What is the correct brain region for depression?

Brain Regions Implicated in Depression

The hippocampus is the key anatomical brain region most consistently associated with depression, showing reduced volume and impaired synaptic plasticity in both human patients and animal models. 1

Primary Brain Region: The Hippocampus

The hippocampus stands out as the most robustly implicated single brain region in depression pathophysiology:

• Structural changes include decreased hippocampal volume, reduced number of synapses, altered synaptic plasticity, changes in glutamate receptors (particularly NMDAR), impaired neurogenesis, and glial cell plasticity abnormalities 1
• Hippocampal volume reductions are more pronounced in patients with comorbid depression across multiple psychiatric disorders, suggesting this is a core depression-related change rather than disorder-specific 1
• The hippocampus undergoes neuroinflammatory changes in depression, with elevated IL-1β, IL-6, and TNF-α levels that contribute to neurodegeneration 1

The Prefrontal-Limbic Network

While the hippocampus is central, depression involves a broader interconnected network rather than isolated "pain centers":

Core Network Components

• The medial prefrontal cortex (mPFC), particularly the left dorsolateral prefrontal cortex, forms the hub of a depression circuit 2, 3, 4
• The anterior cingulate cortex, amygdala, and hippocampus form an interconnected prefrontal-limbic network that is dysregulated in major depressive disorder 2
• This network is modulated by the hypothalamus, basal ganglia, and midbrain structures 2

Functional Connectivity Abnormalities

• Depression involves abnormal functional connectivity in the default mode network, central executive network, and salience network 5
• Lesion locations associated with depression are heterogeneous but map to a specific brain circuit centered on the left dorsolateral prefrontal cortex 4

Additional Implicated Regions

Beyond the hippocampus and prefrontal cortex, multiple regions show consistent abnormalities:

• Frontal lobe, temporal lobe, and limbic system structures demonstrate morphological differences in depression compared to healthy controls 5
• Somatosensory, insular, and cingulate cortices, along with subcortical areas including the amygdala, ventral striatum, thalamus, and periaqueductal grey are involved 1
• The dorsomedial prefrontal cortex and insular opercular region show alterations common across psychiatric disorders including depression 1

Clinical Implications

The hippocampus represents the most specific and reproducible structural target for understanding depression pathophysiology, while recognizing that depression involves distributed network dysfunction rather than a single "depression center" 1, 4. This has important implications:

• Hippocampal volume assessment may serve as a biomarker for depression severity and treatment response 1
• Therapeutic interventions targeting hippocampal neuroplasticity, neuroinflammation, and synaptic function show promise 1
• The left dorsolateral prefrontal cortex circuit may have both prognostic utility for identifying at-risk patients and therapeutic utility for refining brain stimulation targets 4