Alzheimer DiseaseNEUROTWINNCT06826261
Digital Twins for Model-driven Non-invasive Electrical Brain Stimulation
A study testing transcranial alternating current stimulation in people with Alzheimer Disease, run by I.R.C.C.S. Fondazione Santa Lucia at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 50 to 85 years
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- transcranial alternating current stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteItaly
- Study dates
- 4 May 2023to 30 Jun 2025
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Home-based Transcranial Electrical Stimulation (tES) in Alzheimer's Disease
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.
Read the 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.
- Conditions
- Alzheimer Disease
- Being tested
- transcranial alternating current stimulation, sham transcranial alternating current stimulation
- Keywords
- Alzheimer Disease, tACS, brain stimulation, gamma
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
transcranial alternating current stimulationDevice
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.
sham transcranial alternating current stimulationDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Device: transcranial alternating current stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
The Clinical Dementia Rating scale (C.D.R.) sum of boxes is used to characterize six domains of cognitive and functional performance applicable to Alzheimer's disease and related dementias: Memory, Orientation, Judgment \& Problem Solving, Community Affairs, Home \& Hobbies, and Personal Care. The score range is from 0 to 18 with the higher score meaning greater disease severity.
Measured: 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
The AD Cooperative Study - Activities of Daily Living (ADCS-ADL) includes 23 items that were derived from a larger set of items describing the performance of activities of daily living. The score range is from 0 to 78 with a lower score indicating more severe functional impairment.
Measured: 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
The Mini-Mental State Examination (MMSE) is a brief, widely used valid, and reliable assessment of cognitive impairment. This 30-point questionnaire is used to screen and estimate the severity of cognitive impairment in addition to being used to follow the course of cognitive change over time. The test assesses orientation, attention and calculation, recall, language, repetition, and ability to follow complex commands. The score range is from 0 to 30, with lower score meaning greater cognitive impairment.
Measured: 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
The Frontal Assessment Battery (F.A.B.) is a brief battery of six neuropsychological tasks designed to assess frontal lobe function at the bedside. The six FAB tasks explore cognitive and behavioral domains that are thought to be under the control of the frontal lobes, most notably conceptualization, and abstract reasoning, lexical verbal fluency and mental flexibility, motor programming and executive control of action, self-regulation, and resistance to interference, inhibitory control, and environmental autonomy. The range score is from 0 to 18 with the higher score meaning less frontal cognitive impairment.
Measured: 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
The Neuropsychiatric Inventory assesses behavioral disturbances in dementia. The NPI is a reliable and valid test measuring the following behavioral areas: delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, night time behaviors, and eating disorders. The score range is from 0 to 144 with the higher score meaning more severe behavioural disturbances.
Measured: 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
The Quality of Life Enjoyment and Satisfaction Questionnaire Short Form is a 16-item, self-report questionnaire that evaluates quality of life and satisfaction in several domains. The first 14 items assess satisfaction with (1) physical health, (2) mood, (3) work, (4) household activities, (5) social relationships, (6) family relationships, (7) leisure activities, (8) daily functioning, (9) sexual life, (10) economic status, (11) living/housing situation, (12) ability to get around physically, (13) vision, and (14) overall well-being. The last two items measure medications, and overall satisfaction and contentment. The items are scored on a 5-point Likert scale from 1 (not at all or never) to 5 (frequently or all the time), with higher scores indicating better enjoyment and satisfaction with life. The total score of the questionnaire is the sum of these 14 items ranging from 14 to 70. Higher scores mean better enjoyment and satisfaction with life.
Measured: 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
The apathy motivation index is a 18-item self-report questionnaire that assesses apathy in terms of Behavioral Activation (tendency to self-initiate goal-directed behavior), Social Motivation (level of engagement in social interactions) and Emotional Sensitivity (affective responses) using a 5-point Likert scale. Item scores are averaged to yield scores for subscales and a total score with higher scores indicating greater apathy (range 0-4).
Measured: From date of randomization until the date of last documented progression, assessed up to 8 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2025
- Study start4 May 2023
- Primary completion30 Jun 2025 (estimated)
- Study completion30 Jun 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- I.R.C.C.S. Fondazione Santa Lucia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Giacomo Koch, I.R.C.C.S. Fondazione Santa Lucia
- Investigators
- Sonia Bonni, PhD, Study chair, I.R.C.C.S. Fondazione Santa LuciaMartina Assogna, MD, Study director, I.R.C.C.S. Fondazione Santa Lucia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06826261
- Sponsor's protocol ID
- 101017716
- Acronym
- NEUROTWIN
- Status last verified
- Feb 2025
- First submitted
- 9 Jan 2025
- Last updated
- 13 Feb 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: This study is part of the 'Horizon 2020' project and all data will be made publicly available in a digital database at the conclusion of the study.
Publications
Dhaynaut M, Sprugnoli G, Cappon D, Macone J, Sanchez JS, Normandin MD, Guehl NJ, Koch G, Paciorek R, Connor A, Press D, Johnson K, Pascual-Leone A, El Fakhri G, Santarnecchi E. Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series. J Alzheimers Dis. 2022;85(4):1667-1676. doi: 10.3233/JAD-215072.
PubMed 34958021Thickbroom GW. Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res. 2007 Jul;180(4):583-93. doi: 10.1007/s00221-007-0991-3. Epub 2007 Jun 12.
PubMed 17562028Tadini L, El-Nazer R, Brunoni AR, Williams J, Carvas M, Boggio P, Priori A, Pascual-Leone A, Fregni F. Cognitive, mood, and electroencephalographic effects of noninvasive cortical stimulation with weak electrical currents. J ECT. 2011 Jun;27(2):134-40. doi: 10.1097/YCT.0b013e3181e631a8.
PubMed 20938352Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, El Fakhri G, Salvador R, Ruffini G, Donohoe K, Shafi MM, Press D, Alsop DC, Pascual Leone A, Santarnecchi E. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease. Alzheimers Res Ther. 2021 Dec 20;13(1):203. doi: 10.1186/s13195-021-00922-4.
PubMed 34930421Ruffini G, Fox MD, Ripolles O, Miranda PC, Pascual-Leone A. Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields. Neuroimage. 2014 Apr 1;89:216-25. doi: 10.1016/j.neuroimage.2013.12.002. Epub 2013 Dec 15.
PubMed 24345389Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull. 2007 May 30;72(4-6):208-14. doi: 10.1016/j.brainresbull.2007.01.004. Epub 2007 Jan 24.
PubMed 17452283Palm U, Kumpf U, Behler N, Wulf L, Kirsch B, Worsching J, Keeser D, Hasan A, Padberg F. Home Use, Remotely Supervised, and Remotely Controlled Transcranial Direct Current Stimulation: A Systematic Review of the Available Evidence. Neuromodulation. 2018 Jun;21(4):323-333. doi: 10.1111/ner.12686. Epub 2017 Sep 15.
PubMed 28913915Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clin Neurophysiol. 2003 Nov;114(11):2220-2; author reply 2222-3. doi: 10.1016/s1388-2457(03)00235-9. No abstract available.
PubMed 14580622Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21.
PubMed 9236948Miranda PC, Mekonnen A, Salvador R, Ruffini G. The electric field in the cortex during transcranial current stimulation. Neuroimage. 2013 Apr 15;70:48-58. doi: 10.1016/j.neuroimage.2012.12.034. Epub 2012 Dec 27.
PubMed 23274187Magni E, Binetti G, Bianchetti A, Rozzini R, Trabucchi M. Mini-Mental State Examination: a normative study in Italian elderly population. Eur J Neurol. 1996 May;3(3):198-202. doi: 10.1111/j.1468-1331.1996.tb00423.x.
PubMed 21284770Koch G, Di Lorenzo F, Bonni S, Ponzo V, Caltagirone C, Martorana A. Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients. J Alzheimers Dis. 2012;31(3):593-9. doi: 10.3233/JAD-2012-120532.
PubMed 22647254Galasko D, Schmitt F, Thomas R, Jin S, Bennett D; Alzheimer's Disease Cooperative Study. Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease. J Int Neuropsychol Soc. 2005 Jul;11(4):446-53. doi: 10.1017/s1355617705050502.
PubMed 16209425Chiaravalloti A, Koch G, Toniolo S, Belli L, Lorenzo FD, Gaudenzi S, Schillaci O, Bozzali M, Sancesario G, Martorana A. Comparison between Early-Onset and Late-Onset Alzheimer's Disease Patients with Amnestic Presentation: CSF and (18)F-FDG PET Study. Dement Geriatr Cogn Dis Extra. 2016 Apr 5;6(1):108-19. doi: 10.1159/000441776. eCollection 2016 Jan-Apr.
PubMed 27195000Chiaravalloti A, Martorana A, Koch G, Toniolo S, di Biagio D, di Pietro B, Schillaci O. Functional correlates of t-Tau, p-Tau and Abeta(1)(-)(4)(2) amyloid cerebrospinal fluid levels in Alzheimer's disease: a (1)(8)F-FDG PET/CT study. Nucl Med Commun. 2015 May;36(5):461-8. doi: 10.1097/MNM.0000000000000272.
