The purpose of this study is to understand the physiology of connectivity between cortical regions in the human brain in healthy participants and in patients with white matter lesions. Specifically, the investigators will examine the effects of paired associative stimulation (PAS) which consists in delivering brief (< 1 ms) current pulses separated by a short millisecond-level time interval ("asynchrony") to two cortical areas. The used techniques are all non-invasive and considered safe in humans: transcranial magnetic stimulation (TMS), electroencephalography (EEG), magnetic resonance imaging (MRI), and functional MRI (fMRI). Based on prior literature in animals and human studies, it is hypothesized that PAS may increase or decrease effective connectivity between the stimulated areas depending on the asynchrony value. The main outcome measure is source-resolved EEG responses evoked by single-pulse TMS; this is a more direct measure of neuronal changes occurring at the targeted cortical area than motor evoked potentials (MEPs) or sensor-level EEG responses used in previous studies.

This study consists of two experiments.

In Experiment A, healthy participants without disorders or medications influencing brain function (N=24) will be recruited. A range of negative and positive asynchronies (from minus 50 to + 50 ms) will be tested. To allow comparison with prior studies that used MEPs as outcome measures, in 12 participants the primary motor cortex in the left and right hemisphere will be targeted. In another 12 participants, two cortical areas within the same hemisphere will be stimulated.

In Experiment B, participants with stroke, traumatic brain injury (TBI), or multiple sclerosis (MS) (total maximum N across all such participants is 52) will be recruited. These participants are required to have one or more subcortical white matter lesions, which would be expected to result in cortico-cortical disconnections. Here, the investigators will only test PAS with positive asynchronies, with the goal of testing if the findings observed in healthy participants are similar in participants with white matter lesions. It will also be examined if the PAS-induced connectivity changes persist beyond the stimulation sessions if PAS is given repeatedly over several days. PAS will be applied to two cortical targets that have been disconnected from each other. The rationale for including more than one disorder in Experiment B is that the disconnections are in all cases caused by white matter lesions and the results may therefore be similar. To detect possible differences between disorders, the data from the three groups will also be analyzed separately.

Inclusion Criteria:

Inclusion Criteria for Healthy Participants:

• Age from 18 to 85 years
• Right-handed
• Normal hearing and (corrected) vision
• Able to understand and give informed consent
• English speaker

Inclusion Criteria for Patients:

• Age from 18 to 85 years
• Stroke (ischemic subcortical, intermediate level, chronic phase 3 weeks or more from lesion)
• TBI (closed-skull, intermediate level, chronic phase 3 weeks or more from lesion)
• MS (white matter subcortical lesion)
• Clinical and radiological evidence supporting the above diagnoses
• One or more behavioral symptoms possibly linked to the white matter lesion(s)
• Stable medical condition
• English speaker

Exclusion Criteria:

Exclusion Criteria for Healthy Participants:

• Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps
• Metal in the body (rods, plates, screws, shrapnel, dentures, IUD) or 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

Exclusion Criteria for Patients:

• Same as above, excluding the requirement of no structural brain lesion, and medications influencing brain function are allowed
• Patients with cortical lesions or CSF-filled cysts/cavities near the TMS sites
• MS patients with acute exacerbation