Clinical trial NCT06826261: Digital Twins for Model-driven Non-invasive Electrical Brain Stimulation
Official title: Home-based Transcranial Electrical Stimulation (tES) in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Alzheimer Disease
Keywords: Alzheimer Disease
tACS
brain stimulation
gamma
Lead sponsor: I.R.C.C.S. Fondazione Santa Lucia
Sponsor class: OTHER
First posted: 2025-02-13
Enrollment: 30
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to obtain preliminary data in advance of a larger clinical trial designed to test whether repeated, daily sessions of at-home transcranial alternating current stimulation (tACS) can lead to a clinically significant improvement in patients with AD.

Given the potentially fragile patient population, the investigators propose a pilot study to test feasibility and safety (primary). In this pilot study 30 mild-to-moderate AD patients will be enrolled. The intervention will consist of daily model-optimized and individualized tES delivered for 8 weeks, 5 days per week (40 sessions). tACS will be applied daily for 1 hour and will be paired with extensive neuroimaging, neurophysiological and neuropsychological evaluation at several time points (pre and post treatment) to better characterize patients and their response to treatment. The physiological target of treatment will be to increase gamma activity in the pre-frontal cortex, as this has been associated with cognitive decline in AD, and prior tES work targeting PFC gamma oscillations has shown promising results.

The investigators hypothesize that active tACS treatment will result in a comparatively slower progression of cognitive decline and loss of gamma power as compared to sham treatment. To assess this, in this pilot study, a cross-over design will be used. Treatment will be multisession since prior tES work indicates a cumulative effect of each session with stronger therapeutic effects, in line with the underlying Hebbian mechanisms putatively involved in non-invasive brain stimulation.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* aged between 50 and 85.
* Clinical Dementia Rating score (CDR) of 0.5-1.
* Mini-Mental State Examination (MMSE) score of 18-26.
* treated with acetylcholinesterase inhibitor for at least one month.
* evidence of low β-amyloid and/or elevated phosphorylated Tau protein as detected by lumbar puncture for cerebrospinal fluid biomarkers analysis for diagnostic purposes or PET.
* have a Caregiver
* have access to wireless internet (wifi) connection in the location where study treatments will be applied

Exclusion Criteria:

* significant neurodegenerative disorder of the central nervous system other than AD.
* significant intracranial focal or vascular pathology verified by an MRI scan.
* history of seizures (except febrile seizures in childhood).
* Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR) criteria met for any of the following (within the specified period): Major depressive disorder (current), Schizophrenia (lifetime), Other psychotic disorders, bipolar disorder, or substance (including alcohol) related disorders (within the past 5 years).
* contraindications to MRI (this includes metal implants in the head, pacemaker, cochlear implants, or any other non-removable items if they are contraindications to MR imaging).
* treatment currently or within 3 months before Baseline with any of the following medications: typical and atypical antipsychotics (i.e., Clozapine, Olanzapine); antiepileptics drugs (i.e., Carbamazepine, Primidone, Pregabalin, Gabapentin).
* skin lesions on the scalp at the proposed electrode sites.
* previous surgeries opening the skull leaving skull defects capable of allowing the insertion of a cylinder with a radius greater or equal to 5 mm.
* any condition that makes the study subject, in the opinion of the investigator, unsuitable for the study.

Primary outcomes:
measure: Number of Participants with Treatment-Related Adverse Events and missed stimulation session
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) 14 immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
Secondary outcomes:
measure: Measurement of change from baseline in the Clinical Dementia Rating scale (C.D.R.) sum of boxes immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the AD Cooperative Study - Activities of Daily Living (ADCS-ADL) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Mini-Mental State Examination (MMSE) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Frontal Assessment Battery (F.A.B.) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Neuropsychiatric Inventory (NPI) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Apathy Motivation Index immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
Other outcomes:
measure: Measurement of change from baseline in the Resting-state EEG activity in specific frequency band of relevance for AD immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the short afferent inhibition (SAI) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Repetitive TMS indexing long term potentiation (LTP) immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the transcranial evoked potentials (TEPs) and oscillatory activity over the fronto-temporal cortices immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the functional and structural connectivity immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
measure: Measurement of change from baseline in the Blood biomarkers immediately after the intervention and at a two-month follow-up
timeFrame: From date of randomization until the date of last documented progression, assessed up to 8 months
Locations:
city: Rome
country: Italy
facility: Irccs Santa Lucia Foundation
Study officials:
affiliation: I.R.C.C.S. Fondazione Santa Lucia
name: Sonia Bonni, PhD
role: STUDY_CHAIR
affiliation: I.R.C.C.S. Fondazione Santa Lucia
name: Martina Assogna, MD
role: STUDY_DIRECTOR
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