Hironobu Fujiwara

Anterior and posterior cingulum abnormalities and their association with psychopathology in schizophrenia: A diffusion tensor imaging study

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus may play a role in the pathophysiology of schizophrenia. The cingulum bundles (CBs; posterior and anterior) are the most prominent white matter tracts in the limbic system, furnishing both input and output to the cingulate gyrus . In previous diffusion tensor imaging (DTI) studies, abnormal integrity has been demonstrated in the anterior CB portion, but not the posterior, in schizophrenia. As well, the relationships between the abnormalities of CB integrity and the psychopathology of schizophrenia remain to be elucidated. Using DTI acquired on a 3 T MRI machine, we examined fractional anisotropy (FA) in the anterior and posterior CBs of 42 patients with schizophrenia and 24 group-matched controls. Moreover, we investigated the relationships between CB abnormalities and the psychopathology of schizophrenia. Bilaterally reduced FA was demonstrated in both anterior and posterior CBs in schizophrenia patients. However, the pattern of FA reduction was different between anterior and posterior CBs: the reduction in FA was left-accentuated in anterior CBs, while no such lateralized abnormality was found in posterior ones. Finally, FA in posterior CBs correlated with positive symptom scores in patients with schizophrenia. These findings suggest that CB abnormalities in schizophrenia are not restricted to the anterior CB, but include the posterior as well. Pathology in the posterior CB would be one of the possible neural underpinnings of positive symptoms in schizophrenia.

Anterior cingulate pathology and social cognition in schizophrenia: a study of gray matter, white matter and sulcal morphometry.

The anterior cingulate gyrus (ACG) is a critical structure for social cognitive processing; the pathology of this structure might be a major source of social dysfunction in schizophrenia. Multiple structural abnormalities of the ACG have been demonstrated in schizophrenia including changes in gray matter volume, white matter microstructures and macroscopic sulcal morphology. However, the interrelationships among these different abnormalities have not been investigated. Thus, the relationship between structural abnormalities in the ACG and social cognition in schizophrenia remains to be elucidated. Magnetic resonance imaging data were acquired at 3.0 T from 26 schizophrenic patients and 20 healthy participants. We performed anterior cingulate cortex (ACC) volumetry, evaluated diffusion tensor imaging of the anterior cingulum, analyzed paracingulate/cingulate sulcus (PCS/CS) morphology and investigated the interrelationships among these measures. We also investigated the association between ACG structural abnormalities and psychopathology, and the social cognition ability of schizophrenic patients as estimated by emotion attribution tasks. Compared with healthy subjects, schizophrenic patients exhibited reduced ACC volume, decreased fractional anisotropy in the anterior cingulum bilaterally and a poorly developed PCS/CS in the left hemisphere. No interrelationship was identified among these measures in the schizophrenic group. Schizophrenic patients performed poorly on emotion attribution tasks. Importantly, clinical symptoms and performance on emotion attribution subtasks were associated with ACC volumes and left PCS/CS variation in different ways. These results suggested that pathology of the ACC, anterior cingulum and PCS/CS is, at least partially, independent and has differential impacts on psychopathology and social cognitive impairment in schizophrenia.

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.

Brain volume and dysexecutive behavior in schizophrenia

OBJECTIVE Behaviors associated with frontal/executive impairments are common in patients with schizophrenia. Our aim was to reconfirm that morphological brain abnormalities in schizophrenia patients would overlap the areas underpinning frontal systems behavior, and examine whether any specific association exists between abnormalities of brain structures and frontal behavioral deficits in schizophrenia patients. METHOD Twenty-six schizophrenia patients and 26 matched healthy controls underwent structural magnetic resonance imaging and their frontal function was assessed by a self-rating questionnaire, Frontal Systems Behavior Scale (FrSBe). We applied voxel-based morphometry (VBM) to investigate regional brain volume alternations. RESULT Compared with healthy controls, schizophrenia patients showed reduced gray matter volume in multiple frontal and temporal structures, namely, the bilateral dorsolateral prefrontal cortices (DLPFC), bilateral medial prefrontal cortices, left ventrolateral prefrontal cortex, bilateral anterior cingulate cortices, and bilateral superior temporal gyri. The scores on the executive dysfunction subscale of the FrSBe were correlated with volume reduction in the bilateral DLPFC in the patient group. CONCLUSION Our result suggests that pathology of the DLPFC could be the neural basis of real-life dysexecutive behaviors in schizophrenia patients.

Quantification of Dopamine Transporter in Human Brain Using PET with 18F-FE-PE2I

18F-(E)-N-(3-iodoprop-2E-enyl)-2β-carbofluoroethoxy-3β-(4-methylphenyl)nortropane (18F-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, 18F-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood–brain barrier than did 11C-PE2I. The aims of this study were to examine the quantification of DAT using 18F-FE-PE2I and to assess the effect of radiometabolites of 18F-FE-PE2I on the quantification in healthy humans. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of 18F-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. Results: After the injection of 18F-FE-PE2I, the whole-brain radioactivity showed a high peak (∼3–5 standardized uptake value) and fast washout. The radioactive uptake of 18F-FE-PE2I in the brain was according to the relative density of the DAT (striatum > midbrain > thalamus). The cerebellum showed the lowest uptake. Tissue time–activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. Conclusion: 18F-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of 18F-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

Structural abnormalities of the adhesio interthalamica and mediodorsal nuclei of the thalamus in schizophrenia

OBJECTIVE Several studies have suggested the existence of thalamic volume reduction in patients with schizophrenia. However, the precise locus of volume reduction within the thalamus has scarcely been investigated. On the other hand, underdevelopment of the adhesio interthalamica [AI; Danos, P., Baumann, B., Kramer, A., Bernstein, H.G., Stauch, R., Krell, D., Falkai, P., Bogerts, B., 2003. Volumes of association thalamic nuclei in schizophrenia: a post-mortem study. Schizophrenia Res. 60 141-155], which bridges bilateral medial edges of the thalamus, has been reported in patients with schizophrenia. We assessed the volumes of mediodorsal nuclei (MDN) of thalami, level of AI development, and their interrelationship, in patients with schizophrenia. METHOD A sample of 58 patients with schizophrenia and 44 matched healthy volunteers underwent assessment with high-resolution 1-mm-thick anatomical MRI. Volume measurements of the MDN of the thalamus and whole thalamus were performed by manual tracing. The level of AI development was quantitatively defined as the maximal anterior-to-posterior length of the AI. RESULTS Schizophrenia patients had significantly smaller volumes of bilateral MDN. AI ratings were twice as high in women than in men among the control subjects; however, no gender difference emerged in the schizophrenia group due to reduced ratings in female patients. No significant correlation was found between MDN volumes and AI ratings among both groups. CONCLUSIONS These results provide evidence of volume reduction of the MDN, and female-specific underdevelopment of the AI in schizophrenia. As we did not demonstrate a relationship between MDN volume and AI ratings, it is suggested that these two measures of medial thalamic abnormality are manifestations of different neuropathological processes in schizophrenia patients.

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.

Is there evidence of brain white-matter abnormalities in obsessive-compulsive disorder?: a narrative review.

Objective: Although several studies have confirmed the occurrence of gray-matter abnormalities in obsessive-compulsive disorder (OCD), the literature on white matter in OCD is more limited. In this study, we reviewed the role of white-matter abnormalities in the pathophysiology of OCD. Method: We reviewed the PubMed studies investigating white-matter integrity in patients with OCD between 1980 and 2010. Results: Case studies of patients who developed obsessive-compulsive symptoms secondary to multiple sclerosis, cerebrovascular diseases, and paraneoplastic leucoencephalopathy and controlled studies of patients with OCD examined with neuroimaging techniques (eg, structural, diffusion, and spectroscopic magnetic resonance imaging) were all consistent with the existence of abnormalities in specific white-matter tracts (eg, internal capsule, cingulate bundle, and corpus callosum) of individuals with OCD. Conclusions: Our review emphasizes that the reported white-matter alterations in OCD complement the broader gray-matter abnormalities identified and may well suggest that OCD is associated with large-scale disruption in brain systems or networks, as opposed to being a consequence of disturbances in isolated brain regions.

Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [11C]DASB and (S,S)-[18F]FMeNER-D2

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.