Transcranial Alternating Current Stimulation in Frontotemporal Dementia (BetaTACSFTD)

Cross-over Study to Evaluate the Safety, Tolerability, and Clinical Efficacy of Transcranial Alternating Current Stimulation (tACS) in Patients With Frontotemporal Dementia

The aim of the study is to evaluate the safety, feasibility, clinical and biological efficacy, and predictors of efficacy of an intervention consisting of transcranial alternating current stimulation (tACS) in patients with Frontotemporal Dementia (FTD).

In addition to typical symptoms, FTD also present alterations in brain oscillations. In animal models of neurodegeneration, restoration of oscillations via neuronal "entrainment" phenomena has demonstrated a significant reduction in toxic protein accumulation, resulting in improved cognitive function.

tACS is a neurophysiological noninvasive method of neuromodulation increasingly studied for its therapeutic potential. It has been shown to safely modulate the oscillatory frequencies underlying multiple cognitive functions, including verbal memory, perception, and working memory.

In light of this evidence, it is proposed to apply a single-session treatment of β-tACS stimulation in patients with FTD and to evaluate its clinical effects, oscillatory modifications by EEG, and changes in neurophysiological indices such as short intracortical inhibition (SICI) and intracortical facilitation (ICF), both compromised in the disease.

The study has a cross-over design (multicenter, randomized, placebo-controlled and double-blind), with FTD patients randomly assigned to one of the two arms: i) Group 1, who will receive a real tACS session first (1h); ii) Group 2, who will instead undergo a sham tACS session (1h). In the next phase (cross-over), one week after the first phase, the groups will reverse the treatment: Group 1 will receive tACS sham and Group 2 will receive real tACS.

The main objectives of the study are: [1] to evaluate the safety and tolerability of the single tACS treatment session; [2] to investigate the effects of the protocol on (short-term) cognitive performance in patients with FTD; [3] to verify intervention-induced changes in brain synchronization; [4] to evaluate changes in neurophysiological indices following treatment; and [5] evaluate any predictors of efficacy.

Study Overview

• Status: Recruiting
• Conditions: Transcranial Alternating Current Stimulation; Frontotemporal Dementia (FTD)
• Intervention / Treatment: Device: Transcranial Alternating Current Stimulation; Device: Sham Transcranial Alternating Current Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • BS
    • Brescia, BS, Italy, 25125
      • Recruiting
      • IRCCS Istituto Centro San Giovanni Di Dio - Fatebenefratelli
      • Principal Investigator: Barbara Borroni, MD
      • Contact: Barbara Borroni, MD; Phone Number: +39 03035358; Email: bborroni@fatebenefratelli.eu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female subjects aged over 40 years at the time of signing the informed consent form;
• Presence of a clinical diagnosis of Frontotemporal Dementia according to clinical criteria (Rascovsky et al., 2011; Gorno-Tempini et al., 2011).

Exclusion Criteria:

