David S. Hong

All Publications

• 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

• Research Priorities of Individuals and Families with Sex Chromosome Aneuploidies. medRxiv : the preprint server for health sciences Carl, A., Bothwell, S., Farah, F., Swenson, K., Hong, D., Prakash, S., Strang, J., Tartaglia, N., Raznahan, A., Ross, J., Davis, S. 2024

  Abstract

  Sex chromosome aneuploidies (SCAs) are chromosomal variations that result from an atypical number of X and/or Y chromosomes. Combined, SCAs affect ~1/400 live births, including individuals with Klinefelter syndrome (47,XXY), Turner syndrome (45,X and variants), Double Y syndrome (47,XYY), Trisomy X (47,XXX), and rarer tetrasomies and pentasomies. Individuals with SCAs experience a wide variety of physical health, mental health, and healthcare experiences that differ from the standard population. To understand the priorities of the SCA community we surveyed participants in two large SCA registries, the Inspiring New Science in Guiding Healthcare in Turner Syndrome (INSIGHTS) Registry and the Generating Advancements in Longitudinal Analysis in X and Y Variations (GALAXY) Registry. 303/629 (48.1% response rate) individuals from 13 sites across the United States responded to the survey, including 251 caregivers and 52 self-advocates, with a range of ages from 3 weeks to 73 years old and represented SCAs including Turner syndrome, XXX, XXY, XYY, XXYY, and combined rare tetrasomies and pentasomies. Results demonstrate the priorities for physical health and emotional/behavioral health identified by the SCA community, as well as preferred types of research. All SCA subtypes indicated intervention studies as the top priority, emphasizing the need for researchers to focus on clinical treatments in response to priorities of the SCA community.

  View details for DOI 10.1101/2024.08.15.24312069

  View details for PubMedID 39185520

  View details for PubMedCentralID PMC11343263

• Clinical Practice Guidelines for the Care of Girls and Women with Turner Syndrome. European journal of endocrinology Gravholt, C. H., Andersen, N. H., Christin-Maitre, S., Davis, S. M., Duijnhouwer, A., Gawlik, A., Maciel-Guerra, A. T., Gutmark-Little, I., Fleischer, K., Hong, D., Klein, K. O., Prakash, S. K., Kanakatti Shankar, R., Sandberg, D. E., Sas, T. C., Skakkebæk, A., Stochholm, K., van der Velden, J. A., Backeljauw, P. F. 2024

  Abstract

  Turner syndrome affects 50 per 100,000 females, affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and US culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: 1) diagnosis and genetics, 2) growth, 3) puberty and estrogen treatment, 4) cardiovascular health, 5) transition, 6) fertility assessment, monitoring, and counselling, 7) health surveillance for comorbidities throughout the lifespan, and 8) neurocognition and its implications for mental health and well-being. Each group produced proposals for the present guidelines, which were meticulously discussed by the entire group. Four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with systematic review of the literature. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with members from the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology, the European Reference Network on Rare Endocrine Conditions, the Society for Endocrinology, and the European Society of Cardiology, Japanese Society for Pediatric Endocrinology, Australia and New Zealand Society for Pediatric Endocrinology and Diabetes, Latin American Society for Pediatric Endocrinology, Arab Society for Pediatric Endocrinology and Diabetes, and the Asia Pacific Pediatric Endocrine Society. Advocacy groups appointed representatives for pre-meeting discussions and the consensus meeting.

  View details for DOI 10.1093/ejendo/lvae050

  View details for PubMedID 38748847

• Editorial: Imaging the Identified Patient: The Importance of Parent-Child Relationships in Pediatric Neuroimaging Research. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2024

  View details for DOI 10.1016/j.jaac.2024.05.003

  View details for PubMedID 38750814

• Identifying a stable and generalizable factor structure of major depressive disorder across three large longitudinal cohorts. Psychiatry research Tseng, V. W., Tharp, J. A., Reiter, J. E., Ferrer, W., Hong, D. S., Doraiswamy, P. M., Nickels, S. 2023; 333: 115702

  Abstract

  The Patient Health Questionnaire 9 (PHQ-9) is the current standard outpatient screening tool for measuring and tracking the nine symptoms of major depressive disorder (MDD). While the PHQ-9 was originally conceptualized as a unidimensional measure, it has become clear that MDD is not a monolithic construct, as evidenced by high comorbidities with other theoretically distinct diagnoses and common symptom overlap between depression and other diagnoses. Therefore, identifying reliable and temporally stable subfactors of depressive symptoms could allow research and care to be tailored to different depression phenotypes. This study improved on previous factor analysis studies of the PHQ-9 by leveraging samples that were clinical (participants with depression only), large (N = 1483 depressed individuals in total), longitudinal (up to 5 years), and from three diverse (matching racial distribution of the United States) datasets. By refraining from assuming the number of factors or item loadings a priori, and thus utilizing a solely data-driven approach, we identified a ranked list of best-fitting models, with the parsimonious one achieving good model fit across studies at most timepoints (average TLI >= 0.90). This model categorizes the PHQ-9 items into four factors: (1) Affective (Anhedonia + Depressed Mood), (2) Somatic (Sleep + Fatigue + Appetite), (3) Internalizing (Worth/Guilt + Suicidality), (4) Sensorimotor (Concentration + Psychomotor), which may be used to further precision psychiatry by testing factor-specific interventions in research and clinical settings.

  View details for DOI 10.1016/j.psychres.2023.115702

  View details for PubMedID 38219346

• Anxiety levels and structural brain connectivity in early pubertal transgender and cisgender youth Gerwig, P., Tang, Y., Hong, D. S., Karipidis, I. I. SPRINGER WIEN. 2023

  View details for Web of Science ID 001126420100045

• Adolescent brain development in girls with Turner syndrome. Human brain mapping Lozano Wun, V., Foland-Ross, L. C., Jo, B., Green, T., Hong, D., Ross, J. L., Reiss, A. L. 2023

  Abstract

  Turner syndrome (TS) is a common sex chromosome aneuploidy in females associated with various physical, cognitive, and socio-emotional phenotypes. However, few studies have examined TS-associated alterations in the development of cortical gray matter volume and the two components that comprise this measure-surface area and thickness. Moreover, the longitudinal direct (i.e., genetic) and indirect (i.e., hormonal) effects of X-monosomy on the brain are unclear. Brain structure was assessed in 61 girls with TS (11.3 ± 2.8 years) and 55 typically developing girls (10.8 ± 2.3 years) for up to 4 timepoints. Surface-based analyses of cortical gray matter volume, thickness, and surface area were conducted to examine the direct effects of X-monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X-monosomy emerging after pubertal onset. Longitudinal analyses revealed that, whereas typically developing girls exhibited normative declines in gray matter structure during adolescence, this pattern was reduced or inverted in TS. Further, girls with TS demonstrated smaller total surface area and larger average cortical thickness overall. Regionally, the TS group exhibited decreased volume and surface area in the pericalcarine, postcentral, and parietal regions relative to typically developing girls, as well as larger volume in the caudate, amygdala, and temporal lobe regions and increased thickness in parietal and temporal regions. Surface area alterations were predominant by age 8, while maturational differences in thickness emerged by age 10 or later. Taken together, these results suggest the involvement of both direct and indirect effects of X-chromosome haploinsufficiency on brain development in TS.

  View details for DOI 10.1002/hbm.26327

  View details for PubMedID 37126641

• Longitudinal investigation of cognition, social competence, and anxiety in children and adolescents with Turner syndrome. Hormones and behavior Jordan, T. L., Klabunde, M., Green, T., Hong, D. S., Ross, J. L., Jo, B., Reiss, A. L. 2023; 149: 105300

  Abstract

  Turner syndrome (TS), a common neurogenetic disorder caused by complete or partial absence of an X chromosome in females, is characterized by distinct physical, cognitive, and social-emotional features. Girls with TS typically display average overall intellectual functioning with relative strength in verbal abilities and weaknesses in visuospatial processing, executive function (EF), and social cognition. This study was designed to better understand longitudinal trajectories of cognitive and social-emotional domains commonly affected in TS. Participants included 57 girls with monosomic 45,X TS and 55 age- and verbal-IQ matched girls who completed behavioral, child-report, and parent-report measures across four timepoints. Group differences in visuospatial processing, EF, social cognition, and anxiety were assessed longitudinally. Potential effects of estrogen replacement therapy (ERT) were assessed cross-sectionally on an exploratory basis. The TS group showed poorer performance on measures of visuospatial processing, EF, and social cognition, but not anxiety, compared to controls throughout childhood and adolescence. There were no significant group differences in the trajectory of skill development over time. Exploratory analyses within the TS group revealed that girls who were receiving ERT showed better performance on measures of overall IQ, expressive vocabulary, and visuospatial processing compared to those not receiving ERT. Consistent with existing literature, weaknesses in visuospatial processing, EF, and social competence among girls with TS persisted throughout childhood and adolescence. Exploratory analyses suggest that ERT may help improve some aspects of cognitive function in TS, although other pre-existing, nonhormonal differences between the two TS subgroups may alternatively explain these findings, given our study design. Future studies are needed to examine potential impacts of ERT on cognitive and social-emotional development in TS.

  View details for DOI 10.1016/j.yhbeh.2022.105300

  View details for PubMedID 36640638

• General Anxiety Disorder-7 Questionnaire as a marker of low socioeconomic status and inequity. Journal of affective disorders Nunes, J. C., Carroll, M. K., Mahaffey, K. W., Califf, R. M., Doraiswamy, P. M., Short, S., Shah, S. H., Swope, S., Williams, D., Hernandez, A. F., Hong, D. S. 2022

  Abstract

  BACKGROUND: The General Anxiety Disorder-7 (GAD-7) questionnaire is a standard tool used for screening and follow-up of patients with Generalized Anxiety Disorder (GAD). Although it is generally accepted that anxiety correlates with clinical and psychosocial stressors, precise quantitative data is limited on the relations among GAD-7, traditional biomarkers, and other measures of health. Further research is needed about how GAD-7 relates to race, ethnicity, and socioeconomic status (SES) as an assembly. We determined how multiple demographic and socioeconomic data correlate with the participants' GAD-7 results when compared with laboratory, physical function, clinical, and other biological markers.METHODS: The Project Baseline Health Study (BHS) is a prospective cohort of adults representing several populations in the USA. We analyzed a deeply phenotyped group of 2502 participants from that study. Measures of interest included: clinical markers or history of medical diagnoses; physical function markers including gait, grip strength, balance time, daily steps, and echocardiographic parameters; psychometric measurements; activities of daily living; socioeconomic characteristics; and laboratory results.RESULTS: Higher GAD-7 scores were associated with female sex, younger age, and Hispanic ethnicity. Measures of low SES were also associated with higher scores, including unemployment, income ≤$25,000, and ≤12 years of education. After adjustment for 158 demographic, clinical, laboratory, and symptom characteristics, unemployment and overall higher SES risk scores were highly correlated with anxiety scores. Protective factors included Black race and older age.LIMITATIONS: Correlations identified in this cross-sectional study cannot be used to infer causal relationships; further, we were not able to account for possible use of anxiety treatments by study participants.CONCLUSIONS: These findings highlight the importance of understanding anxiety as a biopsychosocial entity. Clinicians and provider organizations need to consider both the physical manifestations of the disorder and their patients' social determinants of health when considering treatment pathways and designing interventions.

  View details for DOI 10.1016/j.jad.2022.08.085

  View details for PubMedID 36031002

• Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study. BMJ open Califf, R. M., Wong, C., Doraiswamy, P. M., Hong, D. S., Miller, D. P., Mega, J. L. 2022; 12 (1): e054741

  Abstract

  We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.None.Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001).Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.NCT03154346.

  View details for DOI 10.1136/bmjopen-2021-054741

  View details for PubMedID 34983769

• Effect of sex chromosome number variation on attention-deficit/hyperactivity disorder symptoms, executive function, and processing speed. Developmental medicine and child neurology Green, T., Flash, S., Shankar, G., Bade Shrestha, S., Jo, B., Klabunde, M., Hong, D. S., Reiss, A. L. 2021

  Abstract

  AIM: To study sex differences in attention-deficit/hyperactivity disorder (ADHD) symptoms, we explored whether X chromosome absence or excess is independently associated with deficits in attention and hyperactivity, executive function, and processing speed.METHOD: We assessed 116 children (ages 3y 10mo-11y 11mo, mean 8y 5mo, SD 1y 11mo) with a variable number of sex chromosomes: 36 females with Turner syndrome (45, X0), 20 males with Klinefelter syndrome (47, XXY), 37 typically developing females (XX), and 23 typically developing males (XY).RESULTS: X chromosome absence was associated with increased attention problems, hyperactivity, and deficits in inhibitory control, compared with female children with XX (all p<0.003). Conversely, X chromosome excess was associated with weakness in working memory (p=0.018) and approached significance for attention problems (p=0.071) but not with hyperactivity, or weakness in inhibitory control relative to male children with XY. Using non-parametric effect size to quantify the clinical effect revealed that X chromosome absence affected attention, hyperactivity, executive function, and processing speed (all r>0.4), while X excess affected in-laboratory as well as parent-reported working memory (all r>0.4).INTERPRETATION: Our observations provide compelling evidence that the absence or excess of an X chromosome distinctly affects cognition and behaviors associated with ADHD.

  View details for DOI 10.1111/dmcn.15020

  View details for PubMedID 34431088

• Importance of Social Determinants in Screening for Depression. Journal of general internal medicine Califf, R. M., Wong, C., Doraiswamy, P. M., Hong, D. S., Miller, D. P., Mega, J. L., Baseline Study Group 2021

  Abstract

  IMPORTANCE: The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease.OBJECTIVE: To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health.DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings.INTERVENTIONS: None.MAIN OUTCOMES AND MEASURES: Cross-sectional measures of clinical and socioeconomic status (SES).RESULTS: In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics.CONCLUSIONS AND RELEVANCE: Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.

  View details for DOI 10.1007/s11606-021-06957-5

  View details for PubMedID 34405346

• Neurodevelopmental Effects of Cannabis Use in Adolescents and Emerging Adults with ADHD: A Systematic Review. Harvard review of psychiatry Cawkwell, P. B., Hong, D. S., Leikauf, J. E. 2021

  Abstract

  OBJECTIVE: Systematically review the scientific literature to characterize the effects of cannabis use on brain structure, function, and neurodevelopmental outcomes in adolescents and young adults with ADHD.METHOD: Systematic review following PRISMA guidelines utilizing PubMed, Embase, PsycINFO, and Cochrane CENTRAL trials register from inception until 1 January 2020. Articles that examined the impact of cannabis use on youth with ADHD were included.RESULTS: Eleven studies were identified that compared outcomes for individuals with ADHD who used cannabis or synthetic cannabinoids against those with ADHD who did not. Seven of these studies used neuroimaging techniques, including fMRI, structural MRI, and SPECT. Differential regions of activation were identified, including the right hippocampus and cerebellar vermis, and bilateral temporal lobes. Morphological differences were identified in the right precentral and postcentral gyri, left nucleus accumbens, right superior frontal and postcentral gyri. No study identified any additive or ADHD * cannabis use interaction on neuropsychological tasks of executive function. Two studies found adverse differential impacts of early-onset cannabis use in this population.CONCLUSION: A dearth of evidence is available on the impact of cannabis use on the developing brain and functioning for individuals with ADHD, despite the elevated risk for substance use in this population. The limited, potentially underpowered evidence does not support the hypothesis that cannabis use has a deleterious impact on neuropsychological tasks in transitional age youth with ADHD. Larger and longer-term studies are needed, however, to better inform clinicians and patients as to the impacts of cannabis use in youth with ADHD.

  View details for DOI 10.1097/HRP.0000000000000303

  View details for PubMedID 34138796

• Cortical gray matter structure in boys with Klinefelter syndrome. Psychiatry research. Neuroimaging Foland-Ross, L. C., Gil, M., Shrestha, S. B., Chromik, L. C., Hong, D., Reiss, A. L. 2021; 313: 111299

  Abstract

  Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5±1.8 years) and 22 typically developing (control) boys (8.1±2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatment-naive with respect to testosterone replacement therapy. Reduced volume in the insula and dorsomedial prefrontal cortex was observed in the KS relative to the TD group, as well as increased volume in the parietal, occipital and motor regions. Further inspection of surface-based metrics indicated that whereas KS-associated increases in volume were driven by differences in thickness, KS-associated reductions in volume were associated with decreases in surface area. Exploratory analyses additionally indicated several correlations between brain structure and behavior, providing initial support for a neural basis of cognitive and emotional symptoms of this condition. Taken together, these data add support for a neuroanatomical phenotype of KS and extend previous studies through clarifying the precise neuroanatomical structural characteristics of that give rise to volumetric alterations.

  View details for DOI 10.1016/j.pscychresns.2021.111299

  View details for PubMedID 34038819

• Effects of X Chromosome Monosomy and Genomic Imprinting on Observational Markers of Social Anxiety in Prepubertal Girls with Turner Syndrome. Journal of autism and developmental disorders Hall, S. S., Riley, M. J., Weston, R. N., Lepage, J., Hong, D. S., Jo, B., Hallmayer, J., Reiss, A. L. 2021

  Abstract

  Previous studies have suggested that girls with Turner syndrome (TS) exhibit symptoms of social anxiety during interactions with others. However, few studies have quantified these behaviors during naturalistic face-to-face social encounters. In this study, we coded observational markers of social anxiety in prepubertal girls with TS and age-matched controls during a 10-min social encounter with an unfamiliar examiner. Results showed that girls with TS exhibited significantly higher levels of gaze avoidance compared to controls. Impairments in social gaze were particularly increased in girls with a maternally retained X chromosome (Xm), suggesting a genomic imprinting effect. These data indicate that social gaze avoidance may be a critical behavioral marker for identifying early social dysfunction in young girls with TS.

  View details for DOI 10.1007/s10803-021-04896-y

  View details for PubMedID 33751331

• IDIOPATHIC AUTISM SPECTRUM DISORDER Hong, D. S. ELSEVIER SCIENCE INC. 2020: S82

  View details for DOI 10.1016/j.jaac.2020.07.342

  View details for Web of Science ID 000579844100269

• Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage. Proceedings of the National Academy of Sciences of the United States of America Zhang, X., Hong, D., Ma, S., Ward, T., Ho, M., Pattni, R., Duren, Z., Stankov, A., Bade Shrestha, S., Hallmayer, J., Wong, W. H., Reiss, A. L., Urban, A. E. 2020

  Abstract

  In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X, SEPT6, NKRF, CX0rf57, NAA10, and FLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.

  View details for DOI 10.1073/pnas.1910003117

  View details for PubMedID 32071206

• Glucocorticoid regulation and neuroanatomy in fragile x syndrome Journal of Psychiatric Research Bruno, J. L., Hong, D. S., Lightbody, A. A., Hosseini, S., Hallmayer, J., Reiss, A. L. 2020

  View details for DOI 10.1016/j.jpsychires.2020.12.015

• Specific learning disorders in sex chromosome aneuploidies: Neural circuits of literacy and mathematics. American journal of medical genetics. Part C, Seminars in medical genetics Karipidis, I. I., Hong, D. S. 2020

  Abstract

  Sex chromosome aneuploidies (SCA) are associated with an increased risk for specific learning disorders (SLD). Individuals with Klinefelter Syndrome (KS) show an increased incidence of developmental dyslexia and individuals with Turner Syndrome (TS) are often affected by developmental dyscalculia. Accordingly, KS frequently coincides with verbal deficits, and TS with visual-spatial impairments. Though neurocognitive profiles of KS and TS are well-established, little is known about the neurobiology underling learning in SCA. This review summarizes current structural and functional magnetic resonance imaging (MRI) studies in KS and TS related to literacy and mathematical skills. It includes studies that focus on correlates between brain anatomy and cognition in SCA and on functional brain responses during learning-related tasks and at rest. We highlight important neural circuits that are related to domain-specific skills of literacy and mathematics. We discuss how identifying neuroendophenotypes of learning in SCA might contribute to developing a novel framework for SLD that accounts for potential genetic effects on learning, and from the X and Y chromosomes specifically. Future research directions are considered to establish clear brain-behavior relationships that might ultimately improve the treatment of SLD in SCA across development.

  View details for DOI 10.1002/ajmg.c.31801

  View details for PubMedID 32463563

• Dyslexia in Pediatrics: Simple Practices to Tackle a Complex Issue. Pediatrics Karipidis, I. I., Hong, D. S. 2020

  View details for DOI 10.1542/peds.2020-1470

  View details for PubMedID 32576594

• Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting. Biological psychiatry O'Donoghue, S. n., Green, T. n., Ross, J. L., Hallmayer, J. n., Lin, X. n., Jo, B. n., Huffman, L. C., Hong, D. S., Reiss, A. L. 2019

  Abstract

  The study of Turner syndrome (TS) offers a unique window of opportunity for advancing scientific knowledge of how X chromosome gene imprinting, epigenetic factors, hormonal milieu, and chronologic age affect brain development in females.We described brain growth trajectories in 55 girls with TS and 53 typically developing girls (258 magnetic resonance imaging datasets) spanning 5 years. Using novel nonparametric and mixed effects analytic approaches, we evaluated influences of X chromosome genomic imprinting and hormone replacement therapy on brain development.Parieto-occipital gray and white matter regions showed slower growth during typical pubertal timing in girls with TS relative to typically developing girls. In contrast, some basal ganglia, cerebellar, and limited cortical areas showed enhanced volume growth with peaks around 10 years of age.The parieto-occipital finding suggests that girls with TS may be particularly vulnerable to altered brain development during adolescence. Basal ganglia regions may be relatively preserved in TS owing to their maturational growth before or early in typical pubertal years. Taken together, our findings indicate that particular brain regions are more vulnerable to TS genetic and hormonal effects during puberty. These specific alterations in neurodevelopment may be more likely to affect long-term cognitive behavioral outcomes in young girls with this common genetic condition.

  View details for DOI 10.1016/j.biopsych.2019.07.032

  View details for PubMedID 31561860

• 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

• Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years JOURNAL OF PSYCHIATRIC RESEARCH Sandoval, G. M., Shim, S., Hong, D. S., Garrett, A. S., Quintin, E., Marzelli, M. J., Patnaik, S., Lightbody, A. A., Reiss, A. L. 2018; 107: 138–44

  View details for DOI 10.1016/j.jpsychires.2018.10.014

  View details for Web of Science ID 000451490800020

• Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years. Journal of psychiatric research Sandoval, G. M., Shim, S., Hong, D. S., Garrett, A. S., Quintin, E., Marzelli, M. J., Patnaik, S., Lightbody, A. A., Reiss, A. L. 2018; 107: 138–44

  Abstract

  Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex-matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function.

  View details for PubMedID 30408626

• X-Chromosome Effects on Attention Networks: Insights from Imaging Resting-State Networks in Turner Syndrome CEREBRAL CORTEX Green, T., Saggar, M., Ishak, A., Hong, D. S., Reiss, A. L. 2018; 28 (9): 3176–83

  View details for DOI 10.1093/cercor/bhx188

  View details for Web of Science ID 000443545600008

• "Communities" of Conditions: Novel Methods for Classifying Psychiatric Disorders. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2018; 57 (4): 233–34

  Abstract

  In 1798, Philippe Pinel presented one of the first nosologies for psychiatric disorders, "Nosographie philosophique ou la methode de l'analyse appliquee a la medecine."1 His emphasis on psychological and physical conditions as the basis of mental illness provided a distinct departure from prior reliance on such etiologies such as demonic possession. Establishing classification schema was a much more profound innovation than a simple academic reordering of psychiatric phenomena-under Pinel's leadership at the famed Pitie-Salpetriere hospital, it also led to a radical reformation of clinical interventions, moving away from pseudoscientific practices toward psychologically based interventions. Much of this work influenced his successors in psychiatric taxonomy including Emil Kraeplin and others, ultimately forming the basis of the DSM.2 Although the DSM has been subsequently celebrated and maligned, it has been instrumental in both our conceptualization and treatment approach to psychiatric disorders. Indeed, there has been extensive effort to validate these conditions using factor analytic approaches to confirm that such conditions represent cohesive biologically based disorders, which has presented challenges.3.

  View details for PubMedID 29588048

• "Communities" of Conditions: Novel Methods for Classifying Psychiatric Disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hong, D. S. 2018; 57 (4): 233–34

  View details for DOI 10.1016/j.jaac.2018.02.002

  View details for Web of Science ID 000435626600004

• Attention-Deficit/Hyperactivity Disorder and Learning Disorders STUDENT MENTAL HEALTH: A GUIDE FOR PSYCHIATRISTS, PSYCHOLOGISTS, AND LEADERS SERVING IN HIGHER EDUCATION Chromik, L. C., Hong, D. S., Roberts, L. W. 2018: 197–212

  View details for Web of Science ID 000552225100015

• NEUROIMAGING IN THREE SYNDROMES ASSOCIATED WITH AUTISM SPECTRUM DISORDER Hong, D. S. ELSEVIER SCIENCE INC. 2017: S20

  View details for DOI 10.1016/j.jaac.2017.07.078

  View details for Web of Science ID 000544086200068

• Here/In This Issue and There/Abstract Thinking: The Growing, and Changing, Landscape of Child and Adolescent Mental Healthcare Delivery. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2017; 56 (9): 719–20

  View details for PubMedID 28838572

• Identification of biotypes in Attention-Deficit/Hyperactivity Disorder, a report from a randomized, controlled trial. Personalized medicine in psychiatry Leikauf, J. E., Griffiths, K. R., Saggar, M., Hong, D. S., Clarke, S., Efron, D., Tsang, T. W., Hermens, D. F., Kohn, M. R., Williams, L. M. 2017; 3: 8-17

  Abstract

  Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder. Current subtypes lack longitudinal stability or prognostic utility. We aimed to identify data-driven biotypes using multiple cognitive measures, then to validate these biotypes using EEG, ECG, and clinical response to atomoxetine as external validators. Study design was a double-blind, randomized, placebo-controlled crossover trial of atomoxetine including 116 subjects ages 6 through 17 with diagnosis of ADHD and 56 typically developing controls. Initial features for unsupervised machine learning included a cognitive battery with 20 measures affected in ADHD. External validators included baseline mechanistic validators (using electroencephalogram/EEG and electrocardiogram/ECG) and clinical response (ADHD Rating Scale and correlation with cognitive change). One biotype, labeled impulsive cognition, was characterized by increased errors of commission and shorter reaction time, had greater EEG slow wave (theta/delta) power and greater resting heart rate. The second biotype, labeled inattentive cognition, was characterized by longer/more variable reaction time and errors of omission, had lower EEG fast wave (beta) power, resting heart rate that did not differ from controls, and a strong correlation (r = -0.447, p < 0.001) between clinical response to atomoxetine and improvement in verbal memory immediate recall. ADHD comprises at least two biotypes that cut across current subtype criteria and that may reflect distinct arousal mechanisms. The findings provide evidence that further investigation of cognitive subtypes may be at least as fruitful as symptom checklist-based subtypes for development of biologically-based diagnostics and interventions for ADHD.

  View details for DOI 10.1016/j.pmip.2017.02.001

  View details for PubMedID 35637915

  View details for PubMedCentralID PMC9148272

• Linking ADHD to the Neural Circuitry of Attention TRENDS IN COGNITIVE SCIENCES Mueller, A., Hong, D. S., Shepard, S., Moore, T. 2017; 21 (6): 474-488

  Abstract

  Attention deficit hyperactivity disorder (ADHD) is a complex condition with a heterogeneous presentation. Current diagnosis is primarily based on subjective experience and observer reports of behavioral symptoms - an approach that has significant limitations. Many studies show that individuals with ADHD exhibit poorer performance on cognitive tasks than neurotypical controls, and at least seven main functional domains appear to be implicated in ADHD. We discuss the underlying neural mechanisms of cognitive functions associated with ADHD, with emphasis on the neural basis of selective attention, demonstrating the feasibility of basic research approaches for further understanding cognitive behavioral processes as they relate to human psychopathology. The study of circuit-level mechanisms underlying executive functions in nonhuman primates holds promise for advancing our understanding, and ultimately the treatment, of ADHD.

  View details for DOI 10.1016/j.tics.2017.03.009

  View details for PubMedID 28483638

• Here/In This Issue and There/Abstract Thinking: The First Year: Incorporating Maternal Mental Health Into Child Psychiatric Practice. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2017; 56 (3): 183-184

  View details for DOI 10.1016/j.jaac.2017.01.001

  View details for PubMedID 28219481

• Multi-Table Differential Correlation Analysis of Neuroanatomical and Cognitive Interactions in Turner Syndrome. Neuroinformatics Seiler, C. n., Green, T. n., Hong, D. n., Chromik, L. n., Huffman, L. n., Holmes, S. n., Reiss, A. L. 2017

  Abstract

  Girls and women with Turner syndrome (TS) have a completely or partially missing X chromosome. Extensive studies on the impact of TS on neuroanatomy and cognition have been conducted. The integration of neuroanatomical and cognitive information into one consistent analysis through multi-table methods is difficult and most standard tests are underpowered. We propose a new two-sample testing procedure that compares associations between two tables in two groups. The procedure combines multi-table methods with permutation tests. In particular, we construct cluster size test statistics that incorporate spatial dependencies. We apply our new procedure to a newly collected dataset comprising of structural brain scans and cognitive test scores from girls with TS and healthy control participants (age and sex matched). We measure neuroanatomy with Tensor-Based Morphometry (TBM) and cognitive function with Wechsler IQ and NEuroPSYchological tests (NEPSY-II). We compare our multi-table testing procedure to a single-table analysis. Our new procedure reports differential correlations between two voxel clusters and a wide range of cognitive tests whereas the single-table analysis reports no differences. Our findings are consistent with the hypothesis that girls with TS have a different brain-cognition association structure than healthy controls.

  View details for PubMedID 29270892

• X-Chromosome Effects on Attention Networks: Insights from Imaging Resting-State Networks in Turner Syndrome. Cerebral cortex (New York, N.Y. : 1991) Green, T. n., Saggar, M. n., Ishak, A. n., Hong, D. S., Reiss, A. L. 2017: 1–8

  Abstract

  Attention deficit hyperactivity disorder (ADHD) is strongly affected by sex, but sex chromosomes' effect on brain attention networks and cognition are difficult to examine in humans. This is due to significant etiologic heterogeneity among diagnosed individuals. In contrast, individuals with Turner syndrome (TS), who have substantially increased risk for ADHD symptoms, share a common genetic risk factor related to the absence of the X-chromosome, thus serving as a more homogeneous genetic model. Resting-state functional MRI was employed to examine differences in attention networks between girls with TS (n = 40) and age- sex- and Tanner-matched controls (n = 33). We compared groups on resting-state functional connectivity measures from data-driven independent components analysis (ICA) and hypothesis-based seed analysis. Using ICA, reduced connectivity was observed in both frontoparietal and dorsal attention networks. Similarly, using seeds in the bilateral intraparietal sulcus (IPS), reduced connectivity was observed between IPS and frontal and cerebellar regions. Finally, we observed a brain-behavior correlation between IPS-cerebellar connectivity and cognitive attention measures. These findings indicate that X-monosomy contributes affects to attention networks and cognitive dysfunction that might increase risk for ADHD. Our findings not only have clinical relevance for girls with TS, but might also serve as a biological marker in future research examining the effects of the intervention that targets attention skills.

  View details for PubMedID 28981595

• Here/In This Issue and There/Abstract Thinking: The Data Revolution Has Arrived, but Are We Ready? A Call to Action for Child Psychiatry. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2016; 55 (9): 741-742

  View details for DOI 10.1016/j.jaac.2016.07.002

  View details for PubMedID 27566111

• Sex Differences in Amygdala Shape: Insights from Turner Syndrome Green, T., Fierro, K. C., Raman, M., Foland-Ross, L., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2016: 109S

  View details for Web of Science ID 000432440801107

• Sex differences in amygdala shape: Insights from Turner syndrome. Human brain mapping Green, T., Fierro, K. C., Raman, M. M., Foland-Ross, L., Hong, D. S., Reiss, A. L. 2016; 37 (4): 1593-1601

  Abstract

  Sex differences in the manifestation of psychiatric disorders, including anxiety disorders, are among the most prominent findings in psychiatry. The study of Turner syndrome (TS), caused by X-monosomy, has the potential to reveal mechanisms that underline male/female differences in neuropsychiatric disorders. The amygdala has been implicated in numerous neuropsychiatric disorders. Previous studies suggest an effect of TS on amygdala volume as well as on amygdala-related behaviors such as anxiety. Our objective is to investigate the amygdala shape in TS. Specifically, we tested whether amygdala enlargements in TS are localized to specific nuclei implicated in anxiety, such as the basomedial nucleus.We use a surface-based analytical modeling approach to contrast 41 pre-estrogen treatment girls with TS (mean age 8.6 ± 2.4) with 34 age-and sex-matched typically developing (TD) controls (mean age 8.0 ± 2.8). Anxiety symptoms were assessed using the Revised Children's Manifest Anxiety Scale - 2 (RCMAS-2) in both groups.TS was associated with anomalous enlargement of the amygdala. Surface-based modeling revealed shape differences (increased radial-distances) in bilateral basal and basomedial nuclei within the basolateral complex. RCMAS-2 Total Anxiety t-score was significantly higher in participants with TS compared with TD controls (P = 0.012).Group differences in global amygdala volumes were driven by local morphological increases in areas that are critically involved in face emotion processing and anxiety. In the context of increased amygdala volumes in TS, our results also showed increased worry and social anxiety in young girls with TS compared with TD. Hum Brain Mapp 37:1593-1601, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.23122

  View details for PubMedID 26819071

• Here/In This Issue and There/Abstract Thinking: Wielding Weapons: The Intersection Between Firearms and Child Psychiatry. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2016; 55 (3): 153-154

  View details for DOI 10.1016/j.jaac.2015.12.012

  View details for PubMedID 26903245

• Proceedings From the Turner Resource Network Symposium: The Crossroads of Health Care Research and Health Care Delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Backeljauw, P. F., Bondy, C., Chernausek, S. D., Cernich, J. T., Cole, D. A., Fasciano, L. P., Foodim, J., Hawley, S., Hong, D. S., Knickmeyer, R. C., Kruszka, P., Lin, A. E., Lippe, B. M., Lorigan, G. A., Maslen, C. L., Mauras, N., Page, D. C., Pemberton, V. L., Prakash, S. K., Quigley, C. A., Ranallo, K. C., Reiss, A. L., Sandberg, D. E., Scurlock, C., Silberbach, M. 2015; 167 (9): 1962-1971

  Abstract

  Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

  View details for DOI 10.1002/ajmg.a.37121

  View details for Web of Science ID 000360056700005

  View details for PubMedCentralID PMC4714605

• Here/In This Issue and There/Abstract Thinking: The Secret Lives of Adolescents: Are We Asking the Right Questions? Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2015; 54 (9): 697-698

  View details for DOI 10.1016/j.jaac.2015.06.013

  View details for PubMedID 26299287

• Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function JOURNAL OF PSYCHIATRIC RESEARCH Green, T., Shrestha, S. B., Chromik, L. C., Rutledge, K., Pennington, B. F., Hong, D. S., Reiss, A. L. 2015; 68: 217-225

  Abstract

  To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD.We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD.Within the TS group, 51% scored at or above the "at-risk" range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/-ADHD).ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD.

  View details for DOI 10.1016/j.jpsychires.2015.06.021

  View details for Web of Science ID 000359956100031

• Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function. Journal of psychiatric research Green, T., Bade Shrestha, S., Chromik, L. C., Rutledge, K., Pennington, B. F., Hong, D. S., Reiss, A. L. 2015; 68: 217-225

  Abstract

  To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD.We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD.Within the TS group, 51% scored at or above the "at-risk" range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/-ADHD).ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD.

