Modeling TMS-induced Cortical Network Activity

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Modeling TMS-induced Cortical Network Activity

Conditions
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Healthy

Intervention / Treatment
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* Device: Session 2: Single-pulse TMS (spTMS)
* Device: Sessions 3 - 5: Paired associative stimulation (PAS)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Each subject serves as their own control. First, inter-regional conduction delays are measured in a uni-focal TMS session with EEG. Thereafter, bi-focal TMS (PAS) will be applied in three separate sessions, each using a different asynchrony. PAS may selectively increase or decrease effective connectivity depending on the asynchrony. Specifically, negative asynchronies (a few milliseconds shorter than the inter-regional conduction delay) are expected to decrease effective connectivity, zero asynchrony (equal to conduction delay) is predicted to have no effect, whereas positive asynchronies (a few milliseconds longer than the inter-regional conduction delay) are expected to increase it.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy participants<br>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)<br>* 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.<br>Device: Sessions 3 - 5: Paired associative stimulation (PAS)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortico-cortical evoked potential (ccEP) latencies | 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 | 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 | 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 | 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 | 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) | 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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS-EEG, human, brain, connectivity, paired associative stimulation