Axonal Degeneration in Soft Palate Nerves May Contribute to Obstructive Sleep Apnea
Obstructive sleep apnea (OSA), the intermittent cessation of breathing during sleep, occurs when the upper airway tissues (e.g., tonsils, fatty tissue) repeatedly collapse into the upper airway and partially or fully block airflow.
The collapsibility of the upper airway in people with OSA is believed to occur because the upper airway muscles relax excessively during sleep, which allows structures supported by the muscles to collapse into the upper airway.
Some research indicates that altered neuronal activation may contribute to the reduced tone of the upper airway muscles.1-4 Much of this research has focused on innervation of dilator muscles such as the genioglossus muscle (which forms the bulk of the tongue).
However, another structure that contributes to obstruction is the soft palate. In recent years, scientists have begun examining whether neuronal injury in the soft palate muscles could contribute to OSA.
Anatomical Causes of OSA
People with OSA often have an elongated uvula, a structure that extends like a pendulum from the soft palate just above the tongue at the back of the throat. The soft palate muscles consist of the uvular muscle (which raises the uvula), the levator veli palatini muscle (which raises the soft palate) and the tensor veli palatini muscle (which aids in raising the soft palate). Whether the elongated uvula results from muscle injury due to stretching of the uvular muscle during OSA episodes or results from abnormal neuronal activation is unclear.
During the obstructive phase of an OSA episode, the impeded airflow decreases the amount of oxygen in the blood. As a consequence, a person makes increasingly strong efforts to breathe. When the oxygen level falls to a certain point, the respiratory center in the brain triggers a brief arousal, during which the upper airway muscle tone is restored and a person is able to take some deep, quick breaths to restore the blood oxygen level. During this brief arousal, snoring may occur because the rapid airflow through the upper airway causes soft tissues to flutter, much like the flutter that occurs when air escapes rapidly from a small opening in a balloon.
Snoring, Vibration, and Upper Airway Inflammation
In studies of animal models of OSA and human snorers, the upper airway tissues show signs of damage such as inflammation (e.g., swelling, redness, increased levels of inflammatory substances such as tumor necrosis factor, and increased levels of inflammatory cells).5-7 These changes are believed to result from vibration of the upper airway tissues. Whether the vibration occurring with OSA episodes could also damage the axons of nerves that supply the upper airway muscles has been of recent focus.7
Assessing Axonal Injury or Loss
An indirect way to assess axonal injury or loss is by examining Schwann cells. Schwann cells (named after German physiologist Theodor Schwann, who discovered them in 1939) are involved in nerve growth, nerve repair and nerve impulse conduction. A Schwann cell can be myelinating or nonmyelinating. Within a peripheral nerve, which contains several nerve fibers (i.e., axons), a myelinating Schwann cell spirals around one axon while producing layers of myelin around the axon. Myelin enhances the velocity at which nerve impulses travel through an axon. An axon can have several Schwann cells along its length. A nonmyelinating Schwann cell does not spiral around an axon. It instead envelops several axons within a nerve. When a Schwann cell is damaged, it can stop producing myelin and become unable to participate in nerve growth and nerve repair.
Factors that can damage Schwan cells are impaired immune function, exposure to toxic chemicals, injury to the axon and mechanical factors such as vibration. Some research indicates that the amount of damage to the myelin sheath is directly correlated with the duration of vibration exposure.
Vibratory Studies on Limbs of Rats Associated with Myelinated Nerve Damage
For example, in a study by John Davis and colleagues,8 the researchers exposed rats to vibration for four hours daily for seven days (i.e., short-term) or 14 days (i.e., long-term). To induce vibration, the rats were placed in a restraint tube on a stationary platform. Their tails were taped to a vibrating stage. The control rats were restrained similarly but without vibration. The platform was vibrated at a rate of 60 vertical oscillations per second. After undergoing vibration treatment for seven or 14 days, the rats were allowed a recovery time of zero days, 30 days or 60 days before tissue from their tail was retrieved and examined under a light microscope.
In the experimental group, the severity of myelinated nerve damage increased as the vibration exposure time increased. At recovery day zero, both groups had nerve damage. At recovery day 30, the seven-day group had signs of recovery, but the 14-day group did not. At recovery day 60, the seven-day group showed a near-complete recovery, but the 14-day group still had significant damage. Long-term vibration caused greater damage from which recovery appeared to be limited (i.e., some damage may be permanent).
The focus of the Davis study was on the effect of vibration on a limb rather than the upper airway. However, if upper airway tissue is damaged because of upper airway tissue vibration in snorers and in people diagnosed with OSA, then the loss of Schwann cells or other alterations in Schwann cells in upper airway tissues would be expected. Research with this focus in humans has indicated that the association between upper airway tissue vibration in OSA and neuronal injury may be true.
Neurological Alterations in People With OSA
In a 2015 cadaveric study,9 de Carlo and colleagues analyzed tissue derived from the walls of the oropharynx and hypopharynx of individuals with and without OSA. The tissue samples contained the whole thickness of the pharyngeal walls (i.e., mucosa, muscle tissue). They used immunohistochemical methods (i.e., the use of antibody-antigen reactions and chemicals such as dyes to detect cell structures) to detect axons and Schwann cells, and to detect two proteins — ASIC2 and TRPV4 — on mechanosensory nerve cells, which are stimulated by mechanical stimuli such as stretch, motion and vibration.
They found that, compared to the individuals without OSA, individuals with OSA had a significantly lower density of nerve fibers in the muscle layer. The ASIC2 and TRPV4 proteins were expressed in the axons of mechanosensory cells in the muscular layer of the pharyngeal tissues of individuals without OSA but were virtually absent in individuals with OSA. Based on these findings, De Carlo concluded that neurological alterations may contribute to pathological upper airway activity in people with OSA.
A team of Swedish researchers, headed by Farhan Shah,10 recently demonstrated Schwann cell death and axonal degeneration in the nerves supplying muscles of the soft palate of snorers and patients with OSA. The researchers also examined whether nerve injury in the upper airway of snorers and people with OSA would be associated with the severity of sleep apnea. They compared patients, who had undergone palatal surgery for snoring, with healthy nonsnoring individuals (i.e., the controls). Tissue samples from the base of the uvula were obtained from all participants. The samples were examined using morphologic and immunohistochemical methods.
Compared to the controls, the patients with snoring or OSA had a significantly lower density of axons, a lower percentage of Schwann cells, and a larger percentage of circular myelinating Schwann cells without central axons, which indicates axonal loss. In addition, the low density of axons was significantly correlated with the severity of apnea.
Patients with snoring or OSA more frequently had evidence of regenerating axons (based on the increased level of growth-associated protein 43, which is associated with neuronal growth) than did the controls (11.3% ± 4.2% vs. 4.8% ± 2.4%). Shah suggests that nerve injury is caused by traumatic snoring vibrations and tissue stretch that occur during OSA episodes.
The association between tissue vibration and neuronal injury in the soft palate and other upper airway muscles is an interesting finding and needs further study. More information may provide new avenues for OSA treatment. For example, more research may help scientists determine whether vibration of the upper airway tissues during OSA episodes causes neuronal damage in soft palate muscles and other muscles of the upper airway or whether some other unknown factor actually causes the damage, which then leads to OSA. If the latter, then detecting and/or treating this factor could potentially improve OSA treatment. For now, research continues on investigating the association between vibration-induced nerve damage of the upper airway muscles in people with OSA.
This article was originally Featured in the A2Zzz Magazine Q4 2019 Issue
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