Brain Stimulation for Depression

Recruiting in Palo Alto (17 mi)

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Baylor College of Medicine

Disqualifiers: Epilepsy, Depression, others

No Placebo Group

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.

Trial 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 (Behavioural Intervention)
• sEEG Stimulation (Behavioural Intervention)

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, United States, 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Baylor College of Medicine Houston, TX

Who Is Running the Clinical Trial?

Baylor College of Medicine Lead Sponsor

University of Minnesota Collaborator

University of Texas Collaborator

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] The authors conducted a meta-review of meta-analyses published in the past decade on therapeutic neuromodulation (ie, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation and deep brain stimulation) for major depression. Active repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been generally associated with small to moderate effect sizes vis-à-vis their efficacy and with similar acceptability compared with sham. Vagus nerve stimulation and deep brain stimulation (although more challenging to investigate) have demonstrated preliminary effectiveness, particularly during longer-term follow-up.

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] Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques used as therapeutic interventions in major depression.

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

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. [2019] The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS).

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

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. [2018] There are limited treatment options for patients with chronic, treatment-refractory major depression who do not respond to routinely-available treatments. Vagus Nerve Stimulation (VNS) may represent an alternative to ablative neurosurgery for a specific group of patients.

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

Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. [2021] Neuromodulation appears to be emerging gradually as a new therapeutic field in psychiatric treatment. It encompasses neuropsychiatric medical devices, such as vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and electroconvulsive therapy (ECT). As a therapeutic approach to affective disorders, neuromodulation shifts the focus from the monoamine synapse to neural circuitry of the brain, which is dysregulated in depression. This neural circuitry has been elaborated on over the course of 15 years of neuroimaging research in mood disorders and is now believed to encompass disturbances in a frontolimbic network. These include reduced metabolism and blood flow in the prefrontal cortex and anterior cingulate and pathologically increased activity in the subgenual cingulate and amygdala.VNS is an implanted device that has established efficacy in pharmaco-resistant epilepsy. It was approved by the FDA for the treatment of severe, recurrent unipolar and bipolar depression in July of 2005. VNS adopts a bottom-up approach to modulating the neural circuitry of depression by stimulating vagal afferent fibers in the neck, which carry impulses to the brain stem to target there the locus ceruleus and dorsal raphe nucleus. Now that VNS has moved beyond the experimental phase and into the clinic, psychiatrists are faced with deciding who is an appropriate patient for this surgical implant and how to integrate VNS into existing treatment in order to optimize both efficacy and safety.This review of VNS will assess the efficacy and safety data that led to the FDA approval. We will also review for the busy clinician how VNS is likely to translate into clinical practice as a treatment option for patients in need who are suffering from severe depression.

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

The Efficacy and Safety of Neuromodulation Treatments in Late-Life Depression. [2022] In this review, the efficacy and safety of FDA approved neuromodulation devices (electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS)), as well as emerging neuromodulation treatments currently under investigation.

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

Vagus Nerve Stimulation for the Treatment of Epilepsy. [2022] Vagus nerve stimulation (VNS) was the first neuromodulation device approved for treatment of epilepsy. In more than 20 years of study, VNS has consistently demonstrated efficacy in treating epilepsy. After 2 years, approximately 50% of patients experience at least 50% reduced seizure frequency. Adverse events with VNS treatment are rare and include surgical adverse events (including infection, vocal cord paresis, and so forth) and stimulation side effects (hoarseness, voice change, and cough). Future developments in VNS, including closed-loop and noninvasive stimulation, may reduce side effects or increase efficacy of VNS.

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

Safe use of repetitive transcranial magnetic stimulation in patients with implanted vagus nerve stimulators. [2021] Vagus nerve stimulation (VNS) and repetitive transcranial stimulation (rTMS) devices are FDA cleared for therapeutic use in treatment resistant depression. Since VNS systems have ferromagnetic components and large-scale safety testing has not been done, the implanted VNS device is considered a contraindication for rTMS therapy. This contraindication should not be considered absolute, as VNS components typically lie outside the electromagnetic field generated by an rTMS treatment coil. We solicited information from clinicians at several academic medical centers through an informal survey about their use of rTMS for depressed patients with implanted VNS systems, and reviewed relevant safety issues with one rTMS device manufacturer. rTMS clinical practices may use special consent procedures and take additional precautions to enhance safety in these situations. Specific recommendations are provided for minimizing risks (heating or movement of VNS components and unintended change in VNS stimulation parameters) when delivering rTMS to patients with implanted VNS systems.

