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)

Abstract

Introduction

Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer’s disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

Methods and analysis

The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke’s Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

Ethics and dissemination

The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

Trial registration number

NCT07158216.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Strengths: robust design, blinded, four arms in parallel, comparing each technique, the sum of both and sham intervention. Pragmatic and clinically relevant comparison of approved techniques in other indications. Economic impact of the interventions will also be assessed.

• Weaknesses: difficulties to sham the interventions, which have been solved by specific equipment. Heterogeneity of the disease may limit the identification of differences across primary progressive aphasia (PPA) variants.

Introduction

Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterised by progressive language deterioration. Language impairment is the main cause of disability, although other cognitive and behavioural issues are often present. Three main variants are recognised, including non-fluent/agrammatic (nfvPPA), semantic (svPPA) and logopenic (lvPPA).¹ PPA is considered a form of frontotemporal degeneration (especially nfvPPA and svPPA) or Alzheimer’s disease (especially lvPPA), mainly affecting the language-dominant hemisphere.²

Despite the advances in diagnosis and classification, effective treatments are needed.³ The heterogeneity of disease characteristics, its evolving nature and low incidence pose significant challenges to the conduct of clinical trials. However, in the last few years, some progress has been made in the field of language therapy. Specifically, word retrieval interventions have been examined with positive findings.^{4 5} Additionally, brain stimulation, especially transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), has been proposed.

Most of the studies in PPA have been conducted using tDCS, generally with positive effects in the short term. However, the positive effects are not consistent across the studies, and some design limitations are common (small samples, cross-over trials, different brain targets and protocols of stimulations),⁶ which may be especially relevant considering the heterogeneity of the disease.

Regarding TMS, we recently conducted a randomised, parallel, double-blind, sham-controlled clinical trial in 63 patients with PPA, in which TMS was administered over a 6-month period. In this study, active treatment was associated with a mitigation in the decline of brain metabolism in fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, and improvements in language, activities of daily living and neuropsychiatric symptoms.⁷ In the former study, stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC), a hub involved in attention, executive functions and language processing. Recent electrophysiological evidence shows that the lateral prefrontal cortex exhibits widespread bidirectional connectivity with frontoparietal and attention networks, supporting its role as a key integrative hub. This network-level influence provides a rationale for targeting the DLPFC to modulate distributed language-related circuits.⁸ Excitatory TMS protocols in this region have been associated with favourable outcomes in preliminary studies.^{9 10} The DLPFC supports working memory, planning, organisation and inhibitory control, which may enhance language performance.^{11 12} Stimulation of the left DLPFC can also modulate dopamine and serotonin circuits, potentially improving motivation and engagement during therapy.¹³ Targeting the DLPFC rather than canonical language areas such as Broca’s region allows stimulation of cortical zones that are less affected by neurodegeneration, which may maximise the benefits of neuromodulation.

However, one of the main limitations of TMS is its limited availability in clinical centres, as well as the high cost of the equipment. In this context, tDCS represents an alternative neuromodulation technique that could offer greater clinical applicability. To our knowledge, there are no studies evaluating the efficacy of prolonged tDCS therapy in PPA, as well as studies directly comparing the effects of tDCS and TMS.

Furthermore, TMS is known to modulate cortical excitability and induce both synaptic and non-synaptic changes.¹⁴ These changes can impact cognition, neurotransmitter function and brain neuroplasticity.¹⁵ Experimental studies have also suggested a potential neuroprotective effect.¹⁶ TMS has been shown to promote synaptic plasticity, with effects on neurotransmitter systems and neurotrophic signalling, while tDCS alters neuronal membrane potential, facilitating cortical responsiveness. Changes in brain metabolism measured by FDG-PET, a marker of synaptic activity, further support the neuroplastic and potential neuroprotective effects of these interventions.^{14 17 18} Given that tDCS alters the neuronal resting membrane potential (inducing cortical changes lasting approximately 90 min) and that TMS generates action potentials, recent research has proposed that combining tDCS followed by TMS may enhance treatment efficacy.19,21 This approach could act as a form of prestimulation or preconditioning, thereby amplifying the effects of TMS and producing a synergistic impact on cortical excitability and brain plasticity.

