What areas of the brain are involved in major depressive disorder (MDD)?

Brain Regions Involved in Major Depressive Disorder

The hippocampus, prefrontal cortex (particularly medial prefrontal and anterior cingulate), and limbic structures including the amygdala and insula represent the primary brain regions implicated in major depressive disorder, with the hippocampus showing the most consistent volumetric reductions and the prefrontal-limbic circuits demonstrating the most prominent functional alterations. 1, 2

Structural Brain Alterations

Hippocampus:

• The hippocampus demonstrates the most robust and replicated structural finding in MDD, showing decreased volume compared to healthy controls 3
• Hippocampal volume reductions are more pronounced in patients with comorbid depression across multiple psychiatric conditions, establishing this as a transdiagnostic marker 3
• Specific hippocampal subregions show altered connectivity patterns, with the right hippocampus cornu ammonis (CA) 3/4 demonstrating decreased node strength (reduced connectivity to the rest of the brain) in MDD patients 4
• The right dentate gyrus shows decreased clustering coefficient, indicating it is less embedded within functional brain networks 4

Prefrontal Cortex:

• The dorsomedial prefrontal cortex shows decreased volume in MDD, though this finding is shared with other anxiety and affective disorders 3
• The medial prefrontal cortex (mPFC) demonstrates increased intrinsic brain activity (ALFF) in MDD patients compared to controls 2
• The superior frontal gyrus, including the medial orbitofrontal cortex and anterior cingulate cortex (ACC), shows increased amplitude of low-frequency fluctuations 2

Insular Opercular Region:

• Bilateral insular opercular regions show smaller volumes in MDD, representing a shared feature with other psychiatric conditions 3
• The bilateral insula extending into the striatum demonstrates increased intrinsic brain activity in both MDD and bipolar disorder 2

Functional Network Alterations

Limbic-Prefrontal Circuits:

• MDD involves dysfunction in brain networks linking the limbic system and cortical regions, with altered functional connectivity in resting-state networks 5, 1
• The affective-salience network shows functional changes that are central to MDD pathophysiology 1
• Greater activation in frontal, limbic (including amygdala, insula, nucleus accumbens), and temporal regions during inhibitory control tasks is necessary for MDD patients to achieve performance equivalent to healthy controls 6

Amygdala:

• The amygdala shows altered connectivity patterns, with greater activation during inhibitory control predicting better treatment response 6
• The right amygdala central nucleus (CeA) demonstrates a relationship between its clustering coefficient and depression severity—greater embedding in a cluster correlates with more severe depressive symptoms 4

Connectivity Patterns:

• MDD patients exhibit significantly higher overall coherence (loss of selectivity in functional connectivity) across delta, theta, alpha, and beta frequency bands compared to controls 5
• The frontopolar region contains the greatest number of "hub nodes" with high connectivity 5
• Higher theta and alpha coherence occurs primarily in longer distance connections between frontopolar and temporal or parietooccipital regions 5
• The cognitive control network shows functional alterations that contribute to the cognitive impairments seen in MDD 1

Additional Regions

Cerebellum:

• Bilateral cerebellum shows decreased intrinsic brain activity (ALFF) in MDD, representing a shared finding with bipolar disorder 2

Precuneus:

• Bilateral precuneus demonstrates decreased ALFF in MDD patients 2

Striatum:

• The striatum shows increased intrinsic activity when extending from the insula, though decreased activity in other contexts 2

Clinical Implications

Treatment Response Prediction:

• Greater activation in bilateral inferior frontal cortex, left amygdala, insula, and nucleus accumbens during successful inhibitory control predicts better post-treatment improvement with antidepressants 6
• Activation in rostral anterior cingulate during unsuccessful inhibition (commission errors) also predicts treatment response 6

Common Pitfall: The hippocampal volume reduction in MDD is not specific to depression alone—it occurs across multiple psychiatric disorders with comorbid depression, so this finding should not be used in isolation for diagnosis but rather understood as part of a broader pattern of limbic-prefrontal dysfunction 3.