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  • Measuring socioeconomic adversity in early life ACTA PAEDIATRICA Anand, K. S., Rigdon, J., Rovnaghi, C. R., Qin, F., Tembulkar, S., Bush, N., LeWinn, K., Tylavsky, F. A., Davis, R., Barr, D. A., Gotlib, I. H. 2019; 108 (7): 1267–77

    View details for DOI 10.1111/apa.14715

    View details for Web of Science ID 000471904300016

  • Response to letter to the Editor ACTA PAEDIATRICA Rovnaghi, C. R., Tembulkar, S., Rigdon, J., Anand, K. S. 2019; 108 (7): 1362

    View details for DOI 10.1111/apa.14768

    View details for Web of Science ID 000471904300030

  • Response to letter to the Editor. Acta paediatrica (Oslo, Norway : 1992) Rovnaghi, C. R., Tembulkar, S., Rigdon, J., Anand, K. J. 2019

    Abstract

    We agree with Dr. Meyer (1) that socioeconomic disparities are far from being solved and, in fact, US disparities have increased in the past decade. Most studies on socioeconomic status attempt to disentangle specific factors mediating the inequities linked with poor health outcomes. Because of complex interactions between individual factors, we proposed a socioeconomic adversity index (SAI) combining such factors in the US(2). This article is protected by copyright. All rights reserved.

    View details for PubMedID 30825246

  • Measuring socioeconomic adversity in early life. Acta paediatrica (Oslo, Norway : 1992) Anand, K. J., Rigdon, J., Rovnaghi, C. R., Qin, F., Tembulkar, S., Bush, N., LeWinn, K., Tylavsky, F. A., Davis, R., Barr, D. A., Gotlib, I. H. 2019

    Abstract

    AIM: Early life adversity in leads to enduring effects on physical and mental health, school performance, and other outcomes. We sought to identify potentially modifiable factors leading to socioeconomic adversity in early life.METHODS: We enrolled 1,503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial, and economic variables were analyzed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state, and national levels.RESULTS: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education, and health insurance. Significantly worse health and social outcomes occurred in the lower vs. higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight, and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles.CONCLUSION: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education, and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30614554

  • P300 amplitude attenuation in high risk and early onset psychosis youth. Schizophrenia research Graber, K., Bosquet Enlow, M., Duffy, F. H., D'Angelo, E., Sideridis, G., Hyde, D. E., Morelli, N., Tembulkar, S., Gonzalez-Heydrich, J. 2019

    Abstract

    Little research has investigated the use of electrophysiological biomarkers in childhood and adolescence to distinguish early onset psychosis and the clinical high risk state. The P300 evoked potential is a robust neurophysiological marker of schizophrenia that is dampened in patients with schizophrenia and, less consistently, in those with affective psychoses and those at clinical high risk for psychosis (CHR). How it may differ between patients with psychotic disorders (PS) and CHR is less studied, especially in youth. The current study compared P300 activity among children and adolescents, aged 5-18 years, at CHR (n = 43), with PS (n = 28), and healthy controls (HC; n = 24). Participants engaged in an auditory event-related potential (ERP) task to elicit a P300 response and completed clinical interviews to verify symptoms and diagnoses. Linear regression analyses revealed a decrease in P300 amplitude with increased severity of psychotic symptoms. PS participants showed a diminished P300 response compared to those at CHR and HC, particularly among adolescents aged 13-18. This response was most evident at centroparietal and parietal locations in the right hemisphere. The findings suggest that high risk and psychotic symptomatology is linked to attenuated parietal P300 activity in youth as young as 13 years. Further exploration of the P300 as a biomarker for psychosis in very young patients could inform tailored, appropriate interventions at early stages of disease progression. Future research should evaluate whether specific phenotypic and genotypic characteristics are differentially associated with neurophysiological biomarkers and whether P300 attenuation in CHR youth can predict later symptom severity.

