Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration.
Parkinson’s disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor symptoms and central nervous system pathology. As current drug therapies can often stabilize these cardinal motor symptoms attention has shifted to the other motor and non-motor symptoms of PD which are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug resistant symptom as it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. In this study, we examined the cervical vagal (X) nerve, pharyngeal branch of the X nerve (Ph-X), and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, 10 subjects with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. α-Synuclein aggregates were revealed in the X nerve and Ph-X and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all the PD subjects and in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathological process of PD. Notably, PD subjects with dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves as compared with those without dysphagia. Motor involvement of the pharynx in PD appears to be one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients.
Dysphagia (impaired swallowing) is common in Parkinson disease (PD) patients and is related to aspiration pneumonia, the primary cause of death in PD. Therapies that ameliorate the limb motor symptoms of PD are ineffective for dysphagia. This suggests that the pathophysiology of PD dysphagia may differ from that affecting limb muscles but little is known about potential neuromuscular abnormalities in the swallowing muscles in PD. This study examined the fiber histochemistry of pharyngeal constrictor (PC) and cricopharyngeal (CP) sphincter muscles in postmortem specimens from 8 PD and 4 age-matched control patients. Pharyngeal muscles in PD patients exhibited many atrophic fibers, fiber type grouping, and fast-to-slow myosin heavy chain transformation. These alterations indicate that the pharyngeal muscles experienced neural degeneration and regeneration over the course of PD. Notably, the PD patients with dysphagia had a higher percentage of atrophic myofibers vs. with those without dysphagia and controls. The fast-to-slow fiber type transition is consistent with abnormalities in swallowing, slow movement of food and increased tone in the CP sphincter in PD patients. The alterations in the pharyngeal muscles may play a pathogenic role in the development of dysphagia in PD patients.
1. Inferotemporal, hippocampal, and parahippocampal units were recorded while monkeys were alert (as judged by eye movements) but resting, in both light and dark. 2. Spontaneous saccadic eye movements produced significant changes in unit activity for 108 of 308 cells. This activity is shown to be extraretinal either because it occurred in complete darkness or because of its timing relative to the eye movement. 3. The total saccadic modulation in the ventral temporal lobe is estimated to be over ten million action potentials.
We investigated recognition and association memory in the responses of single units isolated in the inferior temporal cortex of a macaque while it performed a visual discrimination task. The unit responses showed significant recognition memory (a decreased response upon image repetition). Furthermore, a recognition memory appeared to be a permanent feature in these units. Such memory was evident in responses recorded at least 1 h after the most recent presentations of the more familiar images and may have been built up over the months of training. For these cells, the shorter-term recognition memory (seconds) and the longer-term recognition memory (hour plus) were significantly correlated (0.68). In these same cells associative memory was investigated with ten abstract images which had been randomly and permanently paired. The monkey had been taught to discriminate these five pairs from other similar pairs of images. Neither the spike count nor temporal response shape (as determined by a principal-components analysis) showed increased similarity for the images that had been paired. The cells that had both short-term and long-term recognition memory had responses to previously paired stimuli that were no more similar than expected by chance.
Background
As currently existing reinnervation methods result in poor functional recovery, there is a great need to develop new treatment strategies.
Objectives
To investigate the efficacy of our recently developed nerve-muscle-endplate band grafting (NMEG) technique for muscle reinnervation.
Methods
Twenty-five adult rats were used in this study. Sternohyoid (SH) and sternomastoid (SM) muscles served as a donor and a recipient muscle, respectively. Neural organization of the SH and SM muscles and surgical feasibility of the NMEG technique were determined. A NMEG contained a muscle block, a nerve branch with nerve terminals, and a motor endplate (MEP) band with numerous neuromuscular junctions. After a 3-month recovery period, the degree of functional recovery was evaluated using maximal tetanic force measurement. Retrograde horseradish peroxidase (HRP) tracing was used to track the origin of the motor innervation of the reinnervated muscles. The reinnervated muscles were examined morphohistologically and immunohistochemicaly to assess the extent of axonal regeneration.
Results
Nerve supply patterns and locations of the MEP bands in the SH and SM muscles were documented. The results demonstrated that the reinnervated SM muscles gained motor control from the SH motoneurons. NMEG technique yielded extensive axonal regeneration and significant recovery of SM muscle force generating capacity (67% of the control). The mean wet weight of the NMEG reinnervated muscles (87% of the control) was greater than that of the denervated SM muscles (36% of the control).
Conclusion
NMEG resulted in successful muscle reinnervation and functional recovery. This technique holds promise in the treatment of muscle paralysis.
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