Modeling TMS-induced Cortical Network Activity

March 11, 2022 updated by: Aapo Nummenmaa, Massachusetts General Hospital
This is a study of normal brain physiology in healthy human volunteers. The study aims to understand the physiology of connectivity between brain regions. To reach this aim, it delivers single-pulse transcranial magnetic stimulation (spTMS) to one or two brain areas at a time while electroencephalography (EEG) is measured. When only one brain area is stimulated (uni-focal TMS), the goal is to record how many milliseconds it takes for the activity to spread from the stimulated area to other brain regions (conduction delay). When two brain areas are stimulated (bi-focal TMS), the TMS pulses are separated by a short millisecond-level time interval ("asynchrony") in a so-called paired associative stimulation (PAS) design. The central hypothesis is that PAS may increase or decrease connectivity between the stimulated areas depending on the asynchrony value. All techniques in the study are non-invasive and considered safe.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

The goal of the study is to illuminate the physiology of inter-regional connectivity in the human brain. Participants are healthy adult volunteers without disorders or medications influencing brain function (N=80). During uni-focal TMS, only one brain area is stimulated at a time, and the conduction delays and connectivity strengths between the stimulated brain area and other brain regions are quantified with source-resolved EEG. During the bi-focal TMS sessions, a range of negative and positive PAS asynchronies (from minus 50 to + 50 ms relative to the conduction delays) will be tested in separate sessions, and the within-session connectivity changes from PAS are estimated by applying uni-focal TMS before and after PAS. The targeted brain areas include the primary motor cortices in the left and right hemisphere as well as areas outside the primary motor cortices. All techniques included in the study are non-invasive and considered safe: TMS, EEG, electromyography (EMG), magnetic resonance imaging (MRI), diffusion MRI (dMRI), functional MRI (fMRI), and behavioral measures. The TMS parameters in this study are considered safe, as only single or pairs of TMS pulses are delivered.

Study Type

Interventional

Enrollment (Anticipated)

80

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 Contact

Study Contact Backup

Study Locations

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

16 years to 62 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy
  • Normal hearing and (corrected) vision
  • Able to understand and give informed consent

Exclusion Criteria:

  • Metal in the body (rods, plates, screws, shrapnel, dentures, IUD)
  • Metallic particles in the eye
  • Surgical clips in the head or previous neurosurgery
  • Cardiac pacemaker or pacemaker wires
  • Neurostimulators
  • Implanted pumps
  • Any magnetic particles in the body
  • Cochlear implants
  • Prosthetic heart valves
  • Epilepsy or any other type of seizure history
  • Significant claustrophobia
  • Meniere's disease
  • Pregnancy or breast-feeding
  • Diagnoses or medications (neurological or psychiatric) influencing brain function
  • History of, or current, substance abuse
  • History of developmental disorders (e.g., dyslexia)
  • Failure to perform the behavioral tasks
  • Prisoners

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: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Healthy participants

All participants participate in five core sessions. Session 1 consists of MRI scans (T1-weighted, T2-weighted, diffusion MRI, resting-state fMRI). Thereafter, there are four TMS-EEG sessions. Session 2 delivers uni-focal spTMS to various cortical targets while EEG is recorded to determine inter-regional conduction delays. Thereafter, Sessions 3 - 5 deliver bi-focal TMS (PAS), each session using a different asynchrony (shorter, equal to, or longer than the conduction delay). The three PAS sessions are at least one week apart. Each of the PAS sessions have three segments: (a) TMS-EEG-behavioral recordings before PAS, (b) the PAS modulation, and (c) TMS-EEG-behavioral recordings after PAS.

In addition to these core sessions, some participants may be invited for additional sessions for parameter optimization and for assessing test-retest repeatability.
Device: Session 2: Single-pulse TMS (spTMS)
Uni-focal TMS (MagVenture, Farum, Denmark) is delivered to one brain area while EEG/EMG (NeurOne, Bittium, Kuopio, Finland) are recorded. The targeted brain areas and TMS intensities may vary across runs. An MRI-based TMS navigation system (Localite, Bonn, Germany) is used to navigate the TMS coil.
Device: Sessions 3 - 5: Paired associative stimulation (PAS)
During each PAS run, bi-focal TMS (MagVenture, Farum, Denmark) is delivered to two brain areas while EEG/EMG (NeurOne, Bittium, Kuopio, Finland) are recorded. The asynchronies between the two TMS coils are kept constant within each session but differ across sessions. Within each session, to observe PAS effects on connectivity, uni-focal spTMS is delivered to the stimulated areas before and after the PAS modulation while EEG/EMG (NeurOne, Bittium, Kuopio, Finland) are recorded. In addition, resting-state EEG/EMG and a behavioral measure (bimanual task coordination) are recorded before and after the PAS modulation. An MRI-based TMS navigation system (Localite, Bonn, Germany) is used to navigate the TMS coils.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cortico-cortical evoked potential (ccEP) latencies
Time Frame: Recorded in the uni-focal TMS session, on average on Day 14 (Session 2). The ccEPs are measured once for each TMS location and intensity.
EEG/EMG are recorded with a 64/16-channel TMS-compatible device (NeurOne, Bittium, Kuopio, Finland) while spTMS is delivered. Thereafter, the sensor-space evoked potentials (EPs) undergo EEG source analysis to produce source-space ccEPs. For sessions with uni-focal TMS, the ccEPs latencies are used for determining the inter-regional conduction delays.
Recorded in the uni-focal TMS session, on average on Day 14 (Session 2). The ccEPs are measured once for each TMS location and intensity.
Change in cortico-cortical evoked potential (ccEP) amplitudes
Time Frame: Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).
EEG/EMG are recorded with a 64/16-channel TMS-compatible device (NeurOne, Bittium, Kuopio, Finland) while spTMS is delivered. Thereafter, the sensor-space evoked potentials (EPs) undergo EEG source analysis to produce source-space ccEPs. For sessions with bi-focal TMS (PAS), the ccEPs amplitudes are used for determining the within-session effects of PAS by measuring the change in amplitudes before versus after the PAS modulation.
Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRI structural connectivity
Time Frame: Once on Day 1 (Session 1, before first TMS session).
Diffusion MRI will be used to assess structural connectivity strengths between the stimulated areas in bi-focal TMS (PAS). The structural connectivity strengths will be compared with EEG-derived connectivity strengths.
Once on Day 1 (Session 1, before first TMS session).
MRI functional connectivity
Time Frame: Once on Day 1 (Session 1, before first TMS session).
Resting-state fMRI will be used to assess functional connectivity strengths between the stimulated areas in bi-focal TMS (PAS). The functional connectivity strengths will be compared with EEG-derived connectivity strengths.
Once on Day 1 (Session 1, before first TMS session).
Change in bimanual coordination task (BCT) performance
Time Frame: Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).
Behavioral measures of inter-hemispheric communication between the left and right motor cortices will be recorded with the BCT. Change is measured by comparing performance before vs. after the PAS modulation.
Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).
Change in resting-state EEG (rs-EEG) connectivity using phase slope index (PSI)
Time Frame: Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).
EEG/EMG are recorded with a 64/16-channel TMS-compatible device (NeurOne, Bittium, Kuopio, Finland) during rest. Thereafter, unaveraged source-space time courses are extracted from the sensor-space EEG using source analysis techniques. The source-space time courses from the stimulated areas are analyzed for signs of connectivity changes by comparing the within-session PSI values before versus after the PAS modulation.
Recorded in each bi-focal TMS (PAS) session, on average on Days 28, 35, and 42 (Sessions 3, 4, and 5, respectively).

Collaborators and Investigators

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

Sponsor

Massachusetts General Hospital

Investigators

  • Study Director: Aapo Nummenmaa, PhD, Mass General Brigham

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 (Anticipated)

April 1, 2022

Primary Completion (Anticipated)

March 31, 2027

Study Completion (Anticipated)

March 31, 2027

Study Registration Dates

First Submitted

February 22, 2022

First Submitted That Met QC Criteria

March 11, 2022

First Posted (Actual)

March 21, 2022

Study Record Updates

Last Update Posted (Actual)

March 21, 2022

Last Update Submitted That Met QC Criteria

March 11, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 2014p002652
  • R01NS126337-01 (pending) (Other Grant/Funding Number: NIH)
  • R01NS126337-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Anonymized MRI, EEG/EMG, TMS navigator, and behavioral data

IPD Sharing Time Frame

After study completion

IPD Sharing Access Criteria

Academic investigators

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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.

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