Daisuke Koshiyama

Abnormal asymmetries in subcortical brain volume in schizophrenia

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Intact neural activity during a Go/No‐go task is associated with high global functioning in schizophrenia

Go/No‐go derived event‐related potential (ERP) signals have been widely used in schizophrenia research to monitor self‐control deficits in this disorder. However, no study to date has associated Go/No‐go‐related ERP with global functioning.

Reduced Mismatch Negativity is Associated with Increased Plasma Level of Glutamate in First-episode Psychosis

Reduced amplitude of mismatch negativity (MMN) is one of the more promising biological markers of schizophrenia. This finding holds true in both early and chronic phases of the disorder, and is compatible with the glutamatergic dysfunction hypothesis. To further establish MMN as a biomarker of aberrant glutamatergic neurotransmission, an exploration for an association with blood levels of glutamatergic amino acids is an important next step. Despite a large body of work investigating MMN in schizophrenia, no previous studies have undertaken this endeavor. Nineteen patients with first-episode psychosis (FEP), 21 ultra-high risk individuals (UHR), and 16 healthy controls (HC) participated in the study. The MMNs in response to duration change (dMMN) and frequency change (fMMN) were measured. The fasting plasma levels of glutamate, glutamine, glycine, D-serine, and L-serine were measured. dMMN amplitudes were significantly reduced in FEP and UHR, compared to HC. The plasma levels of glutamate of FEP were significantly higher than those of HC. Higher plasma levels of glutamate were associated with smaller dMMN amplitudes in the FEP and HC groups. These findings are compatible with the hypothesis that MMN is a useful biological marker of aberrant glutamatergic neurotransmission in the early stages of schizophrenia.

Duration and frequency mismatch negativity shows no progressive reduction in early stages of psychosis

The auditory mismatch negativity (MMN) is a component of event-related potentials, which is being increasingly recognized as a candidate biomarker for early stages of psychosis. Although previous cross-sectional studies have demonstrated small MMN amplitude in early stages of psychosis, it remains unknown whether small MMN amplitude is due to progressive reduction during the early course. In this study, we investigated longitudinal changes of MMN in early stages of psychosis. Participant included 14 patients with first-episode psychosis (FEP), 16 individuals with ultra-high risk (UHR), and 16 healthy control subjects (HC). We measured MMN in response to duration deviants (dMMN) and that in response to frequency deviants (fMMN), respectively. The amplitudes of dMMN in FEP and UHR were significantly smaller in comparison to those in HC, which did not show a progressive decrease over time. The amplitude of fMMN did not differ among groups, which again did not show progression. There was no significant correlation between the length of the follow-up period and the longitudinal change of either deviant-type MMN in the FEP or UHR. These results suggest that dMMN is a trait marker in the early stages of psychosis, and that small dMMN amplitude in early stages of psychosis may reflect altered developmental process rather than progressive brain pathology. The amplitude of fMMN may not alter in early stages of psychosis. These findings may contribute to the future establishment of MMN as a biomarker in early stages of psychosis.

Marked improvement of elderly postprandial hypotension by dipeptidyl peptidase IV inhibitor

Postprandial hypotension (PPH) is an important and frequent problem, particularly in the elderly. Rapid drops of blood pressure after meals cause syncope, dizziness, falls and muscle weakness, and might result in angina pectoris and stroke. Accordingly, accurate diagnosis and effective treatment of PPH are Figure 1 Computed tomography (CT) images. (a,b) Delayed-phase images obtained by helical dynamic CT. (a) This CT image shows a giant liver cyst (GLC) measuring 18 cm in diameter. The cyst was occupying the right hepatic lobe and compressing the inferior vena cava (IVC; white arrow). (b) The caliber of the IVC on a 3-cm caudad slice from the furcation of the celiac artery was larger than that of the abdominal aorta. The shape of the IVC was round, which indicates a strained IVC (white short arrow). (c) Reconstructed CT image of GLC. This image shows that the caliber of the IVC narrowed on the same level as GLC (white arrow). (d,e) Plain CT images obtained 6 months after the drainage. CT images show no compression of the IVC. (d) This CT image shows that the caliber of the IVC on the 3-cm caudad slice from the furcation of the celiac artery was smaller than that of the abdominal aorta. The shape of the IVC changed to oval, which indicates a lax IVC (white short arrow). (e) The CT image on the same level as that in (b), indicated by paraspinal muscles, shows that the caliber of the IVC was smaller than that of the abdominal aorta (white short arrow). bs_bs_banner

Subcortical association with memory performance in schizophrenia: a structural magnetic resonance imaging study

Memory performance is severely impaired in individuals with schizophrenia. Although several studies have reported a relationship between memory performance and hippocampal volume, only a few structural magnetic resonance imaging (MRI) studies have investigated the relationship between memory performance and subcortical structures other than hippocampus in patients with schizophrenia. We investigated the relationship between memory performance and subcortical regional volumes in a large sample of patients with schizophrenia. Participants included 174 patients with schizophrenia and 638 healthy comparison subjects (HCS). The Wechsler Memory Scale-Revised (WMS-R) has three memory indices (verbal immediate recall, visual immediate recall, and delayed recall (verbal plus visual)) and one control neurocognitive index (attention/concentration). We obtained T1-weighted MRI data and measured the bilateral volumes of the hippocampus, amygdala, thalamus, nucleus accumbens (NA), caudate, putamen, and globus pallidus. Patients with schizophrenia had significantly lower scores for all of the indices of the WMS-R than the HCS. They had more severe impairments in verbal immediate recall and delayed recall than in visual immediate recall and attention/concentration. Verbal immediate recall/delayed recall scores in patients with schizophrenia were significantly correlated not only with hippocampal volume (left: r = 0.34; right: r = 0.28/left: r = 0.33; right: r = 0.31), but also with NA volume (left: r = 0.24; right: r = 0.25/left: r = 0.26; right: r = 0.27). The present investigation with a large sample size did not only replicate hippocampal volume and memory association, but also found that NA volume is associated with memory performances in schizophrenia.

