Brain stimulation in zero gravity: transcranial magnetic stimulation (TMS) motor threshold decreases during zero gravity induced by parabolic flight

Astronauts in microgravity experience environmental factors that can affect physiology, yet acute effects on brain function are not well characterized. Prior MRI studies show structural brain changes after long-duration spaceflight, including upward brain shift and ventricular enlargement. Transcranial magnetic stimulation (TMS) provides a noninvasive measure of corticospinal excitability via the resting motor threshold (rMT), which depends on cortical excitability and scalp-to-cortex distance. The study asks whether rMT changes acutely in zero gravity compared to Earth gravity, hypothesizing that brief exposure to weightlessness will alter neurophysiology and reduce the electromagnetism needed to elicit motor responses.

Previous work has documented brain structural changes following spaceflight (e.g., upward brain shift, narrowing of CSF spaces, ventricular enlargement). TMS rMT is a standard, reliable within-subject index of corticospinal excitability influenced by synaptic factors (e.g., pharmacology) and morphology (scalp-to-cortex distance). Kozel et al. linked rMT variability strongly to scalp–cortex distance, suggesting small positional changes can affect thresholds. Hemodynamic and intracranial dynamics vary with body position; microgravity alters intracranial pressure and jugular venous pressure, potentially influencing cortical excitability. Prior parabolic-flight studies reported EEG changes during 0G (both suppression and increases in specific bands), and one early TMS study observed increased MEP amplitudes in microgravity, implying heightened corticospinal excitability. Together, these findings provide context for expecting acute neurophysiological changes in 0G detectable by TMS.

Design: Within-subject, repeated-measures study assessing rMT at three time points around a parabolic flight: T1 pre-flight at 1G on the runway, T2 during 0G portions of parabolic flight, T3 post-flight at 1G on the runway. Two baseline lab visits were conducted in the week before flight to ensure rMT stability. Participants: N=10 healthy adults (5 men), mean age 41.0 (SD 11.0); 9 right-handed; inclusion: age 25–61, familiarity with TMS equipment, baseline rMT <90% MSO, no seizure history, no seizure-threshold–lowering medications, no metal above neck, no Earth motion sickness. One had prior 0G experience. All provided informed consent (MUSC IRB). Equipment and setup: Two identical closed-loop TMS/EMG systems (Magstim BiStim with D70 remote coil; EMG via Cambridge Electronics CED 1401, 1902; Spike2 software). EMG electrodes on right abductor pollicis brevis (APB). Custom fiberglass, head-cast helmets fixed the coil over left motor cortex and minimized movement; chin straps and manual downward pressure during 0G reduced superior float. Participants were seated and belted; right hand rested palm-down on a foam pad affixed to the thigh with an elastic band to maintain identical positioning across gravity states. rMT determination: Automated, closed-loop parametric estimation by sequential testing (PEST). During baseline lab and on-plane sessions, EMG success criterion was >150 µV to standardize across potentially noisier aircraft environment. Interstimulus interval 3.0–3.5 s. For in-flight pre- and post-runway 1G sessions, three rMTs per participant were collected (1 min apart). During each ~20–25 s 0G parabola, one rMT per team was collected; target 3–5 rMTs per participant during 0G. On-plane rMT script began at each participant’s average baseline rMT (rather than 50% MSO) to limit steps and complete within a 0G window (<25 s). Up to 5 PEST steps were used at each analyzed time point. Parabolic flight: Modified Boeing 727 (Zero Gravity Corporation) flew 30 parabolas alternating 1.8G and 0G; TMS administered only during 0G phases. Two mobile TMS labs were strapped to the aircraft floor, powered by aircraft circuits. Teams of five rotated roles every five parabolas. Emotional arousal: Before each rMT time point (pre-, during-, post-flight), participants verbally rated arousal from 1 (lowest) to 10 (highest). Safety: Single-pulse TMS only; anti-nausea medications were not used to avoid confounding excitability. Data quality and exclusion: No Earth-gravity rMT attempts were excluded (100 baseline, 30 pre-flight, 30 post-flight). During 0G, 10 of 50 rMT attempts were rejected due to poor acquisition quality, determined in-flight by the operator and confirmed post hoc. Statistical analysis: Linear mixed models with unstructured covariance examined effects of session (pre-flight 1G, 0G, post-flight 1G) on rMT, controlling for age, sex, team (A/B), rMT assessment number, and subjective arousal; participant intercepts were random effects. A separate model compared pre- vs post-flight 1G sessions with the same covariates. Analyses performed in IBM SPSS 25.

