Targeted Transcranial Magnetic Stimulation to Improve Language and Speech in Patients With Primary Progressive Aphasia

NCT06921265 | Not Yet Recruiting DMC

• 1 other identifier: NEUROTECH_002_PPA
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

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:

1. 1.Patients with PPA who receive a combination of SLT and rTMS will exhibit greater clinical improvement compared to those receiving SLT alone.
2. 2.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.
3. 3.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.

Conditions

Primary Progressive Aphasia(PPA)

Keywords

Non-Invasive Brain Stimulation; blood sample; Non - Fluent Variant Primary Progressive Aphasia (nfvPPA); Primary Progressive Aphasia (PPA); Speak and Language Therapy (SLT); Functional Magnetic Resonance Imaging (fMRI); electroencephalogram (EEG); Functional Near Infrared Spectroscopy (fNIRS); Semantic Variant Primary Progressive Aphasia (svPPA); Logopenic Variant Primary Progressive Aphasia (lvPPA)

Outcome Measures

Primary Outcomes (4)

• Changes in number of correct naming of trained items for patients lvPPA undergoing LRC alone vs LRC + STIM treatment

  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

  Baseline, week 6, week 24

• Changes in number of correct naming of trained items for patients svPPA undergoing LRC alone vs LRC+STIM treatment

  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

  Baseline, week 6, week 24

• Changes in Percentage of VISTA script words produced correctly for trained scripts for nfvPPA patients undergoing VISTA alone vs VISTA + STIM treatment

  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

  Baseline, week 6, week 24

• Measures of Patient and Caregiver Self-Rating of Communication Effectiveness in all PPA patients undergoing LST alone vs LST + STIM

  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

  Baseline, week 6, week 24

Secondary Outcomes (18)

• 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

Other Outcomes (14)

• Changes in cognitive measures in PPA patients undergoing SLT alone vs SLT + STIM treatment

  Baseline, Week 6, Week18, Week24, Week36, Week48

• Changes in cognitive measures in PPA patients undergoing SLT + STIM according to the crossover design (standard rTMS vs targeted rTMS)

  Baseline, Week 6, Week 18, Week 24, Week 36 and Week 48

• Changes in language measures in PPA patients undergoing SLT alone vs SLT + STIM treatment

  Baseline, Week 6, Week18, Week24, Week36, Week48

Study Arms (4)

Training with SLT

ACTIVE COMPARATOR

The training will be tailored to each PPA variant. svPPA and lvPPA will undergo the LRC training, while nfvPPA will undergo the VISTA training.

Behavioral: Training with Speech Language Therapy

SLT + Brain STIM (Standard rTMS + targeted rTMS)

EXPERIMENTAL

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.

Behavioral: Training with Speech Language Therapy; Device: Standard rTMS; Device: Targeted rTMS; Device: Standard rTMS (first cycle); Device: Targeted rTMS (second cycle)

Healthy controls

NO INTERVENTION

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)

EXPERIMENTAL

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.

Behavioral: Training with Speech Language Therapy; Device: Standard rTMS; Device: Targeted rTMS; Device: Standard rTMS (second cycle); Device: Targeted rTMS (first cycle)

Interventions

Training with Speech Language Therapy BEHAVIORAL

The SLT will consist of an online intervention performed through a web-based platform. 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.

Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS); SLT + Brain STIM (Standard rTMS + targeted rTMS); Training with SLT

Standard rTMS DEVICE

Stimulation of DLPFC; rTMS will be administered as high-frequency (20Hz) in 2 second trains (40 pulses per train) with an inter-train interval of 22 seconds for a total of 50 trains (2000 pulses per session) at 120% of the patient's resting motor threshold. Patients will undergo an induction with 20-minutes rTMS protocol for 5 consecutive days, then they will start a maintenance phase where rTMS will be performed 3 days a week per 20 minutes preceding the SLT session, for a total of 20 sessions (of whom 15 combined with SLT).

Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS); SLT + Brain STIM (Standard rTMS + targeted rTMS)

Targeted rTMS DEVICE

The protocol will be the same as standard STIM. The site of stimulation will be defined using EEG/fMRI recordings of language tasks (syntax production for nfvPPA; silent naming for svPPA and lvPPA) to evidence the areas of higher activation/connectivity of the language network. We will define the area of higher fMRI activation; then, we will use fMRI-EEG connectivity and spectral activity to select the site of stimulation, among the areas with the highest fMRI activation and the highest Beta/Gamma frequencies.

Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS); SLT + Brain STIM (Standard rTMS + targeted rTMS)

Standard rTMS (first cycle) DEVICE

Patients of the SLT + STIM (standard rTMS + targeted rTMS) will firstly undergo the standard rTMS in the first 6 week of training after the baseline visit

SLT + Brain STIM (Standard rTMS + targeted rTMS)

Standard rTMS (second cycle) DEVICE

Patients of the SLT + STIM (targeted rTMS + standard rTMS) will secondly undergo the standard rTMS after 12 week washout period

Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)

Targeted rTMS (first cycle) DEVICE

Patients of the SLT + STIM (targeted rTMS + standardTMS) will firstly undergo the targeted rTMS in the first 6 weeks of training after the baseline visit

Experimental: SLT + Brain STIM (targeted rTMS + Standard rTMS)

Targeted rTMS (second cycle) DEVICE

Patients of the SLT + STIM (standard rTMS + targeted rTMS) will secondly undergo the targeted rTMS after 12 week washout period

SLT + Brain STIM (Standard rTMS + targeted rTMS)

Eligibility Criteria

• Age: 40 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• MMSE\>15
• 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

You may not qualify if:

• 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
• Sex-matched and age-matched (age range: mean age of PPA years ± 15 years)
• MMSE\>27
• Native Italian Speaker

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

San Raffaele Neurotech Hub

Milan, Milano, 20132, Italy

Location

MeSH Terms

Conditions

Aphasia, Primary Progressive; Speech

Interventions

Speech Therapy

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Verbal Behavior; Communication; Behavior

Intervention Hierarchy (Ancestors)

Rehabilitation of Speech and Language Disorders; Rehabilitation; Aftercare; Continuity of Patient Care; Patient Care; Therapeutics

Study Officials

• Prof.Massimo Filippi

  IRCCS Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Federica Agosta, PhD, MD

CONTACT

0226433051; agosta.federica@hsr.it

Elisa Canu, PhD

CONTACT

canu.elisa@hsr.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: March 5, 2025
• First Posted: April 10, 2025
• Study Start: July 15, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: April 10, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)