Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties

Abstract

Background: Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored.

Method: In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties).

Results: Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later.

Conclusions: These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.

Trial registration: ClinicalTrials.gov NCT00101452.

Figure 1

A. Clusters in left and right caudate exhibiting hypo activation in depressed individuals (MDD) compared to healthy controls (HC) in response to monetary gains and penalties vs. responses to neutral outcome (p < 0.005 or Z > 2.58, uncorrected for multiple comparisons across voxels). B. Average activation values as extracted from bilateral caudate mask, indicating that relative to healthy controls, depressed individuals exhibited decreased bilateral caudate activation to both gains and penalties. Bars ±1 S.E.M. * p< 0.05, ** p< 0.005.

Figure 2

A. Two distinct dACC clusters with opposite caudate connectivity abnormalities in MDD. dACC₁ (blue) was more functionally connected to the caudate in controls (HC) compared to MDD during gains, whereas dACC₂ (red) was more functionally connected to the caudate in MDD compared to controls during penalties. B. Mean parameter estimates (connectivity values) from each dACC section for each condition. Bars ±1 S.E.M. * p< 0.05, ** p< 0.005.

Figure 3

Caudate-dACC connectivity in MDD aggregated across both incentives is positively correlated with the percentage of symptom change following 12 weeks of treatment. The closer the pattern of pre-treatment caudate-dACC connectivity was to the controls’ pattern, the larger was the improvement in symptoms. % Symptom change = [(HDRS_17(pre) – HDRS_17(post)) / HDRS_17(pre)]. Caudate-dACC connectivity = [(dACC₁-Caudate connectivity during gains) – (dACC₂-Caudate connectivity during penalties)].