Discovery of a substantial cerebral venous pressure wave component in Spontaneous Tympanic Membrane Displacement: Expanding understanding of composite Aural Pressure Waves

Discovery of a substantial cerebral venous pressure wave component in Spontaneous Tympanic Membrane Displacement: Expanding understanding of composite Aural Pressure Waves | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Discovery of a substantial cerebral venous pressure wave component in Spontaneous Tympanic Membrane Displacement: Expanding understanding of composite Aural Pressure Waves Robert J Marchbanks, Anthony A Birch, Wahbi K El-Bouri, Diederik O Bulters This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6940263/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This study found a measurable venous component in spontaneous tympanic membrane displacement (spTMD) waveforms, which likely represent aural pressure waves in general. These findings suggest that a substantial or dominant venous component exists in most spTMD waveforms, representing the coupling of central venous pressure (CVP) dynamics with the ear. The study was conducted in three stages, including a comparative analysis of changes in CVP and spTMD with forced ventilation on five patients to verify spTMD polarity; a correlation analysis to determine the best representation of spTMD by arterial blood pressure (ABP), intracranial pressure (ICP), or CVP; an analysis of pulse features with ECG synchronisation to compare ABP and CVP pulse profiles with spTMD from 316 healthy individuals. The results supported the hypothesis that the spTMD waveform has a substantial venous component in normal-healthy individuals. The discovery of a cerebral venous drainage component is exciting. It may offer an inexpensive and easily applied non-invasive clinical measurement device for measuring vital biological parameters for all postures. However, the implication is that the amplitude of spTMD and aural pulse may not be a simple surrogate for non-invasive ICP pulse or baseline ICP. Nonetheless, with careful consideration, components of spTMD remain valuable in this respect. Biological sciences/Neuroscience Biological sciences/Physiology Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Spontaneous Tympanic Membrane Displacement (spTMD) Composite aural pressure waves Cerebral haemodynamics Cerebral venous drainage Non-invasive intracranial pressure measurement Vital neurological parameters Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The causes and incidence of abnormal cerebrospinal fluid (CSF) dynamics and cerebral venous drainage are poorly understood due to measurement difficulties. MRI techniques are limited and invasive methods are only practical in specific clinical scenarios. A simple and continuous monitoring technique of dynamic CSF, intracranial pressure (ICP) and cerebral venous outflow pressure would be valuable for research and clinical assessments. Some researchers have utilised the fluid connection between the CSF and the inner ear to explore the relationship between tympanic membrane displacement (TMD) and ICP pulsatility. The association exists. However, it is often weak and only found in some ears [ 1 ]. The cochlear aqueduct (CA) is the principal route that allows for direct pressure transfer between the CSF in the posterior fossa and the perilymph in the cochlea [ 2 – 4 ]. If there are no obstructions or abnormalities, the steady-state perilymphatic pressure should equal CSF pressure, Fig. 1a, 1c. This homeostasis facilitates non-invasive measurements of baseline ICP in the posterior fossa by techniques such as evoked tympanic membrane displacement (TMD) [ 5 ]. Steady-state pressure transfer has been established, however, CSF pulsatility is not understood. Spontaneous tympanic membrane displacements (spTMD) are characterised by periodic waveforms associated with the cardiac cycle and respiration. An electrocardiogram (ECG) signal can isolate individual heartbeats for analysis, and ensemble averaging can reduce noise to provide a representative spTMD pulse waveform, Fig. 1b. The typical shape of the spTMD pulse waveform is likely to be influenced by a combination of multiple waveforms propagating from the heart by different intracranial and extracranial routes. To distinguish between waveform components arriving from CSF pressure and those from direct arterial routes, we have previously assessed the relative associations of radial arterial pressure and intracranial pressure waveforms with the spTMD waveform. We found substantial and independent contributions from each; however, neither showed a strong correlation. We speculated that another source, perhaps venous, contributed substantially to the waveform [ 6 ]. The intra-aural pressure wave is a superimposition of pressure waves from multiple origins [ 6 ], Fig. 1a, 1c. The ear receives pressure pulses and waves from sources including the cerebral arteries, CSF fluids, and this study investigates the contribution of venous drainage. Venous drainage from the ear is directly into the inferior and superior petrosal sinus (PS) or the internal jugular vein (IJV) [ 7 , 8 ]. Venous return from the head to the heart is through five routes and three categories of veins; external jugular veins that are collapsible on moving from supine to sitting, internal jugular veins and vertebral venous plexus. The balance of venous drainage through these veins depends on posture. The deoxygenated blood flows into the superior vena cava and the right atrium empties during the cardiac cycle. The filling of the right ventricle depends on venous return pressure, potential energy, and any hydrostatic pressure depending on posture. The influence of the venous drainage of the ear on the spTMD pulse waveform has yet to be considered. Drainage of the inner ear is intracranial into the jugular vein, while the middle and outer ear venous drainage is extracranial. Both are influenced by central venous pressures (CVP) and the right side of the heart haemodynamics. This paper tests the hypothesis that venous pressures are a substantial missing component of the spTMD pulse waveform. Results/Findings Stage 1: Phase of spTMD during mechanical ventilation Figure 2 shows the coherently averaged ventilator cycle for each of the five patients. As expected, all five patients demonstrate that the CVP, ABP and ICP are all in phase with ventilation. That is, pressures are seen to increase during the inspiration phase of ventilation associated with the increasing thoracic pressure of forced ventilation. The observation that spTMD is also in phase confirms that a positive spTMD represents an increase in pressure. Regarding TMD, an outward displacement represents an increase in external ear pressure, whereas an inward displacement represents a decrease in pressure. Stage 2: Cardiac Cycle correlation analysis For each of the five patients coherent averaging of the cardiac cycle was undertaken for spTMD, ABP, ICP and CVP producing waveforms in a similar manner to that shown in Fig. 1b. Table 1 shows the Pearson correlation coefficients for each variable with the spTMD waveform. Table 1 Showing the Pearson correlation coefficient of each variable with spTMD. X represents missing data. Patient ABP CVP ICP 1 -0.13 -0.35 X 2 -0.79 0.29 -0.9 3 -0.68 0.59 -0.9 4 -0.8 0.45 -0.73 5 -0.08 0.54 -0.2 In all cases, apart from patient 1, the maximum absolute correlation coefficients with CVP are positive, and the correlation with ABP and ICP are negative. This finding is consistent with a strong venous component in the spTMD signal. The patient 1 exception, occurs due to a slightly different CVP profile with the steep negative transition occurring earlier because of an indistinct venous c-wave, Fig. 3 a. These results were determined from a small group of 5 patients under intensive care conditions. The next step was to apply this analysis to healthy subjects to see whether the findings were more generally applicable. This analysis used patient data to generate representative heartbeat cycles for ABP, ICP and CVP. These templates are shown in Fig. 4 , together with the equivalent spTMD cycle. The spTMD waveforms in the sitting position, supine and on a couch with the upper body inclined head-up at 30 degrees were all produced by coherent averaging of results from 316 healthy subjects. Table 2 shows the correlation results with the templates for ABP, CVP, ICP and spTMD derived from the patients. Separate results are given for the control subjects' sitting, supine and inclined posture. The patient heartbeat templates are for a fixed posture of head-up inclination of approximately 30 degrees. The waveforms are illustrated in Fig. 5 . Table 2 Correlation coefficients for coherently averaged spTMD heartbeat from healthy subjects with templates from patients. (Results from left and right ears have been averaged.) Control Posture n Patient spTMD Patient ABP Patient CVP Patient ICP Sitting 256 0.93 -0.81 0.73 -0.84 Inclined 57 0.79 -0.15 0.17 -0.05 Supine 244 0.38 0.38 -0.52 0.49 A good correlation was found between the averaged patient and control waveforms (spTMD), sitting and inclined. A weaker correlation exists between averaged patient and control waveforms (spTMD) for supine. The healthy control spTMD heartbeat was positively correlated with the CVP template in the sitting position, weakly correlated for inclined and negatively correlated for supine. The control spTMD has a strong negative correlation with the ABP and ICP templates for sitting, weakly correlated for inclined and positively correlated for supine. These results show that the spTMD waveform in healthy control subjects is strongly influenced by posture. They also support the presence of a strong contribution from the venous circulation in the sitting position. Stage 3: Direction of pressure transition following the ECG QRS Complex For our final test to assess if the spTMD waveform has a substantial venous influence, we focussed on the pressure transition direction following the QRS complex peak. This transition corresponds to a pressure rise in the arterial system and a pressure reduction in the venous system. The literature indicates that these arterial and venous transitions will lag nominally 30 to 60ms behind the ECG waveform. Consequently, we used the period starting 60ms after the QRS complex to look for a steep gradient in the waveform and recorded if it was in a positive or a negative direction. By starting at 60ms, the transition will be developing. A steep gradient was defined as 0.5h per second (nLs − 1 ), where h is the peak-to-peak value of the waveform. First, for each of the 5 patients, we processed every heartbeat; the results are shown in Table 3 . Table 3 Showing the patient data and the percentage of heartbeats for which the first steep gradient was positive and negative. The direction of pressure transition was taken at 60ms after the ECG QRS Complex peak. (The percentages do not add up to 100% because a minority of beats do not have a gradient following QRS that exceeded the threshold that was defined as ‘steep’). X represents missing data. Patient Number of heartbeats ABP ICP CVP spTMD % +ve % -ve % +ve % -ve % +ve % -ve % +ve % -ve 1 363 95 1 X X 5 76 15 81 2 1362 97 0 95 0 94 3 4 81 3 2189 97 0 98 0 3 89 0 98 4 1454 97 0 97 0 21 58 5 92 5 2386 96 0 95 0 6 90 0 89 As expected, the results show that the first steep gradient following the QRS complex is consistently a positive pressure transition for the arterial and ICP pulse transitions. The spTMD was predominantly a negative pressure transition corresponding to an inward TMD, a tympanic membrane movement toward the middle ear. Likewise, the CVP was predominantly a negative pressure transition corresponding to a reduction in pressure, except for patient 2, who had an exceptionally large venous c-wave, Fig. 3 b. Although CVP waveforms follow a set pattern of events, the relative amplitudes of the CVP peaks are known to be variable. In patient 2, the later c-wave is larger than the a-wave, which is the reason for the analysis discrepancy. Despite this, the spTMD pressure transition is negative and consistent with a venous wave. The same analysis was then performed on the control data, in this case we have spTMD data in terms of a coherent average waveform for each subject. The direction of the first steep gradient was determined from the coherent average such that each subject was either positive or negative. The proportions are then presented as the proportion of subjects rather than the proportion of heartbeats. These results are presented for the different postures in Table 4 . Table 4 Showing the control data and percentage of heartbeats for which the first steep gradient was positive and negative. The direction of pressure transition was taken at 60ms after the ECG QRS Complex peak. (The percentages do not add up to 100% because a minority of beats do not have a gradient following QRS that exceeded the threshold that was defined as ‘steep’). Posture spTMD % of Controls + ve % of Controls -ve Sitting 1 80 Inclined 8 69 Supine 8 67 The spTMD results indicate that a decrease in pressure occurs following the QRS complex, consistent with a dominant venous influence on spTMD for all three postures. Discussion The findings of the current study conclude that an inward spTMD indicates a decrease in vascular pressure, which is consistent with the pressure changes observed in the outer, middle, and inner ear. It is assumed that the inner ear vascular pressure changes act similarly. Although there is no conclusive proof, no evidence suggests otherwise. Stage 1 used respiration to study the spTMD polarity, and it is reasonable to assume that the cardiac pulse has the same polarity. The study also assumes this applies to healthy, normal subjects, not just those sedated and ventilated. We conclude that any vascular or CSF pressure increase will translate to an outward movement of the tympanic membrane, regardless of its origins. Stage 2 of the study analysed whether spTMD was best represented by ABP, ICP or CVP using patient data sets. In all cases, the maximum absolute correlation coefficients of spTMD negatively correlate with both ABP and ICP. The spTMD positively correlates with CVP, except for one patient with a slightly different CVP profile where the steep negative transition occurred earlier because of an indistinct venous c-wave. The correlation analysis in the healthy control data set supports the hypothesis that venous pressure represented by CVP contributes to the spTMD waveform. The spTMD waveform will not be the same as CVP since it will be unique to pressure coupling at the ear location; nevertheless, the waveforms similarly have a pressure reduction around the ECG QRS complex, whereas ICP and ABP show the expected delayed positive pressure pulse. The spTMD pressure reduction sometimes starts before the ECG QRS complex during ventricular diastole, providing further evidence of a venous drainage wave. A consistent and often dominant negative spTMD transition in early ventricular systole corresponds with reduced pressure during accelerated cerebral blood drainage. The shape of the spTMD pulse varies substantially with posture in healthy control data. The study revealed that the correlation coefficients for spTMD were positively correlated with CVP and negatively correlated with ABP and ICP for sitting and inclined postures. This suggests the presence of a substantial or even dominant venous wave component within the spTMD waveform. However, for the supine posture, spTMD was negatively correlated with CVP and positively with ABP and ICP. This finding highlights the importance of considering posture. The inclined healthy patient data set best represent the patient's posture, although the sitting healthy patient data had higher correlation coefficients. The reason for this is unknown, but may be related to a difference in the middle ear pressure or patient pathologies that make sitting a more representative posture for some patients. However, this interpretation should be considered cautiously in the absence of patient ABP, ICP and venous pressure waveforms with similar posture changes for comparison. More sophisticated analysis techniques than correlation that could have been applied for waveform identification. However, we felt nothing would be gained given that the waveforms we used only represented arterial, intracranial and venous pressures and were not definitive. The resulting template waveforms will vary between individuals and the measurement site. Given this, we have used timing relative to the ECG to back up our results. Using timing relative to the ECG to support our analysis assumes that the measurements are well synchronised and accurately reflect the relative arrival time of the respective waveforms at the tympanic membrane. Great care was taken to ensure the waveforms are well synchronised. There will be a small-time difference between our measured waveforms and the ear-based measurements. However, these are sufficiently small to not influence the findings in this paper. Following a careful study of the descriptions of the arterial and venous waveforms in the literature, we chose the period starting 60ms after the QRS complex to look for a steep gradient in the waveform. We recorded if the gradient was in a positive or a negative direction. A steep gradient defined as 0.5h per second (nLs − 1 ), where h is the peak-to-peak value of the waveform. We first applied the steep gradient analysis method to the patient data as a check (stage 2). Except for CVP for