Cycloserine rTMS Plasticity Augmentation

Phase 1

Completed

• Conditions: Motor Activity
• Interventions: Device: Transcranial Magnetic Stimulation; Drug: Placebo Oral Tablet; Drug: Cycloserine

• Registration Number: NCT03432689
• Lead Sponsor: University of Calgary

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.

1. The investigators will recruit 12 healthy participants through community advertisement, carefully screened for exclusion factors related to rTMS and DCS.

2. 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.

3. 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).

4. 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).

5. 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.

6. Using neuronavigation in conjunction with an atlas brain, the M1 hand strip will be localized using single pulse TMS (MagPro X100).

7. 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.

8. 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.

9. 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).

10. 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).

Study Timeline

• Study First Submitted: 2018-02-02
• Study First Submitted QC: 2018-02-07
• Study First Posted: 2018-02-14
• Study Start: 2018-08-06
• Status Verified: 2018-11
• Primary Completion: 2018-11-07
• Study Completion: 2018-11-07
• Last Update Submitted: 2018-11-07
• Last Update Posted: 2018-11-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

1. Healthy individuals 18-60 years of age.

Exclusion Criteria

1. Pregnancy
2. Lactation
3. Epilepsy
4. Previous Stroke
5. Current Renal Disease
6. Current Liver Disease
7. Current Alcohol Use Disorder
8. Inability to refrain from alcohol use for 24 hours prior to each session and following each session.
9. Allergy to antibiotics
10. Use of isoniazid, ethionamide or bupropion
11. Current psychiatric concerns
12. History of bipolar disorder
13. Family history of bipolar disorder
14. Intracranial implants (dental implants are not an exclusion criteria)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Transcranial Magnetic Stimulation	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).
Placebo	Placebo Oral Tablet	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).
D-Cycloserine	Transcranial Magnetic Stimulation	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).
D-Cycloserine	Cycloserine	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).

Primary Outcome Measures

Name	Time	Method
Motor Evoked Potential amplitude	Baseline versus 90 minutes following theta-burst stimulation.	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.

Secondary Outcome Measures

Name	Time	Method
Motor Evoked Potential dose-response curve	Baseline versus 16 hours following theta-burst stimulation.	Motor Evoked Potentials at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order.
Motor Evoked Potential Amplitude Time Course	90 minutes following theta-burst stimulation.	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.

Trial Locations

Locations (1)

University of Calgary; 🇨🇦 Calgary, Alberta, Canada