Deep Brain Stimulation for Cognitive Deficits After Traumatic Brain Injury

Overseen By Anusha Baskaran, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sunnybrook Health Sciences Centre

Disqualifiers: Epilepsy, Alzheimer's, Pregnancy, others

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

Compensation: Varies

Number of Visits: 9

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if deep brain stimulation (DBS), a surgical therapy, is safe and could improve memory and thinking problems in individuals who have suffered a traumatic brain injury (TBI) and haven't responded to standard treatments. DBS involves placing electrodes in the brain to potentially enhance memory. The trial seeks participants who have experienced memory and thinking issues for over a year following a TBI and have not found success with treatments like donepezil. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants should have evidence of failure to certain medications like donepezil and cholinesterase inhibitors, which might imply that these medications are not continued during the trial.

What prior data suggests that this device is safe for treating cognitive deficits after TBI?

In earlier studies, deep brain stimulation (DBS) has shown promise in helping people with brain injuries think more clearly. Research shows that DBS, which involves placing tiny electrodes in the brain, has been used in patients with Alzheimer's disease with some encouraging results. Specifically, a study by Dr. Schiff and his team found that DBS targeting specific brain areas improved thinking and behavior in people recovering from brain injuries.

DBS is generally considered safe. Although it is a surgical procedure and comes with some risks, many patients have successfully received the treatment. Reports of side effects are usually low, but like any surgery, issues such as infection or problems with the device can occur. Overall, the long-term use of DBS in treating other conditions, like Parkinson's disease, supports its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Deep Brain Stimulation (DBS) is unique because it directly targets deep brain structures responsible for cognitive deficits following traumatic brain injury. Unlike traditional treatments that often rely on medication to manage symptoms, DBS involves implanting electrodes in the brain to stimulate precise areas, potentially leading to more targeted and effective results. Researchers are excited because this technique could offer a new way to enhance cognitive function by directly influencing brain activity, which current therapies can't achieve. This approach promises a novel mechanism of action that might provide relief to patients who haven't responded well to existing treatments.

What evidence suggests that Deep Brain Stimulation might be an effective treatment for cognitive deficits after TBI?

Research has shown that deep brain stimulation (DBS), which participants in this trial will receive, might improve thinking and memory for people with traumatic brain injury (TBI). Studies have found that DBS can enhance memory and thinking skills even during later recovery stages. Some individuals also experienced better emotional well-being and increased independence in daily life after DBS treatment. Early research suggests that DBS can help the brain change and adapt, potentially improving memory. Additionally, DBS targeting a specific brain area, the fornix, has shown promise in addressing memory issues in Alzheimer's patients. These findings support the potential of DBS to aid cognitive problems after TBI. ^{1 3 6 7 8}

Who Is on the Research Team?

Nir Lipsman, MD PhD

Principal Investigator

Sunnybrook Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for individuals with memory and cognitive issues after a traumatic brain injury (TBI) who haven't improved with standard treatments. Specific eligibility criteria are not provided, but typically participants must meet certain health standards to undergo surgery.

Inclusion Criteria

I have memory and thinking problems after a brain injury.

Patients with cognitive disorder not otherwise specified, dementia, or amnestic disorder due to TBI

Ability to provide informed consent and comply with all testing, follow-ups, and study appointments

Exclusion Criteria

My kidney function is reduced.

Any contraindication to MRI scanning

Current suicidal or homicidal ideation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and Initial Treatment

Patients undergo surgery for deep brain stimulation with electrode implantation and initial stimulation settings

1 day

1 visit (in-person)

Post-Surgery Monitoring

Participants are monitored for treatment-related adverse events and initial response to DBS

8 weeks

Every 2 weeks (in-person)

Extended Monitoring

Continued monitoring of safety and effectiveness of DBS

6 months

Every 4 weeks (in-person)

Long-term Follow-up

Participants are monitored for long-term safety and effectiveness of DBS

2 years

Every 2 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Deep Brain Stimulation

Trial Overview The study tests Deep Brain Stimulation (DBS), a surgical therapy that may improve memory and cognition in TBI patients. DBS has shown promise in preclinical TBI models and some Alzheimer's patients.

How Is the Trial Designed?

