Physiology of Human Brain Connectivity

Overview

The purpose of this study is to investigate the effective connectivity between different regions of the human brain in healthy participants, and the mechanisms which influence and modulate its development. Specifically, the investigators will examine the effects of cortico-cortical paired associative stimulation (ccPAS) which is induced by the application of brief (\< 1 ms) transcranial magnetic stimulation (TMS) pulses separated by a short millisecond-level time intervals ("asynchrony") to two different areas of the brain. All techniques are non-invasive and considered safe in humans: TMS, electroencephalography (EEG), and magnetic resonance imaging (MRI). Based on previous animal and human studies, it is hypothesized that ccPAS will increase or decrease effective connectivity between the stimulated areas depending on the asynchrony value. The main outcome measure is source-resolved EEG cortico-cortical evoked potentials (ccEPs) elicited by single-pulse TMS.

Detailed description

The purpose of this study is to determine the extent to which effective connectivity between different regions in the human brain can be selectively modulated by cortico-cortical paired associative stimulation (ccPAS) induced by transcranial magnetic stimulation (TMS). Study subjects will consist of healthy adults between the ages of 18 and 64 (N=80) . Participants will have TMS pulses applied to two brain regions, one in each hemisphere, where the two regions will be stimulated at a range of different temporal offsets ("asynchronies") characterized as being either shorter, longer, or approximately equal to the theorized inter-regional conduction delays, with absolute disparities between the asynchrony conditions on the order of milliseconds. Additionally, electroencephalography (EEG) will be concurrently measured to record cortico-cortical evoked potentials (ccEPs), which are the study's primary outcome measure. Asynchronies longer than the delay are hypothesized to increase effective connectivity and ccEP amplitudes, while shorter delays are expected to decrease them. This will be further supported by magnetic resonance imaging (MRI), functional MRI (fMRI), and diffusion MRI (dMRI) scans to provide structural and functional data to assist with ccPAS application.

The initial study visit will consist of the MRI scans followed by a TMS session to record participant motor thresholds. The ccPAS TMS-EEG procedures will then be performed over the course of three additional visits, with each asynchrony condition conducted on its own separate visit and at least a week between them. Prior to ccPAS application, single-pulse TMS will be applied to one brain area to record ccEPs, in addition to resting-state EEG and a behavioral motor test. These will be repeated two additional times, once 5 minutes after ccPAS and again at 60 minutes after, to observe effect duration. All techniques and devices are non-invasive and considered safe within the parameters of the study, with overall participation carrying only non-significant risk.

Interventions

• Device Single-pulse transcranial magnetic stimulation (spTMS)
  Single-pulse TMS (spTMS) will be delivered with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. 80 spTMS will be repeated at 0.2 Hz. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, Bonn, Germany).
• Device Paired associative stimulation (PAS)
  Paired associative stimulation (PAS) will be applied with two TMS stimulators (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and two TMS coils. The pulses from each stimulator/coil will be repeated at 0.2 Hz, duration of run 15 minutes (180 pulses for each stimulator/coil). In different sessions, we will deliver PAS with different asynchrony values to examine their effects on effective connectivity. Coils will be navigated using an MRI-based TMS navigation system (Localite, Bonn, Germany
• Diagnostic test Magnetic resonance imaging (MRI)
  Structural, diffusion, and functional MRI with a 3-Tesla Siemens scanner

Primary outcome measures

• Changes in EEG effective connectivity [Time frame: Within-session (Before PAS, 5 minutes after PAS, 60 minutes after PAS)]

Secondary outcome measures (2)

• Changes in resting-state EEG coherence [Time frame: Within-session (Before PAS, 5 minutes after PAS, 60 minutes after PAS)]
• Changes in bimanual coordination task performance [Time frame: Within-session (Before PAS, 5 minutes after PAS, 60 minutes after PAS)]

Eligibility criteria

Inclusion criteria

• Age from 18 to 64 years
• Right-handed
• Normal hearing and (corrected) vision
• Able to understand and give informed consent

Exclusion criteria

• Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps
• Metal in the body (e.g., rods, plates, screws, shrapnel, dentures that cannot be removed during the recordings, IUD)
• Suspected metallic particles in the eye
• Surgical clips in the head or previous neurosurgery
• Any magnetic particles in the body
• Cochlear implants
• Prosthetic heart valves
• Epilepsy or any other type of seizure history
• Any neurological diagnoses or medications influencing brain function
• History of significant head trauma (i.e., extended loss of consciousness, neurological sequelae)
• Known structural brain lesion
• Significant other disease (heart disease, malignant tumors, mental disorders)
• Significant claustrophobia; Ménière's disease
• Pregnancy (ruled out by urine ß-HCG if answers to screening questions suggest that pregnancy is possible), breast feeding
• Non prescribed drug use
• Failure to perform the behavioral tasks or neuropsychological evaluation tests
• Prisoners

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• Massachusetts General Hospital — Boston

Identifiers

NCT: NCT06246942 · 2024p000098 · 5R01NS126337

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