Dataset Information

Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.

ABSTRACT: Major depressive disorder is a heterogeneous disease involving widespread disruptions in functional brain networks, the neurobiological mechanisms of which are poorly understood. Amassing evidence supports innate immune activation as one pathophysiologic mechanism contributing to depression in a subgroup of patients with elevated inflammatory markers. Although inflammation is known to alter monoamine and glutamate neurotransmitters, little work has been done to understand its role in network dysfunction in patients with depression. Here we conducted a large-scale network-based analyses of resting-state functional magnetic resonance imaging (rfMRI) data acquired from depressed patients with varying levels of inflammation to develop a comprehensive characterization of network alterations as an effect of inflammation. Complementary approaches of global brain connectivity and parcellation-based network analysis applied to the whole brain revealed that increased plasma C-reactive protein (CRP) was associated with reduced functional connectivity in a widely-distributed network including ventral striatum, parahippocampal gyrus/amygdala, orbitofrontal and insular cortices, and posterior cingulate cortex. These broad alterations were centralized in the ventral medial prefrontal cortex (vmPFC), representing a hub for the effects of inflammation on network function in the whole brain. When feeding the identified multivariate network features into a machine learning algorithm of support vector regression, we achieved high prediction accuracies for depressive symptoms that have been associated with inflammation in previous studies including anhedonia and motor slowing. These findings extend and broaden previous observations from hypothesis-driven studies, providing further support for inflammation as a distinct contributing factor to network dysfunction and symptom severity in depression.

SUBMITTER: Yin L

PROVIDER: S-EPMC6660411 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.

Yin Lijun L Xu Xiaodan X Chen Gang G Mehta Neeti D ND Haroon Ebrahim E Miller Andrew H AH Luo Yuejia Y Li Zhihao Z Felger Jennifer C JC

Brain, behavior, and immunity 20190509

Major depressive disorder is a heterogeneous disease involving widespread disruptions in functional brain networks, the neurobiological mechanisms of which are poorly understood. Amassing evidence supports innate immune activation as one pathophysiologic mechanism contributing to depression in a subgroup of patients with elevated inflammatory markers. Although inflammation is known to alter monoamine and glutamate neurotransmitters, little work has been done to understand its role in network dys ...[more]

PMID: 31078690

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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

Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.

Publications

Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.

Similar Datasets

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