Instantaneous effects of prefrontal transcranial magnetic stimulation on brain oxygenation: A systematic review.

This systematic review investigates how prefrontal transcranial magnetic stimulation (TMS) immediately influences neuronal excitability based on oxygenation changes measured by functional magnetic resonance imaging (fMRI) or functional near-infrared spectroscopy (fNIRS). A thorough understanding of TMS-induced excitability changes may enable clinicians to adjust TMS parameters and optimize treatment plans proactively. Five databases were searched for human studies evaluating brain excitability using concurrent TMS/fMRI or TMS/fNIRS. Thirty-seven studies (13 concurrent TMS/fNIRS studies, 24 concurrent TMS/fMRI studies) were included in a qualitative synthesis. Despite methodological inconsistencies, a distinct pattern of activated nodes in the frontoparietal central executive network, the cingulo-opercular salience network, and the default-mode network emerged. The activated nodes included the prefrontal cortex (particularly dorsolateral prefrontal cortex), insula cortex, striatal regions (especially caudate, putamen), anterior cingulate cortex, and thalamus. High-frequency repetitive TMS most consistently induced expected facilitatory effects in these brain regions. However, varied stimulation parameters (e.g., intensity, coil orientation, target sites) and the inter- and intra-individual variability of brain state contribute to the observed heterogeneity of target excitability and co-activated regions. Given the considerable methodological and individual variability across the limited evidence, conclusions should be drawn with caution.

Sex differences in brain excitability revealed by concurrent iTBS/fNIRS.

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.

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 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; I2=82·40%), medium for depressive symptoms (-0·725 [-0·889 to -0·561], p<0·0001; I2=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.

Non-Invasive Brain Stimulation Effects on Biomarkers of Tryptophan Metabolism: A Scoping Review and Meta-Analysis.

Abnormal activation of the kynurenine and serotonin pathways of tryptophan metabolism is linked to a host of neuropsychiatric disorders. Concurrently, noninvasive brain stimulation (NIBS) techniques demonstrate high therapeutic efficacy across neuropsychiatric disorders, with indications for modulated neuroplasticity underlying such effects. We therefore conducted a scoping review with meta-analysis of eligible studies, conforming with the PRISMA statement, by searching the PubMed and Web of Science databases for clinical and preclinical studies that report the effects of NIBS on biomarkers of tryptophan metabolism. NIBS techniques reviewed were electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS). Of the 564 search results, 65 studies were included with publications dating back to 1971 until 2022. The Robust Bayesian Meta-Analysis on clinical studies and qualitative analysis identified general null effects by NIBS on biomarkers of tryptophan metabolism, but moderate evidence for TMS effects on elevating serum serotonin levels. We cannot interpret this as evidence for or against the effects of NIBS on these biomarkers, as there exists several confounding methodological differences in this literature. Future controlled studies are needed to elucidate the effects of NIBS on biomarkers of tryptophan metabolism, an under-investigated question with substantial implications to clinical research and practice.

Protocol for a prospective open-label clinical trial to investigate the utility of concurrent TBS/fNIRS for antidepressant treatment optimisation.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) with theta burst stimulation (i.e. TBS) of the dorsolateral prefrontal cortex (DLPFC) is an innovative treatment for major depressive disorder (MDD). However, fewer than 50% of patients show sufficient response to this treatment; markers for response prediction are urgently needed. Research shows considerable individual variability in the brain responses to rTMS. However, whether differences in individual DLPFC modulation by rTMS can be used as a predictive marker for treatment response remains to be investigated. Here, we present a research programme that will exploit the combination of functional near-infrared spectroscopy (fNIRS) with brain stimulation. Concurrent TBS/fNIRS will allow us to systematically investigate TBS-induced modulation of blood oxygenation as a proxy for induced brain activity changes. The findings from this study will (1) elucidate the immediate effects of excitatory and inhibitory TBS on prefrontal activity in TBS treatment-naïve patients with MDD and (2) validate the potential utility of TBS-induced brain modulation at baseline for the prediction of antidepressant response to 4 weeks of daily TBS treatment. METHODS AND ANALYSIS: Open-label, parallel-group experiment consisting of two parts. In part 1, 70 patients and 37 healthy controls will be subjected to concurrent TBS/fNIRS. Intermittent TBS (iTBS) and continuous TBS (cTBS) will be applied on the left and right DLPFC, respectively. fNIRS data will be acquired before, during and several minutes after stimulation. In part 2, patients who participated in part 1 will receive a 4 week iTBS treatment of the left DLPFC, performed daily for 5 days per week. Psychometric evaluation will be performed periodically and at 1 month treatment follow-up. Statistical analysis will include a conventional, as well as a machine learning approach. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Board. Findings will be disseminated through scientific journals, conferences and university courses. TRIAL REGISTRATION NUMBER: NCT04526002.

