Tamar Green

All Publications

• Comparing Irritability Across Childhood Psychiatric Disorders Using a Large-Scale Longitudinal Dataset Segal, H., Yang, G., Gothelf, D., Green, T. SPRINGERNATURE. 2023: 141-142

  View details for Web of Science ID 001184093500289

• Polygenic Risk for ADHD and its Contributions to Brain and Behavioral Phenotypes in Noonan Syndrome Rai, B., Traglia, M., Green, T. SPRINGERNATURE. 2023: 155-156

  View details for Web of Science ID 001184093500311

• The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy. American journal of medical genetics. Part A Pierpont, E. I., Bennett, A. M., Schoyer, L., Stronach, B., Anschutz, A., Borrie, S. C., Briggs, B., Burkitt-Wright, E., Castel, P., Cirstea, I. C., Draaisma, F., Ellis, M., Fear, V. S., Frone, M. N., Flex, E., Gelb, B. D., Green, T., Gripp, K. W., Khoshkhoo, S., Kieran, M. W., Kleemann, K., Klein-Tasman, B. P., Kontaridis, M. I., Kruszka, P., Leoni, C., Liu, C. Z., Merchant, N., Magoulas, P. L., Moertel, C., Prada, C. E., Rauen, K. A., Roelofs, R., Rossignol, R., Sevilla, C., Sevilla, G., Sheedy, R., Stieglitz, E., Sun, D., Tiemens, D., White, F., Wingbermühle, E., Wolf, C., Zenker, M., Andelfinger, G. 2023

  Abstract

  Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

  View details for DOI 10.1002/ajmg.a.63477

  View details for PubMedID 37969032

• THE INTERACTIVE EFFECTS OF POLYGENIC RISK SCORES AND SINGLE GENE DISORDERS ON THE SUBCORTICAL STRUCTURE Serur, Y., Rai, B., Raman, M., McGee, C., Green, T. ELSEVIER. 2023: S256-S257

  View details for DOI 10.1016/j.euroneuro.2023.08.451

  View details for Web of Science ID 001089437400447

• THE RARE VARIANTS FRAMEWORK: INSIGHTS INTO NEUROPSYCHIATRIC PHENOTYPES PROVIDED BY STUDIES OF RARE GENETIC VARIANTS Green, T., Gur, R. ELSEVIER SCIENCE INC. 2023: S349-S350

  View details for DOI 10.1016/j.jaac.2023.07.717

  View details for Web of Science ID 001098830401450

• INSIGHTS INTO THE RAS-MAPK EFFECT ON NEURODEVELOPMENT: MAPPING THE NEUROPSYCHIATRIC AND BRAIN PHENOTYPES IN CHILDREN WITH NOONAN SYNDROME Green, T. ELSEVIER SCIENCE INC. 2023: S351

  View details for DOI 10.1016/j.jaac.2023.07.722

  View details for Web of Science ID 001098830401455

• Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. Translational psychiatry Rai, B., Naylor, P. E., Siqueiros-Sanchez, M., Wintermark, M., Raman, M. M., Jo, B., Reiss, A. L., Green, T. 2023; 13 (1): 245

  Abstract

  The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

  View details for DOI 10.1038/s41398-023-02504-4

  View details for PubMedID 37407569

  View details for PubMedCentralID 4115674

• Neuropsychiatric phenotypes in children with Noonan syndrome. Developmental medicine and child neurology Naylor, P. E., Bruno, J. L., Shrestha, S. B., Friedman, M., Jo, B., Reiss, A. L., Green, T. 2023

  Abstract

  AIM: We investigated neuropsychiatric outcomes in children with Noonan syndrome and addressed limitations in previous research with a focus on prepubertal children, comparison to typically developing children, comprehensive neuropsychiatric evaluation, and controlling for overall cognitive abilities.METHOD: Forty-five children with Noonan syndrome (mean=8years 6months, SD=2years 2months; 29 females) and 40 typically developing children (mean=8years 9months, SD=2years; 22 females) were evaluated with objective, parent-report, and psychiatric interview measures.RESULTS: Children with Noonan syndrome demonstrated elevated symptoms across attention-deficit/hyperactivity disorder (ADHD) (attention, hyperactivity, and inhibition), autism spectrum disorder (ASD) (maintaining social relationships, behavioral rigidity, and sensory sensitivity), and oppositional defiant disorder (ODD) (aggression) symptom clusters relative to typically developing children (all p<0.05). Group differences in nearly all parent-report measures were significant after accounting for variations in intellectual functioning, suggesting that increased neurodevelopmental symptoms are not simply driven by overall intelligence. Twenty out of 42 children with Noonan syndrome met criteria for ADHD, eight out of 42 for ODD, and 11 out of 43 demonstrated clinically significant symptoms seen in children with ASD.INTERPRETATION: Children with Noonan syndrome are at increased risk for a range of ADHD, ASD, and ODD associated symptoms. A dimensional approach reveals significant ASD symptoms in Noonan syndrome that do not emerge when using the currently accepted categorical diagnostic approach.

  View details for DOI 10.1111/dmcn.15627

  View details for PubMedID 37130201

• 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

• Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. Research square Rai, B., Naylor, P., Sanchez, M. S., Wintermark, M., Raman, M., Jo, B., Reiss, A., Green, T. 2023

  Abstract

  The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: 1. How Ras-MAPK activating variants of PTPN11 / SOS1 protein-coding genes affect brain anatomy. 2. The relationship between PTPN11 gene expression levels and brain anatomy, and 3. The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 ( n  = 30) or SOS1 ( n  = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA) and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area ( d 's<-0.8), and extensive effects on SA ( d 's>|0.8|) and CT ( d 's>|0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

  View details for DOI 10.21203/rs.3.rs-2580911/v1

  View details for PubMedID 36865206

  View details for PubMedCentralID PMC9980214

• 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

• Multidimensional Neuropsychiatric Phenotypes in Children With Noonan Syndrome Bruno, J., Naylor, P., Green, T. SPRINGERNATURE. 2022: 147-148