    View details for DOI 10.1016/j.schres.2018.12.029

    View details for PubMedID 30685392

  • De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report BMC MEDICAL GENETICS Mavros, C. F., Brownstein, C. A., Thyagrajan, R., Genetti, C. A., Tembulkar, S., Graber, K., Murphy, Q., Cabral, K., VanNoy, G. E., Bainbridge, M., Shi, J., Agrawal, P. B., Beggs, A. H., D'Angelo, E., Gonzalez-Heydrich, J. 2018; 19: 197

    Abstract

    TRRAP encodes a multidomain protein kinase that works as a genetic cofactor to influence DNA methylation patterns, DNA damage repair, and chromatin remodeling. TRRAP protein is vital to early neural developmental processes, and variants in this gene have been associated with schizophrenia and childhood disintegrative disorder.Here, we report on a patient with a de novo nonsynonymous TRRAP single-nucleotide variant (EST00000355540.3:c.5957G > A, p.Arg1986Gln) and early onset major depression accompanied by a psychotic episode (before age 10) that occurred in the context of longer standing nonverbal learning disability and a past history of obsessions and compulsions.The de novo variant and presentation of very early onset psychosis indicate a rare Mendelian disorder inheritance model. The genotype and behavioral abnormalities of this patient are reviewed.

    View details for DOI 10.1186/s12881-018-0711-9

    View details for Web of Science ID 000451217500001

    View details for PubMedID 30424743

    View details for PubMedCentralID PMC6234620

  • Potentially traumatic events in youth with and at clinical high risk for psychosis. Early intervention in psychiatry Morelli, N., Fogler, J., Tembulkar, S., Graber, K., Lincoln, S. H., Bosquet Enlow, M., Gonzalez-Heydrich, J., D'Angelo, E. J. 2018

    Abstract

    Previous research has demonstrated a strong association between early trauma exposure and the development of psychotic symptoms. However, few of these studies have included young adolescents and children. This study investigated rates and number of potentially traumatic experiences (PTEs) among typically developing youth (TD; n = 21), youth at clinical high risk for psychosis (CHR; n = 38), and youth with a psychotic disorder (PD; n = 28) between 7 and 18 years of age. CHR participants were further evaluated to determine whether a history of PTEs was associated with prodromal symptom severity.Study group inclusion was determined by structured interviews. Trauma history was assessed using the post-traumatic stress disorder module of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. CHR participants with vs without a history of PTEs were compared on severity of prodromal symptoms.CHR and PD participants reported significantly higher rates and numbers of PTEs than TD participants. Contrary to expectations and prior research, CHR participants with vs without a history of PTEs did not differ in prodromal symptom severity. Explanations and implications for the findings are discussed.These findings suggest that the relationship between trauma and the development of psychotic symptoms extends to children and adolescents as young as 7 years of age. This study underscores the importance of screening for trauma exposure among youth seeking treatment for psychotic symptoms.

    View details for PubMedID 29575640

  • Young children with psychotic symptoms and risk for suicidal thoughts and behaviors: a research note. BMC research notes Sinclair-McBride, K., Morelli, N., Tembulkar, S., Graber, K., Gonzalez-Heydrich, J., D'Angelo, E. J. 2018; 11 (1): 568

    Abstract

    Suicidal thoughts and behaviors (STBs) are prevalent among youth with psychotic disorders (PD) relative to the general population. Recent research now suggests that STBs may present during the prodromal phase of the disease, or the clinical high risk (CHR) state. While this knowledge is important for the development of suicide prevention strategies in adolescent and adult populations, it remains unclear whether risk for suicide extends to children with or at risk for psychosis. The current study is an extension of previous work assessing STBs in youth across the psychosis continuum. We examine STBs in 37 CHR and PD children ages 7-13 years old, and further explore the prodromal symptom correlates of STB severity among CHR children.CHR and PD children endorsed STBs with a frequency and severity similar to what is observed in older CHR and PD populations. A number of children had never previously vocalized their suicidal plans or intent. Among CHR children, Social Anhedonia and Odd Behavior or Appearance were significantly correlated with STB severity. These findings underscore the importance of screening for STBs even in young children presenting with psychotic symptoms.

    View details for PubMedID 30097053

    View details for PubMedCentralID PMC6086075

  • De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome. Molecular genetics and metabolism reports Torres, A., Brownstein, C. A., Tembulkar, S. K., Graber, K., Genetti, C., Kleiman, R. J., Sweadner, K. J., Mavros, C., Liu, K. X., Smedemark-Margulies, N., Maski, K., Yang, E., Agrawal, P. B., Shi, J., Beggs, A. H., D'Angelo, E., Lincoln, S. H., Carroll, D., Dedeoglu, F., Gahl, W. A., Biggs, C. M., Swoboda, K. J., Berry, G. T., Gonzalez-Heydrich, J. 2018; 16: 23–29

    Abstract

    Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

    View details for DOI 10.1016/j.ymgmr.2018.06.001

    View details for PubMedID 29922587

    View details for PubMedCentralID PMC6005789

  • Suicidal behaviors in children and adolescents with psychotic disorders. Schizophrenia research Lincoln, S. H., Norkett, E., Graber, K., Tembulkar, S., Morelli, N., Gonzalez-Heydrich, J., D'Angelo, E. 2017; 179: 13-16

    Abstract

    Suicide is the leading cause of premature death in individuals with psychotic disorders. Risk for onset of suicidal behaviors tends to begin in adolescence, remaining high into young adulthood. The present study aims to evaluate the interplay of early onset psychosis and suicide risk by examining suicidal behaviors (ideation, planning, and attempts) in children and adolescents with psychotic disorders (PD) compared to typically developing peers (TD). Twenty five youths were recruited and were diagnostically evaluated for psychosis. We found that the PD children exhibited significantly higher levels of suicidal behaviors than TD children, even when parsed into individual at-risk behaviors.

    View details for DOI 10.1016/j.schres.2016.09.020

    View details for PubMedID 27707531

  • Suicidal behaviors and their relationship with psychotic-like symptoms in children and adolescents at clinical high risk for psychosis. Comprehensive psychiatry D'Angelo, E. J., Lincoln, S. H., Morelli, N., Graber, K., Tembulkar, S., Gonzalez-Heydrich, J. 2017; 78: 31–37

    Abstract

    Previous research has demonstrated elevated rates of suicide attempts and ideation in individuals with psychosis. This study investigated rates and severity of suicidal behavior in youth with and at clinical high risk for psychosis, and examined the positive, negative, and disorganized symptoms associated with suicidal behaviors among the clinical high risk group.Eighty-six youth ages 7-18 (n=21 non-clinical controls [NCC], n=40 clinical high risk [CHR], n=25 diagnosed psychotic disorder [PD]) were recruited. CHR and PD participants were identified using the Structured Interview for Prodromal Symptoms (SIPS) and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (KSADS-PL). All participants completed the Suicide Behaviors Questionnaire-Revised (SBQ-R).Findings indicated significantly higher levels of suicidal behavior among CHR and PD relative to NCC participants (F=7.64, p=0.001). 17.5% of CHR participants had previously attempted suicide. Dysphoric Mood and Odd Behavior or Appearance were significantly correlated with suicidal behavior severity among CHR youth.Suicidal behavior was observed with greater frequency and severity in the CHR and PD groups than in the NCC group. CHR suicidal behavior severity was correlated most strongly with Dysphoric Mood and Odd Behavior or Appearance, a relationship which warrants further investigation.

    View details for DOI 10.1016/j.comppsych.2017.07.008

    View details for PubMedID 28803039

  • A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Cold Spring Harbor molecular case studies Smedemark-Margulies, N., Brownstein, C. A., Vargas, S., Tembulkar, S. K., Towne, M. C., Shi, J., Gonzalez-Cuevas, E., Liu, K. X., Bilguvar, K., Kleiman, R. J., Han, M., Torres, A., Berry, G. T., Yu, T. W., Beggs, A. H., Agrawal, P. B., Gonzalez-Heydrich, J. 2016; 2 (5)

    Abstract

    We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.