Dose-response relationship between iTBS and prefrontal activation during executive functioning: A fNIRS study.

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 near-infrared 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.

Gender-affirming hormone treatment - A unique approach to study the effects of sex hormones on brain structure and function.

Investigating the effects of the gender-affirming hormone treatment of transgender people using neuroimaging provides a unique opportunity to study the impact of high dosages of sex hormones on human brain structure and function. This line of research is of relevance from a basic neuroscientific as well as from a psychiatric viewpoint. Prevalence rates, etiopathology, and disease course of many psychiatric disorders exhibit sex differences which are linked to differences in sex hormone levels. Here, we review recent neuroimaging studies from others and our group that investigate the effects of gender-affirming hormone treatment in a longitudinal design utilizing structural and functional magnetic resonance imaging and positron emission tomography. Studies point to a general anabolic and anticatabolic effect of testosterone on grey and white matter structure, whereas estradiol and antiandrogen treatment seems to have partly opposite effects. Moreover, preliminary research indicates that gender-affirming hormone treatment influences serotonergic neurotransmission, a finding that is especially interesting for psychiatry. A clear picture of a hormonal influence on brain activity has yet to emerge. In conclusion, the available evidence reviewed here clearly indicates that sex hormone applications influence brain structure and function in the adult human brain.

Non-invasive brain stimulation for posttraumatic stress disorder: a systematic review and meta-analysis.

Approximately 7-9% of people develop posttraumatic stress disorder in their lifetime, but standard pharmacological treatment or psychotherapy shows a considerable individual variation in their effectiveness. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) hold promise for the treatment of posttraumatic stress disorder. The objective of this meta-analysis was to summarize the existing evidence on the therapeutic effects of these brain stimulation treatments on posttraumatic core symptoms. We systematically retrieved articles published between 1st January 2000 and 1st January 2020 comparing the effects of active with sham stimulation or no intervention in posttraumatic patients from eight databases. Random-effects model was used for meta-analysis. Meta-regression and subgroup meta-analysis was performed to investigate the influence of stimulation dose and different stimulation protocols, respectively. 20 studies were included in this review, where of 11 randomized controlled trials were subjected to quantitative analysis. Active stimulation demonstrated significant reductions of core posttraumatic symptoms with a large effect size (Hedge's g = -0.975). Subgroup analysis showed that both excitatory and inhibitory rTMS of the right dorsolateral prefrontal cortex led to symptom reductions with a large (Hedges' g = -1.161, 95% CI, -1.823 to -0.499; p = 0.015) and medium effect size (Hedges' g = -0.680, 95% CI: -0.139 to -0.322; p ≤ 0.001) respectively. Results further indicated significant durability of symptom-reducing effects of treatments during a two to four weeks period post stimulation (Hedges' g = -0.909, 95% CI: -1.611 to -0.207; p = 0.011). rTMS of the right dorsolateral prefrontal cortex appears to have a positive effect in reducing core symptoms in patients with posttraumatic stress disorder.