Investigating Inhibitory Control Networks in Parkinson's Disease

• ClinicalTrials.gov Identifier: NCT04735458
• Recruitment Status: Recruiting
• First Posted: February 3, 2021
• Last Update Posted: November 3, 2023
• Sponsor: University of Alabama at Birmingham
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): J. Nicole Bentley, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: January 28, 2021
• First Posted Date: February 3, 2021
• Last Update Posted Date: November 3, 2023
• Actual Study Start Date: April 1, 2021
• Estimated Primary Completion Date: March 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 1, 2023)

• Accuracy via Simon Task (% correct) [ Time Frame: Baseline ]
  In the Simon task, participants are instructed to respond with a right or left button press (Right = Red, Left = Blue) according to how a word is printed on a screen ("RED" or "BLUE"), regardless of the color in which the word is printed. This is a measurement of accuracy (% correct, ranging from 0-100, with higher scores indicating better performance)
• Response times via Simon Task (sec) [ Time Frame: Baseline ]
  In the Simon task, participants are instructed to respond with a right or left button press according to the word "RIGHT" or "LEFT" that appears on a screen, regardless of where on the screen it actually appears. This is a measurement response times (continuous measure, from 0-4000 milliseconds) between correct and incorrect responses.
• Simon Effect on Response times (sec) [ Time Frame: Baseline ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in response times between congruent and incongruent trials
• Simon Effect on Accuracy (% correct) [ Time Frame: Baseline ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in accuracy between congruent and incongruent trials
• United Parkinson's disease Rating Scale part 3: Motor Examination Score 0-108 (Higher score represents worse symptoms) [ Time Frame: Baseline ]
  Participants will undergo motor evaluation using the validated United Parkinson's disease Rating Scale (UPDRS) part 3.
• Dementia Rating Scale Score 0-144 points (Higher score represents better symptoms) [ Time Frame: Baseline ]
  Participants will undergo neuropsychological testing as part of routine care, including the Dementia Rating Scale

Original Primary Outcome Measures (submitted: January 28, 2021)

• Accuracy via Simon Task (% correct) [ Time Frame: Baseline ]
  In the Simon task, participants are instructed to respond with a right or left button press (Right = Red, Left = Blue) according to how a word is printed on a screen ("RED" or "BLUE"), regardless of the color in which the word is printed. This is a measurement of accuracy (% correct, ranging from 0-100, with higher scores indicating better performance)
• Accuracy via Simon Task (% correct) [ Time Frame: 0-3 month ]
  In the Simon task, participants are instructed to respond with a right or left button press (Right = Red, Left = Blue) according to how a word is printed on a screen ("RED" or "BLUE"), regardless of the color in which the word is printed. This is a measurement of accuracy (% correct, ranging from 0-100, with higher scores indicating better performance)
• Response times via Simon Task (sec) [ Time Frame: Baseline ]
  In the Simon task, participants are instructed to respond with a right or left button press according to the word "RIGHT" or "LEFT" that appears on a screen, regardless of where on the screen it actually appears. This is a measurement response times (continuous measure, from 0-4000 milliseconds) between correct and incorrect responses.
• Response times via Simon Task (sec) [ Time Frame: 0-3 months ]
  In the Simon task, participants are instructed to respond with a right or left button press according to the word "RIGHT" or "LEFT" that appears on a screen, regardless of where on the screen it actually appears. This is a measurement response times (continuous measure, from 0-4000 milliseconds) between correct and incorrect responses.
• Simon Effect on Response times (sec) [ Time Frame: Baseline ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in response times between congruent and incongruent trials
• Simon Effect on Response times (sec) [ Time Frame: 0-3 months ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in response times between congruent and incongruent trials
• Simon Effect on Accuracy (% correct) [ Time Frame: Baseline ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in accuracy between congruent and incongruent trials
• Simon Effect on Accuracy (% correct) [ Time Frame: 0-3 months ]
  Participants will perform the Simon task as described, and the Simon effect will be calculated as the difference in accuracy between congruent and incongruent trials
• UPDRS 3 motor score (0-108) [ Time Frame: Baseline ]
  Participants will undergo motor evaluation using the validated United Parkinson's disease Rating Scale (UPDRS) part 3
• UPDRS 3 motor score (0-108) [ Time Frame: 0-6 months ]
  Participants will undergo motor evaluation using the validated United Parkinson's disease Rating Scale (UPDRS) part 3
• Dementia Rating Scale Score (0-144 points) [ Time Frame: Baseline ]
  Participants will undergo neuropsychological testing as part of routine care, including the Dementia Rating Scale
• Prefrontal theta-power (microvolt/Hertz) [ Time Frame: 0-3 months ]
  Participants will undergo intracranial monitoring during DBS surgery in which a prefrontal strip electrode will be placed, enabling measurement of brain activity.
• Subcortical theta-power (microvolt/Hertz) [ Time Frame: 0-3 months ]
  Participants will undergo intracranial monitoring during DBS surgery in which a DBS electrode will be placed, enabling measurement of brain activity at subcortical targets.
• Subcortical gamma-power (microvolt/Hertz) [ Time Frame: 0-3 months ]
  Participants will undergo intracranial monitoring during DBS surgery in which a DBS electrode will be placed, enabling measurement of brain activity at subcortical targets.
• Prefrontal gamma-power (microvolt/Hertz) [ Time Frame: 0-3 months ]
  Participants will undergo intracranial monitoring during DBS surgery in which a prefrontal strip electrode will be placed, enabling measurement of brain activity.
• Cortical-subcortical coherence (no units) [ Time Frame: 0-3 months ]
  Participants will undergo intracranial monitoring during DBS surgery in which a prefrontal strip electrode and DBS electrode will be placed, enabling measurements of connectivity between these structures.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Investigating Inhibitory Control Networks in Parkinson's Disease
• Official Title: Investigating Inhibitory Control Networks in Parkinson's Disease
• Brief Summary: The purpose of this study is to investigate the brain activity associated with non-motor symptoms of movement disorders, including Parkinson's disease and essential tremor. These movement disorders commonly have significant non-motor features also, including depression, cognitive impairment, decreased attention, and slower processing speeds. The investigators are interested in the brain activity associated with these symptoms, and perform recordings of the surface of the brain, in addition to the typical recordings the investigators perform, during routine deep brain stimulation (DBS) surgery.

Detailed Description

Movement disorders are a prominent cause of disability worldwide. In the United States, it is estimated that more than 4 million people suffer from Parkinson's disease (PD), essential tremor (ET), and dystonia, some of the most prevalent of neurologic disorders. Of these, PD is the most common, and is primarily characterized by tremor, rigidity, and bradykinesia. However, many patients also have prominent non-motor features, including depression and cognitive impairment, with deficiencies in processing speed, memory, attention, and learning. One of the most debilitating cognitive deficiencies is in response inhibition (RI), or the inability to suppress a habitual action. PD patients have significant difficulty with RI, and report its substantial contribution in limiting their quality of life. While some studies show that dopamine can improve this aspect of cognitive function, many patients remain considerably impaired.

RI manifests clinically in many different and important ways, with reduced mental flexibility, task-switching, and concentration. RI may also contribute to motor impairment, with gait dysfunction, falls, and freezing of gait. Unfortunately, these features of PD and RI are less well-studied and lack effective treatment options, necessitating that new treatments be investigated. Deep brain stimulation (DBS), while a highly effective treatment for motor manifestations, is essentially ineffective for, and can even worsen cognition, with few studies currently investigating how different parameters may improve NMS. In an effort to begin addressing these debilitating features of PD, the investigators propose to study RI in patients with movement disorders, and to correlate movement and cognition with underlying neural electrophysiology before and during tasks of motion and response inhibition.

During routine DBS surgery, the stimulating electrode is implanted with the aid of intraoperative recordings in the awake state. These routine recordings enable neurologists and neurosurgeons to directly observe neuronal firing in the brain, identifying characteristic patterns to delineate anatomic structures. Once in place, the DBS electrode is tested using stimulation parameters known to be clinically efficacious for motor impairment. This allows acute, intraoperative testing for therapeutic benefit and side effects, and give information for how a patient will respond to the therapy once the cranial electrode is connected to the battery and turned on.

In addition to this routine recording and stimulation, this setting also provides a unique opportunity to study neural electrophysiology, with minimal increased risk. By measuring brain activity in the outer layers (cortex) as well as from the DBS electrode itself, while patients perform various tasks, it is possible to correlate behavioral function and neural activity. Our center, and several others, already have research paradigms in place to achieve these goals, by placing a subdural strip electrode over cortex prior to placing the DBS lead. These strip electrodes lie along the surface of the brain, and have historically been used for several decades to perform seizure mapping, typically as an array of electrodes placed via a burr hole. Their use has only more recently been implemented for investigation of neural circuits during DBS surgery, however, their safety in this specific setting is now well-established, and their temporary placement is currently being performed in similar studies at this institution. However, though previous studies have placed these strips over prefrontal areas, the vast majority of research in this area is focused on motor circuits, with placement over sensorimotor cortex. In order to study NMS, strips will be placed over prefrontal cortex, with recordings made during various motor and cognitive tasks and during different stimulation patterns.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Parkinson Disease

Intervention

Other: Procedure/Surgery: Response Inhibition and Deep Brain Stimulation in Parkinson's disease

After creation of the burr hole and prior to DBS electrode placement, 1-2 subdural strip electrodes will be placed anteriorly or posteriorly from the cranial opening. These electrodes are routinely placed using this technique for seizure mapping, with arrays of electrodes (up to 6) being placed around the perimeter of the opening.14 Subdural strips vary in length and contact size (e.g., the 6-contact Ad-Tech strip), and are currently placed predominantly for studies of sensorimotor function,13 including at our institution (IRB-140327003). Placement over prefrontal areas is performed at other institutions.11-13 The DBS surgery will then proceed according to routine practice, and following lead placement in the optimal desired location, the research task paradigm will begin.

Study Arms

• Experimental: Treatment
  Parkinson's Disease Patients receiving DBS electrodes
  Intervention: Other: Procedure/Surgery: Response Inhibition and Deep Brain Stimulation in Parkinson's disease
• No Intervention: Control
  Control subjects will be non-Parkinson's Disease patients with essential tremor

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 1, 2023): 90
• Original Estimated Enrollment (submitted: January 28, 2021): 60
• Estimated Study Completion Date: March 31, 2026
• Estimated Primary Completion Date: March 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eligible for DBS surgery based on multi-disciplinary consensus review
• Have a diagnosis of Parkinson's disease or Essential Tremor
• A minimum of 18 years of age
• Willingness to participate in the paradigms described in the protocol

Exclusion Criteria:

• Inability to provide full and informed consent
• Are not surgical candidates due to co-morbid conditions or pregnancy
• Have not undergone an adequate trial of conservative medical management
• Have a clinical presentation for which DBS surgery is not indicated
• Are not able to participate in study-related activities

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Nicole Bentley, MD; 205-975-0011; jbentley@uabmc.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04735458
• Other Study ID Numbers: IRB300003605; 1K23NS117735-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: J. Nicole Bentley, University of Alabama at Birmingham
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Alabama at Birmingham
• Original Study Sponsor: Same as current
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Nicole Bentley, MD; University of Alabama at Birmingham

• PRS Account: University of Alabama at Birmingham
• Verification Date: November 2023