Group I: Deep Brain Stimulation Experimental Treatment 1 Intervention

Patients will arrive on the morning of surgery to the medical imaging department of the Sunnybrook Hospital. They will have a stereotactic frame attached directly to their skull, after infiltration with local anesthesia. The frame allows precise coordinates to be acquired so that deep brain structures can be targeted with implanted electrodes. The patient will then undergo a CT scan with the frame in place, followed by transport directly to the operating room. The anesthesia team will insert an intravenous line and may use gentle sedation to relax the patient prior to and during the operation, as they will remain awake during the first stage of the operation. In the operating room the patient's head, via the frame, will be attached to the operating room table, and their scalp infiltrated with additional local anesthetic. A skin incision will be made and two burr holeswith approximately 1.4cm in diameter drilled through the skull. A small electrode will identify the optimal spot for el

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Published Research Related to This Trial

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) in 25 patients with treatment-resistant depression (TRD) did not show lasting improvements in cognitive function compared to healthy controls, indicating that DBS may not enhance cognitive abilities in these patients.

The study found that while TRD patients did not improve in immediate verbal recognition after DBS, both TRD patients and healthy controls showed improvements in other cognitive areas over time, suggesting that any cognitive effects of DBS may be temporary and not significantly beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression. Bergfeld, IO., Mantione, M., Hoogendoorn, MLC., et al.[2022]

A single session of anodal transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex showed a tendency to improve reaction times in patients with traumatic brain injury, suggesting potential benefits for attention improvement.

While the immediate effects were promising, the improvements were not statistically significant after 3 or 24 hours, indicating that further research is needed to confirm the efficacy of tDCS in enhancing attention in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation of the left prefrontal cortex improves attention in patients with traumatic brain injury: a pilot study. Kang, EK., Kim, DY., Paik, NJ.[2022]

Invasive neurostimulation shows promise in treating deficits from traumatic brain injury (TBI) by enhancing neuronal connectivity and function, with rodent studies indicating significant cognitive and motor recovery from targeted stimulation of brain regions like the hippocampus and motor cortex.

Clinical evidence is limited but suggests that neurostimulation can improve motor symptoms and cognitive functions in TBI patients, highlighting the need for further research to optimize treatment protocols and understand the effects of biological variables on outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurostimulation for Functional Recovery After Traumatic Brain Injury: Current Evidence and Future Directions for Invasive Surgical Approaches. Tiefenbach, J., Chan, HH., Machado, AG., et al.[2023]

In a study of 123 patients undergoing deep brain stimulation (DBS) surgery, adverse events (AEs) occurred in 14.6% of cases, but all resolved without permanent effects, indicating a relatively safe profile for the procedure.

The study found that rates of complications such as infections and lead revisions were comparable to existing literature, suggesting that the proposed categories for assessing AEs are effective for evaluating DBS safety and can help in benchmarking against other studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards unambiguous reporting of complications related to deep brain stimulation surgery: A retrospective single-center analysis and systematic review of the literature. Engel, K., Huckhagel, T., Gulberti, A., et al.[2019]

Deep brain stimulation targeting the central lateral nucleus of the thalamus and medial dorsal tegmental tract was safely performed in six participants with moderate-to-severe traumatic brain injury, with five completing the study successfully.

Participants showed significant improvements in executive control, with processing speed on a cognitive test increasing by 15% to 52% from baseline, indicating potential efficacy of this intervention in enhancing cognitive function post-injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. Schiff, ND., Giacino, JT., Butson, CR., et al.[2023]

Deep brain stimulation is an effective treatment for movement disorders, involving an implanted electrode and pulse generator, but its mechanisms of action are not fully understood and were developed without extensive preclinical safety studies.

Complication rates for deep brain stimulation can exceed 25%, with 4-6% of patients experiencing permanent neurological issues, highlighting the need for better understanding of adverse events and safer stimulation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations for deep brain stimulation: review and analysis. Grill, WM.[2007]

Deep-brain electrical stimulation (DBS) targeting the central thalamus may enhance behavioral responsiveness in patients with severe brain injuries, as these neurons are crucial for regulating arousal and are often affected by such injuries.

Current research emphasizes selecting conscious patients with preserved brain networks for DBS, differing from past studies that focused on chronically unresponsive individuals, which may lead to more meaningful clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central thalamic deep-brain stimulation in the severely injured brain: rationale and proposed mechanisms of action. Schiff, ND.[2009]

Deep brain stimulation (DBS) for Parkinson's disease is generally safe, with a low mortality rate of 0.2% and permanent morbidity at 0.6%, but complications such as intracerebral hemorrhage (ICH) and seizures can occur in a small percentage of cases.

The study found that the type of lead used in DBS can influence complications, with Medtronic's leads associated with higher rates of perielectrode brain edema compared to Boston Scientific's, highlighting the need for further research on hardware design to improve safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications of deep brain stimulation in Parkinson's disease: a single-center experience of 517 consecutive cases. Servello, D., Galbiati, TF., Iess, G., et al.[2023]

In a study of 200 patients undergoing deep brain stimulation (DBS) procedures over a follow-up period of approximately 43 months, 20% experienced surgical or hardware-related adverse events (AEs), but all resolved without permanent effects.

The most common AEs were surgical site infections (9.95%) and wire tethering (2.49%), indicating that while AEs can occur, major complications requiring further surgery are rare, highlighting the overall safety of DBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience. Bouwens van der Vlis, TAM., van de Veerdonk, MMGH., Ackermans, L., et al.[2022]

In a study involving veterans with chronic traumatic brain injury (TBI), anodal high definition transcranial direct current stimulation (HD-tDCS) targeting the pre-supplementary motor area/dorsal anterior cingulate cortex significantly improved verbal retrieval deficits, particularly in individuals with impaired baseline delayed verbal recall.

Baseline delayed verbal recall was identified as a potential predictor of treatment response, suggesting that those with poorer recall may benefit more from HD-tDCS interventions aimed at enhancing verbal retrieval capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline delayed verbal recall predicts response to high definition transcranial direct current stimulation targeting the superior medial frontal cortex. Chiang, HS., Motes, M., O'Hair, R., et al.[2023]

Brain stimulation techniques, particularly transcranial direct current stimulation, show promise in promoting recovery from traumatic brain injury (TBI), especially in chronic phases, but evidence for acute phase efficacy and safety is still limited.

Most current brain stimulation interventions are non-targeted and lack sufficient clinical trials, highlighting the need for larger, well-designed studies to better understand their potential benefits in enhancing neuroplasticity and functional outcomes after TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. Li, S., Zaninotto, AL., Neville, IS., et al.[2022]

In a study of 181 patients undergoing deep brain stimulation (DBS) surgery for movement disorders, no mortality or permanent morbidity was reported, indicating a high safety profile for the procedure.

The study found that complication rates significantly decreased from 31% in the early period to 10% in the later period, suggesting that surgical experience plays a crucial role in minimizing adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience Reduces Surgical and Hardware-Related Complications of Deep Brain Stimulation Surgery: A Single-Center Study of 181 Patients Operated in Six Years. Sorar, M., Hanalioglu, S., Kocer, B., et al.[2022]

Electrical neuromodulation, particularly low frequency stimulation of the septohippocampal circuit, has shown promise in improving cognitive outcomes in traumatic brain injury (TBI) models by enhancing oscillatory rhythms associated with spatial learning.

Understanding the changes in brain oscillations after TBI is crucial for developing effective treatments, and future studies should focus on hypothesis-driven designs to translate these findings into clinical practice for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury. Pevzner, A., Izadi, A., Lee, DJ., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06818864

DBS for Cognitive Deficits After Traumatic Brain Injury An improvement in emotional adjustment and functional independence was reported in 4 TBI patients treated with nucleus accumbens DBS.Aside from ...

2. spauldingrehab.org spauldingrehab.org/about/news/deep-brain-stimulation-improves-cognition-during-chronic-recovery-phase-of-brain-injury

Deep Brain Stimulation Improves Cognition During Chronic ... Our results, although preliminary, suggest that DBS may improve cognitive function well into the chronic phase of recovery,” said Dr. Joseph ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6193266/

Deep brain stimulation for the treatment of disorders of ... The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients.

4. med.stanford.edu med.stanford.edu/news/all-news/2023/12/traumatic-brain-injury-implant.html

Brain implants revive cognitive abilities long after traumatic ... A new technique using deep brain stimulation tailored to each patient exceeded researchers' expectations in treating the cognitive impairments ...

5. biausa.org biausa.org/professionals/research/tbi-model-systems/improved-function-after-deep-brain-stimulation-for-chronic-severe-traumatic-brain-injury

Improved function after deep brain stimulation for chronic ... This is the first study examining the use of DBS of the nucleus accumbens to address executive functioning difficulties in individuals with chronic TBI.

6. braininitiative.nih.gov braininitiative.nih.gov/news-events/blog/deep-brain-stimulation-tested-means-restoring-lost-function-following-traumatic

Deep brain stimulation tested as a means of restoring lost ... A BRAIN-funded study explores a novel approach of applying deep brain stimulation (DBS) to treat the symptoms associated with traumatic brain injury.

7. biausa.org biausa.org/public-affairs/media/deep-brain-stimulation

Deep Brain Stimulation and Traumatic Brain Injury According to the Centers for Disease Control and Prevention (CDC), approximately 1.5 million individuals in the United States survive a traumatic brain injury ...

8. thejns.org thejns.org/focus/view/journals/neurosurg-focus/45/2/article-pE14.xml

Deep brain stimulation for the treatment of disorders of ... A meta-analysis demonstrated that of all the coma patients implanted with DBS leads who had at least 11 months to recover spontaneously, 1 of 1 unilateral and 5 ...