Theta Deep Brain Stimulation for Cognitive Enhancement in Parkinson's Disease
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Objective: The objective of the proposed research is to test the ability of theta stimulation of the STN to modulate cognitive processing in PD patients by stimulating the ventral, putatively associative territory of the STN.
Hypothesis: The hypothesis is that theta stimulation of the ventral (putatively associative) STN will improve performance on cognitive tasks compared to a control condition in which stimulation is delivered to the dorsal (putatively sensorimotor) STN.
Methods: Power analysis - with previously reported moderate effect sizes (Cohen's d=0.57), the investigators anticipate the need to recruit 27 subjects for a within-subject design with a power of 0.8 and an alpha level of 0.05.
Subjects: Patients with deep brain stimulation systems will be recruited from the Vancouver General Hospital DBS clinic. Subjects will be included if they have STN DBS, pre- and post-operative imaging (to allow electrode reconstruction), and are at least three months post-operative. Subjects will be excluded if they are unable to complete the cognitive task (due to language barriers or dementia) or if they have significant DBS related complications.
Study design: This is a double blind, randomized, cross-over within-subject repeated measure design assessing the interaction between stimulation location and behavioural modification. Subjects will be blinded to stimulation condition, and the individual administering the working memory task will also be blinded, as a neutral third party will program the DBS settings for each condition.
Electrode reconstruction and stimulation location: For each subject, the electrode is reconstructed using the Lead-DBS pipeline. A pre-operative MRI and a post-operative CT are co-registered and non-linearly normalized into standard space, and electrodes are identified and reconstructed using the PaCER algorithm, with manual refinement in native space where required. Directional lead orientation is determined from the CT artifact.
The protocol specified an individualized, connectivity-guided selection of stimulation contacts, with a pre-specified fallback to simplified ventral and dorsal configurations in the event that differential activation of the associative and sensorimotor networks proved unachievable given the anatomical location of the electrode or the electrode model. Review of the electrode reconstructions of enrolled and upcoming subjects indicated that configurations satisfying the connectivity criteria did not exist for a sufficient proportion of subjects. The fallback was therefore invoked, and after the first two subjects all stimulation was delivered using standardized ventral and dorsal montages.
These montages are defined by contact position along the lead rather than by individualized connectivity modelling. The ventral (associative) condition uses the most distal ring contact of each lead as cathode against the implantable pulse generator case as anode (left lead 0-/C+; right lead 8-/C+). The dorsal (sensorimotor) condition uses the most proximal ring contact as cathode in the same monopolar configuration (left lead 3-/C+; right lead 11-/C+). Stimulation is bilateral in both conditions. Because contact numbering follows a consistent dorsoventral ordering along the implanted leads, this fixed scheme produces a maximally separated ventral-versus-dorsal contrast within every subject's lead, independent of individual anatomy, and avoids confounding stimulation location with subject-specific programming decisions.
The ventral and dorsal designations are therefore a priori geometric labels, not verified per-subject network assignments. What was actually stimulated in each subject is established post hoc. For each subject and each theta condition, the electric field is simulated using the exact delivered montage, amplitude and pulse width, and overlap of the stimulation volume with the associative and sensorimotor territories of the STN is quantified in standard space using the DISTAL atlas, expressed as absolute volume, as a proportion of total stimulation volume, and as electric-field-weighted overlap. Structural connectivity between the stimulation volume and cortical regions of interest is estimated from normative structural connectomes as the number of streamlines traversing the stimulation volume and terminating in the region of interest; functional connectivity is estimated from normative resting-state connectomes as the Pearson correlation between the stimulation volume and the region of interest.
Baseline cognitive assessment: Each subject will undergo a baseline cognitive screening examination (Montreal Cognitive Assessment, MOCA), and that will be used as a covariate in future analysis.
Theta DBS: Subjects will come into the clinic on their regular medication schedule. The time since their last medication will be obtained, along with the participants levodopa equivalent daily dose (LEDD) to be used as a covariate to help control for the known non-linear contribution of dopamine to working memory. They will undergo a computerized working memory task while being stimulated in each of four following conditions:
- OFF
- Target condition: Theta (6 Hz) stimulation of the ventral (associative) STN.
- Anatomical control condition: Theta (6 Hz) stimulation of the dorsal (sensorimotor) STN.
- Frequency control condition: The subject's own clinically optimized high-frequency program.
These conditions will be randomized within each subject by creating a random integer (1-4) with no repeats. In the two theta conditions, pulse width is held at 60 µs and amplitude is set to the subject's clinical amplitude, matched across the two conditions so that delivered charge is equivalent and only the stimulation site differs. The clinical condition uses the subject's own programmed contacts, amplitude, pulse width and frequency. After changing the stimulation setting, there is a wash-out/wash-in period of at least 10 minutes prior to commencement of the working memory task. The subject will be asked if there is any unwanted stimulation side-effect (for example paresthesia). If the subject has paraesthesia or otherwise complains about the stimulation, the amplitude will be reduced by 0.5mA. If stimulation is not possible, the patient will be excluded from the study. Immediately before the working memory task commences, subjects will undergo a brief motor examination, consisting of items from the Unified Parkinson's Disease Rating Scale III. At the end of the session, the subjects will be placed back on their clinically optimized program and will continue to take their medication according to their normal schedule.
Working Memory Task: A modified Sternberg task will be presented using a laptop computer.
Statistical analysis: The primary outcome will be working memory performance during each stimulation condition as assessed by a linear mixed effect model. The model will be specified as working memory performance ~ age + MoCA + stimulation condition + baseline cognition*stimulation condition + stimulation order + (1|subject). The hypothesis is that there will be a main effect of stimulation condition on working memory performance, with post-hoc one sample t-tests demonstrating an improvement in the theta associative STN condition relative to the other conditions. An interaction effect of baseline cognition with stimulation condition is also expected to be observed. Based on previous literature, it is hypothesized that subjects with lower baseline cognition will have more improvement during associative STN region stimulation.
A secondary analysis will relate working memory performance to what was actually stimulated in each subject. For each subject, the degree to which the ventral and dorsal montages achieved the intended anatomical dissociation is quantified as overlap of the modelled electric field with the associative and sensorimotor STN territories, and as connectivity between the stimulation volume and dorsolateral prefrontal, primary motor and supplementary motor cortex. These measures will be tested as moderators of the effect of stimulation condition on working memory performance. The hypothesis is that subjects in whom the ventral montage produced greater associative-territory engagement will show greater working memory improvement during ventral theta stimulation.
By including the stimulation order variable, the investigators will adjust for the possibility that subjects performance will decline over time (due to fatigue) irrespective of the stimulation condition. Supplementary analysis will assess for motor performance during each stimulation condition, with the hypothesis that high frequency stimulation will have a reduction in motor scores compared to low frequency stimulation. Post-hoc analysis will also be performed to assess the relationship between task performance and functional and structural connectivity between the STN and associative networks, assuming there is some variability in individual connectivity strengths.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Danielle Pietramala
- Phone Number: 68396 604-875-4111
- Email: danielle.pietram@ubc.ca
Study Contact Backup
- Name: Stefan Lang, MD PhD FRCSC
- Phone Number: 604-875-5540
- Email: stefan.lang@vch.ca
Study Locations
-
-
British Columbia
-
Vancouver, British Columbia, Canada, V5Z 1M9
- Recruiting
- Leslie and Gordan Diamond Health Care Centre
-
Contact:
- Stefan Lang, MD PhD FRCSC
- Phone Number: 604-875-5540
- Email: stefan.lang@vch.ca
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Those with STN DBS devices
- Those with pre- and post-operative imaging
- Those that are at least 3 months post-operative
Exclusion Criteria:
- Those unable to complete the cognitive task (due to language barriers or dementia)
- Those with significant DBS complications
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Sham Comparator: Stimulation off
The deep brain stimulation device will be turned off.
|
The DBS device will be turned off while the patient undergoes the working memory task.
|
|
Experimental: Theta stimulation of associative STN region
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.
|
The DBS device will be turned on while the patient undergoes the working memory task.
|
|
Active Comparator: Theta stimulation of STN sensorimotor region
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.
|
The DBS device will be turned on while the patient undergoes the working memory task.
|
|
Active Comparator: High frequency stimulation of associative STN region
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.
|
The DBS device will be turned on while the patient undergoes the working memory task.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change in working memory performance between conditions
Time Frame: Immediately after task performance
|
Working memory performance will be assessed through a modified Sternberg task.
Subjects will undergo the task with and without stimulation.
Measures the main effect of stimulation condition, with hypothesis that theta stimulation of associative STN will improve performance compared to no stimulation.
Outcome measured through percent of correctly recalled sequences.
|
Immediately after task performance
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Interaction effect between groups and stimulation condition
Time Frame: Immediately after task performance
|
A secondary analysis will categorize subjects into two groups: 1) those where differential targeting of the associative and sensorimotor STN networks was achieved and 2) those where differential targeting of these networks was not possible using the imaging-based criteria previously mentioned.
The linear mixed-effect model will be repeated with the addition of an interaction term between group and stimulation condition.
The hypothesis is that there will be a significant interaction effect between group and stimulation condition.
Specifically, the investigators expect to observe an increase in working memory performance during the theta (6 Hz) stimulation of the associative STN network condition, within the subject group where differential targeting of the associative and sensorimotor STN networks was achieved.
|
Immediately after task performance
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Correlation between working memory performance and STN connectivity
Time Frame: Immediately after task performance
|
Connectivity of the stimulated STN region will be calculated with structural (streamline count and strength) and functional (Pearson Correlation) MRI data.
The change in working memory performance will be correlated to the connectivity metrics with a linear regression.
The hypothesis is that there will be a positive correlation between working memory change and connectivity strength of the STN to associative networks (higher connectivity will be related to higher working memory performance).
|
Immediately after task performance
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- thetaDBS
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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