Deep Brain Stimulation for Cognitive Impairment in Parkinson's Disease

Overseen By Danielle Pietramala

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of British Columbia

Disqualifiers: Language barriers, Dementia, DBS complications

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: 5

27 Participants Needed

Trial Summary

What is the purpose of this trial?

Cognitive impairment is common in Parkinson's disease. A recent study demonstrated 40% of people with PD suffer from mild cognitive impairment and \> 80% of patients develop dementia after a disease duration of 20 years. Cognitive impairment significantly impairs quality of life and has limited treatment options. While the pathophysiology of cognitive symptoms in PD is multifactorial, one contributing factor is dysfunction in subthalamic-cortical loops. The subthalamic nucleus (STN) receives input from distributed regions of the cortex, forming partially segregated parallel networks with sensorimotor regions, associative (cognitive) cortical regions, and limbic cortical regions. These subthalamic-cortical networks are thought to play a domain general role in inhibitory control, which is a fundamental mechanism underlying flexible behavior across motor, cognitive, and affective domains. Information processing in these subthalamic-cortical networks is expressed through oscillatory activity within distinct frequency bands. For example, communication between the STN and prefrontal regions involved in executive function is thought to occur through coherence in the theta (4-8 Hz) frequency band. As a result of these observations, stimulation of the STN at a theta frequency has been investigated as a method of modulating cognitive processes. Theta stimulation of the STN has been shown to enhance coherence in subthalamic-cortical networks, facilitating information processing and modulating behavior. For example, a recent study demonstrated that theta stimulation of the STN improved working memory performance in PD subjects, while no effect was seen for other frequency bands. The authors performed a post-hoc analysis and found that the effect may be mediated by connectivity between the stimulated STN region and the right dorsolateral prefrontal cortex (DLPFC). While these studies have demonstrated proof of principle, they are limited by small sample sizes and post-hoc analyses assessing the relationship between stimulation location and outcomes. Further research is needed to directly test the hypothesis that theta stimulation of the STN can improve executive control in PD patients by modulating associative STN circuitry.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the treatment Theta Deep Brain Stimulation for cognitive impairment in Parkinson's Disease?

Research suggests that low frequency theta stimulation of the subthalamic nucleus, which is part of the brain involved in movement and cognition, may improve cognitive functions like verbal fluency and executive function in Parkinson's disease. This is because theta oscillations are linked to cognitive processes such as memory and decision-making. ^{1 2 3 4 5}

Is deep brain stimulation safe for cognitive impairment in Parkinson's disease?

Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease can lead to cognitive side effects, including confusion and acute dementia, especially in older patients. While it helps with motor symptoms, there are risks of serious psychiatric events and cognitive decline. ^{3 4 6 7 8}

How is Theta Deep Brain Stimulation different from other treatments for cognitive impairment in Parkinson's disease?

Theta Deep Brain Stimulation is unique because it uses low frequency theta oscillations (5-12 Hz) targeting the subthalamic nucleus, which are believed to be important for improving cognitive functions like memory and executive function, unlike traditional high frequency stimulation that primarily addresses motor symptoms. ^{2 3 4 5 9}

Eligibility Criteria

This trial is for people with Parkinson's Disease who are experiencing cognitive impairment. Participants should have a stable condition without any planned changes in their medication or therapy, and they must be able to give informed consent.

Inclusion Criteria

I have images from before and after my surgery.

Those with STN DBS devices

I had surgery more than 3 months ago.

Exclusion Criteria

Those with significant DBS complications

I am able to complete cognitive tasks without language or dementia barriers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Cognitive Assessment

Each subject will undergo a baseline cognitive screening examination (Montreal Cognitive Assessment, MOCA) as part of their routine screening prior to DBS surgery.

1 week

1 visit (in-person)

Theta Deep Brain Stimulation

Subjects will undergo a computerized working memory task while being stimulated in four different conditions: OFF, Theta stimulation of associative STN, Theta stimulation of sensorimotor STN, and High-frequency stimulation of associative STN.

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Theta Deep Brain Stimulation

Trial Overview The study tests whether turning Deep Brain Stimulation (DBS) on or off can improve thinking skills by stimulating a brain area called the subthalamic nucleus at theta frequency, which may enhance brain network function.

Participant Groups

Group I: Theta stimulation of associative STN region Experimental Treatment 1 Intervention

The deep brain stimulation device will be set to a frequency of 6 Hz and will stimulate the associative STN region. If differential activation of the associative and sensorimotor STN networks is not feasible, ventral stimulation is employed.

Group II: Theta stimulation of STN sensorimotor region Active Control 1 Intervention

The deep brain stimulation device will be set to a frequency of 6 Hz and will stimulate the sensorimotor region, acting as an anatomical control. If differential activation of the associative and sensorimotor STN networks is not feasible, dorsal stimulation is employed.

Group III: High frequency stimulation of associative STN region Active Control 1 Intervention

The deep brain stimulation device will be set to a frequency of 135 Hz and will stimulate the associative STN region, acting as a frequency control. If differential activation of the associative and sensorimotor STN networks is not feasible, ventral VTA is employed.

Group IV: Stimulation off Placebo Group 1 Intervention

The deep brain stimulation device will be turned off.

Theta Deep Brain Stimulation is already approved in European Union, United States for the following indications:

Approved in European Union as Theta DBS for:

• Motor symptoms of Parkinson's disease

Approved in United States as Theta DBS for:

• Motor symptoms of Parkinson's disease

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Findings from Research

Bilateral high-frequency stimulation (HFS) of the subthalamic nucleus in 20 Parkinson's disease patients showed significant improvements in motor symptoms, quality of life, and daily activities, with a notable decrease in depressive and anxiety symptoms over 12 months.

While there was a decline in verbal fluency and episodic memory shortly after surgery, overall cognitive performance improved in executive function tasks, suggesting that HFS does not impair cognitive abilities and may help mitigate some cognitive decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease. Daniele, A., Albanese, A., Contarino, MF., et al.[2019]

In a study involving 12 Parkinson's disease patients, high-frequency STN-DBS at 130 Hz significantly increased the latency of the P300 component of auditory event-related potentials, indicating potential interference with cognitive functions.

Lower frequencies of STN-DBS (60-80 Hz) showed minimal effects on P300 latency, suggesting they may be less disruptive to attention and cognitive processes in patients, which could be beneficial for managing axial symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low frequency subthalamic stimulation and event-related potentials in Parkinson disease. Romagnolo, A., Zibetti, M., Lenzi, M., et al.[2021]

Short-term cognitive effects of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease show moderate declines in verbal fluency and small declines in psychomotor speed and language compared to unoperated patients.

Long-term cognitive decline rates after STN-DBS can reach up to 32%, similar to the natural progression of Parkinson's disease, with factors like pre-operative executive dysfunction and older age linked to worse cognitive outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short and Long-Term Cognitive Effects of Subthalamic Deep Brain Stimulation in Parkinson's Disease and Identification of Relevant Factors. Jahanshahi, M., Leimbach, F., Rawji, V.[2022]

In a study involving 12 male patients with Parkinson's disease, theta frequency stimulation (10 Hz) of the subthalamic nucleus significantly improved episodic verbal fluency compared to gamma frequency stimulation (130-135 Hz), suggesting a potential cognitive benefit of theta stimulation.

While theta stimulation showed promise for enhancing episodic memory retrieval, further research is needed to explore its mechanisms and whether combining theta and gamma stimulation could optimize both motor and cognitive functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson's disease: A pilot study. Lam, J., Lee, J., Williams, M., et al.[2021]

Acute stimulation of the dorsal subthalamic nucleus (STN) at theta frequencies (5-12 Hz) significantly improves verbal fluency in Parkinson's disease patients compared to no stimulation and traditional high-frequency gamma stimulation (∼130 Hz).

This study suggests that integrating theta frequency stimulation into deep brain stimulation (DBS) strategies could enhance cognitive outcomes, particularly in tasks related to episodic verbal fluency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease. Lee, DJ., Drummond, NM., Saha, U., et al.[2021]

In a study of 49 patients with Parkinson's disease who underwent deep brain stimulation (DBS) surgery, 26.5% experienced postoperative confusion, highlighting a notable risk associated with this treatment.

The analysis revealed that a higher Charlson comorbidity index, which indicates the presence of other health conditions, was significantly linked to the development of confusion after surgery, suggesting that patients with more health issues may be at greater risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Confusion in Patients with Parkinson Disease Undergoing Deep Brain Stimulation of the Subthalamic Nucleus. Paim Strapasson, AC., Martins Antunes, ÁC., Petry Oppitz, P., et al.[2019]

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]

A case study of a 68-year-old woman with Parkinson's disease revealed that she developed new-onset dementia and severe cognitive decline just one day after undergoing deep brain stimulation of the subthalamic nuclei, suggesting a potential cognitive adverse event associated with the procedure.

The findings highlight the importance of thorough cognitive assessments, including standardized methods and volumetric analysis of hippocampal structures, before deep brain stimulation, as well as screening for cerebrospinal fluid biomarkers if cognitive impairments are detected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Dementia After Deep Brain Stimulation in Parkinson Disease. Puy, L., Tir, M., Lefranc, M., et al.[2018]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Low frequency subthalamic stimulation and event-related potentials in Parkinson disease. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Short and Long-Term Cognitive Effects of Subthalamic Deep Brain Stimulation in Parkinson's Disease and Identification of Relevant Factors. [2022]

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

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson's disease: A pilot study. [2021]

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

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease. [2021]

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

Postoperative Confusion in Patients with Parkinson Disease Undergoing Deep Brain Stimulation of the Subthalamic Nucleus. [2019]

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

Acute Dementia After Deep Brain Stimulation in Parkinson Disease. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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