In this study, our main hypothesis is that non-invasive brain stimulation (NIBS) (tDCS, TMS and tDCS plus TMS) combined with language therapy delivered during a period of 6 months may reduce the progression of language impairment in PPA, compared with sham stimulation combined with language therapy. We present the protocol for a randomised, parallel, double-blinded, sham-controlled clinical trial. As secondary endpoints, we assess the effect on naming, global cognition, functional activities of daily living, functional communication and neuropsychiatric symptoms.

Methods and analysis

Study design and setting

This study is a randomised, double-blinded, parallel and sham-controlled clinical trial. The study is conducted in Hospital Clínico San Carlos (Madrid, Spain) and is currently ongoing. The first patient was enrolled on 15 September 2025, and the recruitment is planned to be completed by January 2028, and the last visit by July 2028.

Participants

Inclusion criteria

Patients must fulfil the following inclusion criteria: (1) diagnosis of PPA according to the current consensus criteria proposed by Gorno-Tempini et al,¹ based on the presence of progressive language impairment as the most prominent and primary cause of functional decline and the exclusion of other medical, psychiatric or non-neurodegenerative causes, as well as early prominent memory, visuoperceptual or behavioural disturbances; (2) diagnosis of one of the three variants: nfvPPA, svPPA or lvPPA according to the consensus criteria,¹ based on the language profile and supported by neuroimaging (FDG-PET or MRI); (3) Clinical Dementia Rating scale equal to or less than 1; (4) the language impairment is the main neurological deficit for the patient.

Exclusion criteria

Patients who fulfil the following exclusion criteria will not be included: (1) patient diagnosed with a condition other than PPA that could cause language impairment; (2) history of epilepsy or presence of focal epileptiform pathology on electroencephalogram (EEG) recording; (3) contraindications related to the treatments or procedures to be used (TMS and tDCS), such as ferromagnetic material, pregnancy or breastfeeding; (4) terminal illness or active malignancy; (5) alcohol or substance abuse within the past year; (6) major psychiatric disorders (schizophrenia, schizoaffective disorders, bipolar disorder, obsessive-compulsive disorder or personality disorders); (7) absolute inability to communicate (mutism) or poor command of the language that, in the investigator’s judgement, would prevent participation in the study; (8) severity of PPA that prevents participation in interventions or assessments at the time of inclusion; (9) participation in another clinical trial within the previous 4 months; (10) chronic use of medications that could affect study outcomes; (11) antiepileptic drugs: allowed if on stable doses for at least 3 months before inclusion (if needed during the study due to seizure occurrence, they may be added); (12) diazepam and derivatives: permitted only if on stable doses for at least 3 months before inclusion (dosage adjustments during the study are allowed); (13) donepezil, galantamine, rivastigmine and memantine: allowed if on stable doses for at least 3 months before inclusion; (14) selective serotonin reuptake inhibitors: permitted only if on stable doses for at least 3 months prior to inclusion (if needed during the study, they may be added); (15) medications that may lower the seizure threshold (eg, tricyclic antidepressants, antipsychotics): allowed if on stable doses for at least 3 months before inclusion.

Patients will be classified according to PPA variants (nfvPPA, svPPA, lvPPA) based on consensus criteria and this classification will be used for stratification during randomisation and as a covariate in the statistical analyses.

Recruitment

Patients are recruited from the Departments of Neurology (Cognitive Neurology Unit) of Hospital Clínico San Carlos, a reference unit for cognitive disorders in the region of Madrid and Spain. Study staff will give patients the Informed Consent Form to review before obtaining their signature during the baseline visit. The informed consent template is provided in the online supplemental material.

Withdrawal criteria

Meeting any of the exclusion criteria (with the exception of changes or additions to antidepressant or antiepileptic medications) will be considered a withdrawal criterion. In cases where disease progression prevents continued participation in speech therapy, participants will be offered the option to continue with non-invasive brain stimulation treatment.

Sample size calculation

The sample size calculation is based on a previous study comparing TMS and sham stimulation for 6 months,⁷ where patients receiving active TMS showed a Mini-Linguistic State Examination (MLSE) score of 78.92±1.72 and 79.42±1.96 before and after therapy, respectively. Patients receiving sham TMS scored 73.42±3.55 and 67.55±4.23. This resulted in an effect size η²_p=0.173, derived from the analysis of covariance (ANCOVA) model that was used to estimate the treatment effect. We assumed that both TMS and tDCS are superior to placebo with a similar effect size to that observed in the previous trial, that there are no differences between TMS and tDCS and that the combination of TMS+tDCS has a 50% greater effect than TMS alone. Thus, we calculated the sample size for an ANCOVA model with four groups, adjusting for baseline scores of the primary outcome. Accordingly, a sample size of 12–15 participants per group would be required to achieve 80% power with a 5% alpha error level, accounting for an estimated 10% dropout rate (attrition rate). Finally, considering stratification by groups, the final sample size has been increased to 80 participants (20 per treatment arm). For this study, a statistical power of 80% was chosen, as it provides a reasonable balance between minimising type II error and maintaining feasibility of recruitment, especially considering the low prevalence of PPA.

