Deep brain stimulation (DBS) is an emerging experimental therapy that has shown promise in treating patients with severe, treatment-resistant depression (TRD).
Early research indicates DBS may help patients who have failed to respond to medications, psychotherapy, and other interventions.
Key facts:
- DBS involves surgically implanting electrodes in specific brain regions to deliver mild electrical stimulation.
- Multiple brain targets have been studied for depression, including the subcallosal cingulate cortex, ventral capsule/ventral striatum, medial forebrain bundle, and lateral habenula.
- Response rates in open-label DBS trials range from 20-82% depending on the target and study.
- DBS appears relatively safe, with adverse effects like infection and pain at the device site. Suicide rates are not higher than the TRD population baseline.
- Optimal targeting and stimulation parameters are still being investigated to maximize benefits and minimize side effects.
The Advent of DBS for Depression
DBS has been used since the 1990s to treat movement disorders like Parkinson’s disease.
Researchers began investigating its potential for depression in the early 2000s, after noticing that DBS for OCD improved patients’ mood.
The theory is that stimulating certain brain regions can modulate networks involved in mood regulation.
DBS may act by normalizing abnormally high or low activity within these circuits.
DBS involves surgically implanting thin electrodes into the brain that are connected via wires under the skin to a pacemaker-like device placed in the chest.
This device provides mild electrical stimulation in a continuous or intermittent pattern.
The stimulation parameters can be adjusted over time to tailor treatment.
And unlike irreversible ablation techniques, DBS is adjustable and reversible.
Most research so far has focused on patients with severe TRD who have failed multiple antidepressant medications and psychotherapy.
For these patients who have exhausted other options, DBS provides a glimmer of hope.
DBS: Therapeutic Targets and Techniques for Depression
The search is still on for the optimal brain targets and methods to treat TRD with DBS.
So far, the most researched regions include:
Subcallosal Cingulate Cortex (SCC)
- Located on the front underside of the corpus callosum, involved in mood regulation
- Open-label trials show 20-82% response rates, higher with tractography-guided targeting
- May improve negative affect symptoms like low mood, sadness
Ventral Capsule/Ventral Striatum (VC/VS)
- Includes the nucleus accumbens, part of reward/motivation circuitry
- 23-75% response rates in studies so far
- May improve anhedonia and lack of motivation
Medial Forebrain Bundle (MFB)
- Connects VTA dopamine system to prefrontal cortex
- Response rates of 50-100% in small open-label studies
- Targets motivational symptoms like anhedonia
Lateral Habenula (LHb)
- Linked to regulation of serotonin, norepinephrine, dopamine
- Limited data but promising results in initial open-label studies
- Very small target is challenging for precise stimulation
Inferior Thalamic Peduncle (ITP)
- Connects thalamus and orbitofrontal cortex
- Only studied in a few patients so far, results inconclusive
These targets were selected based on neuroimaging studies and their roles in emotion regulation circuits.
While they show promise, more research is needed to refine targeting approaches.
For example, there is variability in lead locations even for the same named target across patients and studies.
More precise patient-specific targeting using diffusion MRI tractography is being investigated to isolate optimal fiber pathways for each individual.
This connectivity-based approach has improved response rates for SCC stimulation.
Ongoing studies are working to map the specific fiber bundles critically involved in DBS response for each brain target.
Specific DBS Targets: Benefits and Side Effects
Open-label DBS trials have reported significant improvement in depressive symptoms, even remission, for many patients.
However, there is a need for larger randomized controlled trials to definitively demonstrate efficacy over placebo effects.
Results of sham-controlled studies so far are mixed, likely because optimal surgical targeting and stimulation parameters are still being refined.
It can take extensive tuning of settings over months to achieve full benefits.
Patients seem to relapse quickly after DBS is turned off, providing evidence that the effects are not just placebo.
But more research on controlled discontinuation is ethically complex for this vulnerable population.
DBS appears relatively safe overall, with side effects like pain, infection, or discomfort at the implant site generally resolving over time.
Studies show no increased suicide risk compared to the highly suicidal TRD population baseline.
Adverse effects from stimulation itself seem to depend on the target.
For example, VC/VS DBS can cause worsening depression or hypomania, while vision changes are more common with MFB stimulation.
Ongoing Work to Optimize DBS Treatment
Moving forward, research is focused on better identifying who will benefit most from DBS for depression.
Patients with shorter duration, less treatment resistance, and specific symptoms like anhedonia may have better outcomes.
Targeting and programming methods to maximally engage relevant fiber tracts must be optimized, which will require merging connectivity mapping, neurophysiology, and machine learning approaches.
Closed-loop DBS systems that automatically adjust stimulation based on a patient’s brain activity are also being developed.
This could make DBS for depression more personalized and effective.
Finally, studies are needed on combining DBS with medications or psychotherapy for enhanced outcomes.
While DBS shows initial promise for TRD, it will likely work best as part of a comprehensive treatment plan.
The Road Ahead: DBS for Severe Depression
While still experimental, DBS brings new hope for patients stuck in the depths of severe depression.
Rapid innovation in precision targeting and stimulation programming will be key to maximizing benefits and minimizing adverse effects.
Larger controlled trials are underway that will provide more definitive evidence of efficacy.
But early open-label studies and serendipitous reports indicate DBS has the potential to lift some patients out of the dark fog of TRD into the light of remission.
References
- Study: Deep brain stimulation for depression
- Authors: Martijn Figee et al. (2022)
