Acute intermittent hypoxia enhances corticospinal synaptic plasticity in humans

Acute intermittent hypoxia (AIH) enhances voluntary motor output in humans with central nervous system damage. The neural mechanisms contributing to these beneficial effects are unknown. We examined corticospinal function by evaluating motor evoked potentials (MEPs) elicited by cortical and subcortical stimulation of corticospinal axons and the activity in intracortical circuits in a finger muscle before and after 30 min of AIH or sham AIH. We found that the amplitude of cortically and subcortically elicited MEPs increased for 75 min after AIH but not sham AIH while intracortical activity remained unchanged. To examine further these subcortical effects, we assessed spike-timing dependent plasticity (STDP) targeting spinal synapses and the excitability of spinal motoneurons. Notably, AIH increased STDP outcomes while spinal motoneuron excitability remained unchanged. Our results provide the first evidence that AIH changes corticospinal function in humans, likely by altering corticospinal-motoneuronal synaptic transmission. AIH may represent a novel noninvasive approach for inducing spinal plasticity in humans.


Sample-size estimation
 You should state whether an appropriate sample size was computed when the study was being designed  You should state the statistical method of sample size computation and any required assumptions  If no explicit power analysis was used, you should describe how you decided what sample (replicate) size (number) to use Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission:

Replicates
 You should report how often each experiment was performed  You should include a definition of biological versus technical replication  The data obtained should be provided and sufficient information should be provided to indicate the number of independent biological and/or technical replicates  If you encountered any outliers, you should describe how these were handled  Criteria for exclusion/inclusion of data should be clearly stated  High-throughput sequence data should be uploaded before submission, with a private link for reviewers provided (these are available from both GEO and ArrayExpress) Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission: Sample size for the first experiment was estimated based on a pilot experiment that showed increases of 15-25% around standard deviations of 15% along with an assumed Z-value of 1.96, alpha of 0.05 and Beta of 0.2. Two additional subjects were added for the electrical stimulation of the brainstem and scalp experiments. These two additional participants were not represented in the first TMS experiment. However, both participants were familiarized with AIH prior to the experiment and showed increases in corticospinal excitability assessed with transcranial magnetic stimulation following AIH at a previous experiments. Statistical reporting  Statistical analysis methods should be described and justified  Raw data should be presented in figures whenever informative to do so (typically when N per group is less than 10)  For each experiment, you should identify the statistical tests used, exact values of N, definitions of center, methods of multiple test correction, and dispersion and precision measures (e.g., mean, median, SD, SEM, confidence intervals; and, for the major substantive results, a measure of effect size (e.g., Pearson's r, Cohen's d)  Report exact p-values wherever possible alongside the summary statistics and 95% confidence intervals. These should be reported for all key questions and not only when the p-value is less than 0.05.
Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission: (For large datasets, or papers with a very large number of statistical tests, you may upload a single table file with tests, Ns, etc., with reference to sections in the manuscript.)

Group allocation
 Indicate how samples were allocated into experimental groups (in the case of clinical studies, please specify allocation to treatment method); if randomization was used, please also state if restricted randomization was applied  Indicate if masking was used during group allocation, data collection and/or data analysis Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission: Additional data files ("source data")  We encourage you to upload relevant additional data files, such as numerical data that are represented as a graph in a figure, or as a summary table  Where provided, these should be in the most useful format, and they can be uploaded as "Source data" files linked to a main figure or table  Include model definition files including the full list of parameters used  Include code used for data analysis (e.g., R, MatLab)  Avoid stating that data files are "available upon request" Please indicate the figures or tables for which source data files have been provided: Statistical approach is described in the methods. Center and distribution is disclosed in the first paragraph of the result section and in the in figure legends. Cohen's d was calculated as difference in means divided by the pooled standard deviation, with the assumption of equal variance. The statistical approach is described in the methods section L 453 to 470.
The present study is randomized and crossed over for the first experiment and the STDP+AIH experiment (see methods L. 349 and 445). In the other 3 experiments there were only one test condition and accordingly no allocation.
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