  View details for Web of Science ID 000897934700308

• Syndrome specific neuroanatomical phenotypes in girls with Turner and Noonan Syndromes. Biological psychiatry. Cognitive neuroscience and neuroimaging Sanchez, M. S., Rai, B., Chowdhury, S., Reiss, A. L., Green, T. 2022

  Abstract

  BACKGROUND: Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X-chromosome absence, whereas NS results from genetic mutations activating the Ras mitogen-activated protein kinase (RAS-MAPK) signaling pathway. Previous neuroimaging studies in TS and NS have shown neuroanatomical variations relative to typically developing (TD) individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes.METHODS: In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 TD girls, all 5-12 years of age, using univariate and multivariate data-driven analyses.RESULTS: We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. TS was associated with smaller whole-brain cortical surface area (SA) (p=<0.0001) whereas NS was associated with smaller whole-brain cortical thickness (CT) (p=.013) relative to TD. TS was associated with larger subcortical volumes (left amygdala, p=0.002; right hippocampus, p=0.002) whereas NS was associated with smaller subcortical volumes (bilateral caudate, p≤0.003; putamen, p<0.001; pallidum, p<0.001; right hippocampus, p=0.015). Multivariate analyses also showed diverging brain phenotypes in terms of SA and CT, with SA outperforming CT at group separation.CONCLUSION: TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetics etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.

  View details for DOI 10.1016/j.bpsc.2022.08.012

  View details for PubMedID 36084900

• The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery. American journal of medical genetics. Part A Kontaridis, M. I., Roberts, A. E., Schill, L., Schoyer, L., Stronach, B., Andelfinger, G., Aoki, Y., Axelrad, M. E., Bakker, A., Bennett, A. M., Broniscer, A., Castel, P., Chang, C. A., Cyganek, L., Das, T. K., den Hertog, J., Galperin, E., Garg, S., Gelb, B. D., Gordon, K., Green, T., Gripp, K. W., Itkin, M., Kiuru, M., Korf, B. R., Livingstone, J. R., Lopez-Juarez, A., Magoulas, P. L., Mansour, S., Milner, T., Parker, E., Pierpont, E. I., Plouffe, K., Rauen, K. A., Shankar, S. P., Smith, S. B., Stevenson, D. A., Tartaglia, M., Van, R., Wagner, M. E., Ware, S. M., Zenker, M. 2022

  Abstract

  RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

  View details for DOI 10.1002/ajmg.a.62716

  View details for PubMedID 35266292

• Altered canonical and striatal-frontal resting state functional connectivity in children with pathogenic variants in the Ras/mitogen-activated protein kinase pathway. Molecular psychiatry Bruno, J. L., Shrestha, S. B., Reiss, A. L., Saggar, M., Green, T. 2022

  Abstract

  Mounting evidence supports the role of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway in neurodevelopmental disorders. Here, the authors used a genetics-first approach to examine how Ras/MAPK pathogenic variants affect the functional organization of the brain and cognitive phenotypes including weaknesses in attention and inhibition. Functional MRI was used to examine resting state functional connectivity (RSFC) in association with Ras/MAPK pathogenic variants in children with Noonan syndrome (NS). Participants (age 4-12 years) included 39 children with NS (mean age 8.44, SD = 2.20, 25 females) and 49 typically developing (TD) children (mean age 9.02, SD = 9.02, 33 females). Twenty-eight children in the NS group and 46 in the TD group had usable MRI data and were included in final analyses. The results indicated significant hyperconnectivity for the NS group within canonical visual, ventral attention, left frontoparietal and limbic networks (p < 0.05 FWE). Higher connectivity within canonical left frontoparietal and limbic networks positively correlated with cognitive function within the NS but not the TD group. Further, the NS group demonstrated significant group differences in seed-based striatal-frontal connectivity (Z > 2.6, p < 0.05 FWE). Hyperconnectivity within canonical brain networks may represent an intermediary phenotype between Ras/MAPK pathogenic variants and cognitive phenotypes, including weaknesses in attention and inhibition. Altered striatal-frontal connectivity corresponds with smaller striatal volume and altered white matter connectivity previously documented in children with NS. These results may indicate delayed maturation and compensatory mechanisms and they are important for understanding the pathophysiology underlying cognitive phenotypes in NS and in the broader population of children with neurodevelopmental disorders.

  View details for DOI 10.1038/s41380-021-01422-5

  View details for PubMedID 35087195

• Parent Cognition and Behavior Predict Variable Outcomes in Children With Ras/mitogen-Activated Protein Kinase (RMK) Pathway Pathogenic Mutations Bruno, J., Green, T. SPRINGERNATURE. 2021: 123-124

  View details for Web of Science ID 000725511400248

• 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

• Novel Effects of Ras-MAPK Activating Mutations on Brain Development and Neuropsychiatry Rai, B., Naylor, P., Jo, B., Reiss, A., Green, T. ELSEVIER SCIENCE INC. 2021: S371

  View details for Web of Science ID 000645683800891

• Activation Mutation in the Ras/MAPK Pathway Alters the Functional Resting-State Architecture Underlining Executive Function and Attention Bruno, J., Shrestha, S., Reiss, A., Saggar, M., Green, T. SPRINGERNATURE. 2020: 177–78

  View details for Web of Science ID 000596371000337

• PTPN11 Mutations in the Ras-MAPK Signaling Pathway Affect Human White Matter Microstructure. Cerebral cortex (New York, N.Y. : 1991) Fattah, M., Raman, M. M., Reiss, A. L., Green, T. 2020

  Abstract

  We examined whether PTPN11 mutations affect the white matter connectivity of the developing human brain. Germline activating mutations to the PTPN11 gene cause overactivation of the Ras-Mitogen-Activated Protein Kinase pathway. Activating mutations cause Noonan syndrome (NS), a developmental disorder associated with hyperactivity and cognitive weakness in attention, executive function, and memory. In mouse models of NS, PTPN11 mutations cause reduced axon myelination and white matter formation, while the effects of PTPN11 mutations on human white matter are largely unknown. For the first time, we assessed 17 children with NS (9 females, mean age, 8.68±2.39) and 17 age- and sex-matched controls (9 female, mean age, 8.71±2.40) using diffusion brain imaging for white matter connectivity and structural magnetic resonance imaging to characterize brain morphology. Children with NS showed widespread reductions in fractional anisotropy (FA; 82613 voxels, t=1.49, P<0.05) and increases in radial diffusivity (RD; 94044 voxels, t=1.22, P<0.05), denoting decreased white matter connectivity. In NS, the FA of the posterior thalamic radiation correlated positively with inhibition performance, whereas connectivity in the genu of the corpus callosum was inversely associated with auditory attention performance. Additionally, we observed negative and positive correlations, respectively, between memory and the cingulum hippocampus, and memory and the cingulum cingulate gyrus. These findings elucidate the neural mechanism underpinning the NS cognitive phenotype, and may serve as a brain-based biomarker.

