MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Reduced contextual effects on visual contrast perception in schizophrenia and bipolar affective disorder.

BACKGROUND: The salience of a visual stimulus is often reduced by nearby stimuli, an effect known as surround suppression of perceived contrast, which may help in locating the borders of an object. Weaker surround suppression has been observed in schizophrenia but it is unclear whether this abnormality is present in other mental disorders with similar symptomatology, or is evident in people with genetic liability for schizophrenia. METHOD: By examining surround suppression among subjects with schizophrenia or bipolar affective disorder, their unaffected biological relatives and healthy controls we sought to determine whether diminished surround suppression was specific to schizophrenia, and if subjects with a genetic risk for either disorder would show similar deficits. Measuring perceived contrast in different surround conditions also allowed us to investigate how this suppression depends on the similarity of target and surrounding stimuli. RESULTS: Surround suppression was weaker among schizophrenia patients regardless of surround configuration. Subjects with bipolar affective disorder showed an intermediate deficit, with stronger suppression than in schizophrenia but weaker than control subjects. Surround suppression was normal in relatives of both patient groups. Findings support a deficit in broadly tuned (rather than sharply orientation- or direction-selective) suppression mechanisms. CONCLUSIONS: Weak broadly tuned suppression during visual perception is evident in schizophrenia and bipolar affective disorder, consistent with impaired gain control related to the clinical expression of these conditions.

Cognitive deficits in recent-onset and chronic schizophrenia.

Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.

Using biological indices to classify schizophrenia and other psychotic patients.

Although classification of mental disorders using more than clinical description would be desirable, there is scant evidence that available laboratory tests (i.e. biological indices) would provide more valid classifications than current diagnostic systems (e.g. DSM-IV). We used cluster analysis of four biological variables to classify 163 psychotic patients and 83 nonpsychiatric comparison subjects. Analyses revealed a three-cluster solution with the first cluster reflecting electrodermal deviance, the second cluster representing nondeviant biological function, and the third cluster reflecting increased nailfold plexus visibility and ocular motor dysfunction. To assess the construct validity of proband clusters we examined ocular motor performance in 156 first-degree relatives as a function of proband cluster membership. First-degree relatives of third cluster probands exhibited worse ocular motor performance than relatives of other cluster probands. Additionally, better classification sensitivity and specificity were obtained for the relatives when they were grouped by proband cluster than by proband DSM-IV diagnosis. When a single proband characteristic (i.e. eyetracking performance) was used to group relatives, classification sensitivity and specificity failed to significantly increase over grouping by proband DSM-IV diagnosis. Multivariate biologically defined clusters may offer an advantage over DSM-IV classification when examining nosology and etiology of psychotic disorders.

Clinical and biological concomitants of resting state EEG power abnormalities in schizophrenia.

BACKGROUND: This study investigated the clinical and biological concomitants of electroencephalogram power abnormalities in schizophrenia. METHODS: We examined the power characteristics of resting electroencephalograms in 112 schizophrenic patients. Also collected were measures of psychotic symptomatology, brain morphology, ocular motor functioning, electrodermal activity, and nailfold plexus visibility. Seventy-eight nonschizophrenic psychosis patients (e.g., mood disorder patients with psychosis) and 107 nonpsychiatric control subjects were included for comparison. RESULTS: Schizophrenic patients whose electroencephalograms were characterized by augmented low-frequency power and diminished alpha-band power had more negative symptoms, larger third ventricles, larger frontal horns of the lateral ventricles, increased cortical sulci widths, and greater ocular motor dysfunction compared with schizophrenic patients without these electroencephalogram characteristics. In nonschizophrenic psychosis patients, augmented low-frequency and diminished alpha-band powers failed to be associated with any clinical or biological indices. CONCLUSIONS: Results suggest that clinical and biological concomitants of low-frequency and alpha-band power abnormalities in schizophrenia are unique, perhaps indicating the presence of thalamic and frontal lobe dysfunction.

Season of birth and electroencephalogram power abnormalities in schizophrenia.

