Background: Working memory (WM) impairment is a core contributor to functional decline in individuals with mild cognitive impairment (MCI) and dementia. WM relies on multiple cortical and subcortical structures including among the latter, the striatum, the cerebellum and their reciprocal connections. The striatum is variably affected in the early phase of dementia, while the cerebellum is relatively preserved until later stages. Following the hypothesis that the cerebellum might support striatal activity in neurodegenerative diseases, we sequentially applied cerebellar transcranial magnetic stimulation (TMS) and striatal transcranial temporal interference stimulation (tTIS), to enhance WM performance in MCI patients. We hypothesized that the effects of this synergistic dual-target neuromodulation strategy would enhance WM performance in MCI patients, especially in those with early striatal degeneration, like MCI with Lewy bodies (MCI-LB).
Methods: In this multicenter, randomized, quadruple-blind, placebo-controlled, crossover-design study (NCT07090681), we recruited 41 MCI patients, either MCI with Lewy bodies (MCI-LB, n = 21, 16 females) or amnestic MCI (aMCI, n = 20, 11 females), and 20 age-matched healthy controls (HC, 10 females), in Switzerland (EPFL) and Czech Republic (MUNI). After neuropsychological testing, structural and functional cerebral MRI, participants underwent three stimulation sessions in a pseudorandomized order: (1) cerebellar TMS followed by striatal tTIS using an intermittent theta burst (iTBS) stimulation protocol (TMScb+tTISstr) for both stimulation modalities, (2) sham TMS stimulation, followed by striatal iTBS (TMSneck+tTISstr), and (3) an Active control condition combining sham TMS, followed by high-frequency control striatal tTIS (TMSneck+tTIScontrol). During each stimulation session, participants completed a visual WM task involving trials with different memory loads and distractors. The task was completed before, during and after stimulation. We assessed the changes in Accuracy and Mean Reaction Times for correct answers (RTs) during the performance of the task as the primary outcomes and individual resting-state functional connectivity and gray matter volume of regions implicated in WM as potential modulators of the behavioural effects during stimulation.
Findings: MCI-LB and aMCI patients showed impaired working memory compared to controls. During stimulation, striatal tTIS combined with cerebellar TMS (TMScb+tTISstr) increased Accuracy in the MCI-LB group compared to the Active control stimulation (TMSneck+tTIScontrol, p
