Kenji Nobuhara

Diffusion tensor magnetic resonance imaging of disruption of regional white matter in schizophrenia.

Diffusion tensor imaging provides a new approach for quantifying anisotropic diffusion of white matter in vivo. We used this technique to investigate subtle disruption of regional white matter in schizophrenia. Twelve patients with schizophrenia were compared with 11 healthy controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. A significant fractional anisotropy (FA) reduction was found in all white matter regions bilaterally in schizophrenic patients. Higher FA of left frontal white matter correlated significantly with higher dosage of antipsychotic medication. These findings support the view that the pathological process is a distortion of the central nervous system myelination affecting the whole white matter. Our findings also show the effects of antipsychotics on the white matter in the left frontal region in schizophrenia.

Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients.

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

Subtle Disruption of the Middle Cerebellar Peduncles in Patients with Schizophrenia

Diffusion tensor imaging (DTI) was used to investigate subtle disruption in the middle cerebellar peduncles in patients with schizophrenia. Fractional anisotropy (FA) was measured in 25 patients with schizophrenia and 21 healthy subjects using DTI. The FA of the right and left middle cerebellar peduncles was significantly lower in the schizophrenic patients compared to healthy subjects. FA in the left middle cerebellar peduncles was significantly correlated with the dosage of neuroleptics in patients with schizophrenia. There were no significant differences of mean diffusivity in the right and left middle cerebellar peduncles between patients with schizophrenia and healthy subjects. The findings of the study suggest that antipsychotics may improve the subtle disruption in the middle cerebellar peduncles in patients with schizophrenia.

Effects of Electroconvulsive Therapy on Frontal White Matter in Late-Life Depression: A Diffusion Tensor Imaging Study

This study was conducted to elucidate the effects of electroconvulsive therapy (ECT) on frontal white matter in late-life depressed patients. Diffusion tensor imaging was performed on 8 late-life depressed patients and 12 healthy age-matched controls. The patients were scanned before and after a course of ECT. Fractional anisotropy (FA) was determined in the frontal and temporal regions and the corpus callosum. A significant white matter FA reduction was found in widespread frontal and temporal brain regions in patients with depression before ECT treatment compared with controls. A significant increase in frontal white matter FA was seen following ECT treatment. A course of bilateral ECT ameliorated white matter integrity in frontal brain regions. This suggests a strong relationship with the antidepressant action of ECT.

Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism

The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.

Corpus Callosum in Patients with Obsessive-Compulsive Disorder: Diffusion-Tensor Imaging Study

PURPOSE To prospectively examine microstructural white matter abnormalities in the corpus callosum (CC) of patients with obsessive-compulsive disorder (OCD), as compared with control subjects, and to investigate the relationship between diffusion-tensor (DT) imaging measures of the CC region and clinical symptoms of OCD. MATERIALS AND METHODS Institutional review board approval was obtained, and each participant--or the participants parent(s)--provided written informed consent. Sixteen patients with OCD (seven male, nine female; mean age, 28.7 years +/- 9.8 [standard deviation]) and 16 matched healthy volunteers (control subjects) (seven male, nine female; mean age, 29.9 years +/- 9.0) were examined. Mean diffusivity and fractional anisotropy (FA) were measured in five subdivisions of the CC. The paired t test was performed to compare the mean diffusivity or the FA in CC regions between the patients with OCD and the control subjects. RESULTS There were no significant differences (rostrum, P = .15; genu, P = .88; rostral body, P = .12; isthmus, P = .77; splenium, P = .88) in mean diffusivity between the patients with OCD and the healthy volunteers. A significant reduction in FA was observed in the rostrum of the CC in patients with OCD compared with the rostral FA in the control subjects (P < .001). Higher FA in only the rostrum correlated significantly with lower Yale-Brown obsessive-compulsive scale score (r = -0.72, P = .002). CONCLUSION Study results support the widely held view that the orbital prefrontal region is involved in the pathophysiology of OCD and indicate that the orbitofrontal circuit influences symptom severity in patients with OCD.

Olanzapine Increases Grey and White Matter Volumes in the Caudate Nucleus of Patients with Schizophrenia

There are inconsistent reports regarding the caudate nucleus volume in patients with schizophrenia compared with healthy subjects. The reason for this is that neuroleptic medication may affect the volume of the caudate nucleus in schizophrenic patients. To clarify which antipsychotic medication changes the volume of the caudate nucleus in patients with schizophrenia, we measured the volumes of grey and white matter in the caudate nucleus of schizophrenic patients. Ten patients with schizophrenia were examined twice by magnetic resonance imaging (MRI) to measure the grey and white matter volumes in the caudate nucleus. After the first MRI examination, all the patients were treated with olanzapine. The clinical responses were evaluated by the positive and negative rating scale. When the symptoms improved, the patients were examined by a second MRI scan. Ten healthy control subjects also underwent MRI. The schizophrenic patients had reduced volumes of grey and white matter in the caudate nucleus compared to the healthy control subjects. The volumes of grey and white matter in the caudate nucleus of the schizophrenic patients increased after treatment with olanzapine. These findings suggest that treatment with olanzapine may increase the grey and white matter volumes in the caudate nucleus in patients with schizophrenia.

Diffusion tensor imaging study of the middle cerebellar peduncles in patients with schizophrenia.

Recent evidence from neuroimaging studies suggests that neural dysfunction is involved in the pathophysiology of schizophrenia. Diffusion tensor imaging (DTI) is a technique that has the potential to detect subtle disruptions of neural connectivity. Fractional anisotropy (FA), which is measured by DTI, is a measure of the directionality of diffusion anisotropy. Decrease in FA indicates abnormalities of white matter due to increased water diffusion accompanied by an increase in extracellular space. In the literature, previous studies reported that patients with schizophrenia showed widespread lower FA in the white matter. These findings suggest that patients with schizophrenia have microstructural lesions in the cerebral white matter. We used DTI to determine whether neural connectivity was disturbed in the middle cerebellar peduncles in schizophrenic subjects. We found a significant FA reduction in the middle cerebellar peduncle in patients with schizophrenia. Therefore, neural disconnectivity between the cerebellum and cerebrum was considered present in patients with schizophrenia and may be involved in the pathology of schizophrenia. This review provides current findings regarding DTI study on the cerebellar peduncle in patients with schizophrenia.

Cerebellar posterior superior vermis and cognitive cluster scores in drug-naive patients with first-episode schizophrenia.

Previously, we performed an MRI study that revealed smaller volumes of the subregions of the cerebellar vermis in men and women with chronic schizophrenia. An issue that arose from that study was whether similar structural changes in the cerebellum are found in patients with first-episode schizophrenia. In the present study, MRI scans were acquired from 14 drug-naive patients with first-episode schizophrenia and 16 healthy subjects, and used to measure the volumes of their cerebellar subregions. Positive symptom, negative symptom and cognitive cluster scores were attained using the Positive and Negative Syndrome Scale. Patients with first-episode schizophrenia had reduced volumes of the anterior vermis and posterior superior vermis compared with healthy subjects. We confirmed that there was a volume reduction of the cerebellar vermis in drug-naive patients with first-episode schizophrenia. Smaller volumes of the posterior superior vermis were associated with worse cognitive cluster scores in patients with first-episode schizophrenia.

Increased Omega Complexity and Decreased Microstate Duration in Nonmedicated Schizophrenic Patients

To explore brain functions in schizophrenic patients, the global analytic strategy of multichannel EEG was performed that combines measures of global complexity (Ω), total power (Σ) and generalized frequency (Φ), and EEG microstate analysis was applied to multichannel EEG data for 24 nonmedicated patients and 24 healthy subjects. The patients had higher Ω and Σ values, and lower Φ values compared with healthy subjects. Three topographical classes were obtained from all EEG data by EEG microstate analysis. The mean duration of one topographical class in the patients was shortened compared to healthy subjects. These results indicated looser cooperativity, or decreased connectivity of the active brain process and deviant brain information processing in schizophrenic patients.