Prefrontal brain responsiveness to negative stimuli distinguishes familial risk for major depression from acute disorder

J Psychiatry Neurosci. 2017 Sep;42(5):343-352. doi: 10.1503/jpn.160198.


Background: Identifying reliable trait markers of familial risk for major depressive disorder (MDD) is a challenge in translational psychiatric research. In individuals with acute MDD, dysfunctional connectivity patterns of prefrontal areas have been shown repeatedly. However, it has been unclear in which neuronal networks functional alterations in individuals at familial risk for MDD might be present and to what extent they resemble findings previously reported in those with acute MDD.

Methods: We investigated differences in blood oxygen level-dependent (BOLD) response of the medial orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to aversive stimuli between acute MDD and familial risk for the disorder in healthy first-degree relatives of acutely depressed patients with MDD (HC-FH+), healthy age- and sex-matched controls without any family history of depression (HC-FH-), and acutely depressed patients with MDD with (MDD-FH+) and without a family history of depression (MDD-FH-) during a frequently used emotional face-matching paradigm. Analyses of task-specific network connectivity were conducted in terms of psychophysiological interactions (PPI).

Results: The present analysis included a total of 100 participants: 25 HC-FH+, 25 HC-FH-, 25 MDD-FH+ and 25 MDD-FH-. Patients with MDD exhibited significantly increased activation in the medial OFC to negative stimuli irrespective of familial risk status, whereas healthy participants at familial risk and patients with MDD alike showed significant hypoactivation in the DLPFC compared with healthy participants without familial risk. The PPI analyses revealed significantly enhanced task-specific coupling between the medial OFC and differing cortical areas in individuals with acute MDD and those with familial risk for the disorder.

Limitations: The main limitation of our study is its cross-sectional design.

Conclusion: Whereas hypoactivation during negative emotion processing in the DLPFC appears as a common feature in both healthy high-risk individuals and acutely depressed patients, activation patterns of the medial OFC and its underlying connectivity seem to distinguish familial risk from acute disorder.

MeSH terms

  • Adult
  • Brain Mapping
  • Cerebrovascular Circulation / physiology
  • Cross-Sectional Studies
  • Depressive Disorder, Major / diagnostic imaging
  • Depressive Disorder, Major / genetics
  • Depressive Disorder, Major / physiopathology*
  • Emotions / physiology*
  • Family*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Neuropsychological Tests
  • Oxygen / blood
  • Prefrontal Cortex / diagnostic imaging
  • Prefrontal Cortex / physiopathology*


  • Oxygen