• Age younger than that stated in the inclusion criterion;
• Inability to understand;
• Contraindications for tACS and TMS: cardiac pacemaker carriers and metal implants that are not compatible with electric or magnetic fields, history of epilepsy, current pregnancy (Safety Questionnaire)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group 1; Group 1, who will undergo real tACS treatment, in a single 60-minute session and after one week of sham tACS treatment, in a single 60-minute session.	Device: Transcranial Alternating Current Stimulation; The session will consist of the application of a session of tACS (real at 2.5 mA) at the cortical level for a duration of 60 minutes.; Device: Sham Transcranial Alternating Current Stimulation; Application of sham tACS session at the cortical level for a duration of 60 minutes. The electrode placement will be identical to that used for real stimulation. However, the electrical current will be automatically interrupted approximately 30 seconds after the start of stimulation, making it impossible for the patient to distinguish between sham and real stimulation.
Other: Group 2; Group 2, who will undergo sham tACS treatment, in a single 60-minute session and after one week of real tACS treatment, in a single 60-minute session.	Device: Transcranial Alternating Current Stimulation; The session will consist of the application of a session of tACS (real at 2.5 mA) at the cortical level for a duration of 60 minutes.; Device: Sham Transcranial Alternating Current Stimulation; Application of sham tACS session at the cortical level for a duration of 60 minutes. The electrode placement will be identical to that used for real stimulation. However, the electrical current will be automatically interrupted approximately 30 seconds after the start of stimulation, making it impossible for the patient to distinguish between sham and real stimulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Feasibility of Transcranial Alternating Current Stimulation Protocol	Safety will be assessed in terms of the frequency and severity of any adverse events, and feasibility will be assessed based on the study dropout rate. Safety and feasibility will be monitored throughout the study.	Periprocedurally, an average 1 week
Phonemic Fluency Test	Cognitive flexibility and verbal fluency will be evalueted by Phonemic Fluency Test. Subject is asked to generate as many words as possible from a given letter within a limited time (60 seconds); higher scores indicate better perfomance.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.
Semantic Fluency Test	Lexical-semantic access and executive functioning will be evalueted by Semantic Fluency Test. Subject is asked to generate as many words as possible from a given category within a limited time (60 seconds); higher scores indicate better perfomance.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.
Trail Making Test (TMT - AB)	Executive function will be assessed using the Trail Making Test, including Part A (visual attention and processing speed) and Part B (task switching and cognitive flexibility). Higher completion times reflect poorer performance.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.
Digit Span Test	Short-term memory and working memory will be assessed respectively using the Digit Span forward and Digit Span backward. Scores reflect the maximum number of digits recalled in correct order.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.
Modified Emotion Recognition Test	Emotion recognition from facial expressions will be evalueted by Modified Emotion Recognition Test. Subject is asked to choose an emotion from five options for each face showed; higher scores indicate better perfomance.	Immediately after first stimulation. Immediately after second stimulation, after a week.
Berg's Card Sorting Task	Cognitive flexibility and problem solving will be assessed by Berg's Card Sorting Task. Scores reflect correct answer, errors and reaction time.	At the end of first stimulation. At the end of second stimulation, after a week.
Go/No-Go Task	Inhibition control will be assessed by Go/No-Go Task. Scores reflect correct targets, false alarms, misses and response speed.	At the end of first stimulation. At the end of second stimulation, after a week.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demographic characteristics	Demographic characteristics (age, gender, and level of education) will be evaluated as predictors of treatment efficacy and examined for associations with differential treatment response.	Baseline
Change in electroencephalography (EEG)	Using resting-state EEG recorded under eyes-open and eyes-closed conditions, the investigators will assess changes in EEG beta-band power (13-30 Hz). Beta power will be quantified from scalp EEG recordings using spectral power analysis performed on the pre-processed EEG data.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.
Effectiveness in restoring neurotransmission	Neurotransmission will be assessed by measuring changes in glutamatergic (intracortical facilitation, ICF) and GABAergic (short-interval intracortical inhibition, SICI) neurotransmission assessed indirectly through TMS.	Immediately before and immediately after first stimulation. Immediately before and immediately after second stimulation, after a week.

Collaborators and Investigators

• Sponsor: IRCCS Centro San Giovanni di Dio Fatebenefratelli

Publications and helpful links

General Publications

• Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., Van Swieten, J. C., Seelaar, H., Dopper, E. G. P., Onyike, C. U., Hillis, A. E., Josephs, K. A., Boeve, B. F., Kertesz, A., Seeley, W. W., Rankin, K. P., Johnson, J. K., Gorno-Tempini, M.-L., Rosen, H., … Miller, B. L. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain, 134(9), 2456-2477. https://doi.org/10.1093/brain/awr179
• Pettorruso, M., Miuli, A., Di Natale, C., Montemitro, C., Zoratto, F., De Risio, L., d'Andrea, G., Dannon, P. N., Martinotti, G., & Di Giannantonio, M. (2021). Non-invasive brain stimulation targets and approaches to modulate gambling-related decisions: A systematic review. Addictive Behaviors, 112, 106657. https://doi.org/10.1016/j.addbeh.2020.106657
• Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008 Jul;1(3):206-23. Epub 2008 Jul 1. Review.
• Nishida, K., Yoshimura, M., Isotani, T., Yoshida, T., Kitaura, Y., Saito, A., Mii, H., Kato, M., Takekita, Y., Suwa, A., Morita, S., & Kinoshita, T. (2011). Differences in quantitative EEG between frontotemporal dementia and Alzheimer's disease as revealed by LORETA. Clinical Neurophysiology, 122(9), 1718-1725. https://doi.org/10.1016/j.clinph.2011.02.011
• Monaco M, Costa A, Caltagirone C, Carlesimo GA. Forward and backward span for verbal and visuo-spatial data: standardization and normative data from an Italian adult population. Neurol Sci. 2013;34(5):749-54.
• Lindau, M., Jelic, V., Johansson, S.-E., Andersen, C., Wahlund, L.-O., & Almkvist, O. (2003). Quantitative EEG Abnormalities and Cognitive Dysfunctions in Frontotemporal Dementia and Alzheimer's Disease. Dementia and Geriatric Cognitive Disorders, 15(2), 106-114. https://doi.org/10.1159/000067973
• Iyer, M. B., Mattu, U., Grafman, J., Lomarev, M., Sato, S., & Wassermann, E. M. (2005). Safety and cognitive effect of frontal DC brain polarization in healthy individuals. Neurology, 64(5), 872-875. https://doi.org/10.1212/01.WNL.0000152986.07469.E9
• Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F., Ogar, J. M., Rohrer, J. D., Black, S., Boeve, B. F., Manes, F., Dronkers, N. F., Vandenberghe, R., Rascovsky, K., Patterson, K., Miller, B. L., Knopman, D. S., Hodges, J. R., Mesulam, M. M., & Grossman, M. (2011). Classification of primary progressive aphasia and its variants. Neurology, 76(11), 1006-1014. https://doi.org/10.1212/WNL.0b013e31821103e6
• Costa A, Bagoj E, Monaco M, et al. Standardization and normative data obtained in the Italian population for a new verbal fluency instrument, the phonemic/semantic alternate fluency test. Neurol Sci. 2014;35(3):365- 372. doi:10.1007/s10072-013-1520-8
• Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci. 2002;22(6):443-447. doi:10.1007/s100720200003
• Benussi, A., Grassi, M., Palluzzi, F., Koch, G., Di Lazzaro, V., Nardone, R., Cantoni, V., Dell'Era, V., Premi, E., Martorana, A., Di Lorenzo, F., Bonnì, S., Ranieri, F., Capone, F., Musumeci, G., Cotelli, M. S., Padovani, A., & Borroni, B. (2020). Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias. Annals of Neurology, 87(3), 394-404. https://doi.org/10.1002/ana.25677
• Benussi, A., Cantoni, V., Rivolta, J., Zoppi, N., Cotelli, M. S., Bianchi, M., Cotelli, M., & Borroni, B. (2024). Alpha tACS Improves Cognition and Modulates Neurotransmission in Dementia with Lewy Bodies. Movement Disorders, 39(11), 1993-2003. https://doi.org/10.1002/mds.29969
• Benussi, A., Cantoni, V., Grassi, M., Brechet, L., Michel, C. M., Datta, A., Thomas, C., Gazzina, S., Cotelli, M. S., Bianchi, M., Premi, E., Gadola, Y., Cotelli, M., Pengo, M., Perrone, F., Scolaro, M., Archetti, S., Solje, E., Padovani, A., … Borroni, B. (2022). Increasing Brain Gamma Activity Improves Episodic Memory and Restores Cholinergic Dysfunction in Alzheimer's Disease. Annals of Neurology, 92(2), 322-334. https://doi.org/10.1002/ana.26411
• Antal A, Alekseichuk I, Bikson M, Brockmöller J, Brunoni AR, Chen R, Cohen LG, et al. Low Intensity Transcranial Electric Stimulation: Safety, Ethical, Legal Regulatory and Application Guidelines. Clin Neurophysiol. 2017 Sep;128(9):1774-1809.
• Amodio P, Wenin H, Del Piccolo F, et al. Variability of trail making test, symbol digit test and line trait test in normal people. A normative study taking into account age-dependent decline and sociobiological variables. Aging Clin Exp Res. 2002;14(2):117-131. doi:10.1007/BF03324425

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: February 23, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 1, 2026

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Frontotemporal Lobar Degeneration; Nutritional and Metabolic Diseases; Frontotemporal Dementia; Therapeutics; Behavioral Disciplines and Activities; Electric Stimulation Therapy; Convulsive Therapy; Psychiatric Somatic Therapies; Electroshock; Psychological Techniques; Transcranial Direct Current Stimulation
• Other Study ID Numbers: BetaTACSFTD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No