Manabu Kubota

Age-related cortical thinning in schizophrenia

Although the effects of aging on the neural correlates of schizophrenia have been researched for many years, no clear conclusion has been reached. While some studies have demonstrated progressive age-related gray matter reductions in schizophrenia, other studies have not found evidence of progression. Moreover, it remains unclear whether the influence of aging on global or regional cortical thickness differs between schizophrenia patients and healthy controls. This study aimed to confirm previous reports of reduced cortical thickness in schizophrenia, and to investigate the effects of age on global and regional cortical thickness. Eighty-three patients with schizophrenia (six first-episode patients and 77 chronic patients; age range=18-55 years) and 90 age-, gender- and education-matched healthy controls (age range=19-56 years) underwent structural magnetic resonance imaging (MRI) using a 3-Tesla scanner. Surface-based analysis was applied to assess cortical thickness in the whole brain. The patient group exhibited both global and regional cortical thinning in regions including the prefrontal and temporal cortices. The correlation between age and cortical thickness showed a similar pattern in patients and controls, both globally and regionally. These results suggest that the reduction of cortical thickness in schizophrenia might not be progressive over the course of the illness, indicating that pathological processes occur in a relatively limited period of time around the onset of illness.

Impaired empathic abilities and reduced white matter integrity in schizophrenia.

Empathic abilities are impaired in schizophrenia. Although the pathology of schizophrenia is thought to involve disrupted white matter integrity, the relationship between empathic disabilities and altered white matter in the disorder remains unclear. The present study tested associations between empathic disabilities and white matter integrity in order to investigate the neural basis of impaired empathy in schizophrenia. Sixty-nine patients with schizophrenia and 69 age-, gender-, handedness-, education- and IQ level-matched healthy controls underwent diffusion-weighted imaging. Empathic abilities were assessed using the Interpersonal Reactivity Index (IRI). Using tract-based spatial statistics (TBSS), the associations between empathic abilities and white matter fractional anisotropy (FA), a measure of white matter integrity, were examined in the patient group within brain areas that showed a significant FA reduction compared with the controls. The patients with schizophrenia reported lower perspective taking and higher personal distress according to the IRI. The patients showed a significant FA reduction in bilateral deep white matter in the frontal, temporal, parietal and occipital lobes, a large portion of the corpus callosum, and the corona radiata. In schizophrenia patients, fantasy subscales positively correlated with FA in the left inferior fronto-occipital fasciculi and anterior thalamic radiation, and personal distress subscales negatively correlated with FA in the splenium of the corpus callosum. These results suggest that disrupted white matter integrity in these regions constitutes a pathology underpinning specific components of empathic disabilities in schizophrenia, highlighting that different aspects of empathic impairments in the disorder would have, at least partially, distinct neuropathological bases.

Thalamocortical Disconnection in the Orbitofrontal Region Associated With Cortical Thinning in Schizophrenia

CONTEXT Dysfunction of the thalamocortical pathway has been proposed as a putative underlying pathology of schizophrenia. Although the mechanisms involved remain unclear, postmortem studies suggest the involvement of altered neural projections from the thalamus to layers within the prefrontal cortex. OBJECTIVES To investigate thalamocortical connectivity in schizophrenia and to examine its possible association with cortical thinning in vivo. DESIGN Case-control cross-sectional study. SETTING Department of Psychiatry at Kyoto University Hospital, Japan. PATIENTS AND OTHER PARTICIPANTS A total of 37 patients with schizophrenia and 36 age-, sex-, and education-matched healthy controls recruited from the local community underwent diffusion-weighted imaging and T1-weighted 3-dimensional magnetic resonance imaging. MAIN OUTCOME MEASURES Probabilistic tractography was performed to investigate thalamocortical pathways. Group differences in mean fractional anisotropy (FA) values were examined in the entire thalamocortical pathway, the thalamolateral prefrontal pathway, the thalamomedial prefrontal pathway, and the thalamo-orbitofrontal pathway. Surface-based analysis was performed to investigate cortical thickness, and the correlation between FA values and cortical thickness was examined. RESULTS The patient group exhibited reduced FA values within the right thalamo-orbitofrontal pathway (P < .05 for the 8 group comparisons of FA, Bonferroni correction). In the patient group only, the mean FA value for this pathway was positively correlated with thickness of the right frontal polar and lateral orbitofrontal cortices (P < .05, clusterwise correction). CONCLUSIONS These results suggest that, in schizophrenia, regional thalamocortical white matter pathology is specifically associated with cortical pathology in regions where fibers connect.

Abnormal asymmetry of white matter integrity in schizophrenia revealed by voxelwise diffusion tensor imaging.

A number of magnetic resonance imaging (MRI) studies have revealed morphological cortical asymmetry in the normal human brain, and reduction or inversion of such hemispheric asymmetry has been reported in schizophrenia. On the other hand, diffusion tensor imaging (DTI) studies have reported inconsistent findings concerning abnormal asymmetry of white matter integrity in schizophrenia. Our aim was to confirm whether there is reduced or inverted asymmetry of white matter integrity in the whole brain in schizophrenia. For this study, 26 right‐handed schizophrenia patients, and 32 matched healthy control subjects were investigated. Voxelwise analysis of DTI data was performed using the tract‐based spatial statistics. The fractional anisotropy (FA) images were normalized and projected onto the symmetrical white matter skeleton, and the laterality index (LI) of FA, determined by 2 × (left ‐ right)/(left + right), was calculated. The results reveal that schizophrenia patients and healthy controls showed similar patterns of overall FA asymmetries. In the group comparison, patients showed significant reduction of LI in the external capsule (EC), and posterior limb of the internal capsule (PLIC). The EC cluster revealed increased rightward asymmetry, and the PLIC cluster showed reduced leftward asymmetry. Rightward‐shift of FA in the EC cluster correlated with negative symptom severity. Considering that the EC cluster includes the uncinate and inferior occipitofrontal fasciculi, which have connections to the orbitofrontal cortex, abnormal asymmetry of white matter integrity in schizophrenia may play a crucial role in the pathogenesis of schizophrenia, through the altered connectivity to the orbitofrontal cortex. Hum Brain Mapp, 2011.

Alexithymia and regional gray matter alterations in schizophrenia

Alexithymia is characterized by deficits in emotional self-awareness. Although alexithymia refers to a deficit in recognizing ones own emotions, some studies have focused on the relation between alexithymia and impaired social cognition. An association between alexithymia and schizophrenia has been previously reported, but the brain structures involved remain unclear. The present study investigated associations between alexithymia and specific brain structures to determine whether these regions overlapped with key structures underlying social cognition. Twenty-one patients with schizophrenia and 24 age-, gender- and education level-matched healthy controls underwent structural magnetic resonance imaging. Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20). We applied voxel-based morphometry to investigate the correlation between TAS-20 scores and regional brain alterations. TAS-20 scores were significantly higher in patients than controls. Bilateral ventral striatum and left ventral premotor cortex volumes were negatively correlated with TAS-20 total scores in controls, while left supramarginal gyrus (SMG) volume was negatively correlated with TAS-20 total scores in patients. These results suggest that schizophrenia is associated with alexithymia, and that gray matter alterations of the left SMG constitute a key pathology underlying alexithymia in schizophrenia. This association may be related to deficits in self-other distinction, self-disturbance, and language processing in schizophrenia.

Alexithymia and reduced white matter integrity in schizophrenia: A diffusion tensor imaging study on impaired emotional self-awareness

Alexithymia is characterized by deficits in emotional self-awareness. A number of previous studies have revealed impaired emotional self-awareness in schizophrenia. Although the pathology of schizophrenia is thought to involve disrupted white matter integrity, its relationship with alexithymia remains unclear. The present study investigated associations between alexithymia and white matter integrity, to seek the neural basis of impaired emotional self-awareness in schizophrenia. Forty-four patients with schizophrenia and 44 age-, gender- and predicted IQ level-matched healthy controls underwent diffusion-weighted imaging. Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20). We applied tract-based spatial statistics to investigate the correlation between the TAS-20 total score and white matter fractional anisotropy (FA). TAS-20 scores were significantly higher in patients than in controls. In the patient group only, FA was negatively correlated with the TAS-20 total score in the corpus callosum, mostly the left part of the superior and inferior longitudinal fasciculi, the inferior occipito-frontal fasciculus, the anterior and posterior thalamic radiation, and the precuneus white matter. These results suggest that schizophrenia is associated with alexithymia, and that reduced white matter integrity within these regions constitutes an important pathology underlying impaired self-emotional awareness in schizophrenia.

The contribution of cortical thickness and surface area to gray matter asymmetries in the healthy human brain

Human cortical gray matter (GM) is structurally asymmetrical and this asymmetry has been discussed to be partly responsible for functional lateralization of human cognition and behavior. Past studies on brain asymmetry have shown mixed results so far, with some studies focusing on the global shapes of the brains surface, such as gyrification patterns, while others focused on regional brain volumes. In this study, we investigated cortical GM asymmetries in a large sample of right‐handed healthy volunteers (n = 101), using a surface‐based method which allows to analyze brain cortical thickness and surface area separately. As a result, substantially different patterns of symmetry emerged between cortical thickness and surface area measures. In general, asymmetry is more prominent in the measure of surface compared to that of thickness. Such a detailed investigation of structural asymmetries in the normal brain contributes largely to our knowledge of normal brain development and also offers insights into the neurodevelopmental basis of psychiatric disorders, such as schizophrenia. Hum Brain Mapp 35:6011–6022, 2014.

Global Association Between Cortical Thinning and White Matter Integrity Reduction in Schizophrenia

Previous neuroimaging studies have revealed that both gray matter (GM) and white matter (WM) are altered in several morphological aspects in schizophrenia patients. Although several studies reported associations between GM and WM alterations in restricted regions, the existence of a global association between GM and WM pathologies is unknown. Considering the wide distribution of GM morphological changes and the profound genetic background of WM abnormalities, it would be natural to postulate a global association between pathologies of GM and WM in schizophrenia. In this investigation, we studied 35 schizophrenia patients and 35 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) and investigated the association between GM thickness and WM fractional anisotropy (FA) as a proxy of pathology in each tissue. To investigate cortical thickness, surface-based analysis was used. The mean cortical thickness for the whole brain was computed for each hemisphere, and group comparisons were performed. For DTI data, mean FA for the whole brain was calculated, and group comparisons were performed. Subsequently, the correlation between mean cortical thickness and mean FA was investigated. Results showed that the mean cortical thickness was significantly thinner, and the mean FA was significantly lower in schizophrenia patients. Only in the patient group the mean cortical thickness and mean FA showed significant positive correlations in both hemispheres. This correlation remained significant even after controlling for demographic and clinical variables. Thus, our results indicate that the GM and WM pathologies of schizophrenia are intertwined at the global level.

Social impairment in schizophrenia revealed by Autism-Spectrum Quotient correlated with gray matter reduction

One of the difficulties facing schizophrenia patients is a failure to construct appropriate relationships with others in social situations. This impairment of social cognition is also found in autism-spectrum disorder (ASD). Considering such commonality between the two disorders, in this study we adopted the Autism-Spectrum Quotient (AQ) score to assess autistic traits, and explored the association between such traits and gray matter (GM) alterations of the brain in schizophrenia. Twenty schizophrenia patients and 25 healthy controls underwent structural magnetic resonance imaging (MRI), and AQ was assessed, comprising five subscales measuring different facets of autistic traits. Voxel-based morphometry (VBM) was applied to investigate the correlation between these AQ scores and regional GM alterations. Schizophrenia patients showed significantly higher scores in total AQ, and in four of the five subscales, compared to healthy controls. The total AQ score in schizophrenia showed significant negative correlation with GM volume reduction in the cortical area surrounding the left superior temporal sulcus (STS), which is considered to be important in social perception. Our findings suggest a possible neuroanatomical basis of autistic tendencies in schizophrenia.

Altered fronto-striatal fiber topography and connectivity in obsessive-compulsive disorder.

Fronto-striatal circuits are hypothesized to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). Within this circuitry, ventral frontal regions project fibers to the ventral striatum (VS) and dorsal frontal regions to the dorsal striatum. Resting state fMRI research has shown higher functional connectivity between the orbitofrontal cortex (OFC) and the dorsal part of the VS in OCD patients compared to healthy controls (HC). Therefore, we hypothesized that in OCD the OFC predominantly project fibers to the more dorsal part of the VS, and that the structural connectivity between the OFC and VS is higher compared to HC. A total of 20 non-medicated OCD patients and 20 HC underwent diffusion-weighted imaging. Connectivity-based parcellation analyses were performed with the striatum as seed region and the OFC, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex as target regions. Obtained connectivity maps for each frontal region of interest (ROI) were normalized into standard space, and Z-component (dorsal–ventral) coordinate of center-of-gravity (COG) were compared between two groups. Probabilistic tractography was performed to investigate diffusion indices of fibers between the striatum and frontal ROIs. COG Z-component coordinates of connectivity maps for OFC ROI were located in the more dorsal part of the VS in OCD patients compared to HC. Fractional anisotropy of fibers between the OFC and the striatum was higher in OCD patients compared to HC. Part of the pathophysiology of OCD might be understood by altered topography and structural connectivity of fibers between the OFC and the striatum.