patient 1, positive slopes occurred for ABP and ICP, and negative slopes for CVP and spTMD. As explained earlier, the patient 1 CVP exception is due to the waveform morphology, so we were happy that the method is appropriate for the healthy spTMD datasets (stage 3). We considered whether the spTMD transition was positive or negative following within 60ms of the ECG QRS peak. Over 98% (80:1) of the healthy subject in the sitting posture and 88% of the healthy subjects in the inclined and supine postures (69:8, 67:8, respectively) demonstrate a negative pressure spTMD transient following the QRS peak. These findings are consistent with a substantial or even dominant venous influence in spTMD for healthy subjects in all three postures. Specifically, for arterial and intracranial pressure waveforms, the first sustained steep change in pressure following the QRS complex is driven by the left side of the heart and always in a positive direction. In contrast, venous waveforms are influenced by the right side of the heart and in a negative direction. The timing of dominant pressure transitions highlights the physiological differences between a venous drainage waveform and an arterial pulse. Venous drainage occurs before the ECG QRS complex with the opening of the cardiac tricuspid valve that occurs with the start of ventricular diastole. The sequence of events with the cardiac cycle is detailed in Fig. 6 . Accurate measurement of this sequence of events is critical to identifying the arterial-venous composition of the spTMD waveform; however, as demonstrated in our patient data, the relative amplitudes of the venous components vary with factors that make this quite challenging. The ear haemodynamics likely evolved to be compatible with sensitive hearing and balance receptors. The cochlea has a unique arterial supply via the stria vascularis that substantially attenuates any pulsatility through a network of elastic vessels and tortuous arterioles that feed the stria vascularis; consequently, with the arterial pulse attenuation, the venous waveform becomes more apparent. This mechanism is essential for proper hearing and vestibular function of the labyrinth [ 9 ]. The degree to which the arterial pulsing is attenuated is unique to the labyrinth despite a reasonably high blood supply demand. A dual arterial and venous pulsatility exists within the eye where the spontaneous retinal venous pulse ceases with raised ICP. As with the aural pulse waveform, the CSF pressure is considered to play a pivotal role in the retinal venous pulse [ 10 , 11 ]. Although spTMD includes information about the ICP waveform, the aural pathway is more complex than a direct pressure link via the cochlear aqueduct, as found by our earlier research [ 6 ]. The findings of this earlier research are that: - Both ABP and ICP contribute independently to the spTMD signal. Information shared between the ICP and spTMD is not present in ABP. Lower frequencies (e.g., respiration) favour ICP as the driver for spTMD. There was a substantial missing component that was most likely venous. The finding of the current paper supports the presence of a substantial venous component (4), which also, in part, will explain information shared between the ICP and spTMD that is not present in ABP (2). Although a dominant component of the ICP (CSF pressure) wave is arterial, an important venous component also exists and has to be considered when explaining the ICP waveform morphology or the ICP P3 pulse in particular [ 12 , 13 ]. The venous waveform reflects the respiratory component in CVP that occurs due to changes in thoracic pressure and right-side cardiac stroke volume with pulmonary artery pressure. The pressure within the cerebral venous sinuses, ICP and CSF are all known to couple with respiration [ 14 , 15 ]. Figure 7 illustrates this pressure coupling. Both spTMD and the ICP are composite waveforms with characteristics unique to a specific anatomical location. Evensen et al. (2018) tested the assumption that ICP waves transmit through the cochlear aqueduct to dominate the Tympanic Membrane pulse. They found this is likely to be over-simplistic, certainly at cardiac frequencies, in the majority of patients tested. They surmised that the cochlear aqueduct (CA) worked as a physical lowpass filter [ 1 ]. We provide evidence here, that the assumption neglects spTMD to venous coupling, a substantial component of the aural pressure wave. Conceivably, both a direct cochlear aqueduct pressure connection and venous pressure coupling may be occurring. The CA is an open route for the majority of people. However, it may act as a low-pass filter transmitting the ICP signal at frequencies below 20 Hz, and whether its patency reduces with age remains a disputed issue [ 2 , 16 ]. In some individuals, both the cardiovascular and respiratory waves will be transmitted between ICP and perilymph, whereas ICP-perilymph pressure equalisation only occurs at lower respiratory frequencies in other individuals [ 6 , 17 ]. CA transmissibility has been evaluated with distortion-product otoacoustic emissions (DPOAE), and minimal attenuation of the respiratory signal was found, supporting non-invasive aural measurement of CSF pressure [ 18 ]. In addition to the cochlear aqueduct, other routes may exist. Other possible channels are the vestibular aqueduct and the internal auditory canal, perineural and perivascular routes, and through anatomical abnormalities such as dehiscence of the superior semi-circular. Initially, we shared the opinion that the aurally derived pulse was potentially a non-invasive surrogate for ICP or brain compliance. This was based on the observation that the ICP pulsatility increases in amplitude with reduced intracranial compliance caused by an increase in baseline ICP [ 19 – 21 ]. This opinion is challenged, although not negated, in light of our current findings and anatomical considerations, which suggest that spTMD is a complex composite pressure wave of intracranial and venous components. An important implication of this finding is that spTMD amplitude is unlikely to be a simple non-invasive surrogate for measuring baseline ICP but will depend on the make-up of the pressure coupling between all cerebral fluids. More recently, morphological changes, slopes and higher frequency features in the aural pressure waveform have been scrutinised as potentially more valuable non-invasive surrogates for ICP or brain compliance [ 22 ]. A more complex relationship between aural pressure waves and the intracranial pressure pulse is also the conclusion drawn by Evensen et al. (2018) in their paper that reviewed the utility of the tympanic membrane pressure (TMp) waveform for non-invasive estimates of the ICP [ 1 ]. From the clinical perspective, they conclude TMp and mean wave amplitude (MWA) would only provide a rather satisfactory non-invasive estimate of ICP pulse MWA in 4/28 (14%) patients. We concur with the above findings. In unpublished work, we compare spTMD with ICP pressure waves in neuro-intensive care patients undergoing direct ICP monitoring. Sometimes the spTMD (TMp) reflects ICP, but it does not in many patients. It seems that there are limitations to using spTMD as a surrogate for the ICP pulse, which we believe is explained by the intra-aural venous component. The waveform of spTMD may change depending on which pressure source is being coupled to the ear location. This coupling will likely vary based on posture, cerebral compliance, and the baseline CVP with central venous compliance. A complex pressure-coupling postulate for the aural pressure wave is supported by the above observations. Indeed, the implication of the Unnerbäck et al. (2019) findings suggest that if spTMD is venous dominated, then the spTMD amplitude may decrease with increasing ICP under certain circumstances. In a study of 37 neuro-intensive care patients undergoing phase-contrast MRI of cerebral blood flow measurements, it was observed that raised intracranial pressure attenuated the pulsatile component of the cerebral venous outflow [ 23 ]. The authors concluded this could be due to increased pressure requirements to compress intracranial veins with increasing ICP. A similar negative correlation is reported where a reduced venous retinal pulse can be used as a diagnostic indicator in patients with idiopathic intracranial hypertension (IIH) [ 10 ]. The relative size of the various components of the spTMD waveform is likely to be frequency and person-dependent. The respiratory frequencies of the ICP wave are better correlated with spTMD [ 6 ] and this finding is consistent with Evensen et al. (2018) study. The frequency content of the venous component, identified in this paper, requires further research together with the posture or pathology dependencies. In our early research, we found that substantial spectral energy exists at the lower frequency of the spTMD signal and that these lower frequencies favour ICP as the driver for spTMD [ 6 ]. Analysis of the simple coherences found a slight preference for ICP transmission to the spTMD signal at lower frequencies (7/11 {64%} patients at respiration frequencies, 7/10 {70%} patients at respiration 1st harmonic), which was reversed at the higher cardiac frequencies (2/11 {18%} patients at heart rate and its 1st harmonic). We found that most of the power was at the lower respiration harmonics, and we considered pressure coupling with respiration the most likely reason. The current study also supports the respiratory pressure coupling via the venous drainage routes to CVP. The ICP will couple with thoracic pressure via these routes and independently via spinal thoracic to CSF pressure coupling [ 14 ]. Deep breathing has been shown to couple CSF and venous flow dynamics [ 24 ]. The findings of this paper do not necessarily negate the possibility that spTMD is of value for non-invasive ICP pulse measurements; however, it shows it is complex and that spTMD is likely a combination of a direct pressure link via the cochlear aqueduct and pressure coupling with haemodynamics within the ear. Further, that pressure coupling is multifactorial; interdependencies for consideration include aspects of the cardiac cycle, posture and thoracic pressure. The degree of pulse pressure coupling between spTMD and ICP may depend on where it is considered in the cardiac cycle. This coupling will be different during the main drainage phase, when the venous pathway is low impedance during diastole, as opposed to high impedance when the right heart valve (tricuspid) is closed during systole. Speculatively, we expect ICP to spTMD pressure coupling to occur following the ECG QRS complex that marks the beginning of systole. Given this, this region of the cardiac cycle may provide optimum spTMD representation of the ICP pulse to facilitate non-invasive measurements. Posture will be crucial in spTMD coupling with the central venous chamber and CVP. The considerable postural-related difference in the spTMD morphology is likely due to changing venous drainage pathways. The internal and external jugular veins are usually the major cerebral venous drainage routes in the supine position. However, in the upright posture, there is a partial or total collapse of the jugular veins. Consequently, the cerebral venous blood returns through alternative vertebral venous plexus system pathways. This switching of venous drainage pathways occurs with almost no change in the intracranial vessels, indicating maintenance of cerebral blood volume flow [ 25 ]. When abnormally elevated CVP exists in the upright posture, the jugular veins possibly re-open, and the jugular veins abnormally become the primary pathway for venous return [ 26 ]. Considering the above, it is probable that the spTMD waveform contains information that reflects the CVP and cerebral venous drainage. Research and Clinical Importance The existence of a substantial venous drainage component in the aural and spTMD waveform is an exciting and arguably landmark finding. These methods promise to provide a new tool for researching cerebral venous outflow. Our work has yet to establish whether this spTMD venous aspect comprises external, internal or cerebral venous sinus components. However, from the clinical diagnosis perspective, both the internal and external venous routes reflect the central venous pressure (CVP) [ 27 ]. The findings support that the CVP thoracic and likely cardiopulmonary venous pressure dynamics are coupled with the ear, and this promises the opportunity for easily applied non-invasive measurements of these vital biological parameters. Compared with cerebral arterial supply, cerebral venous outflow has historically been an area of relative neglect; however, over the past decade, the importance of this topic has been realised. Non-invasive measurements are required to improve the knowledge base of conditions associated with disturbed and obstructed venous outflow or pulse wave encephalopathies [ 28 ]. Neurodegenerative disease and certain forms of dementia are known to be associated with cerebral outflow impairment [ 29 ]. Non-invasive aural measurements could enhance our understanding of conditions associated with proximal venous outflow and hypertension. The spTMD could, therefore, provide insight into conditions such as venous sinus thrombosis, dural arteriovenous fistular and the differential diagnosis of IIH occurring secondarily to impaired venous outflow. The spTMD as a surrogate for assessing the jugular venous pulse (JVP) needs consideration as JVP measurements are essential indicators of normal right-atrium pressure control [ 30 ]. Further work is necessary to establish the diagnostic value of aural pressure waves and the spTMD signal. Mamikoglu and Gianoli (2023) report that the Cerebral and Cochlear Fluid Pressure (CCFP) Analyser detects abnormalities with otological conditions associated with a mild, borderline elevation of the ICP. They consider this condition to be a distinct pathology separate from IIH and migraine, presenting with head fullness-pressure and dizziness that is often suggestive of a clinical diagnosis of vestibular migraine [ 31 ]. Borderline intracranial hypertension is implicated in chronic fatigue syndrome, both sharing an aetiology of obstructed venous outflow of the transverse sinus [ 32 – 34 ]. Unilateral venous pulsatile tinnitus is a known symptom of transverse sinus stenosis with venous trans-stenotic pressure gradients [ 35 ]. Abnormal spTMD exists in patients with pulsatile tinnitus and balance disorders, including a patient with Arnold Chiari malformation I with persistent dizziness [ 36 ]. Abnormal spTMD is also implicated with a severe disabling form of non-pulsatile tinnitus that occurs with symptoms of head pressure, headache, cognitive complaints of brain fog, and interference in memory and speech expression [ 37 ]. We have also identified abnormal spTMD pressure waves in children with cerebral malaria and shown an association with cognitive test scores in healthy adults [ 38 , 39 ]. Intra-aural pressure waves should be researched further in the above conditions, with attention to the possibility of spTMD asymmetry between ears providing an indicator of the lesion site. The aural methods provide a relatively inexpensive, simple and readily applicable non-invasive measurement technique. They can be applied with manipulations of postures and provide bilateral cerebral measurements that may assist with the location of stenosis or venous outflow abnormalities. Cerebral venous drainage and CVP are also essential physiological measurements missing from our current battery of clinical tests due to the invasive nature of the measurement and associated risks. The method is also suitable for long-term monitoring in the intensive care setting. As a simple screening device, it can provide spTMD data within minutes in the clinic or for roadside trauma. We are confident that this research paper's new and important findings will open many new avenues of research and will be translatable as a valuable new tool for clinical practice. Conclusions The spTMD should be regarded as a complex and composite waveform comprising arterial, ICP and venous components. The relative pressure coupling of these components will change substantially with posture and, presumably, any underlying pathology with a bias on a particular component. The spTMD and presumably aural pressure waves have a substantial or dominant venous wave component in the upright sitting, inclined and probably supine positions, although the latter requires further consideration. The amplitude of the aural pulse and spTMD do not provide a simple surrogate for non-invasive ICP pulse measurements or baseline ICP for all individuals. Nevertheless, spTMD will remain valuable for non-invasive ICP measurement in selected patients or when the complex nature of these waves is considered. The findings support that cerebral venous drainage and CVP dynamics are coupled with the ear, and this promises the opportunity for easily applied and translatable measurements of these vital biological parameters. Abbreviations Optional Scientific Report template indicates that Abbreviation list should not be included] ABP arterial Blood Pressure CA cochlear Aqueduct CCFP Cerebral and Cochlear Fluid Pressure (Analyser) CSF cerebrospinal fluid CVP central venous pressure DPOAE distortion-product otoacoustic emissions ECG electrocardiogram ICP intracranial pressure IIH idiopathic intracranial hypertension IJV internal jugular vein JVP jugular venous pulse MWA mean wave amplitude OW oval window PS petrosal sinus spTMD spontaneous tympanic membrane displacement TM tympanic membrane TMD tympanic membrane displacement TMp tympanic membrane pressure (waveform) Declarations Acknowledgements We thank Cherith Campbell-Bell for her contribution to collecting the control data and Steve Burnage, Gabriella Howard, Chloe Cox, Shannon Cawte and Tom Bower for their work in conducting the measurements. We would like to acknowledge the very helpful support from clinical staff in the Neurological Intensive Care Unit of the Wessex Neurological Centre where the measurements were performed. This work was funded by UKRI Innovate UK through an enhancing in vivo imaging for stratified medicine grant 101675. This NIHR Portfolio Study was supported by the NIHR/Wellcome Trust Southampton Clinical Research Facility. Author Contributions Conception and design: R.J.M. and A.A.B. Acquisition of data: A.A.B., R.J.M., and W.K.E. Analysis and interpretation of data: A.A.B., R.J.M., W.K.E. and D.O.B. Drafting the article: R.J.M., A.A.B., D.O.B. and W.K.E. Statistical analysis: A.A.B. and R.J.M. Critically revising the article: R.J.M., A.A.B., D.O.B. and W.K.E. Reviewed submitted version of manuscript: R.J.M., A.A.B., D.O.B. and W.K.E. Approved the final version of the manuscript on behalf of all authors: R.J.M. Data Availability Statement The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflict of Interests Dr Robert Marchbanks is the Managing Director of the Southampton University spin-out research company that manufactures the TMD/CCFP Analyser (Marchbanks Measurement Systems Ltd). The rest of the authors declare no conflict of interest. ORCID iDs Anthony A Birch https://orcid.org/0000-0002-2328-702X Wahbi K El-Bouri https://orcid.org/0000-0002-2732-5927 Diederik Bulters https://orcid.org/0000-0001-9884-9050 Robert J Marchbanks https://orcid.org/0000-0001-8565-8888 References Evensen, K. B., Paulat, K., Prieur, F., Holm, S. & Eide, P. K. Utility of the Tympanic Membrane Pressure Waveform for Non-invasive Estimation of The Intracranial Pressure Waveform. Sci. Rep. 8 , 15776 (2018). Gopen, Q., Rosowski, J. J. & Merchant, S. N. Anatomy of the normal human cochlear aqueduct with functional implications. Hear. Res. 107 , 9–22 (1997). Hofman, R., Segenhout, J. M., Albers, F. W. J. & Wit, H. P. The relationship of the round window membrane to the cochlear aqueduct shown in three-dimensional imaging. Hear. Res. 209 , 19–23 (2005). Ciuman, R. R. Communication routes between intracranial spaces and inner ear: function, pathophysiologic importance and relations with inner ear diseases. Am. J. Otolaryngol. 30 , 193–202 (2009). Campbell-Bell, C. M., Birch, A. A., Vignali, D., Bulters, D. & Marchbanks, R. J. Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure. Physiol. Meas. 39 , 015008 (2018). El-Bouri, W. K. et al. Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement. Physiol. Meas. 39 , 085002 (2018). Mazzoni, A. The vascular anatomy of the vestibular labyrinth in man. Acta Otolaryngol. Suppl. 472 , 1–83 (1990). Naganawa, S. et al. Cross-sectional Area of the Superior Petrosal Sinus is Reduced in Patients with Significant Endolymphatic Hydrops. Magn. Reson. Med. Sci. 21 , 459–467 (2022). Carraro, M. et al. Attenuating Cardiac Pulsations within the Cochlea: Structure and Function of Tortuous Vessels Feeding Stria Vascularis. ISRN Otolaryngol 941757 (2013). (2013). Jacks, A. S. & Miller, N. R. Spontaneous retinal venous pulsation: aetiology and significance. J. Neurol. Neurosurg. Psychiatry . 74 , 7–9 (2003). Morgan, W. H., Hazelton, M. L. & Yu, D. Y. Retinal venous pulsation: Expanding our understanding and use of this enigmatic phenomenon. Prog Retin Eye Res. 55 , 82–107 (2016). Unnerbäck, M., Ottesen, J. T. & Reinstrup, P. Validation of a mathematical model for understanding intracranial pressure curve morphology. J. Clin. Monit. Comput. 34 , 469–481 (2020). Czosnyka, M. & Czosnyka, Z. Origin of intracranial pressure pulse waveform. Acta Neurochir. (Wien) . 162 , 1815–1817 (2020). Dreha-Kulaczewski, S. et al. Respiration and the watershed of spinal CSF flow in humans. Sci. Rep. 8 , 5594 (2018). Hansen, A. B. et al. Reducing intracranial pressure by reducing central venous pressure: assessment of potential countermeasures to spaceflight-associated neuro-ocular syndrome. J Appl Physiol ( ) 130, 283–289 (2021).) 130, 283–289 (2021). (1985). Włodyka, J. Studies on cochlear aqueduct patency. Ann. Otol Rhinol Laryngol . 87 , 22–28 (1978). Finch, L. C., Marchbanks, R. J., Bulters, D. & Birch, A. A. Refining non-invasive techniques to measure intracranial pressure: comparing evoked and spontaneous tympanic membrane displacements. Physiol. Meas. 39 , 025007 (2018). Traboulsi, R. & Avan, P. Transmission of infrasonic pressure waves from cerebrospinal to intralabyrinthine fluids through the human cochlear aqueduct: Non-invasive measurements with otoacoustic emissions. Hear. Res. 233 , 30–39 (2007). Avezaat, C. J. J., Van Eijndhoven, J. H. M., Wyper, D. J. & Ar, M. Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. J. ofNeurology Neurosurg. Psychiatry . 42 , 0 (1979). Manwaring, P., Wichern, D., Manwaring, M., Manwaring, J. & Manwaring, K. A signal analysis algorithm for determining brain compliance non-invasively. Conf Proc IEEE Eng Med Biol Soc 353–6 (2004). (2006). Dhar, R., Sandler, R. H., Manwaring, K., Cosby, J. L. & Mansy, H. A. Non-invasive ICP Monitoring by Auditory System Measurements. in Signal Processing in Medicine and Biology 121–147Springer International Publishing, Cham, (2023). 10.1007/978-3-031-21236-9_5 Dhar, R., Sandler, R. H., Manwaring, K., Kostick, N. & Mansy, H. A. Noninvasive detection of elevated ICP using spontaneous tympanic membrane pulsation. Sci. Rep. 11 , 21957 (2021). Unnerbäck, M., Ottesen, J. T. & Reinstrup, P. Increased Intracranial Pressure Attenuates the Pulsating Component of Cerebral Venous Outflow. Neurocrit Care . 31 , 273–279 (2019). Kollmeier, J. M. et al. Deep breathing couples CSF and venous flow dynamics. Sci. Rep. 12 , 2568 (2022). Kosugi, K. et al. Posture-induced changes in the vessels of the head and neck: evaluation using conventional supine CT and upright CT. Sci. Rep. 10 , 16623 (2020). Gisolf, J. et al. Human cerebral venous outflow pathway depends on posture and central venous pressure. J. Physiol. 560 , 317–327 (2004). Malik, M. et al. A comparison of external and internal jugular venous pressures to monitor pulmonary artery pressure after superior cavopulmonary anastomosis. Interact. Cardiovasc. Thorac. Surg. 13 , 566–568 (2011). Wilson, M. H. Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure. J. Cereb. Blood Flow. Metab. 36 , 1338–1350 (2016). Marchbanks, R. Neurological ideopathic disease: a shared journey for NASA and medicine. ENT Audiol. News . 5 , 52–55 (2021). García-López, I. & Rodriguez-Villegas, E. Extracting the Jugular Venous Pulse from Anterior Neck Contact Photoplethysmography. Sci. Rep. 10 , 3466 (2020). Mamikoglu, B. & Gianoli, G. J. The clinical findings to notice mild elevation of intracranial pressure in an otology clinic. Am. J. Otolaryngol. 44 , 104004 (2023). Higgins, N., Pickard, J. & Lever, A. Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. J. Neurol. Surg. Rep. 76 , e244–e247 (2015). Higgins, J. N. P., Pickard, J. D. & Lever, A. M. L. Chronic fatigue syndrome and idiopathic intracranial hypertension: Different manifestations of the same disorder of intracranial pressure? Med. Hypotheses . 105 , 6–9 (2017). Hulens, M. et al. The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology. J. Pain Res. 11 , 3129–3140 (2018). Qiu, X. et al. The Relationships Among Transverse Sinus Stenosis Measured by CT Venography, Venous Trans-stenotic Pressure Gradient and Intracranial Pressure in Patients With Unilateral Venous Pulsatile Tinnitus. Front. Neurosci. 15 , 694731 (2021). Lehrer, J. F., Ogunlusi, A., Knutsen, J. & Marchbanks, R. J. The value of transcranial cerebral sonography in diagnosing neurootological disorders. Int. Tinnitus J. 15 , 164–167 (2009). Shulman, A., Goldstein, B. & Marchbanks, R. J. The tympanic membrane displacement test and tinnitus: preliminary report on clinical observations, applications, and implications. Int. Tinnitus J. 17 , 80–93 (2012). Gwer, S. et al. Abnormal intra-aural pressure waves associated with death in African children with acute nontraumatic coma. Pediatr. Res. 78 , 38–43 (2015). Birch, A. A. et al. Pulsatile tympanic membrane displacement is associated with cognitive score in healthy subjects. Cereb. Circ. Cogn. Behav. 3 , 100132 (2022). Sharif, S. J., Campbell-Bell, C. M., Bulters, D. O., Marchbanks, R. J. & Birch, A. A. Does the Variability of Evoked Tympanic Membrane Displacement Data (V m) Increase as the Magnitude of the Pulse Amplitude Increases? Acta Neurochir. Suppl. 126 , 103–106 (2018). Campbell-Bell, C. M. et al. A vascular subtraction method for improving the variability of evoked tympanic membrane displacement measurements. Physiol. Meas. 42 , 025001 (2021). Method To understand the direction of motion of the tympanic membrane in response to vascular pulsing, we consider the effects of pressure changes in the outer ear, middle and inner ear separately. The spontaneous tympanic membrane displacement (spTMD) ear probe seals into the external ear canal to sense pressure changes and interprets them as a tympanic membrane displacement (TMD). Any increase in the middle ear pressure, vascular, inner ear or CSF pressures results in an outward movement of the tympanic membrane regardless of its origins, provided the ossicles do not create a mechanical inversion. Data from ventilated patients with simultaneous measurements of arterial blood pressure (ABP), central venous pressure (CVP), and intracranial pressure (ICP) was analysed to validate this assumption. Unlike normal respiration, in artificially ventilated subjects, all three pressure waveforms increase with increasing thoracic pressure and reduce with reducing thoracic pressure. An outward TMD with increasing thoracic pressure would support our assumption that this direction reflects increasing vascular and/or CSF pressures. To assess if spTMD is more influenced by arterial, intracranial or central venous pressure dynamics, coherently averaged heartbeats were generated for ABP, ICP and CVP for each patient, and the correlation with spTMD was determined for each. This correlation analysis was then extended to a large healthy control data set. For healthy subjects, invasive signals could not be acquired. Therefore, representative waveforms for arterial, intracranial, and central venous pressure obtained from an average of all patients were used instead. The correlation of these “templates” from the patients with the individually measured spTMD waveform from each control subject was determined. Finally, to further test the hypothesis that the waveform has a substantial venous component, we took advantage of the differences in the timing of key waveform features of arterial and venous pulses relative to the ECG. Specifically, for arterial and intracranial pressure waveforms, the first sustained steep transition following the QRS complex is driven by the left side of the heart. This transition is always an increase in pressure that should correspond with a positive and outward spTMD. Conversely, a venous waveform transition generated by the right side of the heart is a decrease in pressure and should correspond with a negative and inward spTMD. We tested this premise first in the ventilated patients and then on the much larger data set of healthy volunteers to confirm general applicability across the population. Subjects All healthy volunteers recruited to the study gave informed consent, and all patient representatives (next of kin) gave informed assent. The National Research Ethics Service Committee East of England – Hatfield approved the control data collection protocol. Southampton & SW Hants B ethics committee approved the patient data collection. All methods were performed in accordance with the relevant guidelines and regulations. Five patients were recruited that had suffered a traumatic brain injury (3 males, 2 females, age 18-55, median 40 years). One patient had data collected slightly differently and without ICP. The sampling frequency was 100Hz with simultaneously recorded analogue signals of ABP, CVP and spTMD. The inclusion criteria were: sedated, ventilated and undergoing invasive CVP, ICP and ABP monitoring for their clinical care. Additionally, we reviewed data collected from 316 healthy volunteers. This control data set has been described previously. In brief: volunteers were recruited via publicity on the radio, in newspapers and through local social society appeals. There were similar numbers in the three age ranges 20-40, 40-60 and 60-80, and number of males and females (mean age 47). All were confirmed not to have any otological, neurological or cardiovascular disease. All had a normal otoscopic examination, middle ear pressure and compliance in at least one ear [5,40,41]. Data collection Patients: Routine patient monitors (G.E. Carescape, Chicago, Illinois),using strain gauge pressure transducers (TruWave, Edwards Lifesciences, Irvine, California) connected by standard manometry lines in the radial artery and superior vena cava, were used to record arterial and central venous pressures, respectively. Intracranial pressure was measured using catheter-tipped intraventricular pressure transducers (Integra Lifesciences, Plainsboro, New Jersey). Tympanic membrane displacement was recorded with an MMS-14 CCFP (Marchbanks Measurements Ltd., Lymington, UK) All data were recorded simultaneously using ICM+ software (Cambridge University, UK). Pressure signals were recorded as digital outputs from the bedside monitors together with the ECG waveform. The spTMD signal was recorded as an analogue signal via an A-D converter (Data Translations Inc, Boston, Massachusetts). An analogue arterial blood pressure output was likewise simultaneously recorded directly from the Carescape patient data module (defib sync port.) This was used to ensure accurate alignment of the digital and analogue signals. Data were recorded continuously for approximately 1 hour while spTMD from one ear was recorded quasi-continuously (typically interrupted for 1 s once every 30 s to allow the displacement microphone to be re-centred.) The patient’s posture was not altered and was typically supine, on a pillow, with the head of the bed inclined by 30 degrees. Healthy controls: Volunteers attended the hospital’s clinical research facility for a single visit of approximately 2 hours, during which at least 100 s of spTMD data was recorded from both ears in the sitting and then the supine posture. In a subset of 60 volunteers, an intermediate measurement was performed in one ear only while the head of the bed was raised by 30 degrees. Five minutes were allowed to elapse between each posture change. Simultaneously with the spTMD measurement, a 3-lead ECG was recorded. The spTMD and ECG analogue data signals were recorded on the same data acquisition system used for the patients, and this utilised ICM+ software. Data analysis All data analysis was completed using in-house software written in MatLab (Mathworks, R2019a. Natick, Massachusetts) The time of every heartbeat was identified from the QRS complex automatically identified and visually checked. The spTMD data was reviewed to determine the start and end of each good data section. These were typically 20 or 30 s in duration, separated by 1 s of non-physiological re-zeroing. Each spTMD section was linearly detrended. All signals were low pass filtered, backwards and forwards, to maintain phase, with an order 6 Butterworth filter with a cut-off frequency of 10Hz. Stage 1: Direction of spTMD during mechanical ventilation The direction of spTMD in response to the pressure changes associated with mechanical ventilation was identified by visual inspection of a coherently averaged ventilatory cycle for each patient. Before producing an average ventilatory cycle, the heartbeat was removed from all waveforms by beat averaging and re-sampling as follows. The average value within each heartbeat was determined, and a new time series was created with a single sample for each heartbeat. These samples were positioned in the middle of the heartbeat and then joined up by linear interpolation, maintaining the correct beat-to-beat time intervals. Thus, a new time series with heartbeats removed was produced for spTMD, ABP, CVP and ICP. The timing of each ventilator cycle was automatically identified and visually checked. A consistent time point corresponding approximately with the start of inspiration was identified in each ventilatory cycle from a simultaneously acquired measurement of either expired CO2 concentration or airway pressure. The time of the minimum pressure was used for airway pressure. With expired CO2, the point that the expired CO2 transitioned from above the median to below the median value was used. A sample of data, 3 s before and 3 s after the selected time point, was then extracted and detrended before being added to the coherent average. The resulting waveforms showing coherently averaged ventilatory cycles of all variables were visually compared and categorised according to polarity of the phase, that is whether in-phase or out-of-phase. Stage 2: Correlation of spTMD cardiac waveform with CVP, ABP and ICP For each patient, a waveform representing the cardiac cycle was produced for spTMD, ABP, CVP and ICP. This was done by extracting 2-second-duration data samples, from 