Functional Brain Network Changes in Patients Undergoing Deep Brain Stimulation for Essential Tremor (TRaNCE)

The purpose of this study is to collect electrophysiological data related to functional brain network changes in patients undergoing deep brain stimulation for the treatment of essential tremor. Participants will either 1) have electroencephalography (EEG) scalp electrodes placed, or 2) remain seated with their head inside of a magnetoencephalography (MEG) recording system, as resting-state and task-related data are acquired. Spontaneous electrophysiological activity will be recorded in both the eyes open and eyes closed conditions with the participant seated comfortably. These recordings will be repeated in the DBS OFF and DBS ON states, with the ON state involving specific settings identified as optimal, sub-optimal, or ineffective at achieving tremor control. They will also be repeated following the optional administration non-DBS tremor mitigation techniques, which may include one or more of the following: 1) cooling the limb, 2) oral administration of alprazolam, 3) oral consumption of ethanol (alcohol), or 4) peripheral nerve stimulation.

Study Overview

• Status: Recruiting
• Conditions: Essential Tremor
• Intervention / Treatment: Drug: Alprazolam; Device: Cold Therapy; Procedure: Peripheral Nerve Stimulation; Drug: Alcohol

Detailed Description

Electrophysiological data from participants will be collected during electroencephalography (EEG) or magnetoencephalography (MEG) procedures. The EEG or MEG experiments will also include recordings from the DBS system that may be synchronized to externally recorded signals (e.g., MEG, EEG, EMG, accelerometry) via gentle tap-induced motion artifacts, and/or by applying a small, barely perceptible electrical current at the skin over the DBS system with use of a transcutaneous electrical nerve stimulation (TENS) unit.

It is hypothesized that the chronic, electrical stimulation of the target region has both local and circuit-wide effects, the net effect of which is to disrupt the pathophysiological neural activity present across both cortical and subcortical brain regions that and thought to underlie disease manifestation (i.e., tremor). By systemically characterizing the pathways involved in propagating tremor-related activity as well as mediating treatment-related benefits, the investigators hope to identify potential new therapeutic targets or treatment paradigms to further optimize tremor control in this population.

• Study Type: Observational
• Enrollment (Estimated): 55

Contacts and Locations

• Study Contact: Name: Jeffrey Negrey, MA; Phone Number: 2163166896; Email: negreyj2@ccf.org
• Study Contact Backup: Name: Madeline Porter; Phone Number: 2167691866; Email: porterm11@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Contact: Jeff Negrey, MA; Phone Number: 216-636-5504; Email: negreyj2@ccf.org
      • Principal Investigator: James Liao, MD
      • Sub-Investigator: Ken Baker, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Participants will be selected from the known patient population from a large research medical center located in a medium-to-large American city.

Description

Inclusion Criteria:

• Between 30 and 80 years of age;
• Ability to provide informed consent;
• Clinical diagnosis of ET by a movement disorders neurologist with a disease duration of at least 3 years and being treated with a DBS; OR
• Clinical diagnosis of ET by a movement disorders neurologist with a disease duration of at least 3 years and not being treated with a DBS; OR
• No known neurological disease or disorder.

Exclusion Criteria:

