These motoneurons are topographically organized with other pharyngeal and laryngeal muscles and the striated muscle esophagus. Pharyngeal motoneurons often have a respiratory rhythm, but not a spontaneous background discharge. Therefore, the CP motoneurons may not generate CP tone. Various reflexes control the tone of the CP.
Distension of the esophagus causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. Pmax shows the positon of maximal pressure defined at all time points and demonstrates the elevation of the sphincter that occurs before complete relaxation.
B A representation of the UES mechanical states predicted during the swallow over time based on the pressure and admittance values determined along the Pmax line. Different phases of the swallow shown are indicated based on the mechanical states predicted.
C Aggregate data from all liquid swallows recorded in this subject showing changes in the proportion of the mechanical states over time. D The inferred level of activation of cricopharyngeal muscle over time. Four mechanical states predominated overall. The timing of occurrence of the different mechanical states during the swallows is shown in Figures 10C—G. Auxotonic states marked the transition between Isometric and Isotonic states Figure 10E and, as previously described, are indicative of the timing of onset of opening and UES closure see also Figures 9B,C.
A similar pattern of mechanical states was observed for both 5 and 10 ml boluses. However, increasing the bolus volume was associated with a longer period of Isotonic Relaxation 5 ml 0. The sum time in the predominant states defined by the UES being open i. Figure Distribution of Mechanical States predicted across Control Subjects and in relation to time during 5 ml swallows.
A The proportion of subjects demonstrating each of the 12 mechanical states. B Pie chart showing the prevelance of the main mechanical states. C The timing of occurrence of all mechanical states. D Isometric States are indicative of CP muscle activation. E Auxotonic states marked the timing of onset of opening and UES closure.
F,G Timing of remaining states. Data were temporally aligned based on the onset of appearance of the first mechanical state consistent with the luminal being open. Profiles of UES pressure recorded during swallowing demonstrated an overall pattern of lower pressures i. Young, but not higher vs. The 0. YC and vs. Bolus volume had no effect on pre-swallow UES pressure 5 ml 81 [48, ] vs. UES nadir pressure and 0. The volume effects did not achieve statistical significance when assessed for the MND group alone.
UES pressure-admittance profiles across study groups. A Median UES pressure over time for 5 ml boluses. B Median UES admittance over time for 5 ml boluses. C Orbit plots based on admittance and pressure for 5 ml boluses. Profiles of UES admittance recorded during swallowing demonstrated an overall pattern of lower admittance i.
UES maximum admittance was significantly higher with greater volume 5 ml 6 [4, 7] vs. Orbits constructed by plotting the median UES admittance profile against the median UES pressure profile clearly differentiate the three groups, with substantial attenuation of both admittance and pressure constraining the extent of the orbit of MND patients Figure 11C.
This translated to differences in relation to the UES mechanical states predicted. Based on the average quantum of time during which the different mechanical states were predicted, Isometric States, both Relaxation and Contraction, occurred for a shorter time in patients with MND Figures 12A,B. The temporal profile of mechanical states Figure 12B also suggests that the typical pattern of increased Isometric Activity consistent with swallow onset as described in Figure 9D is both diminished and delayed in MND patients compared to controls.
B Temporal profles of the five mechanical states in panel A as determined for 5 ml swallows. These are numbered in order from 1 to 5 A. Note this suggests that Isometric activity increase is both diminished and delayed. This observation was consistent for both bolus volumes Figure 12A. Figure 12B shows the temporal profiles and overall distribution of the five Mechanical States which differentiated MND from Control swallows.
Further analyses were performed to examine differences in the rate of pressure and rate of admittance increase or decrease in relation to the different mechanical states. For Isometric States, defined by an increasing or decreasing lumen occluded pressure, the rate of pressure increase or decrease was not significantly different. The volume swallowed also had no effect on the rate of pressure change.
