Objectives:
* To provide a proof of concept by validating the hypoactivity (hypoperfusion) of the anterior insula ("AI biomarker") as a causal factor of the instability of arousal states in DLB.
* To evaluate if improvement of arousal translates clinically into a reduction of cognitive fluctuations and an improvement of other functional parameters (clinical measures of symptoms).
* Evaluation of the relevance of the AI biomarker as a predictive tool for clinical response.
* Assessment of reproducibility of the AI hypoperfusion (biomarker) at an individual level and thereby its potential as a diagnostic or therapeutic biomarker.
* Collection, description and analysis of all adverse events and required information for the implementation of future phase II and III studies
Methodological approach:
The present study will be conducted at the "non-invasive neurostimulation center of Strasburg" (Centre de Neuromodulation Non-invasive de Strasbourg ; CEMNIS) in collaboration with the Memory Clinic of Strasbourg (Centre Mémoire de Ressources et de Recherches ; CM2R) of the University Hospitals of Strasbourg (HUS) and the ICube laboratory (Team IMIS, UMR 7357, CNRS). We propose a single-centre, two-arm, randomized, crossover, double-blind comparative study. N=40 patients will be prospectively recruited in order to create two experimental groups (arms) (Group A and Group B) in a cross-over study design, following two experimental phases (I and II). The protocol will include two rTMS conditions: (1) verum stimulation (target: insular cortex) and (2) control stimulation (target: occipital cortex). The running order for each participant will be counterbalanced: Group A will start with the verum rTMS in phase I, followed by the control rTMS in phase II. Group B will start with the control rTMS in phase I, followed by the verum rTMS in phase II. One phase of rTMS will consist of a total of ten visits. One visit will include two sessions of rTMS, summing up to a total of twenty sessions of rTMS for each patient. Participants will undergo multiple EEG recordings and multimodal cerebral MRI scans, as well as several different clinical assessments (self-reported, reported by the investigator and the patients' main caregiver) numerous times during the protocol, pre- and post-rTMS sessions. In sum, each patient will undergo five MRI scans and three clinical assessments. The clinical trial schedules a total of N=37 visits for each patient.