1 s before to 1 s after, each identified QRS sample. The extracted samples were linearly detrended and coherently averaged to produce average waveforms for each variable centred on the time of the QRS complex. A simple correlation coefficient determined the correlation between each of the variables. A high correlation is expected between spTMD and each of the other parameters because each one will show a similar pulsing waveform driven by the heartbeat. There will be differences in wave shapes between each of the variables; our objective is, therefore, to determine which of the variables shows the strongest correlation with spTMD. Subtle differences in the synchronisation of each measurement will substantially impact this correlation analysis. Ideally, our arterial, venous and intracranial pressure measurements would be taken close to the ear to avoid delays between variables. Our arterial and central venous pressures were measured from the radial artery and vena cava, respectively. ICP was measured in a lateral ventricle or brain parenchyma. The spTMD was recorded in the external ear canal. We know that relative timing errors of the signals are present due to, for example, transmission delays in the pressure lines. A time difference of 30-50ms may exist between our signals. For the comparison of correlation coefficients to be meaningful, the frequency response of all recording instruments should be the same. Alternatively, filtering can be used to make all frequency responses equivalent. The response characteristics of our instruments are nominally 20Hz for the pressure measurements and 10Hz for the spTMD. These were standardised by sampling all signals at a minimum of 100Hz and then digitally low-pass-filtered with a cut-off frequency of 10Hz (Butterworth order 6.) We wanted to perform the same correlation analysis on our large healthy control population; however, invasive ABP, CVP, and ICP measurements are unavailable for these subjects. Instead, we use template waveforms for these variables derived from our patients. A coherently averaged waveform of 1.5 s duration was created for each variable from the patient data described above to produce templates representative of the typical ABP, ICP and CVP waveforms. A waveform warping function was then applied to each patient waveform to standardise the heartbeat's length. The warping was applied such that 1 s corresponds to the median beat length. The size of stretching or shrinking between two consecutive samples increased by the addition of a constant, linearly, from the middle of the sample to each extremity. This method minimised distortion at the time of the QRS complex placed centrally in each template. We have previously used and described a similar method [41]. After warping to a standard beat size, a coherent average was made of all patients for each variable. A coherently averaged spTMD heartbeat waveform of 1.5 s duration was then produced for every healthy control subject. The warping function was also applied to each coherent average to produce a waveform with a standardised 1-second heart rate. The spTMD waveform for each control subject was then correlated against the templates for spTMD, ABP, CVP and ICP derived from the patients. A simple correlation coefficient was determined. The dominant variable was determined as having the highest correlation with the spTMD waveform. For each variable, the proportion of subjects in which a particular variable is dominant was determined. Stage 3: Direction of displacement following the QRS waveform. The coherently averaged waveforms were analysed to determine the direction of the first steep change in pressure or displacement following the QRS complex. A 'steep change gradient' threshold was in a positive or negative direction and was defined as 0.5h per second (nLs -1 ), where h is the peak-to-peak value of the waveform. Every single patient's heartbeat was analysed independently. The first derivative of each waveform was determined, and the first incidence of a steep gradient more than 60ms after the QRS complex was identified. We chose 60ms because the rise in arterial and CSF pressure following the QRS complex will not propagate to the ear for at least 60ms. The CVP descending slope is similarly delayed. The proportion of heartbeats in which the first steep gradient was positive or negative was identified. This was repeated for ICP, ABP, and CVP waveforms. Each patient's results were presented separately. Finally, the same analysis was performed on the control subjects; however, the coherent average for each subject was used instead of individual heartbeats. The proportion of subjects who were positive and negative is reported. Results from sitting, supine, and inclined are reported separately. Additional Declarations Competing interest reported. Dr Robert Marchbanks is the Managing Director of the Southampton University spin-out research company that manufactures the TMD/CCFP Analyser (Marchbanks Measurement Systems Ltd). The rest of the authors declare no conflict of interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6940263","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":481459026,"identity":"819c91a6-616c-4d57-a784-745b860055b4","order_by":0,"name":"Robert J Marchbanks","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Southampton NHS Foundation Trust","correspondingAuthor":true,"prefix":"","firstName":"Robert","middleName":"J","lastName":"Marchbanks","suffix":""},{"id":481459027,"identity":"e9113851-71dd-4e82-a13a-859fe8407bdf","order_by":1,"name":"Anthony A Birch","email":"","orcid":"","institution":"University Hospital Southampton NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"A","lastName":"Birch","suffix":""},{"id":481459028,"identity":"2ab43909-c4b3-4f55-b37a-457119794310","order_by":2,"name":"Wahbi K El-Bouri","email":"","orcid":"","institution":"University of Liverpool","correspondingAuthor":false,"prefix":"","firstName":"Wahbi","middleName":"K","lastName":"El-Bouri","suffix":""},{"id":481459029,"identity":"2c9be004-aa5f-453b-9e4c-68146050b87b","order_by":3,"name":"Diederik O Bulters","email":"","orcid":"","institution":"University of Southampton","correspondingAuthor":false,"prefix":"","firstName":"Diederik","middleName":"O","lastName":"Bulters","suffix":""}],"badges":[],"createdAt":"2025-06-20 15:38:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6940263/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6940263/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86308637,"identity":"a0acc83a-ac0f-474d-8a98-880178b3a07f","added_by":"auto","created_at":"2025-07-09 07:50:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":582816,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(a).\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Static and dynamic fluid pressure exchanges with the ear. Schematic of the ear with key anatomical features. CA - CSF static pressure and pressure pulses via the Cochlear Aqueduct with other additional routes, including vestibular aqueduct, internal auditory meatus, peri-vascular and perineural routes. ICA - Pressure pulses from subsidiary arteries connecting to the Internal Carotid Artery. IJV - Pressure waves and fluid turbulence via venous drainage routes communicate with the internal jugular vein around the location of the sigmoid sinus, with possible acoustic conduction from the jugular bulb and elsewhere. Other routes include transverse sinuses and possibly external jugular veins and subsidiaries. Orientation: a. CSF in the subarachnoid space, b. Perilymph in the inner ear, c. Ossicles of the middle ear, d. Stapes resting in the oval window, e. Tympanic membrane.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(b)\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Showing an example of a coherently averaged of spontaneous tympanic membrane displacement (spTMD) pulse waveform together with the ECG recording from a healthy volunteer in the sitting position. Ensemble averaging has been used to reduce noise to provide a representative spTMD pulse waveform and ECG signals.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(c)\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Causes of the spTMD wave. Schematic of the ear and main fluid pressure coupling routes. \u0026nbsp;CSF – Cerebrospinal fluid, OW – Oval window, TM – Tympanic membrane. RED: Arterial supply. BLUE: Venous drainage. GREEN: CSF and perilymphatic fluid route transmission. GREEN-RED-BLUE: Mechanical middle ear ossicular transmission to the TM comprises inner ear arterial, venous and CSF components. The venous drainage is via the internal auditory vein, vein of the cochlear aqueduct and vein of the vestibular aqueduct. These all drain into the superior petrosal sinus (PS) and inferior PS. The superior PS drains into the transverse sinus and, then, onto the sigmoid sinus and into the internal jugular vein (IJV). The inferior PS drains directly into the IJV.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/b68a1ed5ed0cc8c589be9c7c.png"},{"id":86308636,"identity":"54525d83-3d4d-452b-bb8f-4a1429a67cd8","added_by":"auto","created_at":"2025-07-09 07:50:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":99211,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eA 6 s coherent average is shown for all 5 patients centred on a consistent time point determined from the ventilator cycle. \u0026nbsp;All data was detrended across the length of each spTMD epoch. To filter out the cardiac pulses, all heartbeats were replaced by their average value and the data was then interpolated and re-sampled. The observation that spTMD is also in phase confirms that a positive and outward spTMD represents an increase in pressure.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/03402d0eccafa49c4d59623e.png"},{"id":86308638,"identity":"be2a38c6-1b8d-4522-a806-38abcf983d6d","added_by":"auto","created_at":"2025-07-09 07:50:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":275137,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eShows the location of negative and positive gradients for CVP, ABP and spTMD. Heartbeats are identified using the blood pressure of patient 1, with time '0' indicating the initiation of the pulse. Data samples were extracted from 0.75 s before until 0.75 s after each beat and detrended. Although CVP waveforms follow a set pattern of events, the relative amplitudes of the CVP peaks are known to be variable. Nevertheless, both figures show that the patients consistently demonstrate a negative transition for CVP and spTMD around or after time '0' and before the positive ABP pulse transition.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(a) \u003c/strong\u003e\u003c/em\u003e\u003cem\u003ePatient 1 shows a known variant of the CVP waveform morphology where the steep negative transition occurs earlier because of an indistinct venous c-wave.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(b) \u003c/strong\u003e\u003c/em\u003e\u003cem\u003ePatient 2 shows a known variation of the CVP waveform morphology where the later c-wave is larger than the a-wave, which is the reason for the analysis discrepancy.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/31081fecdffb0aceeaeacf1a.png"},{"id":86308643,"identity":"cf8f5448-5111-44d5-abd6-291d83471be8","added_by":"auto","created_at":"2025-07-09 07:50:26","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":164949,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCoherent averages of the patient data (ABP, ICP, CVP) compared with patient spTMD control data. Shown is 0.75 s of data taken on either side of each QRS. The resulting waveform is stretched or shrunk, so 1 s corresponds to the median beat length. Blue shows average with linear stretching of each beat, and red shows warped stretching with minimal stretching applied to the centre around the QRS (Green Line). The coherently averaged ECG, with linear stretching, is in black. The y values are centred on zero due to the application of detrending, which subtracts the mean value and removes any trends. This is a requirement primarily for the spTMD signal. Three templates are joined and displayed for each signal to make the complete heartbeat cycle easier to visualise.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/21e7fa0fd922abc2f5170a92.jpg"},{"id":86309799,"identity":"0f8b350a-fe9a-460e-92dc-1b705192748d","added_by":"auto","created_at":"2025-07-09 07:58:26","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":116212,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCoherent averages of the patient data spTMD compared with spTMD control subject data for sitting, inclined at approximately 30 degrees, and supine. Shown is 0.75 s of data taken on either side of each QRS. The resulting waveform is stretched or shrunk, so 1 s corresponds to the median beat length. Blue shows average with linear stretching of each beat, and red shows warped stretching with minimal stretching applied to the centre around the QRS (Green Line). The coherently averaged ECG, with linear stretching, is in black. The y values are centred on zero due to the application of detrending, which subtracts the mean value and removes any trends. Three templates are joined and displayed for each signal to make the complete heartbeat cycle easier to visualise.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/de391a1d236939c14177b1b6.png"},{"id":86308645,"identity":"9ab716e5-aa9f-4087-bdef-272e490d1334","added_by":"auto","created_at":"2025-07-09 07:50:26","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":46491,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eThis figure shows the main features of the CVP waveform together with the ABP and ECG waveforms. The ‘a-wave’ is the atrial contraction that aids ventricular filling in late diastole and is referred to as the ‘atrial kick’. Following a mechanical time lag, this pressure wave correlates with the ECG ‘P-wave’. The ‘c-wave’ superimposes the usually distinct and dominant venous x-descent in early ventricular systole. The ‘c-wave’ occurs with the tricuspid valve closing and bulging towards the right atrium. This pressure wave correlates with the end of the ECG ‘QRS-complex’. The ‘x-decent’ is generated by the downward displacement of the atrial-ventricular partition with movement of the right ventricle as it descends with contraction. The atrial diastolic relaxation further decreases the CVP pressure at this stage of the cycle. \u0026nbsp;Around the same time but following the ECG QRS complex and c-wave, the familiar arterial pulse starts as the left heart ventricle contracts to drive the blood supply throughout the body. \u0026nbsp;The ‘v-wave’ marks right atrial filling that leads to the start of diastole and occurs after the ECG ‘T-wave’. The ‘y-decent’ is a pressure reduction with venous drainage caused by the opening of the tricuspid valve and occurs with rapid ventricular filling in early systole. This descent occurs before ECG ‘P-wave’. In the typical case, the pressure rises towards the ‘a-wave’ that marks the repeat of the cardiac cycle.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/15a456a5721c784d48fa02fd.jpg"},{"id":94988467,"identity":"c5128743-f922-4662-80d4-852c21ba4c19","added_by":"auto","created_at":"2025-11-03 07:09:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2166973,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6940263/v1/646de321-e9c2-4009-aec1-df088076aebd.pdf"}],"financialInterests":"Competing interest reported. Dr Robert Marchbanks is the Managing Director of the Southampton University spin-out research company that manufactures the TMD/CCFP Analyser (Marchbanks Measurement Systems Ltd). The rest of the authors declare no conflict of interest.","formattedTitle":"Discovery of a substantial cerebral venous pressure wave component in Spontaneous Tympanic Membrane Displacement: Expanding understanding of composite Aural Pressure Waves","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe causes and incidence of abnormal cerebrospinal fluid (CSF) dynamics and cerebral venous drainage are poorly understood due to measurement difficulties. MRI techniques are limited and invasive methods are only practical in specific clinical scenarios. A simple and continuous monitoring technique of dynamic CSF, intracranial pressure (ICP) and cerebral venous outflow pressure would be valuable for research and clinical assessments.\u003c/p\u003e\n\u003cp\u003eSome researchers have utilised the fluid connection between the CSF and the inner ear to explore the relationship between tympanic membrane displacement (TMD) and ICP pulsatility. The association exists. However, it is often weak and only found in some ears [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe cochlear aqueduct (CA) is the principal route that allows for direct pressure transfer between the CSF in the posterior fossa and the perilymph in the cochlea [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. If there are no obstructions or abnormalities, the steady-state perilymphatic pressure should equal CSF pressure, Fig.\u0026nbsp;1a, 1c. This homeostasis facilitates non-invasive measurements of baseline ICP in the posterior fossa by techniques such as evoked tympanic membrane displacement (TMD) [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Steady-state pressure transfer has been established, however, CSF pulsatility is not understood.\u003c/p\u003e\n\u003cp\u003eSpontaneous tympanic membrane displacements (spTMD) are characterised by periodic waveforms associated with the cardiac cycle and respiration. An electrocardiogram (ECG) signal can isolate individual heartbeats for analysis, and ensemble averaging can reduce noise to provide a representative spTMD pulse waveform, Fig. 1b.