Noninvasive Brain Stimulation for pAD

NCT05468268 | Unknown

• 1 other identifier: UStudidiTrento 2021-004
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Episodic memory refers to the conscious recalling of a personal experience and includes information of an event and the context in which the event took place. This function is the first to be impaired in Alzheimer's disease, a degenerative condition in which pathological changes are found initially in the medial temporal cortex and then spread in the rest of the cortex starting from post-Rolandic areas. This study aims at examining the mechanisms that enhance memory processes, based on the information acquired by studying hypermnesic subjects. The recent discovery of subjects with an extraordinary ability to remember past events (highly above-average autobiographical memory) and the development of techniques to manipulate memory circuits in rodents provide a unique opportunity to study the mechanisms that determine the facilitation of memories. As part of a multicenter project funded by the Ministry of Health in collaboration with La Sapienza University of Rome, the University of Perugia and the Santa Lucia Rehabilitation Center in Rome, the aspect of the project carried out at CIMeC (University of Trento) will consist in evaluating the changes induced by rTMS in patients with prodromal Alzheimer's disease, after stimulation of the regions that appear particularly active in hypermnesic subjects. This project would offer the possibility of accessing an innovative non-invasive, and non-pharmacological treatment. The specific objectives are: (i) To evaluate the effectiveness of rTMS applied to hyperactive areas in hypermnesic subjects in enhancing autobiographical memories; (ii) Analyzing the neural correlates of the behavioral variations. The study will allow us to define whether it is possible to improve the recollection of autobiographical events by stimulating the circuits that are more active in hypermnesic subjects. The results will be crucial to gain a better understanding of the mechanisms through which brain stimulation contributes to the promotion of neuroplasticity and the effects of rTMS in the prodromal stages of Alzheimer's dementia.

Conditions

Alzheimer's Disease - MCI

Keywords

Transcranial Magnetic Stimulation; Prodromal Alzheimer's Disease; Memory; TMS-EEG; Electroencephalography

Outcome Measures

Primary Outcomes (6)

• TMS evoked potentials - TEPs changes. Analysis of cortical excitability and inhibition changes

  180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze cortical excitability and inhibition changes induced in the state of excitability/inhibition of brain circuits following the TMS impulse. The amplitude will be used as a marker of cortical excitability.

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)

• Connectivity Index, cortico-cortical connectivity analysis: changes in the connectivity evoked by TMS

  180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze changes in the latencies and topographical distribution of the TEPs thus providing a connectivity index. This connectivity index will be used to infer the propagation of the activity from the stimulation site to functionally connected areas.

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)

• TMS evoked oscillations changes

  180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze changes in responses induced by TMS in the frequency domain for the intrinsic capacity of the stimulated area to generate oscillatory activity in specific frequency bands

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)

• Autobiographical Memory Interview: change in performance

  The Autobiographical Memory Interview is a method of assessing autobiographical memory using a text-based analysis of transcribed autobiographical protocols. The script is segmented into internal (temporally and contextually specific) details and external (generic or semantic) details, which are then tallied. Internal scores are conceptualized as reflecting the episodic richness of the mental simulation, whereas external scores include non-episodic components of the mental simulation such as generic information, routine simulations, or verbal artifacts like repetitions. Mean changes on test scores: \[score ranges min=N/A, max= no limit, higher score=better outcome\]

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Free and Cued Selective Recall Reminding Test - episodic memory: change in performance

  Free and Cued Selective Recall Reminding Test: the three measures being evaluated include free recall (the cumulative sum of free recall from the trials; range 0-48), total recall (the cumulative sum of free recall + cued recall from the trials, range 0-48), and cue efficiency (total recall-free recall)/(48-free recall, range 0.0-1.0). Mean changes on test scores: \[higher score=better outcome\]

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Montreal Cognitive Assessment Test - cognitive screening: change in performance

  Scores on the Montreal Cognitive Assessment Test range from zero to 30. A score of 26 and higher is considered normal. If the score is below 25, the result indicates a possible cognitive impairment. Mean changes in test scores: \[higher score=better outcome\]

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

Secondary Outcomes (12)

• Raven's Coloured Progressive Matrices™: change in performance

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Forward Digit Span and Reverse Digit Span: change in performance

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Spatial Span: change in performance

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Prose Memory: change in performance

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

• Free And Cued Selective Reminding Test: change in performance

  Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]

Study Arms (2)

20 Hz rTMS

EXPERIMENTAL

rTMS will be applied to the left dorsolateral prefrontal cortex (left DLPFC). The coil will be placed at the EEG 10-20 International System position of the F3 electrode. Stimulation parameters will be rTMS delivery of 1600 pulses divided into blocks: 20 Hz for 2 seconds (40 pulses) followed by 28 seconds of pause, with a stimulation intensity equal to 100% of the motor threshold value at rest.

Device: 20 Hz rTMS

Sham rTMS

SHAM COMPARATOR

Sham rTMS will be administered by applying a 30mm thick piece of wood or plastic to a real TMS coil during "stimulation", and this additional element will be constructed in such a way that it appears to be an integral part of the apparatus such that the patient remains unaware that they are not receiving stimulation. This 30 mm distance is adequate to ensure that the magnetic pulse does not reach the cortex.

Device: Sham rTMS

Interventions

20 Hz rTMS DEVICE

rTMS stimulation

20 Hz rTMS

Sham rTMS DEVICE

Sham stimulation

Sham rTMS

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• right-handed
• to be able to provide information regarding their cognitive and functional skills, or have a caregiver available who is able to provide the patient information necessary for participation in the study and who is present when signing the patient's informed consent.
• Clinical Dementia Rating Scale \<2;
• Diagnosis of prodromal Alzheimer's disease (amnesic MCI) according to the diagnostic criteria;
• Neurodegeneration biomarker for AD (FDG-PET or CSF), diagnosis confirmed by clinical follow-up;
• Montreal Cognitive Assessment (MoCA) test overall score within the normal limits (equivalent score of 1);
• Absence of severe vascular distress; Patients will be selected through clinical evaluation (battery of neuropsychological tests at the Neurocognitive Rehabilitation Center - CeRiN)

You may not qualify if:

• Patients who are unable to perform the tasks required by the experimental procedure;
• History and/or evidence of any other central nervous system disorder that could be interpreted as a cause of dementia such as structural or developmental abnormality, infectious epilepsy, degenerative or inflammatory/demyelinating diseases of the central nervous system such as Parkinson's disease;
• History of significant psychiatric disease which, in the investigator's judgment, could interfere with study participation.
• History of alcohol or other substance abuse, according to DSM-V criteria, if this could be a contributing factor to dementia;
• Presence of cardiac pacemakers, electronic prostheses, bio-stimulators, metal inserts, or electrodes implanted in the brain or skull, or spine;
• Inability to read and /or understand the written information;
• Dermatitis, eczema, extensive scars on the scalp
• presence of cardiac pacemakers, artificial heart valves and/or bio- stimulators;
• presence of hearing aids located in the middle ear;
• presence of metal inserts on the head and shoulders;

Sponsors & Collaborators

• Università degli Studi di Trento: lead
• University of Roma La Sapienza: collaborator
• I.R.C.C.S. Fondazione Santa Lucia: collaborator
• University Of Perugia: collaborator

Study Sites (1)

Centro Interdipartimentale Mente/Cervello (CIMeC); Centro di Riabilitazione Neurocognitiva (CeRiN)

Rovereto, Trento, 38068, Italy

Location

Related Publications (12)

• Bortoletto M, Veniero D, Thut G, Miniussi C. The contribution of TMS-EEG coregistration in the exploration of the human cortical connectome. Neurosci Biobehav Rev. 2015 Feb;49:114-24. doi: 10.1016/j.neubiorev.2014.12.014. Epub 2014 Dec 22.

  PMID: 25541459 BACKGROUND

• Casarotto S, Fecchio M, Rosanova M, Varone G, D'Ambrosio S, Sarasso S, Pigorini A, Russo S, Comanducci A, Ilmoniemi RJ, Massimini M. The rt-TEP tool: real-time visualization of TMS-Evoked Potentials to maximize cortical activation and minimize artifacts. J Neurosci Methods. 2022 Mar 15;370:109486. doi: 10.1016/j.jneumeth.2022.109486. Epub 2022 Jan 21. No abstract available.

  PMID: 35074394 BACKGROUND

• Chung SW, Rogasch NC, Hoy KE, Fitzgerald PB. Measuring Brain Stimulation Induced Changes in Cortical Properties Using TMS-EEG. Brain Stimul. 2015 Nov-Dec;8(6):1010-20. doi: 10.1016/j.brs.2015.07.029. Epub 2015 Jul 17.

  PMID: 26275346 BACKGROUND

• McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.

  PMID: 21514250 BACKGROUND

• Parker ES, Cahill L, McGaugh JL. A case of unusual autobiographical remembering. Neurocase. 2006 Feb;12(1):35-49. doi: 10.1080/13554790500473680.

  PMID: 16517514 BACKGROUND

• Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.

  PMID: 33243615 BACKGROUND

• Rossi S, Ferro M, Cincotta M, Ulivelli M, Bartalini S, Miniussi C, Giovannelli F, Passero S. A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS). Clin Neurophysiol. 2007 Mar;118(3):709-16. doi: 10.1016/j.clinph.2006.11.005. Epub 2006 Dec 22.

  PMID: 17188568 BACKGROUND

• Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.

  PMID: 19833552 BACKGROUND

• Kallioniemi, E., Könönen, M., & Määttä, S. (2018). TMS-EEG: Methods and Challenges in the Analysis of Brain Connectivity. Biomedical Engineering Challenges: A Chemical Engineering Insight, 175 https://doi.org/10.1002/9781119296034.ch9

  BACKGROUND

• Russo S, Sarasso S, Puglisi GE, Dal Palu D, Pigorini A, Casarotto S, D'Ambrosio S, Astolfi A, Massimini M, Rosanova M, Fecchio M. TAAC - TMS Adaptable Auditory Control: A universal tool to mask TMS clicks. J Neurosci Methods. 2022 Mar 15;370:109491. doi: 10.1016/j.jneumeth.2022.109491. Epub 2022 Jan 31.

  PMID: 35101524 BACKGROUND

• Sarasso S, D'Ambrosio S, Fecchio M, Casarotto S, Vigano A, Landi C, Mattavelli G, Gosseries O, Quarenghi M, Laureys S, Devalle G, Rosanova M, Massimini M. Local sleep-like cortical reactivity in the awake brain after focal injury. Brain. 2020 Dec 1;143(12):3672-3684. doi: 10.1093/brain/awaa338.

  PMID: 33188680 BACKGROUND

• Tulving, E. (1983). Elements of episodic memory.

  BACKGROUND

Study Officials

• Costanza Papagno, MD-PhD

  Università di Trento, Centro di Riabilitazione Neurocognitiva (CeRiN), Rovereto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Triple (Participant, Care Provider, Outcomes Assessor) We will implement a randomized, non-pharmacological study, with a double-blind certified medical device (neither the patient nor the clinician / researcher who will carry out the evaluations will be aware of the group to which the patient has been assigned).
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Factorial Assignment 40 patients with pAD. Patients randomly assigned to 1 of 2 rTMS protocols (20 pAD participants real rTMS and 20 sham rTMS). Patients will be balanced using MoCA and age matching to create homogeneous groups. Protocols: 1\. 20 Hz rTMS 1\. Sham rTMS Patients will undergo a clinical, neuropsychological, and neurophysiological evaluation before the start of treatment (baseline, t0), at the end of the rTMS stimulation phase (t1), after 3 (t2) and 6 months (t3) from the end of treatment.

Study Record Dates

• First Submitted: July 1, 2022
• First Posted: July 21, 2022
• Study Start: July 4, 2022
• Primary Completion: December 4, 2025
• Study Completion: December 4, 2025
• Last Updated: July 21, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Data will be made available with the article publication, and the time frame for sharing this data will have no foreseen end-date.
• Access Criteria: Proposals for data sharing should be directed to costanza.papagno@unitn.it following the ethical committee approval. Data requestors need to sign a data access agreement to gain access. The sharing of the data will be contingent on the approval of an independent ethics committee and the relevance of the requested data as it pertains to the research question.

Locations

IT (1)