TRANSLATIONAL STUDIES IN THE DEVELOPMENT OF NEUROSTIMULATION BASED INTERVENTIONS FOR REHABILITATION OF DYSPHAGIA AFTER STROKE

Neural control of swallowing is hierarchical, involving the cerebral cortex and interactions with several other brain regions including the cerebellum. Cortical control of swallowing exhibits functional asymmetry, whereby brain lesions disrupting the stronger ('dominant') hemisphere are implicated in post-stroke dysphagia. A major breakthrough has been the consistent observation that compensatory changes (neuroplasticity) in the undamaged (contralesional) hemisphere are responsible for swallowing recovery. Whilst existing therapies lack evidence-base, neurostimulation interventions capable of facilitating this natural recovery process have the potential to revolutionise swallowing rehabilitation. Whilst data using several neurostimulation modalities have been promising, translating them into much needed clinical therapies has been hampered by clinical study designs lacking homogeneity.In a series of studies, using three different modalities I describe a step-wise approach for developing neurostimulation interventions from bench-to-bedside. Firstly, in a proof of concept experiment, targeted cerebellar repetitive Transcranial Magnetic stimulation (rTMS) was assessed in healthy subjects (n=17), confirming frequency and duration specific (250-pulses of 10-Hz) induction of long-lasting changes in pharyngeal cortical plasticity, effects which were explored with therapeutic potential in a dysphagic patient. Secondly, in a pre-clinical model of post-stroke dysphagia, optimal parameters of cortical transcranial Direct Current Stimulation (tDCS) were tested, confirming reversal of transient neurophysiological and behavioural swallowing deficits induced by a 'virtual-lesion' (10 minutes, 1-Hz rTMS to the 'dominant' hemisphere) in 15 healthy subjects. Finally, in a randomised trial, optimal parameters and dosage (5-Hz, 10 minutes daily for 3-days) of Pharyngeal Electrical Stimulation (PES) were studied in acutely dysphagic stroke patients (n=36) which despite lower than desired recruitment, trended towards reduced dysphagia severity at 2-weeks, earlier hospital discharge and nasogastric tube removal were observed. These studies have shown for the first time that the cerebellum is a viable target for non-invasive brain stimulation swallowing studies and that cortical tDCS can reverse experimental brain lesions, with both techniques having therapeutic potential for post-stroke dysphagia. These clinical trial data add to the increasing evidence base for PES, the modality with the most evidence to date, with longer-term follow-up. The difficulties encountered in the post-stroke clinical trial in both recruitment and outcome measures highlight the importance of mechanistic studies which have often been lacking, in optimising stimulation specific factors; site, duration, intensity, dosing and controls, prior to clinical trials. An independent, larger, multi-centre, international trial of PES, with greater resources is now required to definitively determine its clinical efficacy. In summary, there may be a role for several different neurostimulation modalities in different patient sub-groups and my preliminary observations lead me to hypothesise that future translation of these therapies will depend on targeting population tailored to specific interventions.