Interventions

Participants will be randomised in a 1:1:1:1 ratio to one of the four treatment arms of the study: (a) active tDCS-active TMS; (b) active tDCS-sham TMS; (c) sham tDCS-active TMS; and (d) sham tDCS-sham TMS, with stratification by PPA variant (nfvPPA, svPPA or lvPPA). All patients will receive language therapy immediately after starting NIBS. The period of treatment will be 6 months, comprising 10 consecutive sessions in 2 weeks (intensive period) followed by once per week (maintenance period of 22 weeks) (figure 1).

Figure 1. Summary of the trial. This figure illustrates the study design. MLSE, Mini-Linguistic State Examination; ACE-III, Addenbrooke’s Cognitive Examination III; CDR, Clinical Dementia Rating; CETI, Communicative Effectiveness Index; IDDD, Interview for Deterioration in Daily Living Activities in Dementia; NPI, Neuropsychiatric Inventory; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; FDG-PET, fluorodeoxyglucose-positron emission tomography.

Non-invasive brain stimulation therapy

Electrical stimulation will be performed using a Nurostym tES device (Neuro Device Group S.A., Poland). Participants will receive active transcranial direct current stimulation using sponge-covered electrodes soaked in saline solution. The anode (electrode size 5×5 cm) will be positioned over the left dorsolateral prefrontal cortex. The cathode (5×5 cm) will be placed over the contralateral supraorbital area. The current will be ramped up over 15 s to reach an intensity of 2 mA, maintained for 20 min, and then ramped down over another 15 s at the end of the session. Continuous monitoring of the impedance will be performed during the treatment, maintaining it below 10 kΩ.

Immediately after finishing tDCS, an intermittent theta-burst stimulation protocol will be applied over the left dorsolateral prefrontal cortex, consisting of 10 bursts of triplet pulses at 50 Hz, repeated every 10 s, for a total of 600 pulses. Stimulation will be administered at 120% of the resting motor threshold, not exceeding 50% of the maximum stimulator output. All sessions will be conducted using a Magstim Rapid2 stimulator (Magstim, Whitland, UK) with a figure-of-eight coil, guided by neuronavigation (Brainsight V.2.4.11).

In both tDCS and TMS, individual structural MRI scans will be used to enhance precision in target localisation during neuronavigation using BrainSight neuronavigation system (Rogue Research Inc., Canada). The selection of the left dorsolateral prefrontal cortex as the brain target for all the PPA variants was conducted according to the previous experience after a single session of TMS,⁹ 2 weeks with tDCS²² and 6 months with TMS.⁷

For sham stimulation, the same procedure will be followed. In the case of tDCS, the current will be ramped up at the start and ramped down at the end of the session; however, it will remain off throughout the 20-min stimulation period. In the case of TMS, a sham coil will be employed. These methods are considered the most effective approaches to ensure proper blinding of brain stimulation effects.^{23 24}

Language therapy

The language therapy approach with the strongest evidence for PPA will be employed, which incorporates a modified hierarchy of steps from the Arizona Naming Cascade.²⁵ The intervention focuses on naming through guided retrieval of residual semantic, phonological and orthographic information, aiming to retrain specific vocabulary while also promoting broader word-retrieval strategies. These strategies include semantic circumlocution and the use of word-form knowledge for self-cueing. During the first 2 weeks, the patient will receive 10 language therapy sessions. Thereafter, each patient will receive one session per week. Each session will last 50 min. Language therapy will be conducted during the 20 min of tDCS administration, paused briefly for the 3 min of TMS, and then resumed for an additional period of 30 min to complete the language therapy protocol. Language therapy will be administered during and immediately after each neuromodulation session. Homework will be sent by email during the maintenance period following each weekly session. These consist of slides featuring images of the trained words along with their written forms. Participants are instructed to follow the Copy and Recall Treatment method²⁶ by copying the written word and saying it aloud 10 times.

All language therapy sessions are conducted by neuropsychologists specifically trained in the language therapy protocol. Adherence to the sessions and protocol fidelity are monitored through checklists and session recordings, which are periodically reviewed by the monitoring team of the Clinical and Trials Research Unit (UICEC) of Hospital Clínico San Carlos to ensure consistency across participants.

Overall, each session lasts approximately 50–60 min.

Study process

Patient inclusion in the study will be consecutive. A prospective log will be maintained for all individuals who are not included in the study, documenting the reasons for exclusion. During the screening visit, patients will receive study information, provide written informed consent and undergo evaluation of inclusion and exclusion criteria by a neurologist. The clinical assessments will be administered by trained neuropsychologists. All the study procedures and assessments are summarised in table 1.

Table 1. Schedule of assessments and procedures.

	Visit 0 (screening)	Visit 1	Treatment visits	Mid-study visit	Final visit
Visit	Weeks −12 to 0	Week 0		Week 12	Week 24
Procedure
Informed consent	X
Selection criteria	X
Randomisation	X
Medical history	X
Baseline cognitive assessment	X
MLSE		X		X	X
Naming		X		X	X
ACE-III		X		X	X
IDDD		X		X	X
CETI		X		X	X
CDR-FTLD		X		X	X
NPI		X		X	X
Spontaneous speech		X		X	X
FDG-PET		X			X
qEEG		X		X*	X
Blood collection		X			X
tDCS-TMS			X
Language therapy			X
Review of medication	X	X	X	X	X
Adverse events		X	X	X	X

^*EEG will be acquired at 2 weeks to evaluate the effects of the intensive period of brain stimulation and to determine the persistence of these effects at 24 weeks.

ACE-III, Addenbrooke’s Cognitive Examination III; CETI, Communicative Effectiveness Index; FDG-PET, fluorodeoxyglucose-positron emission tomography; FTLD, Frontotemporal lobar degeneration; FTLD-CDR, The CDR plus NACC FTLD; IDDD, Interview for Deterioration in Daily Living Activities in Dementia; MLSE, Mini-Linguistic State Examination; qEEG, Quantitative Electroencephalogram; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.

Randomisation

Participants will be randomly assigned in a 1:1:1:1 ratio to one of the four treatment arms using a computer-generated algorithm (random allocation software). The interval between randomisation and the initiation of treatment will range from 0 to 7 days. Randomisation will be stratified by the PPA variant (nfvPPA, svPPA, lvPPA). Randomisation will be conducted in fixed blocks of eight.

Blinding

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. The allocation sequence will be generated by an independent researcher not involved in participant recruitment or assessment. Allocation concealment will be ensured by withholding the randomisation sequence from the investigators enrolling and assessing participants. Immediately following randomisation, the technician in charge of administering the intervention will receive an email with the treatment allocation sequence.

The study protocol will be identical for all participants to ensure effective blinding. For TMS, a sham coil identical in appearance and acoustic properties to the active coil will be used, but without inducing physiological effects. For tDCS, the current will be ramped up at the beginning and ramped down at the end of the session to mimic the sensation of active stimulation; however, no current will be delivered during the 20-min stimulation period.

At the end of the trial, participants will be asked which treatment they believe they received, in order to assess the adequacy of blinding.

The success of blinding will be assessed at the end of the study by asking participants to guess their assigned treatment.

Concomitant treatments during the study

No medicines are contraindicated in this trial; however, all of them will be registered. Simultaneous participation in another clinical trial is not permitted. Women before menopause must use effective contraceptive measures.

Assessments

Sociodemographic variables will be documented during the screening visit. Clinical outcomes will be assessed at baseline, 3 months and 6 months immediately after the last session. A comprehensive cognitive and language examination will be conducted at baseline (table 2). This neuropsychological protocol has been described in previous studies.^{27 28}

Table 2. Baseline neuropsychological assessments.

