structure, measurement invariance, reliability, construct validity, screening and diagnostic efficiency, and detection of reliable change were examined for the ASDQ.Strong psychometric properties were observed, including replicable factor structure, strong measurement invariance, adequate-to-excellent scale and conditional reliability, strong convergent and discriminant validity, and good screening efficiency. Importantly, two crucial measurement aspects required for a good treatment outcome measure were found, that is, good test-retest stability and the potential to detect reliable change. As expected for an informant-reported questionnaire, diagnostic efficiency was weak.The ASDQ showed evidence of favorable and well-replicated psychometric properties in two samples. Good screening but weak diagnostic efficiency, coupled with good test-retest stability, suggest that optimal clinical use is in screening and in detailed clinical characterization beyond what is offered by current informant-reported measures, with the potential for monitoring response to intervention. Despite relative brevity, the ASDQ provides good coverage of broad and specific aspects of the autism behavioral phenotype, which is consistent with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

  View details for DOI 10.1111/dmcn.16200

  View details for PubMedID 39699005

• Toward improved understanding and treatment of self-injurious behaviors in autistic individuals with profound intellectual disability. Autism research : official journal of the International Society for Autism Research Ferguson, E. F., Russell, K. M., Licona, S. J., Cai, R. Y., Frazier, T. W., Vivanti, G., Gengoux, G. W., Hardan, A. Y., Uljarević, M. 2024

  Abstract

  Self-injurious behaviors (SIB) commonly occur in autism spectrum disorder (ASD) and span diverse topographies of self-inflicted behaviors ranging from head banging to hitting oneself against hard objects. Despite the high rates of SIB in autistic individuals, relatively little research has focused on psychological factors associated with the development and maintenance of SIB in individuals with autism and moderate-profound intellectual disability (ID). This commentary synthesizes existing literature on SIB and highlights the need for more research focused on psychological correlates and mechanisms in autistic individuals with moderate-profound ID. We highlight the key role of difficulties in emotion regulation (ER) and co-occurring internalizing symptoms in the manifestation of self-harm behaviors in clinical samples and autism. Furthermore, this commentary proposes a framework for understanding the interplay between poor ER and internalizing symptoms in the development and maintenance of SIB in autistic individuals with moderate-profound ID. Specifically, we explore the emergence of SIB in the context of precipitating cues that trigger strong emotions, ER processes and strategy deployment, and co-occurring internalizing symptoms. Future directions and implications for longitudinal research, measurement development, and clinical treatments are discussed.

  View details for DOI 10.1002/aur.3289

  View details for PubMedID 39688125

• Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability. Autism research : official journal of the International Society for Autism Research Frazier, T. W., Busch, R. M., Klaas, P., Lachlan, K., Jeste, S., Kolevzon, A., Loth, E., Harris, J., Pepper, T., Anthony, K., Graglia, J. M., Helde, K., Delagrammatikas, C., Bedrosian-Sermone, S., Smith-Hicks, C., Sahin, M., Youngstrom, E. A., Eng, C., Chetcuti, L., Hardan, A. Y., Uljarevic, M. 2024

  Abstract

  Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome-PHTS; Malan Syndrome-NFIX; and SYNGAP1-related disorder-SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases. Participants (N = 467, age 3-45; PHTS n = 102, NFIX n = 23, SYNGAP1 n = 42, other NDGS n = 63, idiopathic NDD n = 53, neurotypical siblings n = 71, and unrelated neurotypical controls n = 113) completed a 4-min online-administered social attention paradigm that includes a variety of distinct stimuli at three timepoints (baseline, 1-month, and 4-month follow-up). Social attention measures had good scale and test-retest reliability, with the exception of measures of non-social preference and face-specific processing. Unique patterns of social attention emerged across study groups, with near neurotypical levels in PHTS and weaker social attention in NFIX and SYNGAP1 relative to controls. Global social attention had good accuracy in detecting ASD within NDGS participants. Remote monitoring social attention, including distinct aspects of social attention, may be useful for characterizing phenotypic profiles and tracking the natural history of distinct NDGS and idiopathic NDD as well as identifying ASD within NDGS. Given their reproducibility and stability, global social attention and several distinct social attention measures may be useful outcomes for future clinical trials.

  View details for DOI 10.1002/aur.3290

  View details for PubMedID 39643599

• Exploring the Heterogeneity of Self-Injurious Behaviors in Autistic Youth: Patterns, Predictors, and Implications for Intervention. Autism research : official journal of the International Society for Autism Research Ferguson, E. F., Spackman, E., Cai, R. Y., Hardan, A. Y., Uljarević, M. 2024

  Abstract

  Self-injurious behaviors (SIB) encompass a heterogeneous set of self-inflicted aggressive behaviors that are highly prevalent in autistic youth. Existing research on SIB in autism spectrum disorder (ASD) has been limited by significant methodological and conceptual inconsistencies. Thus, the current study leveraged item-level data capturing the severity of unique SIB topographies to further understanding of factors associated with distinct SIB in a sample of 582 autistic youth (Mage = 12.12, SDage = 3.68; range: 3-19 years; 13% females). Results suggest variation in severity endorsements for specific SIB topographies amongst autistic youth, such that 30%-50% of caregivers endorsed slight to very serious concern regarding the SIB topographies of bites nails/skin/fingers, scratches self, hits head/face/neck, bangs head against things, and picks skin. Generalized additive models demonstrated distinct patterns of associations between each SIB topography and dysregulation, sensory hypersensitivity, age, sex, IQ, and language level. Findings underscore the importance of exploring SIB as a multifaceted construct to capture unique correlates of distinct SIB that vary in severity and functional impact, which is critical for the development of effective interventions. This study represents an important step towards more individualized characterization of SIB and support for diverse presentations of these behaviors in autistic youth.

  View details for DOI 10.1002/aur.3269

  View details for PubMedID 39578711

• Neuromonitoring-guided working memory intervention in children with ADHD ISCIENCE Jounghani, A., Gozdas, E., Dacorro, L., Avelar-Pereira, B., Reitmaier, S., Fingerhut, H., Hong, D. S., Elliott, G., Hardan, A. Y., Hinshaw, S. P., Hosseini, S. 2024; 27 (11)

  View details for DOI 10.1016/j.isci.2024.111087

  View details for Web of Science ID 001336675300001

• Neuromonitoring-guided working memory intervention in children with ADHD. iScience Rahimpour Jounghani, A., Gozdas, E., Dacorro, L., Avelar-Pereira, B., Reitmaier, S., Fingerhut, H., Hong, D. S., Elliott, G., Hardan, A. Y., Hinshaw, S. P., Hosseini, S. M. 2024; 27 (11): 111087

  Abstract

  We proposed a personalized intervention that integrates computerized working memory (WM) training with real-time functional neuromonitoring and neurofeedback (NFB) to enhance frontoparietal activity and improve cognitive and clinical outcomes in children with attention-deficit/hyperactivity disorder (ADHD). The study involved 77 children with ADHD aged 7-11 years, who were assigned to either 12 sessions of NFB or treatment-as-usual (i.e., received standard clinical care) groups. Real-time neuromonitoring with functional near-infrared spectroscopy (fNIRS) and fMRI measured frontoparietal activity during n-back task at baseline and post-intervention. Thirty-six participants (21 NFB, 15 treatment-as-usual) completed the study. Significant improvements in NFB group were observed in frontoparietal brain activity and WM performance (primary outcomes). NFB group also showed improvements in Behavior Rating Inventory of Executive Function (BRIEF-2) WM t-scores and Conners 3 ADHD index scores (secondary outcomes) compared to treatment-as-usual group. These findings suggest that neuromonitoring-guided NFB effectively enhances cognitive and clinical outcomes in children with ADHD by targeting brain mechanisms underlying WM deficits.

  View details for DOI 10.1016/j.isci.2024.111087

  View details for PubMedID 39493886

  View details for PubMedCentralID PMC11530911

• Quantifying neurobehavioral profiles across neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders. Developmental medicine and child neurology Frazier, T. W., Busch, R. M., Klaas, P., Lachlan, K., Loth, E., Smith-Hicks, C., Sahin, M., Hardan, A. Y., Uljarevic, M. 2024

  Abstract

  To examine neurobehavioral findings in three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome [mutations in the NFIX gene], and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes (NDGS), idiopathic neurodevelopmental disorder, and neurotypical control participants.Using a longitudinal case-control design, caregivers reported neurobehavioral information for 498 participants (PTEN hamartoma tumor syndrome n = 112, Malan syndrome n = 24, SYNGAP1-related disorder n = 47, other NDGS n = 72, idiopathic neurodevelopmental disorder n = 54, neurotypical siblings n = 74, and unrelated neurotypical control participants n = 115) at three timepoints (baseline, and 1-month and 4-month follow-ups) using the online-administered Neurobehavioral Evaluation Tool (NET).NET scales had good scale and test-retest reliability. Unique patterns of neurobehavioral findings emerged, with SYNGAP1-related disorder and Malan syndrome showing generally more severe symptom and skill patterns than for other groups of patients. Patterns could be partly accounted for by estimated cognitive level, speech level, and the presence of autism spectrum disorder. However, even when accounting for these factors, group differences remained. Reliable change indices are reported.Genetic syndromes associated with neurodevelopmental disorders present with unique neurobehavioral profiles that can inform selection of outcome measures in future clinical trials. The NET may be a useful screening and monitoring instrument in clinical practice, where frequent in-person clinic attendance is difficult for many patients.

  View details for DOI 10.1111/dmcn.16112

  View details for PubMedID 39526825

• Characterizing associations between emotion dysregulation, anxiety, and repetitive behaviors in autistic youth with intellectual disability. Autism research : official journal of the International Society for Autism Research Ferguson, E. F., Spackman, E., Cai, R. Y., Hardan, A. Y., Uljarević, M. 2024

  Abstract

  There is a paucity of research that explores associations between emotion dysregulation and the expression and severity of core and co-occurring characteristics of autism spectrum disorder (ASD), especially in autistic youth with co-occurring intellectual disability (ID). This study explored the interplay between developmental characteristics and emotion dysregulation, anxiety, and specific subtypes of RRBs that are elevated in autistic youth with co-occurring ID. Generalized additive models demonstrated that age, sex, language level, dysregulation, and anxiety showed unique patterns of association with subtypes of RRBs in a sample of 150 autistic youth with co-occurring ID who are non-speaking or minimally verbal. More specifically, higher anxiety levels were significantly associated with elevations in repetitive sensory motor behaviors (RSMB), self-injurious behaviors (SIB), insistence on sameness (IS), and unusual interests (UI). While emotion dysregulation was a significant predictor of UI, it demonstrated positive, albeit not significant, associations with the intensity of SIB and RSMB. Language level was a significant predictor of RSMB, such that the intensity of RSMB was higher for individuals who were non-speaking relative to those who spoke in single words. These findings provide preliminary insights into patterns of associations between emotion dysregulation, anxiety, and specific subdomains of RRBs in autistic youth with ID.

  View details for DOI 10.1002/aur.3207

  View details for PubMedID 39166396

• Adherence and Opportunity Frequency as Predictors of Communication Outcomes from Pivotal Response Parent Training. Journal of autism and developmental disorders Minjarez, M. B., Gengoux, G. W., Paszek, K., Liang, J. A., Ardel, C. M., Hardan, A. Y., Frazier, T. 2024

  Abstract

  Access to intervention is a barrier for children with autism. As parent-mediated interventions have emerged to address this need, understanding implementation components contributing to child gains is critically important. Existing literature documents relationships between parent treatment adherence and child progress; however, less is understood about components, such as frequency of learning opportunities, which could also affect child outcomes.This study is a secondary analysis of data from a randomized controlled trial evaluating Pivotal Response Treatment group parent training (PRTG) compared to psychoeducation. Linear regression and mediational models were employed to identify potential predictors and mediators of outcome.PRTG produced large increases in adherence and learning opportunities. In general, greater frequency of learning opportunities and adherence predicted better child outcomes. The best-fitting cross-sectional mediational models indicated at least partial mediational effects, whereby increased learning opportunities mediated the relationship between greater adherence and improved child outcomes.This study provides preliminary evidence of how early gains in adherence may support parents to provide more frequent learning opportunities, which, in turn, yield positive effects on child social communication. Future large-scale research, with greater granularity of measurement, is needed to further understand the temporal relationships between these variables.

  View details for DOI 10.1007/s10803-024-06447-7

  View details for PubMedID 38976103

  View details for PubMedCentralID 2213686

• Characterising Insistence on Sameness and Circumscribed Interests: A Qualitative Study of Parent Perspectives. Journal of autism and developmental disorders Spackman, E., Geng, A., Smillie, L. D., Frazier, T. W., Hardan, A. Y., Alvarez, G. A., Whitehouse, A., Schuck, R. K., Leekam, S. R., Uljarević, M. 2024

  Abstract

  Manifestations of insistence on sameness (IS) and circumscribed interests (CI) are complex, with individuals varying considerably, not only in the types of behaviours they express, but also in terms of a behaviour's frequency, intensity, trajectory, adaptive benefits, and impacts. However, current quantitative RRB instruments capture only certain aspects of these behaviours (e.g., mostly frequency or general "severity"). Thus, the current study utilised a semi-structured caregiver interview to provide an in-depth, qualitative characterization of different aspects of IS and CI presentation. Caregivers of 27 autistic children and adolescents displaying IS and/or CI behaviours (3-16 years; 18 males; 9 females) participated in a semi-structured interview. Responses were analysed using thematic framework analysis. Framework analysis identified nine different aspects of IS and CI presentation: (1) intensity, (2) frequency, (3) emergence of behaviour, (4) changes over time, (5) day-to-day fluctuations, (6) purpose/adaptive benefit, (7) experiences of distress, (8) challenges for the individual, their family, and their socialisation, and (9) management strategies and their effectiveness. Autistic children and adolescents were reported to vary greatly on each of these dimensions. Findings demonstrate the complexity of IS and CI presentations and highlight the need for more comprehensive quantitative assessments that independently assess the frequency, intensity, and impact of behaviours. Further, findings reported here emphasize the need for ecologically valid measures that assess the contexts in which these behaviours occur and how their presentations can change within and across days.

  View details for DOI 10.1007/s10803-024-06404-4

  View details for PubMedID 38809473

  View details for PubMedCentralID 4543385

• Exploring the neurological features of individuals with germline PTEN variants: A multicenter study. Annals of clinical and translational neurology Dhawan, A., Baitamouni, S., Liu, D., Busch, R., Klaas, P., Frazier, T. W., Srivastava, S., Parikh, S., Hsich, G. E., Friedman, N. R., Ritter, D. M., Hardan, A. Y., Martinez-Agosto, J. A., Sahin, M., Eng, C. 2024

  Abstract

  OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described.METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12months for a mean of 2.1years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported.RESULTS: One hundred and seven patients with PHTS (median age 8.7years; range 3-21years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service.INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

  View details for DOI 10.1002/acn3.52046

  View details for PubMedID 38501559

• Vasopressin deficiency: a hypothesized driver of both social impairment and fluid imbalance in autism spectrum disorder. Molecular psychiatry Clarke, L., Gesundheit, N., Sherr, E. H., Hardan, A. Y., Parker, K. J. 2024

  View details for DOI 10.1038/s41380-024-02497-6

  View details for PubMedID 38454082

• A Pilot Randomized Controlled Trial of Motivation-Based Social Skills Group Treatment with Parent Training. Journal of autism and developmental disorders Shkel, J., Geng, A., Pilchak, E., Millan, M. E., Schwartzman, J. M., Schuck, R., Bundang, M. V., Barnowski, A., Slap, D. M., Stratford, S., Hardan, A. Y., Phillips, J. M., Gengoux, G. W. 2024

  Abstract

  Despite the popularity of social skills groups, there remains a need for empirical investigation of treatment effects, especially when targeting pivotal aspects of social functioning such as initiations to peers. The goal of the present study was to conduct a randomized controlled trial of a 12-week social intervention (SUCCESS), which combined an inclusive social group with a parent education program. Twenty-five 4- to 6-year-olds with Autism Spectrum Disorder (ASD) were randomized to SUCCESS (N=11) or to treatment as usual (N=14). Combining a peer group model with a parent training program, the SUCCESS intervention used naturalistic behavioral techniques (e.g., environmental arrangement, natural reinforcement) to increase social initiations to peers. After 12 weeks, children participating in the SUCCESS program made more frequent initiations to peers than children in the treatment-as-usual group, including more prompted and unprompted initiations to request. Additional gains in clinician-rated social functioning were observed in children randomized to SUCCESS, while differential treatment effects were not detected in parent-rated measures. However, lower baseline social motivation was associated with greater parent-reported initiation improvement. This study provides preliminary support for the efficacy of a naturalistic, behavioral social skills intervention to improve peer initiations for children with ASD. The findings suggest that using a motivation-based social skills group was effective in increasing both prompted and spontaneous initiations to peers, and highlights the need for further research into the role of baseline social motivation in predicting social skills treatment response.

  View details for DOI 10.1007/s10803-024-06302-9

  View details for PubMedID 38446265

• Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial. Cell host & microbe Mazzone, L., Dooling, S. W., Volpe, E., Uljarević, M., Waters, J. L., Sabatini, A., Arturi, L., Abate, R., Riccioni, A., Siracusano, M., Pereira, M., Engstrand, L., Cristofori, F., Adduce, D., Francavilla, R., Costa-Mattioli, M., Hardan, A. Y. 2023

  Abstract

  Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.

  View details for DOI 10.1016/j.chom.2023.11.021

  View details for PubMedID 38113884

• A RESEARCH DOMAIN CRITERIA (RDOC) APPROACH TO CHARACTERIZE SOCIAL COGNITION IN YOUTH WITH ADHD AND ASD Hardan, A., Phillips, J. M., Frazier, T., Uljarevic, M. ELSEVIER SCIENCE INC. 2023: S355

  View details for DOI 10.1016/j.jaac.2023.07.734

  View details for Web of Science ID 001098830401467

• UTILIZING THE RESEARCH DOMAIN CRITERIA (RDOC) FRAMEWORK TO ADVANCE UNDERSTANDING OF SOCIAL DEFICITS ACROSS NEURODEVELOPMENTAL AND NEUROPSYCHIATRIC DISORDERS Uljarevic, M., Hardan, A. ELSEVIER SCIENCE INC. 2023: S389

  View details for DOI 10.1016/j.jaac.2023.07.856

  View details for Web of Science ID 001098830401571

• IDENTIFYING ASD SOCIAL SUBTYPES IN ASD: A PRELIMINARY STUDY USING THE RESEARCH DOMAIN CRITERIA (RDOC) FRAMEWORK Uljarevic, M., Phillips, J. M., Hardan, A. ELSEVIER SCIENCE INC. 2023: S389

  View details for DOI 10.1016/j.jaac.2023.07.857

  View details for Web of Science ID 001098830401572

• ADVANCING UNDERSTANDING OF NEURODEVELOPMENTAL AND NEUROPSYCHIATRIC DISORDERS THROUGH NOVEL ASSESSMENTS Uljarevic, M., Scahill, L., Hardan, A. ELSEVIER SCIENCE INC. 2023: S398

  View details for DOI 10.1016/j.jaac.2023.07.892

  View details for Web of Science ID 001098830401597

• CHARACTERIZING MECHANISMS UNDERPINNING INSISTENCE ON SAMENESS IN CHILDREN AND ADOLESCENTS WITH ASD Pascale, I., Spackman, E., Hardan, A., Uljarevic, M. ELSEVIER SCIENCE INC. 2023: S294-S295

  View details for DOI 10.1016/j.jaac.2023.09.435

  View details for Web of Science ID 001098830401285

• DEVELOPMENT AND VALIDATION OF THE DIMENSIONAL ASSESSMENT OF RESTRICTED AND REPETITIVE BEHAVIORS Uljarevic, M., Hardan, A. ELSEVIER SCIENCE INC. 2023: S399

  View details for DOI 10.1016/j.jaac.2023.07.895

  View details for Web of Science ID 001098830401600

• Characterizing subdomains of insistence on sameness in autistic youth. Autism research : official journal of the International Society for Autism Research Spackman, E., Smillie, L. D., Frazier, T. W., Hardan, A. Y., Uljarevic, M. 2023

  Abstract

  Insistence on sameness (IS) encompasses a range of behavioral patterns, including resistance to change, routines, and ritualized behaviors, that can be present across social and non-social contexts. Given the breadth of behaviors encompassed by IS, it is important to determine whether this domain is best conceptualized and measured as uni- or a multi-dimensional construct. Therefore, the current study aimed to characterize the structure of IS and explore potentially distinct of patterns of associations between identified IS factors and relevant correlates, including age, sex, IQ, anxiety, social abilities, emotional and behavioral dysregulation, and sensory hypersensitivity. Exploratory graph analysis was conducted using the dimensional assessment of restricted and repetitive behaviors to examine the structure of IS in a sample 1892 autistic youth (Mage =10.82, SDage =4.14; range: 3-18years; 420 females) recruited from the Simons Foundation Powering Autism Research for Knowledge cohort. Three distinct IS subdomains labeled as IS-Ritualistic/sameness, IS-Routines, and IS-Others (referring to IS behaviors during interactions with others)were identified. Generalized additive models demonstrated that each of the IS subdomains showed a unique pattern of association with key variables. More specifically, while sensory hypersensitivity was significantly associated with IS-Ritualistic/sameness and IS-Routines, it was not associated with IS-Others. Further, while emotional dysregulation was a unique predictor of IS-Ritualistic/sameness (but not IS-Routines or IS-Others), social interaction abilities were a unique predictor of IS-Routines (but not IS-Ritualistic/sameness or IS-Others). Current findings provide preliminary evidence that the IS may encompass several distinct subdomains.

  View details for DOI 10.1002/aur.3033

  View details for PubMedID 37735979

• Electronic health records identify timely trends in childhood mental health conditions. Child and adolescent psychiatry and mental health Elia, J., Pajer, K., Prasad, R., Pumariega, A., Maltenfort, M., Utidjian, L., Shenkman, E., Kelleher, K., Rao, S., Margolis, P. A., Christakis, D. A., Hardan, A. Y., Ballard, R., Forrest, C. B. 2023; 17 (1): 107

  Abstract

  BACKGROUND: Electronic health records (EHRs) data provide an opportunity to collect patient information rapidly, efficiently and at scale. National collaborative research networks, such as PEDSnet, aggregate EHRs data across institutions, enabling rapid identification of pediatric disease cohorts and generating new knowledge for medical conditions. To date, aggregation of EHR data has had limited applications in advancing our understanding of mental health (MH) conditions, in part due to the limited research in clinical informatics, necessary for the translation of EHR data to child mental health research.METHODS: In this cohort study, a comprehensive EHR-based typology was developed by an interdisciplinary team, with expertise in informatics and child and adolescent psychiatry, to query aggregated, standardized EHR data for the full spectrum of MH conditions (disorders/symptoms and exposure to adverse childhood experiences (ACEs), across 13 years (2010-2023), from 9 PEDSnet centers. Patients with and without MH disorders/symptoms (without ACEs), were compared by age, gender, race/ethnicity, insurance, and chronic physical conditions. Patients with ACEs alone were compared with those that also had MH disorders/symptoms. Prevalence estimates for patients with 1+ disorder/symptoms and for specific disorders/symptoms and exposure to ACEs were calculated, as well as risk for developing MH disorder/symptoms.RESULTS: The EHR study data set included 7,852,081 patients<21 years of age, of which 52.1% were male. Of this group, 1,552,726 (19.8%), without exposure to ACEs, had a lifetime MH disorders/symptoms, 56.5% being male. Annual prevalence estimates of MH disorders/symptoms (without exposure to ACEs) rose from 10.6% to 2010 to 15.1% in 2023, a 44% relative increase, peaking to 15.4% in 2019, prior to the Covid-19 pandemic. MH categories with the largest increases between 2010 and 2023 were exposure to ACEs (1.7, 95% CI 1.6-1.8), anxiety disorders (2.8, 95% CI 2.8-2.9), eating/feeding disorders (2.1, 95% CI 2.1-2.2), gender dysphoria/sexual dysfunction (43.6, 95% CI 35.8-53.0), and intentional self-harm/suicidality (3.3, 95% CI 3.2-3.5). White youths had the highest rates in most categories, except for disruptive behavior disorders, elimination disorders, psychotic disorders, and standalone symptoms which Black youths had higher rates. Median age of detection was 8.1 years (IQR 3.5-13.5) with all standalone symptoms recorded earlier than the corresponding MH disorder categories.CONCLUSIONS: These results support EHRs' capability in capturing the full spectrum of MH disorders/symptoms and exposure to ACEs, identifying the proportion of patients and groups at risk, and detecting trends throughout a 13-year period that included the Covid-19 pandemic. Standardized EHR data, which capture MH conditions is critical for health systems to examine past and current trends for future surveillance. Our publicly available EHR-mental health typology codes can be used in other studies to further advance research in this area.

  View details for DOI 10.1186/s13034-023-00650-7

  View details for PubMedID 37710303

• Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes. American journal of medical genetics. Part C, Seminars in medical genetics Frazier, T. W., Busch, R. M., Klaas, P., Lachlan, K., Jeste, S., Kolevzon, A., Loth, E., Harris, J., Speer, L., Pepper, T., Anthony, K., J Michael, G., Delagrammatikas, C. G., Bedrosian-Sermone, S., Smith-Hicks, C., Huba, K., Longyear, R., Green-Snyder, L., Shic, F., Sahin, M., Eng, C., Hardan, A. Y., Uljarević, M. 2023

  Abstract

  This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.

  View details for DOI 10.1002/ajmg.c.32058

  View details for PubMedID 37534867

• Anxiety, concerns and COVID-19: Cross-country perspectives from families and individuals with neurodevelopmental conditions. Journal of global health Sideropoulos, V., Van Herwegen, J., Meuleman, B., Alessandri, M., Alnemary, F. M., Rad, J. A., Lavenex, P. A., Bolshakov, N., Bolte, S., Buffle, P., Cai, R. Y., Campos, R., Chirita-Emandi, A., Costa, A. P., Costanzo, F., Des Portes, V., Dukes, D., Faivre, L., Famelart, N., Fisher, M. H., Gamaiunova, L., Giannadou, A., Gupta, R., Hardan, A. Y., Houdayer-Robert, F., Hrncirova, L., Iaochite, R. T., Jariabkova, K., Klein-Tasman, B. P., Lavenex, P., Malik, S., Mari, F., Martinez-Castilla, P., Menghini, D., Nuske, H. J., Palikara, O., Papon, A., Pegg, R. S., Pouretemad, H., Poustka, L., Prosetzky, I., Renieri, A., Rhodes, S. M., Riby, D. M., Rossi, M., Sadeghi, S., Su, X., Tai, C., Tran, M., Tynan, F., Uljarevic, M., Van Hecke, A. V., Veiga, G., Verloes, A., Vicari, S., Werneck-Rohrer, S. G., Zander, E., Samson, A. C. 2023; 13: 04081

  Abstract

  Background: The COVID-19 pandemic had a major impact on the mental health and well-being of children with neurodevelopmental conditions (NDCs) and of their families worldwide. However, there is insufficient evidence to understand how different factors (e.g., individual, family, country, children) have impacted on anxiety levels of families and their children with NDCs developed over time.Methods: We used data from a global survey assessing the experience of 8043 families and their children with NDCs (mean of age (m)=13.18 years, 37% female) and their typically developing siblings (m=12.9 years, 45% female) in combination with data from the European Centre for Disease Prevention and Control, the University of Oxford, and the Central Intelligence Agency (CIA) World Factbook, to create a multilevel data set. Using stepwise multilevel modelling, we generated child-, family- and country-related factors that may have contributed to the anxiety levels of children with NDCs, their siblings if they had any, and their parents. All data were reported by parents.Results: Our results suggest that parental anxiety was best explained by family-related factors such as concerns about COVID-19 and illness. Children's anxiety was best explained by child-related factors such as children's concerns about loss of routine, family conflict, and safety in general, as well as concerns about COVID-19. In addition, anxiety levels were linked to the presence of pre-existing anxiety conditions for both children with NDCs and their parents.Conclusions: The present study shows that across the globe there was a raise in anxiety levels for both parents and their children with NDCs because of COVID-19 and that country-level factors had little or no impact on explaining differences in this increase, once family and child factors were considered. Our findings also highlight that certain groups of children with NDCs were at higher risk for anxiety than others and had specific concerns. Together, these results show that anxiety of families and their children with NDCs during the COVID-19 pandemic were predicted by very specific concerns and worries which inform the development of future toolkits and policy. Future studies should investigate how country factors can play a protective role during future crises.

  View details for DOI 10.7189/jogh.13.04081

  View details for PubMedID 37497751

• A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Hegarty, J. P., Monterrey, J. C., Tian, Q., Cleveland, S. C., Gong, X., Phillips, J. M., Wolke, O., McNab, J. A., Hallmayer, J., Reiss, A. L., Hardan, A. Y., Lazzeroni, L. C. 2023

  Abstract

  OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD.METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a new version of the twin-pair difference score analysis method that estimates the contribution of genetic and environmental factors to shared covariance between different brain and behavioral traits.RESULTS: Good quality data were available from 84 twin pairs, 50 ASD pairs [32 concordant for ASD (16 monozygotic; 16 dizygotic), 16 discordant for ASD (3 monozygotic; 13 dizygotic), and 2 pairs in which one twin had ASD and the other exhibited some subthreshold symptoms (1 monozygotic; 1 dizygotic)] and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A=0.80 [0.57,1.02]; A=0.80 [0.55,1.04]) and twins concordant for having ASD (A=0.71 [0.33,1.09]; A= 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD, e.g., our new twin-pair difference-scores analysis indicated that genetic factors may have contributed to 40-50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD, e.g., twin-pair difference-scores suggested that unique environmental factors may have contributed to 10-20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule.CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences.DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

  View details for DOI 10.1016/j.jaac.2023.05.030

  View details for PubMedID 37406770

• Categorical versus dimensional structure of autism spectrum disorder: A multi-method investigation. JCPP advances Frazier, T. W., Chetcuti, L., Al-Shaban, F. A., Haslam, N., Ghazal, I., Klingemier, E. W., Aldosari, M., Whitehouse, A. J., Youngstrom, E. A., Hardan, A. Y., Uljarevic, M. 2023; 3 (2): e12142

  Abstract

  Background: A key question for any psychopathological diagnosis is whether the condition is continuous or discontinuous with typical variation. The primary objective of this study was to use a multi-method approach to examine the broad latent categorical versus dimensional structure of autism spectrum disorder (ASD).Method: Data were aggregated across seven independent samples of participants with ASD, other neurodevelopmental disorders (NDD), and non-ASD/NDD controls (aggregate Ns=512-16,755; ages 1.5-22). Scores from four distinct phenotype measures formed composite "indicators" of the latent ASD construct. The primary indicator set included eye gaze metrics from seven distinct social stimulus paradigms. Logistic regressions were used to combine gaze metrics within/across paradigms, and derived predicted probabilities served as indicator values. Secondary indicator sets were constructed from clinical observation and parent-report measures of ASD symptoms. Indicator sets were submitted to taxometric- and latent class analyses.Results: Across all indicator sets and analytic methods, there was strong support for categorical structure corresponding closely to ASD diagnosis. Consistent with notions of substantial phenotypic heterogeneity, the ASD category had a wide range of symptom severity. Despite the examination of a large sample with a wide range of IQs in both genders, males and children with lower IQ were over-represented in the ASD category, similar to observations in diagnosed cases.Conclusions: Our findings provide strong support for categorical structure corresponding closely to ASD diagnosis. The present results bolster the use of well-diagnosed and representative ASD groups within etiologic and clinical research, motivating the ongoing search for major drivers of the ASD phenotype. Despite the categorical structure of ASD, quantitative symptom measurements appear more useful for examining relationships with other factors.

  View details for DOI 10.1002/jcv2.12142

  View details for PubMedID 37753161

• Arriving at the empirically based conceptualization of restricted and repetitive behaviors: A systematic review and meta-analytic examination of factor analyses. Clinical psychology review Uljarevic, M., Spackman, E. K., Whitehouse, A. J., Frazier, T. W., Billingham, W., Condron, P., Hardan, A., Leekam, S. R. 2023; 103: 102286

  Abstract

  An empirically based understanding of the factor structure of the restricted and repetitive behaviors (RRB) domain is a prerequisite for interpreting studies attempting to understand the correlates and mechanisms underpinning RRB and for measurement development. Therefore, this study aimed to conduct a systematic review and meta-analysis of RRB factor analytic studies. Sets of meta-analyses were performed to examine (a) the factor structure of individual RRB instruments, (b) associations between RRB subdomains across instruments, and (c) the association between RRB factors and other variables. Searches for peer-reviewed articles evaluating the factor structure of the RRB domain were performed in PsycINFO (Ovid), Medline (Ovid), and Embase (Ovid). No age, measurement, or informant-type limits were imposed. Quality and risk of bias for individual studies were assessed using relevant COSMIN sections. Among the 53 studies retained for review, 41 examined RRB factor structures among individuals with autism spectrum disorder (ASD) and 12 among non-ASD samples. Meta-analysis of factor correlations provided evidence that the RRB domain encompasses the following eight specific factors: repetitive motor behaviors, insistence on sameness, restricted interests, unusual interests, sensory sensitivity, and repetitive, stereotyped language. Although interrelated, RRB factors were distinct, showing a unique pattern of associations with demographic, cognitive, and clinical correlates. Meta-analyses of the associations between RRB factors and specific correlates, specifically adaptive functioning and communication impairments, should be considered preliminary due to the limited number of studies. Despite limitations, this review provides important insights into the factor structure of the RRB domain and highlights critical conceptual, measurement, and methodological limitations of the current research that will need to be addressed in order to improve our understanding of RRB.

  View details for DOI 10.1016/j.cpr.2023.102286

  View details for PubMedID 37269778

• Reliability of the Commonly Used and Newly-Developed Autism Measures. Journal of autism and developmental disorders Frazier, T. W., Whitehouse, A. J., Leekam, S. R., Carrington, S. J., Alvares, G. A., Evans, D. W., Hardan, A. Y., Uljarević, M. 2023

  Abstract

  The aim of the present study was to compare scale and conditional reliability derived from item response theory analyses among the most commonly used, as well as several newly developed, observation, interview, and parent-report autism instruments.When available, data sets were combined to facilitate large sample evaluation. Scale reliability (internal consistency, average corrected item-total correlations, and model reliability) and conditional reliability estimates were computed for total scores and for measure subscales.Generally good to excellent scale reliability was observed for total scores for all measures, scale reliability was weaker for RRB subscales of the ADOS and ADI-R, reflecting the relatively small number of items for these measures. For diagnostic measures, conditional reliability tended to be very good (> 0.80) in the regions of the latent trait where ASD and non-ASD developmental disability cases would be differentiated. For parent-report scales, conditional reliability of total scores tended to be excellent (> 0.90) across very wide ranges of autism symptom levels, with a few notable exceptions.These findings support the use of all of the clinical observation, interview, and parent-report autism symptom measures examined, but also suggest specific limitations that warrant consideration when choosing measures for specific clinical or research applications.

  View details for DOI 10.1007/s10803-023-05967-y

  View details for PubMedID 37017861

  View details for PubMedCentralID 4608982

• Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change. Journal of neurodevelopmental disorders Busch, R. M., Frazier Ii, T. W., Sonneborn, C., Hogue, O., Klaas, P., Srivastava, S., Hardan, A. Y., Martinez-Agosto, J. A., Sahin, M., Eng, C. 2023; 15 (1): 3

  Abstract

  BACKGROUND: Individuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2-3 evaluations) over a 2-year time period.METHODS: Comprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6-21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test-retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS.RESULTS: Wide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test-retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12months was small (range-3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS.CONCLUSIONS: Our results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.

  View details for DOI 10.1186/s11689-022-09468-4

  View details for PubMedID 36641436

• The Autism Symptom Dimensions Questionnaire: Development and psychometric evaluation of a new, open-source measure of autism symptomatology. Developmental medicine and child neurology Frazier, T. W., Dimitropoulos, A., Abbeduto, L., Armstrong-Brine, M., Kralovic, S., Shih, A., Hardan, A. Y., Youngstrom, E. A., Uljarevic, M., Quadrant Biosciences - As You Are Team, Speer, L., Wagner, K., West, K., Uhlig, R. 2023

  Abstract

  AIM: To describe the development and initial psychometric evaluation of a new, freely available measure, the Autism Symptom Dimensions Questionnaire (ASDQ).METHOD: After development and revision of an initial 33-item version, informants completed a revised 39-item version of the ASDQ on 1467 children and adolescents (aged 2-17years), including 104 with autism spectrum disorder (ASD).RESULTS: The initial 33-item version of the ASDQ had good reliability and construct validity. However, only four specific symptom factors were identified, potentially due to an insufficient number of items. Factor analyses of the expanded instrument identified a general ASD factor and nine specific symptom factors with good measurement invariance across demographic groups. Scales showed good-to-excellent overall and conditional reliability. Exploratory analyses of predictive validity for ASD versus neurotypical and other developmental disability diagnoses indicated good accuracy for population and at-risk contexts.INTERPRETATION: The ASDQ is a free and psychometrically sound informant report instrument with good reliability of measurement across a continuous range of scores and preliminary evidence of predictive validity. The measure may be a useful alternative to existing autism symptom measures but further studies with comparison of clinical diagnoses using criterion-standard instruments are needed.

  View details for DOI 10.1111/dmcn.15497

  View details for PubMedID 36628521

• Profiles of circumscribed interests in autistic youth. Frontiers in behavioral neuroscience Spackman, E., Smillie, L. D., Frazier, T. W., Hardan, A. Y., Alvares, G. A., Whitehouse, A., Uljarevic, M. 2023; 17: 1037967

  Abstract

  Circumscribed interests (CI) encompass a range of different interests and related behaviors that can be characterized by either a high intensity but otherwise usual topic [referred to as restricted interests (RI)] or by a focus on topics that are not salient outside of autism [referred to as unusual interests (UI)]. Previous research has suggested that there is pronounced variability across individuals in terms of the endorsement of different interests, however, this variability has not been quantified using formal subtyping approaches. Therefore, using Latent Profile Analysis in a sample of 1,892 autistic youth (Mage = 10.82, SDage = 4.14; 420 females), this study aimed to identify subgroups based on the RU and UI profiles. Three profiles of autistic individuals were identified. They were characterized as Low CI, Predominantly RI, and Predominantly UI. Importantly, profiles differed on several key demographic and clinical variables, including age, sex composition, IQ, language level, social and communication abilities, anxiety, and obsessive-compulsive behaviors. Although replication across other samples is needed, the profiles identified in this study are potentially promising for future research given their distinct profiles of RI and UI and unique patterns of associations with key cognitive and clinical variables. Therefore, this study represents an important initial step towards more individualized assessment and support for diverse presentations of CI in autistic youth.

  View details for DOI 10.3389/fnbeh.2023.1037967

  View details for PubMedID 36844650

• Dimensional Assessment of Restricted and Repetitive Behaviors: Development and Preliminary Validation of a New Measure. Journal of the American Academy of Child and Adolescent Psychiatry Uljarević, M., Frazier, T. W., Jo, B., Scahill, L., Youngstrom, E. A., Spackman, E., Phillips, J. M., Billingham, W., Hardan, A. 2022

  Abstract

  This paper provides initial validation of the Dimensional Assessment of Restricted and Repetitive Behaviors (DARB)-a new parent-report measure designed to capture the full range of key of restricted and repetitive behaviors (RRB) subdomains.Parents of 1892 children and adolescents with autism spectrum disorder (ASD) (M= 10.81 years; SD= 4.14) recruited from the Simons Foundation Powering Autism Research for Knowledge (SPARK) research match completed the DARB, several existing RRB instruments, and measures of social and communication impairments and anxiety. A subsample of 450 parents completed the DARB after two weeks to evaluate test-retest stability.Exploratory graph analysis (EGA) conducted in the exploratory subsample identified eight dimensions that were aligned with our hypothesized RRB subdomains: repetitive sensory motor behaviors (RSMB), insistence on sameness (IS), restricted interests (RI), unusual interests (UI), sensory sensitivity (SS), self-injurious behaviors (SIB), obsessions and compulsive behaviors (OCB) and repetitive language (RL). The confirmatory application of the exploratory structural equation modeling conducted in the confirmatory subsample showed that the derived factor structure had a good fit to the data. Derived factors had excellent reliability, convergent and divergent validity, very strong test-retest stability, and showed a distinct pattern of associations with key demographic cognitive and clinical correlates.DARB will be useful in a variety of research and clinical contexts considering the prominence and clinical impact of RRB in ASD. The strong preliminary evidence indicates that the new scale is comprehensive and captures a wide range of distinct RRB subdomains not simultaneously captured by any of the existing instruments.

  View details for DOI 10.1016/j.jaac.2022.07.863

  View details for PubMedID 36526162

• Characterizing restricted and unusual interests in autistic youth. Autism research : official journal of the International Society for Autism Research Spackman, E., Smillie, L., Frazier, T. W., Hardan, A. Y., Alvares, G. A., Whitehouse, A., Uljarević, M. 2022

  Abstract

  A broad range of interests characterized by unusual content and/or intensity, labeled as circumscribed interests (CI), are a core diagnostic feature of autism. Recent evidence suggests that a distinction can be drawn between interests that, although characterized by unusually high intensity and/or inflexibility, are otherwise common in terms of their content (e.g., an interest in movies or animals), labeled as restricted interests (RI), and interests that are generally not salient outside of autism (e.g., an interest in traffic lights or categorization), labeled as unusual interests (UI). The current study aimed to further characterize RI and UI by exploring their association with age, sex, IQ, and social motivation, as well as to examine differences in the adaptive benefits and negative impacts of these two subdomains. Parents of 1892 autistic children and adolescents (Mage  = 10.82, SDage  = 4.14; 420 females) completed an online survey including the Dimensional Assessment of Restricted and Repetitive Behaviors and the Social Communication Questionnaire. Both RI and UI were found to be highly frequent. Sex-based differences were observed in the content, but not intensity, of CI such that females were more likely to show interests with a social component. Finally, RI and UI showed distinct patterns of association with age, sex, IQ, and social motivation, as well as metrics of adaptive benefits and negative impacts. Findings afford a more nuanced understanding of sex-based differences in CI and, crucially, provide preliminary evidence that RI and UI represent distinct constructs that should be studied independently in future research.

  View details for DOI 10.1002/aur.2863

  View details for PubMedID 36453155

• Sleep architecture is associated with core symptom severity in autism spectrum disorder. Sleep Kawai, M., Buck, C., Chick, C. F., Anker, L., Talbot, L., Schneider, L., Linkovski, O., Cotto, I., Parker-Fong, K., Phillips, J., Hardan, A., Hallmayer, J., O'Hara, R. 2022

  Abstract

  OBJECTIVE: While caregiver-reported sleep disturbances are common in children and adolescents with autism spectrum disorder (ASD), few studies have measured objective sleep in ASD compared to controls, and their findings are mixed. We investigated 1) differences in sleep architecture, specifically slow-wave sleep (SWS) and rapid eye movement sleep (REM), between ASD and typically developing controls (TD); and 2) if any observed differences in sleep were associated with core ASD symptoms.METHODS: We used ambulatory polysomnography (PSG) in 53 participants with ASD (ages 6 to 18) and 66 age-matched TD in their home sleeping environment. The primary outcome measures were SWS and REM sleep. Core behavioral ASD symptoms were assessed using the Autism Diagnostic Interview-Revised (ADI-R). Spectral power bands during sleep, and additional behavioral measures, were examined in exploratory analyses.RESULTS: Compared to TD, participants with ASD exhibited a higher SWS ratio and lower REM ratio. Within the ASD group, higher SWS was associated with more severe symptoms on the Restricted, Repetitive, and Stereotyped Behaviors subscale of the ADI-R. No association was observed between REM ratio and any ASD symptom.CONCLUSIONS: Increased SWS and reduced REM sleep ratio differentiated ASD from TD. However, only increased SWS was associated with more severe core ASD symptoms. Increased SWS may reflect neuronal immaturity specific to ASD in this age group. These findings may inform the underlying mechanisms of clinical symptoms observed in children and adolescents with ASD.

  View details for DOI 10.1093/sleep/zsac273

  View details for PubMedID 36385326

• Maladaptive behaviors in children with autism and parental hopelessness: The moderating role of parental reflective functioning. Autism research : official journal of the International Society for Autism Research Enav, Y., Knudtson, M. V., Hardan, A. Y., Gross, J. J. 2022

  Abstract

  Hopelessness in parents has implications for parents' own well-being as well as their ability to meet the needs of their children. In the present study, we examined the effect of maladaptive behaviors in children with autism on parental hopelessness, with particular attention to whether parental reflective functioning would moderate the effect of maladaptive behaviors on parental hopelessness. Our sample included 68 parents of children with autism between the ages of 3 and 18. Findings revealed a significant positive relationship between maladaptive behaviors in the children and hopelessness in the parents. Moreover, parental reflective functioning moderated the effect of child maladaptive behaviors on parental hopelessness, such that children's maladaptive behaviors were positively associated with parental hopelessness in parents with low (but not high) reflective functioning. Findings suggest parental reflective functioning may be a protective factor against parental hopelessness, and thus a possible target for interventions for hopelessness in parents whose children with autism exhibit greater maladaptive behaviors.

  View details for DOI 10.1002/aur.2841

  View details for PubMedID 36333959

• INTRODUCING KIDSFIRST: A DIVERSE, LONGITUDINAL PHENOTYPIC DATABASE FOR FAMILIES WITH ASD McNealis, M., Kent, J., Dunlap, K., Abbeduto, L., Dimitropoulos, A., Dombrose, F., Hardan, A., Lane, J., Phillips, B., Rodriguez, N., Wall, D. P. ELSEVIER SCIENCE INC. 2022: S245-S246

  View details for DOI 10.1016/j.jaac.2022.09.334

  View details for Web of Science ID 000873567901179

• BRAIN STIMULATION INTERVENTIONS IN ASD: EFFORTS FOR THE DEVELOPMENT OF A PROMISING INTERVENTION APPROACH Ameis, S., Freitag, C. M., Hardan, A. ELSEVIER SCIENCE INC. 2022: S313

  View details for DOI 10.1016/j.jaac.2022.07.691

  View details for Web of Science ID 000873567901378

• Understanding the heterogeneity of anxiety in autistic youth: A person-centered approach. Autism research : official journal of the International Society for Autism Research Spackman, E., Lerh, J. W., Rodgers, J., Hollocks, M. J., South, M., McConachie, H., Ozsivadjian, A., Vaughan Van Hecke, A., Libove, R., Hardan, A. Y., Leekam, S. R., Simonoff, E., Frazier, T. W., Alvares, G. A., Schwartzman, J. M., Magiati, I., Uljarevic, M. 2022

  Abstract

  The present study aimed to examine anxiety profiles among children and adolescents on the autism spectrum. It further aimed to characterize the association between the identified anxiety profiles and key clinical and developmental variables. The Spence Children's Anxiety Scale-Parent Version (SCAS-P) data from a large international pooled sample of 870 caregivers of autistic children and adolescents (Mage =11.6years, SDage =2.77; 107 females) was used. Latent profile analysis identified a three-anxiety profile solution exhibiting high entropy (0.80) and high latent profile probabilities, with good classification accuracy. Identified profiles fell along the severity spectrum and were named as the mild (n=498), moderate (n=272) and severe (n=100) anxiety profiles. There were no statistically significant differences between the three anxiety profiles in terms of sex distribution. Participants in the mild profile were significantly younger than those in the severe profile, had significantly fewer social communication difficulties than youth in the moderate anxiety profile group and had significantly fewer restricted and repetitive behaviors and lower cognitive functioning scores compared to participants in moderate and severe anxiety profiles. This is the first study to move beyond identifying associations and group-level differences to exploring and identifying characteristics of anxiety-based subgroups at an individual level that differ on key clinical and developmental variables. The subgroups identified in this study are a preliminary, yet important, first step towards informing future assessment and individualized interventions aiming to support young people on the autism spectrum to reduce and manage anxiety. LAY SUMMARY: This study tried to understand if there are subgroups of autistic young people who may have similar anxiety profiles. We found that we could meaningfully group young people into three groups based on how severe the anxiety symptoms their caregivers reported were: a group with low levels of anxiety, those with moderate anxiety, and those with more severe anxiety. We also found that the young people in the mild group were younger, had fewer autism traits and lower levels of intellectual functioning than young people in the other two groups.

  View details for DOI 10.1002/aur.2744

  View details for PubMedID 35642170

• A randomized controlled trial of Everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Human molecular genetics Srivastava, S., Jo, B., Zhang, B., Frazier, T., Gallagher, A. S., Peck, F., Levin, A. R., Mondal, S., Li, Z., Filip-Dhima, R., Geisel, G., Dies, K. A., Diplock, A., Eng, C., Hanna, R., Sahin, M., Hardan, A. 2022

  Abstract

  PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mTOR (mechanistic target of rapamycin) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism.We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners' Continuous Performance Test hit reaction time, and Purdue Pegboard Test score.Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (p < 0.001). Changes in the primary endpoint between groups from baseline to month 6 were not apparent (Cohen's d = -0.10, p = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior, and global improvement. There was a significant difference in EEG central alpha power (p = 0.049) and central beta power (p = 0.039) six months after everolimus treatment.Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.

  View details for DOI 10.1093/hmg/ddac111

  View details for PubMedID 35594551

• Big Data Approach to Characterize Restricted and Repetitive Behaviors in Autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Uljarevic, M., Frazier, T. W., Jo, B., Billingham, W. D., Cooper, M. N., Youngstrom, E. A., Scahill, L., Hardan, A. Y. 2022; 61 (3): 446-457

  View details for Web of Science ID 000760602800015

• Characterizing Emotion Recognition and Theory of Mind Performance Profiles in Unaffected Siblings of Autistic Children FRONTIERS IN PSYCHOLOGY Uljarevic, M., Bott, N. T., Libove, R. A., Phillips, J. M., Parker, K. J., Hardan, A. Y. 2022; 12: 736324

  Abstract

  Emotion recognition skills and the ability to understand the mental states of others are crucial for normal social functioning. Conversely, delays and impairments in these processes can have a profound impact on capability to engage in, maintain, and effectively regulate social interactions. Therefore, this study aimed to compare the performance of 42 autistic children (Mage = 8.25 years, SD = 2.22), 45 unaffected siblings (Mage = 8.65 years, SD = 2.40), and 41 typically developing (TD) controls (Mage = 8.56 years, SD = 2.35) on the Affect Recognition (AR) and Theory of Mind (TOM) subtests of the Developmental Neuropsychological Assessment Battery. There were no significant differences between siblings and TD controls. Autistic children showed significantly poorer performance on AR when compared to TD controls and on TOM when compared to both TD controls and unaffected siblings. An additional comparison of ASD, unaffected sibling and TD control subsamples, matched on full-scale IQ, revealed no group differences for either AR or TOM. AR and TOM processes have received less research attention in siblings of autistic children and remain less well characterized. Therefore, despite limitations, findings reported here contribute to our growing understanding of AR and TOM abilities in siblings of autistic children and highlight important future research directions.

  View details for DOI 10.3389/fpsyg.2021.736324

  View details for Web of Science ID 000766850000001

  View details for PubMedID 35283803

  View details for PubMedCentralID PMC8907847

• Subdomains of restricted and repetitive behaviors within autism: Exploratory structural equation modeling using the diagnostic interview for social and communication disorders. Autism research : official journal of the International Society for Autism Research Uljarevic, M., Carrington, S. J., Hardan, A. Y., Leekam, S. R. 2022

  Abstract

  The current study aimed to explore the factor structure of a broad range of restricted and repetitive behaviors (RRB) within the autism spectrum. Exploratory structural equation modeling was conducted using individual item-level data from the Diagnostic Interview for Social and Communication Disorders (DISCO). DISCO is a comprehensive semi-structured interview used by clinicians to elicit information from caregivers about the individual's profile of development and behavior. Data from a sample of 226 individuals with a clinical diagnosis of autism spectrum disorder (ASD) (189 males; Mage = 11.82years, SDage =7.87) were analyzed. The six-factor structure provided the most optimal and interpretable fit (comparative fit index=0.944, Tucker-Lewis index=0.923, root mean square error of approximation=0.018). Derived factors were interpreted as repetitive motor behaviors (RMB), unusual sensory and object focused interests (USOI), sensory sensitivity (SS), insistence on sameness (IS), circumscribed interests (CI) and stereotyped language (SL). Age was significantly negatively associated with RMB, USOI and SL but not with SS, IS or CI factor scores. None of the factors were associated with sex. ASD individuals with intellectual disability (ID) had the highest RMB, USOI, SS and SL scores while those without ID had the highest IS and CI scores. Our findings provide preliminary evidence for the utility of the DISCO as a comprehensive measure of several distinct RRB domains in both research and clinical contexts. Importantly, the current investigation highlights crucial areas for measurement development.

  View details for DOI 10.1002/aur.2687

  View details for PubMedID 35178885

• Daily living skills scale: Development and preliminary validation of a new, open-source assessment of daily living skills. Frontiers in psychiatry Uljarević, M., Spackman, E. K., Cai, R. Y., Paszek, K. J., Hardan, A. Y., Frazier, T. W. 2022; 13: 1108471

  Abstract

  Autistic individuals and individuals with a range of other neurodevelopmental conditions (NDD) often present with lower levels of daily living skills (DLS) when compared to their neurotypical peers. Importantly, lower levels of DLS have been linked to a range of negative outcomes, including lower rates of post-secondary education, lower employment rates, and higher daily support needs across autism and NDD. However, there are currently no open-source informant-reported instruments for capturing key aspects of DLS. This study describes the development, refinement, and initial psychometric evaluation of a new, relatively brief (53-item). Daily Living Skills Scale (DLSS) in a sample of 1,361 children aged 2-17 years, Confirmatory Factor Analysis demonstrated an excellent fit of unidimensional model to the data (CFI = 0.953, TLI = 0.951, RMSEA = 0.073 [95% CI: 0.071-0.074]). The single-factor CFA model showed evidence of measurement invariance of factor loadings, thresholds, and residual variance (strict invariance) across sex, age, race, and ethnicity. Model reliability and internal consistency were excellent (ω = 0.98; α = 0.97). Conditional reliability estimates indicated very good reliability (= 0.80) for the total DLS scale from very low (θ = -4.2) to high (θ = +2.4) scores. Conceptually derived self-care, homecare, and community participation subscales also showed strong reliability and internal consistency. With further replication, the EFS has excellent potential for wide adoption across research and clinical contexts.

  View details for DOI 10.3389/fpsyt.2022.1108471

  View details for PubMedID 36756637

  View details for PubMedCentralID PMC9900738

• Characterizing dermatologic findings among patients with PTEN hamartoma tumor syndrome: results of a multi-center cohort study. Journal of the American Academy of Dermatology Morgan, F. C., Yehia, L., McDonald, C., Martinez-Agosto, J. A., Hardan, A. Y., Tamburro, J., Sahin, M., Bayart, C., Eng, C. 2022

  Abstract

  Dermatologic phenotypes in PTEN hamartoma tumor syndrome (PHTS) are heterogeneous and poorly documented.To characterize dermatologic findings among PHTS and conduct an analysis of genotype-dermatologic phenotype associations.Mucocutaneous findings were reviewed in a multi-center cohort study of PHTS. Genotype-dermatologic phenotype associations were tested using multivariable regression.A total of 201 patients were included. Children were significantly less likely than adults to have oral papillomas, vascular malformations, benign follicular neoplasms, and acral keratoses. There were no cases of skin cancer among children. Basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma developed in 5%, 2%, and 1% of white adults, respectively. After adjusting for age, missense mutations were associated with 60% lower odds of developing cutaneous papillomatous papules (Odds Ratio: 0.4; 95% Confidence Interval: [0.2, 0.7]), oral papillomas (0.4; [0.2, 0.9]), and vascular malformations (0.4; [0.2, 0.8]).Partly retrospective data CONCLUSION: Children are less likely than adults to have certain dermatologic findings, likely due to age-related penetrance. The risk of pediatric melanoma and the life-time risk of non-melanoma skin cancer in PHTS may not be elevated. Missense variants may be associated with the development of fewer dermatologic findings but future validation is required.

  View details for DOI 10.1016/j.jaad.2022.01.045

  View details for PubMedID 35143913

• Development and validation of the Executive Functioning Scale. Frontiers in psychiatry Uljarevic, M., Cai, R. Y., Hardan, A. Y., Frazier, T. W. 2022; 13: 1078211

  Abstract

  Executive functioning (EF) processes are essential for adaptive and flexible responding to the demands and complexities of everyday life. Conversely, if impaired, these processes are a key transdiagnostic risk factor that cuts across autism and a range of other neurodevelopmental (NDD) and neuropsychiatric (NPD) conditions. However, there are currently no freely available informant-report measures that comprehensively characterize non-affective (e.g., working memory, response inhibition, and set shifting) and affective (e.g., emotion regulation) EF subdomains. This study describes the development, refinement, and initial psychometric evaluation of a new 52-item Executive Functioning Scale (EFS). Two independent data collections yielded exploratory (n = 2004, 169 with autism, ages 2-17) and confirmatory (n = 954, 74 with autism, ages 2-17) samples. Exploratory Structural Equation Modeling (ESEM) model with six specific factors that closely matched hypothesized executive functioning subdomains of working memory and sequencing, response inhibition, set-shifting, processing speed, emotion regulation, and risk avoidance, and one general factor, showed the best fit to the data and invariance across age, sex, race, and ethnicity groups. Model reliability and internal consistency were excellent for the general factor (omega = 0.98; alpha = 0.97) and specific factors (omega ≥ 0.89-0.96; alpha ≥ 0.84-0.94). Conditional reliability estimates indicated excellent reliability (≥0.90) for the total EF scale and adequate or better reliability (≥0.70) for subscale scores. With further replication, the EFS has excellent potential for wide adoption across research and clinical contexts.

  View details for DOI 10.3389/fpsyt.2022.1078211

  View details for PubMedID 36704728

• FAR: End-to-End Vibrotactile Distributed System Designed to Facilitate Affect Regulation in Children Diagnosed with Autism Spectrum Disorder Through Slow Breathing Miri, P., Arora, M., Malhotra, A., Flory, R., Hu, S., Lowber, A., Goyal, I., Nguyen, J., Hegarty, J., Kohn, M., Schneider, D., Culbertson, H., Yamins, D. K., Fung, L., Hardan, A., Gross, J. J., Marzullo, K., ACM ASSOC COMPUTING MACHINERY. 2022

  View details for DOI 10.1145/3491102.3517619

  View details for Web of Science ID 000922929503024

• Editorial: Precision medicine approaches for heterogeneous conditions such as autism spectrum disorders (The need for a biomarker exploration phase in clinical trials - Phase 2m). Frontiers in psychiatry Beversdorf, D. Q., Anagnostou, E., Hardan, A., Wang, P., Erickson, C. A., Frazier, T. W., Veenstra-VanderWeele, J. 2022; 13: 1079006

  View details for DOI 10.3389/fpsyt.2022.1079006

  View details for PubMedID 36741580

• Cognitive reappraisal training for parents of children with autism spectrum disorder. Frontiers in psychiatry Enav, Y., Hardan, A. Y., Gross, J. J. 2022; 13: 995669

  Abstract

  Parents of children with autism spectrum disorder (ASD) experience higher stress levels than those of typically developing children. The goal of the current study was to examine whether a mentalization-based intervention would enhance parental cognitive reappraisal, an adaptive form of emotion regulation associated with lower levels of stress. Findings from 27 parents who completed a short training indicated an improvement in cognitive reappraisal. In exploratory analyses, two different types of reappraisal were examined. The intervention-related improvement was found mainly with one type of reappraisal, namely reflective reappraisal that consist of cognitive reappraisal with mentalization characteristics. In light of the evidence indicating that high cognitive reappraisal and high reflective functioning are associated with quality caregiving, findings from the current study suggesting that a brief mentalization-based intervention supports ASD parents' cognitive reappraisal with mentalization characteristics are promising and warrant further investigation.

  View details for DOI 10.3389/fpsyt.2022.995669

  View details for PubMedID 36386964

• Toward better characterization of restricted and unusual interests in youth with autism. Autism : the international journal of research and practice Uljarevic, M., Alvares, G. A., Steele, M., Edwards, J., Frazier, T. W., Hardan, A. Y., Whitehouse, A. J. 2021: 13623613211056720

  Abstract

  LAY ABSTRACT: Despite being highly prevalent among people with autism, restricted and unusual interests remain under-researched and poorly understood. This article confirms that restricted interests are very frequent and varied among children and adolescents with autism. It also further extends current knowledge in this area by characterizing the relationship between the presence, number, and type of restricted interests with chronological age, sex, cognitive functioning, and social and communication symptoms.

  View details for DOI 10.1177/13623613211056720

  View details for PubMedID 34818937

• Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations. American journal of medical genetics. Part A Uljarevic, M., Frazier, T. W., Rached, G., Busch, R. M., Klaas, P., Srivastava, S., Martinez-Agosto, J. A., Sahin, M., Eng, C., Hardan, A. Y., Developmental Synaptopathies Consortium 2021

  Abstract

  This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage =8.93years, SDage =4.75), 25 Macro-ASD (Mage =11.99years; SDage =5.15), and 23 PTEN-No ASD (Mage =8.94years; SDage =4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F=4.52, p=0.014, omega2 =0.08), insistence on sameness (IS; F=4.11, p=0.02, omega2 =0.05), and circumscribed interests (CI; F=7.80, p=0.001, omega2 =0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

  View details for DOI 10.1002/ajmg.a.62458

  View details for PubMedID 34423884

• Big Data Approach to Characterize Restricted and Repetitive Behaviors in Autism. Journal of the American Academy of Child and Adolescent Psychiatry Uljarevic, M., Frazier, T. W., Jo, B., Billingham, W. D., Cooper, M. N., Youngstrom, E. A., Scahill, L., Hardan, A. Y. 2021

  Abstract

  OBJECTIVE: Despite being a core diagnostic feature of autism spectrum disorder (ASD), developmental and clinical correlates of restricted and repetitive behaviors and interests (RRB) remain poorly characterized. This study aimed to utilize the largest available RRB data set to date to provide a comprehensive characterization of how distinct RRB domains vary according to a range of individual characteristics.METHOD: Data were obtained from 17,581 children and adolescents with ASD (Mage= 8.24 years, SDage= 4.06) from the Simons Foundation Powering Autism Research for Knowledge cohort. Caregivers completed the Repetitive Behavior Scale-Revised questionnaire as a measure of repetitive motor behaviors, self-injurious behaviors, compulsions, insistence on sameness and circumscribed interests RRB domains. Caregivers also provided information on children's cognitive functioning, language ability and social and communication impairments.RESULTS: Male sex was associated with higher severity of repetitive motor behaviors and restricted interests and lower severity of compulsions and self-injurious behaviors; no sex differences were found for insistence on sameness domain. While repetitive motor behaviors showed a mostly linear (negative) association with age, other RRB domains showed more complex and non-linear associations. Higher severity of social and communication impairments provided significant independent contribution in predicting higher severity of all RRB domains at the p< .001, however, these effects were small (d< .25). The strongest of these effects was observed for Ritualistic/Sameness (d=.24), followed by Stereotypy (d=.21), Compulsions (d=.17), Restricted Interests (d=.14) and SIB (d=.12).CONCLUSION: Findings reported here provide further evidence that RRB subdomains show a somewhat distinct pattern of associations with demographic, developmental and clinical variables with a key implication that separate consideration of these domains can help to facilitate efforts to understand diverse ASD etiology and inform the design of future interventions.

  View details for DOI 10.1016/j.jaac.2021.08.006

  View details for PubMedID 34391858

• Brief Report: Emotion Regulation Influences on Internalizing and Externalizing Symptoms Across the Normative-Clinical Continuum FRONTIERS IN PSYCHIATRY Cai, R., Hardan, A. Y., Phillips, J. M., Frazier, T. W., Uljarevi, M. 2021; 12: 693570

  Abstract

  Emotion regulation is theorized to be a transdiagnostic process and has been empirically shown to be associated with various mental health and neurodevelopmental conditions. However, the relationship between emotion regulation and internalizing and externalizing symptoms has yet to be characterized in a sample of individuals spanning normative and atypical development. Therefore, this study aimed to provide initial evidence for emotion regulation as a transdiagnostic process of internalizing and externalizing symptoms in a community sample of adolescents with and without neuropsychiatric and neurodevelopmental conditions. The sample consisted of 1,705 caregivers of adolescents aged between 11 and 17 years (M age = 14.53, SD age = 1.96). Adolescents were typically developing or had a caregiver-reported diagnosis of autism spectrum disorder, attention-deficit hyperactivity disorder, or anxiety. The typically developing adolescents had significantly better caregiver-reported emotion regulation than adolescents with caregiver-reported neuropsychiatric and neurodevelopmental conditions. Additionally, emotion dysregulation significantly and positively correlated with and predicted internalizing and externalizing symptoms within each subgroup. Importantly, emotion dysregulation had a unique contribution to individual differences in the severity of internalizing and externalizing symptoms, above and beyond the diagnostic status. The research and translational implications of the study findings are discussed.

  View details for DOI 10.3389/fpsyt.2021.693570

  View details for Web of Science ID 000681093200001

  View details for PubMedID 34366922

  View details for PubMedCentralID PMC8333703

• Relationship Between Social Motivation in Children With Autism Spectrum Disorder and Their Parents FRONTIERS IN NEUROSCIENCE Uljarevic, M., Frazier, T. W., Jo, B., Phillips, J. M., Billingham, W., Cooper, M. N., Hardan, A. Y. 2021; 15: 660330

  Abstract

  Impairment in social motivation (SM) has been suggested as a key mechanism underlying social communication deficits observed in autism spectrum disorder (ASD). However, the factors accounting for variability in SM remain poorly described and understood. The current study aimed to characterize the relationship between parental and proband SM. Data from 2,759 children with ASD (M age = 9.03 years, SD age = 3.57, 375 females) and their parents from the Simons Simplex Collection (SSC) project was included in this study. Parental and proband SM was assessed using previously identified item sets from the Social Responsiveness Scale (SRS). Children who had parents with low SM scores (less impairments) showed significantly lower impairments in SM compared to children who had either one or both parents with elevated SM scores. No parent-of-origin effect was identified. No significant interactions were found involving proband sex or intellectual disability (ID) status (presence/absence of ID) with paternal or maternal SM. This study establishes that low SM in children with ASD may be driven, in part, by lower SM in one or both parents. Future investigations should utilize larger family pedigrees, including simplex and multiplex families, evaluate other measures of SM, and include other related, yet distinct constructs, such as social inhibition and anhedonia. This will help to gain finer-grained insights into the factors and mechanisms accounting for individual differences in sociability among typically developing children as well as those with, or at risk, for developing ASD.

  View details for DOI 10.3389/fnins.2021.660330

  View details for Web of Science ID 000658890500001

  View details for PubMedID 34121990

  View details for PubMedCentralID PMC8187582

• A case-control study of visual, auditory and audio-visual sensory interactions in children with autism spectrum disorder. Journal of vision Norcia, A. M., Lee, A., Meredith, W. J., Kohler, P. J., Pei, F., Ghassan, S. A., Libove, R. A., Phillips, J. M., Hardan, A. Y. 2021; 21 (4): 5

  Abstract

  To assess the relative integrity of early visual and auditory processes in autism spectrum disorder (ASD), we used frequency-tagged visual and auditory stimulation and high-density electroencephalogram recordings of unimodal and dual-modality responses in a case-control design. To test for the specificity of effects on ASD, we recorded from a smaller group of children with attention-deficit hyperactivity disorder (ADHD). Horizontal 3 cycle per degree (cpd) gratings were presented at 5 Hz, and a random stream of /ba/, /da/, /ga/ syllables was presented at 6 Hz. Grating contrast response functions were measured unimodally and in the presence of a 64-dB auditory input. Auditory response functions were measured unimodally and in the presence of a 40% contrast grating. Children with ASD (n = 34) and ADHD (n = 13) showed a common lack of audio-visual interaction compared to typically developing children (n = 40) when measured at the first harmonic of the visual stimulus frequency. Both patient groups also showed depressed first harmonic responses at low contrast, but the ADHD group had consistently higher first-harmonic responses at high contrast. Children with ASD had a preferential loss of second-harmonic (transient) responses. The alteredtransient responses in ASD are likely to arise very early in the visual pathway and could thus have downstream consequences for many other visual mechanisms and processes. The alteration in audio-visual interaction could be a signature of a comorbid phenotype shared by ASD and ADHD, possibly due to alterations in attentional selection systems.

  View details for DOI 10.1167/jov.21.4.5

  View details for PubMedID 33830169

• Parenting stress in autism spectrum disorder may account for discrepancies in parent and clinician ratings of child functioning. Autism : the international journal of research and practice Schwartzman, J. M., Hardan, A. Y., Gengoux, G. W. 2021: 1362361321998560

  Abstract

  LAY ABSTRACT: Elevated parenting stress among parents of children with autism spectrum disorder is well-documented; however, there is limited information about differences in parenting stress and potential relationships with parent ratings of child functioning. The aim of this study was to explore profiles of parenting stress among 100 parents of young children with autism spectrum disorder enrolled in two clinical trials and to explore relationships between parenting stress level and parent ratings of child functioning before treatment. Secondary aims examined differential patterns of association between parenting stress profiles and parent versus clinician ratings of child functioning. We show that stress may influence parent ratings of certain child behaviors (e.g. problem behaviors) and not others (e.g. language), yet clinician ratings of these same children do not differ. This new understanding of parenting stress has implications for parent-rated measures, tracking treatment outcome, and the design of clinical trials.

  View details for DOI 10.1177/1362361321998560

  View details for PubMedID 33691519

• A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations. Contemporary clinical trials communications Hardan, A. Y., Jo, B., Frazier, T. W., Klaas, P., Busch, R. M., Dies, K. A., Filip-Dhima, R., Snow, A. V., Eng, C., Hanna, R., Zhang, B., Sahin, M. 2021; 21: 100733

  Abstract

  This randomized, double-blind controlled trial of everolimus in individuals with germline phosphatase and tensin homolog mutations (PTEN) was designed to evaluate the safety of everolimus compared with placebo and to evaluate the efficacy of everolimus on neurocognition and behavior compared to placebo as measured by standardized neurocognitive and motor measures as well as behavioral questionnaires. The safety profile of everolimus is characterized by manageable adverse events that are generally reversible and non-cumulative. The primary safety endpoint of this study was drop-out rate due to side effects, comparing everolimus versus placebo. We also sought to determine the frequency of adverse events by type and severity. The main efficacy endpoint was a neurocognitive composite computed in two ways: 1) an average for working memory, processing speed, and fine motor subtests; and 2) the same average as above except weighted 2/3, and an additional average based on all other available neurocognitive testing measures assessing the additional domains of nonverbal ability, visuomotor skills, verbal learning, and receptive and expressive language, weighted 1/3. Secondary efficacy endpoints examined the effect of everolimus on overall global clinical improvement, autism symptoms, behavioral problems, and adaptive abilities as measured by validated, standardized instruments. We predicted that the rate of adverse events would be no more than 10% higher in the everolimus group compared to placebo, and overall severity of side effects would be minimal. We also expected that individuals receiving everolimus would show more improvement, relative to those taking placebo, on the composite neurocognitive index.

  View details for DOI 10.1016/j.conctc.2021.100733

  View details for PubMedID 33644493

• Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations. Journal of autism and developmental disorders Uljarevic, M., Frazier, T. W., Rached, G., Busch, R. M., Klaas, P., Srivastava, S., Martinez-Agosto, J. A., Sahin, M., Eng, C., Hardan, A. Y., Developmental Synaptopathies Consortium 2021

  Abstract

  This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; Mage=8.93years, SDage=4.75), 23 with PTENmutationwithout ASD (PTEN-no ASD; Mage=8.94years; SDage=4.85) and 25 with ASD and macrocephaly but with noPTENmutation (Macro-ASD; Mage=11.99years; SDage=5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t=4.12, p<0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD.

  View details for DOI 10.1007/s10803-021-04881-5

  View details for PubMedID 33595755

• A Longitudinal Study of Language Trajectories and Treatment Outcomes of Early Intensive Behavioral Intervention for Autism. Journal of autism and developmental disorders Frazier, T. W., Klingemier, E. W., Anderson, C. J., Gengoux, G. W., Youngstrom, E. A., Hardan, A. Y. 2021

  Abstract

  The present study examined language trajectories and placement outcomes for children with autism spectrum disorder (ASD) receiving early intensive behavioral intervention (EIBI). Language measures were collected at baseline and 6, 12, 18, 24, and 36months or until exit from EIBI in 131 children with ASD. Growth models estimated overall and subgroup language trajectories. Overall, children receiving EIBI showed substantial increases in language relative to normative expectations. Earlier age at EIBI start, higher baseline cognitive function, and lower baseline ASD severity predicted better language trajectories. Although there was significant variability in language trajectories and educational outcomes, most children showed significant increases in language scores, relative to normative expectations. Additional research, in more representative samples, is needed to understand this variability.

  View details for DOI 10.1007/s10803-021-04900-5

  View details for PubMedID 33559016

• Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism. Molecular autism Frazier, T. W., Jaini, R., Busch, R. M., Wolf, M., Sadler, T., Klaas, P., Hardan, A. Y., Martinez-Agosto, J. A., Sahin, M., Eng, C., Developmental Synaptopathies Consortium, Warfield, S. K., Scherrer, B., Dies, K., Filip-Dhima, R., Gulsrud, A., Hanson, E., Phillips, J. M. 2021; 12 (1): 5

  Abstract

  BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort.METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model.RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status.LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments.CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures.TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446.

  View details for DOI 10.1186/s13229-020-00406-6

  View details for PubMedID 33509259

• Language Improvement Following Pivotal Response Treatment for Children With Developmental Disorders. American journal on intellectual and developmental disabilities Schwartzman, J. M., Strong, K. n., Ardel, C. M., Schuck, R. K., Millan, M. E., Phillips, J. M., Hardan, A. Y., Gengoux, G. W. 2021; 126 (1): 45–57

  Abstract

  Given the high prevalence of communication deficits in developmental disorders, there is need for efficient early interventions. The aim of this pilot study is to examine benefits of pivotal response treatment (PRT) for improving language in young children with developmental disorders without autism spectrum disorder. Parents of 15 children with developmental disorders received weekly PRT parent training for 12 weeks. Standardized parent-rated assessments were administered at baseline and post-treatment to measure changes in language. Structured laboratory observation indicated children demonstrated significantly greater frequency of utterances and improvement on standardized questionnaires measuring expressive language and adaptive communication skills following PRT. Findings suggest that PRT may be efficacious in improving language abilities among children with developmental disorders.

  View details for DOI 10.1352/1944-7558-126.1.45

  View details for PubMedID 33370790

• SUPPORTING WORKING PARENTS IN AN ACADEMIC PSYCHIATRY DEPARTMENT DURING THE COVID-19 PANDEMIC: THE VIRTUAL CHILD ENGAGEMENT PROGRAM White, D., Aufderheide, C., Figueroa, J., Meza, E., Bundang, M., Libove, R., Gengoux, G., Hardan, A. ELSEVIER SCIENCE INC. 2021: S207

  View details for DOI 10.1016/j.jaac.2021.09.237

  View details for Web of Science ID 000707082801083

• Using the big data approach to clarify the structure of restricted and repetitive behaviors across the most commonly used autism spectrum disorder measures. Molecular autism Uljarević, M., Jo, B., Frazier, T. W., Scahill, L., Youngstrom, E. A., Hardan, A. Y. 2021; 12 (1): 39

  Abstract

  Restricted and repetitive behaviors (RRB) in autism spectrum disorder (ASD) encompass several distinct domains. However, commonly used general ASD measures provide broad RRB scores rather than assessing separate RRB domains. The main objective of the current investigation was to conduct a psychometric evaluation of the ability of the Social Responsiveness Scale (SRS-2), the Social Communication Questionnaire (SCQ), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to capture different RRB constructs.Exploratory Structural Equation Modeling (ESEM) was conducted using individual item-level data from the SRS-2, SCQ, ADI-R and the ADOS. Data were obtained from five existing publicly available databases. For the SRS-2, the final sample consisted of N = 16,761 individuals (Mage = 9.43, SD = 3.73; 18.5% female); for the SCQ, of N = 15,840 (Mage = 7.99, SD = 4.06; 18.1% female); for the ADI-R, of N = 8985 (Mage = 8.86, SD = 4.68; 19.4% female); and for the ADOS, of N = 6314 (Mage = 12.29, SD = 6.79; 17.7% female).The three-factor structure provided the most optimal and interpretable fit to data for all measures (comparative fit index ≥ .983, Tucker Lewis index ≥ .966, root mean square error of approximation ≤ .028). Repetitive-motor behaviors, insistence on sameness and unusual or circumscribed interests factors emerged across all instruments. No acceptable fit was identified for the ADOS.The five datasets used here afforded a large as well as wide distribution of the RRB item scores. However, measures used for establishing convergent and divergent validity were only available for a portion of the sample.Reported findings offer promise for capturing important RRB domains using general ASD measures and highlight the need for measurement development.

  View details for DOI 10.1186/s13229-021-00419-9

  View details for PubMedID 34044873

• Psychiatric Characteristics Across Individuals With PTEN Mutations. Frontiers in psychiatry Steele, M., Uljarevic, M., Rached, G., Frazier, T. W., Phillips, J. M., Libove, R. A., Busch, R. M., Klaas, P., Martinez-Agosto, J. A., Srivastava, S., Eng, C., Sahin, M., Hardan, A. Y. 2021; 12: 672070

  Abstract

  Germline heterozygous PTEN mutations have been associated with high prevalence of autism spectrum disorder (ASD) and elevated rates and severity of broadly defined behavioral problems. However, limited progress has been made toward understanding whether PTEN mutation is associated with specific psychiatric co-morbidity profiles when compared to idiopathic ASD. The current study aimed to utilize a cross-measure approach to compare concurrent psychiatric characteristics across children and adolescents with PTEN mutation with (PTEN-ASD; n = 38) and without ASD (PTEN-No ASD; n = 23), and ASD with macrocephaly but no PTEN mutation (macro-ASD; n = 25) using the Child Behavior Checklist (CBCL) and the Aberrant Behavior Checklist (ABC). There were significant group effects for the CBCL Internalizing and Externalizing broad symptom score, the majority of specific CBCL syndrome scores, and all ABC subscale scores. Post-hoc comparisons revealed greater behavioral symptoms in the ASD groups (PTEN-ASD and macro-ASD) compared to the PTEN-no ASD group on nearly all subtest scores examined. There were no statistically significant differences between the PTEN-ASD and macro-ASD groups; however, there was a trend for the macro-ASD group showing higher levels of aggressive behaviors. Our findings provide evidence of specific behavior profiles across PTEN-No ASD, PTEN-ASD, and macro-ASD groups and highlight the importance of early identification of behavioral vulnerabilities in individuals with PTEN mutations in order to provide access to appropriate evidence-based interventions.

  View details for DOI 10.3389/fpsyt.2021.672070

  View details for PubMedID 34489750

• Examining Effectiveness and Predictors of Treatment Response of Pivotal Response Treatment in Autism: An Umbrella Review and a Meta-Analysis. Frontiers in psychiatry Uljarevic, M., Billingham, W., Cooper, M. N., Condron, P., Hardan, A. Y. 2021; 12: 766150

  Abstract

  The current study aimed to provide a comprehensive appraisal of the current evidence on the effectiveness of Pivotal Response Training (PRT) for individuals with autism spectrum disorder (ASD) and to explore predictors of treatment response. We conducted a systematic review of the following electronic databases and registers: PsycINFO, Medline, Embase, Cochrane Central Register of Controlled Trials, ERIC, Linguistics and Language Behavior Abstracts. Six systematic reviews were identified, two with meta-analytic component. Identified reviews varied widely in terms of their aims, outcomes, and designs which precluded a unified and consistent set of conclusions and recommendations. Ten RCTs were identified. Eight of identified RCTs reported at least one language and communication-related outcome. Statistically significant effects of PRT were identified across a majority of identified RCTs for a range of language and communication skills. However, evidence for positive treatment effects of PRT on outcome measures assessing other domains was less robust and/or specific. Overall, both previous systematic reviews and new meta-analysis of the RCTs suggest that PRT shows promise for improving language and communication. Only four RCTs examined the association between baseline child characteristics and treatment outcomes, however, no consistent pattern emerged. This review has identified several key methodological and design improvements that are needed to enable our field to fully capitalize on the potential of RCT designs and characterize detailed profiles of treatment responders. These findings are essential for informing the development of evidence-based guidelines for clinicians on what works for whom and why.

  View details for DOI 10.3389/fpsyt.2021.766150

  View details for PubMedID 35153850

• Temperament in individuals with Autism Spectrum Disorder: A systematic review. Clinical psychology review Chetcuti, L. n., Uljarević, M. n., Ellis-Davies, K. n., Hardan, A. Y., Whitehouse, A. J., Hedley, D. n., Putnam, S. n., Hudry, K. n., Prior, M. R. 2021; 85: 101984

  Abstract

  The study of temperament in Autism Spectrum Disorder (ASD) has the potential to provide insight regarding variability in the onset, nature, and course of both core and co-morbid symptoms. The aim of this systematic review was to integrate existing findings concerning temperament in the context of ASD. Searches of Medline, PsychInfo and Scopus databases identified 64 relevant studies. As a group, children and adolescents with ASD appear to be temperamentally different from both typically developing and other clinical non-ASD groups, characterized by higher negative affectivity, lower surgency, and lower effortful control at a higher-order level. Consistent with research on typically developing children, correlational findings and emerging longitudinal evidence suggests that lower effortful control and higher negative affect are associated with increased internalizing and externalizing problems in ASD samples. Longitudinal studies suggest there may be temperamental differences between high familial risk infants who do and do not develop ASD from as early as 6-months of age. Limitations of existing research are highlighted, and possible directions for future research to capitalize on the potential afforded through the study of temperament in relation to ASD are discussed.

  View details for DOI 10.1016/j.cpr.2021.101984

  View details for PubMedID 33607568

• Enhancing Social Initiations Using Naturalistic Behavioral Intervention: Outcomes from a Randomized Controlled Trial for Children with Autism. Journal of autism and developmental disorders Gengoux, G. W., Schwartzman, J. M., Millan, M. E., Schuck, R. K., Ruiz, A. A., Weng, Y. n., Long, J. n., Hardan, A. Y. 2021

  Abstract

  Deficits in social skills are common in children with Autism Spectrum Disorder (ASD), and there is an urgent need for effective social skills interventions, especially for improving interactions with typically developing peers. This study examined the effects of a naturalistic behavioral social skills intervention in improving social initiations to peers through a randomized controlled trial. Analyses of multimethod, multi-informant measures indicated that children in the active group (SIMI) demonstrated greater improvement in the types of initiations which were systematically prompted and reinforced during treatment (i.e., behavior regulation). Generalization to joint attention and social interaction initiation types, as well as collateral gains in broader social functioning on clinician- and parent-rated standardized measures were also observed.

  View details for DOI 10.1007/s10803-020-04787-8

  View details for PubMedID 33387236

• Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder MOLECULAR PSYCHIATRY Hegarty, J. P., Pegoraro, L. L., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2020; 25 (10): 2556–66

  View details for DOI 10.1038/s41380-018-0330-z

  View details for Web of Science ID 000572540100029

• NOVEL EARLY INTERVENTION IN AUTISM SPECTRUM DISORDER: BASIC PRINCIPLES AND NEW RESEARCH Hardan, A., Gengoux, G. W., Veenstra-VanderWeele, J. ELSEVIER SCIENCE INC. 2020: S271

  View details for DOI 10.1016/j.jaac.2020.07.565

  View details for Web of Science ID 000579844101294

• A RANDOMIZED CONTROLLED TRIAL OF A DEVELOPMENTAL RECIPROCITY TREATMENT PROGRAM IN YOUNG CHILDREN WITH AUTISM SPECTRUM DISORDER Hardan, A., Millan, M., Baldi, G., Phillips, J., Goodman, R., Gengoux, G. W. ELSEVIER SCIENCE INC. 2020: S272–S273

  View details for DOI 10.1016/j.jaac.2020.07.569

  View details for Web of Science ID 000579844101298

• PIVOTAL RESPONSE TREATMENT: APPLICATION TO NEW POPULATIONS AND SERVICE-DELIVERY MODELS Gengoux, G. W., Shahabuddin, A., Schwartzman, J., Schuck, R., Strong, K., Ardel, C., Hardan, A. ELSEVIER SCIENCE INC. 2020: S271–S272

  View details for DOI 10.1016/j.jaac.2020.07.566

  View details for Web of Science ID 000579844101295

• Exploring Social Subtypes in Autism Spectrum Disorder: A Preliminary Study. Autism research : official journal of the International Society for Autism Research Uljarevic, M., Phillips, J. M., Schuck, R. K., Schapp, S., Solomon, E. M., Salzman, E., Allerhand, L., Libove, R. A., Frazier, T. W., Hardan, A. Y. 2020

  Abstract

  Impairments in social functioning are considered a hallmark diagnostic feature of autism spectrum disorder (ASD). Yet, individuals diagnosed with ASD vary widely with respect to specific presentation, severity, and course across different dimensions of this complex symptom domain. The aim of this investigation was to utilize the Stanford Social Dimensions Scale (SSDS), a newly developed quantitative measure providing parental perspective on their child's social abilities, in order to explore the existence of homogeneous subgroups of ASD individuals who share unique profiles across specific dimensions of the social domain. Parents of 164 individuals with ASD (35 females, 129 males; meanage = 7.54years, SD = 3.85) completed the SSDS, the Social Responsiveness Scale (SRS-2) and the Child Behavior Checklist (CBCL). Data on children's verbal and nonverbal intellectual functioning (FSIQ) were also collected. The Latent Profile Analysis was used to classify participants according to the pattern of SSDS subscale scores (Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach). Five profiles were identified. Profiles did not differ in terms of chronological age nor gender distribution but showed distinct patterns of strengths and weaknesses across different social components rather than simply reflecting a severity gradient. Profiles were further differentiated in terms of cognitive ability, as well as ASD and internalizing symptom severity. The implications of current findings and the necessary further steps toward identifying subgroups of individuals with ASD who share particular constellation of strengths and weaknesses across key social domains as a way of informing personalized interventions are discussed. Autism Res 2020. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) vary greatly in terms of their social abilities and social motivation. However, researchers lack measures that can fully assess different components of social functioning. This paper provides initial evidence for capturing subgroups of individuals with ASD with specific strengths and weakness across different aspects of social functioning.

  View details for DOI 10.1002/aur.2294

  View details for PubMedID 32187854

• Contextual determinants of parental reflective functioning: Children with autism versus their typically developing siblings. Autism : the international journal of research and practice Enav, Y., Erhard-Weiss, D., Goldenberg, A., Knudston, M., Hardan, A. Y., Gross, J. J. 2020: 1362361320908096

  Abstract

  LAY ABSTRACT: In this study, we examined parental reflective functioning using the Parental Developmental Interview when parents were talking about their interactions with their child with autism versus the child's typically developing siblings. Our sample included 30 parents who had a child between the ages of 3 and 18years with a clinical diagnosis of autism spectrum disorder and at least one typically developing child. Findings indicated that parents exhibited significantly higher reflective functioning when interacting with their child with autism spectrum disorder versus the typically developing siblings, and the difference was moderated by parental self-efficacy.

  View details for DOI 10.1177/1362361320908096

  View details for PubMedID 32168987

• Rapid Eye-Tracking Evaluation of Language in Children and Adolescents Referred for Assessment of Neurodevelopmental Disorders JOURNAL OF INTELLECTUAL & DEVELOPMENTAL DISABILITY Frazier, T. W., Hauschild, K. M., Klingemier, E., Strauss, M. S., Hardan, A. Y., Youngstrom, E. A. 2020

  View details for DOI 10.3109/13668250.2019.1698287

  View details for Web of Science ID 000511793000001

• Identifying and measuring the common elements of naturalistic developmental behavioral interventions for autism spectrum disorder: Development of the NDBI-Fi. Autism : the international journal of research and practice Frost, K. M., Brian, J. n., Gengoux, G. W., Hardan, A. n., Rieth, S. R., Stahmer, A. n., Ingersoll, B. n. 2020: 1362361320944011

  Abstract

  Naturalistic developmental behavioral interventions for young children with autism spectrum disorder share key elements. However, the extent of similarity between programs within this class of evidence-based interventions is unknown. There is also currently no tool that can be used to measure the implementation of their common elements. This article presents a multi-stage process which began with defining all intervention elements of naturalistic developmental behavioral interventions. Next, intervention experts identified the common elements of naturalistic developmental behavioral interventions using a survey. An observational rating scheme of those common elements, the eight-item NDBI-Fi, was developed. We evaluated the quality of the NDBI-Fi using videos from completed trials of caregiver-implemented naturalistic developmental behavioral interventions. Results showed that the NDBI-Fi measure has promise; it was sensitive to change, related to other similar measures, and demonstrated adequate agreement between raters. This unique measure has the potential to advance intervention science in autism spectrum disorder by providing a tool to measure the implementation of common elements across naturalistic developmental behavioral intervention models. Given that naturalistic developmental behavioral interventions have numerous shared strategies, this may ease clinicians' uncertainty about choosing the "right" intervention package. It also suggests that there may not be a need for extensive training in more than one naturalistic developmental behavioral intervention. Future research should determine whether these common elements are part of other treatment approaches to better understand the quality of services children and families receive as part of usual care.

  View details for DOI 10.1177/1362361320944011

  View details for PubMedID 32731748

• Quantifying Research Domain Criteria Social Communication Subconstructs Using the Social Communication Questionnaire in Youth. Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53 Uljarević, M. n., Frazier, T. W., Phillips, J. M., Jo, B. n., Littlefield, S. n., Hardan, A. Y. 2020: 1–11

  Abstract

  Research Domain Criteria (RDoC) has posited a set of social dimensions that could be useful in identifying sources of individual variation in social impairments across neurodevelopmental disorders. The current investigation aimed to derive estimates of the RDoC social constructs from the Social Communication Questionnaire (SCQ) and examine whether RDoC social processes, as captured by the SCQ, are best represented by a dimensional, categorical, or hybrid model. Individual SCQ items from 4 databases were combined resulting in a total of 26,407 individuals (Mage = 8.13 years, SDage = 4.19; 69.1% male). The sample consisted of 60.0% of individuals with autism spectrum disorder (ASD), 6.8% with a range of neurodevelopmental disorders and 33.2% of siblings of individuals with ASD. Comparison of a range of factor solutions through the use of exploratory structural equation modeling and confirmatory factor analysis indicated that a 3-factor structure with separate attachment and affiliation, production of nonfacial and facial communication factors provided excellent fit to the data (comparative fit index = .989, Tucker-Lewis index = .984, root mean square error of approximation = .045). and robustness across clinical groups, age, sex, and verbal status. Comparison between the best-fitting factor analysis, latent class analysis, and factor mixture analysis solutions demonstrated that the RDoC social processes domain is best represented as dimensional. Our findings show promise for capturing some of the important RDoC social constructs using the SCQ but also highlight crucial areas for the development of new, dedicated dimensional measures.

  View details for DOI 10.1080/15374416.2019.1669156

  View details for PubMedID 31922427

• Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Molecular psychiatry Fung, L. K., Flores, R. E., Gu, M. n., Sun, K. L., James, D. n., Schuck, R. K., Jo, B. n., Park, J. H., Lee, B. C., Jung, J. H., Kim, S. E., Saggar, M. n., Sacchet, M. D., Warnock, G. n., Khalighi, M. M., Spielman, D. n., Chin, F. T., Hardan, A. Y. 2020

  Abstract

  The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

  View details for DOI 10.1038/s41380-020-0756-y

  View details for PubMedID 32376999

• Effects of pivotal response treatment on reciprocal vocal contingency in a randomized controlled trial of children with autism spectrum disorder. Autism : the international journal of research and practice McDaniel, J. n., Yoder, P. n., Crandall, M. n., Millan, M. E., Ardel, C. M., Gengoux, G. W., Hardan, A. Y. 2020: 1362361320903138

  Abstract

  A recent randomized controlled trial found that children with autism spectrum disorder who received a pivotal response treatment package showed improved language and social communication skills following the intervention. The pivotal response treatment package includes clinician-delivered and parent-implemented strategies. Reciprocal vocal contingency is an automated measure of vocal reciprocity derived from daylong audio samples from the child's natural environment. It may provide stronger and complementary evidence of the effects of the pivotal response treatment package because it is at lower risk for detection bias than parent report and brief parent-child interaction measures. The current study compared reciprocal vocal contingency for 24 children with autism spectrum disorder in the pivotal response treatment package group and 24 children with autism spectrum disorder in the control group. The pivotal response treatment package group received 24 weeks of the pivotal response treatment package intervention. The control group received their usual intervention services during that time. The groups did not differ in reciprocal vocal contingency when the intervention started or after 12 weeks of intervention. However, after 24 weeks the pivotal response treatment package group had higher ranked reciprocal vocal contingency scores than the control group. These findings are consistent with results from parent report and parent-child interaction measures obtained during the trial. The participants in the pivotal response treatment package exhibited greater vocal responsiveness to adult vocal responses to their vocalizations than the control group. Findings support the effectiveness of the pivotal response treatment package on vocal reciprocity of children with autism spectrum disorder, which may be a pivotal skill for language development.

  View details for DOI 10.1177/1362361320903138

  View details for PubMedID 32054315

• Anxiety in young people with autism spectrum disorder: Common and autism-related anxiety experiences and their associations with individual characteristics. Autism : the international journal of research and practice Lau, B. Y., Leong, R., Uljarevic, M., Lerh, J. W., Rodgers, J., Hollocks, M. J., South, M., McConachie, H., Ozsivadjian, A., Van Hecke, A., Libove, R., Hardan, A., Leekam, S., Simonoff, E., Magiati, I. 2019: 1362361319886246

  Abstract

  Anxiety is common in autism spectrum disorder. Many anxiety symptoms in autism spectrum disorder are consistent with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) anxiety disorders (termed "common" anxieties), but others may be qualitatively different, likely relating to autism spectrum disorder traits (herein termed "autism-related" anxieties). To date, few studies have examined both "common" and "autism-related" anxiety experiences in autism spectrum disorder. We explored caregiver-reported Spence Children's Anxiety Scale-Parent version data from a multi-site (United Kingdom, Singapore, and United States) pooled database of 870 6- to 18-year-old participants with autism spectrum disorder, of whom 287 provided at least one written response to the optional open-ended Spence Children's Anxiety Scale-Parent item 39 ("Is there anything else your child is afraid of?"). Responses were thematically coded to explore (a) common and autism-related anxiety presentations and (b) their relationship with young people's characteristics. Nearly half of the responses were autism-related anxieties (mostly sensory, uncommon, or idiosyncratic specific phobias and worries about change and unpredictability). The other half described additional common anxieties not covered in the original measure (mostly social, weather and environmental disasters, and animals). Caregivers of participants who were more severely affected by autism spectrum disorder symptoms reported more autism-related, as compared to common, additional anxieties. Implications for the assessment and understanding of anxiety in autism are discussed.

  View details for DOI 10.1177/1362361319886246

  View details for PubMedID 31852214

• Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies AUTISM Hardan, A. Y., Hendren, R. L., Aman, M. G., Robb, A., Melmed, R. D., Andersen, K. A., Luchini, R., Rahman, R., Ali, S., Jia, X., Mallick, M., Lateiner, J. E., Palmer, R. H., Graham, S. M. 2019; 23 (8): 2096–2111

  View details for DOI 10.1177/1362361318824103

  View details for Web of Science ID 000488875500019

• Genetic and environmental influences on corticostriatal circuits in twins with autism Journal of psychiatry & neuroscience : JPN Hegarty II, J. P., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019; 44 (6): 190030

  Abstract

  Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs.We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity.Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated.We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors.Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

  View details for DOI 10.1503/jpn.190030

  View details for PubMedID 31603639

• Interrelationship Between Cognitive Control, Anxiety, and Restricted and Repetitive Behaviors in Children with 22q11.2 Deletion Syndrome. Autism research : official journal of the International Society for Autism Research Uljarevic, M., McCabe, K. L., Angkustsiri, K., Simon, T. J., Hardan, A. Y. 2019

  Abstract

  Restricted and repetitive behaviors (RRB) are common in individuals with 22q11.2 microdeletion syndrome (22q11.2DS), yet the underlying mechanisms of these behaviors remain poorly characterized. In the present pilot investigation, we aimed to further our understanding of RRB in 22q11.2DS by exploring their relationship with cognitive control and anxiety as well as with sex, chronological age, and full-scale IQ. Parents of 38 children with 22q11.2DS (17 females; Mage = 11.15years, SD = 2.46) completed the Social Communication Questionnaire as a measure of RRB and social and communication (SC) problems and the Behavioral Assessment System for Children-2 as a measure of anxiety and cognitive control. Higher RRB scores were significantly associated with higher anxiety levels (r = 0.44, P = 0.006), more impairments in cognitive control (r = 0.56, P<0.001), and higher SC scores (r = 0.43, P = 0.011). In the first step of the hierarchical regression model, anxiety accounted for 24.5% of variance (F = 10.05, P = 0.003); cognitive control accounted for an additional 18.1% of variance (Fchange = 11.15, P<0.001) in the second step; SC score accounted for only 0.8% of additional variance in the third step (Fchange = 0.40, P = 0.53). The final model explained 43.4% of variance (F = 7.42, P = 0.001), with cognitive control as a unique independent predictor of RRB score (t = 2.52, P = 0.01). The current study provides the first exploration of the cognitive control-anxiety-RRB link in individuals with 22q11.2DS and points to cognitive control as a potentially viable target for treatments aimed at reducing RRB. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with 22q11.2 deletion syndrome show high levels of repetitive behaviors, however, the previous research has not explored why people with this syndrome exhibit high rates of repetitive behaviors. Understanding the reasons for the high levels of repetitive behaviors is important given that these behaviors can be highly impairing. Our study found that repetitive behaviors were associated with impaired ability to self-regulate and high levels of anxiety. These findings need to be further replicated; however, they are important as they suggest potentially promising ways of reducing these behaviors.

  View details for DOI 10.1002/aur.2194

  View details for PubMedID 31433576

• A Pivotal Response Treatment Package for Children With Autism Spectrum Disorder: An RCT. Pediatrics Gengoux, G. W., Abrams, D. A., Schuck, R., Millan, M. E., Libove, R., Ardel, C. M., Phillips, J. M., Fox, M., Frazier, T. W., Hardan, A. Y. 2019

  Abstract

  OBJECTIVES: Our aim was to conduct a randomized controlled trial to evaluate a pivotal response treatment package (PRT-P) consisting of parent training and clinician-delivered in-home intervention on the communication skills of children with autism spectrum disorder.METHODS: Forty-eight children with autism spectrum disorder and significant language delay between 2 and 5 years old were randomly assigned to PRT-P (n = 24) or the delayed treatment group (n = 24) for 24 weeks. The effect of treatment on child communication skills was assessed via behavioral coding of parent-child interactions, standardized parent-report measures, and blinded clinician ratings.RESULTS: Analysis of child utterances during the structured laboratory observation revealed that, compared with the delayed treatment group, children in PRT-P demonstrated greater improvement in frequency of functional utterances (F1,41 = 6.07; P = .026; d = 0.61). The majority of parents in the PRT-P group (91%) were able to implement pivotal response treatment (PRT) with fidelity within 24 weeks. Children receiving PRT-P also demonstrated greater improvement on the Brief Observation of Social Communication Change, on the Clinical Global Impressions Improvement subscale, and in number of words used on a parent-report questionnaire.CONCLUSIONS: This is the first 24-week randomized controlled trial in which community treatment is compared with the combination of parent training and clinician-delivered PRT. PRT-P was effective for improving child social communication skills and for teaching parents to implement PRT. Additional research will be needed to understand the optimal combination of treatment settings, intensity, and duration, and to identify child and parent characteristics associated with treatment response.

  View details for DOI 10.1542/peds.2019-0178

  View details for PubMedID 31387868

• A non randomized mentalization intervention for parents of children with autism AUTISM RESEARCH Enav, Y., Erhard-Weiss, D., Kopelman, M., Samson, A. C., Mehta, S., Gross, J. J., Hardan, A. Y. 2019; 12 (7): 1077–86

  View details for DOI 10.1002/aur.2108

  View details for Web of Science ID 000474485800008

• Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019

  Abstract

  Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

  View details for DOI 10.1002/aur.2135

  View details for PubMedID 31132232

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)

  View details for DOI 10.1126/scitranslmed.aau7356

  View details for Web of Science ID 000467273900004

• A non randomized mentalization intervention for parents of children with autism. Autism research : official journal of the International Society for Autism Research Enav, Y., Erhard-Weiss, D., Kopelman, M., Samson, A. C., Mehta, S., Gross, J. J., Hardan, A. Y. 2019

  Abstract

  Parents of children diagnosed with autism spectrum disorder (ASD) report higher levels of stress and other negative affective states than parents of typically developing children. One important resource in managing these heightened levels of negative affect is emotion regulation, which in turn depends upon the ability to recognize and understand one's own and others' mental states (referred to as mentalization or reflective functioning). In this study, parents of children with ASD either participated in a mentalization-based group intervention (N=36) or a delayed treatment (N=28). Compared to delayed treatment participants, parents in the mentalization-based group had increases in reflective functioning and in the belief that emotions can change. Moreover, they reported decreased behavioral and emotional symptoms in their children, and greater parental self-efficacy. These preliminary findings support previous studies, which have shown that mentalization-based interventions for parents lead to positive outcomes, and suggest that these findings may apply to a diverse population of parents such as those of children with broader autism phenotype or children with different neurological disorders. Further studies to evaluate the effects of the intervention are recommended. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, parents of children with ASD participated in a group intervention designed to increase their awareness of mental states (their own and their children's) and to enhance their emotion regulation. Compared to delayed treatment parents, those in the intervention group showed increased awareness of developmental states, and reported increased belief that emotions can change and decreased levels of behavioral and emotional symptoms in their children.

  View details for PubMedID 31002483

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder AUTISM Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2019; 23 (3): 713–25

  View details for DOI 10.1177/1362361318775538

  View details for Web of Science ID 000464503900017

• A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism JOURNAL OF PSYCHIATRIC RESEARCH Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Milian, M., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 140–44

  View details for DOI 10.1016/j.jpsychires.2019.02.001

  View details for Web of Science ID 000466252700020

• A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism. Journal of psychiatric research Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Millan, M. E., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 140–44

  Abstract

  Children with autism spectrum disorder (ASD) frequently exhibit language delays and functional communication deficits. Pivotal response treatment (PRT) is an effective intervention for targeting these skills; however, similar to other behavioral interventions, response to PRT is variable across individuals. Thus, objective markers capable of predicting treatment response are critically-needed to identify which children are most likely to benefit from this intervention. In this pilot study, we investigated whether structural neuroimaging measures from language regions in the brain are associated with response to PRT. Children with ASD (n = 18) who were receiving PRT to target their language deficits were assessed with MRI at baseline. T1-weighted images were segmented with FreeSurfer and morphometric measures of the primary language regions (inferior frontal (IFG) and superior temporal (STG) gyri) were evaluated. Children with ASD and language deficits did not exhibit the anticipated relationships between baseline structural measures of language regions and baseline language abilities, as assessed by the number of utterances displayed during a structured laboratory observation (SLO). Interestingly, the level of improvement on the SLO was correlated with baseline asymmetry of the IFG, and the size of the left STG at baseline was correlated with the level of improvement on standardized parental questionnaires. Although very preliminary, the observed associations between baseline structural properties of language regions and improvement in language abilities following PRT suggest that neuroimaging measures may be able to help identify which children are most likely to benefit from specific language treatments, which could help improve precision medicine for children with ASD.

  View details for PubMedID 30771619

• Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder. Molecular psychiatry Hegarty, J. P., Pegoraro, L. F., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  Abstract

  Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n=164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

  View details for PubMedID 30659287

• Development of the Stanford Social Dimensions Scale: initial validation in autism spectrum disorder and in neurotypicals. Molecular autism Phillips, J. M., Uljarević, M. n., Schuck, R. K., Schapp, S. n., Solomon, E. M., Salzman, E. n., Allerhand, L. n., Libove, R. A., Frazier, T. W., Hardan, A. Y. 2019; 10: 48

  Abstract

  The aim of this paper was to provide an initial validation of a newly developed parent questionnaire-the Stanford Social Dimensions Scale (SSDS), designed to capture individual differences across several key social dimensions including social motivation in children and adolescents with and without psychiatric disorders.The initial validation sample was comprised of parents of 175 individuals with autism spectrum disorder (ASD) (35 females, 140 males; Mage = 7.19 years, SDage = 3.96) and the replication sample consisted of 624 parents of children who were either typically developing or presented with a range of neurodevelopmental and neuropsychiatric disorders (302 females, 322 males; Mage = 11.49 years, SDage = 4.48). Parents from both samples completed the SSDS and the Social Responsiveness Scale (SRS-2).Exploratory Structural Equation Modeling indicated that a 5-factor model provided adequate to excellent fit to the data in the initial ASD sample (comparative fit index [CFI] = .940, Tucker-Lewis Index [TLI] = .919, root mean square error of approximation [RMSEA] = .048, standardized root mean square residual [SRMR] = .038). The identified factors were interpreted as Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach. This factor structure was further confirmed in Sample 2 (CFI = 946, TLI = .930, RMSEA = .044, SRMR = .026). Internal consistency for all subscales was in the good to excellent range across both samples as indicated by Composite Reliability scores of ≥ .72. Convergent and divergent validity was strong as indexed by the pattern of correlations with relevant SRS-2 and Child Behavior Checklist domains and with verbal and non-verbal intellectual functioning scores in Sample 1 and with the Need to Belong Scale and Child Social Preference Scale scores in Sample 2. Across both samples, females had higher social motivation and expressive social communication scores. Discriminant validity was strong given that across all SSDS subscales, the ASD sample had significantly higher impairment than both the typically developing group and the group with other clinical conditions, which in turn, had significantly higher impairment than the typically developing group.Our findings provide initial validation of a new scale designed to comprehensively capture individual differences in social motivation and other key social dimensions in ASD.

  View details for DOI 10.1186/s13229-019-0298-9

  View details for PubMedID 31890146

  View details for PubMedCentralID PMC6921422

• Neurodevelopmental Disorders AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHIATRY, 7TH EDITION Hong, D. S., Fung, L. K., Hardan, A., Roberts, L. W. 2019: 225–55

  View details for Web of Science ID 000550979400011

• Genetic and Environmental Influences on Lobar Brain Structures in Twins With Autism. Cerebral cortex (New York, N.Y. : 1991) Hegarty, J. P., Lazzeroni, L. C., Raman, M. M., Pegoraro, L. F., Monterrey, J. C., Cleveland, S. C., Hallmayer, J. F., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  Abstract

  This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe.

  View details for DOI 10.1093/cercor/bhz215

  View details for PubMedID 31711118

• Physical Exercise in the Management of Autism Spectrum Disorders LIFESTYLE PSYCHIATRY Venugopalakrishnan, J., Hardan, A., Noordsy, D. L. 2019: 153–67

  View details for Web of Science ID 000552225000012

• Challenges to the social motivation theory of autism: The dangers of counteracting an imprecise theory with even more imprecision BEHAVIORAL AND BRAIN SCIENCES Uljarevic, M., Vivanti, G., Leekam, S. R., Hardan, A. Y. 2019; 42

  View details for DOI 10.1017/S0140525X18002339

  View details for Web of Science ID 000477605900031

• Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies. Autism : the international journal of research and practice Hardan, A. Y., Hendren, R. L., Aman, M. G., Robb, A. n., Melmed, R. D., Andersen, K. A., Luchini, R. n., Rahman, R. n., Ali, S. n., Jia, X. D., Mallick, M. n., Lateiner, J. E., Palmer, R. H., Graham, S. M. 2019: 1362361318824103

  Abstract

  Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

  View details for PubMedID 31027422

• Mapping the Research Domain Criteria Social Processes Constructs to the Social Responsiveness Scale. Journal of the American Academy of Child and Adolescent Psychiatry Uljarević, M. n., Frazier, T. W., Phillips, J. M., Jo, B. n., Littlefield, S. n., Hardan, A. Y. 2019

  Abstract

  Research Domain Criteria (RDoC) operationalizes a set of basic social dimensions that can be used to deconstruct sources of variation in social impairments across affected individuals, regardless of their diagnostic status. This is a necessary step toward the development of etiologically based and individualized treatments. The main objective of this investigation was to derive estimations of the RDoC social constructs from the Social Responsiveness Scale (SRS-2).Exploratory structural equation modeling and confirmatory factor analysis were conducted using individual SRS-2 items from six distinct databases ( N = 27,953; mean age = 9.55 years, SD = 3.79; 71.7% male participants) spanning normative (33.8%) and atypical (66.2%) development. The following models were estimated: a one-factor model; a three-factor model with separate Attachment and Affiliation , Social Communication , and Understanding of Mental States factors; and a four-factor model where Social Communication was further split into Production of Facial and Non-Facial Communication.The one-factor solution showed poor fit. The three-factor solution had adequate fit (comparative fit index = 0.952, Tucker Lewis Index = 0.937, root mean square error of approximation = 0.054). However, the four-factor solution had superior fit (comparative fit index = 0.973, Tucker Lewis Index = 0.961, root mean square error of approximation = 0.042) and was robust across age, sex, and clinical status.To our knowledge, this is the first study examining estimations of the RDoC social constructs from an existing measure. Reported findings show promise for capturing important RDoC social constructs using the SRS-2 and highlight crucial areas for the development of novel dimensional social processing measures.

  View details for DOI 10.1016/j.jaac.2019.07.938

  View details for PubMedID 31376500

  View details for PubMedCentralID PMC7470629

• Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Translational psychiatry Busch, R. M., Srivastava, S. n., Hogue, O. n., Frazier, T. W., Klaas, P. n., Hardan, A. n., Martinez-Agosto, J. A., Sahin, M. n., Eng, C. n. 2019; 9 (1): 253

  Abstract

  Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.

  View details for DOI 10.1038/s41398-019-0588-1

  View details for PubMedID 31594918

• Genetic and environmental influences on cortico-striatal circuits in twins with autism. Genetic and environmental influences on cortico-striatal circuits in twins with autism. Hegarty, J. P., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. C., Cleveland, S. C., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  View details for DOI 10.1503/jpn.190030

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Science translational medicine Parker, K. J., Oztan, O. n., Libove, R. A., Mohsin, N. n., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019

  Abstract

  The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; ηp2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

  View details for PubMedID 31043522

• Socio-Communicative Deficits are Modulated by GABA Concentrations but Not GABA(A) Receptor Densities in Adults With Autism Spectrum Disorder Fung, L., Flores, R., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2018: S317

  View details for Web of Science ID 000509546600584

• Development and Validation of Objective and Quantitative Eye Tracking-Based Measures of Autism Risk and Symptom Levels. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Klingemier, E. W., Parikh, S., Speer, L., Strauss, M. S., Eng, C., Hardan, A. Y., Youngstrom, E. A. 2018; 57 (11): 858–66

  Abstract

  OBJECTIVE: The primary aim of this study was to develop and validate eye tracking-based measures for estimating autism spectrum disorder (ASD) risk and quantifying autism symptom levels.METHOD: Eye tracking data were collected from youth during an initial evaluation visit, with administrators blinded to all clinical information. Consensus diagnoses were given by the multidisciplinary team. Participants viewed a 5-minute video that included 44 dynamic stimuli from 7 distinct paradigms while gaze was recorded. Gaze metrics were computed for temporally defined regions of interest. Autism risk and symptom indices aggregated gaze measures showing significant bivariate relationships with ASD diagnosis and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) symptom severity levels in a training sample (75%, n= 150). Receiver operating characteristic curve analysis and nonparametric correlations were used to cross-validate findings in a test sample (25%; n= 51).RESULTS: Most children (n= 201, 92%) completed a valid eye tracking assessment (ages 1.6─17.6; 80% male; ASD n= 91, non-ASD n= 110). In the test subsample, the autism risk index had high accuracy for ASD diagnosis (area under the curve [AUC]= 0.86, 95% CI=0.75-0.95), whereas the autism symptom index was strongly associated with ADOS-2 total severity scores (r= 0.41, p< .001). Validity was not substantively attenuated after adjustment for language, nonverbal cognitive ability, or other psychopathology symptoms (r= 0.40-0.67, p > .001).CONCLUSION: Eye tracking measures appear to be useful quantitative, objective measures of ASD risk and autism symptom levels. If independently replicated and scaled for clinical use, eye tracking-based measures could be used to inform clinical judgment regarding ASD identification and to track autism symptom levels.

  View details for PubMedID 30392627

• Development and Validation of Objective and Quantitative Eye Tracking-Based Measures of Autism Risk and Symptom Levels JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Klingemier, E. W., Parikh, S., Speer, L., Strauss, M. S., Eng, C., Hardan, A. Y., Youngstrom, E. A. 2018; 57 (11): 858-866

  View details for DOI 10.1016/j.jaac.2018.06.023

  View details for Web of Science ID 000453802900011

• A CONTROLLED STUDY OF INTRANASAL VASOPRESSIN IN ASD Hardan, A. ELSEVIER SCIENCE INC. 2018: S287

  View details for DOI 10.1016/j.jaac.2018.07.681

  View details for Web of Science ID 000544087502018

• Cerebrospinal fluid vasopressin and symptom severity in children with autism ANNALS OF NEUROLOGY Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018; 84 (4): 611–15

  View details for DOI 10.1002/ana.25314

  View details for Web of Science ID 000447367000014

• Cerebrospinal fluid vasopressin and symptom severity in children with autism. Annals of neurology Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018

  Abstract

  Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30152888

• Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Garner, J. P., Oztan, O., Tarara, E. R., Li, J., Sclafani, V., Del Rosso, L. A., Chun, K., Berquist, S. W., Chez, M. G., Partap, S., Hardan, A. Y., Sherr, E. H., Capitanio, J. P. 2018; 10 (439)

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

  View details for PubMedID 29720452

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder. Autism : the international journal of research and practice Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2018: 1362361318775538

  Abstract

  Developmental approaches to autism treatment aim to establish strong interpersonal relationships through joint play. These approaches have emerging empirical support; however, there is a need for further research documenting the procedures and demonstrating their effectiveness. This pilot study evaluated changes in parent behavior and child autism symptoms following a 12-week Developmental Reciprocity Treatment parent-training program. A total of 22 children with autism spectrum disorder between 2 and 6years (mean age=44.6months, standard deviation=12.7) and a primary caregiver participated in 12 weekly sessions of Developmental Reciprocity Treatment parent training, covering topics including introduction to developmental approaches, supporting attention and motivation, sensory regulation and sensory-social routines, imitation/building nonverbal communication, functional language development, and turn taking. Results indicated improvement in aspects of parent empowerment and social quality of life. Improvement in core autism symptoms was observed on the Social Responsiveness Scale total score (F(1,19): 5.550, p=0.029), MacArthur-Bates Communicative Development Inventories number of words produced out of 680 (F(1,18): 18.104, p=0.000), and two subscales of the Repetitive Behavior Scale, Revised (compulsive, p=0.046 and restricted, p=0.025). No differences in sensory sensitivity were observed on the Short Sensory Profile. Findings from this pilot study indicate that Developmental Reciprocity Treatment shows promise and suggest the need for future controlled trials of this developmentally based intervention.

  View details for PubMedID 29775078

• Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112).Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

  View details for PubMedID 29564080

• Comprehensive Examination of the GABAergic System in Adults With Autism by Simultaneous [18F] Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Flores, R., Liu, K., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2017: S206–S207

  View details for Web of Science ID 000416846301148

• Biomarker Discovery for Social Impairments: Translation From a Novel Monkey Model to Patients With Autism Parker, K., Garner, J., Oztan, O., Tarara, E., Li, J., Sclafani, V., Del Rosso, L., Chun, K., Berquist, S., Chez, M., Partap, S., Hardan, A., Sherr, E., Capitanio, J. NATURE PUBLISHING GROUP. 2017: S501–S502

  View details for Web of Science ID 000416846303041

• CO-OCCURRING PSYCHIATRIC DISORDERS IN CHILDREN WITH AUTISM SPECTRUM DISORDER Kerns, C. M., Hardan, A. ELSEVIER SCIENCE INC. 2017: S301

  View details for DOI 10.1016/j.jaac.2017.07.576

  View details for Web of Science ID 000544086202145

• ASSESSING TRADITIONAL AND AMBIGUOUS ANXIETY SYMPTOMS IN YOUTH WITH AUTISM SPECTRUM DISORDER Kerns, C. M. ELSEVIER SCIENCE INC. 2017: S301-S302

  View details for DOI 10.1016/j.jaac.2017.07.577

  View details for Web of Science ID 000544086202146

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedID 28696286

  View details for PubMedCentralID PMC5544319

• A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Strauss, M., Klingemier, E. W., Zetzer, E. E., Hardan, A. Y., Eng, C., Youngstrom, E. A. 2017; 56 (7): 546–55

  Abstract

  Numerous studies have identified abnormal gaze in individuals with autism. However, only some findings have been replicated, the magnitude of effects is unclear, and the pattern of gaze differences across stimuli remains poorly understood. To address these gaps, a comprehensive meta-analysis of autism eye-tracking studies was conducted.PubMed and a manual search of 1,132 publications were used to identify studies comparing looking behavior to social and/or nonsocial stimuli between individuals with autism and controls. Sample characteristics, eye-tracking methods, stimulus features, and regions of interest (ROIs) were coded for each comparison within each study. Multivariate mixed-effects meta-regression analyses examined the impact of study methodology, stimulus features, and ROI on effect sizes derived from comparisons using gaze-fixation metrics.The search yielded 122 independent studies with 1,155 comparisons. Estimated effect sizes tended to be small to medium but varied substantially across stimuli and ROIs. Overall, nonsocial ROIs yielded larger effect sizes than social ROIs; however, eye and whole-face regions from stimuli with human interaction produced the largest effects (Hedges g = 0.47 and 0.50, respectively). Studies with weaker study designs or reporting yielded larger effects, but key effects remained significant and medium in size, even for high-rigor designs.Individuals with autism show a reliable pattern of gaze abnormalities that suggests a basic problem with selecting socially relevant versus irrelevant information for attention and that persists across ages and worsens during perception of human interactions. Aggregation of gaze abnormalities across stimuli and ROIs could yield clinically useful risk assessment and quantitative, objective outcome measurements.

  View details for PubMedID 28647006

  View details for PubMedCentralID PMC5578719

• The measurement properties of the spence children's anxiety scale-parent version in a large international pooled sample of young people with autism spectrum disorder. Autism research Magiati, I., Lerh, J. W., Hollocks, M. J., Uljarevic, M., Rodgers, J., McConachie, H., Ozsivadjian, A., South, M., Van Hecke, A., Hardan, A., Libove, R., Leekam, S., Simonoff, E. 2017

  Abstract

  Anxiety-related difficulties are common in ASD, but measuring anxiety reliably and validly is challenging. Despite an increasing number of studies, there is no clear agreement on which existing anxiety measure is more psychometrically sound and what is the factor structure of anxiety in ASD. The present study examined the internal consistency, convergent, divergent, and discriminant validity, as well as the factor structure of the Spence Children's Anxiety Scale-Parent Version (SCAS-P), in a large international pooled sample of 870 caregivers of youth with ASD from 12 studies in the United Kingdom, United States, and Singapore who completed the SCAS-P. Most were community recruited, while the majority had at least one measure of ASD symptomatology and either cognitive or adaptive functioning measures completed. Existing SCAS-P total scale and subscales had excellent internal consistency and good convergent, divergent and discriminant validity similar to or better than SCAS-P properties reported in typically developing children, except for the poorer internal consistency of the physical injury subscale. Confirmatory Factor Analysis (CFA) of the existing SCAS-P six-correlated factor structure was a poor fit for this pooled database. Principal component analysis using half of the pooled sample identified a 30-item five correlated factor structure, but a CFA of this PCA-derived structure in the second half of this pooled sample revealed a poor fit, although the PCA-derived SCAS-P scale and subscales had stronger validity and better internal consistency than the original SCAS-P. The study's limitations, the use of the SCAS-P to screen for DSM-derived anxiety problems in ASD and future research directions are discussed. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1809

  View details for PubMedID 28574646

• Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Aman, M. G., Findling, R. L., Hardan, A. Y., Hendren, R. L., Melmed, R. D., Kehinde-Nelson, O., Hsu, H., Trugman, J. M., Palmer, R. H., Graham, S. M., Gage, A. T., Perhach, J. L., Katz, E. 2017; 27 (5): 403–12

  Abstract

  Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

  View details for PubMedID 26978327

  View details for PubMedCentralID PMC5510039

• Simultaneous [18F]Flumazenil-Positron Emission Tomography and GABA-Magnetic Resonance Spectroscopy in Adults with Autism and Healthy Volunteers Fung, L., Flores, R., Gu, M., Hjoernevik, T., Hardan, A., Spielman, D., Chin, F. ELSEVIER SCIENCE INC. 2017: S127–S128

  View details for DOI 10.1016/j.biopsych.2017.02.325

  View details for Web of Science ID 000400348700311

• Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking? WORLD NEUROSURGERY Sivanesan, S., Tan, A., Jeyaraj, R., Lam, J., Gole, M., Hardan, A., Ashkan, K., Rajadas, J. 2017; 98: 659-672

  Abstract

  Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles. Recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive. In this review, we seek to provide a contemporary account of the key pathological events pertaining to autism: the theory of oxidative stress and inflammatory causes; ideas of immune dysfunction; the probable biomarkers that can be used for diagnostics - and the use of pharmaceuticals and stem cells as possible candidates for the treatment of ASDs.

  View details for DOI 10.1016/j.wneu.2016.09.100

  View details for Web of Science ID 000397028300082

• Incidental brain MRI findings in an autism twin study. Autism research Monterrey, J. C., Philips, J., Cleveland, S., Tanaka, S., Barnes, P., Hallmayer, J. F., Reiss, A. L., Lazzeroni, L. C., Hardan, A. Y. 2017; 10 (1): 113-120

  Abstract

  Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic "incidental" findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin "case pairs" (at least one twin with diagnosis of ASD) and twin "control pairs" (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P = 0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P = 0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and "family environment" to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins - perhaps in utero - increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1720

  View details for PubMedID 27874265

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedCentralID PMC5544319

• A Longitudinal Pilot Study of Behavioral Abnormalities in Children with Autism. Journal of psychiatry and psychiatric disorders Libove, R. A., Frazier, T. W., O'Hara, R. n., Phillips, J. M., Jo, B. n., Hardan, A. Y. 2017; 1 (4): 215–23

  Abstract

  This longitudinal investigation examined the development of emotional and behavioral functioning in school-age children with autism. The Child Behavior Checklist was obtained at baseline and after an average interval of 28.5 months from 13 boys with autism and 14 age- and gender-matched controls between the ages of 7 and 12 years at baseline. Children with autism demonstrated clinically significant elevations in several domains including Social, Thought, and Attention Problems. Children with autism exhibited significant improvements over time in Total, Externalizing, Social, and Oppositional Defiant Problems and Aggressive Behavior, while there were no changes over time in the controls. These findings suggest that children with autism may demonstrate improvements over time in some clinical domains such as social and behavioral functioning.

  View details for DOI 10.26502/jppd.2572-519X0022

  View details for PubMedID 32587950

  View details for PubMedCentralID PMC7316392

• Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O. n., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 39–45

  Abstract

  Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

  View details for PubMedID 29309996

• A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M. n., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

  Abstract

  Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

  View details for PubMedID 28941767

• Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341

  View details for Web of Science ID 000440365600575

• Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking? World neurosurgery Sivanesan, S., Tan, A., Jeyaraj, R., Lam, J., Gole, M., Hardan, A., Ashkan, K., Rajadas, J. 2016

  Abstract

  Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles. Recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive. In this review, we seek to provide a contemporary account of the key pathological events pertaining to autism: the theory of oxidative stress and inflammatory causes; ideas of immune dysfunction; the probable biomarkers that can be used for diagnostics - and the use of pharmaceuticals and stem cells as possible candidates for the treatment of ASDs.

  View details for DOI 10.1016/j.wneu.2016.09.100

  View details for PubMedID 27725300

• ANXIETY IN INDIVIDUALS WITH AUTISM SPECTRUM DISORDER: CLINICAL ASSESSMENT, BIOLOGY, AND TREATMENTS Hardan, A., Fung, L. K., King, B. H. ELSEVIER SCIENCE INC. 2016: S324

  View details for DOI 10.1016/j.jaac.2016.07.365

  View details for Web of Science ID 000541964302174

• THALAMIC METABOLITE LEVELS AND SENSORY PROCESSING IN TWINS WITH AUTISM SPECTRUM DISORDER Hegarty, J. P., Gu, M., Spielman, D., Cleveland, S., Hallmayer, J. J., Lazzeroni, L. C., Raman, M., Monterrey, J., Frazier, T., Phillips, J. M., Reiss, A. L., Hardan, A. ELSEVIER SCIENCE INC. 2016: S102

  View details for DOI 10.1016/j.jaac.2016.09.011

  View details for Web of Science ID 000541964300345

• THE LENA SYSTEM IN CLINICAL TRIALS: EVIDENCE FROM PIVOTAL RESPONSE TREATMENT STUDIES Hardan, A. ELSEVIER SCIENCE INC. 2016: S302

  View details for DOI 10.1016/j.jaac.2016.07.281

  View details for Web of Science ID 000541964302103

• PSYCHOPHARMACOLOGICAL TREATMENT OF ANXIETY SYMPTOMS IN AUTISM SPECTRUM DISORDER Hardan, A. ELSEVIER SCIENCE INC. 2016: S325-S326

  View details for DOI 10.1016/j.jaac.2016.07.369

  View details for Web of Science ID 000541964302178

• White matter structure in the uncinate fasciculus: Implications for socio-affective deficits in Autism Spectrum Disorder. Psychiatry research Samson, A. C., Dougherty, R. F., Lee, I. A., Phillips, J. M., Gross, J. J., Hardan, A. Y. 2016; 255: 66-74

  Abstract

  Individuals with Autism Spectrum Disorder (ASD) have social and communication deficits and difficulties regulating emotions. The brain bases of these socio-affective deficits are not yet clear, but one candidate is structural connectivity in the left uncinate fasciculus, which connects limbic temporal and frontal areas thought to be involved in socio-affective processing. In this study, we assessed white matter structure in the left and right uncinate fasciculus in 18 high-functioning individuals with ASD and 18 group-matched typically developing (TD) controls using Diffusion Tensor Imaging. To test specificity of the associations, we also examined the association between both uncinate fasciculi and restricted and repetitive behaviors. Compared to TD individuals, individuals with ASD had significantly lower fractional anisotropy (FA) in the left and right uncinate. Group status significantly moderated the association between left uncinate and socio-affective deficits, indicating that within the ASD group, FA was associated with socio-affective deficits: Individuals with ASD with lower FA in the left uncinate had significantly more social and emotion regulation deficits. There was no association with restricted and repetitive behaviors. This study provides evidence that the left uncinate may play a critical role in socio-affective skills in individuals with ASD.

  View details for DOI 10.1016/j.pscychresns.2016.08.004

  View details for PubMedID 27552717

• Endocannabinoid signaling in social functioning: an RDoC perspective. Translational psychiatry Karhson, D. S., Hardan, A. Y., Parker, K. J. 2016; 6 (9)

  Abstract

  Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.

  View details for DOI 10.1038/tp.2016.169

  View details for PubMedID 27676446

  View details for PubMedCentralID PMC5048207

• Equivalence of symptom dimensions in females and males with autism. Autism Frazier, T. W., Hardan, A. Y. 2016

  Abstract

  This study investigated equivalence of autism symptom domains in males and females with autism. Symptom data were obtained from 2643 children and adolescents with autism spectrum disorder (352 females, 2291 males; age range = 4-17 years) included in the Simons Simplex Collection. Items from the Social Responsiveness Scale and Autism Diagnostic Interview-Revised were mapped to nine a priori symptom dimensions. Multi-group confirmatory factor models, including measurement equivalence and item response theory analyses, examined whether males and females showed measurement or structural differences in autism symptom constructs. Results indicated mean differences in restricted interests that were not due to measurement bias. No other symptom dimension showed evidence of measurement bias and autism symptom structure was highly similar between males and females. Future studies are needed to carefully estimate any sex differences in the content, frequency, or intensity/severity of restricted interests in females and males.

  View details for PubMedID 27503465

• The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Schill, L., Schoyer, L., Andresen, B. S., Bakker, A., Bayrak-Toydemir, P., Burkitt-Wright, E., Chatfield, K., Elefteriou, F., Elgersma, Y., Fisher, M. J., Franz, D., Gelb, B. D., Goriely, A., Gripp, K. W., Hardan, A. Y., Keppler-Noreuil, K. M., Kerr, B., Korf, B., Leoni, C., McCormick, F., Plotkin, S. R., Rauen, K. A., Reilly, K., Roberts, A., Sandler, A., Siegel, D., Walsh, K., Widemann, B. C. 2016; 170 (8): 1959-1966

  Abstract

  The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37723

  View details for PubMedID 27155140

• A proton spectroscopy study of white matter in children with autism. Progress in neuro-psychopharmacology & biological psychiatry Hardan, A. Y., Fung, L. K., Frazier, T., Berquist, S. W., Minshew, N. J., Keshavan, M. S., Stanley, J. A. 2016; 66: 48-53

  Abstract

  White matter abnormalities have been described in autism spectrum disorder (ASD) with mounting evidence implicating these alterations in the pathophysiology of the aberrant connectivity reported in this disorder. The goal of this investigation is to further examine white matter structure in ASD using proton magnetic resonance spectroscopy ((1)H MRS). Multi-voxel, short echo-time in vivo(1)H MRS data were collected from 17 male children with ASD and 17 healthy age- and gender-matched controls. Key (1)H MRS metabolite ratios relative to phosphocreatine plus creatine were obtained from four different right and left white matter regions. Significantly lower N-acetylaspartate/creatine ratios were found in the anterior white matter regions of the ASD group when compared to controls. These findings reflect impairment in neuroaxonal white matter tissue and shed light on the neurobiologic underpinnings of white matter abnormalities in ASD by implicating an alteration in myelin and/or axonal development in this disorder.

  View details for DOI 10.1016/j.pnpbp.2015.11.005

  View details for PubMedID 26593330

• Development of an Objective Autism Risk Index Using Remote Eye Tracking JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Klingemier, E. W., Beukemann, M., Speer, L., Markowitz, L., Parikh, S., Wexberg, S., Giuliano, K., Schulte, E., Delahunty, C., Ahuja, V., Eng, C., Manos, M. J., Hardan, A. Y., Youngstrom, E. A., Strauss, M. S. 2016; 55 (4): 301-309

  Abstract

  Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD), and numerous studies have identified abnormal attention patterns in ASD. The primary aim of the present study was to create an objective, eye tracking-based autism risk index.In initial and replication studies, children were recruited after referral for comprehensive multidisciplinary evaluation of ASD and subsequently grouped by clinical consensus diagnosis (ASD n = 25/15, non-ASD n = 20/19 for initial/replication samples). Remote eye tracking was blinded to diagnosis and included multiple stimuli. Dwell times were recorded to each a priori-defined region of interest (ROI) and averaged across ROIs to create an autism risk index. Receiver operating characteristic curve analyses examined classification accuracy. Correlations with clinical measures evaluated whether the autism risk index was associated with autism symptom severity independent of language ability.In both samples, the autism risk index had high diagnostic accuracy (area under the curve [AUC] = 0.91 and 0.85, 95% CIs = 0.81-0.98 and 0.71-0.96), was strongly associated with Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) severity scores (r = 0.58 and 0.59, p < .001), and not significantly correlated with language ability (r ≤| -0.28|, p > .095).The autism risk index may be a useful quantitative and objective measure of risk for autism in at-risk settings. Future research in larger samples is needed to cross-validate these findings. If validated and scaled for clinical use, this measure could inform clinical judgment regarding ASD diagnosis and track symptom improvements.

  View details for DOI 10.1016/j.jaac.2016.01.011

  View details for Web of Science ID 000373315400009

  View details for PubMedCentralID PMC4808563

• Development of an Objective Autism Risk Index Using Remote Eye Tracking. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Klingemier, E. W., Beukemann, M., Speer, L., Markowitz, L., Parikh, S., Wexberg, S., Giuliano, K., Schulte, E., Delahunty, C., Ahuja, V., Eng, C., Manos, M. J., Hardan, A. Y., Youngstrom, E. A., Strauss, M. S. 2016; 55 (4): 301-309

  Abstract

  Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD), and numerous studies have identified abnormal attention patterns in ASD. The primary aim of the present study was to create an objective, eye tracking-based autism risk index.In initial and replication studies, children were recruited after referral for comprehensive multidisciplinary evaluation of ASD and subsequently grouped by clinical consensus diagnosis (ASD n = 25/15, non-ASD n = 20/19 for initial/replication samples). Remote eye tracking was blinded to diagnosis and included multiple stimuli. Dwell times were recorded to each a priori-defined region of interest (ROI) and averaged across ROIs to create an autism risk index. Receiver operating characteristic curve analyses examined classification accuracy. Correlations with clinical measures evaluated whether the autism risk index was associated with autism symptom severity independent of language ability.In both samples, the autism risk index had high diagnostic accuracy (area under the curve [AUC] = 0.91 and 0.85, 95% CIs = 0.81-0.98 and 0.71-0.96), was strongly associated with Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) severity scores (r = 0.58 and 0.59, p < .001), and not significantly correlated with language ability (r ≤| -0.28|, p > .095).The autism risk index may be a useful quantitative and objective measure of risk for autism in at-risk settings. Future research in larger samples is needed to cross-validate these findings. If validated and scaled for clinical use, this measure could inform clinical judgment regarding ASD diagnosis and track symptom improvements.

  View details for DOI 10.1016/j.jaac.2016.01.011

  View details for PubMedID 27015721

  View details for PubMedCentralID PMC4808563

• Irritability and Problem Behavior in Autism Spectrum Disorder: A Practice Pathway for Pediatric Primary Care PEDIATRICS McGuire, K., Fung, L. K., Hagopian, L., Vasa, R. A., Mahajan, R., Bernal, P., Silberman, A. E., Wolfe, A., Coury, D. L., Hardan, A. Y., Veenstra-VanderWeele, J., Whitaker, A. H. 2016; 137: S136-S148

  Abstract

  Pediatric primary care providers (PCPs) caring for patients with autism spectrum disorder (ASD) often encounter irritability (vocal or motoric outbursts expressive of anger, frustration, or distress) and problem behavior (directed acts of aggression toward other people, self, or property). The Autism Intervention Research Network on Physical Health and Autism Speaks Autism Treatment Network charged a multidisciplinary workgroup with developing a practice pathway to assist PCPs in the evaluation and treatment of irritability and problem behavior (I/PB).The workgroup reviewed the literature on the evaluation and treatment of contributory factors for I/PB in ASD. The workgroup then achieved consensus on the content and sequence of each step in the pathway.The practice pathway is designed to help the PCP generate individualized treatment plans based on contributing factors identified in each patient. These factors may include medical conditions, which the PCP is in a key position to address; functional communication challenges that can be addressed at school or at home; psychosocial stressors that may be ameliorated; inadvertent reinforcement of I/PB; and co-occurring psychiatric conditions that can be treated. The pathway provides guidance on psychotropic medication use, when indicated, within an individualized treatment plan. In addition to guidance on assessment, referral, and initial treatment, the pathway includes monitoring of treatment response and periodic reassessment.The pediatric PCP caring for the patient with ASD is in a unique position to help generate an individualized treatment plan that targets factors contributing to I/PB and to implement this plan in collaboration with parents, schools, and other providers.

  View details for DOI 10.1542/peds.2015-2851L

  View details for Web of Science ID 000371393700011

  View details for PubMedID 26908469

• Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics Fung, L. K., Mahajan, R., Nozzolillo, A., Bernal, P., Krasner, A., Jo, B., Coury, D., Whitaker, A., Veenstra-VanderWeele, J., Hardan, A. Y. 2016; 137: S124-35

  Abstract

  Autism spectrum disorder (ASD) is increasingly recognized as a public health issue. Irritability and aggression (IA) often negatively affect the lives of people with ASD and their families. Although many medications have been tested for IA in ASDs in randomized controlled trials (RCTs), critical quantitative analyses of these trials are lacking in the literature.To systematically review and quantitatively analyze the efficacy and safety of pharmacologic treatments for IA in youth with ASD.Studies were identified from Medline, PsycINFO, Embase, and review articles.Original articles on placebo-controlled RCTs of pharmacologic treatments of IA in youth age 2 to 17 years with ASD were included. Data items included study design, study goals, details of study participants, details of intervention, study results, statistical methods, side effects, and risks of bias. The primary study outcome measure was the effect size of reduction in the Aberrant Behavioral Checklist-Irritability (ABC-I) scores in the medication group, as compared with placebo, in RCTs using parallel groups design.Forty-six RCTs were identified. Compared with placebo, 3 compounds resulted in significant improvement in ABC-I at the end of treatment. Risperidone and aripiprazole were found to be the most effective, with the largest effect sizes. Sedation, extrapyramidal sides effects, and weight gain were assessed quantitatively.Although risperidone and aripiprazole have the strongest evidence in reducing ABC-I in youth with ASD, a few other compounds also showed significant efficacy with fewer potential side effects and adverse reactions in single studies.

  View details for DOI 10.1542/peds.2015-2851K

  View details for PubMedID 26908468

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography JOURNAL OF CLINICAL SLEEP MEDICINE Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2016; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for Web of Science ID 000374139600013

  View details for PubMedCentralID PMC4773615

• Pregnenolone in the Treatment of Irritability in Autism Spectrum Disorder: A Post-Hoc Metabolomic Analysis Fung, L., Sun, W., Libove, R., Tanaka, S., Kwa, L., Philips, J., Haddad, F., Rajadas, J., Hardan, A. NATURE PUBLISHING GROUP. 2015: S188

  View details for Web of Science ID 000366597700336

• Maladaptive Behavior in Autism Spectrum Disorder: The Role of Emotion Experience and Emotion Regulation. Journal of autism and developmental disorders Samson, A. C., Hardan, A. Y., Lee, I. A., Phillips, J. M., Gross, J. J. 2015; 45 (11): 3424-3432

  Abstract

  Maladaptive behavior is common in Autism Spectrum Disorder (ASD). However, the factors that give rise to maladaptive behavior in this context are not well understood. The present study examined the role of emotion experience and emotion regulation in maladaptive behavior in individuals with ASD and typically developing (TD) participants. Thirty-one individuals with ASD and 28 TD participants and their parents completed questionnaires assessing emotion experience, regulation, and maladaptive behavior. Compared to TD participants, individuals with ASD used cognitive reappraisal less frequently, which was associated with increased negative emotion experience, which in turn was related to greater levels of maladaptive behavior. By decreasing negative emotions, treatments targeting adaptive emotion regulation may therefore reduce maladaptive behaviors in individuals with ASD.

  View details for DOI 10.1007/s10803-015-2388-7

  View details for PubMedID 25711546

• Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families MOLECULAR AUTISM Frazier, T. W., Youngstrom, E. A., Hardan, A. Y., Georgiades, S., Constantino, J. N., Eng, C. 2015; 6

  Abstract

  Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation.Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels.Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families-this effect was accentuated for male children in female ASD-containing families-or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families.Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.

  View details for DOI 10.1186/s13229-015-0050-z

  View details for Web of Science ID 000363636200001

  View details for PubMedID 26512313

  View details for PubMedCentralID PMC4623917

• Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children MOLECULAR PSYCHIATRY Carson, D. S., Berquist, S. W., Trujillo, T. H., Garner, J. P., Hannah, S. L., Hyde, S. A., Sumiyoshi, R. D., Jackson, L. P., MOSS, J. K., Strehlow, M. C., Cheshier, S. H., Partap, S., Hardan, A. Y., Parker, K. J. 2015; 20 (9): 1085-1090

  Abstract

  The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.

  View details for DOI 10.1038/mp.2014.132

  View details for Web of Science ID 000360175500009

• Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation. Journal of autism and developmental disorders Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

  Abstract

  This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment.

  View details for DOI 10.1007/s10803-015-2452-3

  View details for PubMedID 25911977

• Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

  Abstract

  This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment.

  View details for DOI 10.1007/s10803-015-2452-3

  View details for Web of Science ID 000360545800018

• Emotion regulation in autism spectrum disorder: evidence from parent interviews and children's daily diaries. Journal of child psychology and psychiatry, and allied disciplines Samson, A. C., Wells, W. M., Phillips, J. M., Hardan, A. Y., Gross, J. J. 2015; 56 (8): 903-913

  Abstract

  Although emotion dysregulation is not a defining feature of Autism Spectrum Disorder (ASD), there is a growing consensus that emotional problems play a prominent role in this disorder.The present study examined a wide range of emotion regulation (ER) strategies in 32 individuals with ASD compared to 31 group-matched typically developing (TD) participants in three emotional domains (anger, anxiety, and amusement). Parents of individuals with ASD and TD individuals were interviewed about their child's emotional experience and the use and efficacy of 10 ER strategies. In addition, participants filled out daily diaries on experience and regulation in the same emotional domains.Compared to TD individuals, parents reported that individuals with ASD experienced more anger and anxiety and less amusement, made less frequent use of a variety of adaptive ER strategies (e.g. problem solving, cognitive reappraisal), and made more frequent use of maladaptive strategies (e.g. repetitive behavior). Moreover, individuals with ASD were less effective at utilizing adaptive ER strategies. Self-reports showed differences in experience of amusement and in ER strategies for anger and anxiety, but not in experience of anger and anxiety.This study provides evidence that individuals with ASD less frequently use adaptive - but more frequently use maladaptive - ER strategies. Implications for ASD treatments that focus on increasing the use of adaptive strategies are discussed.

  View details for DOI 10.1111/jcpp.12370

  View details for PubMedID 25442191

• A randomized controlled trial of Pivotal Response Treatment Group for parents of children with autism. Journal of child psychology and psychiatry, and allied disciplines Hardan, A. Y., Gengoux, G. W., Berquist, K. L., Libove, R. A., Ardel, C. M., Phillips, J., Frazier, T. W., Minjarez, M. B. 2015; 56 (8): 884-892

  Abstract

  With rates of autism diagnosis continuing to rise, there is an urgent need for effective and efficient service delivery models. Pivotal Response Treatment (PRT) is considered an established treatment for autism spectrum disorder (ASD); however, there have been few well-controlled studies with adequate sample size. The aim of this study was to conduct a randomized controlled trial to evaluate PRT parent training group (PRTG) for targeting language deficits in young children with ASD.Fifty-three children with autism and significant language delay between 2 and 6 years old were randomized to PRTG (N = 27) or psychoeducation group (PEG; N = 26) for 12 weeks. The PRTG taught parents behavioral techniques to facilitate language development. The PEG taught general information about ASD (clinical trial NCT01881750; http://www.clinicaltrials.gov).Analysis of child utterances during the structured laboratory observation (primary outcome) indicated that, compared with children in the PEG, children in the PRTG demonstrated greater improvement in frequency of utterances (F(2, 43) = 3.53, p = .038, d = 0.42). Results indicated that parents were able to learn PRT in a group format, as the majority of parents in the PRTG (84%) met fidelity of implementation criteria after 12 weeks. Children also demonstrated greater improvement in adaptive communication skills (Vineland-II) following PRTG and baseline Mullen visual reception scores predicted treatment response to PRTG.This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms.

  View details for DOI 10.1111/jcpp.12354

  View details for PubMedID 25346345

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for Web of Science ID 000358597100030

  View details for PubMedCentralID PMC4511760

• Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date. CNS drugs Fung, L. K., Hardan, A. Y. 2015

  Abstract

  Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

  View details for DOI 10.1007/s40263-015-0252-0

  View details for PubMedID 26104862

• Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date CNS DRUGS Fung, L. K., Hardan, A. Y. 2015; 29 (6): 453-463

  Abstract

  Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

  View details for DOI 10.1007/s40263-015-0252-0

  View details for Web of Science ID 000358443400003

• Emotion regulation in children and adolescents with autism spectrum disorder. Autism research Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

  Abstract

  Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1387

  View details for PubMedID 24863869

• Emotion Regulation in Children and Adolescents With Autism Spectrum Disorder AUTISM RESEARCH Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

  Abstract

  Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1387

  View details for Web of Science ID 000350458000002

  View details for PubMedID 24863869

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism. PloS one Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for PubMedID 26200852

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography. Journal of clinical sleep medicine Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2015; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for PubMedID 26564388

  View details for PubMedCentralID PMC4773615

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates. Peptides Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for PubMedID 25148831

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates PEPTIDES Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for Web of Science ID 000344232700003

• Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for Web of Science ID 000343724000027

• Autism in DSM-5 under the microscope: Implications to patients, families, clinicians, and researchers. Asian journal of psychiatry Fung, L. K., Hardan, A. Y. 2014; 11: 93-97

  Abstract

  The changes in the diagnostic classification of the pervasive developmental disorders from the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) to DSM-5 are expected to affect patients with autism, their families, as well as clinicians and researchers in the field of autism. This article reviews the new DSM-5 diagnostic criteria for Autism Spectrum Disorder (ASD) and Social Communication Disorder (SCD), and discusses potential consequences in the perspectives of major stakeholders.

  View details for DOI 10.1016/j.ajp.2014.08.010

  View details for PubMedID 25219947

• Basal ganglia and restricted and repetitive behaviours in Autism Spectrum Disorders: current status and future perspectives EPIDEMIOLOGY AND PSYCHIATRIC SCIENCES Calderoni, S., Bellani, M., Hardan, A. Y., Muratori, F., Brambilla, P. 2014; 23 (3): 235-238

  Abstract

  This editorial offers a concise overview of the recent structural magnetic resonance imaging studies that evaluate the basal ganglia (BG) volumes in autism spectrum disorders (ASD). The putative relationship between the repetitive or stereotyped behaviours of ASD and BG volumes is also explored, with a focus on possible translational approaches.

  View details for DOI 10.1017/S2045796014000171

  View details for Web of Science ID 000340400000006

  View details for PubMedID 24816251

• Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263

  Abstract

  The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

  View details for DOI 10.1073/pnas.1402236111

  View details for Web of Science ID 000340438800080

  View details for PubMedID 25092315

• A twin study of heritable and shared environmental contributions to autism. Journal of autism and developmental disorders Frazier, T. W., Thompson, L., Youngstrom, E. A., Law, P., Hardan, A. Y., Eng, C., Morris, N. 2014; 44 (8): 2013-2025

  Abstract

  The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

  View details for DOI 10.1007/s10803-014-2081-2

  View details for PubMedID 24604525

• Emotion dysregulation and the core features of autism spectrum disorder. Journal of autism and developmental disorders Samson, A. C., Phillips, J. M., Parker, K. J., Shah, S., Gross, J. J., Hardan, A. Y. 2014; 44 (7): 1766-1772

  Abstract

  The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize long-term outcomes for individuals with ASD.

  View details for DOI 10.1007/s10803-013-2022-5

  View details for PubMedID 24362795

• Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis. Autism Frazier, T. W., Youngstrom, E. A., Embacher, R., Hardan, A. Y., Constantino, J. N., Law, P., Findling, R. L., Eng, C. 2014; 18 (5): 571-582

  Abstract

  Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder.

  View details for DOI 10.1177/1362361313481506

  View details for PubMedID 24104512

• Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis AUTISM Frazier, T. W., Youngstrom, E. A., Embacher, R., Hardan, A. Y., Constantino, J. N., Law, P., Findling, R. L., Eng, C. 2014; 18 (5): 571-582

  Abstract

  Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder.

  View details for DOI 10.1177/1362361313481506

  View details for Web of Science ID 000337562700012

  View details for PubMedCentralID PMC4269571

• Dr. Frazier et al. reply. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Georgiades, S., Bishop, S. L., Hardan, A. Y. 2014; 53 (6): 700-701

  View details for DOI 10.1016/j.jaac.2014.04.002

  View details for PubMedID 24839891

• Plasma Vasopressin Levels Positively Predict Social Cognition in Children with Autism Spectrum Disorder but not in Siblings of Probands or Healthy Controls Carson, D. S., Howerton, C. L., Garner, J. P., Libove, R. A., Hyde, S. A., Phillips, J. M., Hardan, A. Y., Parker, K. J. ELSEVIER SCIENCE INC. 2014: 255S–256S

  View details for Web of Science ID 000334101801368

• Behavioral and cognitive characteristics of females and males with autism in the simons simplex collection. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Georgiades, S., Bishop, S. L., Hardan, A. Y. 2014; 53 (3): 329-340 e3

  Abstract

  To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD).We analyzed data from 2,418 probands with autism (304 females and 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure that sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or were driven by cognitive ability.Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability.A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high-functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high-functioning cases are reduced if female-specific indicators of restricted interests are included.

  View details for DOI 10.1016/j.jaac.2013.12.004

  View details for PubMedID 24565360

  View details for PubMedCentralID PMC3935179

• A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism FRONTIERS IN GENETICS Carayol, J., Schellenberg, G. D., Dombroski, B., Amiet, C., Genin, B., Fontaine, K., Rousseau, F., Vazart, C., Cohen, D., Frazier, T. W., Hardan, A. Y., Dawson, G., Frio, T. R. 2014; 5

  Abstract

  Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

  View details for DOI 10.3389/fgene.2014.00033

  View details for Web of Science ID 000346986900001

  View details for PubMedCentralID PMC3927086

• A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Frazier, T. W., Piacenza, L., Minshew, N. J., Keshavan, M. S., Reiss, A. L., Hardan, A. Y. 2014; 48: 124-128

  Abstract

  Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change.Twenty-three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures.Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance.This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence.