  View details for DOI 10.1016/j.jpsychires.2015.06.021

  View details for PubMedID 26228422

• Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery. American journal of medical genetics. Part A Backeljauw, P. F., Bondy, C., Chernausek, S. D., Cernich, J. T., Cole, D. A., Fasciano, L. P., Foodim, J., Hawley, S., Hong, D. S., Knickmeyer, R. C., Kruszka, P., Lin, A. E., Lippe, B. M., Lorigan, G. A., Maslen, C. L., Mauras, N., Page, D. C., Pemberton, V. L., Prakash, S. K., Quigley, C. A., Ranallo, K. C., Reiss, A. L., Sandberg, D. E., Scurlock, C., Silberbach, M. 2015; 167A (9): 1962-1971

  Abstract

  Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

  View details for DOI 10.1002/ajmg.a.37121

  View details for PubMedID 25920614

• Here/In This Issue and There/Abstract Thinking: The Art (and Science) of Psychotherapy. Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2015; 54 (3): 157-158

  View details for DOI 10.1016/j.jaac.2014.12.013

  View details for PubMedID 25721178

• Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L. C., Hong, D. S., Reiss, A. L. 2014; 165B (6): 531-540

  Abstract

  Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32256

  View details for PubMedID 25044604

• Aberrant parietal cortex developmental trajectories in girls with turner syndrome and related visual-spatial cognitive development: A preliminary study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L. C., Hong, D. S., Reiss, A. L. 2014; 165 (6): 531-540

  Abstract

  Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32256

  View details for PubMedID 25044604

• Here/In This Issue and There/Abstract Thinking: Learning Disorders and ADHD: Are LDs Getting the Attention They Deserve? Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2014; 53 (9): 933-934

  View details for DOI 10.1016/j.jaac.2014.06.006

  View details for PubMedID 25151413

• Influence of the x-chromosome on neuroanatomy: evidence from turner and klinefelter syndromes. journal of neuroscience Hong, D. S., Hoeft, F., Marzelli, M. J., Lepage, J., Roeltgen, D., Ross, J., Reiss, A. L. 2014; 34 (10): 3509-3516

  Abstract

  Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

  View details for DOI 10.1523/JNEUROSCI.2790-13.2014

  View details for PubMedID 24599451

• Aberrant neurocognitive processing of fear in young girls with Turner syndrome SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE Hong, D. S., Bray, S., Haas, B. W., Hoeft, F., Reiss, A. L. 2014; 9 (3): 255-264

  Abstract

  Appraisal of fearful stimuli is an integral aspect of social cognition. Neural circuitry underlying this phenomenon has been well-described and encompasses a distributed network of affective and cognitive nodes. Interestingly, this ability to process fearful faces is impaired in Turner syndrome (TS), a genetic disorder of females in which all or part of an X chromosome is missing. However, neurofunctional correlates for this impairment have not been well-studied, particularly in young girls. Given that the core features of TS include X chromosome gene haploinsufficiency and secondary sex hormone deficiencies, investigation of fearful face processing may provide insights into the influence of X chromosome gene expression on this network. Therefore, we examined behavioral and neural responses during an explicit emotional face labeling task in 14 prepubertal girls with TS and 16 typically developing age-matched controls (6-13 years). We demonstrate that girls with TS have a specific impairment in the identification of fearful faces and show decreased activation in several cognitive control regions, including the anterior dorsal anterior cingulate cortex, dorsolateral prefrontal cortex and posterior cingulate gyrus. Our results indicate that aberrant functional activation in dorsal cognitive regions plays an integral role in appraisal of, and regulation of response to fear in TS.

  View details for DOI 10.1093/scan/nss133

  View details for Web of Science ID 000336488300001

  View details for PubMedID 23171616

  View details for PubMedCentralID PMC3980805

• Cognitive and neurological aspects of sex chromosome aneuploidies LANCET NEUROLOGY Hong, D. S., Reiss, A. L. 2014; 13 (3): 306-318

  Abstract

  Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.

  View details for PubMedID 24556008

• Here/In this issue and there/abstract thinking: personalized psychiatry: are we almost there? Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2014; 53 (3): 263-264

  View details for DOI 10.1016/j.jaac.2013.12.014

  View details for PubMedID 24565352

• Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study. Genes, brain, and behavior LePage, J., Hong, D. S., Raman, M., Marzelli, M., Roeltgen, D. P., Lai, S., Ross, J., Reiss, A. L. 2014; 13 (2): 127-134

  Abstract

  The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

  View details for DOI 10.1111/gbb.12107

  View details for PubMedID 24308542

  View details for PubMedCentralID PMC3918511

• Brain morphology in children with 47,XYY syndrome: a voxel-and surface-based morphometric study GENES, BRAIN AND BEHAVIOR Lepage, J., Hong, D. S., Raman, M., Marzelli, M., et al 2014: 127–34

  Abstract

  The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

  View details for DOI 10.1111/gbb.12107

  View details for PubMedCentralID PMC3918511

• Aberrant Functional Network Recruitment of Posterior Parietal Cortex in Turner Syndrome HUMAN BRAIN MAPPING Bray, S., Hoeft, F., Hong, D. S., Reiss, A. L. 2013; 34 (12): 3117-3128

  Abstract

  Turner syndrome is a genetic disorder caused by the complete or partial absence of an X chromosome in affected women. Individuals with TS show characteristic difficulties with executive functions, visual-spatial and mathematical cognition, with relatively intact verbal skills, and congruent abnormalities in structural development of the posterior parietal cortex (PPC). The functionally heterogeneous PPC has recently been investigated using connectivity-based clustering methods, which sub-divide a given region into clusters of voxels showing similar structural or functional connectivity to other brain regions. In the present study, we extended this method to compare connectivity-based clustering between groups and investigate whether functional networks differentially recruit the PPC in TS. To this end, we parcellated the PPC into sub-regions based on temporal correlations with other regions of the brain. fMRI data were collected from 15 girls with TS and 14 typically developing (TD) girls, aged 7-14, while they performed a visual-spatial task. Temporal correlations between voxels in the PPC and a set of seed regions were calculated, and the PPC divided into clusters of voxels showing similar connectivity. It was found that in general the PPC parcellates similarly in TS and TD girls, but that regions in bilateral inferior parietal lobules, and posterior right superior parietal lobule, were reliably recruited by different networks in TS relative to TD participants. These regions showed weaker correlation in TS with a set of regions involved in visual processing. These results suggest that abnormal development of visuospatial functional networks in TS may relate to the well documented cognitive difficulties in this disorder.

  View details for DOI 10.1002/hbm.22131

  View details for PubMedID 22711287

• Here/In this issue and there/abstract thinking: adolescence to adulthood: are some children falling into the gap? Journal of the American Academy of Child and Adolescent Psychiatry Hong, D. S. 2013; 52 (9): 885-886

  View details for DOI 10.1016/j.jaac.2013.06.014

  View details for PubMedID 23972687

• Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome CEREBRAL CORTEX Lepage, J., Mazaika, P. K., Hong, D. S., Raman, M., Reiss, A. L. 2013; 23 (9): 2159-2168

  Abstract

  Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

  View details for DOI 10.1093/cercor/bhs195

  View details for Web of Science ID 000322661100013

  View details for PubMedID 22806268

• Genomic imprinting effects of the x chromosome on brain morphology. journal of neuroscience Lepage, J., Hong, D. S., Mazaika, P. K., Raman, M., Sheau, K., Marzelli, M. J., Hallmayer, J., Reiss, A. L. 2013; 33 (19): 8567-8574

  Abstract

  There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.

  View details for DOI 10.1523/JNEUROSCI.5810-12.2013

  View details for PubMedID 23658194

• Impact of cognitive profile on social functioning in prepubescent females with Turner syndrome CHILD NEUROPSYCHOLOGY Lepage, J., Dunkin, B., Hong, D. S., Reiss, A. L. 2013; 19 (2): 161-172

  Abstract

  Social deficits are prevalent in Turner syndrome (TS); however, the extent to which these difficulties are secondary to characteristic cognitive impairments is not well known. Here, we sought to establish the relative contribution of executive functions, visuospatial abilities, and IQ to social difficulties in young girls with TS. Forty TS girls and 19 typically developing (TD) children were assessed with the Social Responsiveness Scale (SRS), the Motor-Free Visual Spatial Test (MVPT-3), the Behavior Rating Inventory of Executive Function (BRIEF), and an IQ test. Hierarchical multiple regression analyses were conducted with the SRS subscales as outcome variables. In a first step, the cognitive factors were entered (verbal IQ, BRIEF global score, MVPT-3, and age), followed by the group variable in a second step. In comparison to TD, TS participants were significantly impaired on all main measures. All six regression models with the SRS subscales were significant and revealed that global executive functions explained the largest portion of the variance on all subscales and the total score. Even after controlling for cognitive elements, the group factor still explained a significant portion of the variance of the Social Cognition, Social Awareness, and Autistic Mannerisms subscales. In contrast, the group factor was not a significant predictor of Social Motivation and Social Communication scores. These results suggest that executive dysfunctions play a role in social impairments encountered in TS, but also that some specific aspects of social behavior are altered beyond what can be attributed to cognitive difficulties in this population.

  View details for DOI 10.1080/09297049.2011.647900

  View details for PubMedID 22372383

• White Matter Aberrations in Prepubertal Estrogen-Naive Girls with Monosomic Turner Syndrome CEREBRAL CORTEX Yamagata, B., Barnea-Goraly, N., Marzelli, M. J., Park, Y., Hong, D. S., Mimura, M., Reiss, A. L. 2012; 22 (12): 2761-2768

  Abstract

  Turner syndrome (TS) offers a unique opportunity to investigate associations among genes, the brain, and cognitive phenotypes. In this study, we used 3 complementary analyses of diffusion tensor imaging (DTI) data (whole brain, region of interest, and fiber tractography) and a whole brain volumetric imaging technique to investigate white matter (WM) structure in prepubertal, nonmosaic, estrogen-naive girls with TS compared with age and sex matched typically developing controls. The TS group demonstrated significant WM aberrations in brain regions implicated in visuospatial abilities, face processing, and sensorimotor and social abilities compared with controls. Extensive spatial overlap between regions of aberrant WM structure (from DTI) and regions of aberrant WM volume were observed in TS. Our findings indicate that complete absence of an X chromosome in young females (prior to receiving exogenous estrogen) is associated with WM aberrations in specific regions implicated in characteristic cognitive features of TS.

  View details for DOI 10.1093/cercor/bhr355

  View details for PubMedID 22172580

• Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome. Cerebral cortex (New York, N.Y. : 1991) Lepage, J. F., Mazaika, P. K., Hong, D. S., Raman, M., Reiss, A. L. 2012

  Abstract

  Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

  View details for DOI 10.1093/cercor/bhs195

  View details for PubMedID 22806268

• Cognition and behavior in Turner syndrome: a brief review. Pediatric endocrinology reviews : PER Hong, D. S., Reiss, A. L. 2012; 9: 710-712

  Abstract

  There is increasing evidence that Turner syndrome is associated with a distinct pattern of cognitive and neurophysiological characteristics. Typically this has been characterized by relative strengths in verbal skills, contrasting with relative weaknesses in arithmetic, visuospatial and executive function domains. Potential differences in social cognitive processing have also been identified. More recently, applications of neuroimaging techniques have further elucidated underlying differences in brain structure, function and connectivity in individuals with Turner syndrome. Ongoing research in this area is focused on establishing a unified mechanistic model incorporating genetic influences from the X chromosome, sex hormone contributions, neuroanatomical variation and differences in cognitive processes. This review broadly covers current understanding of how X-monosomy impacts neurocognitive phenotype both from the perspective of cognitive-behavioral and neuroimaging studies. Furthermore, relevant clinical aspects of identifying potential learning difficulties and providing anticipatory guidance for affected individuals with TS, are briefly discussed.

  View details for PubMedID 22946281

• Genomic Imprinting Effects on Cognitive and Social Abilities in Prepubertal Girls with Turner Syndrome JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Lepage, J., Hong, D. S., Hallmayer, J., Reiss, A. L. 2012; 97 (3): E460-E464

  Abstract

  Recent evidence suggests that the cognitive and social manifestations associated with Turner syndrome (TS) might be influenced by epigenetic factors in the form of genomic imprinting. However, due to small and heterogeneous samples, inconsistent results have emerged from these studies.The objective of this prospective study was to establish the impact of genomic imprinting on neurocognitive abilities and social functioning in young girls with TS.An extensive battery of neuropsychological assessments was administered to 65 children with TS who had never been exposed to estrogen treatment, 24 of whom had an X-chromosome from paternal origin (Xpat) and 41 from maternal origin (Xmat).The Wechsler scales of intelligence, the Motor-Free Visual Spatial test-3, the Wide Range Assessment of Visual Motor Ability, and the attention/executive domain of the NEPSY were used to assess cognitive abilities. Social functioning was assessed with the Social Responsiveness Scale and the Behavior Assessment System for Children-2.Results showed that although individuals with Xpat obtained lower scores than their counterparts with Xmat on most cognitive and social measures, only the Perceptual Reasoning Index of the intelligence scale yielded significant differences after correction for multiple comparisons.Overall, these results suggest that although some aspects of the neuropsychological profile of TS may be influenced by epigenetic factors, the sociocognitive phenotype associated with the disorder is not modulated by genomic imprinting.

  View details for DOI 10.1210/jc.2011-2916

  View details for PubMedID 22238395

• Contribution of Executive Functions to Visuospatial Difficulties in Prepubertal Girls With Turner Syndrome DEVELOPMENTAL NEUROPSYCHOLOGY Lepage, J., Dunkin, B., Hong, D. S., Reiss, A. L. 2011; 36 (8): 988-1002

  Abstract

  Turner syndrome (TS) is a genetic disorder caused by the absence of one X-chromosome in females. Individuals with TS often demonstrate a cognitive profile characterized by poor visuospatial abilities, which may in part be due to executive function impairments. Here, we assessed the neuropsychological profile of 36 prepubertal girls with TS and 20 typically developing children to examine the relationship between executive function and visuospatial abilities. Multiple linear regression analyses revealed that executive functions were closely associated with visuospatial abilities in TS but not in controls. These results suggest that executive dysfunctions observed in TS contribute to their visuospatial impairments.

  View details for DOI 10.1080/87565641.2011.584356

  View details for PubMedID 22004020

• Reduced Functional Connectivity during Working Memory in Turner Syndrome CEREBRAL CORTEX Bray, S., Dunkin, B., Hong, D. S., Reiss, A. L. 2011; 21 (11): 2471-2481

  Abstract

  Turner syndrome (TS) is a genetic disorder affecting females, resulting from the complete or partial absence of an X chromosome. The cognitive profile of TS shows relative strengths in the verbal domain and weaknesses in the procedural domain, including working memory. Neuroimaging studies have identified differences in the morphology of the parietal lobes, and white matter pathways linking frontal and parietal regions, as well as abnormal activation in dorsal frontal and parietal regions. Taken together these findings suggest that abnormal functional connectivity between frontal and parietal regions may be related to working memory impairments in TS, a hypothesis we tested in the present study. We scanned TS and typically developing participants with functional magnetic resonance imaging while they performed visuospatial and phonological working memory tasks. We generated a seed region in parietal cortex based on structural differences in TS and found that functional connectivity with dorsal frontal regions was reduced during working memory in TS. Finally, we found that connectivity was correlated with task performance in TS. These findings suggest that structural brain abnormalities in TS affect not only regional activity but also the functional interactions between regions and that this has important consequences for behavior.

