Cycloserine rTMS Plasticity Augmentation

Study Overview
=================
Brief Summary
-----------------
Transcranial magnetic stimulation (rTMS) is an investigational and therapeutic modality that impacts the connection strength between neurons by delivering patterned energy. In response to this patterned energy neurons fire and adapt by changing their connection strengths. This change in connection strengths is believed to be the underlying mechanism whereby this intervention has therapeutic benefit for this intervention in conditions such as depression. The purpose of this study is to test a means of enhancing the effect of rTMS using a medication (cycloserine) that has been shown to augment and stabilize activity dependent neuronal changes. The investigators wish to use the motor system, where the associated muscle response to brain stimulation can be measured, to probe activity dependent changes in connection strength between neurons.

Detailed Description
-----------------
This randomized, placebo-controlled, crossover trial will enroll 12 healthy participants. In one arm of the study, participants will randomly receive either 100mg of d-cycloserine (DCS, an antibiotic) or a placebo capsule, and participants will receive the other intervention one week later. The investigators will recruit 12 healthy participants through community advertisement, carefully screened for exclusion factors related to rTMS and DCS. Participants will be randomly assigned by random number sequence with allocation concealment to one of two first arms of the crossover study: a) placebo-DCS 100mg and b) DCS 100mg-placebo. Participants will complete the QIDS-SR (Quick Inventory of Depressive Symptoms-Self Report), the MDQ (Mood Disorders Questionnaire), the BAI (Beck Anxiety Inventory), and the STAI (State Trait Anxiety Inventory). Participants will take their blinded capsule at least 30 minutes hours prior to TBS. (we anticipate that it will take approximately 30 minutes to do steps 5-7). Electromyographic (EMG) electrodes will be positioned over the first dorsal interosseous (FDI) bilaterally to record motor evoked potentials (MEPs). These are non-invasive electrodes that use an adhesive to stick to the skin. Using neuronavigation in conjunction with an atlas brain, the M1 hand strip will be localized using single pulse TMS (MagPro X100). Motor evoked potentials are measurements of muscle activation, in this case in response to TMS stimulation of the brain. The investigators will use single pulse TMS to record the magnitude of responses. As a baseline, the investigators will collect twenty single-pulse (120% resting motor threshold (RMT), 0.25Hz) MEPs every 5 minutes for the 15 minutes preceding TBS rTMS. TBS rTMS will be applied to the FDI 'hotspot'. TBS consists of 2s trains every 10s. Trains are composed of 3 pulses at 50Hz, 200ms intervals, 80% RMT. Total time 190s and 600 pulses. After TBS, twenty MEPs will be acquired (single pulse, 120% RMT, 0.25Hz) every 5 minutes for the first 30 minutes, at 60 minutes, at 90 minutes, and at 16Hrs (the following morning). At the 16 Hrs time point, the investigators will characterize stimulus response curves (MEPs at stimulus intensities ranging from 100-150% resting motor threshold presented in random order). As this is a cross-over study, participants will return 1 week later to repeat the second arm of the protocol and will repeat steps 2-10).

Official Title
-----------------
A Randomized, Placebo-controlled, Crossover Trial of Cycloserine Repetitive Transcranial Magnetic Stimulation Plasticity Enhancement in the Healthy Motor System.

Conditions
-----------------
Motor Activity

Intervention / Treatment
-----------------
* Device: Transcranial Magnetic Stimulation
* Drug: Cycloserine
* Drug: Placebo Oral Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Healthy individuals 18-60 years of age. Exclusion Criteria: Pregnancy Lactation Epilepsy Previous Stroke Current Renal Disease Current Liver Disease Current Alcohol Use Disorder Inability to refrain from alcohol use for 24 hours prior to each session and following each session. Allergy to antibiotics Use of isoniazid, ethionamide or bupropion Current psychiatric concerns History of bipolar disorder Family history of bipolar disorder Intracranial implants (dental implants are not an exclusion criteria)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-Cycloserine<br>Participants will ingest a capsule containing 100mg of the antibiotic d-cycloserine. Their baseline motor evoked potentials (MEP) will be recorded for 30 minutes prior to receiving theta-burst stimulation (TBS; a patterned stimulation) to the motor cortex and change in MEP amplitude will be measured following stimulation up to 90 minutes later and then once again the following morning (16 hours later). | Device: Transcranial Magnetic Stimulation<br>* Single-pulse transcranial magnetic stimulation and theta-burst stimulation<br>Drug: Cycloserine<br>* Cycloserine 100mg<br>|
| Placebo Comparator: Placebo<br>Participants will ingest a capsule identical to that containing the study medication, however this capsule will contain a placebo. Their baseline motor evoked potentials (MEP) will be recorded for 30 minutes prior to receiving theta-burst stimulation (TBS; a patterned stimulation) to the motor cortex and change in MEP amplitude will be measured following stimulation up to 90 minutes later and then once again the following morning (16 hours later). | Device: Transcranial Magnetic Stimulation<br>* Single-pulse transcranial magnetic stimulation and theta-burst stimulation<br>Drug: Placebo Oral Tablet<br>* Placebo capsule matched to cycloserine capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Evoked Potential amplitude | Change in the (electrical) amplitude of muscle responses to stimulation of the motor cortex will be recorded from the first dorsal interosseous muscle of the hand. | Baseline versus 90 minutes following theta-burst stimulation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Evoked Potential dose-response curve | Motor Evoked Potentials at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order. | Baseline versus 90 minutes following theta-burst stimulation. | 
| Motor Evoked Potential dose-response curve | Motor Evoked Potentials at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order. | Baseline versus 16 hours following theta-burst stimulation. | 
| Motor Evoked Potential Amplitude Time Course | Change in the (electrical) amplitude of muscle responses to stimulation of the motor cortex will be recorded from the first dorsal interosseous muscle of the hand. | 90 minutes following theta-burst stimulation. |