Applying Non-invasive Brain Stimulation in Alzheimer's Rehabilitation

NCT04866979 | Unknown

• 1 other identifier: UStudidiTrento
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Presently, few studies have evaluated the clinical impact of rTMS in Alzheimer's disease. Though some studies have demonstrated an improvement, there have been conflicting results, as others do not seem to demonstrate beneficial effects. Furthermore, it is the combined application of rTMS with cognitive training that could represent a real turning point in interventions aiming to slow down cognitive decline resulting from AD. Research has shown that the best way to promote the strengthening of a network is to stimulate the area while simultaneously activating the network (i.e. through cognitive training) which supports the specific function of interest. Recently, there have been new protocols from animal model research showing that "bursts" of repetitive stimulation at a high theta frequency induce synaptic plasticity in a much shorter time period than required by standard rTMS protocols. This type of rTMS stimulation, theta-burst stimulation (TBS), is therefore even more compelling as a therapeutic intervention given that it includes the benefits previously ascribed to other rTMS protocols, but requires less administration time. Furthermore, studies conducted using both types of stimulation suggest that TBS protocols are capable of producing long term effects on cortical excitability that exceed the efficacy of those using standard rTMS protocols. This project offers patients the possibility of accessing an innovative non-invasive, and non-pharmacological treatment. The goal is to evaluate the clinical efficacy TBS in patients diagnosed with mild cognitive decline (MCI) and AD, verifying if TBS in conjunction with cognitive training produces results better than those obtainable with only one of the two methodologies alone. Patients will be evaluated throughout the full scope of the treatment period, through clinical assessments and neuropsychological evaluations. We will examine neuroplastic changes by investigating the neural correlates underlying improvements using the multimodal imaging technique: TMS-EEG co-registration. A secondary objective will be to define the most effective stimulation protocol, verifying if TBS applied continuously (cTBS) or intermittently (iTBS) produces better behavioral outcomes. 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 efficacy of TBS combined with cognitive training.

Conditions

Alzheimer Disease; Mild Cognitive Impairment

Keywords

Transcranial Magnetic Stimulation; Theta Burst Stimulation; Alzheimer Disease; Mild Cognitive Impairment; Memory; TMS-EEG; Electroencephelography

Outcome Measures

Primary Outcomes (2)

• Face-name associative memory performance - Measure of Memory Recall

  Mean change in performance in ability to correctly memorize face/name paired associations \[score range min=7, max=n/a, higher score=better outcome\]. Patients will start at level 7, the level at which the training software begins paired face/name associations. The software will not allow the patient to go below level 7, so this is the minimum score (level) threshold for all patients.

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

• Mini-Mental State Evaluation (MMSE) Score - Non-Trained Measure of Global Function

  Neuropsychological evaluation using mean changes in the Mini-Mental State Evaluation(MMSE) score Score range is from 0-30, with a score of 25 or higher is classed as "normal". If the score is below 25, the result indicates a possible cognitive impairment. A lower score = worse outcome

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

Secondary Outcomes (20)

• TMS evoked potentials - TEP: Analysis of cortical excitability and inhibition changes induced in the state of excitability/inhibition of brain circuits following the TMS impulse.

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

• Connectivity Index - Connectivity evoked by TMS: cortico-cortical connectivity analysis

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

• TMS evoked oscillations: changes induced by TMS and its influence on intrinsic oscillatory activity

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

• Raven's Colored Progressive Matrices: Evaluation of abstract non-verbal reasoning

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

• Digit Span: Evaluation of short and long term memory (verbal)

  Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), at the end of the maintenance phase (t2=Week 8), 3 months post-treatment (t3=Week 12), & 5 months post treatment (t4=Week 20)

Study Arms (5)

Combination of continuous TBS plus cognitive training (cTBS + CT)

EXPERIMENTAL

Continuous mode of TBS applied in conjunction with cognitive training that will commence directly after the stimulation protocol has been completed.

Device: Experimental: Continuous TBS (cTBS); Behavioral: Cognitive training (CT).

Combination of intermittent TBS plus cognitive training (iTBS + CT)

EXPERIMENTAL

Intermittent mode of TBS applied in conjunction with cognitive training that will commence directly after the stimulation protocol has been completed.

Device: Intermittent TBS (iTBS); Behavioral: Cognitive training (CT).

Continuous TBS only (cTBS)

EXPERIMENTAL

TBS in continuous mode application, only (without cognitive training).

Device: Experimental: Continuous TBS (cTBS)

Intermittent TBS only (iTBS)

EXPERIMENTAL

TBS in intermittent mode application, only (without cognitive training).

Device: Intermittent TBS (iTBS)

Cognitive training only (with sham TBS) (CT).

ACTIVE COMPARATOR

TBS Sham will be implemented using the same set-up as a true TBS protocol but with "sham stimulation". Directly following sham stimulation (as in the true combination of stimulation + cognitive training protocols), patients will undergo 25 minutes of cognitive training.

