Repetitive TMS of the Default Mode Network in AD

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by severe disruption of large-scale brain networks connectivity. AD pathophysiology has been mainly associated with a breakdown of the Default Mode Network (DMN) and with a structural disconnection of parietal nodes. It has been shown that the precuneus (PC), a central hub of the DMN, is involved in successful episodic memory retrieval, working as a key area of the network activated by recognition memory. Recent anatomical works have shown that medial parietal regions are interconnected with the medial temporal region, which is implicated in memory retrieval. In particular, the PC was identified as a region demonstrating strong functional interconnectivity with the hippocampal formation. This is of particular relevance because PC is altered in AD. At early clinical stages of AD, PC is selectively vulnerable to early amyloid deposition, and plays a critical role in the conversion towards dementia. Hypothesis: a novel therapeutic intervention for AD is repetitive Transcranial Magnetic Stimulation (rTMS). rTMS is a non- invasive approach that can be used to induce long lasting modulation of specific brain functions, inducing neuroplastic changes not only in the cortical site of stimulation, but also in remote interconnected areas. In a recent double blind randomized cross-over clinical pilot study, we found that a two-week course of daily high-frequency rTMS (20 Hz) treatment targeting the DMN (Stimulation site: PC) was able to induce an improvement in episodic memory compared to placebo. Indeed, TMS-EEG measurements showed that rTMS treatment, applied over the DMN, was capable to modulate the cortical activity in both the targeted areas (PC) as well as in functional connected regions of the DMN (Koch et al., 2018). Specific aims: to investigate clinical efficacy and safety of DMN rTMS applied during 6 months in mild AD patients. To provide novel evidence that non-invasive treatment of network dysfunction, through stimulation of the PC, will represent an effective strategy to enhance cognitive functions and lead to substantial slowing of cognitive and functional decline in patients with mild AD. The findings yielded by the present project will have a potential strong impact on clinical practice of AD patients. Since rTMS is well tolerated and relatively low-priced, a positive result could lead to a fast application of the present proposal to the clinical experience. If successful, the proposed project will provide support for a novel treatment for cognitive dysfunction in AD patients.