Combined STN and NBM Deep Brain Stimulation for Mild Cognitive Impairment in Parkinson's Disease

Study Overview
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Brief Summary
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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.

Official Title
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Neurostimulation of the Nucleus Basalis of Meynert for the Cognitive-Motor Syndrome in Parkinson's Disease

Conditions
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Parkinson's Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Device: Combined STN+NBM DBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Parkinson's disease (PD) Approved (or planning on) for subthalamic nucleus (STN) deep brain stimulation (DBS) Willingness to withdraw from clinical medication regimen when necessary for research visits Ability to provide informed consent Exclusion Criteria: Dementia Unstable medical, psychiatric conditions including significant untreated depression, history of suicidal attempt, or current suicide ideation History of seizures Pregnant Requires MRI Unable to walk 100 feet without an assistive device

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All participants will receive the interventional treatment. Two different surgical trajectories will be used for placing the leads in the NBM. Half the cohort will be randomized to each trajectory.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vertical Nuclear Trajectory<br>Participants will receive combined STN + NBM DBS. The lead placed within the NBM will use a vertical trajectory targeting the nucleus itself. | Device: Combined STN+NBM DBS<br>* This intervention is a 4-lead deep brain stimulation approach targeting the Subthalamic Nucleus (STN) and Nucleus Basalis of Meynert (NBM)<br>|
| Experimental: Lateral NBM Bundle Trajectory<br>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 | Device: Combined STN+NBM DBS<br>* This intervention is a 4-lead deep brain stimulation approach targeting the Subthalamic Nucleus (STN) and Nucleus Basalis of Meynert (NBM)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Any untoward medical occurrence that occurs during this study whether or not considered related to the study device, study procedures, or study requirements that is identified or worsens during the duration of the study | From baseline to 1 year into treatment | 
| Swing Time Coefficient of Variation | Swing time variability will be measured using the dual force plates in the SIP task and IMUs for TBC. It is defined as the mean swing time coefficient of variation (CV) of both legs. | From baseline to 1 year into treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Time Freezing | Duration of freezing episodes during SIP will be measured using IMUs and force plates using a validated offline algorithm. | From baseline to 1 year into treatment | 
| Stride Time Coefficient of Variation | Stride time coefficient of variation will be measured using the dual force plates in the SIP task and IMUs. Stride time coefficient of variation is defined as the mean stride time coefficient of variation (CV) of both legs. A greater stride time CV is indicative of less rhythmic gait/stepping. | From baseline to 1 year into treatment | 
| Shank Angular Velocity | Shank angular velocity will be measured from IMUs work on the participant's leg/ankle. Reductions in this value are indicative of FOG and gait impairment. | From baseline to 1 year into treatment | 
| Tapping Speed | The interstrike-interval of alternating tapping will be measured using an engineered piano keyboard. A higher interstrike-interval indicates slower tapping | From baseline to 1 year into treatment | 
| Tapping Rhythmicity | The variability of the interstrike-interval of alternating tapping, as quantified by the coefficient of variation, will be measured using an engineered piano keyboard. A higher coefficient of variation indicates worse rhythmicity | From baseline to 1 year into treatment | 
| MDS-UPDRS III Score | PD symptoms will be assessed clinically using the MDS-Unified Parkinson's Disease Rating Scale (UPDRS) Section III. This is a motor examination to evaluate speech, facial expression, tremor at rest, action or postural tremor of hands, rigidity, finger taps, hand movements, rapid alternating movement of hands, leg agility, arising from chair, posture, gait, freezing of gait, posture, body bradykinesia, and postural stability. Each item is scored on a scale from 0 (normal) to 4 (severe), with the total possible score ranging from 0 to 132. | From baseline to 1 year into treatment | 
