Emergence of Deglutology, a Transdiciplinary Field

Oropharyngeal dysphagia is a well-known manifestation of a large number of acute and chronic neurologic disorders including Parkinson's disease (PD), and is associated with pulmonary complications as a leading cause of mortality in these patients ¹. Symptoms of dysphagia in PD patients poorly correlate with objective video fluoroscopic findings ²; in addition, age, severity and duration of the disease are not reliable predictors of dysphagia ³. Deglutitive dysfunction in PD does not improve with levodopa therapy ^4-6, and may occasionally deteriorate with dopamine precursor therapy ². The exact underlying neurogenic mechanisms of swallowing dysfunction in PD are not well established and involvement of non-dopaminergic mechanisms has been suggested ⁶. Recent comprehensive postmortem neuropathologic studies of PD patients have indicated that brain pathology (Lewy neurites and Lewy bodies) in PD originates in the olfactory bulb and visceromotor projections of dorsal nucleus of the glossopharyngeal and vagal nerves in medulla oblongata years prior to involvement of nigrostriatal pathway and onset of somatomotor dysfunction ⁷. Furthermore, these histopathologic observations have shown atrophic and denervated pharyngeal constrictors and cricopharyngeus myofibers ⁸; axonal degenerative changes in vagal and sympathetic motoneurons innervating pharyngeal constrictors and cricopharyngeus ⁹, along with degenerative changes of predominantly sensory internal superior laryngeal branch of the vagus nerve ¹⁰. Collectively these central and peripheral autonomic sensorimotor impairments in dysphagic PD patients may explain compromised cough reflex ¹¹, delayed swallow reflex ^{3, 12}, pharyngeal peristaltic incoordination ^{3, 13} and incomplete UES relaxation ^{3, 14}. Together these mechanistic abnormalities contribute to self-reported dysphagia (28-41%) ¹⁵, objective videofluoroscopic metrics of dysphagia (77-87%) ¹⁵ and ultimately aspiration pneumonia (11-45%) in PD patients ^{16, 17}. Current dysphagia management in PD patients is unsatisfactory. A number of approaches including dietary modification and swallowing maneuvers ¹⁶, dopaminergic and anticholinergic pharmacotherapy ¹⁸, expiratory muscle strengthening ¹⁹, video based biofeedback therapy ²⁰, cricopharyngeal myotomy ²¹ and cricopharyngeus Botolinum toxin injection ²² have all been utilized with variable outcomes, necessitating further research to devise pathophysiology based therapeutic modalities ²³.

Tangible progress in management and treatment of neurogenic dysphagia including those due to PD has been slow because of the inability to identify and address the fundamental alterations in various organs that are affected in these patients. Remedying this shortcoming requires collaboration among experts from multiple fields applying a transdisciplinary approach. Contribution of diverse scientific disciplines such as biophysics, neuroimaging, neuroscience, neurology, otolaryngology, gastroenterology and speech language pathology is needed to fully bring the cutting edge advances in their respective disciplines to the field of swallowing disorders. This convergence of disciplines has the potential to shift our focus from merely mechanical peripheral assessment and management strategies of deglutition utilizing video fluoroscopy, manometry and electromyography to a more comprehensive approach that adds the understanding of mechanisms of brainstem control and the cortical modulator effects on deglutition. Better understanding of neuronal mechanisms also may allow us to formulate therapeutic approaches beyond mere rehabilitation to effective interventions inducing neuroplasticity and metaplasticity at cellular and neuronal network levels.

Over the past two decades, our understanding of the human brain function has extended beyond traditional brain lesion studies and its associated behavioral deficits. Simple yet incomplete structure-function relationship that traditionally attributed a specialized relatively independent function (e.g. movement of a muscle) to a distinct brain region (a segment of motor cortex), has not been able to elucidate complex and coordinated behaviors that depend critically on often transient interactions of not only distant brain regions but also brain networks ²⁴. Initial application of noninvasive functional neuroimaging techniques such as functional magnetic resonance imaging^{25, 26}, positron emission tomography ^{27, 28}, and magnetic encephalography ²⁹ extended the classic structure-function observations to humans in-vivo. Recent expansion of imaging technology such as structural ^{30, 31} and functional ^{32, 33} connectivity techniques, and sophisticated analytical concepts like graph theoretical analysis ³⁴ have allowed deeper and broader investigation of dynamic functions of neuronal networks. Moreover, modern and safe noninvasive brain stimulation techniques in humans such as Trancranial magnetic stimulation (TMS) ³⁵ and transcranial direct current stimulation (tDSC ³⁶) not only have offered unique understanding of brain network organization and dynamism ³⁷, but also have shown potential therapeutic applications ³⁸. TMS can be applied in single or paired pulse paradigms or repetitive trains of stimulation ³⁷. Strong evidence suggests that human TMS protocols induce cortical plasticity comparable to NMDA-receptor dependent glutamatergic long-term potentiation (LTP)-like and long-term depression (LTD)-like effects seen in animal models ³⁹. The NMDA receptor antagonists effectively block the facilitatory or inhibitory effects of TMS protocols in humans ⁴⁰, that depend on the underlying state of the targeted brain region⁴¹. Michou et al. in the current issue of this publication have utilized TMS to evaluate cortical excitability in PD patients, investigating neurophysiologic mechanisms of dysphagia off and on dopaminergic therapy ⁴². They show that embracing non-invasive brain stimulation along with neurotransmitter modulation open tremendous opportunities in translational neurosciences, allowing us to address fundamental issues in neurogenic dysphagia patients such as those affected by PD.

Functional magnetic resonance imaging ^{43, 44}, positron emission tomography ^{45, 46}, and magnetic encephalography ⁴⁷ have all confirmed the role of cortex in volitional and reflexive swallow ^48-50. Although a consistent ensemble of brain regions (sensorimotor, cingulate and insular cortices, lateral prefrontal and parietal regions) has been identified in governance of deglutition ^{51, 52}, the specific role of distinct brain regions and their interactions await further study. Functional connectivity of swallowing network and interactions of involved brain regions has just been recently described for resting state and during swallowing ^53-55. These findings may enhance our understanding of the physiology of deglutition. In addition, interventional investigations such as peripheral sensory ⁵⁶ and central cortical stimulation ⁵⁷ of the deglutitive apparatus have not only enriched our understanding of pathophysiology of neurogenic dysphagia but also have opened the possibility to induce enduring cortical neuroplasticity and behavioral swallow improvement ^{58, 59}.

As evidenced by recent findings, the pathobiology of neurogenic dysphagia in general and in Parkinson's disease specifically extends beyond the boundary of any single discipline. Effective management of this disorder requires convergence of several basic and clinical disciplines in a collaborative and complimentary fashion, approaching the deglutition and its disorders in its entirety from the neurons of the cerebral cortex to the muscle fibers of the pharynx and esophagus with a physiologic and pathophysiologic perspective. Michou et al, have used this “deglutology” approach in their study entitled “characterization of corticobulbar pharyngeal neurophysiology in dysphagic patients with Parkinson's disease” in this issue of Clinical Gastroenterology and Hepatology. This is a welcome approach and the authors are congratulated for taking on this important task.