Behavioral: Cognitive training (CT).; Device: Sham Stimulation (shamTBS)

Interventions

Experimental: Continuous TBS (cTBS) DEVICE

Application of cTBS. cTBS 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 TBS delivery of 600 pulses divided into blocks of 3 pulses at 50 Hz, which are applied at 5 Hz (every 200 ms), with a stimulation intensity equal to 80% of the motor threshold value at rest.

Combination of continuous TBS plus cognitive training (cTBS + CT); Continuous TBS only (cTBS)

Intermittent TBS (iTBS) DEVICE

Application of iTBS. iTBS 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 TBS delivery of of 600 pulses divided into blocks of 3 pulses at 50 Hz, which are applied at 5 Hz (every 200 ms), alternating 2 seconds of stimulation with a pause of 8 seconds, with a stimulation intensity equal to 80% of the motor threshold value at rest.

Combination of intermittent TBS plus cognitive training (iTBS + CT); Intermittent TBS only (iTBS)

Cognitive training (CT). BEHAVIORAL

Cognitive training (memory rehabilitation via RehaCom computer software) of 25 min. The training will be focused on memory rehabilitation, implementing a face-name association paradigm. The software uses an individualized adaptive methodology based on the participant's performance.

Cognitive training only (with sham TBS) (CT).; Combination of continuous TBS plus cognitive training (cTBS + CT); Combination of intermittent TBS plus cognitive training (iTBS + CT)

Sham Stimulation (shamTBS) DEVICE

Sham rTMS (TBS) 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 (Rossi et al., 2007 ).This 30mm distance is adequate to ensure that the magnetic pulse does not reach the cortex.

Cognitive training only (with sham TBS) (CT).

Eligibility Criteria

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

You may qualify if:

• right-handed
• normal or corrected to normal vision through lenses
• 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.
• Mini Mental State Examination (MMSE) score ≥ 16;
• Stable intake of cholinesterase inhibitors for at least 3 months before the start of the protocol
• Diagnosis of mild cognitive impairment
• Mini Mental State Examination (MMSE) score ≥ 24;
• Patients will be selected through clinical evaluation (battery of neuropsychological tests at the Neurocognitive Rehabilitation Center (CeRiN) and, in accordance with the APSS, a CSF and PET examination will be performed as well as a further finalized neuropsychological evaluation for research.

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, epilepsy, infectious disease, degenerative or inflammatory/demyelinating diseases of the central nervous system such as Parkinson's disease or Fronto-temporal dementia
• 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, or recent or previous history of drug abuse if this could be a contributing factor to dementia
• Ongoing treatments with drugs that contain / intake of the following substances: imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, (MDMA, ecstasy), phencyclidine (PCP, angel dust), gamma-hydroxybutyrate acid (GHB), theophylline
• Presence of cardiac pacemakers, electronic prostheses, bio-stimulators, metal inserts or electrodes implanted in the brain or skull or spine.
• presence of cardiac pace-makers, 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

Study Sites (1)

Centro Interdipartimentale Mente/Cervello - CIMeC

Rovereto, Trento, 38068, Italy

RECRUITING

Related Publications (34)

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MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

Cognitive Training

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Neurological Rehabilitation; Rehabilitation; Aftercare; Continuity of Patient Care; Patient Care; Therapeutics; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Carlo Miniussi, PhD

  Università degli Studi di Trento

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Carlo Miniussi, PhD

CONTACT

0464 808694; carlo.miniussi@unitn.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: 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: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 200 total patients:100 AD patients,100 MCI patients. Random assignment to 1 of 5 protocols (20 AD patients and 20 MCI patients per protocol). Patients will be balanced using MMSE and age matching to create homogeneous groups. Protocols: 1. Combination of continuous TBS plus cognitive training (cTBS + CT); 2. Combination of intermittent TBS plus cognitive training (iTBS + CT); 3. Continuous TBS only (cTBS); 4. intermittent TBS only (iTBS); 5. Cognitive training only (with placebo TBS) (CT). 2 main treatment phases; 1) intensive phase (2 weeks, applied daily 5 times a week, 10 sessions); 2) maintenance phase, (5 weeks, 2 times a week, 10 sessions). Patients will undergo a clinical, neuropsychological, and neurophysiological evaluation before the start of treatment (baseline, t0=Week1), at the end of the intensive phase (t1= Week 4), at the end of the maintenance phase (t2 = Week 8), and after 3 (t3 = Week 12) and 5 months (t4 = Week 20) from the start of treatment.

Study Record Dates

• First Submitted: April 6, 2021
• First Posted: April 30, 2021
• Study Start: April 6, 2021
• Primary Completion: January 31, 2024
• Study Completion: January 31, 2024
• Last Updated: May 10, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The data will be available immediately following article publication, and the time frame for sharing this data will have no foreseen end-date.
• Access Criteria: The data will be shared with Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose, for research purposes only. The only data will be shared will be those which aid in achieving the research aims of the approved proposal, previously approved by the above mentioned independent ethical review committee. Proposals for data sharing should be directed to carlo.miniussi@unitn.it following ethical committee approval. To gain access, data requestors will need to sign a data access agreement. The sharing of the data will be contingent on the above-mentioned criteria, namely, the approval of an independent ethics committee and the relevance of the requested data as it pertains to the research question.

Locations

IT (1)