PubMed 25646706
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Home-based Transcranial Electrical Stimulation (tES) in Alzheimer's Disease
- ClinicalTrials.gov ID
- NCT06826261
- Acronym / sponsor ID
- NEUROTWIN / 101017716
- Conditions
- Alzheimer Disease
- Keywords
- Alzheimer Disease, tACS, brain stimulation, gamma
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- I.R.C.C.S. Fondazione Santa LuciaUniversity, hospital or other
- Study start
- 4 May 2023 (actual)
- Primary completion
- 30 Jun 2025 (estimated)
- Study completion
- 30 Jun 2025 (estimated)
- First posted
- 13 Feb 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| SHAM-tACS | Sham comparator | Device: sham transcranial alternating current stimulationThe 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. |
| REAL-tACS | Experimental | Device: transcranial alternating current stimulationThe 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. |
Who may qualify
- Ages
- 50 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (9 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| transcranial alternating current stimulationThe 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. | Device | REAL-tACS |
| sham transcranial alternating current stimulationThe 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. | Device | SHAM-tACS |
Primary outcome
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.
7 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: From date of randomization until the date of last documented progression, assessed up to 8 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2025.
- Background: PubMed 34958021Dhaynaut M, Sprugnoli G, Cappon D, Macone J, Sanchez JS, Normandin MD, Guehl NJ, Koch G, Paciorek R, Connor A, Press D, Johnson K, Pascual-Leone A, El Fakhri G, Santarnecchi E. Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series. J Alzheimers Dis. 2022;85(4):1667-1676. doi: 10.3233/JAD-215072.
- Background: PubMed 17562028Thickbroom GW. Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res. 2007 Jul;180(4):583-93. doi: 10.1007/s00221-007-0991-3. Epub 2007 Jun 12.
- Background: PubMed 20938352Tadini L, El-Nazer R, Brunoni AR, Williams J, Carvas M, Boggio P, Priori A, Pascual-Leone A, Fregni F. Cognitive, mood, and electroencephalographic effects of noninvasive cortical stimulation with weak electrical currents. J ECT. 2011 Jun;27(2):134-40. doi: 10.1097/YCT.0b013e3181e631a8.
- Background: PubMed 34930421Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, El Fakhri G, Salvador R, Ruffini G, Donohoe K, Shafi MM, Press D, Alsop DC, Pascual Leone A, Santarnecchi E. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease. Alzheimers Res Ther. 2021 Dec 20;13(1):203. doi: 10.1186/s13195-021-00922-4.
- Background: PubMed 24345389Ruffini G, Fox MD, Ripolles O, Miranda PC, Pascual-Leone A. Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields. Neuroimage. 2014 Apr 1;89:216-25. doi: 10.1016/j.neuroimage.2013.12.002. Epub 2013 Dec 15.
- Background: PubMed 17452283Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull. 2007 May 30;72(4-6):208-14. doi: 10.1016/j.brainresbull.2007.01.004. Epub 2007 Jan 24.
- Background: PubMed 28913915Palm U, Kumpf U, Behler N, Wulf L, Kirsch B, Worsching J, Keeser D, Hasan A, Padberg F. Home Use, Remotely Supervised, and Remotely Controlled Transcranial Direct Current Stimulation: A Systematic Review of the Available Evidence. Neuromodulation. 2018 Jun;21(4):323-333. doi: 10.1111/ner.12686. Epub 2017 Sep 15.
- Background: PubMed 14580622Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clin Neurophysiol. 2003 Nov;114(11):2220-2; author reply 2222-3. doi: 10.1016/s1388-2457(03)00235-9. No abstract available.
- Background: PubMed 9236948Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21.
- Background: PubMed 23274187Miranda PC, Mekonnen A, Salvador R, Ruffini G. The electric field in the cortex during transcranial current stimulation. Neuroimage. 2013 Apr 15;70:48-58. doi: 10.1016/j.neuroimage.2012.12.034. Epub 2012 Dec 27.
- Background: PubMed 21284770Magni E, Binetti G, Bianchetti A, Rozzini R, Trabucchi M. Mini-Mental State Examination: a normative study in Italian elderly population. Eur J Neurol. 1996 May;3(3):198-202. doi: 10.1111/j.1468-1331.1996.tb00423.x.
- Background: PubMed 22647254Koch G, Di Lorenzo F, Bonni S, Ponzo V, Caltagirone C, Martorana A. Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients. J Alzheimers Dis. 2012;31(3):593-9. doi: 10.3233/JAD-2012-120532.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. This study is part of the 'Horizon 2020' project and all data will be made publicly available in a digital database at the conclusion of the study.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sonia Bonni, PhD study chair
I.R.C.C.S. Fondazione Santa Lucia
Martina Assogna, MD study director
I.R.C.C.S. Fondazione Santa Lucia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing transcranial alternating current stimulation in people with Alzheimer Disease, run by I.R.C.C.S. Fondazione Santa Lucia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 13 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06826261, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2025.