To determine the association between season of birth and electroencephalogram (EEG) power abnormalities in schizophrenia, this study examined the resting EEGs of 28 winter-born and 81 nonwinter-born schizophrenia patients. Eighteen winter-born and 58 nonwinter-born nonschizophrenic psychosis patients (e.g., bipolar disorder patients with psychotic features), and 97 normal subjects were also studied. Compared to normal subjects, nonwinter-born schizophrenia patients had augmented low-frequency power and diminished alpha band power, but winter-born schizophrenia patients failed to have any EEG power abnormalities. Nonwinter-born nonschizophrenic psychosis patients had the same low-frequency and alpha band power abnormalities as nonwinter-born schizophrenia patients. The winter-born non-schizophrenic psychosis group failed to show any EEG power abnormalities. The results of this study indicate that in psychosis the functional characteristics of the brain vary depending on the season in which a person is born. Low-frequency and alpha band EEG power abnormalities may help distinguish psychosis stemming from a seasonally varying pathogen from psychosis of other etiologies.

Internal consistency reliability of resting EEG power spectra in schizophrenic and normal subjects.

The reliability of resting electroencephalogram (EEG) power spectra was assessed for 49 normal and 44 schizophrenic subjects. We specifically examined internal consistency reliability to determine how much EEG data are necessary to ensure small measurement error. Twenty-one 8-s epochs of resting EEG were collected from each subject from site Cz. Epochs containing artifacts or blinks were eliminated. Power was computed in the bands delta (0.125-3 Hz), theta (3.125-8 Hz), alpha (8.125-13 Hz), beta1 (13.125-20 Hz) beta 2 (20.125-25 Hz) and beta 3 (25.125-30 Hz). Internal consistency was computed using coefficient alpha (Cronbach, 1951). Results for both groups indicated that eight artifact-free epochs of data were sufficient to give a coefficient alpha value of around .9. The schizophrenic and normal groups did not differ with respect to coefficient alpha. The proportion of artifacts in the data from the schizophrenics indicated that to obtain eight artifact-free epochs from members of each group, 40% more data would be required from the schizophrenics.

Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives.

We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar patients and 35 of their relatives, and 113 nonpsychiatric subjects and 42 of their relatives. The frequency characteristics of the EEG showed moderate stability for a subgroup of these subjects (n = 106) who were tested twice, approximately 9 months apart. Both the schizophrenia and bipolar patients showed a generalized pattern of increased delta and theta and decreased alpha activity. The bipolar patients demonstrated additional right hemisphere activity that was not present among the schizophrenia patients and nonpsychiatric subjects, a finding consistent with hypotheses concerning nondominant hemisphere involvement in the regulation of elated mood. The schizophrenia patients' female relatives and/or relatives with affective disorders and the bipolar patients had significantly reduced peak alpha frequencies. This finding may be related to reduced information processing capacity among these subjects.

Resting EEG in first-episode and chronic schizophrenia.

We examined the frequency characteristics of the electroencephalogram (EEG) in 102 schizophrenic patients (44 first-episode and 58 chronic patients) and 102 normal comparison subjects. EEGs of schizophrenic patients had more delta (1-3 Hz) and theta (3.125-8 Hz) activity and less alpha (8.125-13 Hz) activity than normal comparison subjects. There were no significant differences in the EEG frequency composition of first-episode and chronic patients. Because first-episode and chronic patients were characterized by different disorder durations and treatment histories, the similarity of their EEGs suggests that EEG abnormalities are stable characteristics of schizophrenia and are not treatment-related epiphenomena. A principal components analysis of EEG power bands identified an augmented low frequency-diminished alpha component and a beta component. Schizophrenic patients had significantly higher scores on the augmented low frequency-diminished alpha component than did normal comparison subjects, and there was no significant group difference in scores on the beta component. The findings of this investigation suggest that EEG abnormalities in schizophrenia reflect aspects of brain dysfunction.

Stability of ventricular size after the onset of psychosis in schizophrenia.

This study examined whether ventricular enlargement in schizophrenia is progressive by scanning 15 schizophrenic patients at the onset of their first psychotic episodes and again 1-3 years later. Sizes of the body of the lateral ventricles, the frontal horns, and the third ventricle were assessed. The results indicated no tendency for the ventricles to get larger in this sample, with lateral ventricular size actually showing a significant decrease across the rescanning interval when the ventricle-to-brain ratio was used as the dependent variable. Methodological issues related to computed tomography and the quantification of ventricular size were considered by developing an alternative method of calculating ventricle-to-brain ratios and examining the reliability of measurements made on a group of 11 medical patients who were scanned twice on the same day.