Cortex Of Schizophrenic Patients Research Articles

Same Sexual Orientation as a Potential Risk Factor for Severe Mental Illness

Considered as a minority, the LGBTQ (Lesbian, Gay, Bisexual, Transgender, and Queer) community including homosexual males is more prone to mental distress. Studies on prevalence stated that sexual orientation minorities are susceptible to inept mental health outcomes, and the rate of anxiety disorders, schizophrenia, and psychotic illness is twice higher in gay and bisexual men rather than in heterosexuals. Along with that, several investigations found similarity between structural features in the brain of schizophrenic patients and homosexual males. This study intends to analyze the male homosexuality as a potential risk factor for schizophrenia. According to MRI (magnetic resonance imaging) findings, brain structures similarity is found between schizophrenic patients and homosexual men specifically on the thalamic grey matter volume and cortical thickness of the brain. Both schizophrenic patients and homosexual males exhibit reduced grey matter volume in the thalamus region, meanwhile schizophrenic patients have lower grey matter volume in the left putamen and homosexual males showed higher left putamen grey matter volume compared to heterosexual individuals. The cortex of schizophrenic patients is thinner in left orbitofrontal, right parahippocampal, and superior temporal area, resembling to thinner cortex in the right lateral orbitofrontal regions and regions in the visual cortex of homosexual males. Based on the reviewed journals, male homosexuality can be a potential risk factor for schizophrenia considering their correlation in neurodevelopmental deviations. Nevertheless, further investigations are needed regarding other factors and pathways causing such structural brain changes in both conditions. Keywords: grey matter, homosexual, neurodevelopmental, schizophrenia

The effect of neurostimulation on the intracellular concentrations of proton-containing metabolites and macroergic phosphates in the brain cortex upon schizophrenia according to the data from 1H and 31P magnetic resonance spectroscopy

The effect of neuroactivation on the concentrations of direct (phosphocreatine, PCr; adenosine triphosphate, ATP) and indirect (N-acetylaspartate, NAA) participants of energy metabolism and the intracellular pH values in the activated brain loci in health and upon early-stage schizophrenia is considered. Single-voxel 1H and 2D 31P magnetic resonance spectroscopy methods were used. The neuroactivation areas were localized according to the data from functional magnetic resonance imaging (fMRI). The NAA level after a short stimulus in the premotor cortex in schizophrenic patients remained unchanged, while the health group showed a reversible decrease in this parameter even 12 s after stimulus presentation. The long video stimulation has no effect on the contents of PCr and ATP in the visual cortex upon schizophrenia, while the analogous action on the health brain causes a decrease in the PCr level with the ATP level being constant. In the absence of neurostimulation, all measured indices were identical in both schizophrenic patients and control group.

EPA-0692 – Mice lacking the circadian modulators sharp1 and sharp2 display altered sleep and mixed state endophenotypes of psychiatric disorders

Introduction Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. Methods In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays, global gene expression profiling and bioinformatic modeling. Gene expression in human brains samples was performed with qRT-PCR. Results EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1 , which are also significantly downregulated in the frontal cortex of schizophrenic patients. Conclusions Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2

The effect of DISC1 on regional gray matter density of schizophrenia in Han Chinese population

Schizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia.

Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia

Objectives. Abnormalities of brain white matter and oligodendroglia are replicated findings in schizophrenia research. The largely oligodendroglia-associated enzyme ADAM (A disintegrin and metalloprotease) 12 might be involved in the patho-physiology of schizophrenia, because the gene coding for human ADAM12 is located on chromosome 10q26.3, a gene locus which has been linked to schizophrenia, and some of its putative substrates are altered in schizophrenia. Methods. We studied the numerical density of ADAM12 expressing oligodendrocytes in post-mortem prefrontal brains of patients with haloperidol treated, chronic schizophrenia and matched controls. Results. A significantly reduced numerical density of ADAM12 immunoreactive oligodendrocytes was found in the white matter of the anterior cingulate cortex of schizophrenic patients. Conclusions. Although the pathophysiological implications of this finding are currently unknown, it is well conveyable that reduced ADAM12 protein contributes to a deviant metabolism of some of its substrates. These substrates are either parts of important signalling cascades (EGF, betacellulin, TGF-beta) or chemical components of myelin (neurofascin-ankyrin) known to be compromised in schizophrenia.

Learning potential on the WCST in schizophrenia is related to the neuronal integrity of the anterior cingulate cortex as measured by proton magnetic resonance spectroscopy

Background In recent years, schizophrenia has increasingly been recognized as a neurocognitive disorder, which has led to a growing literature on cognitive rehabilitation, and suggested several potential enhancements to cognitive function. For instance, it has been shown that executive functioning deficits as measured by the Wisconsin Card Sorting Test (WCST) can be modified in a subgroup of schizophrenic patients. The neurobiological basis of cognitive remediation has not been elucidated so far, although structural, functional and metabolic abnormalities of the prefrontal cortex have been associated with cognitive impairment. Methods In this study, learning potential was investigated in 43 schizophrenic patients and 37 age- and education-matched healthy controls, using a dynamic version of the WCST, which integrates instructions and feedback into the testing procedure. Performance was related to cerebral metabolism, assessed by single-voxel proton magnetic resonance spectroscopy of the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). Results N-acetylaspartate (NAA), a marker of neuronal integrity, was significantly reduced in the DLPFC of schizophrenic patients as compared to the healthy control group. The level of NAA in the DLPFC positively correlated with performance in the dynamic WCST in healthy subjects, whereas in schizophrenic patients a significant correlation was observed between NAA and glutamate/glutamine in the ACC and learning potential. Conclusion These data imply a relationship between neuronal plasticity as assessed by learning potential and NAA levels of the prefrontal cortex in schizophrenic patients and healthy subjects, and suggest the involvement of differential neuronal networks in learning for schizophrenic patients compared to healthy controls.

The Auditory Cortex in Schizophrenia

The Auditory Cortex in Schizophrenia

Evidence from increased anticipation of predictive saccades for a dysfunction of fronto-striatal circuits in obsessive–compulsive disorder

In obsessive–compulsive disorder (OCD), a dysfunction of neuronal circuits involving prefrontal areas and the basal ganglia is discussed that implies specific oculomotor deficits. Performance during reflexive and predictive saccades, antisaccades and predictive smooth pursuit was compared between patients with OCD ( n = 22), patients with schizophrenia ( n = 21) and healthy subjects ( n = 24). Eye movements were recorded by infrared reflection oculography. In both patient groups, higher frequencies of anticipatory saccades with reduced amplitudes in the predictive saccade task were observed. Additionally, reduced smooth pursuit eye velocity and increased frequencies of saccadic intrusions during smooth pursuit as well as increased error rates in the antisaccade task were demonstrated for patients suffering from schizophrenia. Patients with OCD and schizophrenia revealed different patterns of oculomotor impairment: whereas increased anticipation of predictive saccades provides evidence for a dysfunction of the circuit between the frontal eye field and the basal ganglia in both groups, results from the antisaccade task imply additional deficits involving the dorsolateral prefrontal cortex in schizophrenic patients. Furthermore, the cortical network for smooth pursuit (especially the frontal eye field) is also assumed to be disturbed in schizophrenia.

Increased water diffusivity in the frontal and temporal cortices of schizophrenic patients

Schizophrenia has been suggested to be the result of both macroscopic and microscopic abnormalities in the brain. Although no definitive clinico-pathological correlations have been found to reconcile the many facets inherent in this disorder, the recent development of the magnetic resonance diffusion tensor imaging (DTI) has allowed us to gather useful information regarding the microcircuitry of the brain. Specifically, the apparent diffusion coefficient (ADC) reflects the degree of diffusion barriers and heterosynaptic communication for the brain neurotransmitter. Nineteen patients with DSM-IV schizophrenia and 21 age- and sex-matched control subjects participated in DTI, and the severity of the patients' symptoms was evaluated according to the Positive and Negative Syndrome Scale (PANSS). The ADC values were determined and compared between patients and control subjects via voxel-based morphometry. The results show an increased ADC in the bilateral fronto-temporal regions of the schizophrenic patients, as compared with those of the control subjects. In addition, the ADC values in the area of the right insular were correlated with the negative syndromes from the PANSS. Our findings of increased water diffusivity in the fronto-temporal regions of schizophrenic patients and the correlation between negative symptom scales and the ADC in the right insular region indicate that damaged brain microcircuitry might contribute to the pathophysiology of schizophrenia. These findings contribute towards integrating micro and macrostructural abnormalities and syndromes of schizophrenia.

The importance of interneurons in schizophrenic and affective disorders

In brains of patients with schizophrenic and affective disorders pathomorphological changes have been shown focussing in frontal and temporal cortex. The volume reduction in prefrontal cortex of schizophrenic patients is hypothesized to be based on a reduction of neuropil. A decrease of synaptic proteins and a decrease of dendritic spines of pyramidal cells can additionally be the origin of disconnections of neurons. Affection of the glutamatergic, GABA-ergic and dopaminergic system and reduction of interneurons could be the correlate of a deficient neuronal network which might be combined with exogen factors generate psychotic symptoms. Reelin and associated proteins are candidate molecules. Their dysregulation might explain essential features of the dysfunctional network of schizophrenia.

Lack of effect of mood stabilizers or neuroleptics on GSK-3 protein levels and GSK-3 activity.

Glycogen synthase kinase (GSK)-3 protein levels and GSK-3 activity were previously found to be over 40% reduced in the post-mortem prefrontal cortex of schizophrenic patients. Lithium and valproate have been reported to selectively inhibit GSK-3. We hypothesized that in-vivo administration of lithium and valproate would result in up-regulation of GSK-3 protein levels and GSK-3 activity. The present study aimed to evaluate the possible involvement of neuroleptic treatment in the decrease of GSK-3 in schizophrenia. Rat frontal cortex GSK-3 protein levels and GSK-3 activity were measured following administration of therapeutic doses of lithium or valproate for 11 d, or of haloperidol, chlorpromazine or clozapine for 21 d. None of the drugs induced a change in GSK-3 protein levels. All the drugs except chlorpromazine (which was not tested) did not affect GSK-3 activity. This suggests that GSK-3 inhibition by lithium or valproate does not induce regulation of protein levels or activity and that the reduction in GSK-3 protein levels and GSK-3 activity in the post-mortem prefrontal cortex of schizophrenic patients is not neuroleptic-treatment related.

Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.

Modelling the influence of thalamo-cortical projections on prefrontal activity

Altered connections between the thalamus and the prefrontal cortex are often implicated in theories concerning the pathogenesis of schizophrenia. Using a model based on anatomically realistic connection patterns between thalamus and prefrontal cortex, we analyzed changes of prefrontal activity resulting from stimulation of the mediodorsal thalamus. Here we demonstrate that the specific influence of thalamo-cortical projections is smaller than the importance of intra-prefrontal connectivity in shaping prefrontal activity patterns. These results might be helpful in explaining experimentally observed hypo- and hyperactive states of prefrontal cortex in schizophrenic patients.

Serotonin 5-HT 2 receptors in schizophrenic patients studied by positron emission tomography

Using positron emission tomography (PET) and [ 11C]N-methylspiperone (NMSP), we examined 5-HT 2 receptors in the cortex of schizophrenic patients in whom we previously observed decereased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [ 11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT 2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [ 11C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT 2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT 2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

401. One Hertz rTMS of left temporoparietal cortex in schizophrenic patients reporting auditory hallucinations

Studies suggest that auditory hallucinations (AHs) of spoken speech arise partly from brain regions responsible for speech processing. One Hz repetitive transcranial magnetic stimulation (rTMS) of ∼15 minutes duration has been shown to reduce cortical activation. We will present two studies testing the hypothesis that 1 Hz rTMS delivered to left temporoparietal cortex, a brain region critical for speech processing, reduces AHs. The first study used once daily rTMS at 80% motor threshold for 4–16 minutes duration built up over four days. Twelve schizophrenic patients with medication-resistant AHs were randomized to active versus sham stimulation and studied using a double-blind, cross-over design. Significant improvements in AHs were detected following 12 minutes (p < .02) and 16 minutes (p < .0001) of active rTMS but not following sham stimulation. Endpoint hallucination severity following the active stimulation trial was significantly less than hallucination severity following sham stimulation trial (p < .006). Duration of symptomatic improvement ranged from 1 day to 2 months. Results of a second, double-blind trial of rTMS utilizing seven instances of rTMS at 16 minutes duration will also be presented. Data from our first nine patients suggest that this more extended trial produces robust and sustained reductions in AHs in ∼70% of patients. Our findings emphasize the role of posterior, speech processing areas of the brain in the generation of AHs. One Hz rTMS deserves further study as a possible treatment for hallucinations and other psychotic symptoms.

148. Altered gene expression of dopaminergic markers in the midbrain of schizophrenic patients

Dopamine has long been implicated in the pathophysiology of schizophrenia. Recent postmortem studies demonstrate a reduction in the density of axons immunoreactive for the dopamine transporter (DAT) or tyrosine hydroxylase (TH) in the prefrontal and entorhinal cortices of schizophrenic patients (Akil et al 1999, Akil et al in press). We hypothesized that these changes reflect alterations in the gene expression of DAT and TH in mesencephalic DA neurons. We used in situ hybridization to compare the levels of DAT and TH mRNA in postmortem tissue specimens from the midbrains of schizophrenic subjects (n 5 12) and normal controls (n 5 12). The groups were matched in a pairwise fashion on the basis of age, race, sex, and postmortem interval. Cytoarchitectonic criteria and TH immunocytochemistry were used to identify 5 dopaminergic cell groups in each subject: the substantia nigra pars lateralis (SNPL), the dorsal and ventral tiers of the pars compacta (DTSN and VTSN respectively), the paranigral nucleus (PN) and the ventral tegmental area (VTA). Quantitative analyses revealed a marked decrease in DAT mRNA levels in a subset of schizophrenic subjects relative to matched controls. Overall group means of DAT mRNA levels were decreased in the schizophrenic group in all nuclei examined. However, this decrease reached statistical significance only in the SNPL (49%, p 5 0.04). Preliminary analysis of TH mRNA expression revealed a pattern of reduction in schizophrenic subjects similar to that found with DAT mRNA. These finding implicate mesencephalic dopaminergic neurons as potential sites of dysfunction in schizophrenia.

Erratum to ``MRI T 2 relaxation times of brain regions in schizophrenic patients and control subjects'' [Psychiatry Res. Neuroimaging 75 (1997) 173

The publisher regrets that an error occurred in the abstract of the above article. The abstract is reprinted below, with words that were inadvertently omitted indicated in bold-faced type. In this MRI investigation T 2 relaxation times were studied in schizophrenic patients compared to normal control subjects. Approximate T 2 relaxation times were calculated using signal intensity at two echo times in several brain regions of 25 male schizophrenic patients and 25 age-matched, normal male control subjects. The schizophrenic patients showed significantly longer T 2 relaxation times as compared to normal control subjects in the left anterior column of the fornix. This is a small structure, prone to partial volume effects and this may account for these findings. There was a trend towards longer T 2 times in the left frontal cortex and shorter T 2 times in right temporal cortex in schizophrenic patients as compared to control subjects. There were right/left differences in relaxation times within each group. In both patients and control subjects, frontal lobe white matter T 2 was longer on the right than on the left side. This finding is probably due to brain asymmetry and unrelated to the presence or absence of psychiatric illness. In schizophrenic patients only the left temporal cortex showed longer T 2 times than the right side. This observation could indicate left sided temporal lobe pathology in schizophrenia. © 1998 Elsevier Science Ireland Ltd.

Operant conditioning and the orbitofrontal cortex in schizophrenic patients: unexpected evidence for intact functioning

Neuroimaging and neuropsychological studies have consistently implicated dorsolateral prefrontal cortex as abnormal in schizophrenia. However, other areas of frontal cortex have received far less attention. In particular, few studies have examined orbital frontal regions with other than olfactory tests. In the present study we wished to assess the functional capability of orbital frontal cortex using a test developed by Bechara et al. (1994) that assesses a subject's capacity to acquire a preference through reward and punishment, using a gambling task that involved gains and losses of play money. Thirty normal subjects and 12 patients with schizophrenia (three undifferentiated, eight paranoid, one schizoaffective) comprised the sample in the present study. We found that patients with schizophrenia exhibited a pattern of findings similar to that of normals and dissimilar to that of patients with known orbital frontal damage. In our study, both normal subjects and schizophrenic patients chose most frequently from decks of cards in which there were frequent rewards and infrequent penalties, as might be expected on the basis of operant conditioning literature. We also found that performance on this task was not correlated with tests of working memory or long-term memory, suggesting that the development of a preference may occur implicitly. Our findings also argue against a general deficit in schizophrenia, as performance on the gambling task appeared relatively uncompromised.

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto-striatal connectivity in schizophrenia.

MRI T 2 relaxation times of brain regions in schizophrenic patients and control subjects

In this MRI investigation T 2 relaxation times were studied in schizophrenic patients compared to normal control subjects. Approximate T 2 relaxation times were calculated using signal intensity at two echo times in several brain regions of 25 male schizophrenic patients and 25 age-matched, normal male control subjects. The schizophrenic patients showed significantly longer T 2 relaxation times as compared to normal control subjects in the left anterior column of the fornix. This is a small structure, prone to partial volume effects and this may account for these findings. There was a trend towards longer T 2 times in the left frontal cortex and right temporal cortex in schizophrenic patients as compared to control subjects. There were right/left differences in relaxation times within each group. In both patients and control subjects, frontal lobe white matter T 2 was longer on the right than on the left side. This finding is probably due to brain asymmetry and unrelated to the presence or absence of psychiatric illness. In schizophrenic patients only the left temporal cortex showed longer T 2 times than the right side. This observation could indicate left sided temporal lobe pathology in schizophrenia.