Transcranial Magnetic Stimulation (TMS) allows for the direct activation of neurons in the human neocortex and has proven to be fundamental for causal hypothesis testing in cognitive neuroscience. By administering TMS concurrently with functional Magnetic Resonance Imaging (fMRI), the effect of cortical TMS on activity in distant cortical and subcortical structures can be quantified by varying the levels of TMS output intensity. However, TMS generates significant fluctuations in the fMRI time series, and their complex interaction warrants caution before interpreting findings. We present the methodological challenges of concurrent TMS-fMRI and a guide to minimize induced artifacts in experimental design and post-processing. Our study targeted two frontal-striatal circuits: primary motor cortex (M1) projections to the putamen and lateral prefrontal cortex (PFC) projections to the caudate in healthy human participants. We found that TMS parametrically increased the BOLD signal in the targeted region and subcortical projections as a function of stimulation intensity. Together, this work provides practical steps to overcome common challenges with concurrent TMS-fMRI and demonstrates how TMS-fMRI can be used to investigate functional brain networks.

Background: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been proposed as a new therapeutic way to enhance the cognition of patients with dementia. However, serious methodological limitations appear to affect the estimates of their efficacy. We reviewed the stimulation parameters and methods of studies that used TMS or tDCS to alleviate the cognitive symptoms of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Moreover, we evaluated the risk of bias in these studies. Our aim was to highlight the current vulnerabilities of the field and to formulate recommendations on how to manage these issues when designing studies.

Methods: Electronic databases and citation searching were used to identify studies administering TMS or tDCS on patients with AD or MCI to enhance cognitive function. Data were extracted by one review author into summary tables with the supervision of the authors. The risk of bias analysis of randomized-controlled trials was conducted by two independent assessors with version 2 of the Cochrane risk-of-bias tool for randomized trials.

Results: Overall, 36 trials were identified of which 23 randomized-controlled trials underwent a risk of bias assessment. More than 75% of randomized-controlled trials involved some levels of bias in at least one domain. Stimulation parameters were highly variable with some ranges of effectiveness emerging. Studies with low risk of bias indicated TMS to be potentially effective for patients with AD or MCI while questioned the efficacy of tDCS.

Conclusions: The presence and extent of methodical issues affecting TMS and tDCS research involving patients with AD and MCI were examined for the first time. The risk of bias frequently affected the domains of the randomization process and selection of the reported data while missing outcome was rare. Unclear reporting was present involving randomization, allocation concealment, and blinding. Methodological awareness can potentially reduce the high variability of the estimates regarding the effectiveness of TMS and tDCS. Studies with low risk of bias delineate a range within TMS parameters seem to be effective but question the efficacy of tDCS.