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Biomedical subjects

Nitin Gogtay

Publications and source records attributed to Nitin Gogtay.

At least 19 recordsLinked to original sources
PubMed2006

Dynamic mapping of hippocampal development in childhood onset schizophrenia.

Prior cross-sectional anatomic brain imaging studies of the hippocampus in schizophrenia have generally shown loss in total hippocampal volume although the progressive course of these changes remains unknown. We report the first prospective sub-regional maps of hippocampal development in childhood onset schizophrenia (COS), reconstructed from serial brain MRI scans of 29 children with COS scanned every 2 years (87 scans) and compared to 31 controls matched for age, sex, and scan interval (94 scans). As expected, the COS subjects showed significant bilateral deficits (9-10%) in total hippocampal volume which remained consistent between age 9 and 26. However sub-regional maps showed heterogeneous changes with loss of hippocampal volume in both anterior as well as posterior ends while the body of the hippocampus gained in volume suggesting that hippocampal subunits are differentially affected in schizophrenia.

Adolescent↗
PubMed2006

Sleep disturbances in childhood-onset schizophrenia.

Sleep disturbances in psychiatric disease have long been reported. However, research on sleep disturbances in child and adolescent psychiatric disorders is limited. We examined the relationship of sleep disturbance to clinical severity and co-morbid diagnoses (e.g. anxiety), for a population with childhood-onset schizophrenia (COS). Sixty-one COS patients underwent a medication-free inpatient observation period as part of an NIMH study of COS. Sleep quantity during the last 5-7 days of a patient's medication-free period was measured using safety records and daily nursing notes. Subjects were divided into two groups: "good sleepers" (>6 h) and "poor sleepers" (<6 h) based on the average of total hours slept per night. Comparisons between groups were made with respect to clinical ratings at both admission and during washout period, co-morbid diagnosis of generalized anxiety disorder (GAD) and a susceptibility gene (G72) for COS. The median average sleep score for the entire group was 6.1 (S.D.=2.01) h. The good and poor sleep groups differed significantly in terms of severity of positive symptoms (SAPS) and negative symptoms at admission (SANS) both on admission and during the medication-free period. There was no significant relationship between G72 genotypes and a past and/or present diagnosis of GAD. COS patients suffer from significant sleep disturbances and the sleep disturbance is highly related to the symptom severity. As there are numerous health implications of poor sleep, clinicians should have a low threshold for treating sleep disturbances in this population.

Adolescent↗
PubMed2006

Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia.

CONTEXT: We previously detected a dynamic wave of gray matter loss in childhood-onset schizophrenia that started in parietal association cortices and proceeded frontally to envelop dorsolateral prefrontal and temporal cortices, including superior temporal gyri. OBJECTIVE: To map gray matter loss rates across the medial hemispheric surface, including the cingulate and medial frontal cortex, in the same cohort studied previously. DESIGN: Five-year longitudinal study. SETTING: National Institute of Mental Health, Bethesda, Md. Subjects Twelve subjects with childhood-onset schizophrenia, 12 healthy controls, and 9 medication- and IQ-matched subjects with psychosis not otherwise specified. INTERVENTIONS: Three-dimensional magnetic resonance imaging at baseline and follow-up. MAIN OUTCOME MEASURES: Gyral pattern and shape variations encoded by means of high-dimensional elastic deformation mappings driving each subject's cortical anatomy onto a group average; changes in cortical gray matter mapped by computing warping fields that matched sulcal patterns across hemispheres, subjects, and time. RESULTS: Selective, severe frontal gray matter loss occurred bilaterally in a dorsal-to-ventral pattern across the medial hemispheric surfaces in the schizophrenic subjects. A sharp boundary in the pattern of gray matter loss separated frontal regions and cingulate-limbic areas. CONCLUSION: Frontal and limbic regions may not be equally vulnerable to gray matter attrition, which is consistent with the cognitive, metabolic, and functional vulnerability of the frontal cortices in schizophrenia.