| SAT Score | Each trial of the SAT will be categorized as a Hit (H), Miss (M), or False Alarm (FA). The SAT score is defined as ((H - FA) / [2× (H + FA) - (H + FA)2]), which ranges from - 1.0 (100% incorrect performance; all misses and false alarms) to +1.0 (100% correct performance; all hits and correct rejections). | From baseline to 1 year into treatment | 
| Percent False Positives | The percent of false positives during the SAT. | From baseline to 1 year into treatment | 
| Percent Misses | The percent of misses of total trials during the SAT | From baseline to 1 year into treatment | 
| Average + standard deviation of response time | The average and standard deviation of the response time during the SAT. | From baseline to 1 year into treatment | 
| Goal-directed focus of attention | Hit rate during the first minute in the no- distractor condition for the CTET. | From baseline to 1 year into treatment | 
| Sustained attention | Hit rate change slope in no-distractor condition for the CTET. | From baseline to 1 year into treatment | 
| Distractibility | Hit rate difference between no-distractor and distractor conditions for the CTET. | From baseline to 1 year into treatment | 
| Parkinson's Disease - Cognitive Rating Scale (PD-CRS) | Cognitive scale composed of 9 tasks that assesses the full range of cognitive dysfunction in PD. It is a scale of 0 to 134, with 134 being the best score. | From baseline to 1 year into treatment | 
| Montreal Cognitive Assessment (MoCA) | Total score to assess of this rapid screening test of different cognitive domains. It is a scale of 0 to 30, with 30 being the best score. | From baseline to 1 year into treatment | 
| Trails A | The time it takes to complete the task and errors. | From baseline to 1 year into treatment | 
| Trails B | The time it takes to complete the task and errors. | From baseline to 1 year into treatment | 
| Symbol Digit Modalities (SDMT) Oral and Written | The summation of the number of correct substitutions within the 90 second interval. | From baseline to 1 year into treatment | 
| visual puzzles from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) | Percentile of performance on visual puzzles for participant's demographic. | From baseline to 1 year into treatment | 
| Judgement of Line Orientation | Percentile of performance on judgement of line orientation for participant's demographic. | From baseline to 1 year into treatment | 
| Patient Health Questionnaire-9 (PHQ-9) | Total score on questionnaire regarding participant's mood the last 2 weeks. The scale ranges from 0 to 27 with a score of 27 indicating the most severe symptoms. | From baseline to 1 year into treatment | 
| General Anxiety Disorder-7 (GAD-7) | Total score on questionnaire regarding participant's anxiety the last two weeks.The scale ranges from 0 to 21 with a score of 21 indicating the most severe symptoms. | From baseline to 1 year into treatment | 
| MDS-UPDRS I | Total score evaluating the non-motor aspects of experiences of daily living. It is a scale from 0 to 52 with 52 being the most severe symptoms. | From baseline to 1 year into treatment | 
| MDS-UPDRS II | Total score evaluating the motor aspects of experiences of daily living. It is a scale from 0 to 52 with 52 being the most severe symptoms. | From baseline to 1 year into treatment | 
| MDS-UPDRS IV | Total score of motor complications experienced by the participant. It is a scale from 0 to 24 with 24 being the most severe symptoms. | From baseline to 1 year into treatment | 
| Neuropsychiatric Inventory (NPI) | Total score for symptom severity and distress via questionnaire. It is a scale from 0 to 60 with 60 indicating worse symptoms. | From baseline to 1 year into treatment | 
| Parkinson's Disease Questionnaire-39 (PDQ-39) | Total score for Parkinson's disease-specific health related quality over the last month across 8 quality of life dimensions assessed via questionnaire. Score ranges from 0 to 100 with 100 indicating more symptoms and problems. | From baseline to 1 year into treatment | 
| Caregiver Burden Assessment | Total score on caregiver self-report to assess the stress-levels of family caregivers. It is a scale from 0 to 88 with higher scores indicating greater or worse burden. | From baseline to 1 year into treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DBS, deep brain stimulation, cognition, parkinson's disease