  View details for DOI 10.1093/cercor/bhaa299

  View details for PubMedID 33119062

• PATHWAYS LEADING TO MENTAL HEALTH PHENOTYPES AND THEIR TREATMENTS: INSIGHTS FROM NEUROGENETIC SYNDROMES Gothelf, D., Green, T., Reiss, A. L. ELSEVIER SCIENCE INC. 2020: S266–S267

  View details for DOI 10.1016/j.jaac.2020.07.547

  View details for Web of Science ID 000579844101279

• MULTIMODAL BRAIN IMAGING TO BETTER UNDERSTAND THE EFFECTS OF RAS-MITOGEN-ACTIVATED PROTEIN KINASE MUTATIONS ON BRAIN- AND ADHD-RELATED BEHAVIORS Green, T. ELSEVIER SCIENCE INC. 2020: S267

  View details for DOI 10.1016/j.jaac.2020.07.550

  View details for Web of Science ID 000579844101282

• The sixth international RASopathies symposium: Precision medicine-From promise to practice. American journal of medical genetics. Part A Gripp, K. W., Schill, L., Schoyer, L., Stronach, B., Bennett, A. M., Blaser, S., Brown, A., Burdine, R., Burkitt-Wright, E., Castel, P., Darilek, S., Dias, A., Dyer, T., Ellis, M., Erickson, G., Gelb, B. D., Green, T., Gross, A., Ho, A., Holder, J. L., Inoue, S., Jelin, A. C., Kennedy, A., Klein, R., Kontaridis, M. I., Magoulas, P., McConnell, D. B., McCormick, F., Neel, B. G., Prada, C. E., Rauen, K. A., Roberts, A., Rodriguez-Viciana, P., Rosen, N., Rumbaugh, G., Sablina, A., Solman, M., Tartaglia, M., Thomas, A., Timmer, W. C., Venkatachalam, K., Walsh, K. S., Wolters, P. L., Yi, J., Zenker, M., Ratner, N. 2019

  Abstract

  The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

  View details for DOI 10.1002/ajmg.a.61434

  View details for PubMedID 31825160

• On the relationship between mathematics and visuospatial processing in Turner syndrome. Journal of psychiatric research Baker, J. M., Klabunde, M., Jo, B., Green, T., Reiss, A. L. 2019; 121: 135–42

  Abstract

  A common neurocognitive phenotype of Turner syndrome (TS) includes coincident deficits in math and visuospatial reasoning while overall IQ remains intact. However, research has highlighted disparities in the relationship between these properties in women with TS, suggesting that not all visuospatial domains are equally related to mathematics in this group. Here, we present findings from a longitudinal investigation of visuospatial processing and its relationship to math performance in adolescent girls with TS and age-matched healthy controls. Participants completed a standardized battery of math and visuospatial tests once a year for 4 years. Linear mixed effects modeling was used to examine the relationship between mathematics and each visuospatial domain over time. Our results indicate that math performance was related to visual tracking, visual-motor coordination, and figure-ground processing. Such visuospatial domains appear to be uniquely affected by TS and could contribute to their deficits in math performance. Furthermore, differences in math and visuospatial test performance between girls with TS and healthy controls remain stable over time. Our results have important implications for the role of visuospatial processing in early math performance and may inform the development of effective interventions aimed at improving math education in children with TS.

  View details for DOI 10.1016/j.jpsychires.2019.11.004

  View details for PubMedID 31812933

• X-chromosome insufficiency alters receptive fields across the human early visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience Green, T., Hosseini, H., Piccirilli, A., Ishak, A., Grill-Spector, K., Reiss, A. L. 2019

  Abstract

  Here, we investigated processing by receptive fields, a fundamental property of neurons in the visual system, using fMRI and population receptive field (pRF) mapping in 20 human females with monosomic Turner syndrome (TS) (mean age, 10.3 ± 2.0) versus 22 age- and sex-matched controls (mean age, 10.4 ± 1.9). TS, caused by X-chromosome haploinsufficiency in females is associated with well-recognized effects on visual-spatial processing, parieto-occipital cortical anatomy, and parietal lobe function. However, it is unknown if these effects are related to altered brain structure and function in early visual areas (V1-V3) versus downstream parietal cortical regions. Results show that girls with TS have: (i) smaller volume of V1-V3, (ii) lower average pRF eccentricity in early visual areas, and (iii) sparser pRF coverage in the periphery of the visual field. Further, we examined whether the lower volume of early visual areas, defined using retinotopic mapping, in TS is due to smaller surface area or thinner cortex. Results show that girls with TS had a general reduction in surface area relative to controls in bilateral V1 and V2. Our data suggest the possibility that the smaller cortical surface area of early visual areas in girls with TS may be associated with a lower number of neurons which, in turn, leads to lesser coverage of the peripheral visual field compared to controls. These results indicate that X-chromosome haploinsufficiency associated with TS affects the functional neuroanatomy of early visual areas and suggest that investigating pRFs in TS may shed insights into their atypical visual-spatial processing.SIGNIFICANCE STATEMENTTurner syndrome is caused by the absence of one of the two X-chromosome in females. Using functional neuroimaging and population receptive field mapping, we find that chromosome dosage variation (X-monosomy) associated with Turner syndrome affects the functional neuroanatomy of the visual cortex. Specifically, girls with Turner syndrome have smaller early visual areas that provide lesser coverage of the peripheral visual field compared to healthy controls. Our observations provide compelling evidence that the X-chromosome affects not only parietal cortex, as described in previous studies, but also affects early visual areas. These findings suggest a paradigm change in understanding the effect of X-monosomy on the development of visual-spatial abilities in humans.

  View details for DOI 10.1523/JNEUROSCI.2745-18.2019

  View details for PubMedID 31434689

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention CEREBRAL CORTEX Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2019; 29 (7): 2915–23

  View details for DOI 10.1093/cercor/bhy158

  View details for Web of Science ID 000477708300011

• 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

• Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies NEUROPSYCHOPHARMACOLOGY Green, T., Flash, S., Reiss, A. L. 2019; 44 (1): 9–21

  View details for DOI 10.1038/s41386-018-0153-2

  View details for Web of Science ID 000450178000003

• 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

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention. Cerebral cortex (New York, N.Y. : 1991) Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2018

  Abstract

  The Ras-MAPK pathway has an established role in neural development and synaptic signaling. Mutations in this pathway are associated with a collection of neurodevelopmental syndromes, Rasopathies; among these, Noonan syndrome (NS) is the most common (1:2000). Prior research has focused on identifying genetic mutations and cellular mechanisms of the disorder, however, effects of NS on the human brain remain unknown. Here, imaging and cognitive data were collected from 12 children with PTPN11-related NS, ages 4.0-11.0 years (8.98 ± 2.33) and 12 age- and sex-matched typically developing controls (8.79 ± 2.17). We observe reduced gray matter volume in bilateral corpus striatum (Cohen's d = -1.0:-1.3), reduced surface area in temporal regions (d = -1.8:-2.2), increased cortical thickness in frontal regions (d = 1.2-1.3), and reduced cortical thickness in limbic regions (d = -1.6), including limbic structures integral to the circuitry of the hippocampus. Further, we find high levels of inattention, hyperactivity, and memory deficits in children with NS. Taken together, these results identify effects of NS on specific brain regions associated with ADHD and learning in children. While our research lays the groundwork for elucidating the neural and behavioral mechanisms of NS, it also adds an essential tier to understanding the Ras-MAPK pathway's role in human brain development.

  View details for PubMedID 30059958

• Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Green, T., Flash, S., Reiss, A. L. 2018

  Abstract

  The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

  View details for PubMedID 30127341

• The Effectiveness and Safety of Antipsychotic and Antidepressant Medications in Individuals with 22q11.2 Deletion Syndrome JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Dori, N., Green, T., Weizman, A., Gothelf, D. 2017; 27 (1): 83-?

  Abstract

  The purpose of this study was to evaluate the effectiveness and safety of antipsychotic and antidepressant medications in individuals with 22q11.2 deletion syndrome (22q11.2 DS) and psychiatric comorbidity.We used a record review, structured clinical interviews, and the Clinical Global Impressions (CGI) scale to retrospectively assess the effectiveness and safety of antipsychotic medications for schizophrenia spectrum disorders and of antidepressant medications for depressive and anxiety disorders in 40 individuals with 22q11.2DS.We observed significant improvement in CGI-Severity scores in individuals with 22q11.2DS treated with antipsychotic or antidepressant medications, and a ∼50% response rate based on the CGI-Improvement score. Adverse events were similar in types and rates to those reported in non-22q11.2 individuals treated with antipsychotics or antidepressants.Our data show that treatment with antipsychotics and antidepressants may be effective while being relatively safe in individuals with 22q11.2DS. Antipsychotic and antidepressant medications should be considered in any individual with 22q11.2DS who has a psychiatric morbidity, such as psychosis or mood or anxiety disorders. Although the psychotropic medications were generally well tolerated in our sample, more rigorous metabolic and cardiovascular measures are required in future studies to conclusively verify the safety of these medications.

  View details for DOI 10.1089/cap.2014.0075

  View details for Web of Science ID 000394376300011

  View details for PubMedID 26131914

• 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

• Attention deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies. Journal of neurodevelopmental disorders Green, T. n., Naylor, P. E., Davies, W. n. 2017; 9: 25

  Abstract

  ADHD (attention deficit hyperactivity disorder) is a common neurodevelopmental disorder. There has been extensive clinical and basic research in the field of ADHD over the past 20 years, but the mechanisms underlying ADHD risk are multifactorial, complex and heterogeneous and, as yet, are poorly defined. In this review, we argue that one approach to address this challenge is to study well-defined disorders to provide insights into potential biological pathways that may be involved in idiopathic ADHD.To address this premise, we selected two neurogenetic conditions that are associated with significantly increased ADHD risk: Turner syndrome and the RASopathies (of which Noonan syndrome and neurofibromatosis type 1 are the best-defined with regard to ADHD-related phenotypes). These syndromes were chosen for two main reasons: first, because intellectual functioning is relatively preserved, and second, because they are strikingly phenotypically similar but are etiologically distinct. We review the cognitive, behavioural, neural and cellular phenotypes associated with these conditions and examine their relevance as a model for idiopathic ADHD.We conclude by discussing current and future opportunities in the clinical and basic research of these conditions, which, in turn, may shed light upon the biological pathways underlying idiopathic ADHD.

  View details for PubMedID 28694877

  View details for PubMedCentralID PMC5502326

• 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

• 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

• Cover Image, Volume 171B, Number 3, April 2016. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171 (3): i-?

  Abstract

  The cover image, by Tamar Green et al., is based on the Research Article Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome, DOI: 10.1002/ajmg.b.32422.

