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Psychiatry"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fpsyt.2022.869070","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T05:22:49Z","timestamp":1651209769000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Sex\/Gender as a Factor That Influences Transcranial Magnetic Stimulation Treatment Outcome: Three Potential Biological Explanations"],"prefix":"10.3389","volume":"13","author":[{"given":"Colleen A.","family":"Hanlon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"McCalley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jad.2020.08.005","article-title":"Clinical outcomes in a large registry of patients with major depressive disorder treated with transcranial magnetic stimulation.","volume":"277","author":"Sackeim","year":"2020","journal-title":"J Affect Disord."},{"key":"B2","doi-asserted-by":"publisher","first-page":"727","DOI":"10.2147\/NDT.S58405","article-title":"More female patients and fewer stimuli per session are associated with the short-term antidepressant properties of repetitive transcranial magnetic stimulation (rTMS): a meta-analysis of 54 sham-controlled studies published between 1997-2013.","volume":"10","author":"Kedzior","year":"2014","journal-title":"Neuropsychiatr Dis Treat."},{"key":"B3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.neuron.2004.12.033","article-title":"Theta burst stimulation of the human motor cortex.","volume":"45","author":"Huang","year":"2005","journal-title":"Neuron."},{"key":"B4","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00221-010-2293-4","article-title":"Simply longer is not better: reversal of theta burst after-effect with prolonged stimulation.","volume":"204","author":"Gamboa","year":"2010","journal-title":"Exp Brain Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1016\/S0140-6736(18)30295-2","article-title":"Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.","volume":"391","author":"Blumberger","year":"2018","journal-title":"Lancet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1017\/cbo9780511698095.026","article-title":"On physical lines of force.","volume":"1","author":"Maxwell","year":"1861","journal-title":"Philos Mag."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2535","DOI":"10.1097\/00001756-199707280-00023","article-title":"Mapping transcranial magnetic stimulation (TMS) fields in vivo with MRI.","volume":"8","author":"Bohning","year":"1997","journal-title":"Neuroreport."},{"key":"B8","doi-asserted-by":"publisher","first-page":"713","DOI":"10.5455\/JPMA.32528","article-title":"Anthropological significance of sexual dimorphism and the unique structural anatomy of the frontal sinuses: review of the available literature.","volume":"70","author":"Javaid","year":"2020","journal-title":"J Pak Med Assoc."},{"key":"B9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1002\/(SICI)1098-2353(1999)12:1<16::AID-CA3>3.0.CO;2-D","article-title":"Anatomical variability of the frontal sinuses and their application in forensic identification.","volume":"12","author":"Nambiar","year":"1999","journal-title":"Clin Anat."},{"key":"B10","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.jcms.2010.02.001","article-title":"CT measurement of the frontal sinus - 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