Cognitive Effects Following Offline High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) in Healthy Populations: A Systematic Review and Meta-Analysis

Abstract

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a commonly used form of rTMS to treat neuropsychiatric disorders. Emerging evidence suggests that ‘offline’ HF-rTMS may have cognitive enhancing effects, although the magnitude and moderators of these effects remain unclear. We conducted a systematic review and meta-analysis to clarify the cognitive effects of offline HF-rTMS in healthy individuals. A literature search for randomised controlled trials with cognitive outcomes for pre and post offline HF-rTMS was performed across five databases up until March 2022. This study was registered on the PROSPERO international prospective protocol for systematic reviews (PROSPERO 2020 CRD 42,020,191,269). The Risk of Bias 2 tool was used to assess the risk of bias in randomised trials. Separate analyses examined the cognitive effects of excitatory and inhibitory forms of offline HF-rTMS on accuracy and reaction times across six cognitive domains. Fifty-three studies (N = 1507) met inclusion criteria. Excitatory offline HF-rTMS showed significant small sized effects for improving accuracy (k = 46, g = 0.12) and reaction time (k = 44, g = -0.13) across all cognitive domains collapsed. Excitatory offline HF-rTMS demonstrated a relatively greater effect for executive functioning in accuracy (k = 24, g = 0.14). Reaction times were also improved for the executive function (k = 21, g = -0.11) and motor (k = 3, g = -0.22) domains following excitatory offline HF-rTMS. The current review was restricted to healthy individuals and future research is required to examine cognitive enhancement from offline HF-rTMS in clinical cohorts.

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial

“…Taken together, these results suggest that a single session of 'offline' iTBS administered over the L-DLPFC has minimal or no cognitive enhancing effects for cognitive flexibility in healthy participants. This is consistent with recent reviews showing limited cognitive effects of rTMS administered to the L-DLPFC [18] and/or other brain regions in healthy participants [13].…”

“…Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that uses magnetic pulses to modulate neural activity and cognitive functions [12,13]. In a meta-analysis of randomised sham-controlled trials conducted in people with MDD, we observed that a therapeutic course of repetitive TMS (rTMS) administered to the dorsolateral prefrontal cortex (DLPFC) significantly improved performance on measures of cognitive flexibility (Hedge's g = 0.26) and attentional processing speed (Hedge's g = 0.28), although not for other individual cognitive measures [14]).…”

“…These impairing effects of 'online' HF-rTMS may be due to the introduction of random neuronal firing during ongoing cognitive processing [12]. Alternatively, when HF-rTMS is administered before the performance of a cognitive task (i.e., 'offline'), performance has been shown to be improved [13,18]. A recent meta-analysis in healthy participants found that for the executive function domain and for all cognitive domains collapsed, 'offline' active HF-rTMS was associated with significantly better accuracy and reaction time performance compared to sham HF-rTMS [13].…”

“…Alternatively, when HF-rTMS is administered before the performance of a cognitive task (i.e., 'offline'), performance has been shown to be improved [13,18]. A recent meta-analysis in healthy participants found that for the executive function domain and for all cognitive domains collapsed, 'offline' active HF-rTMS was associated with significantly better accuracy and reaction time performance compared to sham HF-rTMS [13]. However, the magnitude of the effect sizes for these cognitive enhancing effects of rTMS was small, and the betweenstudy heterogeneity was high, indicating that enhanced 'offline' HF-rTMS protocols are required to further develop rTMS as a novel intervention for cognitive impairment.…”

“…This is because rTMS's neuromodulatory effects are typically highly focal (i.e., approximately 1.5 cm diameter, 2 cm depth). For enhancing cognition, the left DLPFC (L-DLPFC) has been the target site of most research interest [13,15,18,21]. The L-DLPFC is a highly linked node in the central executive network that is associated with mood regulation and higher-level cognitive processes including working memory [22] and cognitive flexibility [23].…”