Repeated iTBS Cycloserine Motor Plasticity

NCT05081986 | Completed Phase 2 FDA Drug FDA Device

• 1 other identifier: REB21-0863
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Repetitive transcranial magnetic stimulation (rTMS) is a modality for probing and altering brain function in humans non-invasively. The technology relies on the principles of electromagnetic induction, whereby magnetic fields have an associated electrical field. By intersecting two magnetic fields safely generated outside the head, one can induce a focal electrical current where the magnetic fields intersect in the brain, and this can depolarize cell membranes and impact brain activity. A well investigated phenomenon in neuroscience is the principle of long term potentiation (LTP), and its converse long term depression (LTD), referring to the ability of neurons to increase or decrease their connection strength in an activity dependent manner. They do this through modifications to their electrochemical junctions, the synapses. We have previously used the motor system as a model system to study the impact D-Cycloserine, an NMDA receptor partial agonist, on synaptic plasticity after TMS. Conventional therapeutic TMS is delivered once daily, however it is increasingly being delivered multiple times per day in an effort to speed treatment effects. It is unclear how adjunctive agents would impact these repeated stimulation designs. Research Question: Does the N-methyl-D-aspartate receptor partial agonist D-Cycloserine stabilize motor plasticity across multiple daily sessions of TMS?

Conditions

Motor Activity

Outcome Measures

Primary Outcomes (1)

• Stimulus Response Curve (SRC): Change in stability through repeated intermittent Theta Burst Stimulation (iTBS)

  SRC will be characterized by collecting Motor evoked potentials (MEPs) at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order. How the SRC will change following multiple rounds of iTBS will be assessed.

  SRC will be administered at baseline, 30 minutes after first iTBS, 60 minutes after first iTBS, 30 minutes after second iTBS, and 60 minutes after second iTBS

Secondary Outcomes (7)

• Motor Evoked Potential (MEP): Amplitude Time Course

  Collected at baseline, 15 minutes following first iTBS, and 15 minutes following second iTBS

• Change in Cognitive Function - THINC-it- PDQ-5

  Administered once during each crossover arm, at 30-minutes following first iTBS.

• Change in Cognitive Function - THINC-it- Choice Reaction Time

  Administered once during each crossover arm, at 30-minutes following first iTBS.

• Change in Cognitive Function - THINC-it- Working Memory

  Administered once during each crossover arm, at 30-minutes following first iTBS.

• Change in Cognitive Function - THINC-it- Digit Symbol Substitution

  Administered once during each crossover arm, at 30-minutes following first iTBS.

Other Outcomes (2)

• Safety outcomes

  Through study completion, on average 1 week

• Side Effects

  Participants will complete the TSES before and after the 3-hour stimulation session.

Study Arms (2)

D-cycloserine

EXPERIMENTAL

Participants will ingest a capsule containing 100mg of the antibiotic d-cycloserine one hour prior to receiving theta-burst stimulation (TBS; a patterned stimulation). Their baseline motor evoked potentials (MEP) will be recorded for 20 minutes prior to receiving the first TBS to the motor cortex and change in MEP amplitude will be measured following stimulation up to 60minutes later. They will then receive a second TBS to the motor cortex and change in MEP amplitude will again be measured following stimulation up to 60minutes later.

Device: Transcranial Magnetic Stimulation; Drug: Cycloserine

Placebo

PLACEBO COMPARATOR

Participants will ingest a capsule identical to that containing the study medication, however this capsule will contain a placebo. They will ingest this capsule one hour prior to receiving theta-burst stimulation (TBS; a patterned stimulation). Their baseline motor evoked potentials (MEP) will be recorded for 20 minutes prior to receiving the first TBS to the motor cortex and change in MEP amplitude will be measured following stimulation up to 60minutes later. They will then receive a second TBS to the motor cortex and change in MEP amplitude will again be measured following stimulation up to 60minutes later.

Device: Transcranial Magnetic Stimulation; Drug: Placebo Oral Tablet

Interventions

Transcranial Magnetic Stimulation DEVICE

Single-pulse transcranial magnetic stimulation and theta-burst stimulation

D-cycloserine; Placebo

Cycloserine DRUG

Cycloserine 100mg

D-cycloserine

Placebo Oral Tablet DRUG

Placebo capsule matched to cycloserine capsule

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy (absence of chronic medical conditions) individuals
• Aged 18-65. The lower limit is justified by the absence of safety studies involving DCS in pediatric studies, and the upper limit is justified by the increasing prevalence of chronic illness.

You may not qualify if:

• Allergy to cycloserine
• Are currently pregnant, breast feeding or plan to become pregnant
• Have an alcohol or substance use disorder within the last 3 months
• Current psychiatric concerns
• are at a significant risk of harm to themselves or others
• Have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes
• Have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
• Have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
• Conditions that may impair the ability to metabolize cycloserine including, but not limited to current Renal or Liver Disease.
• Inability to refrain from alcohol use for 24 hours prior to each session and following each session.
• Use of isoniazid or ethionamide
• Are currently (or in the last 4 weeks) using any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit rTMS efficacy

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

Location

Related Publications (1)

• Wrightson JG, Cole J, Sohn MN, McGirr A. The effects of D-Cycloserine on corticospinal excitability after repeated spaced intermittent theta-burst transcranial magnetic stimulation: A randomized controlled trial in healthy individuals. Neuropsychopharmacology. 2023 Jul;48(8):1217-1224. doi: 10.1038/s41386-023-01575-7. Epub 2023 Apr 11.

  PMID: 37041205 DERIVED

MeSH Terms

Conditions

Motor Activity

Interventions

Transcranial Magnetic Stimulation; Cycloserine

Condition Hierarchy (Ancestors)

Behavior

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics; Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Alexander McGirr, MD, PhD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 27, 2021
• First Posted: October 18, 2021
• Study Start: August 18, 2021
• Primary Completion: October 6, 2021
• Study Completion: February 23, 2022
• Last Updated: September 7, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)