For Isotonic States, defined by the lumen opening or closing, the rate of admittance increase or decrease was significantly altered in MND patients where a slower rate of admittance change was observed indicating a slower rate of UES opening and closure Figure 13A. Furthermore, older Age-Matched Controls had a diminished rate of admittance increase or decrease when compared to Younger Controls. A significant volume effect was also observed in Controls whereby the rate of admittance increase or decrease during Isotonic Contraction or Relaxation was more rapid in relation to the larger 10 ml boluses Figure 13B.
In contrast MND patients did not show a significant effect of volume on the rate of admittance change during Isotonic States Figure 13B.
Rate of admitance change during Isotonic UES mechanical states. A Group comparisons for each volume. B Comparisons in relation to bolus volume.
Paired t -test p -values are shown. The aim of this study was to validate and apply a novel method to objectively define the mechanisms that contribute to deglutitive UES relaxation and opening. The significant advantage of this method is that it not only gives a more complete description of the mechanical state of the muscle but potentially enables the likely neural inputs that generate these to be deduced.
Mechanical states revealed in this study are consistent with the known neural inputs activating the different muscles during swallowing and some indicate more details of the mechanical consequences that result when these complex neuromuscular processes become aberrant due to pathology. Methodology to better assess UES function is clinically relevant for diagnosis of motor dysfunctions causal of dysphagia symptoms. Appropriately diagnosed UES dysfunctions may be treatable through interventions such as dilatation Hatlebakk et al.
Traditionally, the manometric assessment of UES function has been based upon quantification of hypopharyngeal intrabolus pressure, as a marker of UES flow resistance, and UES residual pressure, as a marker of extent of UES relaxation.
However, intrabolus pressure is only a predictor of UES flow resistance when measured in conjunction with an intact pharyngeal swallow and UES residual pressure does not equate to UES opening diameter, such that a fully relaxed UES may nevertheless not open Williams et al. In radiotherapy induced dysphagia the CP muscle can have poor contractile tone due to reduced muscle fibre density, whilst at the same time displaying restricted opening and poor compliance due to interstitial fibrosis.
An important distinction between the traditional approach and the approach we have applied in the current study is that our assessments are based on direct simultaneous measurements of both UES pressure and UES opening. As applied, this provided only a single lateral projection of the UES and therefore could only be considered accurate in this one dimension.
Whilst the largest changes in UES diameter do occur in this anterior-posterior dimension, without 3D cross sectional imaging, our measurements are only a good approximation of the real volume change that occurs within the UES region during swallowing. Nevertheless, by measuring both pressure and opening we aimed to derive novel physiological markers which could provide a more complete assessment of swallowing pathophysiology.
The prediction of mechanical states based on the relationships of diameter change and pressure change is a novel concept that was originally applied to the physiology of gut motility and has further elucidated the neuro-mechanical basis of peristalsis Costa et al. In the current study we have applied this same novel approach to the assessment of UES mechanical function in vivo.
The physiology governing UES relaxation and then opening is very different to gut peristalsis, however the fundamental mechanical principles governing propulsion of contents are essentially the same. That is, the lumen ahead of the moving bolus must relax and open to allow unimpeded passage and the lumen behind the bolus must contract and close to generate propulsive force and prevent retrograde bolus escape Dinning et al. In relation to UES opening during deglutition, past studies have shown that the CP muscle is the major contractile element of the UES which often contracts at the onset of swallow in concert with superior laryngeal movement and then relaxes prior to being opened by traction forces applied by the anterior movement of the hyoid and larynx Asoh and Goyal, ; Cook et al.
A central pattern generator controlled burst of EMG activity then follows luminal closure leading to a post-relaxation pressure peak. As demonstrated in the current study Figure 9D , the mechanical states model allows lumen occluded pressures to be differentiated into distinct periods of Isometric Contraction and Isometric Relaxation. Our measurements show that the onset of swallowing is associated with an increased prediction of Isometric Contraction states followed sequentially by Isometric Relaxation states, a pause in Isometric States and then a post-relaxation increase in Isometric Contraction states.