Role of subcortical structures on cognitive and social function in schizophrenia

Subcortical regions have a pivotal role in cognitive, affective, and social functions in humans, and the structural and functional abnormalities of the regions have been associated with various psychiatric disorders. Although previous studies focused on the neurocognitive and socio-functional consequences of prefrontal and tempolo-limbic abnormalities in psychiatric disorders, those of subcortical structures remain largely unknown. Recently, MRI volume alterations in subcortical structures in patients with schizophrenia have been replicated in large-scale meta-analytic studies. Here we investigated the relationship between volumes of subcortical structures and neurocognitive and socio-functional indices in a large sample of patients with schizophrenia. First, we replicated the results of meta-analyses: the regional volumes of the bilateral hippocampus, amygdala, thalamus and nucleus accumbens were significantly smaller for patients (N = 163) than for healthy controls (HCs, N = 620). Second, in the patient group, the right nucleus accumbens volume was significantly correlated with the Digit Symbol Coding score, which is known as a distinctively characteristic index of cognitive deficits in schizophrenia. Furthermore, the right thalamic volume was significantly correlated with social function scores. In HCs, no significant correlation was found. The results from this large-scale investigation shed light upon the role of specific subcortical nuclei on cognitive and social functioning in schizophrenia.

Association between mismatch negativity and global functioning is specific to duration deviance in early stages of psychosis

BACKGROUND Mismatch negativity (MMN) is a candidate biomarker for early stages of psychosis. Although an association among duration MMN (dMMN), cognitive deficits, and functional outcome in chronic schizophrenia has been shown by a large-scale study, the effects of deviant type and clinical stages have not been investigated. METHODS We investigated the relationships among dMMN, frequency MMN (fMMN), global functioning, and cognitive function in early stages of psychosis. The participants included 26 individuals with recent-onset schizophrenia (ROSZ), 30 individuals with ultra-high risk (UHR), and 20 healthy controls. RESULTS The correlational analyses revealed that dMMN amplitude, which was impaired in the ROSZ group compared to the healthy controls, correlated with global functioning (Global Assessment of Functioning-Functioning scale) in the ROSZ (r=-0.45) and UHR (r=-0.37) groups. The amplitude of fMMN, which did not differ among the groups, correlated with working memory (r=-0.57) only in the ROSZ group. The path analyses indicated that dMMN had a direct effect on global functioning in the ROSZ and UHR groups while fMMN had a direct effect on working memory only in the ROSZ group. CONCLUSIONS Our findings suggested that the association between MMN and global functioning was specific to the duration deviant and was already present in early stages of psychosis. These findings confirm the usefulness of dMMN as a biological marker of early psychosis to guide treatment interventions.

Electrophysiological evidence for abnormal glutamate-GABA association following psychosis onset

Previous studies have shown glutamatergic dysfunction and γ-aminobutyric acid (GABA)-ergic dysfunction in schizophrenia. Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) dysfunction and GABA-ergic dysfunction interact with each other and lead to alterations in excitatory/inhibitory balance. The NMDAR and GABAergic-interneuron functions may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). The MMN amplitude was significantly impaired in ROSZ (p = 0.001, d = 1.20) and UHR (p = 0.003, d = 1.01) compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs (p < 0.001, d = –1.27) and UHR (p = 0.032, d = –0.75). The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs (p < 0.001, d = −1.21). The MMN amplitude was significantly correlated with the ITC in ROSZ (r = −0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.

Role of frontal white matter and corpus callosum on social function in schizophrenia

Patients with schizophrenia show severe impairment in social function and have difficulty in their daily social life. Although a recent large-scale multicenter study revealed alterations in white matter microstructures, the association between these anatomical changes and social dysfunction in schizophrenia remains unknown. Therefore, we investigated the association between the white matter integrity of regions of interest and social function in schizophrenia. A total of 149 patients with schizophrenia and 602 healthy comparison subjects (HCS) underwent DTI and completed the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-Third Edition and the Finance subscale of the University of California, San Diego, Performance-Based Skills Assessment Brief, as social indices of interest. The fractional anisotropy (FA) in the anterior corona radiata and corpus callosum was significantly lower in patients than in HCS, and the radial diffusivity (RD) in the anterior corona radiata and corpus callosum was significantly higher in patients. The Picture Arrangement and Finance scores were both significantly impaired in patients. The effect of the FA of the right anterior corona radiata on the Finance score and the Picture Arrangement score, of the RD of the right anterior corona radiata on the Picture Arrangement score, and of the RD of the corpus callosum on the Picture Arrangement score were significant. In conclusion, our results confirmed the association between structural connectivity in the right frontal white matter and corpus callosum and social function in schizophrenia. These findings may provide a foundation for developing an intervention for functional recovery in schizophrenia.