Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, has emerged as a promising treatment for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Currently, however, the effectiveness of this therapy is unclear due to the low statistical power and heterogeneity of previous trials. The purpose of the meta-analysis was to systematically characterize the effectiveness of various combinations of rTMS parameters on different cognitive domains in patients with MCI and AD. Thirteen studies comprising 293 patients with MCI or AD were included in this analysis. Random effects analysis revealed an overall medium-to-large effect size (0.77) favoring active rTMS over sham rTMS in the improvement of cognitive functions. Subgroup analyses revealed that 1) high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) and low-frequency rTMS at the right DLPFC significantly improved memory functions; 2) high-frequency rTMS targeting the right inferior frontal gyrus significantly enhanced executive performance; and 3) the effects of 5-30 consecutive rTMS sessions could last for 4-12 weeks. Potential mechanisms of rTMS effects on cognitive functions are discussed.

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Significance Noninvasive theta burst stimulation (TBS) guided by brain white matter tractography is a promising approach to strengthen resting-state functional connectivity of the hippocampus and increase associative memory performance in individuals with mild cognitive impairment. With this approach, our findings add insight into how TBS propagates from the superficial stimulation site to the hippocampus along the inferior longitudinal fasciculus. Results of this study provide an innovative platform for developing a noninvasive hippocampal stimulation protocol that has great potential in enhancing memory function in mild cognitive impairment.

Homeostatic metaplasticity is a neuroprotective physiological feature that counterbalances Hebbian forms of plasticity to prevent network destabilization and hyperexcitability. Recent animal models highlight dysfunctional homeostatic metaplasticity in the pathogenesis of Alzheimer’s Disease. However, the association between homeostatic metaplasticity and cognitive status has not been systematically characterized in either demented or non-demented human populations, and the potential value of homeostatic metaplasticity as an early biomarker of cognitive impairment has not been explored in humans. Here we report that, through pre-conditioning the synaptic activity prior to non-invasive brain stimulation, the association between homeostatic metaplasticity and cognitive status could be established in a population of non-demented human subjects (older adults across cognitive spectrums; all within the non-demented range). All participants (n = 40, age range 65-74, 47.5% female) underwent a standardized neuropsychological battery, MRI, and a transcranial magnetic stimulation protocol. Specifically, we sampled motor evoked potentials with an input/output curve immediately before and after repetitive transcranial magnetic stimulation to assess neural plasticity with two experimental paradigms: one with voluntary muscle contraction (i.e., modulated synaptic activity history) to deliberately introduce homeostatic interference, and one without to serve as a control condition. From comparing neuroplastic responses across these experimental paradigms and across cohorts grouped by cognitive status, we found that 1) homeostatic metaplasticity is diminished in our cohort of cognitively impaired older adults, and 2) this neuroprotective feature remains intact in cognitively normal participants. This novel finding suggests 1) future studies should expand their scope beyond just Hebbian forms of plasticity that are traditionally assessed when using non-invasive brain stimulation to investigate cognitive aging, and 2) the potential value of homeostatic metaplasticity in serving as a biomarker for cognitive impairment should be further explored.