Neurogenic changes in the upper airway of patients with obstructive sleep apnea

Abstract

Rationale: Controversy persists regarding the presence and importance of hypoglossal nerve dysfunction in obstructive sleep apnea (OSA).

Objectives: We assessed quantitative parameters related to motor unit potential (MUP) morphology derived from electromyographic (EMG) signals in patients with OSA versus control subjects and hypothesized that signs of neurogenic remodeling would be present in the patients with OSA.

Methods: Participants underwent diagnostic sleep studies to obtain apnea-hypopnea indices. Muscle activity was detected with 50-mm concentric needle electrodes. The concentric needle was positioned at more than 10 independent sites per subject, after the local anatomy of the upper airway musculature was examined by ultrasonography. All activity was quantified with subjects awake, during supine eupneic breathing while wearing a nasal mask connected to a pneumotachograph. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which extracted motor unit potential trains (MUPTs) contributed by individual motor units from the composite EMG signals. Quantitative measurements of MUP templates, including duration, peak-to-peak amplitude, area, area-to-amplitude ratio, and size index, were compared between the untreated patients with OSA and healthy control subjects.

Measurements and main results: A total of 1,655 MUPTs from patients with OSA (n = 17; AHI, 55 ± 6/h) and control subjects (n = 14; AHI, 4 ± 1/h) were extracted from the genioglossus muscle EMG signals. MUP peak-to-peak amplitudes in the patients with OSA were not different compared with the control subjects (397.5 ± 9.0 vs. 382.5 ± 10.0 μV). However, the MUPs of the patients with OSA were longer in duration (11.5 ± 0.1 vs. 10.3 ± 0.1 ms; P < 0.001) and had a larger size index (4.09 ± 0.02 vs. 3.92 ± 0.02; P < 0.001) compared with control subjects.

Conclusions: These results confirm and quantify the extent and existence of structural neural remodeling in OSA.

Figure 1.

Typical example of genioglossus data with four motor units concurrently active during quiet breathing. Shown is a typical example of data extracted from a recording from a single subject. From bottom to top: respiratory airflow, selective concentric needle electromyography (EMG), concentric needle macro (CNMACRO) EMG (recorded from the cannula of the concentric needle), tidal volume, and the instantaneous discharge frequency of four single motor units extracted after the decomposition of the raw composite concentric needle EMG signal. Inset: The averaged selective concentric needle motor unit potential (MUP) templates and the ensemble averaged CNMACRO MUPs. Calibrations of the selective concentric needle MUPs and CNMACRO MUPs, 100 μV and 2 milliseconds.

Figure 2.

Neurophysiological features measured from the selective concentric needle motor unit potential templates. Selective concentric needle motor unit potential (MUP) analysis provides quantitative insight into the physiology of the motor unit. As such, it is possible to differentiate the normal muscle from neurogenic injury by MUP analysis. Global features included in the analysis were the duration of the motor unit potential as measured between the onset of the first and the offset of the last peak of the MUP (22). Duration is related to the number of muscle fibers contributing to the motor unit. Peak-to-peak amplitude is calculated as the voltage difference of the MUP and is determined by the diameter and number of muscle fibers closest to the electrode. Area is calculated by measuring the rectified MUP (over the duration). Area is less sensitive to measurement error than amplitude and is able to characterize atypical potentials. The number of phases (indicated by the black numbered circles) of the MUP are defined as the number of baseline crossings. The number of turns are defined as a change in the direction of the MUP waveform with a magnitude of at least 25 μV. To quantify further MUP complexity, a number of indices were used, including the following: area/phase ratio, which is better able to distinguish myopathic MUPs from normal MUPs than area alone. The area/amplitude ratio (63) and size index are parameters that assist in discriminating between neurogenic and normal MUPs and control for the influence of needle position (43). The relative irregularity coefficient (45) captures the complexity of the MUP by quantifying detailed features of the MUP and is calculated as follows: RIR = [(S – 2A)/2A] × 100 (where A is the amplitude, and S is calculated as the sum of the absolute values of the intersample changes seen in the MUP waveform template, i.e., the irregularity in the MUP template). Thus, with partial denervation there is structural remodeling with surviving axons projecting small braches (“collateral sprouting”) to reinnervate muscle fibers denervated by the loss of axons. These new branches conduct impulses with a lower velocity over longer distances, reflected as more complex MUP waveforms. All parameter values were manually inspected by a single investigator using DQEMG and who was blinded to subject status. The structures of the concentric needle macro (CNMACRO) MUPs were also measured, using these reference points.

Figure 3.

Measured and calculated variables from the selective concentric needle and concentric needle macro (CNMACRO) motor unit potentials (MUPs). Histogram display with the patients with obstructive sleep apnea (OSA) depicted in black and control subjects in white. Gray opacity depicts where there is overlap in the distribution of results for patients with OSA and control subjects. Medians are indicated by arrows in each panel, and in each circumstance the value for control subjects is at left and the distribution for patients with OSA is shifted to the right. (A–G) The measured variables from selective concentric needle MUPs, including the following: (A) duration, (B) peak-to-peak amplitude, and (C) area. (D–G) The calculated variables from the concentric needle MUPs, including the following: size index calculated as 2 × log₁₀(amplitude (mV)) + (area/amplitude (ms)) (D), area to amplitude ratio (E), area/phase ratio (F), and relative irregularity coefficient (G). (H–J) The measured variables from CNMACRO MUPs, including the following: (H) duration, (I) amplitude, and (J) area. Significance is given where appropriate in the respective panels.

Figure 4.

Mean measured and calculated variables from the concentric needle motor unit potentials. Each panel represents key averaged variables measured and calculated from all the individual concentric needle motor unit potentials (MUPs). The solid columns depict patient with obstructive sleep apnea (OSA) data and the shaded columns represent control subject data. Significance is given where appropriate in the respective panels.

Figure 5.

Mean measured variables from the concentric needle macro (CNMACRO) motor unit potentials (MUPs). Each panel represents key averaged variables measured and calculated from all the individual CNMACRO MUPs. The solid columns depict patient with obstructive sleep apnea (OSA) data and the shaded columns represent the control subject data. Significance is given where appropriate in the respective panels.

Figure 6.

Mean relative irregularity coefficient versus minimal oxygen saturation. More complex motor unit potentials (MUPs), as calculated with the relative irregularity, are associated with minimal oxygen saturation detected from the overnight polysomnography examination. The Pearson correlation coefficient was calculated from the mean value of 29 subjects (r = –0.639; P = 0.000188). The open circles depict the healthy control subjects while solid circles depict the untreated patients with obstructive sleep apnea. The two open squares on the x axis represent two control subjects from whom minimal oxygen data were not obtained (not included in the correlation).