Yuki Sakai

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.

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.

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.

Optogenetic activation of CA1 pyramidal neurons at the dorsal and ventral hippocampus evokes distinct brain-wide responses revealed by mouse fMRI.

The dorsal and ventral hippocampal regions (dHP and vHP) are proposed to have distinct functions. Electrophysiological studies have revealed intra-hippocampal variances along the dorsoventral axis. Nevertheless, the extra-hippocampal influences of dHP and vHP activities remain unclear. In this study, we compared the spatial distribution of brain-wide responses upon dHP or vHP activation and further estimate connection strengths between the dHP and the vHP with corresponding extra-hippocampal areas. To achieve this, we first investigated responses of local field potential (LFP) and multi unit activities (MUA) upon light stimulation in the hippocampus of an anesthetized transgenic mouse, whose CA1 pyramidal neurons expressed a step-function opsin variant of channelrhodopsin-2 (ChR2). Optogenetic stimulation increased hippocampal LFP power at theta, gamma, and ultra-fast frequency bands, and augmented MUA, indicating light-induced activation of CA1 pyramidal neurons. Brain-wide responses examined using fMRI revealed that optogenetic activation at the dHP or vHP caused blood oxygenation level-dependent (BOLD) fMRI signals in situ. Although activation at the dHP induced BOLD responses at the vHP, the opposite was not observed. Outside the hippocampal formation, activation at the dHP, but not the vHP, evoked BOLD responses at the retrosplenial cortex (RSP), which is in line with anatomical evidence. In contrast, BOLD responses at the lateral septum (LS) were induced only upon vHP activation, even though both dHP and vHP send axonal fibers to the LS. Our findings suggest that the primary targets of dHP and vHP activation are distinct, which concurs with attributed functions of the dHP and RSP in spatial memory, as well as of the vHP and LS in emotional responses.

Hyper-influence of the orbitofrontal cortex over the ventral striatum in obsessive-compulsive disorder.

Dysfunction of the fronto-striato-thalamic circuit routing through the orbitofrontal cortex (OFC) is thought to play the main role in the pathophysiology of obsessive-compulsive disorder (OCD). Repetitious stimulation of the OFC-ventral striatum (VS) projections in mice has been shown to increase the firing of the postsynaptic VS cells and the frequency of OCD-like symptoms. Moreover, increased functional connectivity (FC) between the OFC and the VS has been reported in patients with OCD. While FC is a synchronous, non-directed correlation, the directed influence between these brain regions remains unclear in patients with OCD. We obtained resting state functional magnetic resonance imaging scans from 37 non-medicated patients with OCD and 38 matched healthy volunteers, and calculated bivariative voxel-wise Granger Causality (GC) to and from three striatal regions of interest (ROI) using a blind deconvolution procedure. Additionally, we conducted multivariative GC analysis to determine if the effect revealed by the bivariative voxel-wise GCA is mediated by another seed ROI. We found a significant hyper-influence of the OFC over the VS of subjects with OCD (p<.05, corrected). Multivariative GC analysis confirmed this effect (p<.05, corrected) and that it was not mediated by another brain area within the striatum. This is the first study investigating the directed influence of the fronto-striato-thalamic loop in non-medicated patients with OCD. We confirmed the hyperactive connection from the OFC to the VS that is consistent with previous animal studies. These findings provide evidence for the more detailed pathophysiology of OCD.

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.

The neural basis of dysfunctional beliefs in non-medicated patients with obsessive–compulsive disorder

Dysfunctional beliefs may contribute to the development and maintenance of obsessive-compulsive disorder (OCD) according to some cognitive theories. As little has been investigated about the pathophysiology of dysfunctional beliefs in OCD, this study aimed to determine the anatomical regions that are related to OCD-related dysfunctional beliefs. We first examined 23 non-medicated patients with OCD by magnetic resonance imaging (MRI) and assessed their dysfunctional beliefs using the Obsessive Beliefs Questionnaire-44 (OBQ-44). OBQ-44 has three factors: (1) inflated personal responsibility and the tendency to overestimate threat (OBQ-RT), (2) perfectionism and intolerance of uncertainty (OBQ-PI), and (3) over-importance and over-control of thoughts (OBQ-IC). Voxelwise analysis was used to investigate the correlation between whole brain gray matter volume and each score of OBQ-44 covarying for age, gender, education, severity, and intracranial volume. We found a significant negative correlation between gray matter volume and OBQ-IC scores in the left amygdala; there was no significant correlation with other scores. Comparison of the amygdala volume between patients with OCD and 23 matched healthy controls indicated no volume difference between groups. Taken together, the left amygdala volume may play a role in the presence of certain dysfunctional beliefs in OCD patients.

Relationship of γ-aminobutyric acid and glutamate+glutamine concentrations in the perigenual anterior cingulate cortex with performance of Cambridge Gambling Task.

The anterior cingulate cortex (ACC), consisting of the perigenual ACC (pgACC) and mid-ACC (i.e., affective and cognitive areas, respectively), plays a significant role in the performance of gambling tasks, which are used to measure decision-making behavior under conditions of risk. Although recent neuroimaging studies have suggested that the γ-aminobutyric acid (GABA) concentration in the pgACC is associated with decision-making behavior, knowledge regarding the relationship of GABA concentrations in subdivisions of the ACC with gambling task performance is still limited. The aim of our magnetic resonance spectroscopy study is to investigate in 20 healthy males the relationship of concentrations of GABA and glutamate+glutamine (Glx) in the pgACC, mid-ACC, and occipital cortex (OC) with multiple indexes of decision-making behavior under conditions of risk, using the Cambridge Gambling Task (CGT). The GABA/creatine (Cr) ratio in the pgACC negatively correlated with delay aversion score, which corresponds to the impulsivity index. The Glx/Cr ratio in the pgACC negatively correlated with risk adjustment score, which is reported to reflect the ability to change the amount of the bet depending on the probability of winning or losing. The scores of CGT did not significantly correlate with the GABA/Cr or Glx/Cr ratio in the mid-ACC or OC. Results of this study suggest that in the pgACC, but not in the mid-ACC or OC, GABA and Glx concentrations play a distinct role in regulating impulsiveness and risk probability during decision-making behavior under conditions of risk, respectively.

A Neural Marker of Obsessive-Compulsive Disorder from Whole-Brain Functional Connectivity

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder with a lifetime prevalence of 2–3%. Recently, brain activity in the resting state is gathering attention for exploring altered functional connectivity in psychiatric disorders. Although previous resting-state functional magnetic resonance imaging studies investigated the neurobiological abnormalities of patients with OCD, there are concerns that should be addressed. One concern is the validity of the hypothesis employed. Most studies used seed-based analysis of the fronto-striatal circuit, despite the potential for abnormalities in other regions. A hypothesis-free study is a promising approach in such a case, while it requires researchers to handle a dataset with large dimensions. Another concern is the reliability of biomarkers derived from a single dataset, which may be influenced by cohort-specific features. Here, our machine learning algorithm identified an OCD biomarker that achieves high accuracy for an internal dataset (AUC = 0.81; N = 108) and demonstrates generalizability to an external dataset (AUC = 0.70; N = 28). Our biomarker was unaffected by medication status, and the functional networks contributing to the biomarker were distributed widely, including the frontoparietal and default mode networks. Our biomarker has the potential to deepen our understanding of OCD and to be applied clinically.