Brain Stimulation for Depression

Overseen By Sameer Sheth, PhD, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Baylor College of Medicine

Disqualifiers: Epilepsy, Depression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

58 Participants Needed

Trial Summary

What is the purpose of this trial?

Depression is one of the most common disorders of mental health, affecting 7-8% of the population and causing tremendous disability to afflicted individuals and economic burden to society. In order to optimize existing treatments and develop improved ones, the investigators need a deeper understanding of the mechanistic basis of this complex disorder. Previous work in this area has made important progress but has two main limitations. (1) Most studies have used non-invasive and therefore imprecise measures of brain activity. (2) Black box modeling used to link neural activity to behavior remain difficult to interpret, and although sometimes successful in describing activity within certain contexts, may not generalize to new situations, provide mechanistic insight, or efficiently guide therapeutic interventions. To overcome these challenges, the investigators combine precise intracranial neural recordings in humans with a suite of new eXplainable Artificial Intelligence (XAI) approaches. The investigators have assembled a team of experimentalists and computational experts with combined experience sufficient for this task. Our unique dataset comprises two groups of subjects: the Epilepsy Cohort consists of patients with refractory epilepsy undergoing intracranial seizure monitoring, and the Depression Cohort consists of subjects in an NIH/BRAIN-funded research trial of deep brain stimulation for treatment-resistant depression (TRD). As a whole, this dataset provides precise, spatiotemporally resolved human intracranial recording and stimulation data across a wide dynamic range of depression severity. Our Aims apply a progressive approach to modeling and manipulating brain-behavior relationships. Aim 1 seeks to identify features of neural activity associated with mood states. Beginning with current state-of-the-art AI models and then uses a "ladder" approach to bridge to models of increasing expressiveness while imposing mechanistically explainable structure. Whereas Aim 1 focuses on self-reported mood level as the behavioral index of interest, Aim 2 uses an alternative approach of focusing on measurable neurobiological features inspired by the Research Domain Criteria (RDoC). These features, such as reward sensitivity, loss aversion, executive attention, etc. are extracted from behavioral task performance using a novel "inverse rational control" XAI approach. Relating these measures to neural activity patterns provides additional mechanistic and normative understanding of the neurobiology of depression. Aim 3 uses recurrent neural networks to model the consequences of richly varied patterns of multi-site intracranial stimulation on neural activity. Then employing an innovative "inception loop" XAI approach to derive stimulation strategies for open- and closed-loop control that can drive the neural system towards a desired, healthier state. If successful, this project would enhance our understanding of the pathophysiology of depression and improve neuromodulatory treatment strategies. This can also be applied to a host of other neurological and psychiatric disorders, taking an important step towards XAI-guided precision neuroscience.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Brain Stimulation for Depression?

Research shows that brain stimulation techniques like vagus nerve stimulation (VNS) and deep brain stimulation (DBS) have demonstrated preliminary effectiveness in treating major depression, especially over longer periods. VNS has been approved by the FDA for severe depression and has shown promise in patients who do not respond to other treatments. ^{1 2 3 4 5}

Is brain stimulation generally safe for humans?

Brain stimulation treatments like vagus nerve stimulation (VNS) have been studied for conditions like epilepsy and depression. While generally safe, they can have side effects such as voice changes, cough, and surgical risks like infection. Newer non-invasive methods improve safety by avoiding surgery. ^{6 7 8 9 10}

How is brain stimulation treatment different from other treatments for depression?

Brain stimulation treatments like sEEG Stimulation are unique because they directly target specific brain areas to alter brain activity, unlike medications or talk therapy. Techniques such as deep brain stimulation and vagus nerve stimulation have shown promise, especially for severe cases that don't respond to other treatments, and may offer long-lasting effects. ^{1 2 11 12 13}

Eligibility Criteria

This trial is for adults with refractory epilepsy scheduled for seizure monitoring and patients already enrolled in a deep brain stimulation (DBS) trial for treatment-resistant depression. Participants must consent to the study.

Inclusion Criteria

Depression cohort: patients enrolled in our DBS for depression trial

I am an adult with epilepsy and have agreed to undergo brain monitoring.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo intracranial neural recordings and stimulation, with mood and behavioral assessments using tasks such as Affective Bias Task and Probabilistic Cognitive Control Task

2 weeks

Daily assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Brain Stimulation
• sEEG Stimulation

Trial Overview The study tests how brain activity relates to mood states using intracranial recordings and stimulation, alongside advanced AI models. It aims to improve understanding of depression's neurobiology and refine neuromodulatory treatments.

Participant Groups

Group I: Epilepsy Cohort Experimental Treatment 1 Intervention

Group II: Depression Cohort Experimental Treatment 1 Intervention

Brain Stimulation is already approved in European Union, United States for the following indications:

Approved in European Union as Deep Brain Stimulation for:

• Parkinson's disease
• Essential tremor
• Dystonia
• Epilepsy

Approved in United States as Deep Brain Stimulation for:

• Parkinson's disease
• Essential tremor
• Dystonia
• Epilepsy
• Obsessive-compulsive disorder

Approved in United States as Responsive Neurostimulation for:

• Epilepsy

Approved in European Union as Vagus Nerve Stimulation for:

• Epilepsy
• Depression

Approved in United States as Vagus Nerve Stimulation for:

• Epilepsy
• Depression

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

University of Minnesota

Collaborator

Trials

1,459

Recruited

1,623,000+

University of Texas

Collaborator

Trials

193

Recruited

143,000+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) show small to moderate effectiveness in treating major depression, with similar levels of acceptability compared to sham treatments.

Vagus nerve stimulation and deep brain stimulation have shown preliminary effectiveness, especially in long-term follow-ups, although they are more complex to study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Usefulness of Therapeutic Neuromodulation for Major Depression: A Systematic Meta-Review of Recent Meta-Analyses. McGirr, A., Berlim, MT.[2019]

In a study of treatment-resistant patients with major depression, neither vagus nerve stimulation (VNS) nor repetitive transcranial magnetic stimulation (rTMS) significantly altered serum levels of brain-derived neurotrophic factor (BDNF).

The findings suggest that unlike some antidepressant medications, these brain stimulation techniques do not influence BDNF concentrations in the serum, indicating a different mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. Lang, UE., Bajbouj, M., Gallinat, J., et al.[2018]

Neuromodulation techniques, including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are gaining attention as effective non-pharmacological treatments for major depressive disorder (MDD), with TMS showing effects comparable to traditional antidepressants.

While electroconvulsive therapy (ECT) remains the first-line treatment for severe depression, TMS and tDCS have a favorable side effect profile, and invasive methods like deep brain stimulation (DBS) and vagus nerve stimulation (VNS) may be considered for treatment-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Brunoni, AR., Teng, CT., Correa, C., et al.[2019]

In a study of 28 patients with chronic major depression who had not responded to multiple treatments, Vagus Nerve Stimulation (VNS) showed a 12-month response rate of 35.7%, indicating it may be an effective alternative for treatment-resistant cases.

A smaller case series of 13 patients in Dundee reported a similar response rate of 30.8%, suggesting that VNS can provide significant relief for patients who have exhausted other treatment options, with response rates at least twice that of standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. Christmas, D., Steele, JD., Tolomeo, S., et al.[2018]

Vagus nerve stimulation (VNS) has been FDA-approved since 2005 for treating severe, recurrent unipolar and bipolar depression, showing established efficacy particularly in patients who do not respond to traditional medications.

VNS works by stimulating vagal afferent fibers, which helps modulate the brain's neural circuitry involved in depression, specifically targeting areas like the locus ceruleus and dorsal raphe nucleus, making it a promising option for integrating into existing treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. O'Reardon, JP., Cristancho, P., Peshek, AD.[2021]

Electroconvulsive therapy (ECT) is considered the gold standard for treating treatment-resistant depression (TRD), despite potential cognitive and cardiovascular side effects, and it remains stigmatized.

Transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS) are effective for late-life depression, with TMS having fewer side effects, but VNS shows limited data in older patients; emerging treatments like magnetic seizure therapy and deep brain stimulation show promise but require more safety and efficacy evidence in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy and Safety of Neuromodulation Treatments in Late-Life Depression. van Rooij, SJH., Riva-Posse, P., McDonald, WM.[2022]

Vagus nerve stimulation (VNS) has been shown to be effective in treating epilepsy, with about 50% of patients experiencing at least a 50% reduction in seizure frequency after 2 years of treatment.

Adverse events related to VNS are rare, primarily involving surgical complications and mild stimulation side effects, suggesting a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation for the Treatment of Epilepsy. González, HFJ., Yengo-Kahn, A., Englot, DJ.[2022]

Vagus nerve stimulation (VNS) and repetitive transcranial stimulation (rTMS) are both FDA-cleared treatments for resistant depression, but VNS devices are generally considered a contraindication for rTMS due to safety concerns.

Despite this contraindication, clinicians have reported using rTMS in patients with implanted VNS systems, suggesting that with proper precautions and consent procedures, rTMS can be safely administered, as VNS components are typically outside the electromagnetic field of rTMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe use of repetitive transcranial magnetic stimulation in patients with implanted vagus nerve stimulators. Philip, NS., Carpenter, SL., Carpenter, LL.[2021]

Vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, but traditional methods involve surgical implantation, which carries risks such as infection and bradycardia.

New non-invasive VNS systems eliminate the need for surgery, improving safety and tolerability, and allowing patients to administer stimulation on demand, potentially expanding its use in various medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Ben-Menachem, E., Revesz, D., Simon, BJ., et al.[2022]

In a study of 52 adult patients with drug-resistant epilepsy treated with neurostimulation devices, 37% exhibited neurostimulation-related artifacts in their EEGs, with the highest incidence in those using deep brain stimulation (75%).

These artifacts can mimic actual seizures or heart conditions in electrodiagnostic studies, highlighting the importance for clinicians to recognize them to prevent misdiagnosis and ensure accurate interpretation of results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrodiagnostic artifacts due to neurostimulation devices for drug resistant epilepsy. Arafat, T., Miron, G., Strauss, I., et al.[2022]

Deep brain stimulation (DBS) is a new treatment method for depressive disorders, first applied in 2005 by Helen Mayberg, targeting Brodmann area 25 to alleviate symptoms of depression.

Only 30-40 patients with treatment-resistant depression have undergone DBS, highlighting the experimental nature of this approach and the challenges associated with its application in psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Deep brain stimulation--the newest physical method of treatment of depression]. Zyss, T., Zieba, A., Hese, RT., et al.[2018]

Electroconvulsive therapy (ECT) is a well-established and effective treatment for severe depression, but it has significant side effects and ongoing research is focused on optimizing its administration methods.

Emerging treatments like magnetic seizure therapy show promise with potentially similar efficacy to ECT but fewer side effects, while techniques like vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) are already available and supported by research, though they require further study to determine optimal treatment parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-pharmacological biological treatment approaches to difficult-to-treat depression. Fitzgerald, PB.[2020]

Electroconvulsive therapy (ECT) remains the most effective treatment for acute depression in patients who do not respond to medications, highlighting its importance in the landscape of depression treatments.

Repeated daily repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has become an established clinical treatment for acute depressive episodes after nearly 20 years of research, although the efficacy of other brain stimulation methods is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating the depressions with superficial brain stimulation methods. George, MS., Taylor, JJ., Short, B.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Clinical Usefulness of Therapeutic Neuromodulation for Major Depression: A Systematic Meta-Review of Recent Meta-Analyses. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

The Efficacy and Safety of Neuromodulation Treatments in Late-Life Depression. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation for the Treatment of Epilepsy. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Safe use of repetitive transcranial magnetic stimulation in patients with implanted vagus nerve stimulators. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Electrodiagnostic artifacts due to neurostimulation devices for drug resistant epilepsy. [2022]

11. Poland pubmed.ncbi.nlm.nih.gov

[Deep brain stimulation--the newest physical method of treatment of depression]. [2018]

12. Australia pubmed.ncbi.nlm.nih.gov

Non-pharmacological biological treatment approaches to difficult-to-treat depression. [2020]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Treating the depressions with superficial brain stimulation methods. [2021]