  View details for DOI 10.1002/ajmg.b.32447

  View details for PubMedID 27001917

• Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171 (3): 402-413

  Abstract

  Morphometric investigations of brain volumes in Williams syndrome (WS) consistently show significant reductions in gray matter volume compared to controls. Cortical thickness (CT) and surface area (SA) are two constituent parts of cortical gray matter volume that are considered genetically distinguishable features of brain morphology. Yet, little is known about the independent contribution of cortical CT and SA to these volumetric differences in WS. Thus, our objectives were: (i) to evaluate whether the microdeletion in chromosome 7 associated with WS has a distinct effect on CT and SA, and (ii) to evaluate age-related variations in CT and SA within WS. We compared CT and SA values in 44 individuals with WS to 49 age- and sex-matched typically developing controls. Between-group differences in CT and SA were evaluated across two age groups: young (age range 6.6-18.9 years), and adults (age range 20.2-51.5 years). Overall, we found contrasting effects of WS on cortical thickness (increases) and surface area (decreases). With respect to brain topography, the between-group pattern of CT differences showed a scattered pattern while the between-group surface area pattern was widely distributed throughout the brain. In the adult subgroup, we observed a cluster of increases in cortical thickness in WS across the brain that was not observed in the young subgroup. Our findings suggest that extensive early reductions in surface area are the driving force for the overall reduction in brain volume in WS. The age-related cortical thickness findings might reflect delayed or even arrested development of specific brain regions in WS. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32422

  View details for Web of Science ID 000373029100011

• 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

• Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171B (3): 402-413

  Abstract

  Morphometric investigations of brain volumes in Williams syndrome (WS) consistently show significant reductions in gray matter volume compared to controls. Cortical thickness (CT) and surface area (SA) are two constituent parts of cortical gray matter volume that are considered genetically distinguishable features of brain morphology. Yet, little is known about the independent contribution of cortical CT and SA to these volumetric differences in WS. Thus, our objectives were: (i) to evaluate whether the microdeletion in chromosome 7 associated with WS has a distinct effect on CT and SA, and (ii) to evaluate age-related variations in CT and SA within WS. We compared CT and SA values in 44 individuals with WS to 49 age- and sex-matched typically developing controls. Between-group differences in CT and SA were evaluated across two age groups: young (age range 6.6-18.9 years), and adults (age range 20.2-51.5 years). Overall, we found contrasting effects of WS on cortical thickness (increases) and surface area (decreases). With respect to brain topography, the between-group pattern of CT differences showed a scattered pattern while the between-group surface area pattern was widely distributed throughout the brain. In the adult subgroup, we observed a cluster of increases in cortical thickness in WS across the brain that was not observed in the young subgroup. Our findings suggest that extensive early reductions in surface area are the driving force for the overall reduction in brain volume in WS. The age-related cortical thickness findings might reflect delayed or even arrested development of specific brain regions in WS. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32422

  View details for PubMedID 26852730

• 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

• Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure BRITISH JOURNAL OF PSYCHIATRY Green, T., Barnea-Goraly, N., Raman, M., Hall, S. S., Lightbody, A. A., Bruno, J. L., Quintin, E., Reiss, A. L. 2015; 207 (2): 143-148

  Abstract

  Background Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals. Aims To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability. Method We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30). Results Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. Conclusions The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

  View details for DOI 10.1192/bjp.bp.114.151654

  View details for Web of Science ID 000359180800009

  View details for PubMedID 25792692

• Hyperactive auditory processing in Williams syndrome: Evidence from auditory evoked potentials PSYCHOPHYSIOLOGY Zarchi, O., Avni, C., Attias, J., Frisch, A., Carmel, M., Michaelovsky, E., Green, T., Weizman, A., Gothelf, D. 2015; 52 (6): 782-789

  Abstract

  The neurophysiologic aberrations underlying the auditory hypersensitivity in Williams syndrome (WS) are not well defined. The P1-N1-P2 obligatory complex and mismatch negativity (MMN) response were investigated in 18 participants with WS, and the results were compared with those of 18 age- and gender-matched typically developing (TD) controls. Results revealed significantly higher amplitudes of both the P1-N1-P2 obligatory complex and the MMN response in the WS participants than in the TD controls. The P1-N1-P2 complex showed an age-dependent reduction in the TD but not in the WS participants. Moreover, high P1-N1-P2 complex was associated with low verbal comprehension scores in WS. This investigation demonstrates that central auditory processing is hyperactive in WS. The increase in auditory brain responses of both the obligatory complex and MMN response suggests aberrant processes of auditory encoding and discrimination in WS. Results also imply that auditory processing may be subjected to a delayed or diverse maturation and may affect the development of high cognitive functioning in WS.

  View details for DOI 10.1111/psyp.12407

  View details for Web of Science ID 000354566600006

  View details for PubMedID 25603839

• Neurodevelopmental risk factors for psychosis in 22q11.2 deletion syndrome and their treatment Gothelf, D., Mekoria, E., Weinberger, R., Midbaria, Y., Dorib, N., Green, T., Weizman, A. SPRINGER. 2015: S76–S77

  View details for Web of Science ID 000367823900193

• Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome JAMA PSYCHIATRY Vorstman, J. S., Breetvelt, E. J., Duijff, S. N., Eliez, S., Schneider, M., Jalbrzikowski, M., Armando, M., Vicari, S., Shashi, V., Hooper, S. R., Chow, E. C., Fung, W., Butcher, N. J., Young, D. A., McDonald-McGinn, D. M., Vogels, A., Gothelf, D., Weinberger, R., Weizman, A., Klaassen, P. J., Koops, S., Kates, W. R., Antshel, K. M., Simon, T. J., Ousley, O. Y., Swillen, A., Gur, R. E., Bearden, C. E., Kahn, R. S., Bassett, A. S., Emanuel, B. S., Zackai, E. H., Kushan, L., Fremont, W., Schoch, K., Stoddard, J., Cubells, J., Fu, F., Campbell, L. E., Fritsch, R., Vergaelen, E., Neeleman, M., Boot, E., Debbane, M., Philip, N., Green, T., van den Bree, M. M., Murphy, D., Canyelles, J., Arango, C., Murphy, K. C., Pontillo, M., Int Consortium Brain Behav 2015; 72 (4): 377–85

  Abstract

  Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age.To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS.Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years).Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test.Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward.In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

  View details for DOI 10.1001/jamapsychiatry.2014.2671

  View details for Web of Science ID 000352487000010

  View details for PubMedID 25715178

  View details for PubMedCentralID PMC4383767

• The Outcome of Severe Internalizing and Disruptive Disorders from Preschool into Adolescence:A Follow-up Study. Israel journal of psychiatry and related sciences Spitzer, S., Freudenstein, O., Peskin, M., Tyano, S., Shrira, A., Pearlson, T., Eilam, A., Zalsman, G., Green, T., Gothelf, D. 2015; 52 (2): 100-105

