Cognitive and Functional Connectivity Outcomes from a Phase I Trial of Accelerated High‐Dose Repetitive Transcranial Magnetic Stimulation in Amnestic MCI

Abstract

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS), most widely used to treat depression, may have secondary benefits for cognition. Accelerated high‐dose protocols such as intermittent theta burst (iTBS)‐rTMS shorten the treatment course by >50%, potentially improving the feasibility of use in patients with cognitive impairments. Here, we present the results of a phase I trial of iTBS‐rTMS for improving cognition in individuals with amnestic mild cognitive impairment (aMCI) and we explore whether functional brain changes relate to improved cognition.MethodTwenty‐two patients with clinically diagnosed aMCI received 24 sessions of open‐label iTBS‐rTMS to left dorsolateral prefrontal cortex (l‐dlPFC) over 3 days. Nineteen had complete brain MRI and cognitive testing pre‐ and immediately post‐treatment. The primary cognitive outcome was the norm‐adjusted fluid cognition composite T‐score from the NIH Toolbox Cognition Battery. Resting‐state functional connectivity was computed from subject‐specific parcellations mapped to each individual’s functional topology. We examined changes in connectivity within and between the FPN (of with the l‐dlPFC is a hub) and networks implicated in cognition (FPN, dorsal and ventral attention, limbic, default mode). We assessed whether connectivity changes (post minus pre) related to change in fluid cognition.ResultWe achieved a high retention rate of 95%. Treatment with iTBS‐rTMS was safe, with no adverse neuroradiological, neuropsychiatric, or neurocognitive effects. Side effects were minimal and acceptability ratings were high. Treatment produced significant, large effect size (d = 0.98) improvements in fluid cognition (Fig. 1A), and we observed preliminary evidence of related changes in functional connectivity. Specifically, there was a numerical increase in within‐FPN connectivity and a marginally significant increase in connectivity between cognitive networks (Fig. 1B). Further, there was a medium‐strength and marginally significant association between increased within‐FPN connectivity and improved fluid cognition (Fig. 1C).ConclusionThis phase I trial demonstrated that iTBS‐rTMS is safe, feasible, and acceptable in aMCI. Although not dosed for efficacy, we observed large improvements in fluid cognition and preliminary evidence of increased functional connectivity in expected brain networks that related to improved cognition. These promising results support iTBS‐rTMS as potentially efficacious in improving cognition in aMCI, directly informing larger, planned follow‐up randomized controlled phase II trials.