Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06518824
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-07-10
Brief Title:
Theta Deep Brain Stimulation for Cognitive Enhancement in Parkinsons Disease
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Theta Deep Brain Stimulation for Cognitive Enhancement in Parkinsons Disease
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Cognitive impairment is common in Parkinsons 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
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
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 directly targeting associative STN circuitry
Hypothesis We hypothesize that theta stimulation of associative STN circuitry will improve performance on cognitive tasks compared to a control condition where stimulation is targeting a sensorimotor STN circuit
Methods Power analysis With previously reported moderate effect sizes Cohens d057 we anticipate the need to recruit 27 subjects for a within-subject design with a power of 08 and an alpha level of 005
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 single blind randomized cross-over within-subject repeated measure design assessing the interaction between stimulation location and behavioral modification Subjects will be blinded to stimulation condition
Identification of associative STN network and optimal electrode configuration Before the subject arrives for stimulation we will reconstruct the location of the electrode using the pipeline in LeadDBS Briefly a pre-operative MRI and a post-operative CT scan will be co-registered and subsequently non-linearly normalized into standard space Electrodes will be identified and reconstructed using the PaCER algorithm as implemented in LeadDBS Using each subjects individualized electrode reconstruction we will calculate VTAs that differentially engage the associative STN region and STN-sensorimotor regions The corresponding electrode configurations will be used during the cognitive task
Baseline cognitive assessment Each subject will undergo a baseline cognitive screening examination Montreal Cognitive Assessment MOCA that will be used as a covariate in future analysis This will be done as part of their routine screening prior to DBS surgery
Theta DBS Subjects will come into the clinic in the OFF-medication state 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 conditions These conditions will correspond to 1 OFF 2 theta 6 Hz stimulation of the associative STN region target condition 3 theta stimulation of the STN sensorimotor region anatomical control condition and 4 high-frequency 135 Hz stimulation of the associative STN region frequency control condition These conditions will be randomized within each subject by creating a random integer 1-4 with no repeats We will keep the amplitude and pulse width constant 25 mA 90us After changing the stimulation setting we will wait 5-10 minutes prior to commencement of the working memory task We will ask the subject if there is any unwanted stimulation side-effect for example paresthesia If the subject has paraesthesia or otherwise complains about the stimulation we will reduce the amplitude by 05mA If we are unable to stimulate 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 Parkinsons Disease Rating Scale III At the end of the session the subjects will be placed back on their clinically optimized program and will take their medication according to their normal schedule
Working Memory Task A modified Sternberg task will be presented using a laptop computer
Statistical analysis Our 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 cognitionstimulation condition stimulation order 1subject Our 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 We also expect to see an interaction effect of baseline cognition with stimulation condition Based on previous literature we hypothesize that subjects with lower baseline cognition will have more improvement during associative STN region stimulation By including the stimulation order variable we 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 We will also perform pos-hoc analysis 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
Hypothesis We hypothesize that theta stimulation of associative STN circuitry will improve performance on cognitive tasks compared to a control condition where stimulation is targeting a sensorimotor STN circuit
Methods Power analysis With previously reported moderate effect sizes Cohens d057 we anticipate the need to recruit 27 subjects for a within-subject design with a power of 08 and an alpha level of 005
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 single blind randomized cross-over within-subject repeated measure design assessing the interaction between stimulation location and behavioral modification Subjects will be blinded to stimulation condition
Identification of associative STN network and optimal electrode configuration Before the subject arrives for stimulation we will reconstruct the location of the electrode using the pipeline in LeadDBS Briefly a pre-operative MRI and a post-operative CT scan will be co-registered and subsequently non-linearly normalized into standard space Electrodes will be identified and reconstructed using the PaCER algorithm as implemented in LeadDBS Using each subjects individualized electrode reconstruction we will calculate VTAs that differentially engage the associative STN region and STN-sensorimotor regions The corresponding electrode configurations will be used during the cognitive task
Baseline cognitive assessment Each subject will undergo a baseline cognitive screening examination Montreal Cognitive Assessment MOCA that will be used as a covariate in future analysis This will be done as part of their routine screening prior to DBS surgery
Theta DBS Subjects will come into the clinic in the OFF-medication state 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 conditions These conditions will correspond to 1 OFF 2 theta 6 Hz stimulation of the associative STN region target condition 3 theta stimulation of the STN sensorimotor region anatomical control condition and 4 high-frequency 135 Hz stimulation of the associative STN region frequency control condition These conditions will be randomized within each subject by creating a random integer 1-4 with no repeats We will keep the amplitude and pulse width constant 25 mA 90us After changing the stimulation setting we will wait 5-10 minutes prior to commencement of the working memory task We will ask the subject if there is any unwanted stimulation side-effect for example paresthesia If the subject has paraesthesia or otherwise complains about the stimulation we will reduce the amplitude by 05mA If we are unable to stimulate 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 Parkinsons Disease Rating Scale III At the end of the session the subjects will be placed back on their clinically optimized program and will take their medication according to their normal schedule
Working Memory Task A modified Sternberg task will be presented using a laptop computer
Statistical analysis Our 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 cognitionstimulation condition stimulation order 1subject Our 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 We also expect to see an interaction effect of baseline cognition with stimulation condition Based on previous literature we hypothesize that subjects with lower baseline cognition will have more improvement during associative STN region stimulation By including the stimulation order variable we 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 We will also perform pos-hoc analysis 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None