Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis

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 crossdiagnostic 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-ofbias 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 center dot 35%) of 7465 patients were male individuals, and 3557 (47 center dot 65%) were female individuals. Mean age was 44 center dot 63 years (range 19 center dot 79-72 center dot 80). Ethnicity data were mostly not available. Effect size was large for craving (Hedges' g -0 center dot 803 [95% CI -1 center dot 099 to -0 center dot 507], p<0 center dot 0001; I-2=82 center dot 40%), medium for depressive symptoms (-0 center dot 725 [-0 center dot 889 to -0 center dot 561], p<0 center dot 0001; I-2=85 center dot 66%), small for anxiety, obsessions or compulsions, pain, global cognition, declarative memory, working memory, cognitive control, and motor coordination (Hedges' g -0 center dot 198 to -0 center dot 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.