Combined Theta-gamma STN Stimulation for Verbal Fluency in Parkinson Disease

December 3, 2024 updated by: Maurizio Zibetti, University of Turin, Italy

Effect of Combined Theta-gamma Frequency Subthalamic Nucleus Stimulation on Verbal Fluency in Parkinson Disease: a Randomized, Double-blind, Crossover Study

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is an established, effective, and relatively safe therapeutic option for Parkinson's disease (PD) patients presenting levodopa-related motor complications despite the best medical therapy . Chronic high-frequency (130-180 Hz) stimulation is known to reduce motor fluctuations and dyskinesia, and to improve quality of life and several non-motor symptoms . However, current evidence suggests a long term decline of cognitive performance in PD patients with STN-DBS compared to those without DBS, especially executive function processes including verbal fluency.

Preliminary evidence from pilot studies suggested that low frequency theta oscillations (4-10 Hz) within the STN and correlated cortical networks are important in cognition, including verbal fluency, color-word interference, and spatial and episodic memory; cortical structures involved in category verbal fluency encompass not only the prefrontal cortex, but also the hippocampus and related medial temporal structures. There is also evidence that theta STN stimulations lead to a worsening of motor symptoms, compared with no stimulation and therapeutic stimulation (gamma frequency).

To date, new DBS systems allow the use of multiple current sources and/or frequency settings at different depths and directions in a single electrode, and then to combine different stimulation frequencies.

Considering this, the aim is to evaluate the use of combined high (gamma) and very low (theta) frequency stimulation in a randomized, cross-over, double-blind trial with this principal research questions:

  1. Can combined theta-gamma theta frequency STN stimulation improve verbal fluency in PD patients?
  2. Can combined theta-gamma frequency STN stimulation improve verbal frequency without worsening cardinal motor symptoms?

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Each patient will receive two treatment periods, each lasting one month, in a randomized, cross-over, double-blind study design.

Patients will be randomly assigned to one of two sequences: Group 1 will receive standard DBS first followed by theta-gamma DBS, while Group 2 will receive theta-gamma DBS first followed by standard DBS. This design ensures that each patient serves as their own control, thereby reducing variability and enhancing the accuracy of the findings. A computer program will generate the randomization list.

One investigator, in charge of changing DBS parameter settings, will be unblinded to stimulation parameters and aware of the randomization sequence. The theta-gamma stimulation will be set maintaining the classical stimulation of the patient (gamma frequency, 100-180 Hz), with bilateral addiction of a ventral contact for stimulation with theta frequency (4-10 Hz).

Two investigators, blinded to stimulation parameters and randomization sequence, will conduct clinical and neuropsychological assessments.

The unblinded investigator will decide on a possible switch to the next sequence if the symptoms will not be well tolerated by the patient. In case of persistent worsening even after the second modification, the patient will be dropped out from the study. Dopaminergic therapy will be stable during the study course.

The clinical and neuropsychological test battery will include: motor state, evaluated with the Movement Disorder Society - Unified Parkinson Disease Rating Scale (MDS-UPDRS); Cognitive screening test, as per Mini Mental State Examination (MMSE); Beck Depression Inventory - Short Form (BDI-SF); Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS); Phonemic and semantic verbal fluency test (letter, episodic category, non-episodic category, and category switching).

The neuropsychological test battery will be conducted at baseline and at the end of first and second month of evaluation. The verbal fluency evaluation will be conducted also one hour after the change of stimulation parameters, to also evaluate its impact at a short time distance.

The evaluation will be conducted in the morning, during the ON phase, in order to avoid possible effects of wearing-off on cognitive performance.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Torino, Italy
        • AOU Città della Salute e della Scienza Torino

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age >18 years old,
  • Optimized DBS therapy in the last month,
  • Stable medication regimen in the last month
  • Able to provide informed consent
  • Fluent in Italian
  • Able to complete cognitive testing
  • Patients implanted with bilateral Vercise Cartesia™ Directional Leads in the STN connected to a Vercise™ or Vercise Gevia™ or Vercise Genus™ DBS system

Exclusion Criteria:

  • History of dementia (MMSE ≤ 25),
  • Major substance abuse,
  • Stimulation provided in the more ventral contact

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Standard Stimulation
Standard STN-DBS stimulation
Experimental: Theta-Gamma Stimulation
Standard STN-DBS stimulation with addiction of bilateral theta frequency stimulation of ventral contacts
Other: STN-DBS Theta Gamma Stimulation
Standard STN-DBS stimulation with addiction of bilateral theta frequency stimulation of ventral contacts

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Verbal Fluency - Phonemic Fluency
Time Frame: Baseline; 1st month; 2nd month
Number of words per three given letters in one minute for each letter
Baseline; 1st month; 2nd month
Verbal Fluency - Semantic Fluency - Episodic category
Time Frame: Baseline; 1st month; 2nd month
Number of words per episodic category (related to personal past experiences, e.g., "memorable events" or "significant places") in one minute
Baseline; 1st month; 2nd month
Verbal Fluency - Semantic Fluency - Non-episodic category
Time Frame: Baseline; 1st month; 2nd month
Number of words per non episodic category (belonging to a specific category, e.g., animals, fruits) in one minute
Baseline; 1st month; 2nd month
Verbal Fluency - Semantic Fluency - Switching
Time Frame: Baseline; 1st month; 2nd month
Number of words with switch of categories: participants are required to alternately generate words from two different non episodic categories (e.g., animals and fruits) in one minute
Baseline; 1st month; 2nd month
Motor symptoms
Time Frame: Baseline; 1st month; 2nd month
Movement Disorder Society - Unified Parkinson Disease Rating Scale part III (MDS-UPDRS III). Change in total MDS UPDRS part III score between standard and Theta-Gamma stimulation. Score range: 0-132 (higher score indicates worse motor performance)
Baseline; 1st month; 2nd month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Turin, Italy

Investigators

  • Principal Investigator: Maurizio Zibetti, AOU Città della Salute e della Scienza Torino

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 10, 2023

Primary Completion (Actual)

September 30, 2024

Study Completion (Actual)

September 30, 2024

Study Registration Dates

First Submitted

July 3, 2024

First Submitted That Met QC Criteria

July 12, 2024

First Posted (Actual)

July 19, 2024

Study Record Updates

Last Update Posted (Estimated)

December 6, 2024

Last Update Submitted That Met QC Criteria

December 3, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Theta-Gamma DBS

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Parkinson Disease

Clinical Trials on STN-DBS Theta Gamma Stimulation

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Nigeria

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe