Brain function and clinical characterization in the Boston adolescent neuroimaging of depression and anxiety study.

We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14-17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and longitudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource.

Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies.

While schizophrenia is substantially heritable, the disorder's molecular genetic basis remains elusive. These efforts have been hindered by an inability to detect nonclinically-penetrant carriers of the predisposing genes and by uncertainties concerning the nature of the non-genetic influences and the extent of locus heterogeneity. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly-inherited traits. Here we describe the application of this method to measures of brain structure and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). Our results suggest that there are likely to be multiple heritable dimensions of the central nervous system pathology in schizophrenia, each under the influence of a partially distinct set of genes, one of which involves disturbances in the structure and functioning of frontal lobe systems involved in working memory and another of which appears to render the brain more susceptible to damage to subcortical systems involved in long-term memory following oxygen deprivation in utero. Measures sensitive to quantitative variation in these dimensions of the central nervous system compromise should allow non-penetrant gene carriers to become informative for genetic linkage and facilitate detection of different genetic loci contributing to discrete aspects of disease liability.

A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia.

In this study, we examined whether fetal hypoxia and other obstetric complications (OCs) are related to risk for adult schizophrenia; whether such effects are specific to cases with an early age at onset; and whether the obstetric influences depend on, covary with, or are independent of familial risk. Subjects were 72 patients with schizophrenia or schizoaffective disorder; 63 of their siblings not diagnosed with schizophrenia; and 7,941 nonpsychiatric controls, whose gestations and births were monitored prospectively with standard research protocols as part of the National Collaborative Perinatal Project. Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. We found that the odds of schizophrenia increased linearly with increasing number of hypoxia-associated OCs and that this effect was specific to cases with an early age at onset/first treatment contact. There were no relationships between schizophrenia and birth weight or other (prenatal/nonhypoxic) OCs. Siblings of patients with schizophrenia were no more likely to have suffered hypoxia-associated OCs than were nonpsychiatric cohort controls. Because the majority of individuals exposed to fetal hypoxia did not develop schizophrenia, such factors likely are incapable of causing schizophrenia on their own. Together, these findings suggest that hypoxia acts additively or interactively with genetic factors in influencing liability to schizophrenia. We propose a model in which the neurotoxic effects of fetal hypoxia may lead to an earlier onset of psychosis because of premature pruning of cortical synapses.

Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study.

Neuromotor dysfunction is a consistent finding in high-risk and archival studies of schizophrenia, but the sources of this dysfunction and its role in the developmental course of the disorder remain poorly understood. This study examined childhood motor predictors of adult psychiatric outcome in a birth cohort sample (72 patients with schizophrenia or schizoaffective disorder, 63 unaffected siblings, and 7,941 nonpsychiatric controls), evaluated prospectively with neurologic examinations at 8 months, 4 years, and 7 years of age. Deviance on motor coordination measures at 7 years was associated with both adult schizophrenia and unaffected sibling status, suggesting that a cofamilial (and perhaps genetic) factor underlies motor coordination deficits in schizophrenia. Unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sibling status, indicating that these deficits may be specific to those who will develop the clinical phenotype. None of the motor precursors were confined to patients with an early age at first treatment contact. Fetal hypoxia predicted unusual movements at 4 but not 7 years among the preschizophrenia subjects, suggesting neurodevelopmental dependence of its functional effects. Neither prenatal complications nor birth weight were associated with motor dysfunction in preschizophrenia subjects or their unaffected siblings at any age. Finally, preschizophrenia children did not show the expected developmental decline in unusual movements, perhaps reflecting aberrant functional maturation of cortical-subcortical pathways.

Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study.

While it is known that children of schizophrenia parents perform more poorly on tests of cognitive functioning than children of normal parents, less certain is the degree to which such deficits predict schizophrenia outcome, whether cognitive functioning deteriorates during childhood in preschizophrenia individuals, and whether nongenetic etiologic factors (such as obstetric complications) contribute to these deficits. In the present study, 72 patients with schizophrenia or schizoaffective disorder, 63 of their siblings not diagnosed with schizophrenia, and 7,941 controls with no diagnosis were ascertained from a birth cohort whose members had been evaluated with standardized tests of cognitive functioning at 4 and 7 years of age. Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. Both the patients with schizophrenia and their unaffected siblings performed significantly worse than the nonpsychiatric controls (but did not differ from each other) on verbal and nonverbal cognitive tests at 4 and 7 years of age. Preschizophrenia cases and their siblings were increasingly overrepresented across decreasing quartiles of the performance distributions. There was not significant intra-individual decline, and there were no significant relationships between obstetric complications and test performance among the preschizophrenia subjects. These results suggest that during the period from age 4 to age 7 years, premorbid cognitive dysfunction in schizophrenia represents a relatively stable indicator of vulnerability deriving from primarily genetic (and/or shared environmental) etiologic influences.

A prospective cohort study of childhood behavioral deviance and language abnormalities as predictors of adult schizophrenia.

Language and behavioral deviance in early childhood in preschizophrenia individuals suggests that the pathologic processes predisposing to schizophrenia are present from early in life. However, the etiologic antecedents of such impairments, and the degree to which they predict adult schizophrenia, have not been conclusively demonstrated. To address this, we examined language and behavioral predictors of adult psychiatric outcome in a population cohort (72 individuals with schizophrenia or schizoaffective disorder, 63 of their unaffected siblings, and 7,941 with no diagnosis) evaluated prospectively with behavioral examinations and a speech and language evaluation at 8 months, 4 years, and 7 years of age. Psychiatric outcome was ascertained via adult treatment contacts, and diagnoses were made by chart review according to DSM-IV criteria. Social maladjustment at age 7 was found to predict adult schizophrenia, and focal deviant behaviors (e.g., echolalia, meaningless laughter) at ages 4 and 7 were significantly associated with both schizophrenia and sibling status. Unintelligible speech at age 7 was a highly significant predictor of adult schizophrenia (odds ratio = 12.7), and poor expressive language ability predicted both schizophrenia and unaffected sibling outcome. Early behavioral and language dysfunction did not differentially characterize preschizophrenia subjects with a history of fetal hypoxia or an early age of first treatment contact. Given that unaffected siblings show similar signs of deviance, such problems may indicate genotypic susceptibility to the disorder, or shared environmental influences, or both.

Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort.

OBJECTIVE: Although case-control investigations have shown an association between obstetric complications and schizophrenia, particularly among patients with early onsets, cohort studies have mostly failed to confirm this effect. The authors examined whether a history of fetal hypoxia and other obstetric complications elevated risk for early-onset schizophrenia in a 1955 Helsinki birth cohort. METHOD: The subjects were 80 randomly selected patients with schizophrenia (36 with early and 44 with later onsets) representative of all available probands in the cohort, 61 of their nonschizophrenic siblings, and 56 demographically matched nonpsychiatric comparison subjects. Psychiatric diagnoses were obtained from structured clinical interviews, and obstetric data were taken from standardized, prospectively ascertained obstetric records. A score for hypoxia-associated obstetric complications was entered into logistic regression models, along with measures of prenatal infection and fetal growth retardation. RESULTS: Hypoxia-associated obstetric complications significantly increased the odds of early-onset schizophrenia but not of later-onset schizophrenia or unaffected sibling status, after prenatal infection and fetal growth retardation were taken into account. CONCLUSIONS: These findings support an association between obstetric complications and increased risk for early-onset schizophrenia. The authors advance a model whereby the neurotoxic effects of fetal hypoxia may lead to an early onset of schizophrenia due to premature cortical synaptic pruning.

A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia.

A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional-developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems.