Schizophrenia: the systematic construction of genetic models.

Methods are described for the systematic construction of genetic models of schizophrenia with one, two, and four loci. All models are constrained to fit the following three parameters: (1) frequency of schizophrenia in the general population = 0.9%; (2) frequency of schizophrenia in the sibs of schizophrenics = 8%; and (3) frequency of "schizophrenic spectrum" in the sibs of schizophrenics = 15%. In addition, a fourth parameter, the frequency of the allele predisposing to schizophrenia, is freely variable. The problems of correcting for ascertainment bias, and of comparing and testing these genetic models, are discussed.     

3H]muscimol binding sites increased in autopsied brains of chronic schizophrenics

[3H]muscimol binding and glutamic acid decarboxylase (GAD) activity in the prefrontal cortex and caudate nucleus of autopsied brains from 19 chronic schizophrenics and 17 control subjects were investigated. In the schizophrenics, saturation analysis with varying concentrations of [3H]muscimol revealed an increase in the number of GABAA receptors, but there was no significant difference in the affinity. In addition, the enhancement of [3H]muscimol binding by diazepam was significantly greater in schizophrenics than in controls. GAD activity did not differ between controls and schizophrenics. The possibility that GABAergic mechanisms might play a role in case of chronic schizophrenia should be given further attention.     

Spectral power and cortical interactions in the beta2 rhythm in normal subjects and schizophrenic patients

Spectral and coherence characteristics of the beta 2 rhythm (20-40 Hz) were compared in patients with acute schizophrenia (the first episode), patients with chronic schizophrenia (disease duration more than two years), and healthy subjects (control group) during cognitive task performance. Examination showed the "excessive" spectral power of this rhythm in the prefrontal cortical areas in patients with acute schizophrenia and its "insufficient" spectral power in all derivations of the right hemisphere in patients with the chronic form as compared to the controls. The similarity of the beta 2 spectral power distribution in different cortical areas measured by covariance method decreased with increase in psychopathologic manifestations. Coherent analysis revealed a substantially lower number of cortico-cortical functional connections in schizophrenic patients than in healthy subjects, absence of interhemispheric connections in patients with acute schizophrenia, and a slight increase in their number if patients with the chronic disease. However, as distinct from the controls revealing many inter- and intrahemispheric connections in all cortical areas, in schizophrenics the interhemispheric connections were observed only in the posterior cortical regions. The results point to a disorder of interhemispheric interaction in schizophrenia.     

Effects of VRK2 (rs2312147) on White Matter Connectivity in Patients with Schizophrenia

Recent genome-wide association studies of schizophrenia reported a novel risk variant, rs2312147 at vaccinia-related kinase 2 gene (VRK2), in multiple Asian and European samples. However, its effect on the brain structure in schizophrenia is little known. We analyzed the brain structure of 36 schizophrenia patients and 18 healthy subjects with regard to rs2312147 genotype groups. Brain magnetic resonance scans for gray matter (GM) and white matter (WM) analysis, and genotype analysis for VRK2 rs2312147, were conducted. The Positive and Negative Syndrome Scale and the Digit Symbol Test were assessed for schizophrenia patients. There was no significant difference in either GM volume or WM connectivity with regard to rs2312147 genotype in healthy subjects. In contrast, we found significant differences in the WM connectivity between rs2312147 CC and CT/TT genotype groups of schizophrenia patients. The related brain areas included the splenium of corpus callosum, the left occipital lobe WM, the internal capsule (left anterior limb and right retrolenticular part), the bilateral temporal lobe WM, the left fornix/stria terminalis, the left cingulate gyrus WM, and the left parietal lobe WM. Voxelwise correlation analysis revealed that the Digit Symbol Test scores (age corrected) correlated with the fractional anisotropy in WM tracts that previously showed significant group differences between the CT/TT and CC genotypes in the rs2312147 CT/TT genotype group, while no significant correlation was found in the CC genotype group. Our data may provide evidence for the effect of VRK2 on WM connectivity in patients with schizophrenia.     

P300 topographic asymmetries are present in unmedicated schizophrenics

Our laboratory has repeatedly found a left < right auditory P300 temporal lobe topographic asymmetry in right-handed, medicated schizophrenics. To determine whether this asymmetry was attributable to the effects of antipsychotic medications, we collected auditory “odd-ball” P300 event-related potentials from 14 right-handed, unmediated schizophrenics (withdrawn from medication for an average of 21 days) and 14 right-handed, normal controls. Analysis of normalized P300 amplitudes showed a statistically significant difference in the voltage distributions between groups (a group by temporal electrode site interaction) that was consistent with a left < right temporal voltage asymmetry in schizophrenics but not in the normal controls. We conclude that P300 topographic asymmetries are present in unmedicated schizophrenics. These data are compatible with the growing body of data suggsting left temporal lobe structural abnormalities in schizophrenia.     

Hemispheric Asymmetry in Prosody Perception by Healthy Subjects and Schizophrenic Patients

The interhemispheric interactions in perception of Russian prosody were studied in the norm and in schizophrenia as a clinical model of impaired hemispheric interactions. Monaural presentation of stimuli and binaural presentation in a free acoustical field were used. Sentences with main variants of Russian prosodic intonations were used as stimuli. The response time and the number of erroneous responses were recorded. In binaural listening without headphones, no significant difference in the percent of errors in identifying the emotional prosody was found between healthy subjects and schizophrenics. Compared with the healthy subjects, the patients made more errors in understanding the logical stress and fewer errors in understanding the syntagmatic segmentation. By response time, a significant dominance of the left ear was revealed in the healthy subjects during monaural listening to sentences with emotional prosody and complete or incomplete sentences, whereas no significant ear dominance was found in the schizophrenics. During monaural listening to sentences with logical stress, the response time was shorter when stimuli were presented to the right ear both in the healthy subjects and in the schizophrenics. The results testified that the functional brain asymmetry in schizophrenics is flattened. The flattening was less evident in the perception of a logical stress in a sentence and did not significantly affect the efficiency of identification of emotional prosody and syntagmatic segmentation of a sentence.     

Structural Alterations of the Social Brain: A Comparison between Schizophrenia and Autism

Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.     

Self-regulation of amygdala activation using real-time FMRI neurofeedback

Real-time functional magnetic resonance imaging (rtfMRI) with neurofeedback allows investigation of human brain neuroplastic changes that arise as subjects learn to modulate neurophysiological function using real-time feedback regarding their own hemodynamic responses to stimuli. We investigated the feasibility of training healthy humans to self-regulate the hemodynamic activity of the amygdala, which plays major roles in emotional processing. Participants in the experimental group were provided with ongoing information about the blood oxygen level dependent (BOLD) activity in the left amygdala (LA) and were instructed to raise the BOLD rtfMRI signal by contemplating positive autobiographical memories. A control group was assigned the same task but was instead provided with sham feedback from the left horizontal segment of the intraparietal sulcus (HIPS) region. In the LA, we found a significant BOLD signal increase due to rtfMRI neurofeedback training in the experimental group versus the control group. This effect persisted during the Transfer run without neurofeedback. For the individual subjects in the experimental group the training effect on the LA BOLD activity correlated inversely with scores on the Difficulty Identifying Feelings subscale of the Toronto Alexithymia Scale. The whole brain data analysis revealed significant differences for Happy Memories versus Rest condition between the experimental and control groups. Functional connectivity analysis of the amygdala network revealed significant widespread correlations in a fronto-temporo-limbic network. Additionally, we identified six regions--right medial frontal polar cortex, bilateral dorsomedial prefrontal cortex, left anterior cingulate cortex, and bilateral superior frontal gyrus--where the functional connectivity with the LA increased significantly across the rtfMRI neurofeedback runs and the Transfer run. The findings demonstrate that healthy subjects can learn to regulate their amygdala activation using rtfMRI neurofeedback, suggesting possible applications of rtfMRI neurofeedback training in the treatment of patients with neuropsychiatric disorders.     

Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders

BACKGROUND: Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. METHOD/PRINCIPAL FINDINGS: 53 healthy individuals between 18-59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3' untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. CONCLUSIONS: Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD.     

Studies of trans-3-methyl-2-hexenoic acid in normal and schizophrenic humans

The report that sweat of certain schizophrenics contains the branched chain fatty acid, trans-3-methyl-2-hexenoic acid (TMHA), stimulated an investigation to evaluate the relationship between this fatty acid and schizophrenia. A sensitive and specific gas-liquid chromatography-mass spectroscopic procedure was developed for analyzing biological fluids for TMHA. Analysis of sweat samples from normal and schizophrenic subjects indicated that the sweat of both groups contains comparable quantities of this fatty acid. In addition, the fate of intravenously administered (14)C-labeled TMHA was shown to be similar in normal and schizophrenic subjects. It is concluded that there is no relationship between TMHA and schizophrenia.     

Dermatoglyphic analysis in borderline personality disorder and schizophrenia--results of a Croatian study

Dermatoglyphic features of 52 male patients with borderline personality disorder (BPD) were compared with those of 200 male controls (control group-CG) and 195 males with schizophrenia (SCH). Quantitative analysis showed statistically significant differences between BPD-CG and between BPD-SCH, mainly regarding the palmar traits, but also the 5th, the 4th and the 1st finger of the right hand as well as the 5th and the 4th finger of the left hand between BPD and SCH patients. The canonical discriminant analysis permitted correct classification with 69.84% probability between the BPD and CG and with 76.11% probability between the BPD and the SCH group. Qualitative finger and palmar traits analysis showed differences between the BPD and SCH groups on the 3rd finger of the left hand, total frequency for all fingers and in the III interdigital space. Significant differences between the BPD and CG were found on the 3rd finger of the left hand. Our results show that the dermatoglyphic features of BPD differ from those of schizophrenia and from those of control subjects. The possible significance of these findings is discussed.     

White matter correlates of neuropsychological dysfunction in systemic lupus erythematosus

Patients diagnosed with Systemic Lupus Erythematosus have similar levels of neuropsychological dysfunction (i.e., 20–50%) as those with Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). We hypothesized a gradient between cognition and white matter integrity, such that strongest brain-behavior relationships would emerge in NPSLE, intermediate in non-NPSLE, and minimal in controls. We studied thirty-one patients (16 non-NPSLE; 15 NPSLE), ranging in age from 18 to 59 years old (100% female), and eighteen age and gender matched healthy controls. DTI examinations were performed on a 1.5T scanner. A broad neuropsychological battery was administered, tapping attention, memory, processing speed, and executive functioning. The Total z-score consisted of the combined sum of all neuropsychological measures. In control subjects, we found no significant FA-Total z-score correlations. NPSLE, non-NPSLE, and control subjects differed significantly in terms of Total z-score (NPSLE = −2.25+/−1.77, non-NPSLE = −1.22+/−1.03, Controls = −0.10+/−.57; F = 13.2, p<.001). In non-NPSLE subjects, FA within the right external capsule was significantly correlated with Total z-score. In NPSLE subjects, the largest FA-Total z-score clusters were observed within the left anterior thalamic radiation and right superior longitudinal fasciculus. In subsequent analyses the largest number of significant voxels linked FA with the Processing Speed z-score in NPSLE. The current results reflect objective white matter correlates of neuropsychological dysfunction in both NPSLE and (to a lesser degree) in non-NPSLE. non-NPSLE and NPSLE subjects did not differ significantly in terms of depression, as measured by the GDI; thus, previous hypotheses suggesting moderating effects of depression upon neuropsychological performance do not impact the current FA results.     

Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH<Subscript>4</Subscript> Deficit in Schizophrenia and Schizoaffective Disorder

Tetrahydrobiopterin (BH₄) is an essential cofactor for amine neurotransmitter synthesis. BH₄ also stimulates and modulates the glutamatergic system, and regulates the synthesis of nitric oxide by nitric oxide synthases. A connection between BH₄ deficiencies and psychiatric disorders has been previously reported; major depression and obsessive-compulsive disorder have been found in subjects with a BH₄ deficiency disorder and more recently we have observed a robust plasma deficit of biopterin (a measure of BH₄), in a large group of schizophrenic patients compared to control subjects. To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders. A significant difference in biopterin was seen among the diagnostic groups (P < 0.0001). Post hoc analyses indicated significant biopterin deficits relative to the normal control group for the schizoaffective group, who had biopterin levels comparable to the schizophrenic group. Bipolar disorder subjects had plasma biopterin levels that were higher that the schizoaffective disorder group and significantly higher than the schizophrenic group. The demonstrated significant biopterin deficit in both schizophrenia and schizoaffective disorder, may suggest an etiological role of a BH₄ deficit in these two disorders, via dysregulation of neurotransmitter systems.     

Lifetime prevalence of mood and anxiety disorders in twin pairs discordant for schizophrenia.

There have been long questions about the relationship of schizophrenia to other mental disorders. Lifetime DSM-III-R diagnoses of mood and anxiety disorders in twins with clinically diagnosed schizophrenia (n = 24) and their non-affected co-twins (n = 24) were compared with twins from pairs without schizophrenia (n = 3327) using a sample from the Vietnam Era Twin Registry. Schizophrenic probands had significantly elevated rates of all included disorders (bipolar disorder, major depression, dysthymia, generalized anxiety disorder, panic disorder, and PTSD) compared with controls (P<0.01). The odd ratios comparing co-twins of schizophrenic probands with controls was greater than three for every disorder, but did not attain statistical significance. A similar pattern was observed when analyses were restricted to only monozygotic twins (n = 12). Consistent with other studies, schizophrenics appeared to have higher rates of a range of mental disorders. Our results suggest that schizophrenia per se represents a risk factor for other psychiatric disorders, but the absence of significantly elevated risk among non-schizophrenic co-twins suggested that family environmental and/or genetic factors that contribute to risk of schizophrenia do not increase the risk of mood and anxiety disorders to the same extent that the risk of these other disorders is increased by the presence of schizophrenia.     

γ-Glutamylglutamine and Taurine Concentrations Are Decreased in the Cerebrospinal Fluid of Drug-Naive Patients with Schizophrenic Disorders

Abstract: HPLC and gas chromatography-mass spectrometry analyses of 18 amino acids, N -acetylaspartate, N -acetylaspartyglutamate, and 5-hydroxyindoleacetic acid, derived from serotonin, and homovanillic acid, derived from dopamine, were performed in CSF collected from a group of patients with schizophrenia who either had been drug free for at least 1 year (n = 5) or were drug naive for psychotropic drugs (n = 21) and in 15 control subjects. Significant differences were found only for taurine (15% lower in the patients) and isoleucine (7% higher). A number of unidentified substances were detected, one of which proved to be markedly reduced (16%) among the schizophrenic patients. Liquid chromatography-mass spectrometry with continuous flow-fast atom bombardment interface allowed us to identify this substance as γ-glutamyglutamine. The decreased level of γ-glutamylglutamine may reflect a deficiency in the γ-glutamyltransferase system, a system probably involved in glutamate uptake, or a deficiency in glutamine, an important precursor of releasable glutamate. Although glutamate was nonsignificantly reduced in the patients, it was one of the five substances (including γ-glutamylglutamine) that were necessary for the best discrimination between the schizophrenic patients and the controls. These findings support the notion that the glutamatergic system is affected in schizophrenic disorders. In addition, they underscore the need to apply rigid bioanalytical techniques and use drug-naive patients to gain in-depth information on the pathophysiology of brain disorders such as schizophrenia.     

Polymorphism of the serotonin receptor (5-HTR2A) gene and verbal fluency in normalcy and schizophrenia

To study the effect of the serotonergic brain system on verbal fluency (i.e., the ability to rapidly extract necessary words from the vocabulary), the T102C polymorphism of the serotonin receptor type 2A (5-HTR2A) gene was tested for association with verbal fluency in 108 patients with schizophrenia or schizotypic disorders and 97 mentally healthy individuals. A significant association was observed only in male schizophrenics (N = 67), with homozygotes A2A2 having lower verbal fluency. The results did not support the association between the 5-HTR2A polymorphism and verbal fluency in normalcy, and agree with the assumed contribution of genotype A2A2 to the severity of schizophrenia.     

Fingerprint pattern frequencies in schizophrenics. Importance of ethnic origin and plexus visualization score ratings.

Our previous work with schizophrenics has suggested that the plexus visualization score (PVS), a characteristic derived from in vivo observation of skin capillaries, may be helpful in distinguishing between biologically different groups of patients. Preliminary fingerprint data demonstrated a significant difference in the frequency of whorls between high PVS and low PVS schizophrenics. A survey of fingerprints in control subjects revealed, however, that their ethnic background, even within the presumably 'mixed' Caucasian population of the USA, should also be taken into account. In the present study, the fingerprint pattern frequencies were, therefore, studied in 242 schizophrenics selected on the basis of both their ethnic origin and PVS ratings. Our results demonstrate a statistically significant difference in fingerprint pattern frequencies between high PVS and low PVS schizophrenics, even when they are matched for ethnic origin. The effect of the ethnic factor on fingerprint pattern frequencies in this patient sample is similar to the one previously reported for normal subjects.     

Dermatoglyphic analysis in bipolar affective disorder and schizophrenia--"continuum of psychosis" hypothesis corroborated?

Dermatoglyphic features are thought to be indicators of events in the early embryonal stages. They might also be associated with the developmental disorders of the central nervous system (CNS) including schizophrenia. Dermatoglyphic features of 92 male patients with bipolar affective disorder (BPAD) (unipolar depression and schizoaffective psychosis were excluded from the study) were compared with those of 195 males with schizophrenia (SCH) and both with those of 200 male controls (control group-CG). DSM-III-R criteria were used for the diagnostic evaluation. Quantitative analysis showed only one statistically significant difference between BPAD and SCH patients groups, regarding the c-d ridge count of the left hand. The canonical discriminant analysis did not permit correct classification (only 59.23% of cases were correctly classified) between BPAD and SCH. Numerous quantitative dermatoglyphic features of both BPAD and SCH differed significantly from those of the control subjects. Finger ridge counts as well as palmar ridge counts were markedly lower in BPAD and SCH as compared to the controls. These findings are not in contradiction with the hypothesis claiming that psychoses are a set of diverse expressions (due also to noninherited factors) of a single underlying entity.