Main Study: Influence on Plasticity of Brain Temperature Sub-Study: Phase Triggered Paired Associative Stimulation (PAS)

1. Objective The dysregulation of synaptic transmission in certain brain areas may be responsible for some neurological disorders. It was demonstrated that synaptic transmission may be modulated through repetitive transcranial magnetic stimulation (rTMS), and this may be a component of the therapeutic effects of rTMS. However, rTMS utility is limited due to an inability to focus the stimulation and variability in intervention response. Cooling was shown to reduce the neuronal activity in targeted brain areas. The goal of this protocol is to examine the ability of cooling to affect rTMS. Sub-study: Phase-triggered paired associative stimulation (PAS) Similarly, response to transcranial magnetic stimulation (TMS) is variable. However, it has been demonstrated that EEG contains information impacting measurable TMS outcomes. The goal of this study is to optimize TMS delivery by utilizing EEG phase-triggered TMS.
2. Study population We intend to study 18 adult healthy volunteers on an outpatient basis. The accrual ceiling requested is 23 subjects to allow for dropouts and screening failures. This portion of the study has been completed and recruitment will not continue for the cooling-related portion of the study. Sub-study: Phase-triggered paired associative stimulation (PAS) We intend to perform a sub-study to develop a new method of plasticity induction- phase-triggered paired associative stimulation (PAS). This sub-study requires an additional intended study population of 24 subjects completing the 3 study arms who may be a sub-set of the initially requested 18 subjects from the main study. The additional accrual ceiling is 40 subjects to allow for dropouts and screening failures (24 participants complete sub-study/40 participants enrolled in sub-study). The total ceiling for the entire protocol is 63.
3. Design Analysis of the data collected during the main study demonstrates the control condition of rPAS/sham cooling did not result in increased motor evoked potentials (MEPs) as expected. This null effect of the control condition made it difficult to ascertain any effects due to the cooling condition. Therefore, we propose a new substudy investigating a better form of plasticity induction using EEG phase-triggered TMS. For the completed, cooling-related portion of the study, we propose using rapid-rate paired associative stimulation (rPAS), modulated by applying cooling to the scalp, to examine the effect of cooling on rTMS. Our hypothesis is that cooling the brain will prevent the potentiation normally induced by rPAS. We will reduce brain temperature by up to 1.5 degrees C by applying a cooling helmet to the scalp and then test the effect on potentiation by applying rPAS. One of our stopping criterion will be reduction in measured temperature reduction by 2 degrees C This study consists of one experiment with18 subjects and accrual has been completed. The experiment is divided into three session visits, each to be carried out at least 1 day apart. The control potentiation in response to rPAS without cooling will be measured during session visit 1 by using the TMS-evoked motor evoked potential (MEP). In session visit 2, after applying a commercially available liquid cooling helmet for 45 minutes to reduce the temperature of the underlying cerebral cortex by up to 1.5oC, we will then assess the response to rPAS. In session visit 3, the MEP will be measured after applying the cooling helmet but with the rPAS procedure substituted with a sham rPAS. Session visit 3 is necessary to determine if there are any changes to the MEP in response to cooling alone. Thus, in the three session visits, we will evaluate cooling alone, rPAS alone, and the two together. Sub-study: Phase-triggered paired associative stimulation (PAS) The proposed sub-study is to test a methodology to decrease the variability in response to and improve reliability of TMS, by utilizing EEG phase-triggered PAS. The new method will utilize EEG phase-triggered paired associative stimulation. Similarly to the rPAS used in the main study, EEG phase-triggered PAS also uses paired median nerve stimulation with TMS to motor cortex. However, the stimuli are triggered when the EEG recorded from the motor cortex (M1; EEGM1) is at a pre-specified phase of the alpha-band (8-12 Hz) oscillation. The sub-study to develop the optimal parameters of phase-triggered PAS will consist of upto 4 visits and 3 arms. The first visit is a screening and piloting visit, the subsequent visits are different arms of the study. Two active arms will trigger the paired median nerve and motor cortex TMS according to the phase of the ongoing EEG. One arm will trigger the stimuli at the trough of the ongoing EEG (phase -90 if the EEG is modeled as a sine wave). Another arm will trigger the stimuli at the peak of the ongoing EEG (phase +90). A control arm will trigger the paired stimuli at a random delay from the through of the ongoing EEG. This control arm serves to deliver paired stimuli at a rate matched to the ongoing EEG, but stimulates at a random phase of each alpha oscillation cycle. These arms will be pseudo-randomized. Our hypothesis is that stimulating at the through of the ongoing EEG will result in increased plastic changes to the brain as measured through our TMS outcome measures of single pulse MEPs, as compared to the control condition of random phase stimulation and stimulation at the peak of the ongoing EEG. We also hypothesize that stimulating at the peak of the ongoing EEG will result in a decrease in TMS outcome measures as compared to the control arm and stimulation at the trough of the ongoing EEG. This will be a within-subject design of 3 visits for each of the 40 sub-study subjects.
4. Outcome measures

The primary outcome measure will be the amplitude of MEPs induced by single TMS pulses.

Sub-study: Phase-triggered paired associative stimulation (PAS)

The primary outcome will be pre-post changes in MEP induced by phase-triggered TMS. Pre post changes in resting-state EEG (rs-EEG) will also be analysed. Associations between these outcomes and demographics will be included in the analyses.