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Sex differences have been claimed an imperative factor in the optimization of psychiatric treatments. Intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation, is a promising non-invasive treatment option. Here, we investigated whether the real-time neural response to iTBS differs between men and women, and which mechanisms may mediate these differences. To this end, we capitalized on a concurrent iTBS/functional near-infrared spectroscopy setup over the left dorsolateral prefrontal cortex, a common clinical target, to test our assumptions. In a series of experiments, we show (1) a biological sex difference in absolute hemoglobin concentrations in the left dorsolateral prefrontal cortex in healthy participants; (2) that this sex difference is amplified by iTBS but not by cognitive tasks; and (3) that the sex difference amplified by iTBS is modulated by stimulation intensity. These results inform future stimulation treatment optimizations towards precision psychiatry., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The left dorsolateral prefrontal cortex is a prime target for repetitive transcranial magnetic stimulation (TMS) to treat neuropsychiatric disorders; thus, abundant efficacy data from controlled trials are available. A cross-diagnostic meta-analysis was conducted to identify the symptom domains susceptible to repetitive TMS to the left dorsolateral prefrontal cortex., Methods: This systematic review and meta-analysis investigated the effects of repetitive TMS to the left dorsolateral prefrontal cortex on neuropsychiatric symptoms presenting across diagnoses. We searched PubMed, MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for randomised and sham controlled trials published from inception to Aug 17, 2022. Included studies assessed symptoms using clinical measures and reported sufficient data to calculate effect sizes pooled with a random effects model. Two independent reviewers conducted screening and used the Cochrane risk-of-bias tool for quality assessment. Summary data were extracted from published reports. The main outcome was the therapeutic effects of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains. This study is registered with PROSPERO (CRD42021278458)., Findings: Of 9056 studies identified (6704 from databases and 2352 from registers), 174 were included in the analysis including 7905 patients. 163 of 174 studies reported gender data; 3908 (52·35%) of 7465 patients were male individuals, and 3557 (47·65%) were female individuals. Mean age was 44·63 years (range 19·79-72·80). Ethnicity data were mostly not available. Effect size was large for craving (Hedges'g -0·803 [95% CI -1·099 to -0·507], p<0·0001; I 2 =82·40%), medium for depressive symptoms (-0·725 [-0·889 to -0·561], p<0·0001; I 2 =85·66%), small for anxiety, obsessions or compulsions, pain, global cognition, declarative memory, working memory, cognitive control, and motor coordination (Hedges'g -0·198 to -0·491), and non-significant for attention, suicidal ideation, language, walking ability, fatigue, and sleep., Interpretation: The cross-diagnostic meta-analysis shows the efficacy of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains, providing a novel framework for assessing target or efficacy interactions of repetitive TMS, and informing personalised applications for conditions for which regular trials are uninformative., Funding: The University Grants Committee of Hong Kong and the Mental Health Research Center, The Hong Kong Polytechnic University., Competing Interests: Declaration of interests FP reports grants from the German Center for Brain Stimulation research consortium, funding from the Federal Ministry of Education and Research, speaker's honoraria from Mag&More, neuroCare Group, and Brainsway, serving as a member of the European Scientific Advisory Board of Brainsway, membership of the International Scientific Advisory Board of Sooma, and support with equipment from neuroConn, Mag&More, and Brainsway, in the past 36 months. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults. Methods: Twenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional nearinfrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation. Results: After stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t.17/= 2.203, P = 0.042, d = 0.523] and 100% iTBS [t.17/ = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t.17/ = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation. Conclusion: The linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT. [ABSTRACT FROM AUTHOR]