These observations are highly consistent with previous EMG studies which have directly measured activation and deactivation of the CP muscle during swallowing Asoh and Goyal, ; Van Overbeek et al.
Our observations show that pressure-impedance based predictions of mechanical states may potentially determine the level CP muscle activity. However, direct correlation of CP EMG activity and pressure-diameter based predictions of the Isometric mechanical states is still needed to confirm this. Given that CP muscle EMG is less applicable to the clinical setting, while high resolution impedance-manometry is already in widespread use, our method may have clinical relevance if proven to be a direct correlate of CP muscle activation.
In healthy individuals, UES opening demonstrates an adaptive response to bolus volume as a consequence of sensory feedback mechanisms. Hence swallowing of larger boluses is accommodated by earlier and larger increases in UES diameter Kahrilas et al. The net effect of this adaptive response is the ability of the pharyngo-esophageal segment to accommodate a faster rate of bolus flow without any increase in flow resistance.
In the current study we observed several effects which elucidate this adaptive response to a larger bolus volume. These were; 1 a wider diameter based on an increase in maximum admittance; 2 a longer UES opening period based on the sum predicted time in mechanical states defined by the lumen being open; and 3 a faster rate of UES opening indicated by the rate of admittance change during Isotonic Relaxation.
In contrast our results show no effect of bolus volume on the UES pressures before or after UES relaxation, a finding which is consistent with past studies that show that pharyngeal and UES contraction is far less adaptive, following a more stereotypical constant contractile pattern Cook et al. Nadir UES pressure and UES integrated relaxation pressure were higher with larger volumes, a finding which is consistent with intrabolus pressure being a factor in maintaining the UES in an open state Cook et al.
Our radiological validation studies showed that three mechanical states were predicted to occur at the onset of radiological UES opening, namely Auxotonic Relaxation, Passive Dilatation and Isotonic Relaxation. Of these, the state of Passive Dilatation is the only state that is mechanically consistent with UES opening being facilitated by bolus pressurization from above.
Across study subjects, Passive Dilatation was by far the least frequently observed mechanical state suggesting that, in health, intrabolus pressures are of minimal importance for initiation of UES opening.
Previous videomanometry studies have concluded the same, showing that anterior hyoid movement initiates opening after which bolus forces determine the extent of opening Cook et al. Analysis of 5 and 10 ml bolus swallows in healthy controls demonstrated minimal age group related effects on pressure measurements. UES contractile pressures were numerically lower and UES nadir pressures were numerically higher in the older age group, however these differences were not statistically significant.
Older healthy subjects demonstrated a similar duration of UES relaxation and opening to younger subjects, but had a lower pre-relaxation pressure and lower maximum admittance during opening. Lower pre-relaxation pressures suggest that passive-elastic forces and basal myogenic and neurogenic activity of the CP muscle may be reduced with aging. In contrast, post-relaxation peak pressures were similar between young and aged subjects, suggesting no age-related effect on the pattern-generator mediated post-relaxation rebound burst CP muscle activity.
Lower UES admittance in aged subjects suggest a reduced UES diameter which is supported by past radiological studies and possibly due to an age-related reduction in UES compliance Shaw et al.
Our measurements also suggest that the rate of diameter change during the early Isotonic phase of UES opening was slower in aged subjects. Reduced compliance of the CP muscle and adjacent structures may explain this observation. An alternative explanation is that the traction forces being applied by the hyoid muscles at the onset of UES opening are weaker in the aged.
Suprahyoid strengthening exercises Shaker exercise are known to improve UES opening in aged subjects Shaker et al. In light of our observations, the beneficial effects of the Shaker exercise may relate to either re-training of weakened muscles to open a normally compliant UES, or augmentation of normal muscles in order to open a less compliant UES.