Adolescent↗
PubMed2006

Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment. OBJECTIVE: To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. DESIGN: Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. SETTING: National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. PATIENTS: Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics. INTERVENTIONS: After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13). MAIN OUTCOME MEASURES: The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. RESULTS: Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1). CONCLUSIONS: While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.

Adolescent↗
PubMed2006

Dynamic mapping of normal human hippocampal development.

The hippocampus, which plays an important role in memory functions and emotional responses, has distinct subregions subserving different functions. Because the volume and shape of the hippocampus are altered in many neuropsychiatric disorders, it is important to understand the trajectory of normal hippocampal development. We present the first dynamic maps to reveal the anatomical sequence of normal human hippocampal development. A novel hippocampal mapping technique was applied to a database of prospectively obtained brain magnetic resonance imaging (MRI) scans (100 scans in 31 children and adolescents), scanned every 2 yr for 6-10 yr between ages 4 and 25. Our results establish that the structural development of the human hippocampus is remarkably heterogeneous, with significant differences between posterior (increase over time) and anterior (loss over time) subregions. These distinct developmental trajectories of hippocampal subregions may parallel differences in their functional development.

Adolescent↗
PubMed2006

Childhood onset schizophrenia: cortical brain abnormalities as young adults.

BACKGROUND: Childhood onset schizophrenia (COS) is a rare but severe form of the adult onset disorder. While structural brain imaging studies show robust, widespread, and progressive gray matter loss in COS during adolescence, there have been no longitudinal studies of sufficient duration to examine comparability with the more common adult onset illness. METHODS: Neuro-anatomic magnetic resonance scans were obtained prospectively from ages 7 through 26 in 70 children diagnosed with COS and age and sex matched healthy controls. Cortical thickness was measured at 40,962 points across the cerebral hemispheres using a novel, fully automated, validated method. Patterns of patient-control differences in cortical development were compared over a 19-year period. RESULTS: Throughout the age range, the COS group had significantly smaller mean cortical thickness compared to controls. However, the COS brain developmental trajectory appeared to normalize in posterior (parietal) regions, and remained divergent in the anterior regions (frontal and temporal) regions, and the pattern of loss became more like that seen in adults. CONCLUSIONS: Cortical thickness loss in COS appears to localize with age to prefrontal and temporal regions that are seen for both medication naïve and medicated adult onset patients.

Adolescent↗
PubMed2005

IQ stabilization in childhood-onset schizophrenia.

OBJECTIVE: To examine the long term IQ trajectory for childhood-onset schizophrenia (COS) in an expanded, prospective longitudinal study. METHODS: Seventy children meeting DSM criteria for schizophrenia were tested at 2 year intervals with age appropriate Wechsler intelligence tests and repeated administration of information and comprehension WISC subtests even after age 18. For a subgroup with 31 patients, pre-NIH IQ test administrations were available including 18 pre-psychotic and 13 post-psychotic subjects. The pattern of IQ performance over time was determined using mixed model regression analysis. RESULTS: No progressive cognitive decline was seen up to 13+ years post psychosis onset. For the subgroup of subjects with pre-illness scores, there had been an initial steep decline in IQ, from about 2 years prior to 1.7 years after onset of psychotic symptoms, as reported for adult patients. CONCLUSIONS: The level long-term trajectory of IQ measures in COS appears stable, similar to that reported for adult onset patients. For COS, level cognitive functioning extends up to 13+ years post psychosis onset, in spite of chronic illness and concomitant, progressive loss of cortical gray matter.

Child↗
PubMed2005

Lack of evidence for elevated obstetric complications in childhood onset schizophrenia.

BACKGROUND: Pre-, peri-, and postnatal obstetric complications (OC) are reported to be more frequent in adult patients with schizophrenia and have been linked to both greater severity and to "earlier" age of onset (before either age 18 or 22) in studies of adult patients. We hypothesized that by extrapolation, patients with childhood-onset schizophrenia (COS), with very early onset and very severe illness, would have had more numerous or more salient OC compared with their healthy siblings. METHODS: We compared the obstetric records of 60 COS children and 48 healthy siblings using the Columbia Obstetrics Complication Scale, a comprehensive measurement scale consisting of 37 variables having included a separate scale for fetal hypoxia. RESULTS: Patients with COS did not have a higher incidence of OC than the healthy sibling control group with the exception of increased incidence of maternal vomiting. CONCLUSIONS: Obstetric complications, with the possible exception of maternal vomiting, are unlikely to play a major role in the etiopathogenesis of childhood-onset schizophrenia.

