Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression

Samuel Rupprechter, Liana Romaniuk, Peggy Series, Takehiro Hirose, Emma Hawkins, Anca-Larisa Sandu-Giuraniuc, Gordon D Waiter, Christopher J McNeil, Xueyi Shen, Mathew A. Harris, Archie Campbell, David Porteous, Jennifer A. Macfarlane, Stephen M. Lawrie, Alison D Murray, Mauricio R Delgado, Andrew M. McIntosh, Heather C. Whalley, J Douglas Steele* (Corresponding Author)

*Corresponding author for this work

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39 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1946-1956
Number of pages11
Issue number6
Early online date8 May 2020
Publication statusPublished - 1 Jun 2020

Bibliographical note

Stratifying Resilience and Depression Longitudinally (STRADL) was supported by the Wellcome Trust through a Strategic Award (Grant No. 104036/Z/14/Z). Parts of the work were supported by a China Scholarship Council (Grant No. 201506040037 to SX), National Institutes of Health (Grant No. DA027764 to MRD), Lister Institute Prize Fellowship 2016–2021 (to DJS), Dr Mortimer and Theresa Sackler Foundation (AMM, HCW, and SML), Centre for Cognitive Ageing and Cognitive Epidemiology (IJD and AMM), Medical Research Council and Biotechnology and Biological Sciences Research Council (Grant No. MR/K026992/1), Royal College of Physicians of Edinburgh John, Margaret, Alfred
and Stewart Sim fellowship (to HCW), and University of Edinburgh, Edinburgh Scientific Academic TmPCk College Fellowship (to HCW). The Chief Scientist Office of the Scottish Government Health Department (Grant No. CZD/16/6) and Scottish Funding Council (Grant No. HR03006) provided core support for Generation Scotland. Data acquisition was additionally supported by the Scottish Mental
Health Research Network and Scottish Government’s Support for Science initiative. LR, HCW, and AMM, received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with schizophrenia and bipolar disorder. AMM has previously received grant support from Lilly and Janssen. SML has received honoraria for lectures, chairing meetings, and consultancy work
from Janssen in connection with brain imaging and therapeutic initiatives for psychosis. JDS has received funding via an honorarium associated with a lecture or Wyeth and funding from Indivior for a study on opioid dependency. No other disclosures were reported. The authors declare no conflict of interest.


  • RDoC
  • effective connectivity
  • reinforcement learning
  • model-based fMRI
  • reward prediction error
  • MDD
  • DCM


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