Project description:This study is a collaboration between the Center for Applied Genomics (CAG) at Children's Hospital of Philadelphia (CHOP) and the Brain Behavior Laboratory at the University of Pennsylvania (Penn). The cohort consists of youths aged 8-21 years who consulted the CHOP network and volunteered to participate in genomic studies of complex pediatric disorders. All participants underwent clinical assessment, including a neuropsychiatric structured interview and review of electronic medical records. They were also administered a neuroscience based computerized neurocognitive battery (CNB) and a subsample underwent neuroimaging. These are described separately below. Clinical Testing: <ul><li>GOASSESS, a computerized, structured screener developed from a modified version of the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS, Kaufman et al. 1997, PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/9204677/" target="_blank">9204677</a>). Components of the interview include a timeline of life events, demographics and medical history, Global Assessment of Functioning, and Interviewer Observations.</li></ul> <ul><li>A psychopathology symptom and criterion-related assessment of mood disorders (depression, mania/hypomania), anxiety disorders (overanxious/generalized-, separation-, social-anxiety, specific phobia, panic disorder, agoraphobia, obsessive compulsive disorder, post-traumatic stress disorder), behavioral disorders (attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder), psychosis spectrum (psychosis and prodromal symptoms), eating disorders, suicidal thinking and behavior, and treatment history. This is also based on K-SADS.</li></ul> <ul><li>An abbreviated Family Interview for Genetics Studies (FIGS) to assess major domains of psychopathology in the proband's first-degree relatives.</li></ul> Computerized Neurocognitive Battery: The CNB, developed for large-scale studies, yields measures of accuracy and speed for domains of executive-control functions (abstraction, attention, working memory), episodic memory (verbal, facial, spatial), complex cognitive processing (language reasoning, nonverbal reasoning, spatial processing), social cognition (emotion identification, emotion intensity differentiation, age differentiation) and sensorimotor and motor speed. The following neurobehavioral domains were assessed: <ul><li>Penn Conditional Exclusion Test is a measure of abstraction and concept formation. Participants decide which of 4 objects does not belong with the other 3, based on one of three sorting principles, which change. Feedback is used.</li></ul> <ul><li>Attention: The Penn Continuous Performance Test. Participants respond to a set of 7-segment displays whenever they form a digit or letter.</li></ul> <ul><li>Working Memory: The Letter N-back Test displays sequences of uppercase letters with a stimulus duration of 500 ms (ISI 2,500 ms.) In the 0-back condition, participants respond to a single target (i.e., X). In the 1-back condition they respond if the letter is identical to that preceding it. In the 2-back condition, they respond if the letter is identical to that presented two trials back.</li></ul> <ul><li>Verbal Memory: The Penn Word Memory Test presents 20 target words that are then mixed with 20 distracters equated for frequency, length, concreteness and low imageability. A 20 min delayed recall procedure is also administered.</li></ul> <ul><li>Face Memory: The Penn Face Memory Test presents 20 digitized faces that are then mixed with 20 distracters equated for age, gender and ethnicity. The procedure is repeated at 20 min delay.</li></ul> <ul><li>Spatial Memory: The Visual Object Learning Test uses Euclidean shapes as stimuli with the same paradigm as the word and face.</li></ul> <ul><li>Language and Analogical Reasoning: The Penn Verbal Reasoning consists of verbal analogy problems.</li></ul> <ul><li>Spatial Processing: Penn Line Orientation Test presents two lines at an angle, and participants click on a button that makes one line rotate until it has the same angle as the other.</li></ul> <ul><li>Emotion Processing: Facial displays of 4 emotions (Happy, Sad, Anger, Fear) and Neutral faces, 8 each, are presented and the subject identifies the emotion in a multiple-choice format. The facial stimuli are balanced for gender, age, and ethnicity.</li></ul> <ul><li>Sensory-motor Processing Speed: The task requires moving the mouse and clicking on a green square that disappears after the click. The square gets increasingly small and appears in unpredictable locations.</li></ul> Neuroimaging Protocol: Studies were performed at Penn using a Siemens Trio (Erlangen, Germany) 3T scanner equipped with 40mT/m gradients and 200 mT/m/s slew-rates. RF transmission utilized a quadrature body-coil, and reception a 12-channel head coil optimized for parallel imaging. Total image acquisition time was about 45 min. Structural Imaging: The T1-weighted protocol utilized a 3D, inversion-recovery, and magnetization-prepared rapid acquisition gradient echo. Relevant imaging procedures include: <ul><li>Structural magnetic imaging</li></ul> <ul><li>Diffusion tensor imaging</li></ul> <ul><li>ASL perfusion</li></ul> <ul><li>BOLD fMRI</li></ul> Neuroimaging tasks: <ul><li>Fractal N-Back Task of Spatial Working Memory</li></ul> <ul><li>Face Emotion Identification Task</li></ul> Neuroimages: The current data release includes over 9700 MRI images that may be downloaded through Authorized Access.

Project description:Prenatal exposure to the anti-seizure drug sodium valproate (VPA) is associated with an increased risk of adverse postnatal neurodevelopmental outcomes, including lowered intellectual ability, autism spectrum disorder and attention-deficit hyperactivity disorder. In this study, we aimed to clarify the molecular mechanisms underpinning the neurodevelopmental consequences of gestational VPA exposure using integrative genomics. First, we assessed the effect of gestational VPA on fetal brain gene expression using a validated rat model of valproate teratogenicity that mimics the human scenario of chronic oral valproate treatment during pregnancy at doses which are therapeutically relevant to the treatment of epilepsy. Two different rat strains were studied - inbred Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic generalized epilepsy, and inbred Non-Epileptic Control (NEC) rats. Female rats were fed standard chow or VPA mixed in standard chow for 2 weeks prior to conception and then mated with same-strain males. In the VPA-exposed rats maternal oral treatment was continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 (one day prior to birth) and fetal brains were snap frozen and genome-wide gene expression data generated. We found that gestational VPA exposure via chronic maternal oral dosing was associated with substantial drug-induced differential gene expression in the pup brains, including dysregulated splicing, and observed that this occurred in the absence of evidence for significant neuronal gain or loss. The set of genes down-regulated by VPA in the pup brains were significantly enriched for pathways related to neurodevelopment and synaptic function, and significantly enriched for heritability to human intelligence, schizophrenia and bipolar disorder. Our results provide a mechanistic link between chronic fetal VPA exposure and adverse neurodevelopmental outcomes mediated by VPA-induced transcriptional dysregulation.

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Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

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