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Sweat production and the sympathetic skin response: Improving the clinical assessment of autonomic function
Autonomic Neuroscience: Basic and Clinical 155 (2010) 109–114
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Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t n e u
Sweat production and the sympathetic skin response: Improving the clinical assessment of autonomic function P.H. Ellaway ⁎, A. Kuppuswamy, A. Nicotra, C.J. Mathias Division of Neuroscience and Mental Health, Imperial College, London W6 8RP, UK
a r t i c l e
i n f o
Article history: Received 14 October 2009 Received in revised form 4 January 2010 Accepted 11 January 2010 Keywords: Sympathetic skin response Sweat Electrodermal potential Spinal cord injury
a b s t r a c t The aim of this project was to establish the relationship between sweat production and the electrodermal events comprising the sympathetic skin response to arousal stimuli. A series of randomly timed magnetic stimuli were applied to the neck of healthy human volunteers. Sympathetic skin responses and the associated sweat responses were recorded from the palms of both hands. Sympathetic skin responses typically had a biphasic shape consisting of a negative initial potential (palm relative to dorsum of hand) followed by a positive deflection. Sweat production was positively correlated with amplitude of the second positive deflection of the sympathetic skin response and negatively correlated with the amplitude of the initial negative deflection. For subjects showing only an initial negative sympathetic skin response, sweat release was low or not detectable. During habituation, the negative initial wave increased relative to the second positive wave, and sweat production fell. The strong correlation between the positive wave of the sympathetic skin response and sweat production suggests that the former may provide a quantitative functional measure of sudomotor activity in situations when it is impractical to measure the amount of sweat produced in the startle response. Thus, the positive component of the biphasic sympathetic skin response may be employed in clinical assessment of the functional efficacy of the sympathetic sudomotor system. © 2010 Elsevier B.V. All rights reserved.
1. Introduction The clinical assessment of sudomotor function, as a component of autonomic sympathetic function, can be achieved using a number of techniques, including recently refined developments such as the quantitative sudomotor axon reflex test (QSART) for sweat production (Sletten et al., 2009a,b). Employed in combination, certain methods allow distinction between central nervous and peripheral components of sudomotor function (see Illigens and Gibbons, 2009) and may be used to monitor deterioration or recovery from trauma or disease. Of the techniques available, the sympathetic skin response (SSR) is widely regarded as being indicative of the integrity of the combined central and peripheral components of the sympathetic cholinergic sudomotor system. However, the relationship between the electrodermal events of the SSR and sweat production remains unclear (Freedman et al., 1994; Krogstad et al., 2004). In order to accept the SSR as a valid tool for the assessment of sudomotor function it would be of value if this relationship could be firmly established. The SSR is a slow change in electrical potential that can be recorded from the palmar and plantar surfaces when a human subject is presented with an unexpected stimulus, such as a loud noise or cutaneous electrical stimulus (Shahani et al., 1984). The presentation of
⁎ Corresponding author. E-mail address: [email protected] (P.H. Ellaway). 1566-0702/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.01.008
an unexpected stimulus is thought to give rise to sympathetic activation through afferent input via hypothalamic, brain stem and other central connections (Isamat, 1961; Yokota et al., 1991; Critchley et al., 2000) leading to excitation of elements of the sympathetic chain and, finally, sweat gland activation (Magnifico et al., 1998). When two surface electrodes are placed one each on the palm and the dorsum of the hand, a biphasic SSR response associated with the sweat gland activation is most often recorded with the palm initially becoming negative with respect to the dorsum of the hand and then reversing. The waveform can however be simpler (monophasic) or more complex (Shahani et al., 1984; Baba et al., 1988; Andary et al., 1993) with variation in form within subjects (Hoeldtke et al., 1992; Levy et al., 1992; Toyokura and Murakami, 1996) and as a result of habituation (Toyokura, 1998; Cariga et al., 2001). Mitani et al. (2003) made monopolar recordings from several sites on both the palm and the dorsum of the hand against a ground electrode at a remote site. The initial potential change during an SSR was negative on the palm and positive on the dorsum of the hand. In none of the above studies was the amount of sweat recorded at the time of an SSR, so the relationship between the various components of the SSR waveform and sweat release is unknown. Others have recorded the sweat produced in response to arousal stimuli that would presumably have elicited an SSR (Asahina et al., 2002; Kuwabara et al., 2008). In the absence of an SSR recording, the profile of sweat production was insufficient to predict any relationship to electrodermal events.
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The SSR is disrupted in a variety of central and peripheral nervous system disorders with sweat disturbances (Vetrugno et al., 2003). Although SSR has been used as a routine test in a number of neurological conditions there is, as yet, no standardised method of measuring the SSR waveform or any direct relation between the SSR and sweat production. The need for improved evaluation of autonomic function has been recognised, at least in spinal cord injury (Krassioukov et al., 2007; Alexander et al., 2009). In order to improve on the usefulness of the SSR as a predictor of functional outcome or as an objective assessment of recovery of cholinergic sympathetic pathways, the precise relationship between the amount of sweat produced and the different components of SSR needs to be understood. In this study we attempt to study the relationship between the different components of palmar SSR and the volume of sweat produced in the palm in healthy subjects. The SSR has already been used (Curt and Dietz, 1999; Nicotra et al., 2005) to provide information about the extent and level of lesions of the spinal cord affecting the sympathetic nervous system. The SSR recordings were regarded as supplementary to the clinical examination (American Spinal Injuries Association — ASIA assessment) and would have the potential to provide additional guidance for the selection of appropriate therapy within a programme of rehabilitation. The present study aims to provide a functional element to the use of the SSR in assessing damage and disorders of the sympathetic sudomotor system particularly when access to direct recording of sweat production may be unavailable.
Following the application of SSR electrodes and sudorometer probes on the hands, the subjects were instructed to close their eyes and relax for approximately 10 min before the start of any recordings. 2.3. Magnetic stimulation SSR and SSwR were elicited in subjects by applying an unexpected magnetic stimulus to the back of the neck. Magnetic stimuli have previously been shown to reliably evoke an SSR (Uozumi et al., 1993; Toyokura, 2003). Such magnetic stimuli are, in our experience, as consistent as other means of stimulation (electrical, acoustic, and inspiratory gasp) at evoking an SSR. A circular coil attached to a MagStim 200 magnetic stimulator (MagStim Co, Dyfed, Wales) was charged up to 65% maximum stimulator output and 15 to 20 stimuli were given at random intervals with the coil positioned over the back of the neck of a subject. To minimise habituation of the responses (Cariga et al., 2001), the stimuli were separated by at least a minute. 2.4. Analysis and statistics Individual, stimulus-triggered SSR and SSwR traces were visually inspected and any anomalous records were discarded. Anomalous records were defined as shifts in the electrodermal signal with a
2. Materials and methods 2.1. Subjects With the approval of the local ethics committee 12 healthy and neurologically normal individuals (21–65 years, 6 females) gave informed consent to participate in the study. 2.2. Recordings Subjects were seated comfortably in a chair with the room temperature maintained at 24 ± 1 °C. The SSR was recorded using surface electrodes placed on the hands. The volar and dorsal surfaces of both hands were cleaned using alcohol swabs. Two Ag–AgCl surface electrodes (2 × 3 cm Arbo neonatal ECG electrodes, Henley's medical) were deployed, one on the palm and the other on the dorsum of the hand. A reference electrode was placed at a remote site on the wrist. A differential isolated biological amplifier (IsoDam 7 — World Precision Instruments, USA) was used to record the potential difference between the palm and the dorsum of the hand. The signal was amplified 100 times and high and low pass filters were set at 0.1 Hz and 100 Hz respectively. Signals were sampled at 1 kHz using a data acquisition interface, host PC and software (Cambridge Electronic Design 1401+ and Signal version 3.1). A sudorometer (Skinos Ltd., Japan) was used to record the sweat response from the palms. Each sudorometer probe consisted of an air chamber (1 cm2 contact area) attached to the palm using adhesive stickers to make an air-tight seal. Two air hoses connected the chamber with the sudorometer, one that delivered dry air by pump action and the other that retrieved air moistened by any sweat. The difference in humidity between the air delivered and the air retrieved was measured by the sudorometer and the signal expressed in mg/ cm2/min. The humidity recording is a measure of the amount of sweat produced and, in response to an arousal stimulus, has been termed the sympathetic skin sweat response (SSwR) by Asahina et al. (2002). The SSwR was sampled at 1 kHz by the data acquisition interface (Cambridge Electronic Design 1401+ and Signal version 3.1) and stored on a computer, with the simultaneously recorded SSR signal, for offline analysis. SSR and SSwR were recorded from both palms.
Fig. 1. The SSR (A) and SSwR (B) recorded from the palm. The responses were elicited by a magnetic stimulus to the neck of the subject at time zero. Polarity of the differential recording of the SSR refers to the voltage recorded from an electrode on the volar surface of the hand (palm) with respect to a second electrode on the back of the hand. A: Horizontal arrows represent measures made for analysis of SSR records. Absolute magnitudes of the first peak (typically negative) and of the second peak (typically positive going) are indicated. B. Vertical arrow represents magnitude of the maximum sweat production (from baseline) immediately following the SSR.
