PURPOSE OF REVIEWSchizophrenia is a severe mental disorder with substantial genetic vulnerability. This review discusses recent neuroimaging studies reporting on impairment in brain functioning ...relevant to language processing in individuals with schizophrenia and those who are at a genetic risk for its development.
RECENT FINDINGSStudies have shown that schizophrenia is associated with deficits in language function, as well as structural and functional abnormalities in brain regions that are involved with language perception and processing. Individuals who are at genetic high risk for schizophrenia also have structural and functional deficits in brain pathways for language processing. These studies consistently suggest that the normal pattern of left hemisphere dominance of language processing is significantly disturbed.
SUMMARYThis review suggests that future studies should examine the underlying mechanism for producing this disturbance in language processing and that prospective studies should be carried out that aim to follow individuals over time to determine whether these anomalies eventually lead to clinical symptoms of schizophrenia.
Reversal or reduction of normal structural cerebral asymmetries may be related to the pathogenesis of schizophrenia, but this relationship remains controversial. We review the literature and describe ...a further study designed to detect whether anomalous asymmetries are present early in the illness (at the first episode), whether they predict deficits in language processing, and whether they may be related to a genetic predisposition for schizophrenia. Asymmetries of brain widths and segments of the sylvian fissure were assessed in a magnetic resonance imaging study of 87 patients with a first episode of schizophrenia and 52 normal controls. These asymmetries were correlated with specific measures of language processing, memory, and hand skill. An independent group of 14 pairs of siblings with schizophrenia were also evaluated for evidence of heritability to cerebral asymmetries. Width asymmetries were reduced in patients compared with controls in the posterior (p = 0.02) and occipital (p = 0.05) regions. Brain horizontal length, on the other hand, was significantly more asymmetrical in patients (left > right; p = 0.04). For sylvian fissure measurements, asymmetries in controls (left > right) were greatest for the horizontal component; this asymmetry tended to detect differences in patients by comparison with controls (p < 0.06). In a range of tests of language and memory, few significant correlations between performance and cerebral asymmetries were detected either in patients or controls, although patients consistently scored poorer than controls in the majority of tests. In 14 pairs of psychotic siblings, within-pair correlations for the horizontal sylvian fissure asymmetry were significantly greater than between-pair correlations. These findings are consistent with the early presence (possibly genetic) of anomalous cerebral asymmetry. However, the functional correlates of reduced asymmetry remain obscure.
Age of onset is the single most important characteristic of schizophrenia that could yield clues to its origin. To identify the age of onset, however, the onset of the pathological process must be ...determined. This process may have more than one component occurring at distinctly different times in the life of an individual. Nevertheless, many studies, using either the first appearance of psychosis or the age of first hospitalization, have found gender, familial, and other "age of onset" differences among patients with schizophrenia. These differences may aid in examining genetic mechanisms for schizophrenia.
PURPOSE OF REVIEWThis review explores what is known about the association of cannabis with schizophrenia, its effects on the brain, and whether the brain changes known to be present in schizophrenia ...could be caused by cannabis and thus lead to a psychosis.
RECENT FINDINGSThe heavy use of cannabis is known to be associated with some adverse consequences, such as the occurrence of acute psychotic episodes and the development of chronic schizophrenia in some people even after its use has terminated. Recent studies have produced controversy about whether cannabis in heavy use can cause irreversible brain damage, particularly to adolescents, and thus whether a chronic psychosis could be a result of brain changes caused by cannabis.
SUMMARYFrom the evidence that exists, it appears that the above view is unlikely and that cannabis may even have benign effects on brain structure, not producing deleterious damage. Its neurochemical interactions with the dopaminergic pathway, however, may, particularly in genetically vulnerable individuals, have adverse consequences.
Chronic schizophrenia is characterized by change in the normal brain cortical structure, asymmetric reduction, and ventricular enlargement. The debate continues as to whether these anomalies occur ...early in development or represent an active progressive process continuing after the onset of psychosis. The case is made in the present manuscript for a continuing aberrant lifetime brain process. It is proposed that the underlying basis for the neuropathology of schizophrenia resides in the periodic activation of a defective gene or genes that determine the rate of cerebral growth. This process causes subtle cortical maldevelopment prenatally and through early childhood, is activated again during adolescent pruning of neurons, and again during the gradual aging process in the brain throughout adulthood. The case for a progressive active brain process in schizophrenia is thus presented.
IMPORTANCE Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease ...understanding and address the urgent need for new drug targets. OBJECTIVE To identify SCZ susceptibility genes. DESIGN We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. SETTING Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. PATIENTS We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. MAIN OUTCOMES AND MEASURES Case-control status for SCZ. RESULTS Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P <. 01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10−16) and 93% in subjects of European ancestry only (P < 2.20 × 10−16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10−10) and NOTCH4 (P = 3.16 × 10−7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10−7), AS3MT (P = 9.01 × 10−7), CNNM2 (P = 6.07 × 10−7), and NT5C2 (P = 4.09 × 10−7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). CONCLUSIONS AND RELEVANCE We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode ...schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.
Whether the brain structural abnormalities seen in schizophrenia are progressive is controversial. We previously reported on a longitudinal study of 50 first-episode patients with schizophrenia and ...20 controls who had serial MRI scans during the first 5 years of illness. Greater enlargement of lateral ventricles and reduction of hemispheric volume was observed over time in the patients compared with controls. The present study obtained MRI scans from 26 of these patients and 10 controls at a follow-up 10 years subsequent to their first evaluations. The initial, 4–5th and 10th year scans were examined for the degree of change in ventricular and hemispheric volume. Significantly greater ventricular enlargement during the second 5 years was detected in the patient cohort compared with controls (
P<0.05) with nine of the patients having ventricular enlargement (as measured by percent change) occurring at a rate exceeding that of any of the controls from years 1 through 10. The rate of ventricular change during the first 5 years was significantly correlated with age at first hospitalization, and ventricular enlargement in years 5–10 was correlated with the amount of time spent in hospital. Paradoxically, greater change in ventricles over time was correlated with better, not worse, outcome at the 10th year of follow-up with regard to the presence of symptoms. These data suggest heterogeneity in the course of brain change whereby some patients may exhibit active structural brain change only early in their illness or not at all after their first episode, while others continue to exhibit ventricular change spanning the decade subsequent to their first episode. Despite these differences among patients, the present study fails to detect any relationship of ventricular enlargement to poorer outcome as has been reported by other investigators.
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