Effects of menopause on brain structural changes in schizophrenia.

AIM: The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). METHODS: Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. RESULTS: Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. CONCLUSION: Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia.

GABAA/Benzodiazepine receptor binding in patients with schizophrenia using [11C]Ro15-4513, a radioligand with relatively high affinity for alpha5 subunit.

Dysfunction of the GABA system is considered to play a role in the pathology of schizophrenia. Individual subunits of GABA(A)/Benzodiazepine (BZ) receptor complex have been revealed to have different functional properties. alpha5 subunit was reported to be related to learning and memory. Changes of alpha5 subunit in schizophrenia were reported in postmortem studies, but the results were inconsistent. In this study, we examined GABA(A)/BZ receptor using [(11)C]Ro15-4513, which has relatively high affinity for alpha5 subunit, and its relation to clinical symptoms in patients with schizophrenia. [(11)C]Ro15-4513 bindings of 11 patients with schizophrenia (6 drug-naïve and 5 drug-free) were compared with those of 12 age-matched healthy control subjects using positron emission tomography. Symptoms were assessed using the Positive and Negative Syndrome Scale. [(11)C]Ro15-4513 binding was quantified by binding potential (BP) obtained by the reference tissue model. [(11)C]Ro15-4513 binding in the prefrontal cortex and hippocampus was negatively correlated with negative symptom scores in patients with schizophrenia, although there was no significant difference in BP between patients and controls. GABA(A)/BZ receptor including alpha5 subunit in the prefrontal cortex and hippocampus might be involved in the pathophysiology of negative symptoms of schizophrenia.

Language processing and human voice perception in schizophrenia: a functional magnetic resonance imaging study.

BACKGROUND: Neuroimaging studies have demonstrated either reduced left-lateralized activation or reversed language dominance in schizophrenia. These findings of left hemispheric dysfunction could be attributed to language processing tasks, which activate mainly left hemispheric function. Recent functional magnetic resonance imaging studies reported right-lateralized temporal activation by human voice perception, but few studies have investigated activation by human voice in schizophrenia. We aimed to clarify the cerebral function of language processing in schizophrenia patients by considering cerebral activation of human voice perception. METHODS: Fourteen right-handed schizophrenia patients and 14 right-handed controls with matched handedness, sex, and education level were scanned by functional magnetic resonance imaging while listening to sentences (SEN), reverse sentences (rSEN), and identifiable non-vocal sounds (SND). RESULTS: Under the SEN-SND and SEN-rSEN contrasts including language processing, patients showed less activation of the left hemisphere than controls in the language-related fronto-tempo-parietal region, hippocampus, thalamus and cingulate gyrus. Under the rSEN-SND contrast including human voice perception, patients showed less activation than controls in the right-lateralized temporal cortices and bilateral posterior cingulate. CONCLUSIONS: Our results indicate that schizophrenia patients have impairment of broader bilateral cortical-subcortical regions related to both the semantic network in the left hemisphere and the voice-specific network in the right hemisphere.

[Investigation of recent problems in an acute care psychiatric ward considering the number psychiatrists working in the ward].

In July 2001, psychiatric wards for acute treatments (PWAT) were investigated in Japan using a questionnaire to clarify current and recent problems in 79 PWAT. The questionnaires were sent to wards, patients and psychiatrists and were returned by 72.2% overall. The number of admissions per ward was calculated as 21 patients per one month, and comprised half of all admissions to the hospital. 50% were schizophrenia, 17% were affective disordes and 16% involved drug abuse. Seventeen patients were discharged from PWAT per one month, and comprised 43% of all patients discharged from the hospital. These results indicate that both 21 patients admitted and 17 patients discharged per month and needs to maintain the essential standard for PWAT and the standard should be come more flexible as admission from the other unit of ward than PWAT. As rate of re-admission within 3 months after discharge was around 10% of the total number of patients in the ward, 3 months was considered suitable length of acute treatment in the field of psychiatry in Japan. There was one psychiatrist working in PWAT, and specialized psychiatrists had 17.4 patients, the most number of patients among types of psychiatrist. Simulations of one psychiatrist to 16 and to 32 patients in PWAT were performed to determine how many psychiatrists were needed for a ward. When the ratio was 32 patients to 1 psychiatrist, it was necessary to increase the number of psychiatrists to a ward by 1, and in the case of 16 patients, 1-3 psychiatrists were needed. These indicate the standard number of psychiatrists for PWAT should be at most one psychiatrist for the ward or all of the psychiatrists working in PWAT should be allowed to work simultaneously in other wards. Preparing wards to treat acute phase psychiatric patients is a very important role of each psychiatric hospital, the standard for PWAT should include not only a high level of medical staff, but also preparing easy criteria for each hospital.

[The review of seclusion and restraint in psychiatric practice].

In order to create the least restrictive setting in psychiatric practice, we investigated the effects of an assessment by a committee on seclusion and restraint. Using consistent procedures, the committees, which were established in 9 hospitals, reviewed seclusion and restraint maintained for periods of over 2 weeks during a 4-month period. Frequency and duration of seclusion and restraint, staff perceptions of and attitudes to the review system, and patient satisfaction were evaluated before and after the study period. As a result of this review process, the frequency of seclusion decreased slightly in 7 hospitals and 1 of the remaining 2 hospitals showed an increased frequency of seclusion days that were partially interrupted. Frequency of restraint decreased slightly in 5 hospitals, and of the remaining 3, 1 interrupted all periods of restraint, while the other 2 institutions showed an increase in interruption of restraint periods. As there were no common patients in 2 specialist psychiatric emergency hospitals between before and after the study periods, statistical analyses were performed. Only minor variables such as duration of partially interrupted periods of restraint, and duration of periods of restraint that were partially released showed a statistically significant increase. Although patient satisfaction showed a significant increase, staff attitudes to and perceptions of the review system became appreciably more negative. These findings suggest that although the review system had the potential to slightly reduce the use of seclusion and restraint, and to increase patient satisfaction, staff burnout was risked because staff effort was perceived to be disproportionately high in relation to the effect achieved. Furthermore, the possibility remains that the slight decrease of seclusion and restraint demonstrated did not necessarily reflect the appropriate use of these strategies, and were not necessarily lasting effects. However, as differences in opinion existed between the review system committee and treating clinicians regarding continuation of long term seclusion and restraint, the review system could have a role in monitoring the long term use of seclusion and restraint. Further investigation is needed into the long term effectiveness of procedures reviewing the use of seclusion and restraint in the psychiatric setting, taking into account both positive and negative outcomes.

Cerebral responses to vocal attractiveness and auditory hallucinations in schizophrenia: a functional MRI study.

Impaired self-monitoring and abnormalities of cognitive bias have been implicated as cognitive mechanisms of hallucination; regions fundamental to these processes including inferior frontal gyrus (IFG) and superior temporal gyrus (STG) are abnormally activated in individuals that hallucinate. A recent study showed activation in IFG-STG to be modulated by auditory attractiveness, but no study has investigated whether these IFG-STG activations are impaired in schizophrenia. We aimed to clarify the cerebral function underlying the perception of auditory attractiveness in schizophrenia patients. Cerebral activation was examined in 18 schizophrenia patients and 18 controls when performing Favorability Judgment Task (FJT) and Gender Differentiation Task (GDT) for pairs of greetings using event-related functional MRI. A full-factorial analysis revealed that the main effect of task was associated with activation of left IFG and STG. The main effect of Group revealed less activation of left STG in schizophrenia compared with controls, whereas significantly greater activation in schizophrenia than in controls was revealed at the left middle frontal gyrus (MFG), right temporo-parietal junction (TPJ), right occipital lobe, and right amygdala (p < 0.05, FDR-corrected). A significant positive correlation was observed at the right TPJ and right MFG between cerebral activation under FJT minus GDT contrast and the score of hallucinatory behavior on the Positive and Negative Symptom Scale. Findings of hypo-activation in the left STG could designate brain dysfunction in accessing vocal attractiveness in schizophrenia, whereas hyper-activation in the right TPJ and MFG may reflect the process of mentalizing other person's behavior by auditory hallucination by abnormality of cognitive bias.

Cerebral activation associated with speech sound discrimination during the diotic listening task: an fMRI study.

Comprehending conversation in a crowd requires appropriate orienting and sustainment of auditory attention to and discrimination of the target speaker. While a multitude of cognitive functions such as voice perception and language processing work in concert to subserve this ability, it is still unclear which cognitive components critically determine successful discrimination of speech sounds under constantly changing auditory conditions. To investigate this, we present a functional magnetic resonance imaging (fMRI) study of changes in cerebral activities associated with varying challenge levels of speech discrimination. Subjects participated in a diotic listening paradigm that presented them with two news stories read simultaneously but independently by a target speaker and a distracting speaker of incongruent or congruent sex. We found that the voice of distracter of congruent rather than incongruent sex made the listening more challenging, resulting in enhanced activities mainly in the left temporal and frontal gyri. Further, the activities at the left inferior, left anterior superior and right superior loci in the temporal gyrus were shown to be significantly correlated with accuracy of the discrimination performance. The present results suggest that the subregions of bilateral temporal gyri play a key role in the successful discrimination of speech under constantly changing auditory conditions as encountered in daily life.

Functional deficits in the extrastriate body area during observation of sports-related actions in schizophrenia.

Exercise and sports are increasingly being implemented in the management of schizophrenia. The process of action perception is as important as that of motor execution for learning and acquiring new skills. Recent studies have suggested that body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex is involved not only in static visual perception of body parts but also in the planning, imagination, and execution of actions. However, functional abnormality of the EBA in schizophrenia has yet to be investigated. Using functional magnetic resonance imaging (fMRI) with a task designed to activate the EBA by sports-related actions, we aimed to elucidate functional abnormality of the EBA during observation of sports-related actions in patients with schizophrenia. Twelve schizophrenia patients and 12 age-sex-matched control participants participated in the study. Using sports-related motions as visual stimuli, we examined brain activations during observation of context-congruent actions relative to context-incongruent actions by fMRI. Compared with controls, the patients with schizophrenia demonstrated diminished activation in the EBA during observation of sports-related context-congruent actions. Furthermore, the EBA activation in patients was negatively correlated with the severity of negative and general psychopathology symptoms measured by the Positive and Negative Syndrome Scale. Dysfunction of the EBA might reflect a difficulty in representing dynamic aspects of human actions and possibly lead to impairments of simulation, learning, and execution of actions in schizophrenia.

Alteration in serum neural cell adhesion molecule in patients of schizophrenia.

INTRODUCTION: The neural cell adhesion molecule (N-CAM) plays important roles in neural migration, synaptogenesis and CNS development. Change of N-CAM fragments in CSF of schizophrenic patients was reported previously, and we aimed to detect difference in circulating N-CAM in the serum of schizophrenic patients and healthy controls. METHODS: Samples were from 14 chronic schizophrenic patients including 3 drug naïve patients and 11 healthy controls. After removal of albumin and globulin, N-CAM fragments were measured by Western blot technique with monoclonal antibody. RESULTS: N-CAM immunoreactive bands were detected primarily at 180, 140, 120, 75, 68 and 52 kDa. Samples from patients and controls showed similar patterns of bands, but schizophrenic patients showed increases or decreases at some bands intensity compared to healthy controls. The 68 kDa/73-75 kDa bands intensity ratio was substantially elevated in schizophrenic patients (0.262+/-0.14 in patients, 0.065+/-0.04 in controls) especially, the three drug naïve patients had a higher value of this ratio compared to the medicated patients. One drug naïve patient showed a decrease in this ratio after one month of antipsychotic medication. CONCLUSIONS: The results suggest elevated membrane turnover and/or abnormalities in the regulation of proteolysis of N-CAM in schizophrenia.

Effects of dopaminergic and serotonergic manipulation on emotional processing: a pharmacological fMRI study.

