Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the DMN in Mild AD Patients

NCT07075770 | Recruiting DMC

• 1 other identifier: PNRR-MCNT2-2023-12377518
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

Alzheimer's disease (AD) is increasingly recognized as a disorder marked by early synaptic dysfunction and disrupted brain network connectivity, beyond the traditional focus on amyloid pathology. Synaptic plasticity (crucial for learning and memory) is compromised in AD and represents a promising therapeutic target. In particular, alterations in the Default Mode Network (DMN), especially in regions like the precuneus, suggest that restoring connectivity and enhancing plasticity may improve cognitive outcomes. This project proposes a novel, precision-delivered non-invasive brain stimulation protocol that combines repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) over the DMN. The intervention will be evaluated through cognitive testing, blood-based biomarkers, MRI and TMS-EEG, alongside immersive virtual environments to assess sensorimotor and cognitive function. This approach aims to test neuromodulation strategies capable of slowing neurodegeneration and supporting early detection and rehabilitation in AD.

Conditions

Alzheimer Disease

Keywords

Non Invasive Brain Stimulation; Transcranial Magnetic Stimulation; Intermittent Theta Burst Stimulation; Transcranial Electrical Stimulation; Transcranial Alternating Current Stimulation; Default Mode Network

Outcome Measures

Primary Outcomes (1)

• integrated Alzheimer Disease Rating Scale (iADRS)

  The iADRS is an integrated assessment of cognition and daily function from the 13-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog13) and Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL), measuring global disease severity across the Alzheimer disease continuum as a single summary score. The iADRS is validated and captures clinical progression from MCI due to Alzheimer disease through moderate dementia due to Alzheimer disease, and treatment effects have been demonstrated across MCI and Alzheimer disease with mild dementia. The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment).

  Change from baseline to the end of treatment at week 24.

Secondary Outcomes (10)

• Change in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score.

  Change from baseline to the end of treatment at week 24.

• Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).

  Change from baseline to week 24.

• Change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SoB) score.

  Change from baseline to the end of treatment at week 24.

• Change in the Alzheimer Disease Assessment Cognitive Scale (ADAS-Cog13) score.

  Change from baseline to the end of treatment at week 24.

• Change in the Neuropsychiatric Personal Inventory (NPI) score.

  Change from baseline to the end of treatment at week 24.

Other Outcomes (5)

• Change in cortical activity

  Change from baseline to the end of treatment at week 24.

• Change in the cortical connectivity

  Change from baseline to the end of treatment at week 24.

• Change in Virtual Reality task performance.

  Change from baseline to the end of treatment at week 24.

Study Arms (3)

combined iTBS-tACS

EXPERIMENTAL

32 sessions of combined iTBS-tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)

Device: Combined iTBS-tACS

iTBS-sham tACS

ACTIVE COMPARATOR

32 sessions of combined iTBS-sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)

Device: iTBS-sham tACS

sham iTBS- sham tACS

PLACEBO COMPARATOR

32 sessions of sham iTBS- sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)

Device: sham iTBS- sham tACS

Interventions

Combined iTBS-tACS DEVICE

The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. iTBS and tACS will be synchronized using a BrainTrigger and SIGNAL Software so that both stimulations will start simultaneously

combined iTBS-tACS

iTBS-sham tACS DEVICE

The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. For the tACS sham condition, the electric current will not be applied, but there will be a 2 s 1 mA ramp up and 2 s 1 mA ramp down, to give the participant real stimulation feelings.

iTBS-sham tACS

sham iTBS- sham tACS DEVICE

The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. For the iTBS sham condition, stimulation was delivered with the coil angled at 90°, with only the edge of the coil resting on the scalp.. For the tACS sham condition, the electric current will not be applied, but there will be a 2 s 1 mA ramp up and 2 s 1 mA ramp down, to give the participant real stimulation feelings.

sham iTBS- 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:

• Patients with a diagnosis of AD according to IWG criteria
• \> MMSE \< 28
• Patients with CSF specific biomarker profile or with a positive Amyloid Pet Scan consistent with the presence of amyloid pathology
• Global Clinical Dementia Rating (CDR) ≤1
• Previous decline in cognition for more than six months as documented in patient medical records
• A caregiver available and living in the same household or interacting with the patient and available
• Patients living at home or nursing home setting without continuous nursing care
• General health status acceptable for a participation in a 6-month clinical trial
• Stable pharmacological treatment for at least one month prior to screening
• No regular intake of prohibited medications.
• Signed informed consent by the patient. If there are any doubts that the patient is mentally capable of giving informed consent, the patient will be examined and verified to be mentally capable by an independent physician/ neurologist, prior to the initiation of any study specific procedure. Signed consent of the caregiver

