A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer's disease

Highlights

• Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to enhance cognitive functions in Alzheimer's disease and mild cognitive impairment.

• High-frequency left dorsolateral prefrontal cortex and low-frequency right dorsolateral prefrontal cortex rTMS may improve memory function.

• High-frequency right inferior frontal gyrus rTMS may enhance executive performance.

• rTMS effects on cognition are documented at both acute and chronic time points.

• Chronic effects of consecutive rTMS sessions reportedly persist at 12 weeks.

Abstract

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive 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 because of 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 and low-frequency rTMS at the right dorsolateral prefrontal cortex 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.

Introduction

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that is increasingly used for a growing number of research and clinical applications. To perform TMS, a magnetic field that reaches a strength of up to 2 Tesla is rapidly generated in <1 ms. Typically, this transient magnetic field is focally applied with a figure-of-eight coil that is carefully placed on the surface of the scalp over a targeted stimulation site. Leveraging Faraday's principle of electromagnetic induction, this magnetic field penetrates the skull and generates an electric current in the more conductive brain tissue in a direction that is perpendicular to the applied magnetic field (Barker et al., 1985, Hallett, 2007). If this orthogonal electrical current is strong enough to surpass a physiological threshold, it can depolarize neurons in the targeted cortical tissue. Due to the nature of the exponentially decaying electromagnetic field, the penetration depth is limited to 2–3 centimeters. Thus, only superficial brain tissue can be directly stimulated by TMS, but this excitation can be propagated to distal targets through circuits that are structurally and/or functionally connected to the stimulation site (Chou et al., 2015b, Liston et al., 2014, Wang et al., 2014). In the corticospinal system, for example, when the motor cortex is stimulated with a suprathreshold TMS pulse, this direct excitation evokes a series of descending corticospinal volleys in the form of direct (D-) and indirect (I-) waves, which ultimately elicits a motor response in the corresponding limb (Bestmann and Krakauer, 2015).

Contrary to single-pulse TMS, patterned repetitive TMS (rTMS) can produce long-lasting effects on neural activity and behavior beyond the stimulation period (Chou et al., 2015a, Fitzgerald et al., 2006). Careful manipulation of the parameters comprising these patterned rTMS pulse trains can induce neuroplastic changes that resemble either long-term potentiation (LTP) or depression (Chen et al., 1997, Pascual-Leone et al., 1994). Early studies targeting the motor cortex helped elucidate which rTMS parameters promote particular responses and their neurophysiological underpinnings (Klomjai et al., 2015). More recently, this ability to evoke distinct long-lasting changes in neural activity has been leveraged for therapeutic applications in neuropsychiatric disease. In 2008, for example, TMS devices were cleared for market by the Food and Drug Administration for the clinical treatment of medication-resistant Major Depression Disorder. The specific Food and Drug Administration-approved protocol comprises a high-frequency stimulation protocol, which is known to produce an excitatory LTP-like effect, over the left dorsolateral prefrontal cortex (DLPFC) (O'Reardon et al., 2007). However, as an extension of the prefrontal asymmetry phenomenon, it has also been reported that inhibitory long-term depression–like low-frequency rTMS over the right DLPFC is equally efficacious in producing antidepressive outcomes in this patient population (Fitzgerald et al., 2009, Sutton and Davidson, 1997). In other words, prefrontal activity in patients with major depressive disorder (MDD) is abnormally imbalanced with right-sided hyperactivity and left-sided hypoactivity. Thus, distinct rTMS protocols that are known to produce opposite neurophysiological effects must be specifically applied depending on the targeted site of stimulation. This interaction between rTMS protocol and stimulation site has also been documented in the treatment of neurodegenerative disease (Chou et al., 2015a). Accordingly, it is necessary to carefully discern the rTMS parameters when evaluating its potential efficacy in all neurologic and psychiatric conditions.

In recent years, rTMS has been closely investigated to evaluate its potential to modulate cognitive functions in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Here, we extend previous important reviews (Birba et al., 2017, Cheng et al., 2017, Dong et al., 2018, Hsu et al., 2015, Liao et al., 2015, Nardone et al., 2014) by including rTMS studies among both patients with AD or MCI to evaluate and update the efficacy of rTMS intervention compared to sham controls. In addition, we sought to give greater attention to the methodological components of these existing studies. Considerable heterogeneity exists among the various rTMS treatment protocols that have been reported for cognitive enhancement for AD and MCI in the literature (e.g., different combinations of stimulation site, pulse frequency, stimulation intensity, number of stimuli delivered, and number of treatment sessions). A systematic and quantitative review that delineates rTMS effects based on various rTMS treatment protocols is not available. It is important to integrate these findings in a manner that accounts for this methodological heterogeneity to more accurately estimate the effects of rTMS in AD and MCI. Furthermore, we systematically characterize the effectiveness of various combinations of rTMS parameters on different cognitive domains in patients with AD and MCI. The distilled findings presented herein can be used to improve the experimental design of future rTMS clinical trials.