Tailored Neuromodulation Intervention to Enhance Speech and Language Training in Patients With Primary Progressive Aphasia: EEG and MRI Targeted Transcranial Magnetic Stimulation
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 75
- 试验地点
- 1
- 主要终点
- Changes in number of correct naming of trained items for patients lvPPA undergoing LRC alone vs LRC + STIM treatment
研究概览
简要总结
This is a monocenter randomized controlled clinical trial with cross-over arm - assessor blinded. The aims is investigating the effects of the speech language therapy (SLT) alone vs SLT + non-invasive brain stimulation (STIM), using canonic repetitive Transcranial Magnetic Stimulation (rTMS), on speech and language, clinical, neuropsychological, neuroimaging, neurophysiology, and blood features in patients with PPA.
The trial will include 45 participants suffering from semantic (svPPA), logopenic (lvPPA) or nonfluent (nfvPPA) variants of Primary Progressive Aphasia (PPA) and 30 healthy controls.
At baseline (T0) patients will undergo in-depth clinical, neuropsychological and language assessment, structural and functional magnetic resonance imaging (MRI) scan, electroencephalography (EEG) recording, functional Near Infrared Spectroscopy (fNiRS) scans, and blood sample.
PPA patients will be randomized into 2 training groups: the speech language therapy (SLT) group and the SLT + STIM (standard rTMS group or targeted rTMS).
The SLT will consist of an online intervention performed through a web-based platform. The training will be tailored to each PPA variant. svPPA and lvPPA will undergo the lexical retrieval cascade (LRC) treatment, while nfvPPA will undergo the Video-implemented Script Training (VISTA).
The SLT+ STIM group will perform the same SLT combined with non-invasive stimulation with a cross-over design: canonic repetitive Transcranial Magnetic Stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC) or targeted rTMS in which the site and the protocol of stimulation will be defined based on single-subject EEG combined with functional MRI (EEG+fMRI).
This design will aid in determining not only whether non-invasive stimulation can enhance clinical outcomes, but also which non-invasive stimulation is the best to improve results.
The SLT training of the SLT group will consist of 2 cycles of training lasting 1 (rest) + 5 (training) weeks, 3 times per week, 1 hour each session, separated by a 12-week washout period.
The SLT + standard or targeted STIM groups will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design: half of subjects will first receive 6-week SLT training associated with DLPFC rTMS followed by 6-week SLT associated with targeted rTMS, while the other half will follow the reverse order, according to a randomization procedure.
After the training (i.e., 6-week visit [W6] and 24-week visit [W24]), PPA patients will be re-evaluated through neurological, language, neuroimaging/neurophysiology assessments, and blood sample.
Evaluations will be also repeated at the 18-week (W18) after the wash-out and before the second cycle of treatment, as well as at 36-week (W36) and 48-week (W48) follow-up visits to assess maintenance of results. MRI and blood sample will be repeated at all visits but W18 and W36. The comprehensive neuropsychological assessment will be repeated at W48 only.
30 healthy controls will also be recruited among the spouses of patients, by word of mouth or through flyers and project awareness campaigns. They will undergo the same assessments administered to PPA patients at T0 (neurological, neuropsychological/language assessments, neuroimaging/neurophysiology, and blood sample).
Hypothesis:
- Patients with PPA who receive a combination of SLT and rTMS will exhibit greater clinical improvement compared to those receiving SLT alone.
- Choosing the rTMS approach and stimulation site based on individualized MRI and EEG characterization will be more effective as compared to using the standard rTMS approaches described by the literature.
- The integration of specific clinical, cognitive, language, neuroimaging, neurophysiological, and blood features will enable the prediction of individual responses to SLT and rTMS, facilitating the development of optimized, personalized treatment plans for PPA.
详细描述
In the landscape of neurodegenerative disorders, neuromodulation emerges as a promising avenue for therapeutic intervention, particularly for focal neurodegenerative diseases like primary progressive aphasia (PPA). There are currently no disease-modifying drugs for PPA. Speech language training (SLT) protocols have shown some efficacy in PPA. However, the results are heterogeneous, often not sustained over time, and likely influenced by individual differences, including variations in brain reorganization. Non-invasive neuromodulation techniques, ranging from TMS to transcranial direct current stimulation, offer unique opportunities to directly influence neural activity and potentially alleviate cognitive deficits. The efficacy of such interventions, though, greatly hinges on the precision and individualization of treatment protocols. Targeted and tailored neuromodulation protocols, informed by patients' neurophysiological and structural data, could be crucial for optimizing therapeutic outcomes. By leveraging patient-specific information, such as neuroimaging and electrophysiological data, these protocols can precisely engage crucial dysfunctional neural circuits and adapt stimulation parameters to suit individual variations. In the context of PPA, where the neural substrates and symptomatology can vary widely among patients, such personalized approaches hold great promise in enhancing treatment efficacy and improving patient outcomes. Transcranial Magnetic Stimulation (TMS) has already proven to be among the most effective forms of non-invasive brain stimulation. Repetitive TMS (rTMS) of the Dorso-Lateral PreFrontal Cortex (DLPFC) has shown to be effective in PPA. Recent studies have explored the personalization of TMS treatment according to the patients' features. Here we propose a multimodal in-depth assessment that will inform precise neuro-navigated rTMS to improve functional plasticity in the most beneficial way.
PPA patients will be randomized into 2 training arms with a 1:2 ratio: the SLT group and the SLT + STIM (standard rTMS group or targeted rTMS).
Training in the SLT training will consist of 2 cycles of training lasting 1 (rest) + 5 (training) weeks, 3 times per week, 1 hour each session, separated by a 12-week washout period.
The SLT + standard or targeted STIM groups will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design: half of subjects will first receive 6-week SLT training associated with DLPFC rTMS followed by 6-week SLT associated with targeted rTMS, while the other half will follow the reverse order, according to a randomization procedure. Specifically, an induction with 20-minutes rTMS protocol for 5 consecutive days will be performed, followed by a maintenance phase where 20-minutes rTMS will be performed before each SLT session per 5 weeks, for a total of 20 rTMS sessions of whom 15 combined with SLT.
According to this design, patients will receive:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •for patients
- •Clinical and imaging-supported diagnosis of any variant of PPA (svPPA, lvPPA, nfvPPA) according to international diagnostic criteria (Gorno- Tempini et al., 2011)
- •Age range: 40-85
- •Native Italian Speaker
- •Right handedness
- •Stable pharmacological treatment of at least 4 weeks and without any change during the observation period (48 weeks)
- •Oral and written informed consent to study participation
排除标准
- •for patients
- •Any major systemic, psychiatric, neurological, and visual disturbance
- •Medical conditions or substance abuse that could interfere with cognition
- •Hypoacusis or severe visual deficits
- •Pacemaker and/or other implanted neurostimulation devices in the head/neck district
- •(Other) Contraindications to undergoing MRI examination
- •Brain damage at routine MRI, including extensive cerebrovascular disorders
- •Denied oral and written informed consent to study participation
- •Inability to repeat multisyllabic words (4 syllables)
- •Concomitant participation to other pharmacological and non pharmacological studies
- •Traumatic or surgical wounds that could determine a risk of infection in the site of non-invasive stimulation
- •Scalp alterations that could determine the spread of excessive current from the device.
- •Known history of epilepsy (due to small risk of seizure induction from rTMS in epileptic patients
- •Inclusion criteria for healthy controls:
- •Sex-matched and age-matched (age range: mean age of PPA years ± 15 years)
- •Native Italian Speaker
- •Right handedness
- •Oral and written informed consent to study participation
- •Exclusion criteria for healthy controls:
- •Any major systemic, psychiatric, neurological, and visual disturbance
- •Medical conditions or substance abuse that could interfere with cognition
- •Hypoacusis or severe visual deficits
- •Pacemaker and/or other implanted neurostimulation devices in the head/neck district
- •(Other) Contraindications to undergoing MRI examination
- •Brain damage at routine MRI, including extensive cerebrovascular disorders
- •Denied oral and written informed consent to study participation
研究组 & 干预措施
Training with SLT
The training will be tailored to each PPA variant. svPPA and lvPPA will undergo the LRC training, while nfvPPA will undergo the VISTA training.
干预措施: Training with Speech Language Therapy (Behavioral)
SLT + Brain STIM (Standard rTMS + targeted rTMS)
Patients will perform the same exercises as SLT group, combined with brain STIM. The SLT + non invasive brain STIM (standard rTMS + targeted rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure.