P.H. Ellaway et al. / Autonomic Neuroscience: Basic and Clinical 155 (2010) 109–114
latency of less than 1 s to the stimulus. The expected latency for palmar SSR in normal subjects is 1473 ± 82 ms (mean ± SD) at the start and 1550 ± 90 ms at the end of 20 consecutive randomly delivered stimuli (Cariga et al., 2001). Thus, an event with a latency of less than 1 s was likely to be a spontaneous shift in electrodermal potential and not a response to the stimulus. The SSR and SSwR illustrated in Fig. 1 are typical for the majority of subjects. The SSR and SSwR have latencies of 1.4 s and 3.3 s respectively with a time to peak SSwR of 5.5 s. Offline analysis of SSR and SSwR records was performed using Signal software (CED, version 3.1). Fig. 1 illustrates the methods used to measure the amplitudes of the SSR and SSwR recordings. Typically the form of the SSR was a biphasic potential change but, less frequently, could present simply as a monophasic potential. The amplitude from baseline of the first peak of each biphasic SSR (a negative deflection) and the absolute amplitude of the second peak (positive going from an initial negative peak) were measured, as was the peak to peak (negative to positive) amplitude. The absolute amplitude (negative) from baseline was also measured for monophasic SSRs. The amplitude of the SSwR was measured from the sudorometer recordings as the change from baseline to the peak of the deflection following the magnetic stimulus. Statistics (regression analysis) were performed using Sigmastat (Systat software, version 3.1) and the graphs were plotted using Sigmaplot (Systat software, version 10.0). 3. Results An SSR was elicited in response to magnetic stimulation of the back of the neck in all twelve subjects. In one subject it was possible to elicit an SSR only from one palm (left) and not the other. The SSR
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varied in form between subjects and even within a subject in response to repeated stimuli. Most frequently (9 of 12 subjects), the SSR in response to a stimulus had a predominantly biphasic shape with the initial peak representing increased negativity of the volar aspect of the hand with respect to the dorsum of the hand. The second peak was either positive or positive going with respect to the first peak. In several of these nine subjects a biphasic response was observed in response to the stimuli occurring early during the series but the SSR changed to a monophasic response as the series progressed. Monophasic responses consisted solely of a negative potential, the palm being negative with respect to the dorsum of the hand. For three subjects (2 female and one male), including the one subject with no detectable SSR in the right hand, no biphasic waveforms were recorded and the SSR consisted solely of a monophasic peak (palm negative with respect to the dorsum of the hand). The absence of a biphasic peak was not age-related. The main finding of this study is that sweat production in response to stimulation appeared to be associated with the second (positive) peak of the SSR and not with the first (negative) peak. Fig. 2 shows the SSR and associated SSwR records for two subjects. Recordings have been selected from the start of the series of twenty randomly timed stimuli, towards the middle of the run and at the end of the run for both subjects. For subject 1, the SSR was consistently biphasic (negative followed by a positive peak) and each SSR was accompanied by a substantial SSwR. In the case of subject 2, the SSwR habituated during the series of stimuli. The biphasic SSR at the start of the series of stimuli is accompanied by a substantial SSwR whereas at the end of the series the SSR is monophasic (negative) and the SSwR is greatly attenuated. In the middle of the series, the SSR is complex with an initially large negative deflection followed by a smaller positive-going component. The associated SSwR is intermediate in size compared to
Fig. 2. Relationship between components of the SSR and sweat production. For both subjects the left column shows the SSR and the right column the related SSwR response with stimuli having been applied at the start of all traces. The responses in the first row were recorded at the beginning of a series of twenty stimuli, randomly timed with a minimum separation of 1 min. The responses in the second row were recorded in the middle of the sequence and the bottom row towards the end of the sequence of stimuli. Note the lack of habituation of the SSR and SSwR in subject 1. In subject 2, the SSR changes from a biphasic wave with a dominant positive second peak and large SSwR at the start of the sequence to a monophasic negative peak with a small SSwR towards the end of the sequence. Calibrations at left for the SSR and at right for SSwR are the same for all traces.