    View details for DOI 10.1101/mcs.a001008

    View details for PubMedID 27626066

    View details for PubMedCentralID PMC5002930

  • Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports. American journal of medical genetics. Part A Brownstein, C. A., Kleiman, R. J., Engle, E. C., Towne, M. C., D'Angelo, E. J., Yu, T. W., Beggs, A. H., Picker, J., Fogler, J. M., Carroll, D., Schmitt, R. C., Wolff, R. R., Shen, Y., Lip, V., Bilguvar, K., Kim, A., Tembulkar, S., O'Donnell, K., Gonzalez-Heydrich, J. 2016; 170A (5): 1165-1173

    Abstract

    Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

    View details for DOI 10.1002/ajmg.a.37595

    View details for PubMedID 26887912

    View details for PubMedCentralID PMC4833544

  • N100 Repetition Suppression Indexes Neuroplastic Defects in Clinical High Risk and Psychotic Youth NEURAL PLASTICITY Gonzalez-Heydrich, J., Enlow, M. B., D'Angelo, E., Seidman, L. J., Gumlak, S., Kim, A., Woodberry, K. A., Rober, A., Tembulkar, S., O'Donnell, K., Hamoda, H. M., Kimball, K., Rotenberg, A., Oberman, L. M., Pascual-Leone, A., Keshavan, M. S., Duffy, F. H. 2016

    Abstract

    Highly penetrant mutations leading to schizophrenia are enriched for genes coding for N-methyl-D-aspartate receptor signaling complex (NMDAR-SC), implicating plasticity defects in the disease's pathogenesis. The importance of plasticity in neurodevelopment implies a role for therapies that target these mechanisms in early life to prevent schizophrenia. Testing such therapies requires noninvasive methods that can assess engagement of target mechanisms. The auditory N100 is an obligatory cortical response whose amplitude decreases with tone repetition. This adaptation may index the health of plasticity mechanisms required for normal development. We exposed participants aged 5 to 17 years with psychosis (n = 22), at clinical high risk (CHR) for psychosis (n = 29), and healthy controls (n = 17) to an auditory tone repeated 450 times and measured N100 adaptation (mean amplitude during first 150 tones - mean amplitude during last 150 tones). N100 adaptation was reduced in CHR and psychosis, particularly among participants <13 years old. Initial N100 blunting partially accounted for differences. Decreased change in the N100 amplitude with tone repetition may be a useful marker of defects in neuroplastic mechanisms measurable early in life.

    View details for DOI 10.1155/2016/4209831

    View details for Web of Science ID 000371056900001

    View details for PubMedID 26881109

    View details for PubMedCentralID PMC4737454

  • Early auditory processing evoked potentials (N100) show a continuum of blunting from clinical high risk to psychosis in a pediatric sample. Schizophrenia research Gonzalez-Heydrich, J., Bosquet Enlow, M., D'Angelo, E., Seidman, L. J., Gumlak, S., Kim, A., Woodberry, K. A., Rober, A., Tembulkar, S., Graber, K., O'Donnell, K., Hamoda, H. M., Kimball, K., Rotenberg, A., Oberman, L. M., Pascual-Leone, A., Keshavan, M. S., Duffy, F. H. 2015; 169 (1-3): 340-345

    Abstract

    The N100 is a negative deflection in the surface EEG approximately 100 ms after an auditory signal. It has been shown to be reduced in individuals with schizophrenia and those at clinical high risk (CHR). N100 blunting may index neural network dysfunction underlying psychotic symptoms. This phenomenon has received little attention in pediatric populations.This cross-sectional study compared the N100 response measured via the average EEG response at the left medial frontal position FC1 to 150 sinusoidal tones in participants ages 5 to 17 years with a CHR syndrome (n=29), a psychotic disorder (n=22), or healthy controls (n=17).Linear regression analyses that considered potential covariates (age, gender, handedness, family mental health history, medication usage) revealed decreasing N100 amplitude with increasing severity of psychotic symptomatology from healthy to CHR to psychotic level.Longitudinal assessment of the N100 in CHR children who do and do not develop psychosis will inform whether it predicts transition to psychosis and if its response to treatment predicts symptom change.

    View details for DOI 10.1016/j.schres.2015.10.037

    View details for PubMedID 26549629

    View details for PubMedCentralID PMC4821005