  Abstract

  In this study we aimed to examine the outcome of children's severe psychiatric disorders from preschool into later childhood and adolescence.Forty preschool children (28 boys and 12 girls) treated in a tertiary referral mental health center, evaluated at admission and 5.5 ± 1.2 years thereafter.Seven (58.3%) children diagnosed with internalizing disorders at baseline were free of any psychiatric diagnosis at follow-up (p=0.02). Conversely, only one child (8.3%) diagnosed with comorbid disruptive-internalizing disorders at baseline was free of any psychiatric disorder at follow-up (p=1.0). Seven (43.7%) children diagnosed with disruptive disorders at baseline were free of psychiatric diagnoses at follow-up (p=0.02).The small sample size and naturalistic nature of the study.The trajectories of severe psychiatric disorders at preschool years are similar to those reported in community samples and differ according to the baseline diagnosis. Children with internalizing disorders show a much better recovery rate than those with comorbid disruptive and internalizing disorders.

  View details for PubMedID 26431413

• 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

• Psychiatric Disorders From Childhood to Adulthood in 22q11.2 Deletion Syndrome: Results From the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome AMERICAN JOURNAL OF PSYCHIATRY Schneider, M., Debbane, M., Bassett, A. S., Chow, E. W., Fung, W. L., van den Bree, M. B., Owen, M., Murphy, K. C., Niarchou, M., Kates, W. R., Antshel, K. M., Fremont, W., McDonald-McGinn, D. M., Gur, R. E., Zackai, E. H., Vorstman, J., Duijff, S. N., Klaassen, P. W., Swillen, A., Gothelf, D., Green, T., Weizman, A., van Amelsvoort, T., Evers, L., Boot, E., Shashi, V., Hooper, S. R., Bearden, C. E., Jalbrzikowski, M., Armando, M., Vicari, S., Murphy, D. G., Ousley, O., Campbell, L. E., Simon, T. J., Eliez, S. 2014; 171 (6): 627-639

  Abstract

  Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years.Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills.To the authors’ knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

  View details for DOI 10.1176/appi.ajp.2013.13070864

  View details for Web of Science ID 000336638600010

  View details for PubMedID 24577245

• Aberrant Parietal Cortex Developmental Trajectories in Girls with Turner Syndrome and Related Visual-Spatial Cognitive Development: A Preliminary Study 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 346S–346S

  View details for Web of Science ID 000334101802222

• How Fragile X Syndrome Influences White Matter Structure? Investigating Differences in White Matter Between Individuals with Fragile X Syndrome and IQ-matched Controls Green, T., Barnea-Goraly, N., Raman, M. M., Quintin, E., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 99S

  View details for Web of Science ID 000334101800308

• Risk Factors and the Evolution of Psychosis in 22q11.2 Deletion Syndrome: A Longitudinal 2-Site Study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Gothelf, D., Schneider, M., Green, T., Debbane, M., Frisch, A., Glaser, B., Zilkha, H., Schaer, M., Weizman, A., Eliez, S. 2013; 52 (11): 1192-1203

  Abstract

  22q11.2 Deletion syndrome (22q11.2DS) is associated with high rates of schizophrenia, other neuropsychiatric disorders, and cognitive deficits. The objectives of this 2-center study were to longitudinally assess the trajectories of psychiatric disorders in 22q11.2DS from childhood to adulthood, and to identify risk factors for their emergence.A total of 125 children and adults with 22q11.2DS were evaluated at 2 time points, baseline and follow-up (4 years apart), using standardized psychiatric and cognitive measures.The rate of mood disorders tended to decrease during childhood and increase during late adolescence. Statistically significant predictors for the presence of a psychotic disorder as well as the severity of positive symptoms at follow-up were identical, and consisted of an anxiety disorder at baseline, lower baseline Full Scale IQ, and a greater decrease in verbal IQ scores between time points. Nine of 10 individuals with an emerging psychotic disorder had an anxiety disorder at baseline. The age of onset for a psychotic disorder was between 14 and 22 years in 82.6% of cases.It is important to evaluate the presence of anxiety disorders in children and adolescents with 22q11.2DS, as they are major risk factors for the emergence of psychotic disorders, which usually occur during late adolescence in this at-risk population.

  View details for DOI 10.1016/j.jaac.2013.08.008

  View details for Web of Science ID 000326480800010

  View details for PubMedID 24157393

• Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes. J Psychiatr Res. Zarchi , O., Carmel , ., Avni, C., Attias, J., Frisch, A., Michaelovsky, E., Patya, M., Green, T., Weinberger, R., Weizman, A., Gothelf, D. 2013
• Genotype-phenotype correlation in 22q11.2 deletion syndrome BMC MEDICAL GENETICS Michaelovsky, E., Frisch, A., Carmel, M., Patya, M., Zarchi, O., Green, T., Basel-Vanagaite, L., Weizman, A., Gothelf, D. 2012; 13

  Abstract

  The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

  View details for DOI 10.1186/1471-2350-13-122

  View details for Web of Science ID 000314113600001

  View details for PubMedID 23245648

• The feasibility and safety of S-adenosyl-l-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial JOURNAL OF NEURAL TRANSMISSION Green, T., Steingart, L., Frisch, A., Zarchi, O., Weizman, A., Gothelf, D. 2012; 119 (11): 1417-1423

  Abstract

  The goal of this trial was to assess the feasibility and safety of using S-adenosyl-L-methionine (SAMe) to treat depressive disorder, attention deficit/hyperactivity disorder (ADHD) and cognitive deficits in individuals with the 22q11.2 deletion syndrome (22q11.2DS). SAMe supposedly enhances the activity of the COMT enzyme. Because individuals with 22q11.2DS have only one copy of the gene responsible for the enzyme, COMT haploinsufficiency may be associated with their psychiatric morbidity and cognitive deficits. We assessed twelve 22q11.2DS individuals with depressive disorder or ADHD in a randomized double-blind cross-over placebo-controlled trial, using SAMe 800 mg bid. Individuals were evaluated for treatment safety and effectiveness during the trial and upon completion at sixth week. Compared to placebo, there were no significant differences in the rate of reported side effects between SAMe and placebo. Despite a general concern that SAMe might induce mania in vulnerable individuals, no manic or psychotic symptoms were exhibited during the SAMe treatment. Individuals with 22q11.2DS with comorbid depressive disorder with or without psychotic symptoms (n = 5) had a larger numerical improvement on relevant clinical scales compared to placebo. No treatment effect was found on ADHD symptoms in subjects who suffered from 22q11.2DS with comorbid ADHD (n = 7). Cognitive performance did not improve or deteriorate following treatment with SAMe compared to placebo. In conclusion SAMe treatment up to 1,600 mg/day for 6 weeks in 22q11.2DS individuals appears to be safe, well tolerated and with no serious side effects. No significant benefit in depressive or ADHD symptoms was detected.

  View details for DOI 10.1007/s00702-012-0831-x

  View details for Web of Science ID 000310086500019

  View details for PubMedID 22678699

• Phenotypic psychiatric characterization of children with Williams syndrome and response of those with ADHD to methylphenidate treatment AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Green, T., Avda, S., Dotan, I., Zarchi, O., Basel-Vanagaite, L., Zalsman, G., Weizman, A., Gothelf, D. 2012; 159B (1): 13-20

  Abstract

  Williams syndrome (WS) is associated with cognitive deficits, special behavioral phenotype, and high rates of psychiatric disorders. The aims of the present study were: (1) To compare the rates of psychiatric disorders and repetitive behaviors in children with WS to children with idiopathic developmental disability (DDs); (2) To longitudinally assess the change in psychiatric disorders during adolescence in WS; (3) To assess retrospectively the effectiveness and safety of methylphenidate (MPH) treatment in WS children with ADHD. The study consisted of a cohort of 38 children and adolescents (age 13.1 ± 5.2 years) with WS and a sample of age-matched DDs (age 15.0 ± 3.1 years). A current follow-up evaluation was conducted after 5.6 ± 1.6 years for 25 subjects (65.8%) of the WS cohort. The rate of most psychiatric disorders was found similar in children with WS and DD controls. Specific phobia, especially from noises, obsessive-compulsive symptoms (e.g., aggressive obsessions and repetitive questions), and stereotypic behaviors (e.g., glancing), were more common in WS than DDs. In a longitudinal follow-up of the WS children, we found a decrease in the rate of anxiety disorders. In addition, a clinically significant improvement was reported in 72.2% of WS children with ADHD following MPH treatment. Sadness/unhappiness was the most common side effect associated with MPH treatment in WS, occurring in 2/3 of treated individuals. The present study further elucidates the neuropsychiatric phenotype of WS. Our results also suggest that MPH treatment for ADHD in WS warrants future prospective controlled trials.

  View details for DOI 10.1002/ajmg.b.31247

  View details for Web of Science ID 000298536800003

  View details for PubMedID 22052570

• The Effect of Methylphenidate on Prefrontal Cognitive Functioning, Inattention, and Hyperactivity in Velocardiofacial Syndrome JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Green, T., Weinberger, R., Diamond, A., Berant, M., Hirschfeld, L., Frisch, A., Zarchi, O., Weizman, A., Gothelf, D. 2011; 21 (6): 589-595

  Abstract

  Methylphenidate (MPH) is commonly used to treat attention-deficit/hyperactivity disorder (ADHD) in all children, including those with velocardiofacial syndrome (VCFS). Yet concerns have been raised regarding its safety and efficacy in VCFS. The goal of this study was to examine the safety and efficacy of MPH in children with VCFS.Thirty-four children and adolescents with VCFS and ADHD participated in a randomized, controlled trial with a 2:1 ratio of MPH versus placebo. All subjects underwent a cardiological evaluation before and after MPH administration. The primary outcome measure was prefrontal cognitive performance following a single dose of MPH or placebo. A follow-up assessment was conducted after a 6-month treatment with MPH.Compared with placebo, single MPH administration was associated with a more robust improvement in prefrontal cognitive performance, including achievements in the Hearts and Flowers executive function task and the visual continuous performance task. After 6 months of treatment, a 40% reduction in severity of ADHD symptoms was reported by parents on the Revised Conners Rating Scale. All subjects treated with MPH reported at least one side effect, but it did not necessitate discontinuation of treatment. MPH induced an increase in heart rate and blood pressure that was usually minor, but was clinically significant in two cases. No differences in response to MPH were observed between catechol-O-methyltransferase Met versus Val carriers.The use of MPH in children with VCFS appears to be effective and relatively safe. A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended.

  View details for DOI 10.1089/cap.2011.0042

  View details for Web of Science ID 000298399800010

  View details for PubMedID 22149470

• [The metabolic syndrome and antipsychotics in children and adolescents]. Harefuah Dori, N., Green, T. 2011; 150 (10): 791-?

  Abstract

  Significant weight gain is a well known side-effect of atypical (second generation) antipsychotics. In recent years there is a growing body of evidence that atypical antipsychotics may cause metabolic syndrome which includes: increased waist circumference, lipid and glucose metabolism changes, and in some cases - elevation of blood pressure. During the last decade there has been a substantial increase in the use of atypical antipsychotics among children and adolescents, mainly due to lower rates of extrapyramidal side-effects, but also due to increased diagnosis of schizophrenia and bipolar disorder in youth, and the widespread use of atypical antipsychotics in disruptive behavior disorders. The definition of the metabolic syndrome in youth derives from the adult definition, but it is not universally accepted in pediatrics. The main difficulty lies in establishing the normal values of height and weight during the different stages of growth in childhood and adolescence. The long term implications of the metabolic syndrome diagnosed in young ages are yet to be studied, as are treatment and preventive options. A literature review of recent studies indicates that youth are more susceptible to adverse metabolic side-effects of atypical antipsychotics compared to adults. These side-effects also occur during treatment with lower doses as in disruptive behavioral disorders. Monitoring these metabolic parameters among adults treated with antipsychotics is lacking, and even more so in children and adolescents. Since youth treated with atypical antipsychotics are likely to be treated for long periods of time, it is crucial to diagnose, treat, and prevent those side-effects.

  View details for PubMedID 22111125

• Psychiatric Disorders and Intellectual Functioning Throughout Development in Velocardiofacial (22q11.2 Deletion) Syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Green, T., Gothelf, D., Glaser, B., Debbane, M., Frisch, A., Kotler, M., Weizman, A., Eliez, S. 2009; 48 (11): 1060-1068

  Abstract

  Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample.Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests.The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects.Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.

  View details for DOI 10.1097/CHI.0b013e3181b76683

  View details for Web of Science ID 000271068100005

  View details for PubMedID 19797984

• Creatine monohydrate in resistant depression: a preliminary study BIPOLAR DISORDERS Roitman, S., Green, T., Osher, Y., Karni, N., Levine, J. 2007; 9 (7): 754-758

  Abstract

  Creatine plays a pivotal role in brain energy homeostasis, and altered cerebral energy metabolism may be involved in the pathophysiology of depression. Oral creatine supplementation may modify brain high-energy phosphate metabolism in depressed subjects.Eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatine monohydrate in an open add-on design. Outcome measures were the Hamilton Depression Rating Scale, Hamilton Anxiety Scale, and Clinical Global Impression scores, recorded at baseline and at weeks 1, 2, 3 and 4.One patient improved considerably after one week and withdrew. Both bipolar patients developed hypomania/mania. For the remaining seven patients, all scale scores significantly improved. Adverse reactions were mild and transitory.This small, preliminary, open study of creatine monohydrate suggests a beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of a manic switch in bipolar depression.

  View details for Web of Science ID 000250644300011

  View details for PubMedID 17988366

• [Complex posttraumatic stress disorder]. Harefuah Green, T., Kotler, M. 2007; 146 (11): 883-?

  Abstract

  The characteristic symptoms resulting from exposure to an extreme trauma include three clusters of symptoms: persistent experience of the traumatic event, persistent avoidance of stimuli associated with the trauma and persistent symptoms of increased arousal. Beyond the accepted clusters of symptoms for posttraumatic stress disorder exists a formation of symptoms related to exposure to extreme or prolonged stress e.g. childhood abuse, physical violence, rape, and confinement within a concentration camp. With accumulated evidence of the existence of these symptoms began a trail to classify a more complex syndrome, which included, but was not confined to the symptoms of posttraumatic stress disorder. This review addresses several subjects for study in complex posttraumatic stress disorder, which is a complicated and controversial topic. Firstly, the concept of complex posttraumatic stress disorder is presented. Secondly, the professional literature relevant to this disturbance is reviewed and finally, the authors present the polemic being conducted between the researchers of posttraumatic disturbances regarding validity, reliability and the need for separate diagnosis for these symptoms.

  View details for PubMedID 18087837

• [The treatment of mood stabilizers in children and adolescents suffering from bipolar affective disorder]. Harefuah Green, T., Shoval, G., Weizman, A. 2005; 144 (11): 810-?

  Abstract

  Bipolar disorder is defined as a mood disorder. It is characterized by alteration in mood, from elation and/or irritability to depression. The prevalence of this disorder in children and adolescents is 1%, and it disrupts the lives of children and adolescents. The treatment of bipolar disorder includes mood stabilizers. In contrast to the extensive literature in adult bipolar disorder, controlled studies of lithium and anticonvulsants in the management of mood disorders in childhood are scarce. This review summarizes recent clinical pharmacologic studies of mood stabilizers, including lithium and anticonvulsants in the management of bipolar disorder in children and adolescents who suffer from this syndrome. In addition, the authors review new anticonvulsants such as lamotrigine, gabapentin and topiramate as mood stabilizers.

  View details for PubMedID 16358659

• Relative-assessed psychological factors predict sedation requirement in critically ill patients PSYCHOSOMATIC MEDICINE Green, T., Gidron, Y., Friger, M., Almog, Y. 2005; 67 (2): 295-300

  Abstract

  Sedation is frequently required in critically ill, mechanically ventilated patients. Sedation and analgesia requirements may vary substantially among patients. This study examined whether psychological factors predict amount of sedation requirements beyond the effects of other biomedical parameters.This study used a prospective correlative design in an eight-bed medical intensive care unit at a tertiary university hospital. Fifty-five adult patients requiring mechanical ventilation were included. We evaluated by questionnaires three psychological factors of patients--hostility, anxiety and desire for control (DC)--as completed by patients' relatives at entry to the intensive care unit. Daily doses of sedatives required were monitored. The primary outcome measurement was midazolam dose expressed in mg/kg/h.There was a statistically significant correlation between psychological factors and midazolam dose (mg/kg/h): r values = 0.40 for anxiety, 0.43 for hostility, and 0.46 for DC. Age and pulmonary edema were inversely related to midazolam requirements, whereas smoking, chronic obstructive pulmonary disease, fentanyl dose, and therapeutic intervention scoring system were positively correlated with midazolam doses. In a multiple regression, DC accounted for an additional and significant 5.4% of the variance in midazolam after controlling statistically for the effects of the significant background and biomedical predictors. In the final regression equation, DC and fentanyl were the only significant factors associated with higher sedation requirement.Premorbid psychological profile independently predicts sedation requirement in critically ill, mechanically ventilated patients. Early identification of such a profile may help in sedation management and patient care. The possible mechanisms and clinical implications are discussed.

  View details for DOI 10.1097/01.psy.000156928.12980.99

  View details for Web of Science ID 000227885500020

  View details for PubMedID 15784797

• Acute myelogenous leukemia with splenic infarcts presenting as fulminant multi-organ failure LEUKEMIA & LYMPHOMA Green, T., Rabinovitz, A., Sinelnikov, I., Yermiahu, T., Almog, Y. 2003; 44 (12): 2143-2145

  Abstract

  A 60-year-old male was admitted with leukopenia, thrombocytopenia, splenic infarcts and a normal peripheral smear. Within few hours he rapidly deteriorated with fatal multi-organ failure. Autopsy revealed massive infiltration of leukemic cells in several organs. Acute myelogenous leukemia should be considered in a patient presenting with unexplained multiorgan failure.

  View details for DOI 10.1080/1042819031000119244

  View details for Web of Science ID 000186108900018

  View details for PubMedID 14959861