Half of subjects will first receive 6-week SLT training + standard rTMS followed by 6-week SLT training associated with targeted rTMS, according to the crossover design.
干预措施: Targeted rTMS (Device)
SLT + Brain STIM (Standard rTMS + targeted rTMS)
Patients will perform the same exercises as SLT group, combined with brain STIM. The SLT + non invasive brain STIM (standard rTMS + targeted rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure.
Half of subjects will first receive 6-week SLT training + standard rTMS followed by 6-week SLT training associated with targeted rTMS, according to the crossover design.
干预措施: Training with Speech Language Therapy (Behavioral)
SLT + Brain STIM (Standard rTMS + targeted rTMS)
Patients will perform the same exercises as SLT group, combined with brain STIM. The SLT + non invasive brain STIM (standard rTMS + targeted rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure.
Half of subjects will first receive 6-week SLT training + standard rTMS followed by 6-week SLT training associated with targeted rTMS, according to the crossover design.
干预措施: Standard rTMS (Device)
SLT + Brain STIM (Standard rTMS + targeted rTMS)
Patients will perform the same exercises as SLT group, combined with brain STIM. The SLT + non invasive brain STIM (standard rTMS + targeted rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure.
Half of subjects will first receive 6-week SLT training + standard rTMS followed by 6-week SLT training associated with targeted rTMS, according to the crossover design.
干预措施: Standard rTMS (first cycle) (Device)
SLT + Brain STIM (Standard rTMS + targeted rTMS)
Patients will perform the same exercises as SLT group, combined with brain STIM. The SLT + non invasive brain STIM (standard rTMS + targeted rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure.
Half of subjects will first receive 6-week SLT training + standard rTMS followed by 6-week SLT training associated with targeted rTMS, according to the crossover design.
干预措施: Targeted rTMS (second cycle) (Device)
Healthy controls
Age- and sex-matched healthy subjects recruited to compare neuropsychological, functional magnetic resonance imaging and neurophysiological characteristics at baseline
Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)
Patients will perform the same exercises as SLT group, combined with non invasive brain STIM. The SLT + STIM (targeted rTMS + standard rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure. Half of subjects will first receive 6-week SLT training + targeted rTMS followed by 6-week SLT training associated with standard rTMS, according to the crossover design.
干预措施: Training with Speech Language Therapy (Behavioral)
Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)
Patients will perform the same exercises as SLT group, combined with non invasive brain STIM. The SLT + STIM (targeted rTMS + standard rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure. Half of subjects will first receive 6-week SLT training + targeted rTMS followed by 6-week SLT training associated with standard rTMS, according to the crossover design.
干预措施: Standard rTMS (Device)
Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)
Patients will perform the same exercises as SLT group, combined with non invasive brain STIM. The SLT + STIM (targeted rTMS + standard rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure. Half of subjects will first receive 6-week SLT training + targeted rTMS followed by 6-week SLT training associated with standard rTMS, according to the crossover design.
干预措施: Targeted rTMS (Device)
Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)
Patients will perform the same exercises as SLT group, combined with non invasive brain STIM. The SLT + STIM (targeted rTMS + standard rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure. Half of subjects will first receive 6-week SLT training + targeted rTMS followed by 6-week SLT training associated with standard rTMS, according to the crossover design.
干预措施: Standard rTMS (second cycle) (Device)
Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)
Patients will perform the same exercises as SLT group, combined with non invasive brain STIM. The SLT + STIM (targeted rTMS + standard rTMS) group will undergo 2 cycles of 6-week training, separated by a 12-week washout period with a cross-over design, according to a randomization procedure. Half of subjects will first receive 6-week SLT training + targeted rTMS followed by 6-week SLT training associated with standard rTMS, according to the crossover design.
干预措施: Targeted rTMS (first cycle) (Device)
结局指标
主要结局
Changes in number of correct naming of trained items for patients lvPPA undergoing LRC alone vs LRC + STIM treatment
时间窗: Baseline, week 6, week 24
The primary objective is assessing the effect of SLT alone vs SLT + STIM (standard and targeted rTMS) on PPA speech and language features. This will be measured trough the primary endpoint regarding changes in number of correct naming of trained items for lvPPA patients undergoing the LRC alone vs LRC + STIM treatment
Changes in number of correct naming of trained items for patients svPPA undergoing LRC alone vs LRC+STIM treatment
时间窗: Baseline, week 6, week 24
The primary objective is assessing the effect of SLT alone vs SLT + STIM (standard and targeted rTMS) on PPA speech and language features. This will be measured trough the primary endpoint regarding changes in number of correct naming of trained items for svPPA patients undergoing the LRC alone vs LRC + STIM treatment
Changes in Percentage of VISTA script words produced correctly for trained scripts for nfvPPA patients undergoing VISTA alone vs VISTA + STIM treatment
时间窗: Baseline, week 6, week 24
The primary objective is assessing the effect of SLT alone vs SLT + STIM (standard and targeted rTMS) on PPA speech and language features. This will be measured trough the primary endpoint regarding changes in percentage of VISTA words produced correctly for trained scripts for nfvPPA patients undergoing VISTA alone vs VISTA + STIM treatment
Measures of Patient and Caregiver Self-Rating of Communication Effectiveness in all PPA patients undergoing LST alone vs LST + STIM
时间窗: Baseline, week 6, week 24
The primary objective is assessing the effect of SLT alone vs SLT + STIM (standard and targeted rTMS) on PPA speech and language features. This will be measured trough the primary endpoint regarding Measures of Patient and Caregiver Self-Rating of Communication Effectiveness in all PPA patients undergoing SLT alone vs SLT + STIM treatment
次要结局
- Changes in number of correct naming of trained items for patients lvPPA undergoing the LRC + STIM treatment , according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in number of correct naming of trained items for patients svPPA undergoing the LRC + STIM treatment , according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in Percentage of VISTA script words produced correctly for trained scripts for nfvPPA patients undergoing the VISTA + STIM treatment, according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Measures of Patient and Caregiver Self-Rating of Communication Effectiveness (all PPA) undergoing SLT + STIM treatment, according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in number of correct naming of untrained items for lvPPA patients undergoing LRC alone vs LRC + STIM treatment(Baseline, week 6, week 24)
- Changes in number of correct naming of untrained items for svPPA patients undergoing LRC alone vs LRC + STIM treatment(Baseline, week 6, week 24)
- Changes in percentage of VISTA script words produced correctly for untrained scripts for nfvPPA patients undergoing VISTA alone vs VISTA + STIM treatment(Baseline, week 6, week 24)
- Changes in number of correct naming of untrained items for patients lvPPA undergoing the LRC + STIM treatment according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in number of correct naming of untrained items for patients svPPA undergoing the LRC + STIM treatment according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in Percentage of VISTA script words produced correctly for untrained scripts, for nfvPPA patients undergoing VISTA + STIM treatment, according to the cross-over design (standard vs targeted rTMS)(Baseline, week 6, week 24)
- Changes in number of correct items for lvPPA patients undergoing the LRC alone vs LRC + STIM(Week 6, Week 18, Week 24, Week 36, Week 48)
- Changes in number of correct items for svPPA patients undergoing the LRC alone vs LRC + STIM(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Changes in Percentage of VISTA script words produced correctly for trained scripts for nfvPPA patients undergoing VISTA alone vs VISTA + STIM(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Changes in number of correct naming of trained items for lvPPA patients undergoing LRC + STIM treatment, according to the crossover design (standard rTMS vs targeted rTMS)(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Changes in number of correct naming of trained items for svPPA patients undergoing LRC + STIM treatment, according to the crossover design (standard rTMS vs targeted rTMS)(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Changes in Percentage of VISTA script words produced correctly for trained scripts for nfvPPA patients undergoing VISTA + STIM treatment, according to the crossover design (standard rTMS vs targeted rTMS)(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Measures of Patient and Caregiver Self-Rating of Communication Effectiveness in all PPA patients undergoing SLT alone vs SLT+ STIM treatment(Week 6, Week 18, Week 24, Week 36 and Week 48)
- Measures of Patient and Caregiver Self-Rating of Communication Effectiveness for all PPA patients undergoing SLT +STIM treatment, according to the crossover design(Week 6, Week 18, Week 24, Week 36 and Week 48)
研究者
Prof. Massimo Filippi
Prof.
Università Vita-Salute San Raffaele