The NEUROTWIN project is grounded in the hypothesis that brain oscillations, particularly in the gamma band (40 Hz), play a central role in cognitive processes, and their disruption is associated with the cognitive decline seen in Alzheimer's disease (AD). Gamma oscillations are generated by excitatory-inhibitory neural circuits that include GABAergic interneurons, which are often impaired in patients with AD. This deficit is linked to reduced synchronization of gamma oscillations, which are essential for cognitive functions such as memory and attention.
Recent studies have shown that inducing gamma oscillations can reduce levels of amyloid-beta (Aβ) and phosphorylated tau (p-tau)-key pathological markers of AD-in animal models of the disease. These findings suggest that stimulating gamma oscillations through non-invasive methods may have a positive impact on specific brain functions affected by AD. Transcranial electrical stimulation (tES), including transcranial alternating current stimulation (tACS), can modulate these gamma oscillations in a safe, non-invasive manner.
The rationale for targeting gamma oscillations with tACS in Alzheimer's therapy is supported by:
* Preclinical and clinical evidence: Studies in murine AD models have demonstrated a significant reduction in amyloid plaques and p-tau levels in mice exposed to gamma stimulation (40 Hz), along with cognitive improvements.
* Previous clinical experiments: The use of 40 Hz tACS has enhanced episodic memory and cerebral perfusion in small cohorts of human patients with AD. These preliminary results indicate that gamma stimulation may represent a promising therapeutic approach for modulating cognitive function in AD patients.
* Impact of neural dysfunction in AD: Dysfunction in neural circuits, especially involving inhibitory interneuron control, can lead to an excitatory-inhibitory imbalance, resulting in cognitive impairments. Stimulating gamma oscillations may improve the function of altered neural circuits, contributing to cognitive stabilization.
However, a significant constraint of many Non-invasive brain stimulation protocols is their reliance on multiple sessions to achieve enduring effects. These sessions are typically conducted in clinical settings, necessitating patient travel. This obstacle hampers the delivery of extended interventions, particularly for individuals with neurodegenerative conditions. We thus adopt a home-based approach using tACS because of its ability to entrain gamma oscillations, commonly impaired in AD, and its low cost and potential for home-based application. in particular, the Starstim-home device has been developed for home use with remote supervision, making gamma stimulation accessible and scalable for patients. A home-based protocol allows for a higher treatment frequency (5 times a week for 8 weeks per arm), reducing costs and increasing convenience for patients and caregivers.
In this study, participants will use the Starstim-home device for one-hour tACS sessions (real or sham), targeting the fronto-temporal cortex. These electrode positions were obtained from a group montage optimization using the Stimweaver algorithm performed on a database of biophysical head models of patients with AD, i.e. volume conductor models built from structural head T1w-MRIs that model the passive electrical properties of the primary head tissues.
The device will be configured to administer personalized and model-optimized gamma-frequency tES, always assuming a 180° phase-shift between the currents in the electrodes in the opposite hemispheres. This is done using a linear model that predicts the currents based on morphometric characteristics of the patient's scalp, namely the head perimeter along axial, sagittal, and coronal planes. The current intensity will be ramped up over the first 30 seconds, then sustained at the stimulation intensity for 60 minutes, then ramped down over the final 30 seconds for the Real condition. The Sham condition will rely on the classical 30-second ramp-up/ramp-down protocol.
The subject will receive a pre-configured Starstim Home Kit, including the device, tablet, all needed supplies, and training materials. The Starstim Home Kit tablet contains a sequence of simplified instructions and step-by-step touchscreen prompts for the participant/administrator to follow. This process has been designed to be easy to use, even for individuals who are not computer savvy.
The first two daily visits will be performed at the memory clinic. During the first daily visit, the study staff will lead a training session while the home-based administrator observes. The study staff will review the step-by-step process, the accompanying training manual, and the photos depicting each step. During the second daily visit, the administrator will then practice setting up the tES session on the participant with oversight and coaching from the study staff. The administrator will also be trained to take care of the devices. Then, caregivers or designated administrators will oversee the sessions at home, ensuring device use and protocol adherence under remote supervision by clinical staff.
In this randomized, double-blind, sham-controlled, crossover pilot study, the participants will receive both active and sham tES conditions, each lasting 8 weeks, with a washout period of two months in between. tES sessions will be held daily, 5 days a week, for a total of 40 sessions per condition. Neuroimaging, neurophysiological, and cognitive assessments will occur at multiple points before, after, and in a follow-up period of two months for each treatment condition.
