Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.
The human brain is a complex network in which hundreds of brain regions are interconnected via thousands of axonal pathways. The capability of such a complex system emerges from specific interactions among smaller entities, a set of events that can be described by the activation of interconnections between brain areas. Studies that focus on brain connectivity have the aim of understanding and modeling brain function, taking into account the spatiotemporal dynamics of neural communication between brain regions. Much of the current knowledge regarding brain connectivity has been obtained from stand-alone neuroimaging methods. Nevertheless, the use of a multimodal approach seems to be a powerful way to investigate effective brain connectivity, overcoming the limitations of unimodal approaches. In this review, we will present the advantages of an integrative approach in which transcranial magnetic stimulation–electroencephalography coregistration is combined with magnetic resonance imaging methods to explore effective neural interactions. Moreover, we will describe possible implementations of the integrative approach in open- and closed-loop frameworks where real-time brain activity becomes a contributor to the study of cognitive brain networks.
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