Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder

Abstract

Background: Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral, data-driven approach to the analysis of connectivity is vital.

Methods: We analyzed resting-state functional connectivity data collected at 3T in 27 OCD patients and 66 matched control subjects with a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain.

Results: We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within regions of interest in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD.

Conclusions: These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD.

Keywords: Basal ganglia; functional connectivity; global connectivity; obsessive-compulsive disorder; prefrontal cortex; resting-state fMRI.

Figure 1. Reduced PFC rGBC in Obsessive-compulsive Disorder (OCD)

(A) Clusters where OCD patients showed significantly decreased PFC-restricted rGBC connectivity relative to HCS (see Table 2 for all cluster coordinates). The black border marks the approximate PFC boundary. (B) PFC rGBC reductions for OCD patients (red distribution) relative to HCS (blue distribution), across all voxels in identified clusters of dysconnectivity (see Table 2 for individual cluster statistics). Reported effect sizes are computed across subjects; histograms of voxel distribution within regions of between-group difference are provided for illustrative purposes.

Figure 2. Reduced Prefrontal and Increased Striatal-Cerebellar Whole-brain GBC in Obsessive-compulsive Disorder (OCD)

(A) Clusters where OCD patients showed significantly decreased whole-brain GBC connectivity relative to HCS. This pattern was centered on the left middle frontal gyrus, inferior frontal gyrus, and precentral gyrus (see Table 2 for cluster coordinates). (B) GBC reductions for OCD patients (red histogram) relative to HCS (blue histogram), averaged across all identified clusters (see Table 2 for individual cluster statistics). (C) Clusters where OCD patients showed significantly increased whole-brain GBC connectivity relative to HCS. This pattern was centered on the right putamen and left cerebellum (see Table 2 for cluster coordinates and statistics). (D) GBC increases for OCD patients (red histogram) relative to HCS (blue histogram) across both clusters (see Table 2 for individual cluster statistics). Blue vertical dashed line marks the mean for the HCS group.

Figure 3. Conjunction of PFC and Whole-brain GBC Effects in Obsessive-compulsive Disorder (OCD)

(A) Red clusters mark regions where OCD patients showed significantly decreased whole-brain GBC connectivity relative to HCS (Figure 2). Yellow clusters show regions where OCD patients significantly decreased PFC rGBC connectivity relative to HCS (Figure 1). Blue foci mark the conjunction. The PFC and whole-brain effects are partially independent (as the whole-brain analysis involves many more voxels). (B) Reductions for OCD patients (red histogram) relative to HCS (blue histogram) averaged across the two clusters surviving the conjunction (see Table 2 for individual cluster statistics)

Figure 4. Region-of-interest (ROI)-focused Analyses of Accumbens, Caudate, Putamen and Thalamic GBC

(A) Differences between OCD and HCS within striatum and thalamus, defined on the basis of subjects’ individual anatomy. Red-yellow foci mark regions where OCD patients showed increased GBC relative to HCS, while blue foci show regions where OCD patients showed reduced GBC relative to HCS. Note the dissociation between the accumbens and the rest of the striatum and thalamus: OCD was associated with reduced GBC in the accumbens, but increased GBC elsewhere, as illustrated in the bar graph on the right. (B–E) GBC across all voxels in a priori anatomically-defined ROIs for the accumbens, caudate, putamen and thalamus (insets highlight each region). As noted in the main text, there was a significant dissociation between accumbens and other ROIs across the groups (F(3,273)=3.55, p<.02).

Figure 5. Seed-based Anatomically-defined Nucleus Accumbens Group Difference in Connectivity

Prior seed-based connectivity analyses of striatal structures in OCD have reported an increase in coupling between the nucleus accumbens and ventral anterior cingulate cortex (ACC)(32, 33). We performed a similar analysis to see whether such increased seed-based connectivity coexisted with the reduced GBC seen in the accumbens (Figure 4). (A) Increased connectivity with the anatomically-defined accumbens seed was seen in the ventral ACC (Talairach coordinates: x=−16, y=27, z=14, 864mm³ in size, Mean t-statistic=3.19). (B) Increased accumbens-ACC connectivity, across all voxels in the area of significant between-group difference. Given a priori evidence for increased connectivity between ACC and accumbens in OCD(32), to increase power, we employed a small-volume type I error correction for PFC voxels identical to that used in our restricted GBC approach reported in the main text. (C) The positive relationship between accumbens-MPFC over-connectivity positively correlated with symptom severity across all four measures reported in the main text (HAM-D=.31; HAM-A=.55; YBOCS-O=.17; YBOCS-C=.24), particularly prominent for HAM-A (r=.55, p<.0035, surviving Bonferroni correction across four comparisons, panel C).