Repetitive TMS of the Default Mode Network in AD
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Study type: Interventional

Summary: 
      Alzheimer's disease is a global health challenge. Efforts aim at developing an effective
      treatment able to meet the needs of patients and their families. Thus, the primary aim of
      this project is to investigate the efficacy of a non-invasive brain stimulation, namely
      repetitive transcranial magnetic stimulation (rTMS), on cognition in patients with mild
      Alzheimer's disease. rTMS is considered a safe, well tolerated and relatively cheap
      treatment. The appealing idea of the intervention is to improve memory by directly modulating
      the activity of precuneus, key area linked to memory impairment. Patients will be treated
      with rTMS in two phases: an intensive phase and a maintenance phase for a total of six
      months. This project aims to provide a valid treatment to slow the worsening of symptoms and
      improve quality of life for those with Alzheimer's and their caregivers.
    

Detailed description: 
      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.
    

Intervention name(s): REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION
Intervention type(s): Device
Intervention description(s): daily treatment session of REPETITIVE TRANSCRANIAL MAGNETIC STIMULATIO will be applied over precuneus for 20 minutes of consecutive blocks of 20Hz pulses for two seconds followed by 28 seconds of no stimulation.
Other intervention name(s): RTMS
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment