Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal-Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity

Matilde M Vaghi, Petra E Vértes, Manfred G Kitzbichler, Annemieke M Apergis-Schoute, Febe E van der Flier, Naomi A Fineberg, Akeem Sule, Rashid Zaman, Valerie Voon, Prantik Kundu, Edward T Bullmore, Trevor W Robbins, Matilde M Vaghi, Petra E Vértes, Manfred G Kitzbichler, Annemieke M Apergis-Schoute, Febe E van der Flier, Naomi A Fineberg, Akeem Sule, Rashid Zaman, Valerie Voon, Prantik Kundu, Edward T Bullmore, Trevor W Robbins

Abstract

Background: A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity.

Methods: Multiecho resting-state acquisition, combined with micromovement correction by blood oxygen level-dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal-directed performance (planning of sequential response sequences) by means of well-validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal-directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived.

Results: Reduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects.

Conclusions: These data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms.

Keywords: Cognitive flexibility; Frontostriatal circuits; Functional connectivity; Goal-directed planning; Obsessive-compulsive disorder; Resting state.

Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Cognitive flexibility and role of striatal connectivity in obsessive-compulsive disorder (OCD) patients. (A) Schematic illustration of the intra-/extradimensional set shift (IED) task testing cognitive flexibility in which stimuli comprising two dimensions (i.e., line and color-filled shape) are presented. (B) Mean number of errors by learning stage on the IED task. OCD patients showed impaired cognitive flexibility, evidenced by selectively more errors at the extradimensional shift (EDs) stage compared with matched healthy subjects (CTL). (C) Set of brain areas, including left ventrolateral prefrontal cortex (PFC; Brodmann area [BA] 10/11/47), for which significant reduced connectivity with the left dorsal caudate (DCd) was found to be significantly related to worse cognitive flexibility in OCD patients (cluster size after applying a per voxel threshold of p < .01; cluster-corrected significance at least p < .01). (D) The correlation plot shows that reduced functional connectivity between the left dorsal caudate and the left ventrolateral PFC (BA 10/11/47) predicted higher number of errors at the EDs stage in OCD patients. Regression line and 95% confidence interval are shown. (E) Bar plot showing mean functional connectivity between the left dorsal caudate and the left ventrolateral PFC (BA 10/11/47) in OCD patients (mean split according to EDs performance). Error bars represent SEM. **p ≤ .01, ***p ≤ .001. CD, superimposed compound discrimination; C_D, separated compound discrimination; CDr, superimposed compound discrimination reversal; CTL, control subjects; EDr, extradimensional shift reversal; IDs, intradimensional shift; IDr, intradimensional shift reversal; SD, simple discrimination; SDr, simple discrimination reversal.
Figure 2
Figure 2
Goal-directed planning and role of striatal connectivity in obsessive-compulsive disorder (OCD) patients. (A) Schematic illustration of the One-Touch Stockings of Cambridge (OTS) task testing executive planning. Examples from easy (2 moves) and difficult (5 moves) problems are shown. (B) Mean number of attempts to reach correct solution at different difficulty levels on the OTS task. OCD patients show impairment in goal-directed planning compared with matched control subjects (CTL) by requiring more attempts to reach the correct solution at the hard levels of difficulty; there was no group difference for the easy problems. (C) Set of brain areas, including right dorsolateral prefrontal cortex (PFC; Brodmann area [BA] 46), for which significant connectivity with the right putamen (PUT) was found to be significantly related to goal-directed executive planning in OCD patients (cluster size after applying a per voxel threshold of p < .01; cluster-corrected significance at least p < .01). Blue and yellow coloration for weakened and increased connectivity predicting worse or better performance, respectively. (D) The correlation plot shows that reduced functional connectivity between the right PUT and the right dorsolateral PFC (BA 46) predicted higher number of attempts at the most difficult level of goal-directed planning (6 moves) in OCD patients. Regression line and 95% confidence interval are shown. (E) Bar plot showing mean functional connectivity between the right PUT and the right dorsolateral PFC (BA 46) in OCD patients (mean split according to OTS performance at the most difficult level). Error bars represent SEM. *p ≤ .05, ***p ≤ .001.
Figure 3
Figure 3
Relation between obsessive-compulsive disorder (OCD) severity and goal-directed performance. Impoverished goal-directed performance at the hardest level of goal-directed planning positively correlated with (A) self-reported severity of OCD symptoms (OCI-R: r24 = .6, p = .001, surviving Bonferroni correction) and (B) anxiety (STAI-State: r24 = .531, p = .005, surviving Bonferroni correction) in OCD-medicated patients. OCI-R, Obsessive-Compulsive Inventory-Revised (59); STAI, State-Trait Anxiety Inventory (61).
Figure 4
Figure 4
Network modular organization in obsessive-compulsive disorder (OCD) and healthy subjects (CTL). (A) Differences in modular organization in OCD and healthy volunteers represented by an alluvial diagram. Each module is separated by white gaps. The flows indicate the nodes for which community structure changes as a function of diagnosis. Red-highlighted module in OCD patients correspond to nodes of the basal ganglia and cerebellum. These nodes are clustered in one module on their own in OCD patients; the same nodes are integrated within separate large cortico-subcortical modules in CTL. (B) Nodes for OCD and healthy subjects in anatomical space, color-coded according to module membership. The size of the nodes depends on their number of connections. Respectively, for CTL and OCD patients, lower panels highlight the nodes identified by the modularity algorithm as being part of an independent functional unit in OCD patients (and corresponding to basal ganglia and cerebellum). Nodes are colored according to module membership, highlighting that nodes corresponding to different parts of the basal ganglia (caudate, putamen) and cerebellum are clustered in one single module in OCD patients. In contrast, in healthy subjects the same brain areas are integrated within separate modules. (C) Box plot summarizing mean number of connections for nodes identified as being part of an independent functional unit in OCD patients and corresponding to the basal ganglia and the cerebellum. For those nodes, there were no group differences in total number of connections or in the number of interconnections. However, they were significantly more intraconnected in OCD patients than in healthy CTL. *p ≤ .05.

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