Corticomotor Plasticity Predicts Clinical Efficacy of Combined Neuromodulation and Cognitive Training in Alzheimer’s Disease

Abstract

Objective: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training for treatment of cognitive symptoms in patients with Alzheimer's disease (AD). A secondary objective was to analyze associations between brain plasticity and cognitive effects of treatment. Methods: In this randomized, sham-controlled, multicenter clinical trial, 34 patients with AD were assigned to three experimental groups receiving 30 daily sessions of combinatory intervention. Participants in the real/real group (n = 16) received 10 Hz repetitive transcranial magnetic stimulation (rTMS) delivered separately to each of six cortical regions, interleaved with computerized cognitive training. Participants in the sham rTMS group (n = 18) received sham rTMS combined with either real (sham/real group, n = 10) or sham (sham/sham group, n = 8) cognitive training. Effects of treatment on neuropsychological (primary outcome) and neurophysiological function were compared between the 3 treatment groups. These, as well as imaging measures of brain atrophy, were compared at baseline to 14 healthy controls (HC). Results: At baseline, patients with AD had worse cognition, cerebral atrophy, and TMS measures of cortico-motor reactivity, excitability, and plasticity than HC. The real/real group showed significant cognitive improvement compared to the sham/sham, but not the real/sham group. TMS-induced plasticity at baseline was predictive of postintervention changes in cognition, and was modified across treatment, in association with changes of cognition.

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study

“…In fact, as shown in a previous study ( 8 ), the concept of “brain reserve” is critical not only for determining the expression of cognitive decline in the natural evolution of the disease ( 44 – 46 ), but also for the impact of possible treatments. Our sample had a relatively severe cognitive impairment, and lack of cortical plasticity to rTMS has been found associated with a more severe rate of cognitive decline ( 47 ) and to predict less benefits from rTMS treatment associated with cognitive rehabilitation ( 11 ). We can therefore argue that rTMS may be potentially more effective especially when applied in the earlier disease stages, when the neurodegenerative process is not overwhelming and there are still preserved neuronal networks to be stimulated and strengthened by rTMS.…”

“…Converging evidence suggests that neuromodulation with repetitive transcranial magnetic stimulation (rTMS) may be useful as an additional, non-invasive and safe treatment for AD ( 1 , 2 ). Previous rTMS studies on AD were conducted with focal traditional figure-of-eight coils ( 3 – 11 ). High rTMS frequencies (>5 Hz), considered to have an excitatory effect ( 12 ) probably through synaptic long-term potentiation (LTP) mechanisms.…”

Past, Present, and Future of Non-invasive Brain Stimulation Approaches to Treat Cognitive Impairment in Neurodegenerative Diseases: Time for a Comprehensive Critical Review

“…When applied to the fronto-parietal-temporal lobes, high frequency rTMS induced improvement in the ADAS-cog scale, whereas the same pattern over the right inferior frontal gyrus (IFG) improved visual attention ( Eliasova et al, 2014 ). A series of seven studies combining high frequency rTMS over six different brain regions combined with cognitive training during stimulation customized to activate the contributions of these regions, showed 4–18 weeks thereafter, improvement in the ADAS-cog, the Clinical Global Impression of Change score ( Schneider et al, 1997 ; Brem et al, 2020 ) and the MMSE ( Bentwich et al, 2011 ; Brem et al, 2013 ; Rabey et al, 2013 ; Lee et al, 2016 ; Rabey and Dobronevski, 2016 ; Sabbagh et al, 2019 ). Finally, a recent study also applying high frequency rTMS over the left and right parietal and posterior temporal lobes combined with online cognitive tasks, showed improvements that lasted for at least 6 weeks in the ADAS-cog scale, in MMSE scores, in the Montreal Cognitive Assessment (MoCA) and in an auditory verbal learning test ( Zhao et al, 2017 ).…”

“…A recent study applied high frequency rTMS over the precuneus in patients with prodromal AD and found a selective improvement in episodic memory but not in other cognitive functions ( Koch et al, 2018 ). Importantly, the study from Brem et al (2020) used TMS combined with electromyography (EMG) at baseline and following stimulation and showed that TMS-induced plasticity at baseline was predictive of changes of cognitive performance measured after the intervention.…”

Repetitive Transcranial Magnetic Stimulation in the Treatment of Alzheimer’s Disease and Other Dementias

“…[26] HF (10 Hz) Improved cognitive function, persisted in the maintenance period [14] HF (10 Hz) Improved cognitive function, persisted in the maintenance period [27] HF (20 Hz) Improved cognitive function [28] HF (10 Hz) Improved cognitive function, stronger results for milder cognitive decline [29] HF (10 Hz) Improved cognitive function, persisted in the maintenance period [30] HF (10 Hz) Improved cognitive function, persisted at 6 months for those with better baseline scores [31] HF (10 Hz) Improved cognitive function that persisted, specifically for those with better baseline scores [32] HF (10 Hz) Improved cognitive function, persisted in follow-up, no differences between groups receiving real or sham cognitive training * Left inferior frontal gyrus, left superior temporal gyrus, left and right dorsolateral prefrontal cortex, left and right parietal somatosensory association cortices.…”