Influence on Plasticity of Brain Temperature

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. 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.

2. Study population

We intend to study 20 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.

We intend to perform a sub-study to develop a new method of plasticity induction -
phase-triggered paired associative stimulation. This sub-study requires an additional
intended study population of 12 subjects who may be a sub-set of the initially requested
18 subjects from the main study. The additional accrual ceiling is 20 subjects to allow
for dropouts and screening

failures. The total ceiling for the entire protocol is 43.

3. Design

Analysis of the data collected during the main study demonstrates the control condition
of rPAS/sham cooling did not result in increased 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 sub-study 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 Celsius 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 Celsius.

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 1.5 degrees Celsius,
we will then assess the response to rPAS. In session 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.

The proposed sub-study is to develop a method to improve the reliability of the primary
endpoint. The new method will utilize EEG phase-triggered paired associative
stimulation. Similarly to the rapid-rate paired associative stimulation (rPAS) used in
the main study, EEG phase-triggered paired associative stimulation also uses paired
median nerve stimulation with TMS to motor cortex. However, the stimuli are triggered
when the EEG is at a prespecified phase of the alpha-band (8-12 Hz) oscillation. The
sub-study to develop the optimal parameters of phase-triggered paired associative
stimulation will consist of 3 arms. Two active arms will trigger the paired median nerve
and motor cortex TMS according to the phase of the ongoing EEG. The first arm will
trigger the stimuli at the trough of the ongoing EEG (phase -90 if the EEG is modeled as
a sine wave). The second arm will trigger the stimul at the peak of the ongoing EEG
(phase +90). The third 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. 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. 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. This
will be a withinsubject design of 3 visits for each of the 12 sub-study subjects.

4. Outcome measures

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

- INCLUSION CRITERIA:

To be eligible for this research study participants must:

- Be between 18 and 50 years of age.

- Be right-handed.

- Able to abstain from food or drinks containing caffeine 24 hours before the last 3
session visits. The screening visit does not require the ability to abstain from food
or drinks containing caffeine.

- Able to abstain from tobacco on the day of the last three session visits. The
screening visit doesn t require the ability to abstain from tobacco.

EXCLUSION CRITERIA:

Participants will be excluded from this research study if they:

- Are taking medications of the following classes: antidepressants, anxiolytics,
anticonvulsants, antipsychotics, antiparkinson, hypnotics, stimulants, and
antihistamines.

- Have a heart rate that exceeds 100 bpm (resting tachycardia).

- Have a history of psychiatric condition(s).

- Have a neurologic disorder such as a history of brain tumor, stroke, central nervous
system infection, epilepsy, cerebrovascular disease, dementia, head trauma, or
increased intracranial pressure.

- Have surgically or traumatically implanted metallic foreign bodies such as,
pacemakers, medication pumps, implanted hearing aids, defibrillators, metal plates in
the skull or metal implants in the skull or eyes (other than dental fillings),
intracardiac lines, or any other condition/device that might be physically hazardous
during TMS or magnetic resonance imaging (MRI), or might distort the images.

- Are unable to lie flat on back for up to 1 hour.

- Have claustrophobia or a feeling of discomfort from being in small, enclosed spaces of
enough severity to prevent MRI scanning.

- Are pregnant or have a positive pregnancy test before the research procedure due to
-the risks associated with MRI scans and TMS.

- Have abnormal findings in clinical MRI that we will do during the screening visit.

- Have any abnormal or focal finding on the neurological exam.

- Have a known hearing loss.

- Have an alcohol or substance abuse problem, as determined by the Alcohol, Smoking and
Substance Abuse Screening Test (ASSIST).

- Have sensitivity to coldness.(main experiment only, not an exclusion for the sub-study
which does not utilize cooling)

- NIMH employees and staff and their immediate family members will be excluded from the
study per NIMH policy.