Sex/Gender as a Factor That Influences Transcranial Magnetic Stimulation Treatment Outcome: Three Potential Biological Explanations

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which is now being used in psychiatry clinics across the world as a therapeutic tool for a variety of neural-circuit based disorders (e.g., major depression, obsessive compulsive disorder, substance use disorders, post-traumatic stress disorder, headache, pain). The higher volume of use and publication of multiple large-scale clinical trials has provided researchers with a unique opportunity to retrospectively evaluate factors influencing TMS treatment responses in large samples of patients. While many studies have focused on TMS protocol parameters as moderators of treatment efficacy, sex/gender is another critical, often overlooked factor influencing TMS treatment outcome. Women, especially during periods of high estradiol, appear to be particularly sensitive to the therapeutic effects of rTMS. This manuscript makes a case for three potential biological explanations for these findings. Drawing on literature from cranio-facial anatomy, neuroimaging, and neuroendocrine fields, we posit that observed increases in response rates of women in clinical rTMS trials may be related to: (1) Closer proximity of the brain to the scalp at the prefrontal cortex, leading to larger TMS induced electric fields especially at the medial prefrontal cortex, (2) Greater gray matter density and gyrification in the prefrontal cortex, and (3) High levels of estradiol which facilitate cortical excitability. These biological explanations are empirical ideas which have been evaluated in laboratory studies and lend themselves to prospective evaluation in multisite clinical rTMS trials. The existing literature on this topic and these three potential biological explanations all indicate that the TMS field should routinely evaluate sex/gender (and associated biological metrics like scalp-to-cortex distance, gray matter density, estradiol/progesterone levels) as a factor that may influence treatment outcome.

Exposure to 10 Hz Pulsed Magnetic Field Induced Slight Apoptosis and Reactive Oxygen Species in Primary Human Gingival Fibroblasts

“…Sexdependent effect of ELF-MFs on biological process in vitro had been previously reported by Baranowska et al [2018] that the effect of pulsed EMFs (7 Hz, 30 mT) on the release of proinflammatory cytokines from adipose-derived stem cells (ADSCs) of Wistar rats were different between male and female. And, more similar phenomenon in in vivo studies [Vallejo and Hidalgo, 2012;Acikgoz et al, 2022;Hanlon and McCalley, 2022]. But, none of these studies uncovered the mechanisms.…”

Theta burst stimulation is not inferior to high frequency repetitive transcranial magnetic stimulation in reducing symptoms of post-traumatic stress disorder in Veterans with depression: a retrospective case series

“…Analysis of over 5,000 patients treated with TMS for depression found female participants more likely to respond to treatment and enter remission (Sackeim et al, 2020). Several possible biological explanations stemming from differences in patient sex have since been described (Hanlon & McCalley, 2022). We reported unbalanced gender distribution among the two groups, with the 10 Hz group having more women overall and as a higher proportion of participants.…”

“…Several possible biological explanations stemming from differences in patient sex have since been described (Hanlon & McCalley, 2022). We reported unbalanced gender distribution among the two groups, with the 10 Hz group having more women overall and as a higher proportion of participants.…”

The effectiveness and safety of repetitive transcranial magnetic stimulation on spasticity after upper motor neuron injury: A systematic review and meta-analysis

“…Brihmat et al (2022) concluded that young patients usually had greater potential for inducing plasticity changes in response to rTMS than elder participants. Hanlon and McCalley (2022) found that gender maybe a critical influencing factor on the effect of rTMS, and they inferred that the reason may be related with gender difference in gray matter density and gyrification, proximity of the brain to the scalp and cortical excitability. Furthermore, Fitzgerald et al (2016) reported that the response to rTMS was greater in patients with shorter duration of illness.…”