According WHO, oropharyngeal dysphagia (OD) is a prevalent post-stroke (PS) condition involving the digestive system (ICD-10: I69.391) and an independent risk factor for malnutrition and pulmonary infection; and leads to greater morbimortality and healthcare costs and poorer quality of life (QoL). Currently, OD therapy is mainly compensatory, with low rates of compliance and small benefit, and there is no pharmacological treatment, so new treatments that improve patients' condition are crucial. PS-OD patients present both oropharyngeal sensory and motor deficits, so neurorehabilitation treatments which target both could be optimum. Benefits of paired peripheral sensory stimulation with oral capsaicin and of central motor noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) will be studied. Pairing pharmacological peripheral and central stimulation may produce greater benefits. The main aim of the project is to study the efficacy of two novel protocols of paired stimulation on PS-OD patients. The investigators will assess whether 5-day application of tDCS/capsaicin or rTMS/capsaicin in the chronic phase of stroke, will improve PS-OD. One RCT (200 patients in the chronic stroke phase divided in 4 study arms) will assess changes in swallow safety, biomechanics and neurophysiology of the swallow response, hospital stay, respiratory and nutritional complications, mortality and QoL.

• Main hypothesis: Paired neurorehabilitation treatment targeting both pharyngeal sensory and motor components simultaneously through a peripheral pharmacological stimulant (Transient Receptor Potential Cation Channel [TRPV1] agonist, capsaicin) and central stimulation (NIBS) strategies (rTMS or tDCS) can improve swallowing function in chronic PS-OD patients by promoting cortical plasticity, their QoL and reduce OD associated complications.
• Main aim: To assess the effects on swallowing of 2 neurostimulation strategies applied for 5 days to treat PS-OD in the chronic phase (>3 months from stroke onset) of ambulatory patients, the application of rTMS + capsaicin vs. tDCS + capsaicin in two independent RCTs. The main outcome measure for these three RCTs will be changes in prevalence of impaired safety of swallow assessed by videofluoroscopy.
• Secondary aims To assess: 1) safety and adverse events; 2) the effects on safety of swallow with a standardized protocol of swallowing evaluation; 3) clinical outcomes at 3 months follow up; 4) the effect of the treatments on SSF and responsiveness to treatment according to stroke characteristics; 5) the effect in the chronic phase on: i) assessment of afferent and efferent pathways with sensory and motor evoked-potentials to electrical pharyngeal stimulation and TMS, respectively; ii) prevalence of signs of impaired safety/efficacy on videofluoroscopy (VFS), the penetration-aspiration score (PAS) (Rosenbek scale) and the biomechanics of the swallow response; and iii) specific clinical outcomes such as mid-term complications, readmission rate and QoL.
• Design: Single-center, double-blinded, two-arm, double-randomization RCT. Patients are distributed into two parallel subgroups (each with its own sham group) according to intervention type.Blinding will be applicable for clinical and instrumental assessments for investigators, and for intervention condition for patients. Patients undergo V-VST, biomechanical (VFS) and neurophysiological (sEMG and evoked potentials) swallowing evaluation, and double randomization, first for intervention type (tDCS or rTMS) and then for intervention condition (active or sham), using the same software as Task1. Treatment is applied for 5 consecutive days using either rTMS (G1: active rTMS+capsaicin; G2: sham rTMS+placebo) or tDCS (G1: active tDCS+capsaicin; G2: sham tDCS+placebo) as NIBS procedures. Finally, patients are reevaluated as before and clinical outcome at 3 months.
• Study population: 200 Chronic PS-OD ambulatory patients.
• Inclusion criteria: Chronic (>3 and <24 months) unilateral hemispheric stroke adult patients; ISS (V-VST); can follow the study protocol and give written informed consent.
• Exclusion criteria: Pregnancy; life expectancy <3m or palliative care; neurodegenerative disorder or previous OD; implanted electronic device; epilepsy; metal in the head; participation in another clinical trial in the previous month.
• Sample size/power calculation: The main outcome measure is the prevalence of patients with ISS according to VFS at post-treatment visit. To compare the prevalence between groups, using the arcsinus approximation, accepting an alpha risk of 0.05 and a beta risk of 0.2 in a 2-sided test, 50 patients/group are needed for each NIBS procedure, 2 for rTMS and 2 for tDCS (4 groups=total of 200 patients) to find a significant difference in the proportion of 0.4 in the control group and 0.7 in treated group (drop-out rate of 15%).
• Recruitment: Patients will be consecutively recruited and randomly allocated to the groups, according first to NIBS procedure (1:1, tDCS/rTMS) and then to intervention condition (1:1, active/sham).
• Study Intervention:

tDCS: G1: Active treatment consists of swallowing 10mL capsaicin (150μM) and, just after, of applying 30min of 2.0mA tDCS (DC-Stimulator Plus, NeuroConn, Germany) with the anode placed over the pharyngeal primary motor cortex (M1) of the unaffected hemisphere (3.5cm lateral / 1cm anterior to the vertex) and the cathode over the opposite supraorbital region. Treatment applied over 5 consecutive days.

rTMS: G1: each session (5 consecutive days) of active treatment consists of swallowing 10mL capsaicin (150μM) and, just after, of applying focal (alpha D70 coil) rTMS (Magstim Rapid2, UK) over the pharyngeal M1 hotspot of the unaffected hemisphere. Neuronavigation (Brainsight TMS navigation, UK) ensures the exact hotspot over 5 days. A total of 500 pulses/session are delivered consisting of 10 5Hz-trains of 10s of 50 pulses each (total 2500 pulses), with a 1min interval between trains at an intensity of 90% of the resting motor threshold (RMT). G2: Sham rTMS+oral placebo (10mL of potassium sorbate). The same protocol will be applied, but with the coil tilted 90º from the tangent of the skull, as a standard method for sham rTMS application.

• Swallowing assessment (pre- and post-intervention): Patients with impaired safety of swallow will be screened with volume-viscosity swallowing test (V-VST), and videofluoroscopy (VFS) recordings are obtained in a lateral projection (25 frames/s). Swallow biomechanics are analyzed at VFS with Swallowing Observer (Image&Physiology SL, Spain). The spontaneous swallowing frequency (SSF) during 10min will be measured with surface electromyography (sEMG) over the digastric-mylohyoid complex.
• Pharyngeal sensory evoked potentials (pSEPs) are recorded with a 32-electrode electroencephalographic (EEG) recording cap (10/20 system) during a series of electrical stimuli (4 sets of 50 pulses of 0.2ms at 0.2Hz, intensity of 75% tolerance threshold; Digitimer DS7A & DG2A pulse generator, UK) applied to the pharynx with an intra-pharyngeal catheter (Gaeltec Ltd, Scotland).
• Pharyngeal motor evoked potentials (pMEPs) and RMTs for both hemispheres are recorded with the same catheter to TMS (20 pulses to each hotspot at intensity +20%RMT; Magstim Bistim2, UK).

Primary outcomes: Pre- vs post-intervention changes in VFS signs of safety and efficacy of swallow, PAS scoring, timing of swallow response and amplitude and latency of pSEPs and pMEPs.

• Secondary outcomes: Pre/post-intervention changes in sEMG for SSF, safety (adverse events rate), clinical outcomes during admission and at 3-month follow-up (length of stay, aspiration pneumonia, nutritional [MNA-sf] and functional status [Rankin scale, Barthel], readmissions and mortality), and V-VST at 3 months.
• Additional secondary outcomes: differences in the magnitude of the effect in primary outcomes found in chronic PS phase between the tDCS (+capsaicin) and rTMS (+capsaicin) interventions.

Inclusion Criteria:

• Chronic (>3 and <24 months) unilateral hemispheric stroke adult patients.
• Patients with impaired safety of swallow with a penetration-aspiration score (PAS) ≥ 2 with videofluoroscopy (VFS).
• Patient able to follow the study protocol and give the written informed consent.

Exclusion Criteria:

• Pregnancy.
• Life expectancy less than 3m or palliative care.
• Neurodegenerative disorder.
• Previously diagnosed oropharyngeal dysphagia (dysphagia not related to stroke).
• Implanted electronic device.
• Epilepsy.
• Metal in the head.
• Participation in another clinical trial in the previous month.

No IPD will be available to other researchers.

Double-blinded. Blinding will be applicable for clinical and instrumental assessments for investigators, and for intervention condition for patients.