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

ABSTRACT: 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.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).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.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.

SUBMITTER: Admon R

PROVIDER: S-EPMC4233014 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Admon R R Nickerson L D LD Dillon D G DG Holmes A J AJ Bogdan R R Kumar P P Dougherty D D DD Iosifescu D V DV Mischoulon D D Fava M M Pizzagalli D A DA

Psychological medicine 20140515 1

<h4>Background</h4>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.<h4>Method</h4>In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functiona ...[more]

PMID: 25055809

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Project description:Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD.

Project description:Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Dataset Information

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

Publications

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

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