Cognitive assessments

Digit span forward and backward Corsi block-tapping test Trail Making Test Symbol Digit Modalities test Visual Object and Space Perception battery (subtests for object decision, progressive silhouettes, position discrimination and number location) Judgment Line Orientation Tower of London-Drexel version Rey-Osterrieth Complex Figure (copy and memory) Stroop Color-Word Interference test

Language assessments

Cookie Theft picture description Reading narrative text Reading of words, capitalised words, foreign words and non-words Omission of the initial phoneme Spelling words Repetition of words, non-words, syllables, pairs of syllables and sentences Semantic association Naming objects Naming actions Word-object matching Synonyms judgement Picture-action matching Verb-tense agreement Sentence comprehension

Sociodemographic and medical variables

The following variables will be registered: age, sex, country of origin, history of bilingualism, ethnicity and race, years of formal schooling, time since disease onset, medications and comorbidities.

Primary outcome

The Mini-Linguistic State Examination is a brief language battery specifically designed for PPA.²⁹ It includes a series of tasks grouped in five language domains: motor, phonology, semantics, syntax and working memory. The test has been translated and adapted to different languages, and validated in two different cohorts in our setting.^{30 31}

Secondary outcomes

Secondary outcomes include the following: (a) naming of trained words, which will be evaluated using a list of 261 words from eight semantic categories (animals, food, objects, places, furniture, clothing, transportation and body parts); (b) ACE-III, a neuropsychological test specifically developed for the assessment of atypical causes of dementia and examining five cognitive domains (attention/orientation, episodic memory, verbal fluency, language and visuospatial abilities);³² (c) interview for Deterioration in Daily Living Activities in Dementia, a caregiver-administered scale assessing decline in basic and instrumental activities of daily living;^{33 34} (d) Spanish version of the Communicative Effectiveness Index, a 16-item caregiver-administered questionnaire for assessing functional communication in individuals with aphasia;³⁵ (e) Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration - Sum of Boxes (CDR plus NACC FTLD-SB), a clinician-rated scale that assesses global cognitive and functional impairment, including domains specific to frontotemporal dementia;³⁶ (f) Neuropsychiatric Inventory; also completed by caregivers, which evaluates 12 symptom domains including delusions, hallucinations, agitation, depression, anxiety, apathy, disinhibition, irritability, aberrant motor behaviour, sleep disturbances and appetite changes;³⁷ (g) regional brain metabolism in a region of interest capturing a large part of the left hemisphere and associated with clinical decline in PPA.⁷

Safety assessment

All study personnel, including TMS technicians, neurologists and clinical raters, will systematically monitor and inquire about adverse events (AEs) during each visit. Each AE will be recorded by the investigator present at the visit using the AE form provided by the monitoring team, and all recorded events will be reviewed during each monitoring visit by the UICEC of Hospital Clínico San Carlos. An AE will be defined as any unfavourable medical occurrence in a participant enrolled in the trial, regardless of its causal relationship with the intervention. An adverse reaction (AR), by contrast, refers to any unintended and harmful response that is suspected to be related to the intervention, irrespective of the administered dose.

AEs and ARs will be considered serious if they result in death, are life-threatening, require hospitalisation, cause significant or permanent disability, involve a congenital anomaly or necessitate medical intervention to prevent such outcomes. Events that do not meet these criteria may still be classified as serious if they pose a potential risk to the participant or require intervention to avert serious consequences.

Causality will be categorised as either related to the intervention—when a temporal association exists and no alternative explanation (such as underlying disease, comorbidities or concurrent treatments) is more likely—or unrelated, when the timing does not support a connection or the event can be explained by other factors. The severity of adverse effects will be graded as mild (no limitation in daily activities), moderate (some interference with daily functioning) or severe (inability to perform normal daily activities). Additionally, all AEs and ARs will be classified as expected or unexpected based on the known safety profiles of tDCS and TMS.

The trial will be paused or stopped if any of the following occurs: (1) a serious AE occurs that is considered related to the intervention and poses a significant risk to participant safety, (2) an unexpected pattern of multiple moderate or severe AEs emerges or (3) the ethics committee or the UICEC of Hospital Clínico San Carlos determines that continuation of the study would compromise participant safety or ethical standards. Any decision to pause or terminate the trial will be made in consultation with the principal investigator and the ethics committee.

Exploratory substudies

Patients will be invited to exploratory substudies, including blood biomarkers, electroencephalography and spontaneous speech analysis. The first two will provide insights about potential mechanisms associated with changes induced by each treatment.

Blood samples will be collected before and after each period of treatment, and serum and plasma samples (18 mL each) will be stored at −80 °C. Samples will be measured using the Quanterix Simoa technology or an equivalent procedure, including the markers glial fibrillary acid protein, brain-derived neurotrophic factor and neurofilament light chain. All the samples will be analysed at the end of the study.

Quantitative EEG (qEEG) data will be acquired using a 32-channel actiCHamp Plus system (Brain Products GmbH, Germany) with active electrodes arranged according to the international 10–20 system. Data will be recorded at a sampling rate of 1000 Hz, with electrode impedance maintained below 10 kΩ. Continuous EEG data will be referenced online to the vertex and re-referenced offline to the common average of all electrode sites. Participants will undergo 5 min of resting-state EEG with eyes open and 5 min with eyes closed, in a quiet, dimly lit room to minimise artefacts. Differences in power of neural oscillations, including variations both in power of neural oscillations in resting-state eyes-closed/open EEG (alpha, delta, theta, beta, gamma) and EEG brain connectivity (eg, measured by band coherence, phase lag index) will be analysed between four treatment groups.

Spontaneous speech will be examined showing the patient a wordless book (Frog stories by Mercer Mayer). Participant description for 3 min will be audiotaped using a Zoom H4n voice recorder and Audix HT2P headset dynamic microphone. Spontaneous speech will be processed by one of the researchers, blinded to the treatment group and clinical data, using the procedure described elsewhere.³⁸ Spontaneous speech analysis will be useful to further characterise the impact of NIBS and language therapy in communication abilities.

Data management and analysis plan

The original protocols of the study will be stored in a locked office. De-identified data will be saved on a secure electronic database. We will use Research Electronic Data Capture(REDCap) (Vanderbilt University), a secure, browser-based web application (http://project-redcap.org). Trial data, including scales and questionnaires, will be completed in paper form, and then will be uploaded to REDCap.

Analyses will follow the intention-to-treat principle, including all participants with available post-baseline data. Missing data will not be imputed. Normality and homogeneity of variance will be assessed using the Shapiro-Wilk and Levene’s tests, respectively. Baseline group characteristics will be analysed using χ² tests, Fisher’s exact test, Student’s t-test or the Mann-Whitney U test, as appropriate.

To evaluate the effect of the intervention, an ANCOVA will be conducted for each outcome. The dependent variable will be the outcome measure (eg, MLSE at 6 months), and the treatment arm will be included as the independent variable. The PPA variant and baseline assessment (eg, baseline MLSE) will be included as covariates. Additionally, any baseline variables showing potential differences between treatment groups will also be entered as covariates. After confirming the effect between baseline and 6 months, comparisons between baseline and 3 months will be conducted. Effect size estimates will also be calculated. A p value <0.05 will be considered the threshold for statistical significance.

Cost analysis

If the effect of TMS (or the combination of tDCS+TMS) is superior to tDCS alone, a cost-effectiveness analysis will be conducted to estimate the incremental cost associated with TMS based on the number needed to treat, in order to assess the cost-effectiveness of TMS in this scenario.

Data monitoring

The study will be monitored in accordance with Good Clinical Practice guidelines and applicable regulations. Monitoring will be carried out by personnel from the hospital’s Clinical Trials Unit, who are independent of the research team. Monitoring activities will include regular onsite visits and telephone communications as required by the study’s progress. During these visits, the monitor will review source documents and study files and will address any relevant issues with the investigator and/or the sponsor. Any protocol deviations identified will be reported to the principal investigator and the sponsor. Serious protocol violations will be reported in compliance with current regulatory requirements.

Patient and public involvement

Patients and the public were not involved in the design, planning, recruitment or conduct of this study. However, participants will be invited to share their opinions and experiences regarding the study and its procedures, and their feedback will be considered in the design of future research. The findings of the trial will be shared with participants through a dedicated newsletter and during patient-specific meetings. Participation in the study is entirely voluntary, and no financial compensation will be provided to participants.

Ethics and dissemination

The study will be conducted in compliance with applicable regulations and guidelines on Good Clinical Practice, biomedical research and clinical trials. Ethical approval has been obtained from the Ethics Committee of Hospital Clínico San Carlos. Written informed consent will be obtained from all participants prior to the initiation of any study-related procedures. The UICEC of Hospital Clínico San Carlos will supervise ethical compliance through monitoring visits during the trial. The outcomes of the study will be disseminated through presentations at scientific conferences and publication in peer-reviewed journals, irrespective of the nature of the results.