- Safety: No adverse events from single-pulse TMS. Three of 10 participants experienced transient nausea with vomiting during flight, each after their rMT acquisitions; no nausea during rMT recordings. - rMT by session (n=10): Significant effect of gravity state on rMT (F(2,85.21)=18.56, p<0.0001), controlling for covariates. Means (SE): pre-flight 1G = 55.0 (3.61), 0G = 48.1 (2.38), post-flight 1G = 55.4 (3.50). - Pairwise contrasts: 0G thresholds were 6.6 points lower than Earth 1G thresholds collapsed across pre/post (SE 1.08), t(86.18)=6.13, p<0.0001. Pre-flight 1G vs 0G: difference 6.6 points (SE 1.11), t(85.09)=5.98, p<0.0001 (~12.6% reduction). Post-flight 1G vs 0G: difference 6.5 points (SE 1.48), t(85.41)=4.39, p<0.0001. No significant difference pre- vs post-flight 1G (F(1,47.35)=0.772, ns). - Covariates: No significant effects of team, age, sex, subjective arousal, or assessment number on rMT. - Individual consistency: For all 10 participants, mean 0G rMT was lower than both pre- and post-flight 1G values; standard errors were similar across time points. - Emotional arousal: Main effect of time on arousal ratings (pre mean 5.2±0.55, during 6.0±0.25, post 3.7±0.63; F(1.540,13.86)=9.92, p=0.0035) driven by post-flight reduction; no significant effect of arousal on rMT (F(1,85.79)=0.61, ns).

The study demonstrates that rMT can be safely and reliably obtained during brief 0G periods and that gravity state acutely modulates corticospinal excitability: rMT decreased by approximately 12.6% in 0G and returned to baseline immediately after flight. Given the typical within-subject stability of rMT, these transient changes likely reflect true neurophysiological alterations associated with weightlessness rather than measurement noise or participant factors (age, sex, arousal). Several mechanisms could contribute: (1) Physical brain displacement reducing scalp-to-cortex distance in 0G; applying prior estimates (≈2.9 rMT points per 1 mm distance) suggests an upward brain shift of ~2.3 mm would account for the 6.6-point reduction, a plausible magnitude. (2) Microgravity-related changes in intracranial dynamics (e.g., reduced ICP in 0G, altered venous pressures, posture-related hemodynamics) may modulate cortical excitability. (3) Peripheral factors (neuromuscular junction or altered muscle biomechanics) could increase responsiveness to cortical output. Prior parabolic-flight EEG and TMS studies report mixed cortical excitability changes, but at least one study observed increased MEP amplitudes in 0G, aligning with the present reduction in rMT. These findings support the hypothesis that acute exposure to weightlessness alters neural function and establish TMS rMT as a practical biomarker for monitoring brain function in altered gravity, informing future countermeasure development for spaceflight.

Administering closed-loop, single-pulse TMS with custom helmets during parabolic flight is feasible and safe. Resting motor threshold significantly decreases during brief 0G exposure and returns to pre-flight levels post-flight, indicating acute, reversible neurophysiological changes in weightlessness. This work provides a foundational benchmark for brain stimulation use in spaceflight and underscores the need for expanded studies—longer 0G exposures, inclusion of hypergravity phases, additional TMS metrics (e.g., paired-pulse, cortical silent period, input–output curves), and multimodal measures—to elucidate mechanisms and guide clinical and operational applications in microgravity.

- Only rMT was measured; other informative TMS metrics (MEP latency, paired-pulse measures, cortical silent period, input–output curves) were not collected. - No data were acquired during hypergravity phases, limiting attribution specifically to gravity state versus flight-related factors. - Magnetic field strength (Tesla) of the TMS coil was not independently quantified in-flight; although unlikely, coil output characteristics could conceivably vary. - Brain position was not directly measured; proposed brain shift remains inferential. - Potential peripheral/musculoskeletal contributions in 0G were not characterized; EMG from additional muscles was not recorded to assess generalized changes. - Findings reflect brief 0G exposures during parabolic flight and may not generalize to long-duration spaceflight. - During 0G, 10/50 rMT attempts were rejected for quality; however, each participant had ≥3 clean 0G rMTs.