The Dosage Gap in Neuromodulation: How Female Anatomy Challenges Standard TMS Protocols

Key takeaways

• Women’s shorter scalp-to-cortex distance (STCD) results in significantly stronger electrical fields during transcranial magnetic stimulation (TMS), potentially leading to supratherapeutic dosing.
• Efficacy is protocol-dependent: while high-frequency (10 Hz) stimulation may be more effective in women, intermittent theta-burst stimulation (iTBS) shows reduced utility compared to men.
• New FDA guidance mandates sex-specific data evaluation for medical devices, highlighting the need for updated clinical guidelines that account for biological differences.
• Clinicians are advised to prioritize individualized titration and close monitoring of adverse events until sex-adjusted dosing algorithms become standard.

Why do standard neuromodulation protocols raise concerns for women?

Standard repetitive transcranial magnetic stimulation (rTMS) protocols were largely validated using male-dominant clinical trial cohorts, creating a potential treatment gap where device settings optimized for male neuroanatomy may inadvertently alter electrical field distribution in female brains. As of 2026, clinical practice guidelines still generally rely on uniform dosing strategies such as percentage-of-motor-threshold, rather than sex-adjusted parameters.

This reliance on aggregate averages overlooks critical physiological differences. Because magnetic field strength decays rapidly with distance, anatomical variance can cause women to receive significantly higher electric field intensities at the target cortex for a given machine output compared to men. This discrepancy suggests that "one-size-fits-all" dosing may not be biologically neutral, potentially exposing women to different risk profiles and efficacy outcomes.

How does scalp-to-cortex distance affect electric field dosing in women?

Women consistently demonstrate a shorter scalp-to-cortex distance (STCD)—the physical distance between the scalp surface and the cerebral cortex—at major rTMS targets, including the dorsolateral prefrontal cortex (dlPFC), compared to men. This anatomical variance means that for identical stimulation settings, the induced electrical field strength in a woman’s brain is approximately 20% to 30% greater than in a man’s brain.

• Anatomical Basis: Research by McCalley et al. (2026) indicates that skull morphology and cortical folding in women result in statistically significant shorter distances across frontal pole regions. This structural reality dictates that energy deposition occurs closer to the target tissue.
• Implication: If a clinician applies a "safe" standard dose calibrated for a generic average, a woman may effectively experience a supratherapeutic load. While early meta-analyses suggested women had higher remission rates possibly due to this increased field exposure, emerging data suggest this variable confounds outcome interpretation. It remains unclear whether this heightened engagement drives remission or merely increases side effect severity without proportional benefit.

Do women respond differently to various rTMS frequencies?

Efficacy appears to be protocol-dependent rather than uniformly superior. Recent stratified analyses highlight that the interaction between biological sex and stimulation frequency yields divergent outcomes, challenging the assumption that all rapid protocols perform equally across sexes.

• High-Frequency (10 Hz): A 2024 analysis by Slan et al. found that 10 Hz rTMS demonstrated greater efficacy in females than males, potentially reinforcing the hypothesis that heightened electrical field engagement benefits women in specific frequency bands.
• Theta-Burst Stimulation (iTBS): Conversely, the same study indicated that intermittent theta-burst stimulation (iTBS) was significantly less efficacious in females compared to males. This challenges the widespread adoption of ultra-rapid protocols like iTBS, which are often chosen for convenience but may offer reduced utility for women.

Hormonal fluctuations also play a modulatory role; periods of high estradiol have been associated with enhanced cortical excitability and potentially better response to rTMS in women, adding a temporal layer of uncertainty to static dosing guidelines described by Hanlon et al. (2022).

What recent regulatory changes address device design gaps?

The landscape of medical device evaluation is shifting to explicitly account for sex-specific data. In March 2025, the U.S. Food and Drug Administration (FDA) finalized the guidance document Evaluation of Sex-Specific Data in Medical Device Clinical Studies. This regulation updates the 2014 framework, mandating that future device approvals include rigorous analysis of sex-based performance.

"This document provides guidance on the study and evaluation of sex-specific data in medical device clinical studies... outlining requirements for sponsors to ensure devices function safely and effectively across diverse populations." — FDA Guidance (March 2025)

For rTMS manufacturers, this necessitates demonstrating that coil designs and dosimetry algorithms do not disproportionately expose one sex to adverse effects or suboptimal efficacy. This regulatory shift aims to close the historical gap where safety and efficacy data were extrapolated from male-dominated trials.

How can clinicians mitigate potential risks until dosing standards evolve?

Until sex-specific dosing algorithms are codified into clinical guidelines, practitioners should prioritize individualized titration and monitoring to manage the inherent variability in female neuroanatomy.

• Motor Threshold Verification: Regularly re-assess the resting motor threshold (RMT) at each visit to account for daily physiological variability and ensure accurate dosing calibration.
• Adverse Event Monitoring: Women report higher incidences of headache and scalp discomfort during rTMS sessions. Clinicians should consider starting at conservative intensities and titrating slowly, acknowledging the risk of inadvertent overdosing due to shortened STCD.
• Protocol Selection: When considering iTBS for female patients, clinicians should monitor closely for signs of reduced responsiveness, keeping the findings of Slan et al. in mind regarding differential efficacy.

Comparison of rTMS Protocol Efficacy by Sex