How is Brain Connectivity Altered in Depression and Those at Genetic Risk?

What you need to know

• People with depression show reduced integrity of white matter tracts in the brain, particularly in regions connecting different parts of the cortex and the thalamus.
• These brain connectivity changes are seen in both currently depressed individuals and those with a history of depression, suggesting they may be a lasting feature.
• Healthy individuals with higher genetic risk for depression show similar reductions in white matter integrity, indicating altered brain connectivity may be an inherited trait that increases depression risk.

Understanding brain connectivity and depression

Depression is one of the most common mental health disorders worldwide, affecting millions of people. While we know that both genetic and environmental factors play a role in depression, researchers are still working to understand exactly how these factors lead to the disorder. One area of intense study is how depression relates to the physical structure and connections in the brain.

Our brains are made up of gray matter, which contains the cell bodies of neurons, and white matter, which contains the long fibers (axons) that connect different brain regions. These white matter connections form the “wiring” of the brain, allowing different areas to communicate. The integrity or health of these white matter tracts can be measured using a brain imaging technique called diffusion MRI.

Key findings on brain connectivity in depression

This study used data from over 19,000 participants in the UK Biobank to investigate white matter integrity in depression. The researchers compared three groups: currently depressed individuals, those with a history of depression but no current symptoms, and people with no history of depression.

The key findings were:

1. Overall reduced white matter integrity: Both currently and formerly depressed individuals showed lower overall integrity of white matter tracts compared to never-depressed individuals.

2. Specific affected regions: The reductions were most prominent in white matter tracts connecting different parts of the cerebral cortex (the outer layer of the brain involved in higher-level functions) and in tracts connecting the cortex to the thalamus (a structure that relays sensory and motor signals).

3. Lasting changes: Importantly, the reductions in white matter integrity were seen in both currently depressed individuals and those with a history of depression but no current symptoms. This suggests these brain connectivity changes may be a lasting feature associated with depression vulnerability, rather than just occurring during depressive episodes.

Genetic risk and brain connectivity

Depression tends to run in families, and genetic studies have identified many genetic variants that each contribute a small amount to depression risk. By combining information from many of these variants, researchers can calculate a “polygenic risk score” that estimates an individual’s genetic liability for depression.

A key question is whether the brain connectivity changes seen in depression are related to this genetic risk. To investigate this, the researchers looked at the relationship between polygenic risk scores for depression and white matter integrity in healthy individuals with no history of depression.

They found that higher polygenic risk scores for depression were associated with reduced white matter integrity, particularly in the same regions affected in diagnosed depression. This means that even in people who have never been depressed, higher genetic risk for the disorder is linked to similar brain connectivity alterations as seen in diagnosed depression.

What does this mean?

These findings suggest that altered brain connectivity, particularly in regions connecting different parts of the cortex and the thalamus, may be an “endophenotype” for depression. An endophenotype is a measurable trait that falls between genes and observable symptoms. It’s thought to be closer to the underlying biology of a disorder than overt symptoms.

The fact that these brain connectivity changes are:

1. Present in depression
2. Seen even after recovery from depression
3. Heritable (as shown by their link to genetic risk scores)
4. Present at a milder level in at-risk but healthy individuals

All of these factors support the idea that altered white matter integrity may be an inherited trait that increases vulnerability to depression, rather than simply being a consequence of the disorder.

Conclusions

• Reduced integrity of white matter tracts, especially those connecting cortical regions and the thalamus, is associated with both current and past depression.
• Similar reductions in white matter integrity are linked to genetic risk for depression, even in never-depressed individuals.
• These findings suggest altered brain connectivity may be an inherited trait that increases vulnerability to depression, providing new insights into how genetic risk may lead to the disorder.
• Understanding these brain connectivity changes could potentially lead to new ways to identify those at risk for depression or to develop targeted treatments in the future.