\u003c/p\u003e\n\u003cp\u003eThe typical shape of the spTMD pulse waveform is likely to be influenced by a combination of multiple waveforms propagating from the heart by different intracranial and extracranial routes. To distinguish between waveform components arriving from CSF pressure and those from direct arterial routes, we have previously assessed the relative associations of radial arterial pressure and intracranial pressure waveforms with the spTMD waveform. We found substantial and independent contributions from each; however, neither showed a strong correlation. We speculated that another source, perhaps venous, contributed substantially to the waveform [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eThe intra-aural pressure wave is a superimposition of pressure waves from multiple origins [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e], Fig.\u0026nbsp;1a, 1c. The ear receives pressure pulses and waves from sources including the cerebral arteries, CSF fluids, and this study investigates the contribution of venous drainage. Venous drainage from the ear is directly into the inferior and superior petrosal sinus (PS) or the internal jugular vein (IJV) [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Venous return from the head to the heart is through five routes and three categories of veins; external jugular veins that are collapsible on moving from supine to sitting, internal jugular veins and vertebral venous plexus. The balance of venous drainage through these veins depends on posture. The deoxygenated blood flows into the superior vena cava and the right atrium empties during the cardiac cycle. The filling of the right ventricle depends on venous return pressure, potential energy, and any hydrostatic pressure depending on posture.\u003c/p\u003e\n\u003cp\u003eThe influence of the venous drainage of the ear on the spTMD pulse waveform has yet to be considered. Drainage of the inner ear is intracranial into the jugular vein, while the middle and outer ear venous drainage is extracranial. Both are influenced by central venous pressures (CVP) and the right side of the heart haemodynamics. This paper tests the hypothesis that venous pressures are a substantial missing component of the spTMD pulse waveform.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"Results/Findings","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStage 1: Phase of spTMD during mechanical ventilation\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the coherently averaged ventilator cycle for each of the five patients. As expected, all five patients demonstrate that the CVP, ABP and ICP are all in phase with ventilation. That is, pressures are seen to increase during the inspiration phase of ventilation associated with the increasing thoracic pressure of forced ventilation. The observation that spTMD is also in phase confirms that a positive spTMD represents an increase in pressure. Regarding TMD, an outward displacement represents an increase in external ear pressure, whereas an inward displacement represents a decrease in pressure.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStage 2: Cardiac Cycle correlation analysis\u003c/h3\u003e\n\u003cp\u003eFor each of the five patients coherent averaging of the cardiac cycle was undertaken for spTMD, ABP, ICP and CVP producing waveforms in a similar manner to that shown in Fig.\u0026nbsp;1b. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the Pearson correlation coefficients for each variable with the spTMD waveform.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eShowing the Pearson correlation coefficient of each variable with spTMD. X represents missing data.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eABP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCVP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eICP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn all cases, apart from patient 1, the maximum absolute correlation coefficients with CVP are positive, and the correlation with ABP and ICP are negative. This finding is consistent with a strong venous component in the spTMD signal.\u003c/p\u003e\u003cp\u003eThe patient 1 exception, occurs due to a slightly different CVP profile with the steep negative transition occurring earlier because of an indistinct venous c-wave, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003ea.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThese results were determined from a small group of 5 patients under intensive care conditions. The next step was to apply this analysis to healthy subjects to see whether the findings were more generally applicable. This analysis used patient data to generate representative heartbeat cycles for ABP, ICP and CVP. These templates are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, together with the equivalent spTMD cycle.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe spTMD waveforms in the sitting position, supine and on a couch with the upper body inclined head-up at 30 degrees were all produced by coherent averaging of results from 316 healthy subjects. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the correlation results with the templates for ABP, CVP, ICP and spTMD derived from the patients. Separate results are given for the control subjects' sitting, supine and inclined posture. The patient heartbeat templates are for a fixed posture of head-up inclination of approximately 30 degrees. The waveforms are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelation coefficients for coherently averaged spTMD heartbeat from healthy subjects with templates from patients. (Results from left and right ears have been averaged.)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eControl Posture\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient spTMD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePatient ABP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePatient CVP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePatient ICP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSitting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e256\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInclined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA good correlation was found between the averaged patient and control waveforms (spTMD), sitting and inclined. A weaker correlation exists between averaged patient and control waveforms (spTMD) for supine.\u003c/p\u003e\u003cp\u003eThe healthy control spTMD heartbeat was positively correlated with the CVP template in the sitting position, weakly correlated for inclined and negatively correlated for supine. The control spTMD has a strong negative correlation with the ABP and ICP templates for sitting, weakly correlated for inclined and positively correlated for supine. These results show that the spTMD waveform in healthy control subjects is strongly influenced by posture. They also support the presence of a strong contribution from the venous circulation in the sitting position.\u003c/p\u003e\n\u003ch3\u003eStage 3: Direction of pressure transition following the ECG QRS Complex\u003c/h3\u003e\n\u003cp\u003eFor our final test to assess if the spTMD waveform has a substantial venous influence, we focussed on the pressure transition direction following the QRS complex peak. This transition corresponds to a pressure rise in the arterial system and a pressure reduction in the venous system. The literature indicates that these arterial and venous transitions will lag nominally 30 to 60ms behind the ECG waveform. Consequently, we used the period starting 60ms after the QRS complex to look for a steep gradient in the waveform and recorded if it was in a positive or a negative direction. By starting at 60ms, the transition will be developing. A steep gradient was defined as 0.5h per second (nLs\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ), where h is the peak-to-peak value of the waveform.\u003c/p\u003e\u003cp\u003eFirst, for each of the 5 patients, we processed every heartbeat; the results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eShowing the patient data and the percentage of heartbeats for which the first steep gradient was positive and negative. The direction of pressure transition was taken at 60ms after the ECG QRS Complex peak. (The percentages do not add up to 100% because a minority of beats do not have a gradient following QRS that exceeded the threshold that was defined as \u0026lsquo;steep\u0026rsquo;). X represents missing data.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePatient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eNumber of heartbeats\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eABP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eICP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eCVP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e\u003cp\u003espTMD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e% +ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e% -ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e% +ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e% -ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e% +ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e% -ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e% +ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e% -ve\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e363\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1362\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2189\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1454\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2386\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAs expected, the results show that the first steep gradient following the QRS complex is consistently a positive pressure transition for the arterial and ICP pulse transitions. The spTMD was predominantly a negative pressure transition corresponding to an inward TMD, a tympanic membrane movement toward the middle ear. Likewise, the CVP was predominantly a negative pressure transition corresponding to a reduction in pressure, except for patient 2, who had an exceptionally large venous c-wave, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eb. Although CVP waveforms follow a set pattern of events, the relative amplitudes of the CVP peaks are known to be variable. In patient 2, the later c-wave is larger than the a-wave, which is the reason for the analysis discrepancy. Despite this, the spTMD pressure transition is negative and consistent with a venous wave.\u003c/p\u003e\u003cp\u003eThe same analysis was then performed on the control data, in this case we have spTMD data in terms of a coherent average waveform for each subject. The direction of the first steep gradient was determined from the coherent average such that each subject was either positive or negative. The proportions are then presented as the proportion of subjects rather than the proportion of heartbeats. These results are presented for the different postures in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eShowing the control data and percentage of heartbeats for which the first steep gradient was positive and negative. The direction of pressure transition was taken at 60ms after the ECG QRS Complex peak. (The percentages do not add up to 100% because a minority of beats do not have a gradient following QRS that exceeded the threshold that was defined as \u0026lsquo;steep\u0026rsquo;).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePosture\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003espTMD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e% of Controls\u0026thinsp;+\u0026thinsp;ve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e% of Controls -ve\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSitting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInclined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe spTMD results indicate that a decrease in pressure occurs following the QRS complex, consistent with a dominant venous influence on spTMD for all three postures.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of the current study conclude that an inward spTMD indicates a decrease in vascular pressure, which is consistent with the pressure changes observed in the outer, middle, and inner ear. It is assumed that the inner ear vascular pressure changes act similarly. Although there is no conclusive proof, no evidence suggests otherwise. Stage 1 used respiration to study the spTMD polarity, and it is reasonable to assume that the cardiac pulse has the same polarity. The study also assumes this applies to healthy, normal subjects, not just those sedated and ventilated.\u003c/p\u003e\u003cp\u003eWe conclude that any vascular or CSF pressure increase will translate to an outward movement of the tympanic membrane, regardless of its origins.\u003c/p\u003e\u003cp\u003eStage 2 of the study analysed whether spTMD was best represented by ABP, ICP or CVP using patient data sets. In all cases, the maximum absolute correlation coefficients of spTMD negatively correlate with both ABP and ICP. The spTMD positively correlates with CVP, except for one patient with a slightly different CVP profile where the steep negative transition occurred earlier because of an indistinct venous c-wave.\u003c/p\u003e\u003cp\u003eThe correlation analysis in the healthy control data set supports the hypothesis that venous pressure represented by CVP contributes to the spTMD waveform. The spTMD waveform will not be the same as CVP since it will be unique to pressure coupling at the ear location; nevertheless, the waveforms similarly have a pressure reduction around the ECG QRS complex, whereas ICP and ABP show the expected delayed positive pressure pulse. The spTMD pressure reduction sometimes starts before the ECG QRS complex during ventricular diastole, providing further evidence of a venous drainage wave. A consistent and often dominant negative spTMD transition in early ventricular systole corresponds with reduced pressure during accelerated cerebral blood drainage.\u003c/p\u003e\u003cp\u003eThe shape of the spTMD pulse varies substantially with posture in healthy control data. The study revealed that the correlation coefficients for spTMD were positively correlated with CVP and negatively correlated with ABP and ICP for sitting and inclined postures. This suggests the presence of a substantial or even dominant venous wave component within the spTMD waveform. However, for the supine posture, spTMD was negatively correlated with CVP and positively with ABP and ICP. This finding highlights the importance of considering posture. The inclined healthy patient data set best represent the patient's posture, although the sitting healthy patient data had higher correlation coefficients. The reason for this is unknown, but may be related to a difference in the middle ear pressure or patient pathologies that make sitting a more representative posture for some patients. However, this interpretation should be considered cautiously in the absence of patient ABP, ICP and venous pressure waveforms with similar posture changes for comparison.\u003c/p\u003e\u003cp\u003eMore sophisticated analysis techniques than correlation that could have been applied for waveform identification. However, we felt nothing would be gained given that the waveforms we used only represented arterial, intracranial and venous pressures and were not definitive. The resulting template waveforms will vary between individuals and the measurement site. Given this, we have used timing relative to the ECG to back up our results.\u003c/p\u003e\u003cp\u003eUsing timing relative to the ECG to support our analysis assumes that the measurements are well synchronised and accurately reflect the relative arrival time of the respective waveforms at the tympanic membrane. Great care was taken to ensure the waveforms are well synchronised. There will be a small-time difference between our measured waveforms and the ear-based measurements. However, these are sufficiently small to not influence the findings in this paper.\u003c/p\u003e\u003cp\u003eFollowing a careful study of the descriptions of the arterial and venous waveforms in the literature, we chose the period starting 60ms after the QRS complex to look for a steep gradient in the waveform. We recorded if the gradient was in a positive or a negative direction. A \u003cem\u003esteep gradient\u003c/em\u003e defined as 0.5h per second (nLs\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e ), where h is the peak-to-peak value of the waveform.\u003c/p\u003e\u003cp\u003eWe first applied the steep gradient analysis method to the patient data as a check (stage 2). Except for CVP for patient 1, positive slopes occurred for ABP and ICP, and negative slopes for CVP and spTMD. As explained earlier, the patient 1 CVP exception is due to the waveform morphology, so we were happy that the method is appropriate for the healthy spTMD datasets (stage 3). We considered whether the spTMD transition was positive or negative following within 60ms of the ECG QRS peak. Over 98% (80:1) of the healthy subject in the sitting posture and 88% of the healthy subjects in the inclined and supine postures (69:8, 67:8, respectively) demonstrate a negative pressure spTMD transient following the QRS peak. These findings are consistent with a substantial or even dominant venous influence in spTMD for healthy subjects in all three postures.\u003c/p\u003e\u003cp\u003eSpecifically, for arterial and intracranial pressure waveforms, the first sustained steep change in pressure following the QRS complex is driven by the left side of the heart and always in a positive direction. In contrast, venous waveforms are influenced by the right side of the heart and in a negative direction.\u003c/p\u003e\u003cp\u003eThe timing of dominant pressure transitions highlights the physiological differences between a venous drainage waveform and an arterial pulse. Venous drainage occurs before the ECG QRS complex with the opening of the cardiac tricuspid valve that occurs with the start of ventricular diastole. The sequence of events with the cardiac cycle is detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAccurate measurement of this sequence of events is critical to identifying the arterial-venous composition of the spTMD waveform; however, as demonstrated in our patient data, the relative amplitudes of the venous components vary with factors that make this quite challenging.\u003c/p\u003e\u003cp\u003eThe ear haemodynamics likely evolved to be compatible with sensitive hearing and balance receptors. The cochlea has a unique arterial supply via the stria vascularis that substantially attenuates any pulsatility through a network of elastic vessels and tortuous arterioles that feed the stria vascularis; consequently, with the arterial pulse attenuation, the venous waveform becomes more apparent. This mechanism is essential for proper hearing and vestibular function of the labyrinth [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The degree to which the arterial pulsing is attenuated is unique to the labyrinth despite a reasonably high blood supply demand.\u003c/p\u003e\u003cp\u003eA dual arterial and venous pulsatility exists within the eye where the spontaneous retinal venous pulse ceases with raised ICP. As with the aural pulse waveform, the CSF pressure is considered to play a pivotal role in the retinal venous pulse [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAlthough spTMD includes information about the ICP waveform, the aural pathway is more complex than a direct pressure link via the cochlear aqueduct, as found by our earlier research [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The findings of this earlier research are that: -\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eBoth ABP and ICP contribute independently to the spTMD signal.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eInformation shared between the ICP and spTMD is not present in ABP.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eLower frequencies (e.g., respiration) favour ICP as the driver for spTMD.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eThere was a substantial missing component that was most likely venous.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eThe finding of the current paper supports the presence of a substantial venous component (4), which also, in part, will explain information shared between the ICP and spTMD that is not present in ABP (2). Although a dominant component of the ICP (CSF pressure) wave is arterial, an important venous component also exists and has to be considered when explaining the ICP waveform morphology or the ICP P3 pulse in particular [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe venous waveform reflects the respiratory component in CVP that occurs due to changes in thoracic pressure and right-side cardiac stroke volume with pulmonary artery pressure. The pressure within the cerebral venous sinuses, ICP and CSF are all known to couple with respiration [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e illustrates this pressure coupling. Both spTMD and the ICP are composite waveforms with characteristics unique to a specific anatomical location.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eEvensen et al. (2018) tested the assumption that ICP waves transmit through the cochlear aqueduct to dominate the Tympanic Membrane pulse. They found this is likely to be over-simplistic, certainly at cardiac frequencies, in the majority of patients tested. They surmised that the cochlear aqueduct (CA) worked as a physical lowpass filter [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. We provide evidence here, that the assumption neglects spTMD to venous coupling, a substantial component of the aural pressure wave. Conceivably, both a direct cochlear aqueduct pressure connection and venous pressure coupling may be occurring.\u003c/p\u003e\u003cp\u003eThe CA is an open route for the majority of people. However, it may act as a low-pass filter transmitting the ICP signal at frequencies below 20 Hz, and whether its patency reduces with age remains a disputed issue [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In some individuals, both the cardiovascular and respiratory waves will be transmitted between ICP and perilymph, whereas ICP-perilymph pressure equalisation only occurs at lower respiratory frequencies in other individuals [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. CA transmissibility has been evaluated with distortion-product otoacoustic emissions (DPOAE), and minimal attenuation of the respiratory signal was found, supporting non-invasive aural measurement of CSF pressure [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition to the cochlear aqueduct, other routes may exist. Other possible channels are the vestibular aqueduct and the internal auditory canal, perineural and perivascular routes, and through anatomical abnormalities such as dehiscence of the superior semi-circular.\u003c/p\u003e\u003cp\u003eInitially, we shared the opinion that the aurally derived pulse was potentially a non-invasive surrogate for ICP or brain compliance. This was based on the observation that the ICP pulsatility increases in amplitude with reduced intracranial compliance caused by an increase in baseline ICP [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This opinion is challenged, although not negated, in light of our current findings and anatomical considerations, which suggest that spTMD is a complex composite pressure wave of intracranial and venous components.\u003c/p\u003e\u003cp\u003eAn important implication of this finding is that spTMD amplitude is unlikely to be a simple non-invasive surrogate for measuring baseline ICP but will depend on the make-up of the pressure coupling between all cerebral fluids. More recently, morphological changes, slopes and higher frequency features in the aural pressure waveform have been scrutinised as potentially more valuable non-invasive surrogates for ICP or brain compliance [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA more complex relationship between aural pressure waves and the intracranial pressure pulse is also the conclusion drawn by Evensen et al. (2018) in their paper that reviewed the utility of the tympanic membrane pressure (TMp) waveform for non-invasive estimates of the ICP [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. From the clinical perspective, they conclude TMp and mean wave amplitude (MWA) would only provide a \u003cem\u003erather satisfactory\u003c/em\u003e non-invasive estimate of ICP pulse MWA in 4/28 (14%) patients.\u003c/p\u003e\u003cp\u003eWe concur with the above findings. In unpublished work, we compare spTMD with ICP pressure waves in neuro-intensive care patients undergoing direct ICP monitoring. Sometimes the spTMD (TMp) reflects ICP, but it does not in many patients.\u003c/p\u003e\u003cp\u003eIt seems that there are limitations to using spTMD as a surrogate for the ICP pulse, which we believe is explained by the intra-aural venous component. The waveform of spTMD may change depending on which pressure source is being coupled to the ear location. This coupling will likely vary based on posture, cerebral compliance, and the baseline CVP with central venous compliance.\u003c/p\u003e\u003cp\u003eA complex pressure-coupling postulate for the aural pressure wave is supported by the above observations. Indeed, the implication of the Unnerb\u0026auml;ck et al. (2019) findings suggest that if spTMD is venous dominated, then the spTMD amplitude may decrease with increasing ICP under certain circumstances. In a study of 37 neuro-intensive care patients undergoing phase-contrast MRI of cerebral blood flow measurements, it was observed that raised intracranial pressure attenuated the pulsatile component of the cerebral venous outflow [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The authors concluded this could be due to increased pressure requirements to compress intracranial veins with increasing ICP. A similar negative correlation is reported where a reduced venous retinal pulse can be used as a diagnostic indicator in patients with idiopathic intracranial hypertension (IIH) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe relative size of the various components of the spTMD waveform is likely to be frequency and person-dependent. The respiratory frequencies of the ICP wave are better correlated with spTMD [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and this finding is consistent with Evensen et al. (2018) study. The frequency content of the venous component, identified in this paper, requires further research together with the posture or pathology dependencies.\u003c/p\u003e\u003cp\u003eIn our early research, we found that substantial spectral energy exists at the lower frequency of the spTMD signal and that these lower frequencies favour ICP as the driver for spTMD [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Analysis of the simple coherences found a slight preference for ICP transmission to the spTMD signal at lower frequencies (7/11 {64%} patients at respiration frequencies, 7/10 {70%} patients at respiration 1st harmonic), which was reversed at the higher cardiac frequencies (2/11 {18%} patients at heart rate and its 1st harmonic). We found that most of the power was at the lower respiration harmonics, and we considered pressure coupling with respiration the most likely reason. The current study also supports the respiratory pressure coupling via the venous drainage routes to CVP. The ICP will couple with thoracic pressure via these routes and independently via spinal thoracic to CSF pressure coupling [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Deep breathing has been shown to couple CSF and venous flow dynamics [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe findings of this paper do not necessarily negate the possibility that spTMD is of value for non-invasive ICP pulse measurements; however, it shows it is complex and that spTMD is likely a combination of a direct pressure link via the cochlear aqueduct and pressure coupling with haemodynamics within the ear. Further, that pressure coupling is multifactorial; interdependencies for consideration include aspects of the cardiac cycle, posture and thoracic pressure.\u003c/p\u003e\u003cp\u003eThe degree of pulse pressure coupling between spTMD and ICP may depend on where it is considered in the cardiac cycle. This coupling will be different during the main drainage phase, when the venous pathway is low impedance during diastole, as opposed to high impedance when the right heart valve (tricuspid) is closed during systole. Speculatively, we expect ICP to spTMD pressure coupling to occur following the ECG QRS complex that marks the beginning of systole. Given this, this region of the cardiac cycle may provide optimum spTMD representation of the ICP pulse to facilitate non-invasive measurements.\u003c/p\u003e\u003cp\u003ePosture will be crucial in spTMD coupling with the central venous chamber and CVP. The considerable postural-related difference in the spTMD morphology is likely due to changing venous drainage pathways. The internal and external jugular veins are usually the major cerebral venous drainage routes in the supine position. However, in the upright posture, there is a partial or total collapse of the jugular veins. Consequently, the cerebral venous blood returns through alternative vertebral venous plexus system pathways. This switching of venous drainage pathways occurs with almost no change in the intracranial vessels, indicating maintenance of cerebral blood volume flow [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. When abnormally elevated CVP exists in the upright posture, the jugular veins possibly re-open, and the jugular veins abnormally become the primary pathway for venous return [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Considering the above, it is probable that the spTMD waveform contains information that reflects the CVP and cerebral venous drainage.\u003c/p\u003e\n\u003ch3\u003eResearch and Clinical Importance\u003c/h3\u003e\n\u003cp\u003eThe existence of a substantial venous drainage component in the aural and spTMD waveform is an exciting and arguably landmark finding. These methods promise to provide a new tool for researching cerebral venous outflow. Our work has yet to establish whether this spTMD venous aspect comprises external, internal or cerebral venous sinus components. However, from the clinical diagnosis perspective, both the internal and external venous routes reflect the central venous pressure (CVP) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The findings support that the CVP thoracic and likely cardiopulmonary venous pressure dynamics are coupled with the ear, and this promises the opportunity for easily applied non-invasive measurements of these vital biological parameters.\u003c/p\u003e\u003cp\u003eCompared with cerebral arterial supply, cerebral venous outflow has historically been an area of relative neglect; however, over the past decade, the importance of this topic has been realised. Non-invasive measurements are required to improve the knowledge base of conditions associated with disturbed and obstructed venous outflow or pulse wave encephalopathies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Neurodegenerative disease and certain forms of dementia are known to be associated with cerebral outflow impairment [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNon-invasive aural measurements could enhance our understanding of conditions associated with proximal venous outflow and hypertension. The spTMD could, therefore, provide insight into conditions such as venous sinus thrombosis, dural arteriovenous fistular and the differential diagnosis of IIH occurring secondarily to impaired venous outflow. The spTMD as a surrogate for assessing the jugular venous pulse (JVP) needs consideration as JVP measurements are essential indicators of normal right-atrium pressure control [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Further work is necessary to establish the diagnostic value of aural pressure waves and the spTMD signal.\u003c/p\u003e\u003cp\u003eMamikoglu and Gianoli (2023) report that the Cerebral and Cochlear Fluid Pressure (CCFP) Analyser detects abnormalities with otological conditions associated with a mild, borderline elevation of the ICP. They consider this condition to be a distinct pathology separate from IIH and migraine, presenting with head fullness-pressure and dizziness that is often suggestive of a clinical diagnosis of vestibular migraine [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Borderline intracranial hypertension is implicated in chronic fatigue syndrome, both sharing an aetiology of obstructed venous outflow of the transverse sinus [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eUnilateral venous pulsatile tinnitus is a known symptom of transverse sinus stenosis with venous trans-stenotic pressure gradients [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Abnormal spTMD exists in patients with pulsatile tinnitus and balance disorders, including a patient with Arnold Chiari malformation I with persistent dizziness [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Abnormal spTMD is also implicated with a severe disabling form of non-pulsatile tinnitus that occurs with symptoms of head pressure, headache, cognitive complaints of brain fog, and interference in memory and speech expression [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. We have also identified abnormal spTMD pressure waves in children with cerebral malaria and shown an association with cognitive test scores in healthy adults [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Intra-aural pressure waves should be researched further in the above conditions, with attention to the possibility of spTMD asymmetry between ears providing an indicator of the lesion site.\u003c/p\u003e\u003cp\u003eThe aural methods provide a relatively inexpensive, simple and readily applicable non-invasive measurement technique. They can be applied with manipulations of postures and provide bilateral cerebral measurements that may assist with the location of stenosis or venous outflow abnormalities. Cerebral venous drainage and CVP are also essential physiological measurements missing from our current battery of clinical tests due to the invasive nature of the measurement and associated risks. The method is also suitable for long-term monitoring in the intensive care setting. As a simple screening device, it can provide spTMD data within minutes in the clinic or for roadside trauma.\u003c/p\u003e\u003cp\u003eWe are confident that this research paper's new and important findings will open many new avenues of research and will be translatable as a valuable new tool for clinical practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe spTMD should be regarded as a complex and composite waveform comprising arterial, ICP and venous components. The relative pressure coupling of these components will change substantially with posture and, presumably, any underlying pathology with a bias on a particular component. The spTMD and presumably aural pressure waves have a substantial or dominant venous wave component in the upright sitting, inclined and probably supine positions, although the latter requires further consideration.\u003c/p\u003e\u003cp\u003eThe amplitude of the aural pulse and spTMD do not provide a simple surrogate for non-invasive ICP pulse measurements or baseline ICP for all individuals. Nevertheless, spTMD will remain valuable for non-invasive ICP measurement in selected patients or when the complex nature of these waves is considered. The findings support that cerebral venous drainage and CVP dynamics are coupled with the ear, and this promises the opportunity for easily applied and translatable measurements of these vital biological parameters.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cem\u003eOptional Scientific Report template indicates that Abbreviation list should not be included]\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eABP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;arterial Blood Pressure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;cochlear Aqueduct\u003c/p\u003e\n\u003cp\u003eCCFP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cerebral and Cochlear Fluid Pressure (Analyser)\u003c/p\u003e\n\u003cp\u003eCSF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;cerebrospinal fluid\u003c/p\u003e\n\u003cp\u003eCVP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;central venous pressure\u003c/p\u003e\n\u003cp\u003eDPOAE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;distortion-product otoacoustic emissions\u003c/p\u003e\n\u003cp\u003eECG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;electrocardiogram\u003c/p\u003e\n\u003cp\u003eICP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;intracranial pressure\u003c/p\u003e\n\u003cp\u003eIIH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;idiopathic intracranial hypertension\u003c/p\u003e\n\u003cp\u003eIJV \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;internal jugular vein\u003c/p\u003e\n\u003cp\u003eJVP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;jugular venous pulse\u003c/p\u003e\n\u003cp\u003eMWA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;mean wave amplitude\u003c/p\u003e\n\u003cp\u003eOW\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;oval window\u003c/p\u003e\n\u003cp\u003ePS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;petrosal sinus\u003c/p\u003e\n\u003cp\u003espTMD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;spontaneous tympanic membrane displacement\u003c/p\u003e\n\u003cp\u003eTM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;tympanic membrane\u003c/p\u003e\n\u003cp\u003eTMD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;tympanic membrane displacement\u003c/p\u003e\n\u003cp\u003eTMp \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; tympanic membrane pressure (waveform)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Cherith Campbell-Bell for her contribution to collecting the control data and Steve Burnage, Gabriella Howard, Chloe Cox, Shannon Cawte and Tom Bower for their work in conducting the measurements. \u0026nbsp;We would like to acknowledge the very helpful support from clinical staff in the Neurological Intensive Care Unit of the Wessex Neurological Centre where the measurements were performed. This work was funded by UKRI Innovate UK through an enhancing in vivo imaging for stratified medicine grant 101675. This NIHR Portfolio Study was supported by the NIHR/Wellcome Trust Southampton Clinical Research Facility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: R.J.M. and A.A.B. Acquisition of data: \u0026nbsp;A.A.B., R.J.M., and W.K.E. Analysis and interpretation of data: A.A.B., R.J.M., W.K.E. and D.O.B. \u0026nbsp;Drafting the article: R.J.M., A.A.B., D.O.B. and W.K.E. Statistical analysis: A.A.B. and R.J.M.\u003c/p\u003e\n\u003cp\u003eCritically revising the article: R.J.M., A.A.B., D.O.B. and W.K.E. \u0026nbsp;Reviewed submitted version of manuscript: R.J.M., A.A.B., D.O.B. and W.K.E. Approved the final version of the manuscript on behalf of all authors: R.J.M.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Robert Marchbanks is the Managing Director of the Southampton University spin-out research company that manufactures the TMD/CCFP Analyser (Marchbanks Measurement Systems Ltd). \u0026nbsp;The rest of the authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID iDs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnthony A Birch https://orcid.org/0000-0002-2328-702X\u003c/p\u003e\n\u003cp\u003eWahbi K El-Bouri https://orcid.org/0000-0002-2732-5927\u003c/p\u003e\n\u003cp\u003eDiederik Bulters https://orcid.org/0000-0001-9884-9050\u003c/p\u003e\n\u003cp\u003eRobert J Marchbanks https://orcid.org/0000-0001-8565-8888\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEvensen, K. B., Paulat, K., Prieur, F., Holm, S. \u0026amp; Eide, P. K. Utility of the Tympanic Membrane Pressure Waveform for Non-invasive Estimation of The Intracranial Pressure Waveform. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e, 15776 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGopen, Q., Rosowski, J. J. \u0026amp; Merchant, S. N. Anatomy of the normal human cochlear aqueduct with functional implications. \u003cem\u003eHear. Res.\u003c/em\u003e \u003cb\u003e107\u003c/b\u003e, 9\u0026ndash;22 (1997).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHofman, R., Segenhout, J. M., Albers, F. W. J. \u0026amp; Wit, H. P. The relationship of the round window membrane to the cochlear aqueduct shown in three-dimensional imaging. \u003cem\u003eHear. Res.\u003c/em\u003e \u003cb\u003e209\u003c/b\u003e, 19\u0026ndash;23 (2005).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCiuman, R. R. Communication routes between intracranial spaces and inner ear: function, pathophysiologic importance and relations with inner ear diseases. \u003cem\u003eAm. J. Otolaryngol.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e, 193\u0026ndash;202 (2009).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampbell-Bell, C. M., Birch, A. A., Vignali, D., Bulters, D. \u0026amp; Marchbanks, R. J. Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure. \u003cem\u003ePhysiol. Meas.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e, 015008 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl-Bouri, W. K. et al. Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement. \u003cem\u003ePhysiol. Meas.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e, 085002 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMazzoni, A. The vascular anatomy of the vestibular labyrinth in man. \u003cem\u003eActa Otolaryngol. Suppl.\u003c/em\u003e \u003cb\u003e472\u003c/b\u003e, 1\u0026ndash;83 (1990).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaganawa, S. et al. Cross-sectional Area of the Superior Petrosal Sinus is Reduced in Patients with Significant Endolymphatic Hydrops. \u003cem\u003eMagn. Reson. Med. Sci.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 459\u0026ndash;467 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarraro, M. et al. Attenuating Cardiac Pulsations within the Cochlea: Structure and Function of Tortuous Vessels Feeding Stria Vascularis. \u003cem\u003eISRN Otolaryngol\u003c/em\u003e 941757 (2013). (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJacks, A. S. \u0026amp; Miller, N. R. Spontaneous retinal venous pulsation: aetiology and significance. \u003cem\u003eJ. Neurol. Neurosurg. Psychiatry\u003c/em\u003e. \u003cb\u003e74\u003c/b\u003e, 7\u0026ndash;9 (2003).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorgan, W. H., Hazelton, M. L. \u0026amp; Yu, D. Y. Retinal venous pulsation: Expanding our understanding and use of this enigmatic phenomenon. \u003cem\u003eProg Retin Eye Res.\u003c/em\u003e \u003cb\u003e55\u003c/b\u003e, 82\u0026ndash;107 (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUnnerb\u0026auml;ck, M., Ottesen, J. T. \u0026amp; Reinstrup, P. Validation of a mathematical model for understanding intracranial pressure curve morphology. \u003cem\u003eJ. Clin. Monit. Comput.\u003c/em\u003e \u003cb\u003e34\u003c/b\u003e, 469\u0026ndash;481 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCzosnyka, M. \u0026amp; Czosnyka, Z. Origin of intracranial pressure pulse waveform. \u003cem\u003eActa Neurochir. (Wien)\u003c/em\u003e. \u003cb\u003e162\u003c/b\u003e, 1815\u0026ndash;1817 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDreha-Kulaczewski, S. et al. Respiration and the watershed of spinal CSF flow in humans. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e, 5594 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHansen, A. B. et al. Reducing intracranial pressure by reducing central venous pressure: assessment of potential countermeasures to spaceflight-associated neuro-ocular syndrome. \u003cem\u003eJ Appl Physiol (\u003c/em\u003e) 130, 283\u0026ndash;289 (2021).) 130, 283\u0026ndash;289 (2021). (1985).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWłodyka, J. Studies on cochlear aqueduct patency. \u003cem\u003eAnn. Otol Rhinol Laryngol\u003c/em\u003e. \u003cb\u003e87\u003c/b\u003e, 22\u0026ndash;28 (1978).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFinch, L. C., Marchbanks, R. J., Bulters, D. \u0026amp; Birch, A. A. Refining non-invasive techniques to measure intracranial pressure: comparing evoked and spontaneous tympanic membrane displacements. \u003cem\u003ePhysiol. Meas.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e, 025007 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTraboulsi, R. \u0026amp; Avan, P. Transmission of infrasonic pressure waves from cerebrospinal to intralabyrinthine fluids through the human cochlear aqueduct: Non-invasive measurements with otoacoustic emissions. \u003cem\u003eHear. Res.\u003c/em\u003e \u003cb\u003e233\u003c/b\u003e, 30\u0026ndash;39 (2007).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAvezaat, C. J. J., Van Eijndhoven, J. H. M., Wyper, D. J. \u0026amp; Ar, M. Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships. \u003cem\u003eJ. ofNeurology Neurosurg. Psychiatry\u003c/em\u003e. \u003cb\u003e42\u003c/b\u003e, 0 (1979).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eManwaring, P., Wichern, D., Manwaring, M., Manwaring, J. \u0026amp; Manwaring, K. A signal analysis algorithm for determining brain compliance non-invasively. \u003cem\u003eConf Proc IEEE Eng Med Biol Soc\u003c/em\u003e 353\u0026ndash;6 (2004). (2006).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDhar, R., Sandler, R. H., Manwaring, K., Cosby, J. L. \u0026amp; Mansy, H. A. Non-invasive ICP Monitoring by Auditory System Measurements. in \u003cem\u003eSignal Processing in Medicine and Biology\u003c/em\u003e 121\u0026ndash;147Springer International Publishing, Cham, (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/978-3-031-21236-9_5\u003c/span\u003e\u003cspan address=\"10.1007/978-3-031-21236-9_5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDhar, R., Sandler, R. H., Manwaring, K., Kostick, N. \u0026amp; Mansy, H. A. Noninvasive detection of elevated ICP using spontaneous tympanic membrane pulsation. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e, 21957 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUnnerb\u0026auml;ck, M., Ottesen, J. T. \u0026amp; Reinstrup, P. Increased Intracranial Pressure Attenuates the Pulsating Component of Cerebral Venous Outflow. \u003cem\u003eNeurocrit Care\u003c/em\u003e. \u003cb\u003e31\u003c/b\u003e, 273\u0026ndash;279 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKollmeier, J. M. et al. Deep breathing couples CSF and venous flow dynamics. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e, 2568 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKosugi, K. et al. Posture-induced changes in the vessels of the head and neck: evaluation using conventional supine CT and upright CT. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e, 16623 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGisolf, J. et al. Human cerebral venous outflow pathway depends on posture and central venous pressure. \u003cem\u003eJ. Physiol.\u003c/em\u003e \u003cb\u003e560\u003c/b\u003e, 317\u0026ndash;327 (2004).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalik, M. et al. A comparison of external and internal jugular venous pressures to monitor pulmonary artery pressure after superior cavopulmonary anastomosis. \u003cem\u003eInteract. Cardiovasc. Thorac. Surg.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 566\u0026ndash;568 (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWilson, M. H. Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure. \u003cem\u003eJ. Cereb. Blood Flow. Metab.\u003c/em\u003e \u003cb\u003e36\u003c/b\u003e, 1338\u0026ndash;1350 (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarchbanks, R. Neurological ideopathic disease: a shared journey for NASA and medicine. \u003cem\u003eENT Audiol. News\u003c/em\u003e. \u003cb\u003e5\u003c/b\u003e, 52\u0026ndash;55 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-L\u0026oacute;pez, I. \u0026amp; Rodriguez-Villegas, E. Extracting the Jugular Venous Pulse from Anterior Neck Contact Photoplethysmography. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e, 3466 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMamikoglu, B. \u0026amp; Gianoli, G. J. The clinical findings to notice mild elevation of intracranial pressure in an otology clinic. \u003cem\u003eAm. J. Otolaryngol.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 104004 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins, N., Pickard, J. \u0026amp; Lever, A. Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. \u003cem\u003eJ. Neurol. Surg. Rep.\u003c/em\u003e \u003cb\u003e76\u003c/b\u003e, e244\u0026ndash;e247 (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins, J. N. P., Pickard, J. D. \u0026amp; Lever, A. M. L. Chronic fatigue syndrome and idiopathic intracranial hypertension: Different manifestations of the same disorder of intracranial pressure? \u003cem\u003eMed. Hypotheses\u003c/em\u003e. \u003cb\u003e105\u003c/b\u003e, 6\u0026ndash;9 (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHulens, M. et al. The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology. \u003cem\u003eJ. Pain Res.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e, 3129\u0026ndash;3140 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQiu, X. et al. The Relationships Among Transverse Sinus Stenosis Measured by CT Venography, Venous Trans-stenotic Pressure Gradient and Intracranial Pressure in Patients With Unilateral Venous Pulsatile Tinnitus. \u003cem\u003eFront. Neurosci.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 694731 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLehrer, J. F., Ogunlusi, A., Knutsen, J. \u0026amp; Marchbanks, R. J. The value of transcranial cerebral sonography in diagnosing neurootological disorders. \u003cem\u003eInt. Tinnitus J.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 164\u0026ndash;167 (2009).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShulman, A., Goldstein, B. \u0026amp; Marchbanks, R. J. The tympanic membrane displacement test and tinnitus: preliminary report on clinical observations, applications, and implications. \u003cem\u003eInt. Tinnitus J.\u003c/em\u003e \u003cb\u003e17\u003c/b\u003e, 80\u0026ndash;93 (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGwer, S. et al. Abnormal intra-aural pressure waves associated with death in African children with acute nontraumatic coma. \u003cem\u003ePediatr. Res.\u003c/em\u003e \u003cb\u003e78\u003c/b\u003e, 38\u0026ndash;43 (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBirch, A. A. et al. Pulsatile tympanic membrane displacement is associated with cognitive score in healthy subjects. \u003cem\u003eCereb. Circ. Cogn. Behav.\u003c/em\u003e \u003cb\u003e3\u003c/b\u003e, 100132 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharif, S. J., Campbell-Bell, C. M., Bulters, D. O., Marchbanks, R. J. \u0026amp; Birch, A. A. Does the Variability of Evoked Tympanic Membrane Displacement Data (V m) Increase as the Magnitude of the Pulse Amplitude Increases? \u003cem\u003eActa Neurochir. Suppl.\u003c/em\u003e \u003cb\u003e126\u003c/b\u003e, 103\u0026ndash;106 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampbell-Bell, C. M. et al. A vascular subtraction method for improving the variability of evoked tympanic membrane displacement measurements. \u003cem\u003ePhysiol. Meas.\u003c/em\u003e \u003cb\u003e42\u003c/b\u003e, 025001 (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Method","content":"\u003cp\u003eTo understand the direction of motion of the tympanic membrane in response to vascular pulsing, we consider the effects of pressure changes in the outer ear, middle and inner ear separately. The spontaneous tympanic membrane displacement (spTMD) ear probe seals into the external ear canal to sense pressure changes and interprets them as a tympanic membrane displacement (TMD). Any increase in the middle ear pressure, vascular, inner ear or CSF pressures results in an outward movement of the tympanic membrane regardless of its origins, provided the ossicles do not create a mechanical inversion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData from ventilated patients with simultaneous measurements of arterial blood pressure (ABP), central venous pressure (CVP), and intracranial pressure (ICP) was analysed to validate this assumption. Unlike normal respiration, in artificially ventilated subjects, all three pressure waveforms increase with increasing thoracic pressure and reduce with reducing thoracic pressure. An outward TMD with increasing thoracic pressure would support our assumption that this direction reflects increasing vascular and/or CSF pressures. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo assess if spTMD is more influenced by arterial, intracranial or central venous pressure dynamics, coherently averaged heartbeats were generated for ABP, ICP and CVP for each patient, and the correlation with spTMD was determined for each. This correlation analysis was then extended to a large healthy control data set. For healthy subjects, invasive signals could not be acquired. Therefore, representative waveforms for arterial, intracranial, and central venous pressure obtained from an average of all patients were used instead. The correlation of these \u0026ldquo;templates\u0026rdquo; from the patients with the individually measured spTMD waveform from each control subject was determined.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, to further test the hypothesis that the waveform has a substantial venous component, we took advantage of the differences in the timing of key waveform features of arterial and venous pulses relative to the ECG. \u0026nbsp; Specifically, for arterial and intracranial pressure waveforms, the first sustained steep transition following the QRS complex is driven by the left side of the heart. \u0026nbsp;This transition is always an increase in pressure that should correspond with a positive and outward spTMD. \u0026nbsp; Conversely, a venous waveform transition generated by the right side of the heart is a decrease in pressure and should correspond with a negative and inward spTMD. \u0026nbsp;We tested this premise first in the ventilated patients and then on the much larger data set of healthy volunteers to confirm general applicability across the population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubjects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll healthy volunteers recruited to the study gave informed consent, and all patient representatives (next of kin) gave informed assent. The National Research Ethics Service Committee East of England \u0026ndash; Hatfield approved the control data collection protocol. Southampton \u0026amp; SW Hants B ethics committee approved the patient data collection. \u0026nbsp;All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003eFive patients were recruited that had suffered a traumatic brain injury (3 males, 2 females, age 18-55, median 40 years). One patient had data collected slightly differently and without ICP. \u0026nbsp; \u0026nbsp;The sampling frequency was 100Hz with simultaneously recorded analogue signals of ABP, CVP and spTMD. \u0026nbsp; \u0026nbsp; The inclusion criteria were: sedated, ventilated and undergoing invasive CVP, ICP and ABP monitoring for their clinical care.\u003c/p\u003e\n\u003cp\u003eAdditionally, we reviewed data collected from 316 healthy volunteers. This control data set has been described previously. In brief: volunteers were recruited via publicity on the radio, in newspapers and through local social society appeals. There were similar numbers in the three age ranges 20-40, 40-60 and 60-80, and number of males and females (mean age 47). \u0026nbsp;All were confirmed not to have any otological, neurological or cardiovascular disease. All had a normal otoscopic examination, middle ear pressure and compliance in at least one ear [5,40,41].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients:\u003c/strong\u003e Routine patient monitors (G.E. Carescape, Chicago, Illinois),using strain gauge pressure transducers (TruWave, Edwards Lifesciences, Irvine, California) connected by standard manometry lines in the radial artery and superior vena cava, were used to record arterial and central venous pressures, respectively. Intracranial pressure was measured using catheter-tipped intraventricular pressure transducers (Integra Lifesciences, Plainsboro, New Jersey).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTympanic membrane displacement was recorded with an MMS-14 CCFP (Marchbanks Measurements Ltd., Lymington, UK) All data were recorded simultaneously using ICM+ software (Cambridge University, UK). Pressure signals were recorded as digital outputs from the bedside monitors together with the ECG waveform. The spTMD signal was recorded as an analogue signal via an A-D converter (Data Translations Inc, Boston, Massachusetts). An analogue arterial blood pressure output was likewise simultaneously recorded directly from the Carescape patient data module (defib sync port.) \u0026nbsp;This was used to ensure accurate alignment of the digital and analogue signals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData were recorded continuously for approximately 1 hour while spTMD from one ear was recorded quasi-continuously (typically interrupted for 1 s once every 30 s to allow the displacement microphone to be re-centred.) \u0026nbsp;The patient\u0026rsquo;s posture was not altered and was typically supine, on a pillow, with the head of the bed inclined by 30 degrees.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHealthy controls:\u003c/strong\u003eVolunteers attended the hospital\u0026rsquo;s clinical research facility for a single visit of approximately 2 hours, during which at least 100 s of spTMD data was recorded from both ears in the sitting and then the supine posture. In a subset of 60 volunteers, an intermediate measurement was performed in one ear only while the head of the bed was raised by 30 degrees. Five minutes were allowed to elapse between each posture change. Simultaneously with the spTMD measurement, a 3-lead ECG was recorded. The spTMD and ECG analogue data signals were recorded on the same data acquisition system used for the patients, and this utilised ICM+ software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analysis was completed using in-house software written in MatLab (Mathworks, R2019a. Natick, Massachusetts) \u0026nbsp;The time of every heartbeat was identified from the QRS complex automatically identified and visually checked. The spTMD data was reviewed to determine the start and end of each good data section. These were typically 20 or 30 s in duration, separated by 1 s of non-physiological re-zeroing. Each spTMD section was linearly detrended. All signals were low pass filtered, backwards and forwards, to maintain phase, with an order 6 Butterworth filter with a cut-off frequency of 10Hz.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStage 1: Direction of spTMD during mechanical ventilation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe direction of spTMD in response to the pressure changes associated with mechanical ventilation was identified by visual inspection of a coherently averaged ventilatory cycle for each patient. Before producing an average ventilatory cycle, the heartbeat was removed from all waveforms by beat averaging and re-sampling as follows. The average value within each heartbeat was determined, and a new time series was created with a single sample for each heartbeat. These samples were positioned in the middle of the heartbeat and then joined up by linear interpolation, maintaining the correct beat-to-beat time intervals. Thus, a new time series with heartbeats removed was produced for spTMD, ABP, CVP and ICP.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe timing of each ventilator cycle was automatically identified and visually checked. \u0026nbsp;A consistent time point corresponding approximately with the start of inspiration was identified in each ventilatory cycle from a simultaneously acquired measurement of either expired CO2 concentration or airway pressure. \u0026nbsp; The time of the minimum pressure was used for airway pressure. \u0026nbsp;With expired CO2, the point that the expired CO2 transitioned from above the median to below the median value was used. \u0026nbsp;A sample of data, 3 s before and 3 s after the selected time point, was then extracted and detrended before being added to the coherent average. \u0026nbsp;The resulting waveforms showing coherently averaged ventilatory cycles of all variables were visually compared and categorised according to polarity of the phase, that is whether in-phase or out-of-phase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStage 2: Correlation of spTMD cardiac waveform with CVP, ABP and ICP\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each patient, a waveform representing the cardiac cycle was produced for spTMD, ABP, CVP and ICP. This was done by extracting 2-second-duration data samples, from 1 s before to 1 s after, each identified QRS sample. The extracted samples were linearly detrended and coherently averaged to produce average waveforms for each variable centred on the time of the QRS complex. A simple correlation coefficient determined the correlation between each of the variables.\u003c/p\u003e\n\u003cp\u003eA high correlation is expected between spTMD and each of the other parameters because each one will show a similar pulsing waveform driven by the heartbeat. There will be differences in wave shapes between each of the variables; our objective is, therefore, to determine which of the variables shows the strongest correlation with spTMD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubtle differences in the synchronisation of each measurement will substantially impact this correlation analysis. Ideally, our arterial, venous and intracranial pressure measurements would be taken close to the ear to avoid delays between variables. Our arterial and central venous pressures were measured from the radial artery and vena cava, respectively. ICP was measured in a lateral ventricle or brain parenchyma. The spTMD was recorded in the external ear canal. We know that relative timing errors of the signals are present due to, for example, transmission delays in the pressure lines. A time difference of 30-50ms may exist between our signals. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor the comparison of correlation coefficients to be meaningful, the frequency response of all recording instruments should be the same. \u0026nbsp;Alternatively, filtering can be used to make all frequency responses equivalent. \u0026nbsp;The response characteristics of our instruments are nominally 20Hz for the pressure measurements and 10Hz for the spTMD. \u0026nbsp; \u0026nbsp;These were standardised by sampling all signals at a minimum of 100Hz and then digitally low-pass-filtered with a cut-off frequency of 10Hz \u0026nbsp;(Butterworth order 6.)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe wanted to perform the same correlation analysis on our large healthy control population; however, invasive ABP, CVP, and ICP measurements are unavailable for these subjects. \u0026nbsp;Instead, we use template waveforms for these variables derived from our patients. \u0026nbsp; A coherently averaged waveform of 1.5 s duration was created for each variable from the patient data described above to produce templates representative of the typical ABP, ICP and CVP waveforms. \u0026nbsp; A waveform warping function was then applied to each patient waveform to standardise the heartbeat\u0026apos;s length. \u0026nbsp;The warping was applied such that 1 s corresponds to the median beat length. \u0026nbsp; The size of stretching or shrinking between two consecutive samples increased by the addition of a constant, linearly, from the middle of the sample to each extremity. \u0026nbsp;This method minimised distortion at the time of the QRS complex placed centrally in each template. \u0026nbsp;We have previously used and described a similar method [41]. \u0026nbsp; After warping to a standard beat size, a coherent average was made of all patients for each variable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA coherently averaged spTMD heartbeat waveform of 1.5 s duration was then produced for every healthy control subject. \u0026nbsp;The warping function was also applied to each coherent average to produce a waveform with a standardised 1-second heart rate. \u0026nbsp;The spTMD waveform for each control subject was then correlated against the templates for spTMD, ABP, CVP and ICP derived from the patients. \u0026nbsp; A simple correlation coefficient was determined. \u0026nbsp;The dominant variable was determined as having the highest correlation with the spTMD waveform. \u0026nbsp;For each variable, the proportion of subjects in which a particular variable is dominant was determined. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStage 3: Direction of displacement following the QRS waveform.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe coherently averaged waveforms were analysed to determine the direction of the first steep change in pressure or displacement following the QRS complex. \u0026nbsp; A \u0026apos;steep change gradient\u0026apos; threshold was in a positive or negative direction and was defined as 0.5h per second (nLs\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003e), where h is the peak-to-peak value of the waveform.\u003c/p\u003e\n\u003cp\u003eEvery single patient\u0026apos;s heartbeat was analysed independently. \u0026nbsp;The first derivative of each waveform was determined, and the first incidence of a steep gradient more than 60ms after the QRS complex was identified. \u0026nbsp;We chose 60ms because the rise in arterial and CSF pressure following the QRS complex will not propagate to the ear for at least 60ms. \u0026nbsp;The CVP descending slope is similarly delayed. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe proportion of heartbeats in which the first steep gradient was positive or negative was identified. \u0026nbsp;This was repeated for ICP, ABP, and CVP waveforms. \u0026nbsp; Each patient\u0026apos;s results were presented separately.\u003c/p\u003e\n\u003cp\u003eFinally, the same analysis was performed on the control subjects; however, the coherent average for each subject was used instead of individual heartbeats. \u0026nbsp;The proportion of subjects who were positive and negative is reported. \u0026nbsp;Results from sitting, supine, and inclined are reported separately.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Spontaneous Tympanic Membrane Displacement (spTMD), Composite aural pressure waves, Cerebral haemodynamics, Cerebral venous drainage, Non-invasive intracranial pressure measurement, Vital neurological parameters","lastPublishedDoi":"10.21203/rs.3.rs-6940263/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6940263/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study found a measurable venous component in spontaneous tympanic membrane displacement (spTMD) waveforms, which likely represent aural pressure waves in general. These findings suggest that a substantial or dominant venous component exists in most spTMD waveforms, representing the coupling of central venous pressure (CVP) dynamics with the ear.\u003c/p\u003e\u003cp\u003eThe study was conducted in three stages, including a comparative analysis of changes in CVP and spTMD with forced ventilation on five patients to verify spTMD polarity; a correlation analysis to determine the best representation of spTMD by arterial blood pressure (ABP), intracranial pressure (ICP), or CVP; an analysis of pulse features with ECG synchronisation to compare ABP and CVP pulse profiles with spTMD from 316 healthy individuals. The results supported the hypothesis that the spTMD waveform has a substantial venous component in normal-healthy individuals.\u003c/p\u003e\u003cp\u003eThe discovery of a cerebral venous drainage component is exciting. It may offer an inexpensive and easily applied non-invasive clinical measurement device for measuring vital biological parameters for all postures. However, the implication is that the amplitude of spTMD and aural pulse may not be a simple surrogate for non-invasive ICP pulse or baseline ICP. Nonetheless, with careful consideration, components of spTMD remain valuable in this respect.\u003c/p\u003e","manuscriptTitle":"Discovery of a substantial cerebral venous pressure wave component in Spontaneous Tympanic Membrane Displacement: Expanding understanding of composite Aural Pressure Waves","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-09 07:50:21","doi":"10.21203/rs.3.rs-6940263/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7293c1b-412d-442b-857a-2662e594c59a","owner":[],"postedDate":"July 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51116444,"name":"Biological sciences/Neuroscience"},{"id":51116445,"name":"Biological sciences/Physiology"},{"id":51116446,"name":"Health sciences/Biomarkers"},{"id":51116447,"name":"Health sciences/Diseases"},{"id":51116448,"name":"Health sciences/Medical research"},{"id":51116449,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2025-11-03T05:39:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-09 07:50:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6940263","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6940263","identity":"rs-6940263","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}