Depression Doesn’t Just Affect the Thinking Brain

The brain scans showed something nobody was looking for.

Source: Keith Tanner / Unsplash

If you have spent any time reading about the neuroscience of depression, you have probably encountered the same effects in the same brain regions again and again: The hippocampus shrinks. The prefrontal cortex, the part of the brain responsible for planning and emotional regulation, becomes less active. The default mode network, the system that hums along when the mind is at rest, loses its coherence. That picture puts depression largely in the brain’s higher-order systems: the circuits involved in thinking, mood and memory.

That story is not wrong, exactly. But a study published this month in Nature Mental Health suggests it is considerably more incomplete than the field has assumed (Hamilton et al., 2026).

What Was Learned About Depression From 23,417 Brain Scans

Researchers at Washington University in St. Louis pooled data from six large population datasets, covering 23,417 participants, making this one of the largest-ever neuroimaging studies of depression. The scale matters because smaller studies are vulnerable to noise; a finding that shows up in 200 participants may disappear in 2,000. With nearly 25,000 participants, the researchers could test whether findings from smaller studies held up at a much larger scale, including findings they expected to see but didn’t.

Some findings confirmed the standard story: Reductions in gray matter volume and cortical surface area appeared in the frontal cortex, the anterior cingulate, and the insula—the regions associated with mood regulation, emotional processing, and self-awareness. Prior research was right about those.

But two results were particularly notable:

They didn’t find significant changes in subcortical brain regions, including the hippocampus. Reduced hippocampal volume has been described as one of the most consistent findings in depression research for decades, but at this sample size, it simply did not emerge as a reliable correlate.

They also found significant reductions in brain volume and surface area in somatomotor and visual regions—the parts of the brain involved in movement, physical sensation, and visual processing. These areas rarely appear in discussions of depression’s neuroscience.

The Importance of Motor and Visual Regions in Depression

Taken together, these findings raise the possibility that some of depression’s physical symptoms have their own neural correlates. The heaviness, slowed movement and changes in visual experience that people describe may not be simply consequences of low mood.

Someone who is depressed may feel heaviness in their limbs, find that movement takes more effort, or experience the world as flatter or duller, as if the contrast has been turned down. Getting out of bed may feel like a physical challenge, not just a motivational one. People experiencing depression describe these experiences routinely, and clinicians tend to treat them as consequences of low mood rather than symptoms in their own right.

These line of research could change how we think about those symptoms. Rather than being secondary effects of low mood, some may have their own neural correlates alongside changes in mood and memory.

Kassandra Hamilton, the study’s first author, is already planning follow-up work to test whether visual and motor regions encode specific symptoms of depression rather than just overall severity. If particular brain regions track particular symptoms, that could eventually help researchers distinguish between different forms of depression and their symptoms.

At 23,417 participants, this study found no significant functional connectivity differences between depressed and non-depressed brains, a result that raises questions about the widely held “disconnection syndrome” model of depression. The model describes depression as a kind of ‘disconnection syndrome,’ in which the default mode network loses coherent communication with other brain systems. It has generated a substantial body of research and influenced ideas about how antidepressants and brain stimulation might work.

For these 23,000 participants, though, that effect did not consistently emerge. We may have been overestimating how central functional connectivity is to depression, at least as a universal feature of the disorder.

Depression Is Both a Mental and Physical Disorder

For anyone who has been told that depression is essentially a problem in the thinking and feeling parts of the brain, this study offers a broader picture. In other words, depression may involve more than the brain regions traditionally associated with mood and cognition. The new findings suggest that motor and visual systems deserve more attention, too.