Exp Brain Res (2012) 221:427–436 DOI 10.1007/s00221-012-3185-6
RESEARCH ARTICLE
Evidence from bilateral recordings of sympathetic nerve activity for lateralisation of vestibular contributions to cardiovascular control Khadigeh El Sayed • Tye Dawood • Elie Hammam Vaughan G. Macefield
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Received: 9 June 2012 / Accepted: 3 July 2012 / Published online: 19 July 2012 Ó Springer-Verlag 2012
Abstract Using low-frequency (0.08–0.18 Hz) sinusoidal galvanic vestibular stimulation (sGVS), we recently showed that two peaks of modulation of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) occurred for each cycle of stimulation: a large peak associated with the positive peak of the sinusoid (defined as the primary peak) and a smaller peak (defined as the secondary peak) related to the negative peak of the sinusoid. However, these recordings were only made from the left common peroneal nerve, so to investigate lateralisation of vestibulosympathetic reflexes, concurrent recordings were made from both sides of the body. Tungsten microelectrodes were inserted into muscle or cutaneous fascicles of the left and right common peroneal nerves in 17 healthy individuals. Bipolar binaural sinusoidal GVS (±2 mA, 100 cycles) was applied to the mastoid processes at 0.08 Hz. Cross-correlation analysis revealed that vestibular modulation of MSNA (10 bilateral recordings) and SSNA (6 bilateral recordings) on the left side was expressed as a primary peak related to the positive phase of the sinusoid and a secondary peak related to the negative phase of the sinusoid. Conversely, on the right side, the primary and secondary peaks were reversed: the secondary peak on the right coincided with the primary peak on the left and vice versa. Moreover, differences in pattern of outflow were apparent across sides. We believe the results support the conclusion that the left and right vestibular nuclei send both
K. El Sayed T. Dawood E. Hammam V. G. Macefield (&) School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith, Sydney, NSW 2751, Australia e-mail:
[email protected] V. G. Macefield Neuroscience Research Australia, Sydney, Australia
an ipsilateral and contralateral projection to the left and right medullary output nuclei from which MSNA and SSNA originate. This causes a ‘‘flip-flop’’ patterning between the two sympathetic outflows: when vestibular modulation of a burst is high on the left, it is low on the right, and when modulation is low on the left, it is high on the right. Keywords Sympathetic Vestibular Vestibulosympathetic reflexes Lateralisation
Introduction It is becoming increasingly clear that, in addition to the baroreceptors, afferents from the vestibular apparatus play an important role in the regulation of blood pressure. For instance, lesions of vestibular afferents reduce the compensatory increases in blood pressure during nose-up tilt in the cat (Doba and Reis 1974; Jian et al. 1999). There is also strong anatomical and physiological evidence supporting the existence of vestibulosympathetic reflexes in experimental animals: the rostral ventrolateral medulla (RVLM), the primary output nucleus for muscle vasoconstrictor neurons (Dampney et al. 2003), has been shown to receive excitatory inputs from the vestibular apparatus—primarily the otoliths (Yates et al. 1991, 1993; Holstein et al. 2012). While vestibular lesions in humans are rarely bilateral (McCall and Yates 2011), recent evidence from patients with vestibular damage supports the idea that disturbances in the vestibular apparatus, specifically the otoliths, contribute to postural hypotension (Aoki et al. 2012). Moreover, several experimental techniques for modulating vestibular inputs have provided evidence in support of the existence of vestibulosympathetic reflexes in humans: caloric vestibular stimulation (Cui et al. 1997), head-down neck flexion
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(Shortt and Ray 1997; Hume and Ray 1999), off verticalaxis rotation (Kaufmann et al. 2002) and linear sinusoidal acceleration in the horizontal plane (Cui et al. 1999, 2001; Grewal et al. 2012) have all been shown to increase or decrease the muscle sympathetic nerve activity (MSNA) depending on the direction of the vestibular stimulus (for review see Carter and Ray 2008). Our laboratory has been exploring vestibulosympathetic reflexes through the application of galvanic vestibular stimulation (GVS), which provides a means of selectively changing the firing of vestibular nerve afferents without affecting any other sensory channel that could potentially provide a gravity-related signal (Goldberg et al. 1984; Minor and Goldberg 1991; Fitzpatrick and Day 2004). Delivery of a 1-s step of GVS at different times within the cardiac cycle had no effect on MSNA (Bolton et al. 2004), whereas brief trains of GVS could modulate MSNA (Voustianiouk et al. 2006). We have shown that sinusoidal galvanic vestibular stimulation (sGVS), applied bilaterally to the mastoid processes at 0.5–0.8 Hz, induces a potent modulation of MSNA, with the occasional generation of de novo bursts time-locked to the vestibular input (Bent et al. 2006). Subsequent studies from our laboratory showed that sGVS at 0.2–2.0 Hz causes partial phase-locking of sympathetic outflow directed to both muscle (Grewal et al. 2009) and skin (James et al. 2010). The vestibular modulation of MSNA appears to be independent of the cardiac modulation (Bent et al. 2006), but competes with inputs from the arterial baroreceptors (Grewal et al. 2009; James and Macefield 2010). Our laboratory recently studied the effects of vestibular inputs on sympathetic outflow when sGVS was delivered at lower frequencies: 0.08–0.18 Hz (Hammam et al. 2011, 2012). We found that low-frequency sinusoidal GVS induced two bursts of modulation of MSNA for each cycle of stimulation (Hammam et al. 2011). This was interpreted as reflecting bilateral projections from the vestibular nuclei to the primary output nuclei responsible for generating MSNA—the RVLM. We also recently documented a similar phenomenon when recording skin sympathetic nerve activity; again, we interpreted this as reflecting bilateral projections from the vestibular nuclei to the primary output nuclei for skin sympathetic nerve activity (SSNA), the medullary raphe´ (Hammam et al. 2012). Because the recordings of sympathetic nerve activity were always undertaken from the left common peroneal nerve in both of these studies, and because sGVS was applied bilaterally, we believe the primary peak of modulation occurs when the left vestibular nerve is depolarised and the right vestibular nerve hyperpolarised, the secondary peak occurring when the current shifts to the right side and depolarises the right vestibular nerve while hyperpolarising the left vestibular nerve. The purpose of the present study is to determine whether this interpretation is correct. We
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assessed vestibular modulation of sympathetic outflow to muscle and skin by making bilateral recordings of MSNA and SSNA from the left and right peroneal nerves during delivery of binaural sGVS at 0.08 Hz.
Methods Recording procedures Experiments were performed on 17 subjects aged between 18 and 50 years old, each of whom provided informed consent. All studies were conducted under the approval of the Human Research Ethics Committee of the University of Western Sydney (H8614). In 10 experiments, muscle MSNA was recorded concurrently from fascicles of the left and right common peroneal nerves supplying the ankle and toe extensor and foot evertor muscles via tungsten microelectrodes (FHC, Bowdoinham, ME, USA) inserted percutaneously at the level of the fibular head. In seven experiments, bilateral recordings were made of SSNA from fascicles supplying the skin on the lateral aspect of the leg or the dorsum of the foot. In two experiments, bilateral recordings could not be obtained. The microelectrodes were connected to the input terminals of an isolated amplifier headstage (NeuroAmp EX, ADInstruments, Sydney, Australia). Intraneural stimulation (0.2 ms, 1 Hz, 1 mA) through the recording microelectrode, relative to the reference electrode, was performed while the experimenter advanced the microelectrode towards the nerve. Visible muscle twitches of the foot indicated that the tip of the electrode was approaching a muscle fascicle; entry into a muscle fascicle was indicated by muscle twitches at 0.02 mA or less, the absence of radiating cutaneous sensations during intraneural stimulation and the presence of spontaneous or stretch-evoked muscle spindle afferent activity. Small movements of the microelectrode tip were used to find spontaneous bursts of muscle sympathetic nerve activity, which possessed a clear cardiac rhythmicity. The absence of muscle twitches yet the presence of radiating paraesthesia at 0.02 mA, coupled with afferent responses to stroking the innervation territory, indicated that the microelectrode had entered a cutaneous fascicle. The microelectrode was manually advanced until spontaneous bursts of SSNA were encountered, identified by the following features: (1) a burst could be evoked by a brisk sniff and, with the subject’s eyes closed, an arousal burst could be evoked by an unexpected tap on the nose or a loud shout (Delius et al. 1972), (2) the bursts were typically longer than those comprising MSNA and (3) unlike MSNA, there was no sustained increase in burst amplitude and frequency during an inspiratory-capacity apnoea (Macefield and Wallin 1995). In addition, although present,
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cardiac and respiratory modulation of SSNA were weak (Macefield and Wallin 1999). Neural signals were displayed and stored on computer (10 kHz sampling) using a computer-based data acquisition and analysis system (PowerLab 16SP hardware and LabChart 7 software; ADInstruments, Sydney, Australia). Blood pressure was recorded non-invasively, via digital arterial plethysmography (Finometer; Finapres Medical System, Amsterdam, The Netherlands) and sampled at 400 Hz. ECG (0.3–1.0 kHz) was recorded with Ag–AgCl surface electrodes on the chest sampled at 2 kHz. Respiration was recorded via a piezoelectric (strain-gauge)
transducer around the chest, sampled at 0.4 kHz (Pneumotrace, UFI, Morro Bay, CA, USA).
Fig. 1 Bilateral recordings of muscle sympathetic nerve activity, together with ECG, blood pressure and respiration, during sinusoidal galvanic vestibular stimulation (GVS) at 0.08 Hz in one subject. Overall, sympathetic outflow was similar between the two sides, but close inspection revealed subtle differences. In the expanded section,
the sympathetic bursts have been shifted back 1.25 s in time to account for peripheral conduction delays, allowing those bursts aligned with the cardiac cycle (‘c’) or vestibular stimulus (‘v’) to be identified
Stimulation procedures Sinusoidal galvanic vestibular stimulation was delivered binaurally via Ag–AgCl surface electrodes over the mastoid processes (with the anode on the right and cathode on the left) using an isolated constant-current source (Linear Stimulus Isolator, World Precision Instruments, Sarasota, USA). Sinusoidal stimuli (100 cycles, 0.08 Hz) were generated by the data acquisition system (PowerLab) and
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delivered with a current between -2 and ?2 mA. Subjects were asked to relax with their eyes closed during the control and stimulation periods and to report their perceptions during GVS at the conclusion of the stimulation. Subjects were asked not to talk during the recording and the experimenters also refrained from talking; extraneous noise or distractions in the laboratory were avoided. Analysis MSNA or SSNA was displayed as an RMS-processed (root mean square: moving average, time-constant 200 ms) signal, but the primary analysis of muscle sympathetic nerve activity was performed using the raw negative-going sympathetic spikes in order to avoid contamination from spikes generated by positive-going myelinated axons (such as spontaneously active muscle spindles) or motor units associated with spontaneous electromyographic activity (Bent et al. 2006; Grewal et al. 2009). Negative-going spikes in the neurogram, R-waves of the ECG and the positive peaks of the sinusoidal stimulus were detected using window discriminator software (Spike Histogram for Macintosh v2.2, ADInstruments, Sydney, Australia). Using the same software, both cross-correlation and auto-correlation histograms were constructed (correlograms and
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autocorrelograms). For each event, the program plots the time of the current event (time 0) and the times of events before (negative times) and after (positive times) the current event. In this way, the periodicity of the signal can be illustrated in the form of an auto-correlation histogram and compared with the periodicities revealed by the crosscorrelation histograms. Discriminator levels were adjusted so that negative-going spikes exhibited a robust cardiac modulation, as revealed by cross-correlation between the neural activity and the ECG; the same discriminator settings were used for construction of cross-correlograms between MSNA and the positive peaks of the sGVS. For the MSNA versus ECG cross-correlogram, 50-ms bins were used, while for the MSNA versus sGVS cross-correlogram, 100-ms bins were used. The histogram data were exported as text to a statistical and graphical analysis program (Prism 5 for Windows v 5.03, GraphPad Software, USA), to fit the data to a mathematical function—a smoothed polynomial. Lower-order polynomials were used to fit curves to the slower vestibular cross-correlation histograms while higher-order polynomials were required to fit curves to the cardiac cross-correlation histograms. For the cross-correlation histograms between MSNA and sGVS, the smoothing eliminates any cardiac-related peaks and enables us to further examine the nerve activity more
Fig. 2 Cross-correlation histograms between MSNA recorded from the left and right nerves and the sinusoidal GVS for two subjects (a, b). A representation of the GVS is superimposed. Note the differences in pattern between the left and right sides
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accurately with respect to the galvanic vestibular stimulation.
Results As described previously during delivery of sGVS at 0.08 Hz (Hammam et al. 2011, 2012), binaural bipolar stimulation (-2 to 2 mA) across the mastoid processes generated robust illusions of either ‘‘rocking in a boat’’ or ‘‘swinging from side to side in a hammock.’’ Nausea was reported by seven of 17 subjects, which was accompanied by a slight feeling of dizziness; six subjects experienced only a slight degree of dizziness and only four subjects reported no symptoms. Successful recordings of MSNA from the left and right common peroneal nerves were obtained in 10 subjects. Bilateral recordings of SSNA were obtained in an additional seven subjects; one subject was excluded because signal quality from one of the nerves was not adequate for analysis. Bilateral recordings of MSNA during sGVS Experimental records from one subject, during application of sGVS at 0.08 Hz, are shown in Fig. 1. It can be seen that
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the overall pattern of sympathetic outflow was similar for the left and right nerves, yet it is also apparent that there were subtle differences across the two sides. As described previously (Bent et al. 2006), we could occasionally discern double peaks of MSNA within a single cardiac interval, in which one peak was aligned to the cardiac cycle (indicated by ‘c’) and the other was aligned to the vestibular stimulus (indicated by ‘v’). Indeed, focussing on the expanded regions in Fig. 1 reveals that this second peak was of different amplitudes on each side of the body, with vestibular-related peaks being occasionally present on one side but absent on the other (Fig. 1b). It is also apparent that there is a dynamic interaction between cardiac-related (i.e. baroreceptor-mediated) and vestibular inputs during sGVS; the two sources of modulation seemed to be competing, such that it can be difficult to assign a burst exclusively to a cardiac- or vestibular-mediated event. Importantly, by recording sympathetic outflow bilaterally, we can see that this interaction is differentially expressed on the two sides. As described previously (Hammam et al. 2011), crosscorrelation analysis between MSNA and the sinusoidal vestibular stimulus revealed two peaks of modulation of MSNA for each cycle of stimulation: a primary peak located close to the peak of the sinusoid and a secondary
Fig. 3 Cross-correlation histograms between MSNA recorded from the left and right nerves and the sinusoidal GVS for two subjects (a, b). A representation of the GVS is superimposed. Note the differences in pattern between the left and right sides
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peak that was usually smaller and related to the negative peak. However, the location of the two peaks within the cycle differed across the two sides of the body: when the peak of modulation was highest on the left, it tended to be lowest on the right, and vice versa. This can be seen in the cross-correlograms for the left and right nerves for one subject in Fig. 2a. Although the effect was not marked in this subject, differences in the amplitudes of the peaks can be seen across the two sides. Note that the superimposed sinusoid, representing the vestibular stimulation, is reversed across the two sides: the positive phase of the sinusoid represents a positive (hyperpolarising) current at the anode, whereas on the opposite side, the current will be negative (depolarising). Data from another subject are shown in Fig. 2b. In this subject, the pattern of modulation differed across the two sides: on the right side, there was a single peak associated with the negative phase (trough) of the sinusoid, whereas on the left, the peaks are broader—it appears that there is a primary peak associated with the positive phase and a secondary peak associated with negative phase, the two fusing together. Data from two additional subjects, both of whom showed patterns of peaks that were temporally aligned with different phases of the sinusoid on either side of the body, are shown in Fig. 3. Calculation of the modulation indices showed that there were no significant differences in amplitude of the primary peak or amplitude of the secondary peak on either side, though the primary peak was significantly larger on both sides. Mean data are illustrated graphically in Fig. 4.
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Fig. 4 Mean ± SE modulation indices for the primary (dark grey) and secondary (light grey) peaks of modulation of MSNA. Data obtained from 10 subjects
Bilateral recordings of SSNA during sGVS Discussion Figure 5 shows a bilateral recording of skin sympathetic nerve activity during sGVS in one subject. As with bilateral recordings of MSNA, the overall levels of SSNA were similar on the two sides, but differences in burst pattern could be seen. In the first expanded section of Fig. 5, it can be seen that a burst present in the left peroneal nerve was not present in the right. Cross-correlation histograms are shown for two subjects in Fig. 6. Again, differences in temporal coupling of SSNA to the vestibular stimulus were evident between the two sides. For the subject illustrated in Fig. 6a, there was a single broad peak of modulation for each cycle of vestibular stimulation, while on the right side, there were two peaks. A similar difference was shown for the subject in Fig. 6b, but the order was reversed: there were two clear peaks of modulation on the left side for each cycle of stimulation, whereas on the right side, there was only a single peak. Mean modulation indices for the SSNA data, calculated from six subjects, are shown in Fig. 7. There were no significant differences in amplitude of the primary and secondary peaks of modulation.
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For the first time, we have made bilateral recordings in awake human subjects to assess the contribution of the left and right vestibular systems in the control of sympathetic outflow to muscle and skin during the application of lowfrequency (0.08 Hz) sinusoidal galvanic vestibular stimulation. These experiments were undertaken with the aim of further expanding our understanding of the role of the vestibular apparatus on cardiovascular control and to explore how vestibular inputs from each side of the head interact in modulating sympathetic nerve activity to muscle and skin; this required recording sympathetic outflow from the left and right common peroneal nerves. These were difficult experiments, as recordings of sympathetic nerve activity on both sides of the body had to be identical: that is, the microelectrodes in both the left and right common peroneal nerves had to be located within a muscle fascicle or within a cutaneous fascicle. This was very time consuming, and in some experiments, not reported, it was not possible to obtain two identical sites in both the left and right nerves.
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Fig. 5 Bilateral recordings of skin sympathetic nerve activity, together with ECG, blood pressure and respiration, during sinusoidal galvanic vestibular stimulation (GVS) at 0.08 Hz in one subject. Overall, sympathetic outflow was similar between the two sides, but close inspection revealed subtle differences. In the expanded panels,
the sympathetic bursts have been shifted back 1.25 s in time to account for peripheral conduction delays. We did not identify bursts specifically locked to the cardiac and vestibular rhythms, because of the difficulty in defined cardiac-locked bursts of SSNA
The present investigation extends recent work from our laboratory, in which we have been applying sGVS to examine the influence of the vestibular system on sympathetic nerve activity to muscle and skin (Bent et al. 2006; Grewal et al. 2009; James and Macefield 2010; Hammam et al. 2011, 2012). In each of these studies, we showed that sympathetic nerve activity to either muscle or skin can be partially entrained to the sinusoidal vestibular input, with recent evidence suggesting that this modulation of sympathetic outflow reflected the integration of inputs from the vestibular organs in both sides of the head (Hammam et al. 2011, 2012). In these earlier studies, we always placed the stimulating anode over the right mastoid process and the
cathode over the left; moreover, we always recorded sympathetic outflow from the left common peroneal nerve, which—fortuitously—made interpretation of the data more straightforward. It is known that hyperpolarisation occurs at the anode and depolarisation at the cathode during galvanic vestibular simulation (Wardman and Fitzpatrick 2002; Fitzpatrick and Day 2004). So, during the positive phase of the sinusoidal stimulus, hyperpolarisation occurs at the right vestibular nerve, while depolarisation occurs concurrently at the left vestibular nerve occurs (Hammam et al. 2011, 2012). This means that the positive phase of the stimulus induces depolarisation of the left vestibular nerve, causing an increase in firing of vestibular nerve afferents