You may not qualify if:

• Failure to undergo screening or baseline exams
• Hospitalization or change in chronic concomitant medications one month before the screening or during the screening period
• Clinical, laboratory, or neuroimaging results consistent with:
• other primary degenerative dementia (Lewy body dementia, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, etc.);
• other neurodegenerative conditions (Parkinson's disease, amyotrophic lateral sclerosis, etc.);
• orthostatic hypotension and autonomic disorders
• cerebrovascular disease (major infarction, a strategic infarction or multiple lacunar infarctions, extensive white matter lesions \> one quarter of total white matter);
• other central nervous system diseases (severe traumatic brain injury, tumors, subdural hematoma, or other space-occupying processes, etc.);
• seizure disorder.
• Other infectious, metabolic, or systemic diseases affecting the central nervous system (syphilis, existing hypothyroidism, current vitamin B12 or folate deficiency, serum electrolytes outside normal limits, juvenile diabetes, etc.).
• A current DSM-V diagnosis of major depression, schizophrenia, or bipolar disorder.
• Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable assessments and may affect the assessment of the patient's clinical or mental state, or expose the patient to special risk, such as:
• Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulties, etc.);
• Opioid-containing analgesics
• Suspected or known drug or alcohol abuse, i.e., more than about 60 g of alcohol (about 1 liter of beer or 500 ml of wine) per day, indicated by a high mean corpuscular volume (MCV) above the normal value at screening;

Sponsors & Collaborators

• IRCCS Centro Neurolesi Bonino Pulejo: collaborator
• I.R.C.C.S. Fondazione Santa Lucia: lead

Study Sites (2)

IRCCS Santa Lucia Foundation

Rome, Italy, 00179, Italy

RECRUITING

I.R.C.C.S. Centro Neurolesi Bonino Pulejo

Messina, Sicily, 98124, Italy

NOT YET RECRUITING

Related Publications (7)

• Chou HY, Chen SC, Yen TH, Han HM. Effect of a Virtual Reality-Based Exercise Program on Fatigue in Hospitalized Taiwanese End-Stage Renal Disease Patients Undergoing Hemodialysis. Clin Nurs Res. 2020 Jul;29(6):368-374. doi: 10.1177/1054773818788511. Epub 2018 Jul 15.

  PMID: 30009636 BACKGROUND

• Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. 2018 Dec;284(6):643-663. doi: 10.1111/joim.12816. Epub 2018 Aug 19.

  PMID: 30051512 BACKGROUND

• Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage. 2012 Oct 1;62(4):2232-43. doi: 10.1016/j.neuroimage.2012.03.035. Epub 2012 Mar 19.

  PMID: 22465297 BACKGROUND

• Gili T, Cercignani M, Serra L, Perri R, Giove F, Maraviglia B, Caltagirone C, Bozzali M. Regional brain atrophy and functional disconnection across Alzheimer's disease evolution. J Neurol Neurosurg Psychiatry. 2011 Jan;82(1):58-66. doi: 10.1136/jnnp.2009.199935. Epub 2010 Jul 16.

  PMID: 20639384 BACKGROUND

• Koch G, Casula EP, Bonni S, Borghi I, Assogna M, Minei M, Pellicciari MC, Motta C, D'Acunto A, Porrazzini F, Maiella M, Ferrari C, Caltagirone C, Santarnecchi E, Bozzali M, Martorana A. Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial. Brain. 2022 Nov 21;145(11):3776-3786. doi: 10.1093/brain/awac285.

  PMID: 36281767 BACKGROUND

• Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.

  PMID: 29277405 BACKGROUND

• Hu Y, Kirmess KM, Meyer MR, Rabinovici GD, Gatsonis C, Siegel BA, Whitmer RA, Apgar C, Hanna L, Kanekiyo M, Kaplow J, Koyama A, Verbel D, Holubasch MS, Knapik SS, Connor J, Contois JH, Jackson EN, Harpstrite SE, Bateman RJ, Holtzman DM, Verghese PB, Fogelman I, Braunstein JB, Yarasheski KE, West T. Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment. JAMA Netw Open. 2022 Apr 1;5(4):e228392. doi: 10.1001/jamanetworkopen.2022.8392.

  PMID: 35446396 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

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

Study Officials

• Giacomo Koch, Prof.

  IRCCS Santa Lucia Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giacomo Koch, Prof

CONTACT

+390651501181; g.koch@hsantlucia.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Four-blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Three arms randomized sham-controlled trial

Study Record Dates

• First Submitted: July 10, 2025
• First Posted: July 20, 2025
• Study Start: January 1, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: January 13, 2026

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)