StimoLaMente - La Stimolazione Cerebrale Non Invasiva Applicata Alla Riabilitazione Della Malattia di Alzheimer/ StimoLaMente - Applying Non-invasive Brain Stimulation in Alzheimer's Rehabilitation
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- Mini-Mental State Evaluation (MMSE) Score - Non-Trained Measure of Global Function
研究概览
简要总结
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.
详细描述
METHODS AND PROCEDURES
The materials and methods of investigation proposed will be the following:
- Administration of rTMS in theta burst mode (TBS - intermittent and continuous)
- Administration of computerized cognitive training
- Administration of a battery of neuropsychological tests
- Administration of questionnaires and scales
- Recording of the electroencephalogram (EEG)
- Combination of EEG recording with single-pulse TMS administration (TMS-EEG)
Different TBS stimulation protocols will be applied:
- Intermittent theta burst stimulation (iTBS): this protocol consists in the administration of 600 pulses divided into blocks of 3 pulses at 50 Hz which are applied at 5 Hz (every 200 ms), alternating 2 s of stimulation with 8 s of pause.
- Continuous theta burst stimulation (cTBS): this protocol consists in the administration of 600 pulses divided into blocks of 3 pulses at 50 Hz that are applied at 5 Hz (every 200 ms).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
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).
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •General Inclusion Criteria (must be met for both AD and MCI group):
- •right-handed
- •normal or corrected to normal vision through lenses
- •meet inclusion criteria related to TMS
- •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.
- •AD Patient Inclusion Criteria:
- •Mini Mental State Examination (MMSE) score ≥ 16;
- •Stable intake of cholinesterase inhibitors for at least 3 months before the start of the protocol
- •MCI Patient Inclusion Criteria:
- •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.
排除标准
- •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.
- •Absolute exclusion criteria (Criteria for TMS), which in detail are:
- •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;
结局指标
主要结局
Mini-Mental State Evaluation (MMSE) Score - Non-Trained Measure of Global Function
时间窗: 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)
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
Face-name associative memory performance - Measure of Memory Recall
时间窗: 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)
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.
次要结局
- 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))
- 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))
- Stroop test Error and Time: Evaluation of attention and executive function(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))
- Geriatric Depression Scale, GDS:Evaluation of depressive symptoms in the elderly(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))
- Questionnaire of Identification of Deficits (QID): Evaluation on quality of life and identification of deficit questionnaire for the patient and caregiver(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))
- Prose Memory:Evaluation of short and long term memory(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))
- Multiple Features Cancellation task: Evaluation of attention and executive function "MFCT"(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))
- Jefferson Scale: Evaluation of the patient's perception of empathy(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 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))
- Spatial Span: Evaluation of short and long term memory (visuospatial)(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))
- Free And Cued Selective Reminding Test: Evaluation of short and long term memory(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))
- Token Test: Evaluation of linguistic production(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))
- Semantic fluency and Phonemic fluency(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))
- Deferred re-enactment of the Complex Figure by Rey Osterrieth: Long term memory evaluation(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))
- Trail Making test (for A, B and B-A conditions): Evaluation of attention and executive function(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))
- Attentional Matrices: Evaluation of attention and executive function(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))
- Copy of Rey's Complex Figure: Evaluation of practical and visual-constructive skills(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))
- Clinical Insight Rating Scale, (CIRS): Evaluation of awareness of deficits and disease(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))