Resistance training in patients with schizophrenia: Concept and proof of principle trial.

Resistance training has been shown to contribute to the prevention and management of cardiovascular diseases, which is why it can help reducing morbidity and mortality in schizophrenia patients. Moreover, positive effects on different schizophrenia symptom domains have been proposed. However, a specific resistance training tailored to the needs of schizophrenia patients and its evaluation is still lacking. The objective in this proof of principle trial was to evaluate the feasibility and efficacy of a newly developed 12-week resistance program according to current recommendations of the WHO and the American College of Sports Medicine. We employed a single blind, parallel assignment clinical trial design with participants randomized to attend either a resistance training including three 50min units per week or a balance and tone program as control condition. The primary outcome was the impact on health-related difficulties assessed with the World Health Organization Disability Assessment Schedule (WHO-DAS). Secondary outcome parameters included the level of functioning, schizophrenia symptoms, selected cognitive parameters as well as risk factors for cardiovascular diseases. In our proof of principle trial, we could not find significant time or group effects of resistance training on the WHO-DAS. However, we could observe significant positive effects on the level of functioning assessed with the Global Assessment of Functioning Scale (GAF) over the course of time, which were more pronounced in the intervention group. Our findings indicated that patients with schizophrenia could safely participate in resistance training with relevant improvements in their level of functioning. Well-powered replication trials are needed to provide more efficacy data.

Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia.

Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.

Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Influence of DGKH variants on amygdala volume in patients with bipolar affective disorder and schizophrenia.

The diacylglycerol kinase eta (DGKH) gene, first identified in a genome-wide association study, is one of the few replicated risk genes of bipolar affective disorder (BD). Following initial positive studies, it not only was found to be associated with BD but also implicated in the etiology of other psychiatric disorders featuring affective symptoms, rendering DGKH a cross-disorder risk gene. However, the (patho-)physiological role of the encoded enzyme is still elusive. In the present study, we investigated primarily the influence of a risk haplotype on amygdala volume in patients suffering from schizophrenia or BD as well as healthy controls and four single nucleotide polymorphisms conveying risk. There was a significant association of the DGKH risk haplotype with increased amygdala volume in BD, but not in schizophrenia or healthy controls. These findings add to the notion of a role of DGKH in the pathogenesis of BD.

Sex-dependent metabolic alterations of rat liver after 12-week exposition to haloperidol or clozapine.

Antipsychotic drugs are known to have sex-dependent effects on metabolic homeostasis. Liver plays a crucial role in drug degradation as well as in glucose and lipid metabolism. The present study examines the influence of clozapine and haloperidol on metabolic liver parameters. Over 12 weeks, male and female Sprague-Dawley rats were fed ground pellets containing clozapine or haloperidol. Liver mass was weighed and liver index calculated. Liver transaminases (ALAT, ALP), malondialdehyde, glucose, triglycerides, total cholesterol, HDL-cholesterol, and glycogen were determined. Finally, SREBP-1 and SREBP-2 as well as neutral fat deposits were examined. In male rats fed with clozapine, we found increased liver mass correlated with an increased liver index, high triglyceride levels, a high ratio of SREBP-1, and an elevated neutral fat distribution. Male and female haloperidol treated rats showed decreased liver mass and increased neutral fat deposition. Malondialdehyde was increased in all rats receiving antipsychotic medication indicating elevated oxidative stress. In both male and female clozapine treated rats, we found glycogen depletion related to decreased glucose levels in females. While liver transaminases were unchanged in the clozapine group, ALAT was elevated after haloperidol treatment in both sexes. Chronic clozapine intake exerts sex-dependent effects on hepatic metabolism. Although haloperidol has been shown to change fewer metabolic parameters, it causes oxidative stress and neutral fat deposits in liver tissue in both sexes.

Comorbid substance abuse in first-episode schizophrenia: effects on cognition and psychopathology in the EUFEST study.

UNLABELLED: Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients. METHOD: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N=119, consisting of N=88 patients with persisting SUD at baseline and N=31 patients with previous SUD) and without SUD (FE-non-SUD, N=204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding. RESULTS: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p=0.033, Cohen's d=0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p=0.008, Cohen's d=0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption. CONCLUSIONS: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment.

The sex-dependent impact of chronic clozapine and haloperidol treatment on characteristics of the metabolic syndrome in a rat model.

INTRODUCTION: An increased risk for metabolic syndrome has been described for patients with psychotic disorders. Antipsychotic drugs possibly contribute to metabolic changes. METHODS: Haloperidol or clozapine was orally fed to male and female Sprague Dawley rats for 12 weeks, and body weight gain, food and water intake were measured. The serum levels of fasting glucose, HbA1c, triglycerides, cholesterol, HDL and LDL, insulin, leptin, adiponectin and ghrelin were determined. Gonadal and perirenal fat pads were removed and weighed. RESULTS: We found increased body weight in the male clozapine group, but decreased ones in the male haloperidol group. Clozapine-treated male and female animals had higher fasting glucose, adiponectin, leptin, ghrelin, cholesterol, HDL and LDL levels, whereas haloperidol caused increased levels of insulin and decreased values of HbA1c, cholesterol, HDL and LDL. CONCLUSION: Both antipsychotic drugs cause sex-dependent metabolic changes, which are risk factors for the metabolic syndrome, be it hyperinsulinemia under haloperidol treatment or hyperglycemia, hyperleptinemia and hyperlipidemia under clozapine.

Thalamic volumes in patients with bipolar disorder.

There are several hypotheses on functional neuronal networks that modulate mood states and which might form the neuroanatomical basis of bipolar disorder. The thalamus has been reported to be a key structure within the circuits that modulate mood states and might thus play an important role within the aetiology of the bipolar affective disorder. Nevertheless, structural brain imaging studies on the thalamus volume of bipolar patients have shown heterogeneous results. Using structural MRI scanning, we compared the thalamus volume of 41 euthymic bipolar patients to the thalamus volume of 41 well-matched healthy controls. Taking the concomitant medication as a co-variable within the patient group, the analysis of variance revealed a significantly smaller relative volume of the right thalamus in patients not treated with lithium when compared with healthy controls. In contrast, there are no significant differences concerning the thalamus volume between all euthymic bipolar patients and healthy controls. The study only shows findings of a transverse section. No longitudinal analysis was performed. More detailed information on patients' pharmacological histories could not be obtained. In conclusion, this result may be interpreted as an indication of the impact of the thalamus in the pathogenesis of the bipolar I disorder and emphasises the need for further longitudinal studies in bipolar patients with special attention paid to the concomitant medication, in particular to the role of lithium.

Increased right amygdala volume in lithium-treated patients with bipolar I disorder.

OBJECTIVE: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. METHOD: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. RESULTS: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. CONCLUSION: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled, randomized multicenter study.

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

Motor circuit abnormalities in first-episode schizophrenia assessed with transcranial magnetic stimulation.

INTRODUCTION: Abnormalities in corticosubcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Previous studies assessing excitability of the motoneural system by measuring cortical silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) with transcranial magnetic stimulation (TMS) revealed conflicting results. METHODS: We assessed resting motor threshold (RMT), SICI (interstimulus interval 3 milliseconds), ICF (interstimulus interval 7 milliseconds) and the duration of the contralateral CSP in the left and right first dorsal interosseus muscles (FDI) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment compared to 44 healthy control subjects (HC). CSP was measured during isometric contraction using stimulation intensities of 120, 140, 160 and 180% of RMT. RESULTS: Patients with FE-SZ demonstrated significant prolongation of CSP using stimulation intensities of 120% RMT (p=0.027), 140% RMT (p=0.015) and 160% RMT (p =0.010) of left motor cortex (right FDI) compared to HC. In addition, reduced SICI after stimulation of the right motor cortex was observed in FE-SZ (58.9% in FE-SZ vs. 31.4% in HC; p=0.050). RMT was similar in patients and controls. DISCUSSION: The reduced SICI in first-episode patients points towards a GABA(A)ergic deficit in schizophrenia. The prolonged CSP may reflect compensatory increased GABA(B)ergic transmission induced by hyperactivity of the dopaminergic system, although effects of antipsychotic medication could not be excluded.

Reduced cortical inhibition in first-episode schizophrenia.

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.

[Schizophrenia as a brain disorder and its development]. / Die "Hirnstörung" Schizophrenie und ihre Entwicklung.

Schizophrenia is a psychiatric disease associated with functional und structural brain abnormalities. Beside global deficits, like a reduction of the whole brain volume and an enlargement of the ventricular system, there are circumscribed changes especially in the gray matter of the frontal lobe. Regarding possible causes for these changes some are related to the vulnerability of the disease, some to the manifestation of the disorder and some are very likely related to the course of the illness and the associated treatment options. It is hypothesised that the neurobiological changes of schizophrenia are different in each stage of the illness ranging from the prodromal state, over the first manifestation of the illness up to the relapsing course. It is assumed, that the hypofunction of the gabaergic system is essential to the vulnerability of the disorder, while a destabilisation of the glutamatergic system especially of the NMDA-receptor-system forms the next step to first break schizophrenia. When the illness develops into a relapsing course these mechanisms are destabilised, which inhibits the recovery from functional und structural changes. The outlined pathophysiological hypotheses are used to discuss possible causal pharmacological treatment options.

Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.

OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

Cerebrospinal fluid diagnostic markers correlate with lower plasma copper and ceruloplasmin in patients with Alzheimer's disease.

Increasing evidence links Alzheimer's disease (AD) with misbalanced Cu homeostasis. Recently, we have shown that dietary Cu supplementation in a transgenic mouse model for AD increases bioavailable brain Cu levels, restores Cu, Zn-super oxide-1 activity, prevents premature death, and lowers A beta levels. In the present report we investigated AD patients with normal levels of A beta 42, Tau and Phospho-Tau in the cerebrospinal fluid (CSF) in comparison with AD patients exhibiting aberrant levels in these CSF biomarkers. The influence of these cerebrospinal fluid (CSF) diagnostic markers with primary dependent variables blood Cu, Zn and ceruloplasmin (CB) and secondary with CSF profiles of Cu, Zn and neurotransmitters was determined. Multivariate tests revealed a significant effect of factor diagnostic group (no AD diagnosis in CSF or AD diagnosis in CSF) for variables plasma Cu and CB (F=4.80; df=2, 23; p=0.018). Subsequent univariate tests revealed significantly reduced plasma Cu (-12.7%; F=7.05; df=1, 25; p=0.014) and CB (-14.1%; F=9.44; df=1, 24; p=0.005) levels in patients with aberrant CSF biomarker concentrations. Although only AD patients were included, the reduced plasma Cu and CB levels in patients with a CSF diagnosis of advanced AD supports previous observations that a mild Cu deficiency might contribute to AD progression.

Etiopathogenetic mechanisms in long-term course of schizophrenia.

Schizophrenia is a severe mental disorder with a relapsing long-term course in 80 % of the sufferers. The underlying neurobiological principles of the long-term course are widely unknown. Therefore an attempt is made to evaluate data from structural imaging and neuropsychology to shed some light on these mechanisms. Interestingly there was a significant correlation between length of illness and volume reduction in the prefrontal grey matter in schizophrenia. There was a lack of such a correlation for the whole brain volume, white matter volume or the grey matter volume outside the prefrontal lobe. Furthermore none of the neuropsychological measures correlated with length of illness. Both findings are supported by data from prospective studies up to five years demonstrating a significant loss of frontal grey matter volume, but no change of cognitive dysfunction in the course of time. The attempt is made to connect prefrontal grey matter loss with post-mortem findings of reduced neuropil but preserved cytoarchitecture leading to recently described candidate genes and their function.

Regio entorhinalis in schizophrenia: more evidence for migrational disturbances and suggestions for a new biological hypothesis.

Recently we were able to replicate the original finding of migrational disturbances in the entorhinal cortex (ERC) of schizophrenic patients by measuring the distance of pre-alpha cell clusters to the pial surface. In order to replicate this finding, we performed a detailed analysis of the pre-alpha cell clusters in the ERC in post mortem brains of 22 schizophrenic patients and 15 control subjects. Cluster position relative to gray/white matter boundary were measured and normalized by the widths of the gray matter. In the ERC the pre-alpha cell clusters were situated significantly closer to the gray/white matter junction compared to normal controls (around 30 %, F = 9.52, p = 0.004). No specific effects of sex, age or region of investigation were found. In summary, this is another quantitative replication of pre-alpha cell cluster migrational disturbances in schizophrenia, which are possibly linked to neurobiological abnormalities, e.g. myeloarchitectonic changes. This supports the notion that developmental abnormalities are a core feature of schizophrenia and that the search for candidate genes has to include this aspect, too. However, it is very probable that vulnerability-associated changes - as outlined here - have to be distinguished from disease-related changes.

Right frontal hypergyria differentiation in affected and unaffected siblings from families multiply affected with schizophrenia: a morphometric mri study.

OBJECTIVE: The authors used magnetic resonance imaging to corroborate the postmortem finding of right frontal hypergyria associated with schizophrenia. METHOD: Twelve affected-unaffected sibling pairs from families multiply affected with schizophrenia were studied. Bilateral measurement of the gyrification index, the ratio of the inner and outer surface contours, was performed on three different slices of the prefrontal region. RESULTS: The mean gyrification index on the right side was significantly higher in siblings with schizophrenia or schizoaffective disorder than in the unaffected siblings. CONCLUSIONS: In this family cohort study, the postmortem finding of right-sided hypergyria in subjects with schizophrenia was replicated in vivo with magnetic resonance imaging. This observation provides further support for a neurodevelopmental mechanism in the pathogenesis of schizophrenia.

Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality.

BACKGROUND: Previous studies using semiquantitative or qualitative techniques demonstrated abnormalities of positioning of clusters of neurons (pre-alpha cells) in the entorhinal cortex in schizophrenia, suggesting a developmental mechanism could contribute to the illness. Recent quantitative studies of laminar thickness and laminar cell counts have been less consistent, and several failed to replicate the finding. However, none of the quantitative studies focused on the position of the pre-alpha cell clusters. METHODS: To study pre-alpha cell position in detail, we examined the entorhinal cortex in serial sections from 21 control and 19 schizophrenic brains. Cluster position relative to the gray-white matter junction and cluster size were measured. RESULTS: Quantitative assessment of 1991 clusters indicated clusters were positioned relatively closer to the gray-white matter junction in the anterior half of schizophrenic entorhinal cortices. In addition, the size of clusters in males with schizophrenia was reduced. CONCLUSIONS: These results support the model of schizophrenia as an illness in which brain development is impaired. The findings in males with schizophrenia may indicate the presence of more severe pathology, or an additional pathogenic mechanism.

Disturbed gyrification of the prefrontal region in male schizophrenic patients: A morphometric postmortem study.

OBJECTIVE: The goal was to test the hypothesis that abnormalities of gyrification are present in the prefrontal region of postmortem brains from schizophrenic patients. METHOD: The authors compared the prefrontal regions in brains from 24 schizophrenic patients and 24 normal comparison subjects. The gyrification index, the ratio of inner and outer surface contours, was measured bilaterally in three different slices from each brain. Area measurements of gray and white matter were studied separately by planimetric analysis in the same sections. In addition, a gray-to-white-matter ratio and an asymmetry coefficient were computed. RESULTS: The mean gyrification index on the right side was significantly higher in the male schizophrenic patients than in the comparison men. The gyrification index of the female patients was not significantly different from that of the female comparison subjects. Analysis of area measurements revealed no significant differences. CONCLUSIONS: As gyrification is an ontogenetic stable feature unaffected by atrophic processes during aging, the gyrification abnormalities of the prefrontal region provide further evidence of the importance of a neurodevelopmental mechanism in the etiology of schizophrenia, at least in males.