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

Trial Summary

What is the purpose of this trial?

Patients with memory and cognitive deficits following TBI that do not respond to conventional treatments experience a decrease in quality of life. Despite advances in neuroimaging, genetics, pharmacology and psychosocial interventions in the last half century, little progress has been made in altering the natural history of the condition or its outcome. This study would explore whether a surgical therapy is safe and potentially effective in patients who develop refractory memory and cognitive deficits following TBI. Preclinical studies suggest that DBS may improve memory deficits in TBI models. Moreover, DBS delivered to the fornix has shown promising clinical results in patients with Alzheimer's disease. The main mechanism for the improvements induced by DBS in memory tests is the development of multiple forms of plasticity.

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 data supports the effectiveness of the treatment Deep Brain Stimulation for cognitive deficits after traumatic brain injury?

Research shows that deep brain stimulation (DBS) can improve cognitive functions like processing speed in patients with moderate-to-severe traumatic brain injury. In a study, participants showed a 15% to 52% improvement in processing speed, indicating that DBS may help enhance executive control in these patients. ^{1 2 3 4 5}

Is deep brain stimulation generally safe for humans?

Deep brain stimulation (DBS) is generally considered safe, but it can have complications. Studies show that overall complication rates can exceed 25%, with 4-6% of cases resulting in permanent neurological issues. It's important to understand these risks and how to minimize them as DBS is used for more conditions. ^{6 7 8 9 10}

How is deep brain stimulation different from other treatments for cognitive deficits after traumatic brain injury?

Deep brain stimulation (DBS) is unique because it involves surgically implanting electrodes in specific brain areas to deliver electrical impulses, which can help reorganize brain networks and improve cognitive functions. Unlike other treatments, DBS directly targets brain regions involved in cognitive processing, potentially offering more precise and effective improvements for patients with traumatic brain injury. ^{1 4 11 12 13}

Research Team

Nir Lipsman, MD PhD

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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 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]

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]

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]

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]

References

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

Neurostimulation for Functional Recovery After Traumatic Brain Injury: Current Evidence and Future Directions for Invasive Surgical Approaches. [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression. [2022]

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

Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. [2023]

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

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

6. Austria pubmed.ncbi.nlm.nih.gov

Complications of deep brain stimulation in Parkinson's disease: a single-center experience of 517 consecutive cases. [2023]

7. England pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2019]

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

Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience. [2022]

10. United States 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. [2022]

11. Sweden 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. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury. [2020]

13. Ireland pubmed.ncbi.nlm.nih.gov

Baseline delayed verbal recall predicts response to high definition transcranial direct current stimulation targeting the superior medial frontal cortex. [2023]