The effects of olanzapine treatment on brain regional glucose metabolism in neuroleptic-naive first-episode schizophrenic patients.

OBJECTIVE: The current study examined metabolic alterations associated with a positive response to olanzapine and identified brain regions associated with treatment-related improvement of symptoms in neuroleptic-naive first-episode schizophrenic patients using [18 F]fluoro-deoxy-glucose positron emission tomography analysis. METHODS: Neuroleptic-naive first-episode schizophrenic patients who showed good or poor clinical responses to olanzapine were assessed using the Positive and Negative Syndrome Scale. Data were analyzed using statistical nonparametric mapping. RESULTS: Before treatment, responders showed significantly increased metabolism in the superior temporal gyrus and cerebellum compared with healthy controls. Glucose metabolism in responders was significantly increased after treatment in the left precentral gyrus, left postcentral gyrus, and left paracentral lobule, and significantly decreased in the left hypothalamus. An analysis of the Positive and Negative Syndrome Scale symptoms associated with olanzapine treatment revealed that "suspiciousness/persecution" scores were positively correlated with metabolic changes in the right superior frontal gyrus. CONCLUSIONS: These findings provide evidence of the neural mechanisms underlying the effects of olanzapine on metabolism in the early stages of schizophrenia.

Sex Differences in Gamma Band Functional Connectivity Between the Frontal Lobe and Cortical Areas During an Auditory Oddball Task, as Revealed by Imaginary Coherence Assessment.

We studied sex-related differences in gamma oscillation during an auditory oddball task, using magnetoencephalography and electroencephalography assessment of imaginary coherence (IC). We obtained a statistical source map of event-related desynchronization (ERD) / event-related synchronization (ERS), and compared females and males regarding ERD / ERS. Based on the results, we chose respectively seed regions for IC determinations in low (30-50 Hz), mid (50-100 Hz) and high gamma (100-150 Hz) bands. In males, ERD was increased in the left posterior cingulate cortex (CGp) at 500 ms in the low gamma band, and in the right caudal anterior cingulate cortex (cACC) at 125 ms in the mid-gamma band. ERS was increased in the left rostral anterior cingulate cortex (rACC) at 375 ms in the high gamma band. We chose the CGp, cACC and rACC as seeds, and examined IC between the seed and certain target regions using the IC map. IC changes depended on the height of the gamma frequency and the time window in the gamma band. Although IC in the mid and high gamma bands did not show sex-specific differences, IC at 30-50 Hz in males was increased between the left rACC and the frontal, orbitofrontal, inferior temporal and fusiform target regions. Increased IC in males suggested that males may acomplish the task constructively, analysingly, emotionally, and by perfoming analysis, and that information processing was more complicated in the cortico-cortical circuit. On the other hand, females showed few differences in IC. Females planned the task with general attention and economical well-balanced processing, which was explained by the higher overall functional cortical connectivity. CGp, cACC and rACC were involved in sex differences in information processing and were likely related to differences in neuroanatomy, hormones and neurotransmitter systems.

Dysfunctional cortical connectivity during the auditory oddball task in patients with schizophrenia.

BACKGROUND: We studied the imaginary coherence (IC) of gamma frequency oscillations between brain regions of male schizophrenia patients during an auditory oddball task using magnetoencephalography (MEG) and electroencephalography (EEG). METHODS: Subjects were 10 right-handed male schizophrenia patients, evaluated by the positive and negative symptom scale (PANSS), and 10 healthy controls. Functional connectivity during the auditory oddball task was reconstructed in low (30-50 Hz) and high (50-100 Hz) gamma bands, and represented by imaginary coherence (IC) based on significant oscillatory power changes. We calculated correlations between PANSS scores and IC. RESULTS: In the high gamma band, IC between left occipital and right prefrontal lobe areas during the time window 750-1000 ms from stimulus onset showed negative correlations with total negative scores, total positive scores, the sum of positive and negative scores in PANSS, conceptual disorganization, and social avoidance scores. In the low gamma band, IC between the same areas from 250-500 ms also showed a negative correlation with the conceptual disorganization score. In the same time window, IC between left occipital and right frontoparietal lobe areas in the low gamma band showed a positive correlation with hallucinatory behavior; IC between right temporal pole and left prefrontal lobe areas showed a positive correlation with delusion scores, although these ICs were decreased relative to controls. CONCLUSIONS: Functional disconnection of high and low gamma bands in auditory oddball task may play an important role in the auditory processing in schizophrenia patients.

Changes in Event-Related Desynchronization and Synchronization during the Auditory Oddball Task in Schizophrenia Patients.

OBJECTIVE: We studied differences in the spatiotemporal dynamics of cortical oscillation across brain regions of patients with schizophrenia and normal subjects during the auditory oddball task using magnetoencephalography (MEG) and electroencephalography (EEG). METHODS: Ten right-handed male schizophrenia patients were studied. We used a newly developed adaptive spatial filtering algorithm optimized for robust source time-frequency reconstruction of MEG and EEG data, and obtained consecutive images in functional maps of event-related desynchronization (ERD) and synchronization (ERS) in theta, lower alpha (8-10 Hz), upper alpha (10-13 Hz), and beta bands. RESULTS: Beta ERD power at 750-1000 ms in patients was significantly increased in large right upper temporal and parietal regions and small upper portions of bilateral dorsal frontal and dorsal-medial parietal regions. Theta ERS power in schizophrenic patients during the oddball task was significantly increased in the left temporal pole at 250-500 ms, and was significantly increased in dorsal, medial frontal, and anterior portions of the anterior cingulate cortex in both hemispheres, and the left portion of lateral temporal regions at 500-750 ms, compared to the control group (family-wise error correction p<0.05). Lower alpha ERS power was significantly decreased in the right occipital region at 500-750 ms and in the right midline parietal and bilateral occipital regions at 750-1000 ms. Upper alpha ERS power was significantly decreased in right midline parietal and left occipital regions at 750-1000 ms. CONCLUSIONS: ERD/ERS changes were noted in the left temporal pole and midline frontal and anterior cingulate cortex in theta ERS, occipital lobe in alpha ERS, and right temporal-frontal-parietal, midline frontal, and anterior cingulate cortex in beta ERD. These findings may reflect disturbances in interaction among active large neuronal groups and their communication with each other that may be related to abnormal cognitive and psychopathological function. SIGNIFICANCE: Study of ERD and ERS by time-frequency analyses using MEG is useful to clarify data processing dysfunction in schizophrenia.

Effects of Yokukansan on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer's disease.

Yokukansan (YKS) is used frequently against behavioral and psychological symptoms of dementia (BPSD) together with donepezil in patients with Alzheimer's disease (AD). Here, we investigated the efficacy and safety of YKS in patients with AD in a non-blinded, randomized, parallel-group comparison study. Patients who had at least one symptom score of four or more on the Neuropsychiatric Inventory (NPI) subscales were enrolled in the study. The subjects were randomly assigned to the YKS-treated group (YKS/donepezil combination therapy group) and the non-YKS-treated group (donepezil monotherapy group). TSUMURA Yokukansan (TJ-54, 7.5g, t.i.d.) was administered in a four-week study treatment period. The subjects were evaluated twice at the start (Week 0) and completion (Week 4) of the study treatment in terms of NPI, Mini-Mental Status Examination (MMSE), Disability Assessment for Dementia (DAD), Zarit Burden Interview, and Self-rating Depression Scale (SDS). The efficacy analysis was performed in 29 patients (YKS-treated group) and 32 patients (non-YKS-treated group). The NPI total score improved significantly more in the YKS-treated group than in the non-YKS-treated group. In the NPI subscales of agitation/aggression and irritability/lability, the YKS-treated group showed significantly greater improvement than the non-YKS-treated group, but no statistically significant improvement was seen with YKS in the other subscales. There were no significant differences between the YKS-treated group and the non-YKS-treated group in MMSE, DAD, Zarit Burden Interview and SDS. No adverse reactions were noted in either group. The results of this study showed that YKS is safe and effective in the treatment of BPSD in AD patients.

Treatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukansan in clinical practice.

The efficacy and safety of the kampo medicine Yokukansan (YKS, TJ-54) in the treatment of behavioral and psychological symptoms of dementia (BPSD) were investigated in patients with Alzheimer's disease (AD) in an open-label study. This study included 26 patients who had been diagnosed as having AD and were not treated with donepezil hydrochloride. These patients were administered YKS (7.5g/day) for four weeks to investigate the changes in neuropsychological test results and care burden in the period from the start to completion of the study treatment. The Neuropsychiatric Inventory (NPI) was used for evaluation of BPSD, the Mini-Mental State Examination (MMSE) for evaluation of cognitive functions, the Zarit burden interview for evaluation of the caregiver's burden, Disability Assessment of Dementia (DAD) for evaluation of activities of daily living (ADL) and Self-Rating Depression Scale (SDS) for evaluation of the caregiver's depression. No significant change was seen in MMSE and DAD after four weeks of treatment, but the mean NPI total score decreased significantly. Furthermore, among the NPI subscales, a statistically significant decrease in score was not seen, however, a clinically significant decrease was seen in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior. No significant changes were seen in caregiver's burden after four weeks of treatment. No serious adverse reactions to YKS were observed. The results of this study suggested that YKS may be an effective and well-tolerated drug in the treatment of BPSD in AD patients.

Metabolic changes in the brain of patients with late-onset major depression.

Positron emission tomography (PET) with fluorodeoxyglucose-F18 was used to examine glucose metabolism in patients with late-onset major depression, all hospitalized non-responders to antidepressant medication. The three-dimensional stereotactic surface projection (3D-SSP) method provided 3D-SSP images and relative metabolic values with minimal partial volume effects. The 3D-SSP score map showed decreased relative metabolism in the prefontal, cingulate and parietal regions in both hemispheres, and in the temporal region on the right, and increased relative metabolism in the occipital pole, vermis, cerebellum, dorsal-frontal, central convexity areas and basal ganglia in both hemispheres in patients compared with controls. The ratio of the parietal to occipital values in right plus left hemispheres was significantly decreased. Correlation coefficients of the anterior cingulate-primary sensorimotor, posterior cingulate-primary sensorimotor and occipital-media frontal in both hemispheres, of the frontal-primary sensorimotor, occipital-parahippocampal, primary visual-medial frontal and parahippocampal-amygdala in the right, and the frontal-vermis, parietal-thalamus, temporal-vermis, occipital-putamen, primary visual-putamen, thalamus-vermis and thalamus-cerebellum in the left were significantly different in patients compared with controls. Patients with late-onset depression who were treatment non-responders showed alterations not only in limbic-cortical circuits, but also in a wider network of thalamo-cortical circuits.

Changes in glucose metabolism due to aging and gender-related differences in the healthy human brain.

Using [(18)F]fluoro-deoxy-glucose-PET, we studied relative metabolic changes due to age- and gender-related differences in the brain of 126 healthy subjects from their twenties to seventies. We used a data-extraction technique, the three-dimensional stereotactic surface projections (3D-SSP) method, to measure metabolic changes with fewer effects of regional anatomic variances. Simple regression analysis revealed significant age-related increases in relative metabolic values in the parahippocampal and amygdala regions in both sexes in their twenties to forties, and significant age-related decreases in both sexes in their fifties to seventies. Relative values in the frontal lobe showed significant age-related decreases in both sexes in their twenties to forties, but these effects were not seen in subjects in their fifties to seventies. Significant gender differences in correlation coefficients of relative values with age were shown in the parahippocampal, primary sensorimotor, temporal, thalamus and vermis regions in subjects in their 20s to 40s, but disappeared in subjects in their twenties to forties, but were not apparent in subjects in their fifties to seventies except in the vermis. Males in their twenties to sixties and females in their fifties showed significant laterality in relative values in the temporal lobes. Our study demonstrated age- and gender-related differences in glucose metabolism in healthy subjects.

Spatiotemporal characteristics of MEG and EEG entrainment with photic stimulation in schizophrenia.

We examined the periodic synchronous characteristic response to photic stimulation in schizophrenia using electroencephalography (EEG) and magnetoencephalography (MEG). We tested whether neural synchronization deficits were present in subjects with schizophrenia using photic stimulation to evaluate the frequency entrainment in 18 normal subjects and 19 schizophrenia patients. A conventional vertical-type 160-channel MEG (PQ1160C, Yokogawa Electric Corporation) was used. Photic stimulation was at frequencies from 8 to 10.5 Hz at intervals of 0.5 Hz. There were ten stimuli at each frequency, and each lasted 10 seconds. The power spectrum at each site was based on the international 10/20 derivation. The power spectrum in schizophrenia patients was smaller than that in normal subjects at each site. A gender difference was observed in normal subjects, but not in schizophrenia patients. MEG, like EEG, is an effective method for research on neuropathy of the psyche.