Clinical trial NCT06818864: DBS for Cognitive Deficits After Traumatic Brain Injury
Official title: Deep Brain Stimulation (DBS) for the Treatment of Cognitive Deficits After Traumatic Brain Injury (TBI): Pilot Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: TBI Traumatic Brain Injury
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2025-02-11
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a phase I, non-blinded, non-randomized, open-label, pilot trial for safety and efficacy of deep brain stimulation for TBI. Patients who meet inclusion and exclusion criteria will be identified and recruited from the practices of psychiatrists and neurologists who specialize in treating patients with TBI who develop cognitive deficits. The study will proceed according to the schedule laid out below. Both patients and treating team will be aware of treatment parameters at all times. Up to ten (10) subjects will be enrolled. Study duration for each patient will be of one (1) year. Previous phase I trials of DBS in psychiatric populations have utilized 5-6 subjects per surgical target. Such a number has been sufficient to demonstrate initial safety, feasibility and provide preliminary data on clinical effectiveness.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Traumatic brain injury (TBI) remains a significant public health issue with an incidence of 55-70 million individuals worldwide. In Canada, TBI leads to 23,000 hospitalizations per year with 8% of individuals succumbing to their injuries. In addition to neurologic deficits, TBI may lead to a spectrum of long-term impairments, including cognitive difficulties (e.g., attention, memory), neurologic symptoms (e.g., headaches, dizziness) and neuropsychiatric sequalae (e.g. anxiety, post-traumatic stress disorder). TBI has also been associated with neurodegenerative disorders, such as chronic traumatic encephalopathy and the development of Alzheimer's-type pathology.

Cognitive rehabilitation programs are important tools for clinical recovery of TBI patients, improving functional outcomes and the quality of life. Some of these strategies are based on the development of compensatory strategies and neuroplasticity. Due to the short liver nature of some of the associated improvements and neuroplastic phenomena, stimulating specific neuronal circuits has been proposed.

To date, class I evidence suggests that cognitive improvement following rehabilitation is more effective than sham treatment. In general, however, cognitive rehabilitation therapy is effective in 80-90% of patients. This means that 10-20% of patients remain severely disabled despite treatment.

Deep Brain Stimulation is a neurosurgical tool that has been widely used for over twenty years. Most of the experience with DBS comes from the movement disorder literature where significant success has been had with the management of disabling Parkinson's Disease (PD) and dystonia. Owing to similar underlying circuitry, and the frequent co-occurrence of psychiatric and neurologic conditions, DBS has been suggested for the management of treatment resistant neuropsychiatric conditions, with some promising results.

To date, clinical studies using DBS following TBI are largely comprised of case reports and small case series. The most common application of invasive neurostimulation has been for the treatment of post-TBI dystonic symptoms and tremor. In addition to motor improvement, Miller et al reported a series of 4 patients who presented an improvement in visuospatial memory following fornix burst stimulation. Zhou et al reported that DBS delivered to the anterior limb of internal capsule and the region of the nucleus accumbens improved post-TBI auditory hallucinations, mood changes, and insomnia in a single female patient. Kuhn et al. reported a patient who had a substantial reduction in post- TBI self-mutilating behavior following posterior hypothalamus stimulation. An improvement in emotional adjustment and functional independence was reported in 4 TBI patients treated with nucleus accumbens DBS.Aside from the cognitive, psychiatric and mood improvements described above, DBS has also been investigated for the recovery of consciousness in patients in minimally conscious states. Out of 10 patients reported in the literature, an improvement was observed in 8 individuals using coma scales and related metrics.

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.

Eligibility criteria: Inclusion Criteria:

1. Female or male patients between age 18-70.
2. Diagnosis of memory and cognitive deficits in patients who suffered TBI will be defined according to the Diagnostic and Statistical Manual 5th edition (DSM-5).
3. Patients with cognitive disorder not otherwise specified, dementia, or amnestic disorder due to TBI will be considered.
4. Performance at least 1.5 standard deviations below the estimated premorbid intelligence (assessed by the American National Adult Reading Test) on memory tests (assessed by the California Verbal Learning Test; CVLT).
5. History of TBI for at least 1 year, preferably with evidence of failure to donepezil, cholinesterase inhibitors and cognitive therapy.
6. Ability to provide informed consent and comply with all testing, follow-ups and study appointments.

Exclusion Criteria:

1. Active neurologic disease, such as epilepsy or Alzheimer's disease.
2. Any contraindication to magnetic resonance imaging (MRI) scanning.
3. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure
4. Current suicidal or homicidal ideation.
5. Active neurologic disease, such as epilepsy.
6. Pregnancy.
7. Likely to relocate or move during the study's one year duration
8. Patients with renal dysfunction (GFR\<60)

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by SAFTEE
timeFrame: Every 2 weeks until the 8 weeks mark, every 4 weeks until 6 month mark and every two months until the 2 year mark
Secondary outcomes:
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Nir Lipsman, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: