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The goal of this clinical trial is to investigate the effect of non-invasive brain stimulation techniques in the progression of primary progressive aphasia for 6 months. We will compare three modalities of brain stimulation (TMS, tDCS, TMS+tDCS) against sham stimulation. All patients will receive also language therapy.
Transcranial Magnetic Stimulation will follow an intermitent theta-burst protocol targetting the left dorsolateral prefrontal cortex. Transcranial electrical stimulation will also follow an excitatory protocol over the same region. All brain stimulation procedures will be conducted under neuronavigation. Language therapy will follow the lexical retrieval cascade protocol and will be conducted after each brain stimulation session.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active TMS + active tDCS | Experimental |
| |
| active TMS + sham tDCS | Experimental |
| |
| sham TMS + active tDCS | Experimental |
| |
| sham TMS + sham tDCS | Sham Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TMS | Device | Active TMS + sham tDCS. All patients will receive language therapy immediately after brain stimulation. The period of treatment will be 6 months, comprising 10 consecutive sessions in two weeks (intensive period) followed by once per week (maintenance period of 22 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Mini-Linguistic State Examination | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Naming of trained words | It will be evaluated using a list of 261 words from eight semantic categories (animals, food, objects, places, furniture, clothing, transportation, and body parts) | 6 monhts |
| ACE-III |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jordi Matias-Guiu, PhD MD | Contact | +34913303000 | jordi.matias-guiu@salud.madrid.org |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Clinico San Carlos | Recruiting | Madrid | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42161537 | Derived | Fernandez-Romero L, Diez-Cirarda M, Delgado-Alonso C, Cabrera-Martin MN, Gonzalez-Rosa JJ, Sanz-Nieto C, Perez-Macias N, Balugo P, Gomez-Ruiz N, Matias-Guiu J, Portoles-Perez A, Matias-Guiu JA. Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS). BMJ Open. 2026 May 20;16(5):e112999. doi: 10.1136/bmjopen-2025-112999. |
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| ID | Term |
|---|---|
| D018888 | Aphasia, Primary Progressive |
| D057180 | Frontotemporal Dementia |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
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Both outcome assessors and participants will be blinded to the assigned treatment. Only the technicians administering TMS will be aware of the brain stimulation assignment.
|
| tDCS | Device | sham TMS + active tDCS. All patients will receive language therapy immediately after brain stimulation. The period of treatment will be 6 months, comprising 10 consecutive sessions in two weeks (intensive period) followed by once per week (maintenance period of 22 weeks) |
|
| Sham TMS | Device | Sham TMS. All patients will receive language therapy immediately after brain stimulation. The period of treatment will be 6 months, comprising 10 consecutive sessions in two weeks (intensive period) followed by once per week (maintenance period of 22 weeks) |
|
| Sham tDCS | Device | Sham tDCS. All patients will receive language therapy immediately after brain stimulation. The period of treatment will be 6 months, comprising 10 consecutive sessions in two weeks (intensive period) followed by once per week (maintenance period of 22 weeks) |
|
General cognition
| 6 months |
| Interview for Deterioration in Daily Living Activities in Dementia (IDDD) | Functional activities | 6 months |
| Communicative Effectiveness Index (CETI) | Functional communication questionnaire | 6 months |
| CDR(R) plus NACC FTLD-SB | Clinical Dementia Rating | 6 months |
| Neuropsychiatric Inventory (NPI) | Neuropsychiatric symptoms | 6 months |
| FDG-PET imaging | Regional brain metabolism in a region of interest capturing a large part of the left hemisphere and associated with clinical decline in PPA (Fernandez-Romero et al. 2025) | 6 months |
| D001037 |
| Aphasia |
| D013064 | Speech Disorders |
| D007806 | Language Disorders |
| D003147 | Communication Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D057174 | Frontotemporal Lobar Degeneration |
| D057177 | TDP-43 Proteinopathies |
| D019636 | Neurodegenerative Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |