Takashi Nakamae

Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder

OBJECTIVE Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. METHOD A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. RESULTS Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). CONCLUSIONS These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

Corticostriatal functional connectivity in non-medicated patients with obsessive-compulsive disorder.

The basal ganglia represents a key component of the pathophysiological model for obsessive-compulsive disorder (OCD). This brain region is part of several neural circuits, including the orbitofronto-striatal circuit and dorsolateral prefronto-striatal circuit. There are, however, no published studies investigating those circuits at a network level in non-medicated patients with OCD. Resting state functional magnetic resonance imaging scans were obtained from 20 non-medicated patients with OCD and 23 matched healthy volunteers. Voxelwise statistical parametric maps testing strength of functional connectivity of three striatal seed regions of interest (ROIs) with remaining brain regions were calculated and compared between groups. We performed additional correlation analyses between strength of connectivity and the severity scores for obsessive-compulsive symptoms, depression, and anxiety in the OCD group. Positive functional connectivity with the ventral striatum was significantly increased (P(corrected) < .05) in the orbitofrontal cortex, ventral medial prefrontal cortex and dorsal lateral prefrontal cortex of subjects with OCD. There was no significant correlation between measures of symptom severity and the strength of connectivity (P(uncorrected) < .001). This is the first study to investigate the corticostriatal connectivity in non-medicated patients with OCD. These findings provide the first direct evidence supporting a pathophysiological model involving basal ganglia circuitry in OCD.

Alteration of fractional anisotropy and apparent diffusion coefficient in obsessive-compulsive disorder: a diffusion tensor imaging study.

BACKGROUND Abnormalities of fractional anisotropy (FA) have been reported in previous diffusion tensor imaging (DTI) studies in patients with obsessive-compulsive disorder (OCD). However, there are some inconsistencies in the results and the apparent diffusion coefficient (ADC) has not been investigated. The goal of this study was to investigate white matter abnormalities and water diffusivity, as reflected by FA and ADC, using DTI in patients with OCD. METHODS Fifteen patients with OCD and 15 healthy volunteers underwent DTI. Voxelwise analysis was used to compare FA in white matter and ADC in gray matter/white matter of the two groups. RESULTS Compared with healthy volunteers, the patients had higher FA in the bilateral semioval center extending to the subinsular white matter; and a higher ADC in the left medial frontal cortex. There were no areas with a significantly lower FA or ADC in patients compared with healthy volunteers. CONCLUSIONS A significantly higher FA was found in regions associated with the emotion of disgust and a trend for a higher ADC was found in a region associated with the regulation of emotions. These findings suggest that neurocircuits involved in disgust processing may play an important role in the pathophysiology of OCD.

Relationships among burnout, coping style and personality: Study of Japanese professional caregivers for elderly

Aim:  To investigate relationships among burnout, coping style and personality.

Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis.

OBJECTIVE Structural brain imaging studies in obsessive-compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta- and mega-analyses of data from OCD sites worldwide. METHOD T1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta-analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. RESULTS The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohens d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. CONCLUSIONS The results indicate different patterns of subcortical abnormalities in pediatric and adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Anterior insular volume is larger in patients with obsessive-compulsive disorder.

There has been increasing evidence indicating gray matter abnormalities in patients with obsessive-compulsive disorder (OCD). Several voxel-based morphometry (VBM) studies have reported volume changes in the insular cortex. Although there are distinct differences in the connectivity and functions in the anterior and posterior insular cortices, these two regions have never been distinguished in previous VBM studies. In this study, we adopted a region of interest (ROI) method to measure insular volume separately. We investigated insular volume in 32 drug-free patients with OCD and in 34 healthy controls using magnetic resonance imaging (MRI). Repeated measures multivariate analysis of covariance (MANCOVA) was conducted to examine the difference between the patients and the controls. Compared with the healthy controls, the patients had a significantly larger gray matter volume in the anterior insular cortex bilaterally (post hoc test, p=0.036; left, p=0.047; right). This is the first volumetric MRI study to separately investigate the anterior and posterior insular cortex volumes in non-medicated patients with OCD. The results suggest that the anterior insular cortex may be related to the pathophysiology of OCD.

Brain circuitry of compulsivity

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.

A tract-based spatial statistics study in anorexia nervosa: abnormality in the fornix and the cerebellum.

There has been an increasing interest in white matter abnormalities in patients with anorexia nervosa (AN). However, to date, there have been only a few diffusion tensor imaging (DTI) studies investigating AN, and the results are inconsistent. In this study, we employed tract-based spatial statistics (TBSS), a robust technique for whole-brain analysis of DTI data, to detect white matter abnormalities in AN patients compared with healthy controls. Seventeen women with AN and 18 age matched healthy women were included. The mean body mass index of patients was 13.6 kg/m(2) (controls: 19.9 kg/m(2)). DTI data were acquired on a 3-Tesla magnetic resonance imaging system. Fractional anisotropy (FA) and mean diffusivity (MD) maps were calculated from the DTI data of each patient, and voxel-wise group comparisons of FA and MD were performed using TBSS. Compared with the healthy comparisons, the patients showed a significantly higher MD value in the fornix and lower FA value in the left cerebellum. We also found significant positive correlations between the mean FA value of the left cerebellar hemisphere cluster and BMI, as well as between the mean MD value of the cluster in the anterior body of the fornix and the duration of illness. The results suggest that the white matter abnormalities in the fornix and the cerebellum may be related to the pathophysiology of AN.

Neural correlates of performance on the different scoring systems of the clock drawing test

The aim of this study was to identify brain regions associated with performance on various measures of the clock drawing test (CDT) using magnetic resonance imaging (MRI).We recruited 48 participants (four healthy, eight with mild cognitive impairment and 36 with Alzheimers disease). Multiple regression analyses identified relationships between each CDT scoring system (Shulman CDT, Rouleau CDT and CLOX1) and regional gray matter (GM) volume.CDT scores were positively correlated with regional GM volume in the right parietal lobe for all three CDT scoring systems. In addition, CDT scores were positively correlated with regional GM volume in the bilateral posterior temporal lobes for the Shulman CDT, in the right posterior inferior temporal lobe for the Rouleau CDT and in the right posterior superior temporal lobe for the CLOX1.Although the scoring systems share commonalities, each CDT scoring system may reflect different areas of brain damage.

Effect of traditional Japanese herbal medicine toki-shakuyaku-san for mild cognitive impairment: SPECT study.

Traditional Japanese herbal medicines (so-called Kampo) are widely used in clinical settings in Japan. Toki-shakuyaku-san (TSS) was described in the classic Kampo text Kinkiyoryaku approximately 1000 years ago and is mainly used for gynecologic disorders (climacteric disorders, dysmenorrhea, anemia), because it improves peripheral circulation disturbance (so-called ‘Oketsu syndrome’); but TSS may also have neuroprotective and antidementia effects. Amnestic mild cognitive impairment (MCI) is defined as a subtle but measurable memory disorder, in which memory problems are greater than normally expected with aging, but no other symptoms of dementia are observed. Amnestic MCI carries a high risk of progression to Alzheimer’s disease (AD). Cholinesterase inhibitors (ChEI) may prevent progression to AD, but pharmacological therapy for MCI has not been established; therefore, we examined the efficacy of TSS for treatment of amnestic MCI. The subjects were three patients with amnestic MCI diagnosed based on criteria of the international working group on MCI. The patients were treated with TSS for 8 weeks. TSS is registered in the Pharmacopoeia of Japan as Kampo Medicine TJ-23 and was provided by Tsumura (Tokyo, Japan). TSS is prepared from the extract of a mixture of dried plants: 4.0 g peony root, 4.0 g Atractylodes lancea rhizome, 4.0 g Alisma rhizome, 4.0 g Hoelen, 3.0 g Cnidium rhizome, and 3.0 g Japanese angelica root, giving 7.5 g of powder as a daily dose. Magnetic resonance imaging (MRI) was performed before treatment and N-isopropyl-p[I]iodoamphetamine single-photon emission computed tomography (SPECT) and a mini-mental state examination (MMSE) were performed before and after treatment. SPECT images were analyzed using 3-D stereotactic surface projections (3D-SSP). This study was approved by the ethics committee of Kyoto Prefectural University of Medicine (C-97) and written informed consent was obtained from the subjects. Patient 1 was a 74-year-old woman with 11 years of education.MRI showed very mild brain atrophy, including in the hippocampus; MMSE scores before and after treatment were 23 (time, -2; place, -1; recall, -3; 3-step order -1) and 26 (time, -2; serial 7, -2), respectively; and SPECT showed decreased regional cerebral blood flow (rCBF) in the bilateral posterior cingulate before treatment. The decrease diminished following treatment. Patient 2 was a 79-year-old woman with 11 years of education. MRI showed left-dominant very mild brain atrophy, including in the hippocampus; MMSE scores before and after treatment were 26 (place, -1; recall, -3) and 27 (place, -1; recall, -2), respectively; and SPECT showed decreased rCBF in the left temporoparietal lobe and the left superior lateral frontal lobe before treatment. The decrease diminished following treatment. Patient 3 was a 76-year-old woman with 10 years of education. MRI showed left-dominant mild brain atrophy, including the hippocampus; MMSE scores before and after treatment were 22 (time, -1; place, -1; serial 7, -4; recall, -1; 3-step order, -1) and 25 (serial 7, -4; recall, -1), respectively; and SPECT showed decreased rCBF in the bilateral anterior temporal and inferior frontal lobes before treatment. Although the decrease diminished following treatment, a new decrease in rCBF appeared in the bilateral frontal poles. An 8-week prescription of TSS improved cognitive dysfunction in all three cases of amnestic MCI, rCBF decrease markedly in two of the patients, and no marked adverse effects were observed in any of the patients. This suggests that TSS may improve central nervous circulation and enhance cognitive function in amnestic MCI. TSS activates the central nervous acetylcholinergic system, similarly to ChEI, and may also affect the activities of superoxide dismutase, lipid peroxides, glutamate, monoamine, and nerve growth factors in the central nervous system; these properties suggest that TSS exerts neuroprotective effects via pathways that are unaffected by conventional antidementia drugs. Although studies in more subjects are required, TSS may be a pharmacotherapeutic option for MCI to prevent progression to AD because its safety and cost-effectiveness have been established over its long history of use. This study was supported by the research fund of the Institute of Kampo Medicine (Japan).