Deep Brain Stimulation for Frontotemporal Dementia

(FRONSTIM Trial)

Overseen By Tasnuva Hoque

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University Health Network, Toronto

Must be taking: FTD medications

Must not be taking: Chemotherapy, Steroids

Disqualifiers: Other psychiatric, CNS disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests deep brain stimulation (DBS), a procedure involving the placement of electrodes in the brain, for individuals with behavioral variant frontotemporal dementia (bvFTD). The researchers aim to stimulate the subgenual cingulate to determine if it can improve symptoms such as lack of motivation and impulsive behaviors. Participants will maintain their current treatments while receiving DBS. The study seeks individuals diagnosed with bvFTD who experience apathy and have been on stable medication doses for at least three months. As an unphased trial, it offers a unique opportunity to contribute to groundbreaking research that could lead to new treatment options for bvFTD.

Will I have to stop taking my current medications?

The trial requires that participants have been on a stable dose of their current FTD medications for at least 3 months, so you won't need to stop taking them.

What prior data suggests that this deep brain stimulation is safe for frontotemporal dementia?

Research shows that deep brain stimulation (DBS) is generally well-tolerated by patients with a type of dementia affecting behavior. Studies have found that patients usually handle the procedure without significant problems, and no major side effects have been reported. This suggests the treatment is reasonably safe. However, as with any medical procedure, risks may exist, so discussing these with the trial team is important for those considering participation. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard treatments for frontotemporal dementia, which primarily involve medications to manage symptoms, deep brain stimulation (DBS) offers a novel approach by directly targeting brain regions. This treatment is unique because it involves implanting electrodes in the subgenual cingulate area of the brain, which is thought to play a key role in mood and behavior. Researchers are excited about DBS because it could potentially modify brain activity in a more precise way, offering hope for improved cognitive and behavioral outcomes that current drug therapies might not achieve.

What evidence suggests that deep brain stimulation is effective for frontotemporal dementia?

Research has shown that bilateral subgenual cingulate deep brain stimulation (SGC DBS) might improve some symptoms of behavioral variant frontotemporal dementia (bvFTD). These symptoms include lack of interest, impulsive behavior, and reduced empathy. The treatment stimulates a key brain area, potentially activating parts that aren't functioning properly. This method might help restore the reduced brain activity seen in bvFTD. Early results suggest that this type of brain stimulation can effectively address these challenging symptoms. All participants in this trial will receive SGC DBS as the sole treatment under investigation. ^{1 2 3 4 6}

Who Is on the Research Team?

Carmela Tartaglia, MD

Principal Investigator

University Health Network, Toronto

Andres M Lozano, MD, PhD

Principal Investigator

University Health Network, Toronto

Cletus Cheyuo, MD, PhD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for adults aged 40-85 with behavioral variant frontotemporal dementia, showing symptoms like apathy. They must have stable medication use for the past 3 months and a caregiver or decision-maker to consent. Exclusions include pregnancy, substance dependence, other major CNS diseases, past significant brain surgery, MRI contraindications like metal implants, and conditions making anesthesia risky.

Inclusion Criteria

I have been diagnosed with a specific type of dementia affecting behavior.

I have someone who can reliably report on my daily activities and function.

The patient must also have a substitute decision maker, if different from caregiver, to sign the informed consent for participation in the study

Exclusion Criteria

I am a woman who could become pregnant and am not using effective birth control.

Is unable to comply with study visit schedule and timeline

I have had major brain surgery in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Surgery Baseline Assessment

Baseline neuroimaging, neuropsychological testing, and biomarker assessments are conducted before DBS surgery

4 weeks

Multiple visits (in-person)

Surgery and Initial Recovery

Bilateral subgenual cingulate deep brain stimulator implantation and initial recovery

2 weeks

Inpatient stay for surgery and recovery

Post-Surgery Programming and Monitoring

DBS device activation and programming sessions to optimize therapy, along with regular neuropsychological and biomarker assessments

24 months

Regular visits at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 3 months, 6 months, 9 months, 12 months, and 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Bilateral subgenual cingulate deep brain stimulation (SGC DBS)

Trial Overview The study tests deep brain stimulation of the subgenual cingulate to treat frontotemporal dementia symptoms by activating dysfunctional networks in the brain. It will monitor changes in cerebral metabolism, connectivity, atrophy and biomarkers to evaluate safety and preliminary effectiveness.

How Is the Trial Designed?

Group I: Bilateral subgenual cingulate deep brain stimulation (SGC DBS) Experimental Treatment 1 Intervention

Deep Brain Stimulation (DBS) is a neurosurgical procedure involving the implantation of deep brain electrodes, connected via a subcutaneous extension wire, to an implantable pulse generator (IPG, or 'battery') that is implanted below the collarbone. All patients will receive deep brain stimulation (DBS) targeting the subgenual cingulate (SGC) bilaterally. No other changes to pre-existing treatment will be made. This is the only arm in this experiment.

Bilateral subgenual cingulate deep brain stimulation (SGC DBS) is already approved in United States, European Union for the following indications:

Approved in United States as Deep Brain Stimulation for:

• Parkinson's disease
• Essential tremor
• Dystonia
• Obsessive-compulsive disorder
• Medically refractory epilepsy

Approved in European Union as Deep Brain Stimulation for:

• Parkinson's disease
• Essential tremor
• Dystonia
• Obsessive-compulsive disorder
• Medically refractory epilepsy

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Weston Brain Institute

Collaborator

Trials

13

Recruited

990+

Published Research Related to This Trial

Deep brain stimulation (DBS) targeting the nucleus basalis of Meynert shows promise in enhancing cognitive function and potentially slowing the progression of Alzheimer's disease, based on recent human and animal studies.

The effectiveness of DBS may depend on stimulation parameters, with lower frequencies or intermittent patterns likely being more beneficial for cognitive enhancement compared to the high-frequency stimulation used for movement disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic Deep Brain Stimulation for Memory and Cognitive Disorders. Subramaniam, S., Blake, DT., Constantinidis, C.[2023]

In a study of 18 patients with advanced Parkinson's disease, bilateral deep brain stimulation (DBS) of the subthalamic nuclei significantly reduced the daily intake of antiparkinsonian medications from an average of 12.05 tablets to 7.00 tablets one year after implantation (p < 0.001).

The reduction in medication usage was accompanied by a substantial improvement in motor symptoms, as indicated by a 48.6% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS-III), suggesting that DBS not only lowers medication needs but also enhances patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of antiparkinsonian drug reduction after bilateral subthalamic deep brain stimulation]. Fehér, G., Balás, I., Komoly, S., et al.[2010]

In a study of 25 patients with advanced Parkinson's disease, deep brain stimulation targeting the subthalamic nucleus significantly improved motor symptoms and reduced levodopa-induced dyskinesias, as evidenced by better UPDRS III scores.

Most effective electrode contacts were found near the dorsal margin of the subthalamic nucleus, suggesting that stimulation in this border area between the sensorimotor part of the nucleus and surrounding regions may enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: evaluation of active electrode contacts. Hamel, W., Fietzek, U., Morsnowski, A., et al.[2019]

In a study of 233 Parkinson's Disease patients who underwent Deep Brain Stimulation (DBS) of the subthalamic nucleus, only 11.76% of procedures resulted in surgical adverse events (SAEs), indicating a relatively low risk associated with the procedure.

Most SAEs were reversible, with only two cases leading to long-term effects, demonstrating that STN DBS is a safe surgical option with a high reliability rate of 95.59% for correct lead implantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical adverse events of deep brain stimulation in the subthalamic nucleus of patients with Parkinson's disease. The learning curve and the pitfalls. Seijo, F., Alvarez de Eulate Beramendi, S., Santamarta Liébana, E., et al.[2022]

In a study involving 9 patients with severe, treatment-resistant depression, subcallosal cingulate deep brain stimulation (SCC DBS) produced immediate increases in autonomic sympathetic responses, indicating a physiological reaction to the stimulation that correlated with behavioral changes.

The research suggests that the midcingulate cortex is a key pathway mediating these autonomic responses, highlighting the importance of specific brain networks in the effectiveness of SCC DBS as a treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autonomic arousal elicited by subcallosal cingulate stimulation is explained by white matter connectivity. Riva-Posse, P., Inman, CS., Choi, KS., et al.[2019]

Deep brain stimulation (DBS) for advanced Parkinson's disease, using Multiple Sequences Image Fusion (MuSIF) for accurate targeting, led to a significant reduction of 76% in L-dopa equivalent daily dose after 3 months.

Patients experienced a 50% reduction in dyskinesias and a 45% decrease in motor fluctuations, demonstrating the efficacy of the combined imaging techniques in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple sequential image-fusion and direct MRI localisation of the subthalamic nucleus for deep brain stimulation. Rampini, PM., Locatelli, M., Alimehmeti, R., et al.[2017]

Deep brain stimulation (DBS) has been explored as a treatment for dementia, with three studies focusing on its effects, including one on fornix DBS for Alzheimer's disease and two on nucleus basalis of Meynert for Alzheimer's and Parkinson's disease dementia.

Current evidence for the effectiveness of DBS in treating dementia is still preliminary and limited, indicating a need for further research to understand its potential clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation for the treatment of Alzheimer disease and dementias. Laxton, AW., Lozano, AM.[2022]

Deep brain stimulation (DBS) targeting the fornix shows promise in potentially slowing cognitive decline and improving brain health in patients with mild Alzheimer's disease, with ongoing phase III trials to assess its efficacy.

DBS may offer disease-modifying effects rather than just symptomatic relief, as seen in animal studies that suggest it can enhance neuroprotection and influence the progression of neurodegenerative disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modifying the progression of Alzheimer's and Parkinson's disease with deep brain stimulation. Jakobs, M., Lee, DJ., Lozano, AM.[2021]

Deep brain stimulation (DBS) therapy for Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) has been explored in 7 clinical studies involving 57 AD patients and 7 PDD patients, showing acceptable surgical safety with serious adverse events occurring in only 9% of patients, none resulting in death or disability.

While some individual cases reported improved clinical responses to DBS, larger studies did not find significant or consistent cognitive benefits, indicating that more research is needed to refine patient selection and treatment parameters for effective outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation for dementias. Xu, DS., Ponce, FA.[2020]

In a phase I study involving 5 patients with mild Alzheimer's disease, deep brain stimulation (DBS) targeting the fornix significantly increased cerebral glucose metabolism in key brain networks after one year, suggesting enhanced neural activity.

The increased metabolism was correlated with improved clinical outcomes in cognition, memory, and quality of life, indicating that DBS may offer a more extensive and effective treatment option compared to traditional pharmacotherapy for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. Smith, GS., Laxton, AW., Tang-Wai, DF., et al.[2021]

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) for treatment-resistant depression can be affected by brain shift, with an average displacement of 2.2 mm observed shortly after surgery, which may alter the effectiveness of the treatment.

Electrode displacements from the planned target location resulted in a 3.6% decrease in activation of pathways to the ventral striatum, suggesting that precise targeting is crucial for optimizing therapeutic outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of brain shift on subcallosal cingulate deep brain stimulation. Choi, KS., Noecker, AM., Riva-Posse, P., et al.[2021]

In a study of 69 patients with advanced Parkinson's disease who underwent deep brain stimulation (DBS), 53% of those with subthalamic nucleus (STN) stimulation reported ongoing adverse events (AEs) four years post-surgery, compared to 35% in the internal globus pallidus (GPi) group.

Most AEs were not severe and affected cognitive, psychiatric, and motor functions, with a notable correlation between the presence of AEs and longer disease duration and pre-existing gait and psychiatric issues in STN DBS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter study on deep brain stimulation in Parkinson's disease: an independent assessment of reported adverse events at 4 years. Hariz, MI., Rehncrona, S., Quinn, NP., et al.[2008]

Deep brain stimulation (DBS) is a safe and effective surgical treatment for advanced Parkinson's disease, with a low incidence of serious complications, as shown in a study of 130 patients over several years.

In this study, 62% of patients experienced no complications, and the most common issues were minor, such as aborted procedures (5.14%) and seizures (4.7%), indicating that DBS has a favorable safety profile compared to other surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications in subthalamic nucleus stimulation surgery for treatment of Parkinson's disease. Review of 272 procedures. Seijo, FJ., Alvarez-Vega, MA., Gutierrez, JC., et al.[2019]

Bilateral deep brain stimulation (DBS) of the fornix in 42 patients with mild Alzheimer's disease was found to be feasible and well-tolerated, with no neurological deficits or deaths reported after the procedure.

While 61.9% of patients experienced adverse events related to the procedure, most were not serious, and the mean length of hospitalization was only 1.4 days, indicating a relatively safe intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial. Ponce, FA., Asaad, WF., Foote, KD., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05699330

Subgenual Cingulate Deep Brain STIMulation for Apathetic ... Bilateral subgenual deep brain stimulation may improve some of the six core clinical features of behavioral variant frontotemporal dementia. In AIM 3 ...

2. trialx.com trialx.com/clinical-trials/listings/264249/subgenual-cingulate-deep-brain-stimulation-for-apathetic-behavioral-variant-frontotemporal-dementia/

Subgenual Cingulate Deep Brain STIMulation for Apathetic ... Bilateral subgenual deep brain stimulation may improve some of the six core clinical features of behavioral variant frontotemporal dementia. In ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/condition/1105/frontotemporal-dementia

Frontotemporal Dementia Clinical Research Trials Bilateral subgenual deep brain stimulation may improve some of the six core clinical features of behavioral variant frontotemporal dementia. In AIM 3 ...

4. withpower.com withpower.com/trial/phase-dementia-2023-43085

Deep Brain Stimulation for Frontotemporal Dementia This trial is testing a brain implant that sends electrical signals to help people with a specific type of dementia that causes severe symptoms like apathy.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24679386/

Effectiveness and acceptability of deep brain stimulation ... DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10936049/

Deep brain stimulation of the subgenual cingulum and ... In this phase 1 trial, we treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus.