Apathy in Parkinson Disease TMS Study (PDTMSAPATHY)

Investigation of Non-invasive Brain Stimulation for the Treatment of Apathy

The goal of this clinical trial is to develop non-invasive brain stimulation targets for the treatment of apathy, or motivation problems, in Parkinson Disease.

The main questions the study aims to answer are:

1. Does transcranial magnetic stimulation change effort task performance in Parkinson's Disease patients?
2. Is there a link between brain signals and apathy?

Participants will

• complete questionnaires and assessments
• perform an effort task
• have their brain activity recorded (EEG)
• receive non-invasive brain stimulation (TMS)

Researchers will compare two stimulation locations (experimental site and control site) to see if TMS of the experimental site has an effect on apathy. Participants will receive stimulation of both sites (during separate visits).

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation (TMS)

Detailed Description

Participants will be asked to come for 3 study visits.

During visit 1, after being informed about the study and potential risks, all patients giving written informed consent will undergo a brief cognitive assessment, a movement examination, and answer questionnaires. Additionally, the individual motor threshold will be determined for each participant. Visit 1 will take 2-3 hours.

Visits 2 and 3 will involve:

• completing questionnaires,
• performing a task where fictitious rewards can be earned by squeezing a dynamometer,
• recording brain activity with an electroencephalogram (EEG), and
• receiving transcranial magnetic stimulation (TMS). Visits 2 and 3 will take approximately 3 hours each and will be separated from each other by at least 3 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Miriam Sklerov, MD; Phone Number: 984-974-4401; Email: miri@email.unc.edu
• Study Contact Backup: Name: Cole Shumate; Phone Number: 919-445-0979; Email: shumatec@neurology.unc.edu

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • UNC-Chapel Hill, Cassidy Lab
      • Contact: Cole Shumate, BA; Phone Number: 919-445-0979; Email: shumatec@neurology.unc.edu
      • Principal Investigator: Miriam Sklerov, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of idiopathic Parkinson Disease.
• At least 4 years of symptoms.
• On dopaminergic medication for Parkinson Disease.
• Stable on dopaminergic medication and other medications which may influence apathy (such as selective serotonin re-uptake inhibitors, stimulant medications) for at least 4 weeks prior to first study visit and remain stable throughout the study period.
• Hospital's study-specific informed consent must be obtained.
• Must have capacity to provide informed consent in English.
• For female participants, confirmation that they have not had a menstrual period in over 12 months, or that they will use an effective form of contraception during the study.

Exclusion Criteria:

• Inability to provide informed consent.
• Inability to perform effort task (determined during the titration session).
• Presence of dementia (Montreal Cognitive Assessment (MoCA) score < 21).
• History of epilepsy or brain surgery.
• Severe tremor or dyskinesia that would interfere with EEG (determined by the PI).
• Patients with clinically significant medical or neurological conditions which may be an alternative cause of parkinsonism such as repeated brain injury, anti-dopaminergic medications, anoxic brain injury, or significant basal ganglia strokes.
• Presence of other known central nervous system disease that may interfere with performance or interpretation of EEG or TMS.
• Presence of any implanted metal devices including, but not limited to, pacemakers, deep brain stimulators, vagal nerve stimulators, bladder stimulators, or cochlear implants.
• Presence of medical contraindications to TMS such as implanted stimulators, history of mania or bipolar disorder, history of epilepsy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Medial Prefrontal Cortex - Control Site; Participants first undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3-week washout period, participants then undergo transcranial magnetic stimulation to the control site.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. TMS is FDA approved for the treatment of depression and other neuropsychiatric disorders and is regularly used in neurologic and psychiatric research. ITBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatment lasts approximately 3 minutes.; Other Names: Intermittent Theta-Burst Stimulation (iTBS)
Experimental: Control Site - Medial Prefrontal Cortex; Participants first undergo transcranial magnetic stimulation to the control site. After a 3-week washout period, participants then undergo transcranial magnetic stimulation to the medial prefrontal cortex.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial magnetic stimulation (or TMS) is a non-invasive form of brain stimulation in which a magnetic pulse is applied directly to the scalp. TMS is FDA approved for the treatment of depression and other neuropsychiatric disorders and is regularly used in neurologic and psychiatric research. ITBS is a particular TMS protocol which delivers the magnetic field in triplet bursts (three stimulations very close together at a frequency of 50 Hz). The triplet bursts are repeated at a rate of 5 Hz for 2 seconds (30 pulses), followed by 8 seconds rest, repeated 20 times for a total of 600 pulses. Each treatment lasts approximately 3 minutes.; Other Names: Intermittent Theta-Burst Stimulation (iTBS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in goal-directed behavior after transcranial magnetic stimulation (TMS)	Differences in the degree of change in goal-directed behavior after brain stimulation at each site (medial prefrontal cortex or control site). Goal-directed behavior will be determined using the streamlined version of the Expenditure of Effort for Reward Task (S-EEfRT). In the S-EEfRT, participants choose to complete either a "Hard" task or an "Easy" task for variable monetary incentives.	Immediately before stimulation and 15 minutes after stimulation.
Change in reward evaluation after transcranial magnetic stimulation (TMS)	Differences in the degree of change in reward evaluation after brain stimulation at each site (medial prefrontal cortex or control site). Reward evaluation will be determined using the streamlined version of the Expenditure of Effort for Reward Task (S-EEfRT). In the S-EEfRT, participants choose to complete either a "Hard" task or an "Easy" task for variable monetary incentives.	Immediately before stimulation and 15 minutes after stimulation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between frontal midline theta EEG power and goal-oriented behavior	Degree of association between frontal midline theta EEG power and goal-oriented behavior. Goal-directed behavior will be determined using the streamlined version of the Expenditure of Effort for Reward Task (S-EEfRT). In the S-EEfRT, participants choose to complete either a "Hard" task or an "Easy" task for variable monetary incentives.	Approximately 45 minutes before and 45 minutes after stimulation.
Association between frontal midline theta EEG power and reward evaluation	Degree of association between frontal midline theta EEG power and reward evaluation. Reward evaluation will be determined using the streamlined version of the Expenditure of Effort for Reward Task (S-EEfRT). In the S-EEfRT, participants choose to complete either a "Hard" task or an "Easy" task for variable monetary incentives.	Approximately 45 minutes before and 45 minutes after stimulation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between frontal midline theta EEG power and subjective apathy	Degree of association between frontal midline theta EEG power and subjective apathy as measured with the Lille Apathy Rating Scale (LARS). The LARS has been validated in Parkinson Disease. It consists of a structured interview that includes 33 items. Responses are scored on a dichotomous scale. The LARS score will be investigated as an effect measure modifier in the association between performance on the S-EEfRT and frontal midline theta power.	Approximately 45 minutes before and 45 minutes after stimulation.

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Miriam Sklerov, MD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: October 11, 2023
• First Submitted That Met QC Criteria: October 11, 2023
• First Posted (Actual): October 18, 2023

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Motivation; Apathy
• Additional Relevant MeSH Terms: Synucleinopathies; Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurobehavioral Manifestations; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Parkinson Disease; Lethargy; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: 23-1829; K23MH132884 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: Beginning 9 and continuing for 36 months after publication.
• IPD Sharing Access Criteria: Data will be made available to investigators who have approval from an IRB, IEC, or REB and an executed data use/sharing agreement with UNC.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No