Adult↗
PubMed2005

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members.

BACKGROUND: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. AIMS: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). METHOD: Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. RESULTS: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. CONCLUSIONS: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. DECLARATION OF INTEREST: The study was done at the National Institutes of Health.

Adult↗
PubMed2005

Multidimensionally impaired: the good news.

INTRODUCTION: Long-term outcomes in children with atypical psychosis have been poorly studied. Four to 6 weeks of inpatient observation and up to 11 years (mean, 4.0 +/- 1.3 years) of follow- up have afforded us some experience with this probably heterogeneous group of transiently psychotic patients commonly mislabeled as schizophrenic. Despite severe preadmission morbidity, some patients have successfully remained neuroleptic-free since discharge. Predictors of good versus poor outcome were sought. METHODS: Of roughly 150 patients admitted with the presumptive diagnosis of schizophrenia, 32 patients were discharged meeting criteria for psychosis not otherwise specified (NOS), otherwise labeled by the NIMH team as "multidimensionally impaired" (MDI). Admission and biannual follow-up data included a semistructured clinical interview with the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS), IQ testing, clinical rating scales (e.g., Clinical Global Impression Scale (CGI), Children's Global Assessment Scale (C-GAS), Brief Psychiatric Rating Scale (BPRS), Scales for the Assessment Negative and Positive Symptoms (SANS and SAPS), and Bunney-Hamburg (B-H)). At follow-up (as of February 2005) 38% of patients (12 of 32) met criteria for bipolar 1 disorder, 12% (4 of 23) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free ("good outcome," n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy ("poor outcome," n = 10) at follow-up. RESULTS: Good-outcome patients had a significantly higher baseline level of functioning (on admission and on medications). This was demonstrated by better scores on CGI (3.5 +/- 0.6 versus 4.8 +/- 0.8; p = 0.03) and C-GAS (66.3 +/- 6.3 versus 38.6 +/- 11.5; p = 0.01). Groups were otherwise comparable in demographic data (gender, race, socioeconomic status, age at onset), months of neuroleptic exposure, severity of psychotic symptoms, and level of premorbid functioning. CONCLUSION: C-GAS (which correctly classified 85.7% of good-outcome subjects) and CGI at baseline appear to predict outcome. On other variables, MDI subgroups were remarkably similar.

Adolescent↗
PubMed2005

Hormonal correlates of clozapine-induced weight gain in psychotic children: an exploratory study.

OBJECTIVE: Weight gain is a serious side effect of atypical antipsychotics, especially in childhood. In this study, the authors examined six weight gain-related hormones in patients with childhood-onset schizophrenia (COS) after 6 weeks of clozapine treatment. METHOD: Fasting serum samples for 24 patients with COS and 21 matched healthy controls (HC) were obtained. Levels of leptin, insulin, adiponectin, amylin, ghrelin, and tumor necrosis factor alpha were measured and compared between the groups. For 23 patients with COS, hormonal levels were measured at background and week 6 of clozapine treatment. Change in body mass index was correlated with levels of clozapine and changes in hormonal levels and clinical ratings. RESULTS: At baseline, COS did not differ significantly from HC on any hormonal measure. Clozapine treatment was associated with significant (7.9% +/- 8.5%) increase in mean body mass index. Only leptin levels increased significantly from baseline to week 6 on clozapine (p = .003). Body mass index increase was significantly correlated with decrease in ghrelin and adiponectin and was positively correlated with clinical improvement. CONCLUSIONS: This is the first study of weight gain-related hormones in children on clozapine. Hormonal changes are correlated with weight gain. How effectiveness of clozapine is linked to weight gain remains uncertain.

Adolescent↗
PubMed2004

Childhood onset schizophrenia: familial neurocognitive measures.

OBJECTIVE: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). METHODS: Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. RESULTS: COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. CONCLUSIONS: Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

Adult↗
PubMed2004

Dynamic mapping of human cortical development during childhood through early adulthood.

We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.

Adolescent↗
PubMed2004

Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness?

BACKGROUND: Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. METHODS: Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). RESULTS: Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD (n = 12) than for the non-PDD (n = 27) subgroup (-19.5 +/- 11.3 mL/year vs. -9.6 +/- 15.3 mL/year; p =.05). None of eight candidate genes for autism were associated with COS or COS-PDD. CONCLUSIONS: Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.

Adolescent↗
PubMed2004

Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified.

BACKGROUND: Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. METHODS: We studied a rare cohort consisting of 98 probands; 71 of these probands received a DSM-defined diagnosis of schizophrenia, and the remaining 27 were diagnosed as psychosis not otherwise specified (NOS) (upon 2-6 year follow-up, 13 have subsequently developed bipolar disorder). Two overlapping genes, G72 and G30 on 13q33.2, were identified through linkage-disequilibrium-based positional cloning. Single nucleotide polymorphisms (SNPs) at the G72/G30 locus were independently associated with both bipolar illness and schizophrenia. We analyzed SNPs at this locus with a family-based transmission disequilibrium test (TDT) and haplotype analyses for the discrete trait, as well as quantitative TDT for intermediate phenotypes, using the 88 probands (including COS and psychosis-NOS) with parental participation. RESULTS: We observed significant pairwise and haplotype associations between SNPs at the G72/G30 locus and psychotic illness. Furthermore, these markers showed associations with scores on a premorbid phenotype measured by the Autism Screening Questionnaire, and with age of onset. CONCLUSIONS: These findings, although limited by potential referral bias, confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder.

Age of Onset↗
PubMed2004

Comparison of progressive cortical gray matter loss in childhood-onset schizophrenia with that in childhood-onset atypical psychoses.

BACKGROUND: Recent anatomical brain magnetic resonance imaging (MRI) studies show a striking postpsychotic progressive loss of cortical gray matter (GM) in patients with childhood-onset schizophrenia (COS), which appears greater than that seen for adult patients. However, the diagnostic specificity and the relationship of these changes to drug treatment and cognitive functioning remain unclear. We performed a comparative prospective brain MRI study in patients with COS and pediatric patients with transient psychosis with behavior problems (psychosis not otherwise specified) provisionally considered multidimensionally impaired (MDI). We hypothesized that cortical GM loss would occur in patients with COS but not in adolescents with atypical psychoses. METHODS: Anatomical brain MRI was performed at baseline and follow-up in 19 patients in the MDI group (mean [SD] age of 13.3 [3.1] years); in 23 patients with COS matched for age, sex, IQ score, and drug treatment (mean [SD] age of 13.9 [2.5] years); and 38 healthy control subjects matched for age and sex (mean [SD] age of 13.3 [3.1] years). The mean (SD) follow-up was 2.5 (0.8) years. Volumes of the cerebrum and total and regional GM were obtained by using automated analysis, and percent change in volume across time was calculated. One-way analyses of variance with post hoc Tukey Honestly Significantly Different comparisons were performed to examine group differences in the percent change in GM across follow-up. RESULTS: The COS group had significantly greater total, frontal, temporal, and parietal GM loss than did the MDI or healthy control groups; analysis of variance post hoc P values ranged from.03 to.001. The MDI and control groups did not differ significantly from each other. CONCLUSIONS: The cortical GM volume loss in COS appears diagnostically specific; it was not seen in children and adolescents with atypical psychosis. Because both patient groups had similar early developmental patterns, cognitive functioning, medications, and hospitalizations, this progressive loss appears to be intrinsic to COS. An ongoing neurodevelopmental process and/or brain response specific to the illness could account for these changes.

Adolescent↗
PubMed2004

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia.

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

Algorithms↗