Recent neuroimaging studies have demonstrated abnormal central emotional processing in psychiatric disorders. The dopamine (DA) systems and serotonin (5-HT) systems are the main target of psychopharmacotherapy. DA D2 receptor antagonists and selective serotonin reuptake inhibitors (SSRIs) are widely used in psychiatric practice. Investigating the effects of these drugs on emotional processing should lead to a better understanding of the pathophysiology and pharmacotherapy of neuropsychiatric disorders. We aimed to examine effects of dopaminergic and serotonergic manipulation on neural responses to unpleasant pictures in healthy volunteers using pharmacological fMRI. Thirteen healthy male subjects participated in a single-blind, randomized, placebo-controlled design study. Each subject participated in three fMRI sessions. In each session, participants were orally administered either 25 mg of sultopride or 50 mg of fluvoxamine or placebo prior to scanning, and neural responses to unpleasant and neutral pictures were recorded. Despite no significant differences being found in the subjective ratings of affective pictures across three sessions, compared to placebo, acute treatments of DA D2 receptor antagonists and SSRIs commonly attenuated the amygdala activity, although both treatments had slightly different modulatory effects on other components of the neural circuit of emotional processing. This study has shown that even acute treatment of drugs that manipulate neurotransmitter systems could affect brain activation associated with emotional processing in human brain. At the same time, our findings suggest that pharmacological fMRI could be a powerful tool for investigating the neurophysiological properties of drugs targeting neuropsychiatric disorders.

Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study.

We aimed to investigate the neural substrates associated with evaluative process of moral emotions. Using functional magnetic resonance imaging (fMRI), we examined the similarities and differences between evaluative process of guilt and that of embarrassment at the neural basis level. Study of the neural basis of judgments of moral emotions might contribute to a better understanding of the amoral behavior observed in neurological and psychiatric disorders. Nineteen healthy volunteers were studied. The participants read sentences carrying neutral, guilty, or embarrassing contents during the scans. Both guilt and embarrassment conditions commonly activated the medial prefrontal cortex (MPFC), left posterior superior temporal sulcus (STS), and visual cortex. Compared to guilt condition, embarrassment condition produced greater activation in the right temporal cortex (anterior), bilateral hippocampus, and visual cortex. Most of these regions have been implicated in the neural substrate of social cognition or Theory of Mind (ToM). Our results support the idea that both are self-conscious emotions, which are social emotions requiring the ability to represent the mental states of others. At the same time, our functional fMRI data are in favor of the notion that evaluative process of embarrassment might be a more complex process than that of guilt.

Fine mapping of an isodicentric Y chromosomal breakpoint from a schizophrenic patient.

We report on a male schizophrenic patient who carried an isodicentric Y chromosome [idic(Y)] with a mosaic karyotype [mos 45,X/46,X,idic(Y)(q11)]. Although a potential association between sex chromosome abnormalities and a susceptibility to psychoses has been documented, there has only been one previous report of idic(Y) coincident with schizophrenia. The [45,X] karyotype is known to be associated with Turner syndrome (TS), but our patient lacked most of the phenotypic features of TS, except for short stature. To define the precise position of the breakpoint on the patient's abnormal Y chromosome, we carried out polymerase chain reaction (PCR) analysis, using primers for 15 marker loci along the chromosome. The breakpoint was localized to between the marker loci sY118 and sY119 on Yq in the 5M interval of the deletion map. This position represents the most centromeric breakpoint recorded for idic(Y). We cannot exclude the possibility that the development of schizophrenia is unrelated to the Y chromosome abnormality in this patient but we hope that this study will stimulate further cytogenetic and molecular genetic analyses of Y chromosome regions that may influence psychiatric traits.

An fMRI study of differential neural response to affective pictures in schizophrenia.

Although emotional dysfunction is considered a fundamental symptom of schizophrenia, studies investigating the neural basis of emotional dysfunction in schizophrenia are few. Using functional magnetic resonance imaging (fMRI) and a task viewing affective pictures, we aimed to examine automatic emotional response and to elucidate the neural basis of impaired emotional processing in schizophrenia. Fifteen healthy volunteers and 15 schizophrenics were studied. During the scans, the subjects were instructed to indicate how each of the presented pictures made them feel. Whole brain activities in response to the affective pictures were measured by fMRI. Controls recruited the neural circuit including amygdaloid-hippocampal region, prefrontal cortex, thalamus, basal ganglia, cerebellum, midbrain, and visual cortex while viewing unpleasant pictures. Despite an equal behavioral result to controls, the patients showed less activation in the components of the circuit (right amygdala, bilateral hippocampal region, medial prefrontal cortex (MPFC), basal ganglia, thalamus, cerebellum, midbrain, and visual cortex). This study demonstrated functional abnormalities in the neural circuit of emotional processing in schizophrenia. In particular, decreased activation in the right amygdala and MPFC appears to be an important finding related to dysfunctional emotional behavior in schizophrenia.