The Motor Network in Essential Tremor: Mechanisms of Therapy

Essential tremor (ET) is among the most common movement disorders, and is the most prevalent tremor disorder. It is a progressive, degenerative brain disorder that results in increasingly debilitating tremor, and afflicts an estimated 7 million people in the US (2.2% of the population) and estimates from population studies worldwide range from 0.4% to 6.3%. ET is directly linked to progressive functional impairment, social embarrassment, and even depression. Intention (kinetic) tremor of the arms occurs in approximately half of ET patients, and is typically a slow tremor (~5-10Hz) that occurs at the end of a purposeful movement, and is insidiously progressive over many years. Based on direct and indirect neurophysiological studies, it has been suggested that a pathological synchronous oscillation in a neuronal network involving the ventral intermediate nucleus (Vim) of the thalamus, the premotor (PM), primary motor (M1) cortices, and the cerebellum, may result in the production of ET. In spite of the numerous therapeutic modalities available, 65% of those suffering from upper limb tremor report serious difficulties during their daily lives. Deep brain stimulation (DBS) has emerged as an effective treatment option for those suffering from medically refractory ET. The accepted target for ET DBS therapy is the Vim thalamus. Vim projects to PM, M1, and supplementary motor areas (SMA) and receives afferents from the ipsilateral cerebellum. Moreover, electrophysiological recordings from Vim during stereotactic surgery have identified "tremor cells" that synchronously discharge with oscillatory muscle activity during tremor. Clinical and computational findings indicate that DBS suppresses tremor by masking these "burst driver" inputs to the thalamus. The overall goal is to investigate the neural signatures of tremor generation in the thalamocortical network by recording data during DBS implantation surgery. Investigators will record data from the macroelectrode implanted in the Vim for DBS therapy, and through an additional 6-contact subdural cortical strip that will be placed on the hand motor cortical area temporarily through the same burr hole opened for the implantation of the DBS electrode.

Study Overview

• Status: Recruiting
• Conditions: Parkinson's Disease; Essential Tremor
• Intervention / Treatment: Procedure: Deep brain stimulation implantation surgery; Device: Ad-Tech Medical Instrumentation Corp. electrodes/subdural strips; Device: FHC Guideline 4000+ system and/or Medtronic RC+S

Detailed Description

The research study goal is to advance the understanding of the mechanisms for essential tremor through brain recordings. The investigators will collect brain signals in persons with essential tremor undergoing neurosurgical treatment (deep brain stimulation implantation). By recording from the implanted electrodes for deep brain stimulation along with two other non-invasive intraoperative monitoring electrodes, the origins of tremor will be studied in the human motor network. Moreover, by performing recordings during deep brain stimulation delivery, the mechanisms in which deep brain stimulation modulates this network to suppress tremor will be investigated.

During the standard of care DBS procedure neural recordings are performed as the participant is in a reclined position on the operating table. In addition to neural recordings it is standard to ask the patient to move their arms and legs during the procedure. An additional intraoperative monitoring subdural electrode strip, used in epilepsy and tumor surgeries to perform functional mapping, will be placed by the neurosurgeon after the DBS electrode is placed per the clinical need of the patient. In addition, the Ad-Tech Medical Instrumentation Corp. device will be used to test responses with wireless sensors placed on the participant's arms, which can record EMG activity. Brain signals will be recorded using the clinical FHC Guideline 4000+ system or Medtronic RC+S, which are devices capable of recording during stimulation. This additional testing will add approximately 30-45 minutes to the surgical time. The Medtronic RC+S stimulator will not be implanted in these subjects, and will not used as a therapy. No interventions are compared against any controls for this study.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Aysegul Gunduz, PhD; Phone Number: 3522736877; Email: agunduz@ufl.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32611
      • Recruiting
      • University of Florida
      • Contact: Aysegul Gunduz, PhD; Phone Number: 352-273-6877; Email: agunduz@bme.ufl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Neurosurgical patient populations with essential tremor (main cohort) and Parkinson's disease (control cohort)

Description

Inclusion Criteria:

• Neurosurgical patient populations with essential tremor (main cohort) and Parkinson's disease (control cohort)

Exclusion Criteria:

• Non surgical candidates

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Essential tremor; Participants in this group will be undergoing deep brain stimulation implantation surgery as part of the standard of care. In addition, the Ad-Tech Medical Instrumentation Corp. device will be used to test responses with wireless sensors placed on the participant's arms, which can record EMG activity. Brain signals will be recorded using the clinical FHC Guideline 4000+ system and/or Medtronic RC+S devices, which are capable of recording during stimulation.	Procedure: Deep brain stimulation implantation surgery; Deep brain stimulation is a neuromodulatory therapy in which electrodes are implanted in deep brain structures. Electrical pulses are delivered through these electrodes to suppress pathological activity that are causing the symptoms of essential tremor or Parkinson's disease.; Device: Ad-Tech Medical Instrumentation Corp. electrodes/subdural strips; Ad-Tech Medical Instrumentation Corp. electrodes are intraoperative monitoring subdural strips will be placed on the surface of the cortex (non-penetrating).; Other Names: Ad-tech intraoperative monitoring subdural strips; Device: FHC Guideline 4000+ system and/or Medtronic RC+S; Brain signals will be recorded using the clinical Participants in this group with Parkinson's disease will be undergoing deep brain stimulation implantation surgery as part of the standard of care. In addition, the Ad-Tech Medical Instrumentation Corp. device will be used to test responses with wireless sensors placed on the participant's arms, which can record EMG activity. Brain signals will be recorded using the clinical FHC Guideline 4000+ system and/or Medtronic RC+S devices, which are capable of recording during stimulation.
Parkinson's disease and dystonia; Participants in this group with Parkinson's disease and/or dystonia will be undergoing deep brain stimulation implantation surgery as part of the standard of care. In addition, the Ad-Tech Medical Instrumentation Corp. device will be used to test responses with wireless sensors placed on the participant's arms, which can record EMG activity. Brain signals will be recorded using the clinical FHC Guideline 4000+ system and/or Medtronic RC+S devices, which are capable of recording during stimulation.	Procedure: Deep brain stimulation implantation surgery; Deep brain stimulation is a neuromodulatory therapy in which electrodes are implanted in deep brain structures. Electrical pulses are delivered through these electrodes to suppress pathological activity that are causing the symptoms of essential tremor or Parkinson's disease.; Device: Ad-Tech Medical Instrumentation Corp. electrodes/subdural strips; Ad-Tech Medical Instrumentation Corp. electrodes are intraoperative monitoring subdural strips will be placed on the surface of the cortex (non-penetrating).; Other Names: Ad-tech intraoperative monitoring subdural strips; Device: FHC Guideline 4000+ system and/or Medtronic RC+S; Brain signals will be recorded using the clinical Participants in this group with Parkinson's disease will be undergoing deep brain stimulation implantation surgery as part of the standard of care. In addition, the Ad-Tech Medical Instrumentation Corp. device will be used to test responses with wireless sensors placed on the participant's arms, which can record EMG activity. Brain signals will be recorded using the clinical FHC Guideline 4000+ system and/or Medtronic RC+S devices, which are capable of recording during stimulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain signals between the groups	FHC Guideline 4000+ system or Medtronic devices will be connected to Ad-Tech Medical Instrumentation Corp. electrodes and deep brain electrodes to measure brain signals between the groups	intraoperative

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Medtronic
• Investigators: Principal Investigator: Aysegul Gunduz, PhD, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Estimated): November 3, 2023
• Study Completion (Estimated): November 3, 2023

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 17, 2016
• First Posted (Estimated): March 18, 2016

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Dyskinesias; Parkinson Disease; Tremor; Essential Tremor
• Other Study ID Numbers: IRB201600172-N; 03UH3NS095553 (Other Grant/Funding Number: National Institute of Neurological Disorders and Stroke)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED