Brain Stimulation for Severe Treatment-Resistant Depression

Overseen By Rachel Johnson, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Minnesota

Disqualifiers: Suicidal, Schizophrenia, Dementia, Seizures, others

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

Compensation: Varies

Number of Visits: 21

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is designed to test if electrical stimulation of the surface of the brain in the frontal region will help treat depressive symptoms. Participants receive intermittent electrical stimulation to the brain, which involves surgically placing electric leads in between the tough fibrous membrane covering the surface of the brain and the surface of the brain itself. This type of stimulation is referred to as bilateral subdural prefrontal cortical stimulation (PCS) because it will specifically target the outer layer of the brain at the midline, right behind the forehead. It uses a pacemaker-like device, the Proclaim Elite SCS System (non-rechargeable) or the Eterna SCS System (rechargeable), both by Abbott Laboratories for stimulation. Although the U.S. Food and Drug Administration (FDA) has approved the Proclaim Elite SCS system for brain stimulation for patients with chronic pain and muscular diseases, such as Parkinson's, its use is still investigational, and the surgery is still experimental for patients who have depression.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team and your healthcare provider.

What data supports the effectiveness of the treatment Epidural Prefrontal Cortical Stimulation (EpCS) for severe treatment-resistant depression?

Research shows that Epidural Prefrontal Cortical Stimulation (EpCS) has been effective in treating major depressive disorder, especially in cases where other treatments have failed. Studies indicate that EpCS can provide long-term benefits for patients with treatment-resistant depression. ^{1 2 3 4 5}

Is brain stimulation for severe treatment-resistant depression safe?

Epidural and subdural brain stimulation have been used for various conditions, including depression, with some risks. Subdural stimulation can lead to higher complication rates, such as seizures and infections, compared to epidural stimulation, which is generally safer. However, complications are rare with minimally invasive techniques. ^{4 5 6 7 8}

How is Epidural Prefrontal Cortical Stimulation (EpCS) different from other treatments for treatment-resistant depression?

Epidural Prefrontal Cortical Stimulation (EpCS) is unique because it targets specific areas of the brain involved in emotional and cognitive processing, offering a focused approach for treatment-resistant depression. Unlike some other brain stimulation methods, EpCS is less invasive than deep brain stimulation and may have fewer side effects compared to electroconvulsive therapy (ECT). ^{1 2 3 9 10}

Research Team

Ziad Nahas, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

This trial is for adults with severe, treatment-resistant depression who have not responded to multiple antidepressant treatments and are under a psychiatrist's care. They must be able to consent, complete necessary evaluations, and have support within a 30-minute drive. Excluded are those with recent suicide attempts or high risk of suicide, active drug use, pregnancy, certain mental health conditions like schizophrenia or psychotic features in their depression.

Inclusion Criteria

Participant must be able to complete the evaluations needed for this study including the functional imaging scans and the EEG Bayesian optimization sessions

Participant must be able to provide written informed consent

I can provide contacts of two people over 22, living within 30 minutes from me, for the study.

Exclusion Criteria

I have a Deep Brain Stimulator implanted.

Participant with a positive urine pregnancy test

Participant is unable to undergo required full body magnetic resonance imaging (MRI) during the clinical study

Timeline

Baseline Assessments

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Surgery

Participants undergo surgery to implant the device and leads, with testing of the leads to explore optimal parameters

3 days

Hospitalization for a minimum of 3 days

Acute phase

Participants undergo follow-up visits for assessments and stimulator programming

19 weeks

10 follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 months

7 monthly follow-up visits

Long Term Follow-up

Participants continue treatment with follow-up visits every three months

4 years

Quarterly visits alternating between in-person and virtual

Treatment Details

Interventions

• Epidural Prefrontal Cortical Stimulation (EpCS)
• Prefrontal Cortical Stimulation (PCS)

Trial Overview The study tests Prefrontal Cortical Stimulation (PCS) using the Proclaim Elite SCS System by Abbott Laboratories. This involves surgical placement of electrical leads on the brain surface behind the forehead to stimulate it intermittently. Although FDA-approved for other conditions like chronic pain and Parkinson's disease, its effectiveness for depression is still being investigated.

Participant Groups

Group I: Prefrontal Cortical Stimulation (PCS) Experimental Treatment 1 Intervention

Stereotactically implanted bilateral PCS

Epidural Prefrontal Cortical Stimulation (EpCS) is already approved in United States for the following indications:

Approved in United States as Proclaim Elite SCS System / Eterna SCS System for:

• Chronic pain
• Muscular diseases (such as Parkinson's)

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Findings from Research

Epidural prefrontal cortical stimulation (EpCS) showed promising long-term efficacy for treatment-resistant depression (TRD) in a study of 5 adults, with 60% of participants remaining in remission after 5 years and significant improvements in depression scores over time.

The therapy was generally well-tolerated, although there were serious adverse events related to device malfunctions and infections, highlighting the need for careful monitoring in patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression. Williams, NR., Short, EB., Hopkins, T., et al.[2018]

Chronic epidural stimulation (EpCS) of the left dorsolateral prefrontal cortex (DLPFC) showed significant improvement in patients with refractory major depressive disorder (MDD), particularly with mixed mode and continuous anodic stimulation, indicating its potential as an effective treatment option.

The study found that optimal electrode placement in the lateral and anterior regions of the DLPFC correlated with the greatest improvement in depression symptoms, suggesting that careful consideration of stimulation parameters is crucial for maximizing therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. Pathak, Y., Kopell, BH., Szabo, A., et al.[2021]

Chronic and intermittent epidural prefrontal cortical stimulation (EpCS) was well-tolerated by all five patients with treatment-resistant depression, indicating a favorable safety profile for this new treatment approach.

At a 7-month follow-up, patients showed significant improvements in depression scores, with an average reduction of 54.9% on the Hamilton Rating Scale and 60.1% on the Inventory of Depressive Symptoms, and three patients achieved remission, suggesting promising efficacy for EpCS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Nahas, Z., Anderson, BS., Borckardt, J., et al.[2022]

Motor cortex stimulation (MCS) is a promising minimally invasive neurosurgical method for treating advanced Parkinson's disease (PD), showing significant improvements in motor symptoms, particularly axial symptoms and L-dopa-induced dyskinesia, across 13 out of 16 studies involving 130 patients.

MCS has a low risk of complications, especially when performed extradurally, making it a viable alternative to deep brain stimulation (DBS) for PD patients who are not candidates for DBS, with the ability to relieve major PD symptoms bilaterally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimally invasive motor cortex stimulation for Parkinson's disease. Lavano, A., Guzzi, G., DE Rose, M., et al.[2022]

Implanted cortical stimulation, whether epidural or subdural, can provide long-term treatment benefits for neuropsychiatric diseases, especially when transcranial stimulation is ineffective.

While subdural stimulation allows for more precise targeting and lower current use, it carries a higher risk of complications such as seizures and infections compared to epidural stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidural and subdural stimulation. Tronnier, V., Rasche, D.[2013]

Cortical stimulation techniques, including epidural cortical stimulation (ECS) and repetitive transcranial magnetic stimulation (rTMS), have been used to treat conditions like drug-resistant neuropathic pain and major depression, showing promising therapeutic effects.

These stimulation methods can influence brain networks far from the stimulation site, potentially activating or inhibiting various neural pathways, and may lead to long-lasting changes in brain function due to synaptic plasticity, highlighting their potential for neuroprotective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods of therapeutic cortical stimulation. Lefaucheur, JP.[2017]

Cortical spreading depression (CSD) was used in unanesthetized curarized rats to study its effects on epileptic seizures induced by direct cortical stimulation, showing that CSD can be a reversible and repeatable method for such analysis.

Inducing CSD in the hemisphere opposite to the stimulated cortex reduced the duration of epileptic afterdischarges by 40% and altered their characteristics, suggesting that both cortical and subcortical structures play a significant role in the generation of these after-discharges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical afterdischarges during Leao's cortical spreading depression. Aquino-Cias, J., Aneiros-Riba, R., Hernandez-Mesa, N.[2013]

Chronic electrical cortical stimulation (ECS) using a modified technique involving interdural electrode placement showed significant and sustained pain relief in 4 patients with treatment-refractory chronic pain, with follow-up periods ranging from 9 to over 24 months.

The new technique demonstrated stable impedance values post-surgery, suggesting improved efficacy and consistency of ECS without increasing procedural risks compared to traditional implantation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bifocal cortical electrical stimulation for pain by interdural implantation of the electrodes. Sakas, DE., Flaskas, TN., Panourias, IG., et al.[2011]

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]

Transcranial magnetic stimulation (TMS) is a safe and noninvasive treatment option for severe treatment-resistant psychiatric disorders, but its clinical application needs further clarification.

Magnetic seizure therapy, a refined version of TMS that induces seizures under anesthesia, has shown significant antidepressant effects with fewer cognitive side effects, while deep brain stimulation, an invasive method, shows promise for severe obsessive-compulsive disorders and depression, though ethical considerations are crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Brain stimulation procedures. Transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation]. Schläpfer, TE., Kayser, S.[2021]

References

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

Five-Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression. [2018]

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

The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. [2021]

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

Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. [2022]

4. Italy pubmed.ncbi.nlm.nih.gov

Minimally invasive motor cortex stimulation for Parkinson's disease. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Epidural and subdural stimulation. [2013]

6. France pubmed.ncbi.nlm.nih.gov

Methods of therapeutic cortical stimulation. [2017]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

Cortical afterdischarges during Leao's cortical spreading depression. [2013]

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

Bifocal cortical electrical stimulation for pain by interdural implantation of the electrodes. [2011]

9. Australia pubmed.ncbi.nlm.nih.gov

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

10. Germany pubmed.ncbi.nlm.nih.gov

[Brain stimulation procedures. Transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation]. [2021]