MND patients showed marked deterioration in their swallowing function. Interestingly, the differences seen between MND patients and Age-Matched Controls were of a similar, but more severe, pattern to the subtle differences seen between Age-Matched and Young Controls. Hence the changes documented across the groups suggest a continuum of progression of a similar overall pattern of change in motor function. Whilst the healthy Aged can still swallow effectively, they retain less functional reserve, meaning that they will develop swallowing difficulties earlier should a disease process, such as MND, supervene.
Mechanical state predictions suggested that MND patients have significantly diminished Isometric activity which we have interpreted as being consistent with diminished neurogenic activation of the CP muscle. However, in order to confirm this, further studies are needed to correlate these findings with simultaneous EMG recordings. Consistent with a past videofluoroscopy study Higo et al.
Age-Matched Controls. These findings are consistent with the attenuation of force generation capacity of the hyoid muscles. The fact that volume related changes were still observed in MND despite substantial mechanical weakness suggests that the sensory coding for volume may still be preserved.
Passive-Isometric Pressure States were only rarely observed during healthy swallowing. Hence emergence in MND suggests a marker of disease severity in relation to its impact on swallowing. Moreover, the prediction of Passive-Isometric Pressure Increase suggests UES contraction when the lumen still contains swallowed bolus. We therefore conclude that Passive-Isometric Pressure Increase is seen because the swallowed bolus fails to fully transit the UES region and therefore the UES contracts onto, rather than behind, the bolus.
Hence, rather than the bolus being fully propelled distally when the UES closes, some residual bolus material may be trapped within the UES lumen, which would be consistent with catheter based measurement of higher UES admittance and the definition of Passive Isometric Pressure, rather than Isometric Contraction see patient examples provided in Figure Delayed bolus transit through the pharynx has been previously reported in MND patients using videofluoroscopy Higo et al.
A slower rate of transit is most likely due to weak lingual propulsion in combination with weak pharyngeal pressure generation and a reduced UES aperture.
Illustrative examples from MND patients. Spatio-temporal pressure plots show the pressures of UES high pressure zone during a 5 ml liquid swallow. Pmax defines the position of maximum axial pressure. A representation of the UES mechanical states predicted for the swallows is shown below each plot color scheme identical to previous Figures, PIPI in colored purple. Admittance-pressure Orbit plots for each swallow are shown right. Videofluoroscopy images from a barium swallow investigation of Patient B performed within 1 week of the high resolution impedance manometry study are shown at the bottom of the figure.
The images captured during 5 ml liquid barium swallow show UES closure onto, rather than behind, the swallowed bolus. Hence the bolus is divided into two as the UES closes and bolus is retained in the pharynx above the UES as residue yellow arrow in magnified image.
Residual bolus material is most likely also trapped within the UES lumen. These observations suggest a paradoxically enhanced, yet uncoordinated, UES myogenic activity in MND in a setting of diminished central pattern generator mediated activity overall. In contrast, our findings showed attenuated Isometric activity with UES opening of normal duration but restricted aperture. The fact that evidence for paradoxically augmented CP activity was not clearly demonstrated in our MND patients may suggest a lack of detection sensitivity of the mechanical states method or that there are differences in relation to the specific MND sub-pathology of the patients' we studied.
Simultaneous EMG studies would be needed to confirm whether the previously reported CP activity was absent in our patients, or present, but undetected by our method. In conclusion, we present findings in relation to a novel method to assess UES function using the prediction of UES mechanical states based on the relationship of admittance and pressure.
Changes in mechanical states in health emulate the established understanding of UES opening mechanics as previously determined using videomanometry. Mechanical state predictions were simple to apply using software and revealed patterns consistent with the known neural inputs activating the different muscles during swallowing.
Future simplification of the analysis and key interpretations will allow this method to be more readily applied. Further validation studies are needed to correlate mechanical states predictions with EMG recordings and to determine UES mechanical states in patients with obstructive pathologies. Taher I. Omari, Philip Dinning, Lukasz Wiklendt, and Charles Cock; study concept and design, analysis and interpretation of data, draft and critical review of manuscript.
Nathalie Rommel and Marcello Costa critical manuscript review and interpretation of data. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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