Single brain region linked to depression and anxiety, heart disease and response to treatment

Marmoset study published in Nature Communications finds single brain region linking depression and anxiety, heart disease, and people’s sensitivity to treatment

Researchers in PDN including previous PhD student and newly qualified Academic Foundation Doctor, Laith Alexander, and senior postdoctoral scientist, Christian Wood, along with Phil Gaskin, Steve Sawiak, Tim Fryer, Young Hong, Lauren McIver and Hannah Clarke, led by Angela Roberts, show that over-activity in a single brain region called the subgenual anterior cingulate cortex (sgACC) underlies several key symptoms of mood and anxiety disorders, but an antidepressant only successfully treats some of the symptoms.

Depression is a debilitating disorder affecting hundreds of millions of people worldwide, but people experience it differently. Some mainly have symptoms of elevated negative emotion like guilt and anxiety; some have a loss of ability to experience pleasure (called anhedonia); and others a mix of the two. In this latest study it has been found that increased activity in sgACC – a key part of the emotional brain– could underlie increased negative emotion, reduced pleasure and a higher risk of heart disease in depressed and anxious people. More revealing still is the discovery that these symptoms differ in their sensitivity to treatment with an antidepressant, despite being caused by the same change in brain activity. 

Using a glutamate transporter blocker, the team over-activated marmoset sgACC to show that over-activity increases heart rate, elevates cortisol levels and exaggerates animals’ responsiveness to threat, mirroring the stress-related symptoms of depression and anxiety. This builds on their earlier work showing that over-activity also reduces anticipation and motivation for rewards, mirroring the loss of ability to experience pleasure seen in depression.

Brain imaging revealed the neural network affected by sgACC over-activity during threat, with increased activity observed within the amygdala and hypothalamus, two key parts of the brain’s stress network. Corresponding reductions in activity were seen in parts of the lateral prefrontal cortex – a region important in regulating emotional responses and shown to be underactive in depression.

These were a different set of brain regions to those identified when sgACC was over-activated in rewarding contexts. This may be key, because the distinct brain networks might explain the differential sensitivity of threat-related and reward-related symptoms to ketamine treatment.  For example, ketamine – which has rapidly acting antidepressant properties – ameliorated anhedonia-like symptoms but did not improve the elevated anxiety-like responses displayed by the marmosets.

Overall, this research shows that the sgACC may sit at the head and the heart of the matter when it comes to the symptoms and treatment of depression and anxiety.

This research was funded by the Wellcome Trust.

Reference: Alexander L., Wood C.M., Gaskin P.R.L., Sawiak S.J., Fryer T.D., Hong Y.T., McIver L., Clarke H.F., Roberts A.C. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioural and neural responses to threat.’ Nature Communications, October 2020. DOI: 10.1038/s41467-020-19167-0