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Fig. 6 Cross-correlation histograms between SSNA recorded from the left and right nerves and the sinusoidal GVS for two subjects (a, b). A representation of the GVS is superimposed. Note the differences in pattern between the left and right sides
and a resultant reflexly mediated modulation of sympathetic outflow in the left common peroneal nerve; this is expressed as the primary peak of modulation. When the current slowly shifts towards the right side, it causes depolarisation of the right vestibular nerve and hyperpolarisation of the left vestibular nerve; this corresponds to the negative phase (trough) of the sinusoid. It is this secondary depolarisation of the right vestibular nerve that we proposed accounts for the secondary (smaller) peak in modulation of sympathetic nerve activity as recorded from the left side. In other words, we believed this secondary peak is due to a contralateral projection from the right vestibular nerve to the medullary nuclei responsible for generating sympathetic outflow. Of course, this was pure speculation that necessitated the current investigation— recording from the two sides to see whether the primary peak occurring on the left side was reflected in a secondary peak recorded on the right side and vice versa. As we predicted, during bilateral recording of MSNA, cross-correlation analysis did indeed reveal a reversal of modulation in the primary and secondary peaks recorded from the left and right sides: a primary peak on the left was associated with a secondary peak on the right, and a secondary peak on the left was associated with a primary peak on the right. As described above, when the sinusoidal current is applied, depolarisation at the left vestibular nerve
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occurs during the positive peak of the sinusoid, that is, when the right vestibular nerve is hyperpolarised. It is for this reason that recordings on the right side were synchronised to the negative phase (trough) of the sinusoid, as it is depolarisation of the vestibular nerve that leads to modulation of sympathetic outflow. So, when the positive phase of the sinusoid occurs over the right mastoid process, this generates the primary peak in the left common peroneal nerve and also sends a contralateral projection to the medullary nuclei on the right, modulating sympathetic outflow in the right common peroneal nerve. This is expressed as the secondary peak (corresponding to the negative phase of the GVS) in the right cross-correlogram. Interestingly, the pattern of modulation of MSNA or SSNA could differ between the two sides: in some cases, two peaks of modulation were found on one side, but only single peaks were found on the opposite side. This is probably of greater interest physiologically, given that it supports the idea that sympathetic control of blood pressure and blood flow is lateralised, at least with respect to the vestibulo-sympathetic reflexes studied here. It is generally accepted that sympathetic outflow is symmetrical: resting burst rates and amplitude distributions of muscle sympathetic nerve activity have been shown to be similar on the two sides (Sundlof and Wallin 1977; Sverrisdottir et al. 1998); the same has been shown for skin sympathetic nerve
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References
Fig. 7 Mean ± SE modulation indices for the primary (dark grey) and secondary (light grey) peaks of modulation of SSNA. Data obtained from 6 subjects
activity (Bini et al. 1980). However, we found evidence that—while the overall outflow was indeed qualitatively similar, close inspection of the recordings revealed side-toside differences in the expression of bursts linked to the vestibular inputs. To our knowledge, only one study has specifically addressed lateralisation of sympathetic control: Diedrich et al. (2009) showed that loading of carotid sinus baroreceptors by sinusoidal neck suction caused a differential expression of MSNA on the left and right sides, abolishing the normally right-sided dominance of MSNA. The current study indicates that the influence of vestibular, as well as baroreceptor, inputs is partially lateralised. Conclusions Using sGVS to selectively modulate vestibular inputs, coupled with bilateral recordings of sympathetic nerve activity to muscle, we have shown—for the first time—that the vestibular systems on both sides of the head interact with sympathetic outflow on both sides of the body to produce an integrated modulation of sympathetic outflow.
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