STN+NBM DBS for Mild Cognitive Impairment in Parkinson's Disease

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Helen M. Bronte-Stewart

Disqualifiers: Dementia, Seizures, Untreated depression, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The goal of this clinical trial is to evaluate the safety and tolerability of a novel deep brain stimulation (DBS) of the Subthalamic Nucleus (STN) and Nucleus Basalis of Meynert (NBM) to treat cognitive and cognitive-motor symptoms in individuals with Parkinson's disease. The main question it aims to answer is: Is a combined deep brain stimulation approach targeting the STN and NBM with four DBS leads safe and tolerable for cognitive and cognitive-motor symptoms in individuals with Parkinson's disease with Mild Cognitive Impairment. Ten participants are anticipated to be enrolled. Participants will undergo a modification of the traditional STN DBS approach for motor symptoms of PD. In addition to the two leads placed within the STN, two additional leads will be placed with the NBM for treatment of cognitive and cognitive-motor symptoms. Novel stimulation patterns will be used within the NBM to target cognitive and cognitive-motor symptoms using an investigational software. Participants will be followed over two years while receiving this therapy with assessments at baseline and every six months. Assessments will include a combination of neuropsychological evaluations, cognitive assessments, motor tasks (including gait/walking), and questionnaires to evaluate the treatment. Two different surgical trajectories will be used, with half the cohort randomized to each group. This will allow comparison of the impact of surgical trajectory on the intervention.

Will I have to stop taking my current medications?

The trial requires participants to be willing to stop their current medications when necessary for research visits.

Is STN+NBM DBS safe for humans?

Subthalamic deep brain stimulation (STN-DBS) has been used in Parkinson's disease patients and is generally considered safe, but it can lead to cognitive decline in some cases, especially in older patients or those with mild cognitive impairment. Some patients may experience serious psychiatric side effects or develop dementia over time. ^{1 2 3 4 5}

How is the STN+NBM DBS treatment different from other treatments for mild cognitive impairment in Parkinson's disease?

The STN+NBM DBS treatment is unique because it combines deep brain stimulation (DBS) of both the subthalamic nucleus (STN) and the nucleus basalis of Meynert (NBM), targeting both motor and cognitive symptoms in Parkinson's disease with mild cognitive impairment. This dual-target approach is novel compared to traditional treatments that typically focus on either motor or cognitive symptoms separately. ^{1 2 6 7 8}

What data supports the effectiveness of the treatment Combined STN+NBM DBS for Mild Cognitive Impairment in Parkinson's Disease?

Research shows that subthalamic nucleus deep brain stimulation (STN-DBS) can improve motor functions in Parkinson's patients, even those with mild cognitive impairment. Additionally, unintentional stimulation of the nucleus basalis of Meynert (NBM) did not lead to faster cognitive decline, suggesting potential safety and effectiveness of NBM-DBS in cognitive aspects. ^{1 2 3 6 9}

Who Is on the Research Team?

Helen M Bronte-Stewart, MD MSE

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals with Parkinson's disease who have mild cognitive impairment. They must be willing to adjust their medication for research visits, able to consent, approved for STN DBS surgery, and can walk 100 feet without help. It excludes pregnant individuals, those with unstable conditions or significant depression, dementia, a history of seizures, or the need for MRI.

Inclusion Criteria

I am approved for or planning on getting deep brain stimulation in the subthalamic nucleus.

I am willing to stop my current medications for research visits if needed.

Ability to provide informed consent

Exclusion Criteria

I need help to walk 100 feet.

I have been diagnosed with dementia.

Unstable medical, psychiatric conditions including significant untreated depression, history of suicidal attempt, or current suicide ideation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and Initial Treatment

Participants undergo surgery for the placement of DBS leads in the STN and NBM, followed by initial treatment with novel stimulation patterns

4 weeks

1 visit (in-person)

Treatment and Monitoring

Participants receive ongoing DBS therapy with assessments at baseline and every six months, including neuropsychological evaluations, cognitive assessments, motor tasks, and questionnaires

104 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Combined STN+NBM DBS

Trial Overview The study tests a new deep brain stimulation method combining STN and NBM targeting both motor and cognitive symptoms in Parkinson's patients. Ten participants will receive this treatment over two years with regular assessments using neuropsychological evaluations and motor tasks.

How Is the Trial Designed?

Group I: Vertical Nuclear Trajectory Experimental Treatment 1 Intervention

Participants will receive combined STN + NBM DBS. The lead placed within the NBM will use a vertical trajectory targeting the nucleus itself.

Group II: Lateral NBM Bundle Trajectory Experimental Treatment 1 Intervention

Participants will receive combined STN + NBM DBS. The lead placed within the NBM will use a lateral trajectory targeting the lateral efferent bundle from the NBM

Who Is Running the Clinical Trial?

Helen M. Bronte-Stewart

Lead Sponsor

Trials

1

Recruited

10+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

In a study of 126 Parkinson's disease patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS), those with mild cognitive impairment (MCI) experienced a lower risk of cognitive decline post-surgery compared to patients with normal cognitive function (NC).

Pre-operative cognitive status was identified as a significant predictor of post-operative cognitive changes, indicating that patients' cognitive abilities before surgery can influence their outcomes after STN-DBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parkinson's disease with mild cognitive impairment may has a lower risk of cognitive decline after subthalamic nucleus deep brain stimulation: A retrospective cohort study. Xie, H., Zhang, Q., Jiang, Y., et al.[2022]

In a study of 33 Parkinson's disease patients with high-frequency deep brain stimulation (DBS) in the internal Globus pallidus (GPi), unintentional stimulation of the nucleus basalis of Meynert (NBM) did not lead to a significant decline in cognitive function over one year.

These findings suggest that high-frequency NBM-DBS may not have the detrimental effects on cognition that were initially hypothesized, indicating a need for further research to explore the therapeutic potential of NBM-DBS in treating cognitive symptoms associated with Parkinson's disease dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serendipitous Stimulation of Nucleus Basalis of Meynert-The Effect of Unintentional, Long-Term High-Frequency Stimulation on Cognition in Parkinson's Disease. Bogdan, ID., Oterdoom, DLM., van Laar, T., et al.[2022]

In a long-term study of 184 Parkinson's disease patients treated with subthalamic deep brain stimulation (STN-DBS), those with mild cognitive impairment (MCI) showed a higher prevalence of cognitive decline over time, with dementia affecting over 30% of these patients after 6 years.

Despite the cognitive challenges, STN-DBS demonstrated sustained efficacy on motor functions in both patients with MCI and those with normal cognition, indicating that the surgery remains beneficial for motor symptoms regardless of cognitive status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subthalamic deep brain stimulation: clinical and neuropsychological outcomes in mild cognitive impaired parkinsonian patients. Merola, A., Rizzi, L., Artusi, CA., et al.[2021]

Subthalamic nucleus deep brain stimulation (STN-DBS) significantly improves motor function and quality of life in patients with Parkinson's disease, as shown in a study of 21 patients over 6 months.

While STN-DBS is considered safe regarding cognitive functions, there was a notable decline in phonemic verbal fluency, which may be linked to the progression of Parkinson's disease and a reduction in medication dosage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive effects of subthalamic nucleus stimulation in Parkinson's disease: a controlled study. Sáez-Zea, C., Escamilla-Sevilla, F., Katati, MJ., et al.[2022]

In a study of 320 candidates for subthalamic deep brain stimulation (STN-DBS), 48% were found to have mild cognitive impairment (PD-MCI), with the majority classified as frontostriatal (80%) and a smaller group as posterior cortical (20%).

Patients with PD-MCI exhibited significant cortical thinning and changes in the left caudate nucleus and hippocampus compared to those with normal cognition, indicating that cognitive impairment in Parkinson's disease is associated with structural brain alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heterogeneity of PD-MCI in Candidates to Subthalamic Deep Brain Stimulation: Associated Cortical and Subcortical Modifications. Devignes, Q., Daoudi, S., Viard, R., et al.[2022]

A 75-year-old woman with Parkinson's disease experienced severe cognitive decline and developed dementia following deep brain stimulation (DBS) of the bilateral subthalamic nuclei, despite an initial brief improvement.

This case highlights the potential cognitive risks associated with STN DBS, suggesting that certain patients may be at higher risk for developing dementia after the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dementia after DBS Surgery: A Case Report and Literature Review. Rektorova, I., Hummelova, Z., Balaz, M.[2021]

In a study of 26 elderly patients with Parkinson's disease undergoing subthalamic deep brain stimulation (STN-DBS), there was a higher incidence of serious adverse events, particularly psychosis and hallucinations, compared to younger patients from the EARLYSTIM study.

Despite these psychiatric complications being transient, the overall benefits of STN-DBS in improving Parkinson's symptoms were found to outweigh the risks, highlighting the importance of thorough psychiatric evaluations before and after the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Older Candidates for Subthalamic Deep Brain Stimulation in Parkinson's Disease Have a Higher Incidence of Psychiatric Serious Adverse Events. Cozac, VV., Ehrensperger, MM., Gschwandtner, U., et al.[2020]

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease patients affects their ability to switch from automatic to controlled cognitive processing, particularly during tasks requiring higher cognitive load.

In a study of 15 Parkinson's patients, it was found that with STN DBS on, patients relied more on automatic counting strategies under increased cognitive load, while they could use more controlled strategies when DBS was off, indicating a load-dependent effect of STN DBS on cognitive control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson's Disease. Williams, IA., Wilkinson, L., Limousin, P., et al.[2018]

In a study of 24 patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease, significant declines in both semantic and phonemic verbal fluency were observed immediately after surgery and persisted for at least six months.

The acute decline in phonemic verbal fluency post-surgery may indicate a long-term deficit, but this cognitive impairment does not predict the development of Parkinson's disease dementia, which is more closely related to the disease itself rather than the surgical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does early verbal fluency decline after STN implantation predict long-term cognitive outcome after STN-DBS in Parkinson's disease? Borden, A., Wallon, D., Lefaucheur, R., et al.[2014]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Parkinson's disease with mild cognitive impairment may has a lower risk of cognitive decline after subthalamic nucleus deep brain stimulation: A retrospective cohort study. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Serendipitous Stimulation of Nucleus Basalis of Meynert-The Effect of Unintentional, Long-Term High-Frequency Stimulation on Cognition in Parkinson's Disease. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Subthalamic deep brain stimulation: clinical and neuropsychological outcomes in mild cognitive impaired parkinsonian patients. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Cognitive effects of subthalamic nucleus stimulation in Parkinson's disease: a controlled study. [2022]

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

Heterogeneity of PD-MCI in Candidates to Subthalamic Deep Brain Stimulation: Associated Cortical and Subcortical Modifications. [2022]

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

Dementia after DBS Surgery: A Case Report and Literature Review. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Older Candidates for Subthalamic Deep Brain Stimulation in Parkinson's Disease Have a Higher Incidence of Psychiatric Serious Adverse Events. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson's Disease. [2018]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Does early verbal fluency decline after STN implantation predict long-term cognitive outcome after STN-DBS in Parkinson's disease? [2014]