The orbitofrontal cortex (OFC)—a region of the brain involved in processing emotions and reward—plays a key role in major depressive disorder, wrote the authors of a review article in Molecular Psychiatry. They describe evidence supporting the different ways that dysfunction in the OFC contributes to major depression and how conventional antidepressants only mitigate some of these problems.
“Despite strong evidence for anatomic and functional heterogeneity within the OFC, some studies have treated this region as a unified whole,” wrote Bei Zhang, M.D., of Fudan University in China and colleagues. “Our proposal, which distinguishes between the medial and lateral OFC in a reward and non-reward/punishment framework, describes functional differentiation within the OFC, and importantly, proposes how this differentiation is associated with different symptoms of [major depressive disorder].”
The authors reviewed numerous neuroimaging studies comparing the brain structure and brain activity of people with or without depression. They reported that people with major depression have reduced connectivity between the medial OFC (the middle segment of the region) and other brain regions that are involved in emotional learning, such as the amygdala. Zhang and colleagues suggested that lower connectivity between these regions may reduce individuals’ sensitivity to positive rewards, leading to greater anhedonia (inability to experience pleasure). In contrast, people with major depression tend to have increased connectivity between the lateral OFC (left and ride sides) and regions that regulate attention and decision making, such as the anterior cingulate cortex. Zhang and colleagues suggested that higher connectivity between these regions may increase individuals’ sensitivity to aversive stimuli, leading to negative bias (the tendency to dwell on negative events).
Zhang and colleagues described other studies that show that antidepressants such as selective serotonin reuptake inhibitors mainly restore normal connectivity in the lateral OFC but have minimal impact on the medial OFC. However, emerging data suggest that ketamine—which targets glutamate rather than serotonin—may boost connectivity in the medial OFC and may be a more promising option when anhedonia is a primary symptom. Psychedelics may also improve connectivity to and from the medial OFC, though to date, only one study has demonstrated this.
“[A]lthough we have underscored the critical role of the OFC in depression, it is unlikely that depression can be solely attributed to impairments in a single brain region due to its complexity and heterogeneity,” the authors concluded. “More evidence is needed to examine how these other brain regions interact with the orbitofrontal cortex in MDD or different subtypes of MDD.”
To read more on this topic, see The American Journal of Psychiatry review, “Toward a Better Understanding of the Mechanisms and Pathophysiology of Anhedonia: Are We Ready for Translation?”
(Image: Getty Images/iStock/BlackJack3D)
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