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Clinical manifestations of Alzheimer's disease (AD)are associated with a breakdown in large-scale communication, such that AD may be considered as a “disconnection syndrome.” An established method to test effective connectivity is the combination of transcranial magnetic stimulation with electroencephalography (TMS–EEG)because the TMS-induced cortical response propagates to distant anatomically connected regions. To investigate whether prefrontal connectivity alterations may predict disease severity, we explored the relationship of dorsolateral prefrontal cortex connectivity (derived from TMS–EEG)with cognitive decline (measured with Mini Mental State Examination and a face–name association memory task)in 26 patients with AD. The amplitude of TMS–EEG evoked component P30, which was found to be generated in the right superior parietal cortex, predicted Mini Mental State Examination and face–name memory scores: higher P30 amplitudes predicted poorer cognitive and memory performances. The present results indicate that advancing disease severity might be associated with effective connectivity increase involving long-distance frontoparietal connections, which might represent a maladaptive pathogenic mechanism reflecting a damaged excitatory–inhibitory balance between anterior and posterior regions.

Background: Anodal transcranial direct current stimulation (A-tDCS) is a non-invasive technique in which cortical polarization can be used to increase excitability and facilitate learning through the modulation of neuroplasticity. Although the facilitatory effects of A-tDCS are well documented, there is evidence that they are not always present and may even be reversed during task execution. Objective: In this study, we explored the interaction between A-tDCS and task execution. We aimed to test how the excitability induced by the task interacts with the excitability induced by A-tDCS and determines the behavioral outcome. Methods: We performed an experiment in which A-tDCS or a control stimulation (Ctrl) were combined with one of two motor practices (MP), one inducing learning and increasing cortical excitability (F-MP) and the other neither inducing learning nor changing cortical excitability (S-MP). Six blocks of MP were performed while the primary motor cortex was stimulated. Moreover, one block of F-MP was performed before the stimulation (baseline) and one after. In an additional experiment, motor evoked potentials (MEPs) were recorded before the baseline block (TMS-pre) and after the MP (TMS-post). Results: We observed that A-tDCS reduced learning when participants performed the F-MP and facilitated learning for the S-MP. MEPs data paralleled behavioral results, confirming that the effects generated by A-tDCS depend on the excitability changes induced by the task. Conclusions: Our results demonstrate that tDCS-induced plasticity is task-dependent, and the concurrent combination of A-tDCS with another excitability-increasing event, e.g., motor practice, may trigger non-additive mechanisms, hindering neuroplasticity.