Understanding the Brain’s Reward System in Deep Brain Stimulation for Depression

For patients with treatment-resistant depression (TRD)—those who do not respond to multiple antidepressant trials—deep brain stimulation (DBS) offers a promising yet still experimental option. Recent research published in Molecular Psychiatry explores how brain activity within the reward circuit relates to treatment outcomes following DBS targeting the ventral anterior limb of the internal capsule (vALIC).

What Did the Researchers Study?

The reward circuit, which includes the nucleus accumbens (NAc), caudate nucleus, and midcingulate cortex, regulates how we experience pleasure and motivation—functions often disrupted in depression. Researchers from Amsterdam UMC investigated whether brain activity in these regions could predict who benefits most from vALIC DBS.

Fifteen patients with severe TRD underwent functional MRI (fMRI) before and after DBS surgery, performing a task that simulated winning or losing money. The team compared their brain activity to healthy volunteers and examined how reward processing changed after DBS treatment.

Key Findings

• Baseline brain activity predicted outcomes:
  • Patients with lower NAc activation during “loss anticipation” and higher caudate and midcingulate activation during “reward feedback” tended to have worse treatment outcomes.
• DBS improved symptoms but didn’t change reward processing overall:
  • While patients showed a significant reduction in depression severity, their overall brain reward responses did not differ significantly from healthy controls after treatment.
• A new clue emerged:
  • Those who showed increased activation in the middle frontal gyrus (MFG) after DBS—an area involved in decision-making and emotional regulation—experienced better clinical improvement.

Why This Matters

These results suggest that individual differences in reward circuit functioning may help explain why some patients benefit from DBS while others do not. The findings also highlight the middle frontal gyrus as a potential biomarker or complementary target for future interventions, possibly linking DBS outcomes with noninvasive neuromodulation therapies like repetitive transcranial magnetic stimulation (rTMS).

As we move toward precision psychiatry, understanding these brain-based predictors could one day help clinicians personalize interventional treatments, improving response rates for those struggling with refractory depression.

Reference:
Runia N, van de Mortel L.A., Smith C.L.C., et al. Reward circuit function and treatment outcome following vALIC deep brain stimulation in treatment-resistant depression. Molecular Psychiatry. 2025. doi:10.1038/s41380-025-03284-7

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Disclaimer:
This article was created with the help of artificial intelligence (AI) to improve clarity and readability. All medical content has been carefully reviewed and approved by Joao L. de Quevedo, MD, PhD, Director, UTHealth Houston Center for Interventional Psychiatry. It is provided for educational purposes only and should not replace professional medical advice.

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