Abstract
ObjectiveTo 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.MethodsIn 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).ResultsAt 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 post-intervention changes in cognition, and was modified across treatment, in association with changes of cognition.InterpretationCombined rTMS and cognitive training may improve the cognitive status of AD patients, with TMS-induced cortical plasticity at baseline serving as predictor of therapeutic outcome for this intervention, and potential mechanism of action.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT01504958.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease (Alzheimer’s Association, 2012) with cognitive decline significantly affecting quality of life (Alzheimer’s Association, 2012)
Plasticity indices measured up to 30 min after intermittent theta-burst stimulation (iTBS) were significantly different between AD patients and healthy controls (HC) at T5 (U = 183, z = 2.13, p = 0.033, r = 0.37), T10 (U = 179, z = 1.98, p = 0.048, r = 0.35), and averaged over T5 to T30 (U = 181, z = 2.06, p = 0.040, r = 0.36) (Figure 2A)
intracortical facilitation (ICF) was similar in AD and HC, while short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) were significantly reduced in AD (SICI: U = 56, z = −2.23, p = 0.025, r = −0.40; LICI: U = 42, z = −2.81, p = 0.005, r = −0.50) (Figure 2B)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease (Alzheimer’s Association, 2012) with cognitive decline significantly affecting quality of life (Alzheimer’s Association, 2012). When applied as single or paired pulses to the motor cortex, it provides a diagnostic tool to interrogate cortico-motor reactivity and inhibitory/excitatory intracortical circuits, respectively. TMS is applied in trains of pulses, termed repetitive TMS (rTMS) to induce changes in excitability of the activated neural circuits that outlast the period of stimulation. Over the last 15 years, a low-intensity form of patterned rTMS, termed intermittent theta-burst stimulation (iTBS), has emerged as a means to induce NMDA receptor (NMDAR)-dependent longterm potentiation (LTP)-like plasticity (Huang et al, 2005, 2007). When applied over the motor cortex, the after-effects of iTBS are measured as the change in the amplitude of motor-evoked potentials (MEPs) elicited by suprathreshold single-pulse TMS, i.e., the change in cortico-motor reactivity, which is thought to reflect cortical plasticity (Pascual-Leone et al, 1994). Targeting neural networks with rTMS while engaging them, for example in cognitive exercises, has been suggested to lead to functional improvements (Freitas et al, 2011) resulting from synergistic effects if repeated in time
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