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

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022] Vagus nerve stimulation (VNS) is effective in refractory epilepsy and depression and is being investigated in heart failure, headache, gastric motility disorders and asthma. The first VNS device required surgical implantation of electrodes and a stimulator. Adverse events (AEs) are generally associated with implantation or continuous on-off stimulation. Infection is the most serious implantation-associated AE. Bradycardia and asystole have also been described during implantation, as has vocal cord paresis, which can last up to 6 months and depends on surgical skill and experience. The most frequent stimulation-associated AEs include voice alteration, paresthesia, cough, headache, dyspnea, pharyngitis and pain, which may require a decrease in stimulation strength or intermittent or permanent device deactivation. Newer non-invasive VNS delivery systems do not require surgery and permit patient-administered stimulation on demand. These non-invasive VNS systems improve the safety and tolerability of VNS, making it more accessible and facilitating further investigations across a wider range of uses.

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

Electrodiagnostic artifacts due to neurostimulation devices for drug resistant epilepsy. [2022] Neurostimulation devices including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) are approved therapeutic options for drug resistant epilepsy (DRE). As these devices are increasingly used in clinical practice, it is of importance to recognize their artifacts in electrodiagnostic studies.

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

[Deep brain stimulation--the newest physical method of treatment of depression]. [2018] The deep brain stimulation DBS is the newest physical method of the treatment of depressive disorders. When applying of this technique in neurological illnesses (e.g., Parkinson's disease), mood changes were observed. In 2005, Helen Mayberg et al. used DBS in the therapy of the depression for the first time. Stimulating electrodes were placed in Brodmann areas 25. In the period of some past years, only about 30-40 patients with refractory depression have undergone DBS treatment. Numerous problems connected with applying DBS in patients with psychiatric disorders are described in the paper.

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

Non-pharmacological biological treatment approaches to difficult-to-treat depression. [2020] There has been substantial recent interest in novel brain stimulation treatments for difficult-to-treat depression. Electroconvulsive therapy (ECT) is a well established, effective treatment for severe depression. ECT's problematic side-effect profile and questions regarding optimal administration methods continue to be investigated. Magnetic seizure therapy, although very early in development, shows promise, with potentially similar efficacy to ECT but fewer side effects. Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) are clinically available in some countries. Limited research suggests VNS has potentially long-lasting antidepressant effects in a small group of patients. Considerable research supports the efficacy of rTMS. Both techniques require further study of optimal treatment parameters. Transcranial direct current stimulation may provide a low-cost antidepressant option if its efficacy is substantiated in larger samples. Deep brain stimulation is likely to remain reserved for patients with the most severe and difficult-to-treat depression, requiring further exploration of administration methods and its role in depression therapy. New and innovative forms of brain stimulation, including low-intensity ultrasound, low-field magnetic stimulation and epidural stimulation of the cortical surface, are in early stages of exploration and are yet to move into the clinical domain. Ongoing work is required to define which brain stimulation treatments are likely to be most useful, and in which patient groups. Clinical service development of brain stimulation treatments will likely be inconsistent and variable.

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

Treating the depressions with superficial brain stimulation methods. [2021] Many, if not most, of the different superficial brain stimulation methods are being either used or investigated to treat the depressions. There are likely many reasons why there is this much interest and research involving brain stimulation treatments for depression, including that the depressions are common, there is dissatisfaction with other treatments, and some patients do not respond to medications or talking therapies. This is coupled with the fact that depressive episodes are a periodic or temporary state of the brain, and that when patients are no longer in that state they return to normal functioning. Additionally, the oldest brain stimulation method, electroconvulsive therapy (ECT), is also the most effective antidepressant available for the acute treatment of depression in patients who do not respond to medications. The newer brain stimulation methods have followed in the path blazed by ECT, showing that stimulation of key regions can cause a change in brain state and treat the depression. After almost 20 years of research, repeated daily repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex for several weeks is now also an established clinical treatment for acute episodes. The data are less convincing for the other brain stimulation methods, but all are being investigated. Using brain stimulation (as opposed to medications or talking therapy) to treat depression is a rapidly expanding area of research with already established clear indications. Much more work is needed to understand best which methods should be used in any given patient, and in what order.