  View details for DOI 10.1093/cercor/bhr017

  View details for PubMedID 21441396

• Psychosocial Functioning and Social Cognitive Processing in Girls with Turner Syndrome JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Hong, D. S., Dunkin, B., Reiss, A. L. 2011; 32 (7): 512-520

  Abstract

  Turner syndrome (TS) is a common genetic disorder caused by partial or complete absence of the second X chromosome in females and is associated with a characteristic neurocognitive profile traditionally described by discrepancy between verbal and performance IQ. Difficulties in social functioning have also been increasingly identified in this population. The purpose of this study was to examine elements of social competence and cognition in a pre-estrogen population of girls with TS.The authors administered psychosocial and neurocognitive measures to examine metrics of social function and intelligence in a group of young girls with TS, pre-estrogen treatment (n = 42) and control peers (n = 32), aged between 3 and 12 years.Girls with TS demonstrated significantly decreased social competency on all dimensions of the Social Responsiveness Scale, with the exception of the Social Motivation subscale, where ratings were comparable with typically developing peers. Performance on social cognitive tasks was also impaired on NEPSY Memory for Faces and Theory of Mind tasks. Differences were further observed on Behavioral Assessment Scales for Children subscales of Hyperactivity, Atypicality, Attention, Social Skills, Activities of Daily Living, and Functional Communication. Group differences in social cognition or behavior remained significant after adjusting for verbal IQ.This study supports the hypothesis that young girls with TS who have not yet received estrogen treatment demonstrate significantly impaired social cognition. Improved understanding of differences in social competence and cognition can increase awareness and inform clinical approaches to identifying and treating social difficulties in individuals with TS.

  View details for DOI 10.1097/DBP.0b013e3182255301

  View details for PubMedID 21743350

• White Matter Aberrations in Non-Mosaic and Estrogen-Naive Girls with Turner Syndrome Yamagata, B., Barnea-Goraly, N., Park, Y., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2011: 84S

  View details for Web of Science ID 000290641800267

• Neuroanatomical spatial patterns in Turner syndrome NEUROIMAGE Marzelli, M. J., Hoeft, F., Hong, D. S., Reiss, A. L. 2011; 55 (2): 439-447

  Abstract

  Turner syndrome (TS) is a highly prevalent genetic condition caused by partial or complete absence of one X-chromosome in a female and is associated with a lack of endogenous estrogen during development secondary to gonadal dysgenesis. Prominent cognitive weaknesses in executive and visuospatial functions in the context of normal overall IQ also occur in affected individuals. Previous neuroimaging studies of TS point to a profile of neuroanatomical variation relative to age and sex matched controls. However, there are no neuroimaging studies focusing on young girls with TS before they receive exogenous estrogen treatment to induce puberty. Information obtained from young girls with TS may help to establish an early neural correlate of the cognitive phenotype associated with the disorder. Further, univariate analysis has predominantly been the method of choice in prior neuroimaging studies of TS. Univariate approaches examine between-group differences on the basis of individual image elements (i.e., a single voxel's intensity or the volume of an a priori defined brain region). This is in contrast to multivariate methods that can elucidate complex neuroanatomical profiles in a clinical population by determining the pattern of between-group differences from many image elements evaluated simultaneously. In this case, individual image elements might not be significantly different between groups but can still contribute to a significantly different overall spatial pattern. In this study, voxel-based morphometry (VBM) of high-resolution magnetic resonance images was used to investigate differences in brain morphology between 13 pediatric, pre-estrogen girls with monosomic TS and 13 age-matched typically developing controls (3.0 T imaging: mean age 9.1±2.1). A similar analysis was performed with an older cohort of 13 girls with monosomic TS and 13 age-matched typically developing controls (1.5 T imaging: mean age 15.8±4.5). A multivariate, linear support vector machine analysis using leave-one-out cross-validation was then employed to discriminate girls with TS from typically developing controls based on differences in neuroanatomical spatial patterns and to assess how accurately such patterns translate across heterogeneous cohorts. VBM indicated that both TS cohorts had significantly reduced gray matter volume in the precentral, postcentral, and supramarginal gyri and enlargement of the left middle and superior temporal gyri. Support vector machine (SVM) classifiers achieved high accuracy for discriminating brain morphology patterns in TS from typically developing controls and also displayed spatial patterns consistent with the VBM results. Furthermore, the SVM classifiers identified additional neuroanatomical variations in individuals with TS, localized in the hippocampus, orbitofrontal cortex, insula, caudate, and cuneus. Our results demonstrate robust spatial patterns of altered brain morphology in developmentally dynamic populations with TS, providing further insight into the neuroanatomical correlates of cognitive-behavioral features in this condition.

  View details for DOI 10.1016/j.neuroimage.2010.12.054

  View details for PubMedID 21195197

• COGNITIVE PROFILE OF TURNER SYNDROME DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Hong, D., Kent, J. S., Kesler, S. 2009; 15 (4): 270-278

  Abstract

  Turner syndrome (TS) is a relatively common neurogenetic disorder characterized by complete or partial monosomy-X in a phenotypic female. TS is associated with a cognitive profile that typically includes intact intellectual function and verbal abilities with relative weaknesses in visual-spatial, executive, and social cognitive domains. In this report, we review previous and current research related to the cognitive profile of TS. We also discuss how cognitive impairments in this syndrome may reflect integrative rather than modular deficits. For example, the less commonly reported areas of verbal difficulty in TS and certain visual-spatial deficits seem significantly influenced by impairments in executive function and spatially loaded stimuli. We provide a summary of cognitive testing measures used in the assessment of visual-spatial and executive skills, which includes test domain descriptions as well as a comprehensive examination of social cognitive function in TS. This review concludes with a discussion of ecological interpretations regarding the meaning of cognitive deficits in TS at the individual level.

  View details for DOI 10.1002/ddrr.79

  View details for Web of Science ID 000273207500002

  View details for PubMedID 20014362

  View details for PubMedCentralID PMC3114458

• Posttraumatic stress disorder following traumatic injury: Narratives as unconscious indicators of psychopathology BULLETIN OF THE MENNINGER CLINIC Hashemi, B., Shaw, R. J., Hong, D. S., Hall, R., Nelson, K., Steiner, H. 2008; 72 (3): 179-190

  Abstract

  Current conventional assessment methodologies used to diagnose posttraumatic stress disorder (PTSD) rely heavily on symptom counts obtained from clinical interviews or self-report questionnaires. Such measures may underestimate the impact of traumatic events, particularly in individuals who deny or repress emotional distress. This case report illustrates the use of two methods of narrative analysis to assess unconscious representations of PTSD. Linguistic analysis and a computerized analysis of referential activity were able to capture unconscious aspects of the traumatic experience.

  View details for PubMedID 18990054

• EOSINOPHILIC MENINGOENCEPHALITIS: PSYCHIATRIC PRESENTATION AND TREATMENT INTERNATIONAL JOURNAL OF PSYCHIATRY IN MEDICINE Hong, D. S., Bernstein, M., Smith, C., Gans, H., Shaw, R. J. 2008; 38 (3): 287-295

  Abstract

  Eosinophilic meningoencephalitis (EM) is usually a self-limited neurological illness commonly accompanied by a variety of neurological symptoms. The presence of acute psychotic symptoms in EM, however, has not previously been reported, and there is no literature to guide its treatment and management. In this case report, the onset of psychotic symptoms in a hypoactive delirium and their significant improvement following the administration of atypical antipsychotics are described in a boy with EM. This case report demonstrates the efficacy and safety of antipsychotic agents during the acute phase of meningoencephalitis.

  View details for DOI 10.2190/PM.38.3.e

  View details for Web of Science ID 000261315400005

  View details for PubMedID 19069573