Digital Twins for Model-driven Non-invasive Electrical Brain Stimulation

NCT06826261 | Active Not Recruiting

• 1 other identifier: 101017716
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer Disease

Keywords

Alzheimer Disease; tACS; brain stimulation; gamma

Outcome Measures

Primary Outcomes (2)

• Number of Participants with Treatment-Related Adverse Events and missed stimulation session

  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.

  From date of randomization until the date of last documented progression, assessed up to 8 months

• 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

  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.

  From date of randomization until the date of last documented progression, assessed up to 8 months

Secondary Outcomes (7)

• 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

Other Outcomes (6)

• 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

  From date of randomization until the date of last documented progression, assessed up to 8 months

• Measurement of change from baseline in the short afferent inhibition (SAI) 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 Repetitive TMS indexing long term potentiation (LTP) 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

Study Arms (2)

SHAM-tACS

SHAM COMPARATOR

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.

Device: sham transcranial alternating current stimulation

REAL-tACS

EXPERIMENTAL

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.

Device: transcranial alternating current stimulation

Interventions

transcranial alternating current stimulation DEVICE

The intervention employs transcranial alternating current stimulation (tACS), a non-invasive brain stimulation technique designed to modulate neural oscillations in targeted brain regions. tACS operates by applying low-intensity, alternating electrical currents through electrodes placed on the scalp, synchronizing with the brain's natural frequency patterns. In this arm, a frequency of 40 Hz (gamma frequency) is used to enhance oscillatory activity related to cognitive functions often impaired in Alzheimer's disease (AD). The Neuroelectrics Starstim-home device will be used. This compact, portable device allows for easy use within the home setting, reducing the need for daily clinic visits. Designated caregivers will administer the one-hour tACS sessions under remote supervision via a digital monitoring portal, which tracks adherence, technical performance, and safety data in real time.

REAL-tACS

sham transcranial alternating current stimulation DEVICE

The intervention employs transcranial alternating current stimulation (tACS), a non-invasive brain stimulation technique designed to modulate neural oscillations in targeted brain regions. tACS operates by applying low-intensity, alternating electrical currents through electrodes placed on the scalp, synchronizing with the brain's natural frequency patterns. In this arm, the stimulation will be delivered in 'sham' mode 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 delivered. The Neuroelectrics Starstim-home device will be used. This compact, portable device allows for easy use within the home setting, reducing the need for daily clinic visits. Designated caregivers will administer the sham tACS sessions under remote supervision via a digital monitoring portal, which tracks adherence, technical performance, and safety data in real time.

SHAM-tACS

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• I.R.C.C.S. Fondazione Santa Lucia: lead

Study Sites (1)

Irccs Santa Lucia Foundation

Rome, ROME, 00179, Italy

Location

Related Publications (22)

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Related Links

• Related Info

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Transcranial Direct Current Stimulation

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques

Study Officials

• Sonia Bonni, PhD

  I.R.C.C.S. Fondazione Santa Lucia

  STUDY CHAIR

• Martina Assogna, MD

  I.R.C.C.S. Fondazione Santa Lucia

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof

Study Record Dates

• First Submitted: January 9, 2025
• First Posted: February 13, 2025
• Study Start: May 4, 2023
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: February 13, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: 30/06/2025
• Access Criteria: The IPD supporting information will be made available upon request and accessed using a password.

Locations

IT (1)