• The individual has a condition that, in the opinion of the investigator, would significantly increase the risk for interference with study compliance, safety, or outcome;
• Presence of active psychiatric symptoms meeting Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) criteria for Axis-I disorder on formal psychiatric evaluation other than depression or anxiety;
• History of cognitive impairment meeting Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) criteria for dementia on formal neuropsychological evaluation, as documented in chart;
• Lack of English-language fluency which would interfere with the ability to understand the study consenting process and potential study risks;
• Hearing or visual impairment precluding testing;
• Motor impairment impacting test responses (i.e., orthopedic injury or disease);
• Anyone currently taking medications with Antabuse-like effects (e.g. Flagyl, Bactrim, Tindamax) will be excluded from any alcohol administration.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Essential Tremor with DBS; 30-80 years of age; Diagnosis of ET; Previously implanted with a DBS system for disease management per standard of care	Drug: Alprazolam; Alprazolam is shown to reduce tremor in individuals with essential tremor. The primary investigator will select the appropriate dose for the patient (0.5mg for patients with a body weight of up to 75kg, and 0.75mg for participants with a body weight of 75kg and higher). Participants will swallow the drug with a glass of water in the presence of the research team. If participants have not reached a sufficient level of tremor improvement, a subsequent dose of up to a total of 1.0mg of alprazolam per participant will be requested. Participants will then repeat motor task and data collection.; Other Names: Xanax; Device: Cold Therapy; One or both of the participant's upper limbs will be wrapped with pre-chilled ice packs or a cold water circulating device such as a cryomanchet (e.g., the Breg PolarCare Glacier), and the skin temperature monitored until it lowers to 15-25°C. Participants will then repeat motor task and data collection while the limb is cool.; Other Names: BREG Polar Care Glacier Cold Therapy System; Procedure: Peripheral Nerve Stimulation; Electrical stimulation will be applied using techniques similar to those applied during standard somatosensory evoked potential testing. Specifically, adhesive surface electrodes will be placed above the median and radial nerves at the wrist. Stimulation paradigms will be tailored to each participant based on the frequency characteristics of their tremor. Participants will receive between 20-60 minutes of stimulation, then will repeat motor task and data collection. Transcutaneous peripheral nerve stimulation may help mitigate tremor, with effects lasting beyond cessation of stimulation1-3.; Drug: Alcohol; Alcohol consumption is shown to reduce tremor in individuals with essential tremor. The alcoholic beverage will be dispensed by the a clinician study investigator, and the participant will be administered the alcoholic beverage until their tremor is decreased, as determined by the clinician. Individual sensitivity to the tremor-mitigating effects of alcohol varies, but it is anticipated that only light (1-2 40% ABV drinks, containing 1-2 units of absolute alcohol [10 mL. or 8 g of pure ethanol]) consumption will be necessary. Participants will then repeat motor task and data collection while the alcohol is effective at controlling tremor, beginning approximately 15-20 minutes after consumption.; Other Names: Vodka
Essential Tremor without DBS; 30-80 years of age; Diagnosis of ET; Has not been previously implanted with a DBS system for disease management per standard of care	Drug: Alprazolam; Alprazolam is shown to reduce tremor in individuals with essential tremor. The primary investigator will select the appropriate dose for the patient (0.5mg for patients with a body weight of up to 75kg, and 0.75mg for participants with a body weight of 75kg and higher). Participants will swallow the drug with a glass of water in the presence of the research team. If participants have not reached a sufficient level of tremor improvement, a subsequent dose of up to a total of 1.0mg of alprazolam per participant will be requested. Participants will then repeat motor task and data collection.; Other Names: Xanax; Device: Cold Therapy; One or both of the participant's upper limbs will be wrapped with pre-chilled ice packs or a cold water circulating device such as a cryomanchet (e.g., the Breg PolarCare Glacier), and the skin temperature monitored until it lowers to 15-25°C. Participants will then repeat motor task and data collection while the limb is cool.; Other Names: BREG Polar Care Glacier Cold Therapy System; Procedure: Peripheral Nerve Stimulation; Electrical stimulation will be applied using techniques similar to those applied during standard somatosensory evoked potential testing. Specifically, adhesive surface electrodes will be placed above the median and radial nerves at the wrist. Stimulation paradigms will be tailored to each participant based on the frequency characteristics of their tremor. Participants will receive between 20-60 minutes of stimulation, then will repeat motor task and data collection. Transcutaneous peripheral nerve stimulation may help mitigate tremor, with effects lasting beyond cessation of stimulation1-3.; Drug: Alcohol; Alcohol consumption is shown to reduce tremor in individuals with essential tremor. The alcoholic beverage will be dispensed by the a clinician study investigator, and the participant will be administered the alcoholic beverage until their tremor is decreased, as determined by the clinician. Individual sensitivity to the tremor-mitigating effects of alcohol varies, but it is anticipated that only light (1-2 40% ABV drinks, containing 1-2 units of absolute alcohol [10 mL. or 8 g of pure ethanol]) consumption will be necessary. Participants will then repeat motor task and data collection while the alcohol is effective at controlling tremor, beginning approximately 15-20 minutes after consumption.; Other Names: Vodka
No Known Neurological Disease or Disorder; 30-80 years of age; No known neurological disease or disorder	Drug: Alprazolam; Alprazolam is shown to reduce tremor in individuals with essential tremor. The primary investigator will select the appropriate dose for the patient (0.5mg for patients with a body weight of up to 75kg, and 0.75mg for participants with a body weight of 75kg and higher). Participants will swallow the drug with a glass of water in the presence of the research team. If participants have not reached a sufficient level of tremor improvement, a subsequent dose of up to a total of 1.0mg of alprazolam per participant will be requested. Participants will then repeat motor task and data collection.; Other Names: Xanax; Device: Cold Therapy; One or both of the participant's upper limbs will be wrapped with pre-chilled ice packs or a cold water circulating device such as a cryomanchet (e.g., the Breg PolarCare Glacier), and the skin temperature monitored until it lowers to 15-25°C. Participants will then repeat motor task and data collection while the limb is cool.; Other Names: BREG Polar Care Glacier Cold Therapy System; Procedure: Peripheral Nerve Stimulation; Electrical stimulation will be applied using techniques similar to those applied during standard somatosensory evoked potential testing. Specifically, adhesive surface electrodes will be placed above the median and radial nerves at the wrist. Stimulation paradigms will be tailored to each participant based on the frequency characteristics of their tremor. Participants will receive between 20-60 minutes of stimulation, then will repeat motor task and data collection. Transcutaneous peripheral nerve stimulation may help mitigate tremor, with effects lasting beyond cessation of stimulation1-3.; Drug: Alcohol; Alcohol consumption is shown to reduce tremor in individuals with essential tremor. The alcoholic beverage will be dispensed by the a clinician study investigator, and the participant will be administered the alcoholic beverage until their tremor is decreased, as determined by the clinician. Individual sensitivity to the tremor-mitigating effects of alcohol varies, but it is anticipated that only light (1-2 40% ABV drinks, containing 1-2 units of absolute alcohol [10 mL. or 8 g of pure ethanol]) consumption will be necessary. Participants will then repeat motor task and data collection while the alcohol is effective at controlling tremor, beginning approximately 15-20 minutes after consumption.; Other Names: Vodka

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CTCM Coherence	Coherence, a unitless measure of correlation between signals, calculated across the cerebellothalmocorticomuscular (CTCM) circuit, will be computed from neurophysiological recordings including electroencephalography (EEG), electromyography (EMG), magnetoencephalography (MEG), and/or local field potential (LFP), using data collected at rest, during tremor-eliciting tasks, with DBS OFF, with DBS ON (when available), and when using non-DBS tremor interventions (limb cooling and/or peripheral nerve stimulation and/or alprazolam or alcohol).	up to 8 hours in-lab during experiment
Power of oscillatory activity across the CTCM network in response to tremor interventions	Power of tremor-related oscillatory activity, in the form of mean power in the 4-12Hz frequency band with units in mV^2, will be computed from neurophysiological recordings including electroencephalography (EEG), electromyography (EMG), magnetoencephalography (MEG), and/or local field potential (LFP), using data collected at rest, during tremor-eliciting tasks, with DBS OFF, with DBS ON (when available), and when using non-DBS tremor interventions (limb cooling and/or peripheral nerve stimulation and/or alprazolam or alcohol).	up to 8 hours in-lab during experiment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Essential tremor severity: Grip force	A hand-held force sensor will measure grip force (Newtons). Data is collected at rest, during tremor-eliciting tasks, with DBS OFF, with DBS ON (when available), and when using non-DBS tremor interventions (limb cooling and/or peripheral nerve stimulation and/or alprazolam or alcohol).	up to 8 hours in-lab during experiment
Essential tremor severity: Limb acceleration	Accelerometers placed on the limb will measure tremor energy in the 4-12Hz band, in units of mG^2/Hz. Data is collected at rest, during tremor-eliciting tasks, with DBS OFF, with DBS ON (when available), and when using non-DBS tremor interventions (limb cooling and/or peripheral nerve stimulation and/or alprazolam or alcohol).	up to 8 hours in-lab during experiment
Essential tremor severity: Tremor Research Group Essential Tremor Rating Scale (TETRAS)	Numerical clinical tremor assessment scale correlated with severity of tremor. Data is collected with DBS OFF, with DBS ON (when available), and when using non-DBS tremor interventions (limb cooling and/or peripheral nerve stimulation and/or alprazolam or alcohol). Items are scored 0-4 with "0" being normal and "4" being severely abnormal.	up to 8 hours in-lab during experiment

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: James Liao, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: deep brain stimulation; essential tremor; DBS; tremor; ET; hand tremors
• Additional Relevant MeSH Terms: Neurologic Manifestations; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Dyskinesias; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Tremor; Essential Tremor; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Alcohols; Benzazepines; Benzodiazepines; Ethanol; Alprazolam; Cryotherapy
• Other Study ID Numbers: 23-1125

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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