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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 volume 48, pages 1217–1224 (2023)Cite this article

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Abstract

Repeated spaced TMS protocols, also termed accelerated TMS protocols, are of increasing therapeutic interest. The long-term potentiation (LTP)-like effects of repeated spaced intermittent theta-burst transcranial magnetic stimulation (iTBS) are presumed to be N-Methyl-D-Aspartate receptor (NMDA-R) dependent; however, this has not been tested. We tested whether the LTP-like effects of repeated spaced iTBS are influenced by low-dose D-Cycloserine (100 mg), an NMDA-R partial-agonist. We conducted a randomized, double-blind, placebo-controlled crossover trial in 20 healthy adults from August 2021-Feb 2022. Participants received repeated spaced iTBS, consisting of two iTBS sessions 60 minutes apart, to the primary motor cortex. The peak-to-peak amplitude of the motor evoked potentials (MEP) at 120% resting motor threshold (RMT) was measured after each iTBS. The TMS stimulus-response (TMS-SR; 100–150% RMT) was measured at baseline, +30 min, and +60 min after each iTBS. We found evidence for a significant Drug*iTBS effect in MEP amplitude, revealing that D-Cycloserine enhanced MEP amplitudes relative to the placebo. When examining TMS-SR, pairing iTBS with D-Cycloserine increased the TMS-SR slope relative to placebo after both iTBS tetani, and this was due to an increase in the upper bound of the TMS-SR. This indicates that LTP-like and metaplastic effects of repeated-spaced iTBS involve NMDA-R, as revealed by two measures of corticospinal excitability, and that low-dose D-Cycloserine facilitates the physiological effects of repeated spaced iTBS. However, extension of these findings to clinical populations and therapeutic protocols targeting non-motor regions of cortex requires empirical validation.

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Fig. 1: Peak-to-peak MEP amplitude after repeated spaced iTBS.
Fig. 2: Stimulus response curves after repeated spaced iTBS.
Fig. 3: Normalized peak-to-peak amplitude at each stimulation intensity within the stimulus response curve after repeated spaced iTBS.
Fig. 4: Individual variability and consistency of the MEP amplitude after iTBS.

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Data availability

Data from this study is available upon reasonable request from the corresponding author.

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Acknowledgements

The authors would like to acknowledge the technical contribution of the Non-invasive neurostimulation Network (N3) at the University of Calgary.

Funding

This study was funded through the Brain and Behaviour Research Foundation Young 2018 Investigator Award (27548) and the Campus Alberta Innovates Program Chair in Neurostimulation.

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Authors and Affiliations

  1. Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    James G. Wrightson, Jaeden Cole, Maya N. Sohn & Alexander McGirr

  2. Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Jaeden Cole, Maya N. Sohn & Alexander McGirr

  3. Mathison Centre for Mental Health Research and Education, Calgary, AB, Canada

    Jaeden Cole, Maya N. Sohn & Alexander McGirr

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Contributions

JGW, JC, MNS, and AM made substantial contributions to the study conception, data acquisition and analysis and interpretation of the work. All authors were involved in the drafting and final approval of the manuscript and agree to be accountable for all aspects of the work.

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Correspondence to Alexander McGirr.

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Competing interests

JGW, JC, and MNS have no competing interests. AM has a provisional method of use patent application for the combination of D-Cycloserine with intermittent theta-burst stimulation for depression and obsessive-compulsive disorder.

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Wrightson, J.G., Cole, J., Sohn, M.N. et al. The effects of D-Cycloserine on corticospinal excitability after repeated spaced intermittent theta-burst transcranial magnetic stimulation: A randomized controlled trial in healthy individuals. Neuropsychopharmacol. 48, 1217–1224 (2023). https://doi.org/10.1038/s41386-023-01575-7

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