Brain & Behavior Research Foundation Webinar, September 9, 2013 Judith L. Rapoport MD NIMH, Bethesda MD
Schizophrenia:Theoretical Framework (Childhood Onset Salience) Karyotype Social Environmental Pre-Perinatal Factors CNVs ?iPSC Complications/. Synaptic Pruning? Neural System Vulnerabilities Neural System Vulnerabilities (E.g., Frontal Systems, Mesolimbic Dopamine System, Stress Responsivity Deterioration Systems) Psychosis Onset (More Frequent Multi Modal) Prodromal Symptoms Hallucinations) Functional Deterioration Premorbid Behavior Disturbance Delayed Language/PDD Motor/social abnormalities Conception Birth Infancy Childhood Adolescence Adulthood
Childhood Onset Schizophrenia Defined as Onset before 13 Very rare – but over diagnosed in children Observation off medication important for diagnosis NIMH study has been ongoing since 1990 Early onset illness has been helpful in understanding genetics and biology of many disorders (e.g. breast cancer, Alzheimers) throughout medicine
Over-diagnosis of Childhood-Onset Schizophrenia: Primary Diagnosis after initial Two-day Out-Patient Screenings ( N = 361) national recruiting – selected from over 3000 referrals Other Dx (Dissociative Disorder, Organic/Lesions, OCD Dx 6 (2%) PTSD, Schizotypal etc Anxiety 7 (2%) Conduct 9 (3%) 25 (7%) Psychotic Disorder NOS Presumptive 11 (3.0%) Schizophrenia 19 (5%) ASD 22 (6%) 229 (63%) Bipolar 33 (9%) Depression
Childhood-Onset Schizophrenia: Discharge Diagnosis after 228 In-Patient Admissions* Other Dx (Conduct Disorder, PTSD, Childhood Disintegrative Disorder etc.) Psychotic Disorder NOS 22 (10%) Bipolar Dx Schizophrenia 26 (12%) (Admitted to Study) Depression/Mood 126 (55% ) Dx 3 (~1%) 24 (11%) Pervasive *Includes 1-3 week Developmental Drug Free Observation Disorder 11 (5%) Anxiety Dx 7 (3%) Brain Injury 2 (1%)
High Rates of Pre- Psychotic Neurodevelopmental Impairment for Childhood Onset Schizophrenia Probands (January, 2013) Pervasive Developmental Disorder (PDD) 20 Educational, language, % 67% social, and/or motor 13% difficulties No Earlier Developmental Impairments Genetic/familial risk? Not a high rate of sibling neurodevelopmental impairment Model: our patients have some higher rare genetic risk and lack protective factors.
Previous clinical studies Continuity with AOS Risk: no strong indication Unmodified DSM IV Diagnosis of: Neuropsychological Profile Skin conductance Obstetrical risk (obstetrical SPEM (eye movements) record comparison vs. Anatomic brain MRI (increased siblings) ventricular and decreased Early puberty hippocampal volumes) Paternal age Treatment Season of birth Double blind superiority of Trauma clozapine vs haloperidol Sibling neurodevelopmental Double blind superiority of impairment clozapine vs olanzapine Safety study of TDCS
Ongoing Clinical Studies TDCS Intranasal Oxytocin (transcranial direct current stimulation) Double blind, (sham control), parallel design Double blind study with New very small brain measures of social interaction stimulator (can be carried in pocket) Has been shown to increase Testing for treatment of social interaction in autism cognitive deficits and for Pre-post Imaging with resting psychotic symptoms fMRI, MEG and emotional task
Brain Imaging Studies of COS Childhood Schizophrenia Healthy Children Patients We first establish the first Childhood onset patients lost “norms” for MRI measures of brain tissue during human brain development adolescence Studied children Their healthy siblings showed prospectively throughout some early brain childhood and adolescence abnormalities that improved with age!
Time Course of Critical Events in the Determination of Human Brain Morphometry Conception Birth NIMH Study weeks 4 years months 4 8 12 16 20 24 28 32 2 5 18 60+ Neurulation Neurogenesis Max. growth Synaptogenesis Competitive elimination Migration from ventricular zone Programmed cell death Myelination Dendritic and axonal arborization
(a) Frontal Gray Matter(cc) (b) Parietal Gray Matter (cc) Figure 1 250 135 235 120 220 105 205 190 90 7 9 11 13 15 17 19 7 9 11 13 15 17 19 5 Age 20 (d) Occipital Gray Matter (cc) (c) Temporal Gray Matter (cc) 75 205 70 190 65 60 175 55 Adapted from Gogtay et al. 2004 Giedd et al. 50 160 1999 7 9 11 13 15 17 19 7 9 11 13 15 17 19
Normal Brain Development COS Brain Development Age 4-22 Age 12-16 n=13; 51 scans Gogtay et al. PNAS 2004 COS HAS EXAGGERATION OF COS n=12 Vs Controls n=12; 3 scans each NORMAL PATTERN Age, sex and scan interval matched. PF CORTICAL DEVELOPMENT Thompson et al. PNAS 2001
Relative Cortical Thinning Becomes Circumscribed with Age for COS Probands Previous General Pattern Holds with Extended Sample (COS N= 85, 177scans; NV N= 86,185 scans) and later version of MNI pipeline (CLASP) A. Corrected for MCT 12 14 16.73 18 20 22 7 2 Age 12 16 20 22 14 18 B. Uncorrected
Relative cortical GM thinning in Childhood Onset Schizophrenia (COS) becomes more circumscibed across age 8-24: COS (n=104, 222 scans) Vs Controls (n=104, 233 scans)] LEFTSIB2010(8-24)
Cortical Brain Development in Non-Psychotic Full Sibs of COS Probands A) Normalizing in healthy sibs (n=52 ; 113scans) v Controls (n= 52; 108 scans) (Gogtay et al Arch Gen Psych 2007) B.BReplication with non-overlapping healthy sibs (sib n= 38; 47 scans) vs. (Controls n=80; 182 scans) Mattai et al 2011) Gogtay, 2009 2 10 12 14 16ish
Relative GM thinning in Healthy COS Siblings (combined sample) Healthy Siblings (n=91, 185 scans) Vs Controls ( n=92, 193 scans) t statistics 10 2.2
Schizophrenia:Theoretical Framework (Childhood Onset Salience) Karyotype Social Environmental Pre-Perinatal Factors CNVs ?iPSC Complications/. Synaptic Pruning? Neural System LOSS OF COMPENSATION? Vulnerabilities Neural System Vulnerabilities (E.g., Frontal Systems, Mesolimbic Dopamine System, Stress Responsivity Deterioration Systems) Psychosis Onset (More Frequent Multi Modal) Prodromal Symptoms Hallucinations) Functional Deterioration Premorbid Behavior Disturbance Delayed Language/PDD Motor/social abnormalities Conception Birth Infancy Childhood Adolescence Adulthood
HIPPOCAMPAL VOLUME :FIXED, STATE RELATED: Total Hippocampus Shape COS VS. CONTROLS 9600 Volume Differences 9400 Volume (cmm) NV v COS p=0.001 9200 9000 NV v Sib p=0.414 8800 Sib v COS p=0.004 8600 8400 Johnson et al 2013 8200 8000 7800 AGE 12 13 14 15 16 17 18 19 20 21 22 23 24 Right Left Hippocampus 4600 4600 4500 Volume Difference Volume (cmm) Volume (cmm) Volume Differences 4500 4400 NV v COS p=0.001 NV v COS p=0.001 4400 4300 NV v Sib p=0.818 4300 NV v Sib p=0.515 4200 Sib v COS p=0.001 4200 Sib v COS p=0.006 4100 4100 4000 12 13 14 15 16 17 18 19 20 21 22 23 24 4000 12 13 14 15 16 17 18 19 20 21 22 23 24 AGE AGE MATTAI ET AL 2011 No significant shape differencesbetween any trajector
Childhood onset schizophrenia: Genetic studies Copy Number Variants “Growing Brains in a seem to increase risk for Dish” many neuro- Skin developmental disorders biopsies(fibroblasts) We compared COS with being used to make their siblings and with embryonic stem cells for controls each patient These stem cells then produce lines of neuronal cells for study
COS: Genetic Studies-Copy Number Variants Large number of CNVs reported for neuro-developmental disorders (schizophrenia, autism, Intellectual Disability, and/or epilepsy) Large control populations available for each disorder Sufficient COS sample size to also compare rates with healthy full siblings
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