Home-based Transcranial Electrical Stimulation (tES) in Alzheimer's Disease
Trial Snapshot
- Phase
- Not Applicable
- Status
- Active, not recruiting
- Sponsor
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Number of Participants with Treatment-Related Adverse Events and missed stimulation session
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 50 Years to 85 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •aged between 50 and
- •Clinical Dementia Rating score (CDR) of 0.5-
- •Mini-Mental State Examination (MMSE) score of 18-
- •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.
Arms & Interventions
SHAM-tACS
The Sham condition will rely on the classical ramp up/ramp down protocol, which is characterized by 30 seconds of tACS stimulation at the beginning and end of the protocol to help with blinding. During the rest of the stimulation period (1h) no stimulation will be derivered.
Intervention: sham transcranial alternating current stimulation (Device)
REAL-tACS
The intervention will consist of daily model-optimized and individualized 40Hz-tACS delivered on the dorsolateral prefrontal and temporal cortex bilaterally. 40Hz-tACS will be applied daily for 1 hour, with a ramp up/down of 30 seconds.
Intervention: transcranial alternating current stimulation (Device)
Outcomes
Primary Outcomes
Number of Participants with Treatment-Related Adverse Events and missed stimulation session
Time Frame: From date of randomization until the date of last documented progression, assessed up to 8 months
The investigators will collect data about electrode impedance, tACS progression, and session interruptions or terminations, whether voluntary or due to technical issues. These metrics, including the number of missed sessions, will aid in the assessment of feasibility. At the same time, any adverse events will be documented and used as the primary safety endpoint.
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
Time Frame: From date of randomization until the date of last documented progression, assessed up to 8 months
The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) 14 is a standardized neuropsychological assessment used to measure the severity of symptoms of Alzheimer's Disease in different domains. The tasks assess the domains of language, praxis, memory, attention, visuospatial and executive function. The tasks include: word recall task, naming objects and fingers, commands, constructional praxis, ideational praxis, orientation, word recognition task, comprehension of spoken language, word finding difficulty, remembering test instructions, executive function, and number cancellation. The score range is from 0 to 70 with a lower score indicating more severe functional impairment.
Secondary Outcomes
- 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(From date of randomization until the date of last documented progression, assessed up to 8 months)
- 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(From date of randomization until the date of last documented progression, assessed up to 8 months)
- Measurement of change from baseline in the Mini-Mental State Examination (MMSE) immediately after the intervention and at a two-month follow-up(From date of randomization until the date of last documented progression, assessed up to 8 months)
- Measurement of change from baseline in the Frontal Assessment Battery (F.A.B.) immediately after the intervention and at a two-month follow-up(From date of randomization until the date of last documented progression, assessed up to 8 months)
- Measurement of change from baseline in the Neuropsychiatric Inventory (NPI) immediately after the intervention and at a two-month follow-up(From date of randomization until the date of last documented progression, assessed up to 8 months)
- 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(From date of randomization until the date of last documented progression, assessed up to 8 months)
- Measurement of change from baseline in the Apathy Motivation Index immediately after the intervention and at a two-month follow-up(From date of randomization until the date of last documented progression, assessed up to 8 months)
Investigators
Giacomo Koch
Prof
I.R.C.C.S. Fondazione Santa Lucia