  View details for DOI 10.1016/j.pnpbp.2013.09.010

  View details for Web of Science ID 000328074200018

  View details for PubMedID 24075822

• A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism. Frontiers in genetics Carayol, J., Schellenberg, G. D., Dombroski, B., Amiet, C., Génin, B., Fontaine, K., Rousseau, F., Vazart, C., Cohen, D., Frazier, T. W., Hardan, A. Y., Dawson, G., Rio Frio, T. 2014; 5: 33-?

  Abstract

  Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

  View details for DOI 10.3389/fgene.2014.00033

  View details for PubMedID 24600472

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• A two-year longitudinal pilot MRI study of the brainstem in autism. Behavioural brain research Jou, R. J., Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2013; 251: 163-167

  Abstract

  Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns.

  View details for DOI 10.1016/j.bbr.2013.04.021

  View details for PubMedID 23619132

• Structural MRI Investigations in Twins with Autism 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Hallmayer, J., Lazzeroni, L., Berquist, S., Raman, M. R., Patnaik, S., Phillips, J., Reiss, A. L., Cleveland, S. ELSEVIER SCIENCE INC. 2013: 88S–88S

  View details for Web of Science ID 000318671800269

• Impact of Pivotal Response Training Group Therapy on Stress and Empowerment in Parents of Children With Autism JOURNAL OF POSITIVE BEHAVIOR INTERVENTIONS Minjarez, M. B., Mercier, E. M., Williams, S. E., Hardan, A. Y. 2013; 15 (2): 71-78

  View details for DOI 10.1177/1098300712449055

  View details for Web of Science ID 000319527300002

• Parental Interest in a Genetic Risk Assessment Test for Autism Spectrum Disorders CLINICAL PEDIATRICS Narcisa, V., Discenza, M., Vaccari, E., Rosen-Sheidley, B., Hardan, A. Y., Couchon, E. 2013; 52 (2): 139-146

  Abstract

  To better understand parental opinions regarding the diagnostic process and use of genetic testing to assess risk for autism spectrum disorders (ASDs) in the younger siblings of affected children in the Unites States, we conducted a survey of parents who had at least one child with ASD. A total of 162 surveys were completed anonymously using an Internet-based survey tool. The mean reported time to ASD diagnosis and age at diagnosis were 35.2 months and 56.6 months, respectively. Seventy-two percent of parents felt there was a delay in diagnosis. Most parents indicated they would want to pursue genetic testing if a test were available that could identify risk in a younger sibling (80%). Earlier evaluation/intervention, closer monitoring, and lessened anxiety were reasons cited for testing. Our survey indicates most parents would pursue genetic risk assessment testing in children at high risk for ASD.

  View details for DOI 10.1177/0009922812466583

  View details for Web of Science ID 000314475300005

  View details for PubMedID 23193169

• Priapism Associated with Risperidone in a 21-Year-Old Male with Autism. Journal of child and adolescent psychopharmacology Pradhan, T. n., Hardan, A. n. 2013

  View details for PubMedID 23738870

• Underutilization of Genetics Services for Autism: The Importance of Parental Awareness and Provider Recommendation JOURNAL OF GENETIC COUNSELING Vande Wydeven, K., Kwan, A., Hardan, A. Y., Bernstein, J. A. 2012; 21 (6): 803-813

  Abstract

  Reasons for the underutilization of genetics services by families of children with autism spectrum disorders (ASD) are not well understood. We report the identification of factors associated with this underuse. Survey-based study of parents and/or guardians of children with ASD. One hundred fifty-five families completed the questionnaire. Thirty-one of 155 (20%) children had seen a genetics professional. Forty-nine of 154 (32%) children had undergone genetic testing. Parents whose child saw a genetics professional were more likely to 1) Have a primary provider refer for or suggest a genetics evaluation 2) Have asked for a referral, and/or 3) Know another person with a genetic cause of ASD. amilies of children with ASD who have not received genetics services are less aware of their availability and utility. They are also less likely to have their provider recommend a clinical genetics evaluation. Efforts should be taken to increase awareness of both health providers and parents regarding the usefulness of genetics services for ASD.

  View details for DOI 10.1007/s10897-012-9494-x

  View details for PubMedID 22415587

• A Two-Year Longitudinal MRI Study of the Corpus Callosum in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2012; 42 (11): 2312-2322

  Abstract

  A growing body of literature has identified size reductions of the corpus callosum (CC) in autism. However, to our knowledge, no published studies have reported on the growth of CC volumes in youth with autism. Volumes of the total CC and its sub-divisions were obtained from 23 male children with autism and 23 age- and gender-matched controls at baseline and 2-year follow-up. Persistent reductions in total CC volume were observed in participants with autism relative to controls. Only the rostral body subdivision showed a normalization of size over time. Persistent reductions are consistent with the diagnostic stability and life-long impairment observed in many individuals with autism. Multi-modal imaging studies are needed to identify specific fiber tracks contributing to CC reductions.

  View details for DOI 10.1007/s10803-012-1478-z

  View details for Web of Science ID 000310088600004

  View details for PubMedID 22350341

• Clinical Practice Pathways for Evaluation and Medication Choice for Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Disorders PEDIATRICS Mahajan, R., Bernal, M. P., Panzer, R., Whitaker, A., Roberts, W., Handen, B., Hardan, A., Anagnostou, E., Veenstra-VanderWeele, J. 2012; 130: S125-S138

  Abstract

  Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.

  View details for DOI 10.1542/peds.2012-0900J

  View details for Web of Science ID 000209485500010

• Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics Mahajan, R., Bernal, M. P., Panzer, R., Whitaker, A., Roberts, W., Handen, B., Hardan, A., Anagnostou, E., Veenstra-VanderWeele, J. 2012; 130: S125-38

  Abstract

  Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.

  View details for DOI 10.1542/peds.2012-0900J

  View details for PubMedID 23118243

• A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., Hardan, A. Y. 2012; 22 (3): 245-248

  Abstract

  Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.

  View details for DOI 10.1089/cap.2010.0103

  View details for Web of Science ID 000305337300009

  View details for PubMedID 22537360

• A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., Frazier, T. W., Tirouvanziam, R. 2012; 71 (11): 956-961

  Abstract

  An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

  View details for DOI 10.1016/j.biopsych.2012.01.014

  View details for Web of Science ID 000303814800007

  View details for PubMedID 22342106

• Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836

  Abstract

  The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

  View details for DOI 10.1007/s10803-011-1314-x

  View details for Web of Science ID 000302771500017

  View details for PubMedID 21713591

• Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Youngstrom, E. A., Speer, L., Embacher, R., Law, P., Constantino, J., Findling, R. L., Hardan, A. Y., Eng, C. 2012; 51 (1): 28-40

  Abstract

  The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD).We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD.A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97).Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.

  View details for DOI 10.1016/j.jaac.2011.09.021

  View details for Web of Science ID 000298530300005

  View details for PubMedID 22176937

  View details for PubMedCentralID PMC3244681

• Multivariate Searchlight Classification of Structural Magnetic Resonance Imaging in Children and Adolescents with Autism BIOLOGICAL PSYCHIATRY Uddin, L. Q., Menon, V., Young, C. B., Ryali, S., Chen, T., Khouzam, A., Minshew, N. J., Hardan, A. Y. 2011; 70 (9): 833-841

  Abstract

  Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment.We use voxel-based morphometry along with a novel multivariate pattern analysis approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants.Despite modest voxel-based morphometry differences, multivariate pattern analysis revealed that the groups could be distinguished with accuracies of approximately 90% based on gray matter in the posterior cingulate cortex, medial prefrontal cortex, and bilateral medial temporal lobes-regions within the default mode network. Abnormalities in the posterior cingulate cortex were associated with impaired Autism Diagnostic Interview communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between groups with accuracies between 81% and 90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy.Multiple brain regions, including those belonging to the default mode network, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural magnetic resonance imaging data may contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of targeted early interventions.

  View details for DOI 10.1016/j.biopsych.2011.07.014

  View details for Web of Science ID 000296228000010

  View details for PubMedID 21890111

  View details for PubMedCentralID PMC3191298

• Advances in clinical neuroimaging: implications for autism spectrum disorders. Expert opinion on medical diagnostics Barnea-Goraly, N., Hardan, A. 2011; 5 (6): 475-482

  Abstract

  Introduction: Neuroimaging research has been labeled 'modern phrenology', suggesting that this line of research does not advance our knowledge of neuropsychiatric disorders beyond spatial localization of brain abnormalities. In this paper, we argue against this claim and discuss the application of neuroimaging techniques in neuropsychiatric disorders in general and in autism spectrum disorders (ASDs) in particular. Areas covered: Recent neuroimaging literature, and its role in increasing our understanding of the neurobiologic underpinnings of several disorders, is reviewed. Neuroimaging is discussed, with respect to the identification of at-risk individuals, prediction of treatment response and development of new treatment approaches. Furthermore, the authors discuss the clinical relevance of such methodologies in the context of autism. Specifically, the article shows how recent advances in the understanding of psychiatric and neurologic disorders, through the use of neuroimaging techniques, can be beneficially applied to the unique needs of ASD diagnosis and treatment. Expert opinion: This is an exciting time for neuroimaging research. Studies have already shown the potential of neuroimaging to better inform clinicians about disorders such as depression, anxiety and psychosis. The application of neuroimaging to ASD may provide new insight into the disorder and help deliver better care for affected individuals.

  View details for DOI 10.1517/17530059.2011.595785

  View details for PubMedID 23484746

• Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Handen, B. L., Johnson, C. R., McAuliffe-Bellin, S., Murray, P. J., Hardan, A. Y. 2011; 21 (1): 43-50

  Abstract

  There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD.Thirty-four children and adolescents with ASD (age range 8-17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10 mg), followed by a 10-week open label trial for placebo nonresponders.The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups).The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures.

  View details for DOI 10.1089/cap.2010.0024

  View details for Web of Science ID 000287230000004

  View details for PubMedID 21309696

  View details for PubMedCentralID PMC3037196

• Reduced central white matter volume in autism: Implications for long-range connectivity PSYCHIATRY AND CLINICAL NEUROSCIENCES Jou, R. J., Mateljevic, N., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2011; 65 (1): 98-101

  Abstract

  Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity.

  View details for DOI 10.1111/j.1440-1819.2010.02164.x

  View details for Web of Science ID 000286620700014

  View details for PubMedID 21265943

  View details for PubMedCentralID PMC3114568

• Pivotal Response Group Treatment Program for Parents of Children with Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Minjarez, M. B., Williams, S. E., Mercier, E. M., Hardan, A. Y. 2011; 41 (1): 92-101

  Abstract

  The number of children diagnosed with autism spectrum disorders is increasing, necessitating the development of efficient treatment models. Research has demonstrated that parent-delivered behavioral interventions are a viable treatment model; however, little research has focused on teaching parents in groups. The aim of this study was to demonstrate that parents can learn Pivotal Response Training (PRT) in group therapy, resulting in correlated gains in children's language. Baseline and post-treatment data were obtained and examined for changes in (a) parent fidelity of PRT implementation, and (b) child functional verbal utterances. Significant differences were observed for both variables. These findings suggest that parents can learn PRT in a group format, resulting in correlated child language gains, thus future controlled studies are warranted.

  View details for DOI 10.1007/s10803-010-1027-6

  View details for Web of Science ID 000285928200010

  View details for PubMedID 20440638

• Cortical Gyrification in Autistic and Asperger Disorders: A Preliminary Magnetic Resonance Imaging Study JOURNAL OF CHILD NEUROLOGY Jou, R. J., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2010; 25 (12): 1462-1467

  Abstract

  The validity of Asperger disorder as a distinct syndrome from autism is unclear partly because of the paucity of differentiating neurobiological evidence. Frontal lobe cortical folding between these disorders was compared using the gyrification index. Twenty-three boys underwent structural magnetic resonance imaging: 6 with high-functioning autism, 9 with Asperger disorder, and 8 controls. Using the first coronal slice anterior to the corpus callosum, total and outer cortical contours were traced to calculate the gyrification index. This index was also calculated for superior and inferior regions to examine dorsolateral prefrontal and orbitofrontal cortices, respectively. Analysis of variance revealed differences in the left inferior gyrification index, which was higher in the autism group compared with Asperger and control groups. There were no differences in age, intelligence quotient, and brain volume. These preliminary findings suggest that cortical folding may be abnormally high in the frontal lobe in autism but not Asperger disorder, suggesting distinct frontal lobe neuropathology.

  View details for DOI 10.1177/0883073810368311

  View details for Web of Science ID 000285147100002

  View details for PubMedID 20413799

  View details for PubMedCentralID PMC3115701

• Enlarged right superior temporal gyrus in children and adolescents with autism BRAIN RESEARCH Jou, R. J., Minshew, N. J., Keshavan, M. S., Vitale, M. P., Hardan, A. Y. 2010; 1360: 205-212

  Abstract

  The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5±3.4years; full-scale IQ=103.6±13.4) and 19 healthy controls (mean age=13.7±3.0years; full-scale IQ=103.9±10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder.

  View details for DOI 10.1016/j.brainres.2010.09.005

  View details for Web of Science ID 000284252600020

  View details for PubMedID 20833154

  View details for PubMedCentralID PMC2990401

• Risperidone: Switching from Brand Name to Generic JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Fung, L. K., Amin, H. 2010; 20 (5): 457-458

  View details for DOI 10.1089/cap.2010.0013

  View details for Web of Science ID 000283436700013

  View details for PubMedID 20973719

• Dorsolateral Prefrontal Cortex Magnetic Resonance Imaging Measurements and Cognitive Performance in Autism JOURNAL OF CHILD NEUROLOGY Griebling, J., Minshew, N. J., Bodner, K., Libove, R., Bansal, R., Konasale, P., Keshavan, M. S., Hardan, A. 2010; 25 (7): 856-863

  Abstract

  This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.

  View details for DOI 10.1177/0883073809351313

  View details for Web of Science ID 000279409100008

  View details for PubMedID 20097663

  View details for PubMedCentralID PMC3428128

• Evidence for Anatomical Alterations in the Corpus Callosum in Autism Spectrum Disorders European Psychiatric Review Frazier T, Barnea-Goraly N, Hardan A 2010; 3: 29-33
• A Meta-Analysis of the Corpus Callosum in Autism BIOLOGICAL PSYCHIATRY Frazier, T. W., Hardan, A. Y. 2009; 66 (10): 935-941

  Abstract

  Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism.PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements.Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons.Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

  View details for DOI 10.1016/j.biopsych.2009.07.022

  View details for Web of Science ID 000271497400006

  View details for PubMedID 19748080

  View details for PubMedCentralID PMC2783565

• Corpus callosum volume in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Pabalan, M., Gupta, N., Bansal, R., Melhem, N. M., Fedorov, S., Keshavan, M. S., Minshew, N. J. 2009; 174 (1): 57-61

  Abstract

  The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

  View details for DOI 10.1016/j.pscychresns.2009.03.005

  View details for Web of Science ID 000271686900008

  View details for PubMedID 19781917

  View details for PubMedCentralID PMC2761427

• A Preliminary Longitudinal Magnetic Resonance Imaging Study of Brain Volume and Cortical Thickness in Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Libove, R. A., Keshavan, M. S., Melhem, N. M., Minshew, N. J. 2009; 66 (4): 320-326

  Abstract

  Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism.MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline.No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology.Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

  View details for DOI 10.1016/j.biopsych.2009.04.024

  View details for Web of Science ID 000268840200005

  View details for PubMedID 19520362

  View details for PubMedCentralID PMC2905654

• Brainstem volumetric alterations in children with autism PSYCHOLOGICAL MEDICINE Jou, R. J., Minshew, N. J., Melhem, N. M., Keshavan, M. S., Hardan, A. Y. 2009; 39 (8): 1347-1354

  Abstract

  Although several studies have examined brainstem volume in autism, results have been mixed and no investigation has specifically measured gray- and white-matter structures. The aim of this investigation was to assess gray- and white-matter volumes in children with autism.Subjects included 22 right-handed, non-mentally retarded boys with autism and 22 gender- and age-matched controls. Magnetic resonance imaging (MRI) scans were obtained using a 1.5-T scanner and volumetric measurements were performed using the BRAINS2 software package. Gray- and white-matter volumes were measured using a semi-automated segmentation process.There were no significant differences in age and total brain volume (TBV) between the two groups but full-scale IQ was higher in controls. A decrease in brainstem gray-matter volume was observed in the autism group before and after controlling for TBV. No significant differences were observed in white-matter volume. A significant relationship was observed between brainstem gray-matter volume and oral sensory sensitivity as measured by the Sensory Profile Questionnaire (SPQ).Findings from this study are suggestive of brainstem abnormalities in autism involving gray-matter structures with evidence supporting the existence of a relationship between these alterations and sensory deficits. These results are consistent with previous investigations and support the existence of disturbances in brainstem circuitry thought to be implicated in the sensory dysfunction observed in autism.

  View details for DOI 10.1017/S0033291708004376

  View details for Web of Science ID 000268165300013

  View details for PubMedID 18812009

• Corpus Callosum Volume and Neurocognition in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Keary, C. J., Minshew, N. J., Bansal, R., Goradia, D., Fedorov, S., Keshavan, M. S., Hardan, A. Y. 2009; 39 (6): 834-841

  Abstract

  The corpus callosum has recently been considered as an index of interhemispheric connectivity. This study applied a novel volumetric method to examine the size of the corpus callosum in 32 individuals with autism and 34 age-, gender- and IQ-matched controls and to investigate the relationship between this structure and cognitive measures linked to interhemispheric functioning. Participants with autism displayed reductions in total corpus callosum volume and in several of its subdivisions. Relationships were also observed between volumetric alterations and performance on several cognitive tests including the Tower of Hanoi test. These findings provide further evidence for anatomical alterations in the corpus callosum in autism, but warrant additional studies examining the relationship of this structure and specific measures of interhemispheric connectivity.

  View details for DOI 10.1007/s10803-009-0689-4

  View details for Web of Science ID 000266089900002

  View details for PubMedID 19165587

  View details for PubMedCentralID PMC3229274

• Reduced Central White Matter Volume in Autism: Implications for Long-Range Connectivity Jou, R. J., Hardan, A. Y. ELSEVIER SCIENCE INC. 2009: 87S–88S

  View details for Web of Science ID 000265144200280

• Guanfacine in children with autism and/or intellectual disabilities JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Handen, B. L., Sahl, R., Hardan, A. Y. 2008; 29 (4): 303-308

  Abstract

  Attention-deficit/hyperactivity disorder (ADHD) affects 3%-5% of typical school-age children. However, considerably higher rates of ADHD (15%-25%) are observed in children with intellectual disability and autism. Studies of psychostimulants in the latter two populations have found poorer response rates compared to typically developing children. In addition, evidence suggests that children with developmental disabilities experience higher rates of adverse events. Guanfacine, an alpha2-adrenergic receptor agonist, has shown some promise as an alternative to psychostimulants.The present study involved a double-blind, placebo-controlled, crossover trial of guanfacine in 11 children (ages 5-9 years) with developmental disabilities and symptoms of inattention/overactivity. The 6-week trial involved a maximum dose of 3 mg/day of guanfacine.Significant benefits were observed on the Hyperactivity subscale of the parent and teacher Aberrant Behavior Checklist (ABC) and Global Improvement Ratings. No gains were noted on other ABC subscales. Five of the 11 subjects (45%) were judged to be responders based on a 50% decrease in the ABC Hyperactivity subscale score between the placebo and guanfacine conditions. Several side effects were reported, including drowsiness and irritability.While guanfacine appears to be an alternative to psychostimulants among children with developmental disabilities, clinicians need to remain vigilant to the possibility of side effects.

  View details for Web of Science ID 000258411900012

  View details for PubMedID 18552703

• An MRI and proton spectroscopy study of the thalamus in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Minshew, N. J., Melhem, N. M., Srihari, S., Jo, B., Bansal, R., Keshavan, M. S., Stanley, J. A. 2008; 163 (2): 97-105

  Abstract

  Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

  View details for DOI 10.1016/j.pscychresns.2007.12.002

  View details for Web of Science ID 000257581200001

  View details for PubMedID 18508243

  View details for PubMedCentralID PMC2467447

• Longitudinal study of the corpus callosum in autism Hardan, A. Y., Keshavan, M. S., Bansal, R., Fedorov, S., Minshew, N. J. ELSEVIER SCIENCE INC. 2008: 30S

  View details for Web of Science ID 000254163700095

• Brief report: Abnormal association between the thalamus and brain size in Asperger's disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Melhem, N. M., Keshavan, M. S., Minshew, N. J. 2008; 38 (2): 390-394

  Abstract

  The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different.

  View details for DOI 10.1007/s10803-007-0385-1

  View details for Web of Science ID 000252673600017

  View details for PubMedID 17641963

• Morphology of the orbitofrontal cortex in first-episode schizophrenia: Relationship with negative symptomatology PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Lacerda, A. L., Hardan, A. Y., Yorbik, O., Vemulapalli, M., Prasad, K. M., Keshavan, M. S. 2007; 31 (2): 510-516

  Abstract

  Different studies have documented OFC abnormalities in schizophrenia, but it is unclear if they are present at disease onset or are a consequence of disease process and/or drug exposure. The evaluation of first-episode, drug-naïve subjects allows us to clarify this issue. Magnetic resonance imaging was performed on 43 first-episode, antipsychotic-naïve schizophrenia patients and 53 healthy comparison subjects matched for age, gender, race, and handedness. Gray matter OFC volumes were measured blind to the diagnoses. As compared to controls, patients had greater volumes in left total OFC (p=0.048) and left lateral OFC (p=0.037). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho=0.37, p=0.019; rho=0.317, p=0.041; r=0.307, p=0.048, respectively) and the left total OFC (Spearman's, rho=0.384, p=0.014; rho=0.349, p=0.023; rho=0.309, p=0.047, respectively). The present results suggest that first-episode, antipsychotic-naïve schizophrenia subjects exhibit increased OFC volumes that correlate with negative symptoms severity. The OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning. Although the specific neuropathological mechanisms underlying structural abnormalities of the OFC remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive.

  View details for DOI 10.1016/j.pnpbp.2006.11.022

  View details for Web of Science ID 000244808800031

  View details for PubMedID 17239513

• Volumetric alterations of the orbitofrontal cortex in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY GirgiS, R. R., Minshew, N. J., Melhern, N. M., Nutche, J. J., Keshavan, M. S., Hardan, A. Y. 2007; 31 (1): 41-45

  Abstract

  Recent evidence has implicated the orbitofrontal cortex (OFC) in the pathophysiology of social deficits in autism. An MRI-based morphometric study of the OFC was conducted involving 11 children with autism (age range 8.1-12.7 years) and 18 healthy, age-matched controls (age range 8.9-12.8 years). Decreased grey matter volume in the right lateral OFC in the patient group was found, and correlations were observed between social deficits and white, but not grey, matter structures of the OFC. These findings support the role of OFC in autism and warrant further investigations of this structure using structural and functional methodologies.

  View details for DOI 10.1016/j.pnpbp.2006.06.007

  View details for Web of Science ID 000243738000005

  View details for PubMedID 16863674

  View details for PubMedCentralID PMC2888006

• Abnormal brain size effect on the thalamus in autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Keshavan, M. S., Minshew, N. J. 2006; 147 (2-3): 145-151

  Abstract

  This study was conducted to examine the volume of the thalamus in autism and to investigate the effect of brain size on this structure in an attempt to replicate, in a larger sample, findings from a previous study reporting the existence of a relationship between brain volume and thalamus in healthy controls but not in individuals with autism. Additionally, the relationships between thalamic volumes and clinical features were examined. Volumetric measurements of the right and left thalamic nuclei were performed on MRI scans obtained from 40 high-functioning individuals with autism (age range: 8-45 years) and 41 healthy controls (age range: 9-43 years). No differences were observed between the two groups for unadjusted thalamic volumes. However, the expected linear relationship between TBV and thalamic volume was not observed in individuals with autism. Furthermore, no correlations were observed between thalamic volumes and clinical features. Findings from this larger study are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder.

  View details for DOI 10.1016/j.pscychresns.2005.12.009

  View details for Web of Science ID 000241326800006

  View details for PubMedID 16945509

• Magnetic resonance imaging study of the orbitofrontal cortex in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., GirgiS, R. R., Lacerda, A. L., Yorbik, O., Kilpatiick, M., Keshavan, M. S., Minshew, N. J. 2006; 21 (10): 866-871

  Abstract

  The orbitofrontal cortex is involved in multiple psychologic functions, such as emotional and cognitive processing, learning, and social behavior. These functions are variably impaired in individuals with autism. The present study examined the size of the orbitofrontal cortex, and its medial and lateral subdivisions, using magnetic resonance imaging (MRI) scans obtained from 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any of the orbitofrontal cortex measurements. However, when compared with controls, a smaller right lateral orbitofrontal cortex was observed in children and adolescents with autism, whereas a larger right lateral orbitofrontal cortex was found in adult patients. Interestingly, a positive relationship was found in the patient group between circumscribed interests and all orbitofrontal cortex structures. The present study suggests the absence of global volumetric abnormalities in the orbitofrontal cortex in autism and indicates that the functional disturbances in this structure might not be related to anatomic alterations.

  View details for DOI 10.2310/7010.2006.00199

  View details for Web of Science ID 000243206700007

  View details for PubMedID 17005103

• Open-label, prospective trial of olanzapine in adolescents with subaverage intelligence and disruptive behavior disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Handen, B. L., Hardan, A. Y. 2006; 45 (8): 928-935

  Abstract

  Olanzapine, an atypical antipsychotic, has been shown to be efficacious for treatment of psychotic and mood disorders in adults. This prospective, open-label study was conducted to examine the safety and usefulness of olanzapine in treating disruptive behavior disorders in adolescents with subaverage intelligence.Sixteen adolescents (ages 13-17 years) with borderline to moderate mental retardation and disruptive behavior were enrolled in an 8-week olanzapine trial (5-20 mg/day). Dependent measures included the Aberrant Behavior Checklist, Conners Parent Rating Scale, Clinical Global Impressions, and two side effects scales.Statistically significant improvement (p <.002) was found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist and the Conners Parent Rating Scale Hyperactivity Index. No subjects developed extrapyramidal side effects. However, four were terminated prematurely from the trial because of either worsening of symptoms (requiring psychiatric inpatient hospitalization in two subjects) or side effects. The most common side effect for the sample was weight gain (averaging 12.7 lb), with 67% of subjects gaining > or =10 lb. Although there was also a statistically significant increase in prolactin levels, no subjects reported prolactin-related side effects (e.g., gynecomastia, galactorhea, amenorrhea).Olanzapine may be useful in treating disruptive behavior in adolescents with subaverage intelligence. However, side effects, especially weight gain, are a significant issue. Future double-blind, placebo-controlled studies need to confirm these findings and assess long-term safety and outcome of olanzapine treatment.

  View details for DOI 10.1097/01.chi.0000223312.48406.6e

  View details for Web of Science ID 000239290500006

  View details for PubMedID 16865035

• An MRI study of increased cortical thickness in autism AMERICAN JOURNAL OF PSYCHIATRY Hardan, A. Y., Muddasani, S., Vemulapalli, M., Keshavan, M. S., Minshew, N. J. 2006; 163 (7): 1290-1292

  Abstract

  The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder.Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy comparison subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes.Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes.These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.

  View details for PubMedID 16816240

• An MRI study of minor physical anomalies in autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Keshavan, M. S., Sreedhar, S., Vemulapalli, M., Minshew, N. J. 2006; 36 (5): 607-611

  Abstract

  The objective of this investigation was to examine the existence of minor physical anomalies (MPA) in autism. The interorbital and interlens distances were measured on MRI scans obtained from a sample of 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any measurements. However, when the analysis was conducted using a split median procedure, individuals with autism and either low FSIQ, PIQ, or VIQ had shorter interorbital distances when compared to controls. Hypotelorism is a MPA that may be present in a subgroup of individuals with autism. Additional research is warranted using large sample sizes with a wide range of intellectual functioning.

  View details for DOI 10.1007/s10803-006-0103-4

  View details for Web of Science ID 000239927900004

  View details for PubMedID 16609827

• Volumetric alterations of the corpus callosum in children with autism Hardan, A. Y., Bansal, R., Pabalan, M., Nutche, J., Fedorov, S., Minshew, N. J., Keshavan, M. S. ELSEVIER SCIENCE INC. 2006: 168S

  View details for Web of Science ID 000236767301123

• Brainstern volumetric alterations in children with pervasive developmental disorders Jou, R., Keshavan, M., Minshew, N. J., Hardan, A. Y. ELSEVIER SCIENCE INC. 2006: 49S–50S

  View details for Web of Science ID 000236767300162

• Preliminary findings from a double-blind placebo-controlled study of donepezil in pervasive developmental disorders Hardan, A. Y., Johnson, C., Handen, B. L. ELSEVIER SCIENCE INC. 2006: 50S

  View details for Web of Science ID 000236767300163

• Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study SCHIZOPHRENIA RESEARCH Girgis, R. R., Diwadkar, V. A., Nutche, J. J., Sweeney, J. A., Keshavan, M. S., Hardan, A. Y. 2006; 82 (1): 89-94

  Abstract

  Previous studies have provided evidence supporting a neuroplastic effect of atypical antipsychotics. The present investigation explores the short-term effects of risperidone on brain parenchyma by performing voxel-based morphometry on baseline and 6-week follow-up MRI scans obtained from 15 neuroleptic-naïve individuals with first-episode psychosis treated with risperidone and 15 healthy controls. The risperidone-treated subjects demonstrated changes in grey matter and white matter in several brain regions, including superior temporal gyrus. No areas of change were found in controls. The results of this exploratory investigation support the possibility that risperidone has short-term effects on brain parenchyma in individuals with first-episode psychosis.

  View details for DOI 10.1016/j.schres.2005.10.019

  View details for Web of Science ID 000235664100009

  View details for PubMedID 16413757

• Reduced cortical folding in individuals at high risk for schizophrenia: a pilot study SCHIZOPHRENIA RESEARCH Jou, R. J., Hardan, A. Y., Keshavan, M. S. 2005; 75 (2-3): 309-313

  Abstract

  While cortical gyrification anomalies have been reported in schizophrenia, it is unknown if individuals at high risk for schizophrenia (HR) might also exhibit abnormal cortical folding. Using MRI scans, the gyrification index (GI) was calculated for 9 adolescent HR males and 12 healthy male controls. Using the first coronal slice anterior to the corpus callosum, cortical contours were manually traced to calculate the GI. The left GI was lower in HR when compared to controls, but no difference in the right GI was observed. These results are consistent with studies of affected individuals, supporting genetic and neurodevelopmental models of schizophrenia.

  View details for DOI 10.1016/j.schres.2004.11.008

  View details for Web of Science ID 000229665100017

  View details for PubMedID 15885522

• Retrospective study of quetiapine in children and adolescents with pervasive developmental disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Jou, R. J., Handen, B. L. 2005; 35 (3): 387-391

  Abstract

  A retrospective study was conducted in a clinic specialized in treating individuals with developmental disabilities to examine the effectiveness and tolerability of quetiapine in children and adolescents with pervasive developmental disorders. Ten consecutive outpatients (age = 12.0 +/- 5.1 years) treated with quetiapine (dose = 477 +/- 212 mg, duration = 22.0 +/- 10.1 weeks) were identified and six were judged to be responders based on impressions from chart review and Conners Parent Scale (CPS). Improvements were observed in the conduct, inattention, and hyperactivity subscales of the CPS. Adverse events were mild with sedation being the most common, and no patient required treatment termination. Quetiapine may be beneficial in children and adolescents with pervasive developmental disorders, however open-label and double-blind, placebo-controlled studies are warranted.

  View details for DOI 10.1007/s10803-005-3306-1

  View details for Web of Science ID 000230559200013

  View details for PubMedID 16119479

• Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Jou, R. J., Handen, B. L., Hardan, A. Y. 2005; 15 (2): 325-330

  Abstract

  A retrospective study was conducted to assess the effectiveness and tolerability of atomoxetine in children and adolescents with pervasive developmental disorders (PDD). An outpatient clinic registry of individuals with PDD was used to identify all children and adolescents who received atomoxetine over a period of 12 months. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI) based on the Conners Parent Rating Scale (CPRS) routinely completed by primary caretakers and other clinical information available in the registry. Twenty patients were identified, including 16 males and 4 females (age, 11.5 years; standard deviation, 3.5). Most patients (80%) were taking at least 1 concomitant medication. Treatment dose was 43.3 mg (standard deviation, 18.1) and duration was 19.5 weeks (standard deviation, 10.5). Twelve patients were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Differences between baseline and the end of the trial period were observed in the following CPRS subscales: Conduct, hyperactivity, inattention, and learning. No differences were noted in the anxiety and psychosomatic subscales. One patient discontinued atomoxetine because of severe mood swings. Atomoxetine may be beneficial for treating secondary symptoms of PDD, and prospective open-label or double-blind, placebo-controlled studies are needed to assess its efficacy and safety.

  View details for Web of Science ID 000229787000021

  View details for PubMedID 15910217

• Quetiapine in children and adolescents with subaverage IQ Journal of Pediatric Neurology Jou R, Handen BL, Hardan AY 2005; 3: 35-39
• Psychostimulant treatment of adults with mental retardation and attention-deficit hyperactivity disorder. Australasian psychiatry Jou, R., Handen, B., Hardan, A. 2004; 12 (4): 376-379

  Abstract

  To examine the potential effectiveness and tolerability of psychostimulants in adults with mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD).A retrospective chart review was conducted in a clinic specialized in treating individuals with developmental disabilities. Improvement was assessed using the Aberrant Behaviour Checklist-Community Version (ABC-C) and the global improvement item of the Clinical Global Impression scale.Ten consecutive adult outpatients were identified. Five were judged to be responders, based on impressions from chart review and the ABC-C. Significant improvements were observed in the hyperactivity and irritability subscales of the ABC-C. Adverse events were minimal and no patients required treatment termination.Psychostimulants might be effective and well-tolerated in the treatment of ADHD in adults with MR. However, larger prospective open-label studies, and, eventually, double-blind placebo-controlled studies are needed to confirm these findings.

  View details for PubMedID 15715811

• A retrospective assessment of topiramate in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Jou, R. J., Handen, B. L. 2004; 14 (3): 426-432

  Abstract

  An open-label retrospective study was conducted to assess the effectiveness and tolerability of topiramate in children and adolescents with pervasive developmental disorders (PDD). Topiramate is a novel antiepileptic drug approved as an adjunctive treatment for seizure disorders. A retrospective chart review was conducted in an outpatient clinic specialized in treating individuals with developmental disabilities, to identify all children and adolescents with PDD who received topiramate. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI), based on a review of medical records and the Conners Parent Scale (CPS), as completed by parents. Fifteen patients were identified (12 male, 3 female; age = 14.7 +/- 3.3 years), including 11 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD not otherwise specified (PDD, NOS). Eight patients (4 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD, NOS) were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Treatment duration was 25 +/- 16 weeks, and the mean dose was 235 +/- 88 mg. Differences between baseline and the end-of-trial period were observed in the following CPS subscales: conduct, hyperactivity, and inattention. No differences were noted in the psychosomatic, learning, and anxiety subscales. Three patients discontinued topiramate because of side effects, with 2 patients experiencing cognitive difficulties and 1 patient a skin rash. Topiramate may be beneficial for treating secondary symptoms of PDD, and prospective openlabel studies and double-blind, placebo-controlled studies to assess its efficacy and safety are needed.

  View details for Web of Science ID 000224838500017

  View details for PubMedID 15650499

• Increased frontal cortical folding in autism: a preliminary MRI study PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Jou, R. J., Keshavan, M. S., Varma, R., Minshew, N. J. 2004; 131 (3): 263-268

  Abstract

  The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder.

  View details for DOI 10.1016/j.pscychresns.2004.06.001

  View details for Web of Science ID 000224608800008

  View details for PubMedID 15465295

• Neuropsychiatric problems in tuberous sclerosis complex JOURNAL OF CHILD NEUROLOGY Asato, M. R., Hardan, A. Y. 2004; 19 (4): 241-249

  Abstract

  Tuberous sclerosis complex is an autosomal dominant disorder characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. It is a disease affecting multiple organ systems and typically has brain involvement, causing severe disabilities. This article reviews the literature of the commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, which are discussed in the context of the neuropathology and epilepsy observed in tuberous sclerosis complex. The potential pathogenesis of neuropsychiatric problems is explored, including links to the genetics, neuropathology, neurotrophins, and epilepsy factors associated with tuberous sclerosis complex. Treatment of neuropsychiatric symptoms, including autism-like features, attention deficits, and sleep disorders, is also discussed.

  View details for Web of Science ID 000221419000001

  View details for PubMedID 15163088

• Anatomic evaluation of the orbitofrontal cortex in major depressive disorder BIOLOGICAL PSYCHIATRY Lacerda, A. L., Keshavan, M. S., Hardan, A. Y., Yorbik, O., Brambilla, P., Sassi, R. B., NICOLETTI, M., Mallinger, A. G., Frank, E., Kupfer, D. J., Soares, J. C. 2004; 55 (4): 353-358

  Abstract

  The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects.Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly.The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender.These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.

  View details for DOI 10.1016/j.biopsych.2003.08.021

  View details for Web of Science ID 000188964700004

  View details for PubMedID 14960287

• The functional neuroanatomy of autism FUNCTIONAL NEUROLOGY Brambilla, P., Hardan, A. Y., di Nemi, S. U., Caverzasi, E., Soares, J. C., Perez, J., Barale, F. 2004; 19 (1): 9-17

  Abstract

  Autism is a neurodevelopmental syndrome characterized by impaired social and executive functions. Functional magnetic resonance imaging (fMRI) is a non-invasive technique that allows investigation of the neural networks underlying cognitive impairments in autism. In this article, brain imaging studies investigating the functional brain anatomy of autism are reviewed. Face recognition, theory of mind and executive functions have all been explored in functional neuroimaging studies involving autistic patients. The available literature suggests an involvement of abnormal functional mechanisms in face recognition, mentalization and executive functions in adults with high-functioning autism or Asperger's syndrome, possibly due to brain maturation abnormalities, and resulting in dysfunctional reciprocal cortico-subcortical connections. Future functional neuroimaging research should investigate subgroups of autistic children and adolescents longitudinally and attempt to integrate genetic, cognitive and empirical approaches. Such studies will be instrumental in furthering understanding of the pathophysiology of autism and in exploring the importance of dimensional measures of the broader phenotype currently defined as autism.

  View details for Web of Science ID 000222004200002

  View details for PubMedID 15212111

• Brain anatomy and development in autism: review of structural MRI studies BRAIN RESEARCH BULLETIN Brambilla, P., Hardan, A., di Nemi, S. U., Perez, J., Soares, J. C., Barale, F. 2003; 61 (6): 557-569

  Abstract

  Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.

  View details for DOI 10.1016/j.brainresbull.2003.06.001

  View details for Web of Science ID 000189133800001

  View details for PubMedID 14519452

• Measurement of the orbitofrontal cortex: a validation study of a new method NEUROIMAGE Lacerda, A. L., Hardan, A. Y., Yorbik, O., Keshavan, M. S. 2003; 19 (3): 665-673

  Abstract

  The orbital frontal cortex (OFC) plays a critical role in the pathophysiology of several neuropsychiatric disorders. Few morphometric neuroimaging studies have examined the OFC using different methodologies and have reported discrepant values. Substantial variability in gyri and sulci across individuals as well as unclear landmarks underline the difficulties in obtaining accurate and reliable measurements. We propose a new geometrical method for measuring the OFC taking into account individual brain variability. The OFC was defined by using the intercommissural line and the inferior edge of the frontal lobe as the main landmarks. The medial and lateral subdivisions of OFC were also separately measured using the olfactory sulcus as the boundary to distinguish between them. After resampling and refitting, 10 scans were independently traced by two trained researchers using BRAINS software. Talairach coordinates were identified on each scan from the OFC and surrounding adjacent brain regions to assess the validity of this method. Brain regions were assigned using Talairach Daemon system. OFC volumes were comparable with those previously reported. Sensitivity and specificity for OFC gray matter were 87.6 and 84.8%, respectively. Intraclass coefficients (ICCs) for gray, white, and total OFC were 0.995, 0.994, and 0.997, respectively. ICCs for OFC medial and lateral subdivisions ranged between 0.996 and 0.998. This method appears to be a valid method for measuring the OFC with excellent reliability. This uncomplicated approach is easy to apply and has the potential to be a valuable alternative to the previously published methods.

  View details for DOI 10.1016/S1053(03)00137-X

  View details for Web of Science ID 000184485400017

  View details for PubMedID 12880797

• Motor performance and anatomic magnetic resonance imaging (MRI) of the basal ganglia in autism 57th Annual Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Kilpatrick, M., Keshavan, M. S., Minshew, N. J. SAGE PUBLICATIONS INC. 2003: 317–24

  Abstract

  This study was conducted to examine the volume of the basal ganglia in individuals with autism and to evaluate whether performance on specific motor tasks correlated with the volume of these structures. Volumetric measurements of the caudate nucleus and putamen were obtained from magnetic resonance images (MRI) of 40 non-mentally retarded individuals with autism and 41 healthy controls. Motor performance was assessed in these subjects by using the Finger Tapping Test, the Grooved Pegboard Test, and the measurement of Grip Strength. No volumetric differences of the basal ganglia were found between the two groups after adjusting for brain volume. The autistic subjects' performance was slower on the Grooved Pegboard Test and weaker on Grip Strength. Our findings suggest that the motor deficits observed in autism may not be related to structural abnormalities of the basal ganglia, and other brain regions, such as the cerebellum and the frontal lobe, may be involved in the pathophysiology of motor disturbances in autism.

  View details for Web of Science ID 000183405600002

  View details for PubMedID 12822815

• A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Handen, B. L. 2002; 12 (3): 237-241

  Abstract

  In light of the recently reported neuropathologic and neurochemical abnormalities of the cholinergic pathways in autism, donepezil, a cholinesterase inhibitor, is a potentially useful agent in the treatment of cognitive and behavioral symptoms observed in this disorder. A retrospective pilot study was conducted to determine whether donepezil is effective in the treatment of children and adolescents with autism. Eight patients (mean age = 11.0 +/- 4.1 years; range 7-19 years) who met Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria for autistic disorder were openly treated with donepezil. All patients were on concomitant psychoactive medications. Four of these patients (50%) demonstrated significant improvement as assessed by the Aberrant Behavior Checklist and the Clinical Global Impression Scale. Decreases in the Irritability and Hyperactivity subscales were observed, but no changes in the Inappropriate Speech, Lethargy, and Stereotypies subscales were noted. Limited and transient side effects were reported, with one patient experiencing gastrointestinal disturbances and another reporting mild irritability. Double-blind, placebo-controlled investigations are needed to provide further evidence of the potential benefits of donepezil to patients with autistic disorder.

  View details for Web of Science ID 000178736200007

  View details for PubMedID 12427297

• Posterior fossa magnetic resonance imaging in autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A. Y., Minshew, N. J., Harenski, K., Keshavan, M. S. 2001; 40 (6): 666-672

  Abstract

  To determine whether the sizes and volumes of the posterior fossa structures are abnormal in non-mentally retarded autistic adolescents and adults.Volume measurements of the cerebellum, vermis, and brainstem were obtained from coronal magnetic resonance imaging scans in 16 autistic subjects and 19 group-matched healthy controls. For the purpose of comparison with previous studies, area measurements of the midbrain, pons, medulla, total cerebellar vermis, and its three subregions were also obtained from a larger sample of 22 autistic males (mean age: 22.4 years; range: 12.2-51.8 years) and 22 individually matched controls (mean age 22.4 years; range: 12.9-52.2 years).The total volume of the cerebellum and the cerebellar hemispheres were significantly larger in the autistic subjects with and without correcting for total brain volume. Volumes of the vermis and the brainstem and all area measurements did not differ significantly between groups.There is an increase in the volume of the cerebellum in people with autism consistent with the increase in regional and total brain size reported in this developmental disorder. This finding is also concordant with evidence of cerebellar abnormalities from neuropathological and neuropsychological studies that point to the role of this structure, as part of a complex neural system, in the pathophysiology of autism.

  View details for Web of Science ID 000168786400011

  View details for PubMedID 11392344

• Brain volume in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., Minshew, N. J., Mallikarjuhn, M., Keshavan, M. S. 2001; 16 (6): 421-424

  Abstract

  Increased brain size has been observed in individuals with autism with a wide range of cognitive functioning. The purpose of this investigation was to obtain measurements of the brain volume in a sample of nonmentally retarded autistic individuals. Magnetic resonance imaging scans from 16 nonmentally retarded individuals with autism and 19 male volunteer comparison subjects were obtained and the following structures were measured: third, fourth, and lateral ventricles and intracranial and cerebral volumes. Mean cerebral and third ventricle volumes in the autistic subjects were significantly greater than in the controls when adjusted for intracranial volume. No other significant results were found. Our finding of increased brain volume in autism is consistent with previous reports in the literature. Additional longitudinal neuroimaging and, more importantly, neuropathologic studies are warranted to provide a better understanding of the complexities underlying increased brain size in autism.

  View details for Web of Science ID 000171025800007

  View details for PubMedID 11417608

• Corpus callosum size in autism NEUROLOGY Hardan, A. Y., Minshew, N. J., Keshavan, M. S. 2000; 55 (7): 1033-1036

  Abstract

  The size of the seven subregions of the corpus callosum was measured on MRI scans from 22 non-mentally retarded autistic subjects and 22 individually matched controls. Areas of the anterior subregions were smaller in the autistic group. In a subsample, measurements were adjusted for intracranial, total brain, and white matter volumes and the differences between groups remained significant. No differences were found in the other subregions. This observation is consistent with the frontal lobe dysfunction reported in autism.

  View details for Web of Science ID 000089696500025

  View details for PubMedID 11061265

• Inositol as an add-on treatment for bipolar depression BIPOLAR DISORDERS Chengappa, K. N., Levine, J., Gershon, S., Mallinger, A. G., Hardan, A., Vagnucci, A., Pollock, B., Luther, J., Buttenfield, J., Verfaille, S., Kupfer, D. J. 2000; 2 (1): 47-55

  Abstract

  Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood-brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression.Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) were randomly assigned to receive either 12 g of inositol or D-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged.Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically nonsignificant difference. On the Montgomery-Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p = 0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered.These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.

  View details for Web of Science ID 000089479600007

  View details for PubMedID 11254020

• Prolactin secretion in depressed children BIOLOGICAL PSYCHIATRY Hardan, A., Birmaher, B., Williamson, D. E., Dahl, R. E., Ambrosini, P., Rabinovich, H., Ryan, N. D. 1999; 46 (4): 506-511

  Abstract

  Few studies have examined the involvement of the central dopaminergic system in the pathophysiology of mood disorders. The study of prolactin (PRL) secretion may be an informative indirect method for the assessment of the dopaminergic system in children with major depressive disorder (MDD).Plasma PRL concentrations were measured at 20-min intervals over a 24-hr period in 40 pre-pubertal children with MDD, 18 with non-affective psychiatric disorders (PC), and 6 normal controls (NC). A subgroup of depressed children (n = 21) was restudied after recovery.There was no significant differences in either the amount or the pattern of PRL secretion between the MDD, PC, and NC groups. Children who recovered from their depression secreted less PRL during sleep and more while awake compared to when they were acutely depressed.Overall, there were no differences in baseline PRL secretion between children with MDD, NC and psychiatric control. These results suggest that the dopaminergic system as measured by baseline PRL blood levels is not compromised in children with MDD.

  View details for Web of Science ID 000082036700008

  View details for PubMedID 10459400

• Suicidal behavior in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1999; 20 (4): 287-296

  Abstract

  Children and adolescents with developmental disorders exhibit a wide range of self-destructive behaviors. Interestingly, suicidal ideation and gestures have been underreported in this population. This study was designed to examine suicidality in a clinically referred sample. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at the incidence, the type and the clinical characteristics of any suicidal behavior. Forty-seven patients (20%) experienced either suicidal ideation, threats, or attempts with hanging being the most frequent method considered. Suicidality was more often encountered in individuals diagnosed with oppositional defiant disorder, depressive disorders, and post traumatic stress disorder, and less often in the autistic and the severely/profoundly mentally retarded groups. Suicidal behaviors were frequently encountered in children and adolescents with developmental disabilities. Prospective studies should be conducted to examine rigorously the variables associated with suicidality in this population.

  View details for Web of Science ID 000081321200004

  View details for PubMedID 10425656

• Psychopathology in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1997; 18 (5): 369-382

  Abstract

  Children and adolescents with developmental disorders suffer from a wide range of psychopathology. However, there are no published studies examining this subject exclusively in this population using recent diagnostic criteria. The primary purpose of this paper is to report on the diagnosis encountered in a clinical setting using DSM-III-R. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at their demographic features, diagnoses, and target behaviors. Our sample consisted of 233 subjects and contained significantly more boys than girls. The most common psychiatric diagnoses were oppositional defiant disorder and attention deficit hyperactivity disorder. Pica, organic mental disorder NOS, and Autistic Disorder were more often encountered in individuals with low intellectual functioning. Depressive disorders, posttraumatic stress disorder, and developmental speech/language disorders were diagnosed more in high functioning subjects. The most common symptom was impulsivity. This retrospective study highlights the need for more rigorous examination of current diagnostic concepts and criteria in children and adolescents with developmental disorders. Prospective studies should be conducted with standardized instruments in clinics and community samples to provide more information on psychiatric disorders in this population.

  View details for Web of Science ID A1997XV51300005

  View details for PubMedID 9292930

• Risperidone treatment of children and adolescents with developmental disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A., Johnson, K., Johnson, C., HRECZNYJ, B. 1996; 35 (11): 1551-1556

  Abstract

  In a clinical trial, 20 children and adolescents with developmental disorders (age range 8 through 17 years) refractory to previous psychotropic treatments were administered the atypical neuroleptic risperidone (dose range 1.5 to 10 mg/day). In a follow-up period ranging from 8 to 15 months, risperidone demonstrated clinical efficacy in 13 children. Twelve patients were free of side effects and two had minor ones. Three patients had marked weight increase, and galactorrhea developed in two adolescent girls. In this open study, risperidone was associated with clinical improvement. However, controlled studies are needed to determine its relative efficacy and safety in this special population.

  View details for Web of Science ID A1996VN95400025

  View details for PubMedID 8936923