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the responses at the start and end of the series. It is also noticeable that whereas the latency of the negative wave is relatively constant, the latency of the second, positive-going potential becomes progressively later as the positive wave diminishes in amplitude. Some degree of habituation was observed for all nine subjects in whom biphasic responses were observed at the start of a series of stimuli. However, it varied from minimal reductions in the size of the SSR and SSwR to a substantial reduction in the SSwR accompanied by a change from a biphasic to a monophasic SSR. Occasionally, the process of habituation was not uniform and a transient increase in the SSwR accompanied by an increase in the second (positive) peak of the SSR was observed. Habituation was not clearly evident either for the weak SSwR or the negative peak of the SSR in the three subjects lacking a biphasic SSR. Regression plots were constructed to examine further the relationship between the components of the SSR and the magnitude of the SSwR. Fig. 3 shows plots of the amplitude of the SSwR against the amplitude of the first peak of the SSR (Fig. 3A) and against the second peak (Fig. 3B) for the same subject. Linear regression analysis showed positive and statistically significant correlations for both plots, but with a greater r2 value for the relation between the SSwR and the second peak of the SSR (r2 = 0.87, P < 0.0001) than for the first peak (r2 = 0.43, P = 0.002). Interpreting the plots in Fig. 3, it is evident that a large negative first peak in an SSR is associated with little or no SSwR (Fig. 3C) whereas a large positive second peak is associated with a large SSwR (Fig. 3E). All nine subjects with a biphasic SSR showed significant positive correlations between the amount of sweat (SSwR) and the second positive-going peak of the SSR whereas only six showed correlation between the SSwR and the first negative-going SSR peak and five with the peak to peak SSR measure. A high level of correlation existed for SSR and SSwR measures between the two hands of subjects. The example in Fig. 4 shows plots of the data measured for the train of stimuli presented to one subject.
Linear regression analysis shows high degrees of correlation between the two hands for the amplitude of first peak of the SSR, the amplitude of the second peak of the SSR, peak to peak amplitude of the SSR and the maximum SSwR. 4. Discussion This study has shown that, in healthy subjects, the amount of sweat produced from the palm of the hand during an SSR is most closely related to a positive-going change in the electrodermal potential recorded from the volar surface of the hand with respect to the dorsum of the hand. The positive-going potential recorded from the palm usually follows an initial negative-going potential at the start of the SSR. In these instances, the SSR has an essentially biphasic waveform. When the SSR comprises simply a monophasic negative wave (volar surface negative with respect to the dorsum of the hand) little or no SSwR is produced. In contrast, the biphasic SSR is associated with SSwR production. The greater the SSwR, the larger the size of the positive-going potential of the biphasic SSR and the smaller it is, the larger the amplitude of the initial negative-going potential. The origins of the currents that cause the shifts in potential difference recorded during an SSR are uncertain. Using monopolar recording, Mitani et al. (2003) observed initial negativity of the palm (volar surface) of the hand, followed by a positive-going potential, during an acoustically elicited SSR in all normal subjects. They postulated that the source of the SSR was probably located in the sweat glands on the palm of the hand. The potential changes could be explained by an equivalent current dipole resulting from a Na+ concentration gradient in the fluid within the canals of sweat glands caused by intra-canal re-absorption of Na+. Mitani et al. (2003) also conjectured that the reversal of the potential from negative to positive could be explained by evaporation of water from sweat expressed on
Fig. 3. Correlations between the SSwR and the first (A) and second (B) peaks of the SSR for a sequence of twenty, randomly timed stimuli for the right hand of one subject. Note that sweat production decreases with an increase in the magnitude of the negative first peak of the SSR and increases in magnitude with the amplitude of the positive-going second peak of the SSR. The linear regression between SSR peak and the SSwR is stronger for the second peak (r2 = 0.87, P < 0.0001) than for the first peak (r2 = 0.43, P < 0.01). C, D and E: Sample tracings of the SSwR (above) and SSR (below). All traces have the same (arbitrary) calibrations for amplitude of the SSwR and SSR. Polarity of the SSR recording is indicated by the ± symbol. The duration of all traces is 8 s with stimulus presentation at time zero. The measurements for the three traces (C, D and E) are indicated on the regression plots A and B.
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Fig. 4. Correlations between responses from the left and right palms for one subject for a series of twenty randomly timed stimuli. A: The SSwR. B: The peak to peak amplitude of the SSR, i.e. between the maxima of the first and second peaks. C: The absolute value of the first peak of the SSR. D: The absolute value of the second peak of the SSR. All r2 values are significant at P < 0.001.
to the surface of the skin with a relative increase in sodium ion concentration. Our results are not in disagreement with this hypothesis in that it is the positivity at the palmar site that is associated with production of sweat that is released on to the surface of the palm. Other studies (Toyokura, 1998, 1999) have observed that the SSR may have predominantly negative, positive or mixed (biphasic) potential changes at the palmar surface. The mixed response was observed more frequently than the monophasic forms with negativity always preceding positivity. These findings appear to indicate that activation of the sweat glands first engages a process, likely to be sweat production within the sweat glands or secretion into the sweat ducts of the glands, that is associated with a negative shift in potential at the surface. Only when the negative potential is followed by a positive shift in potential is appreciable sweat expulsion on to the palmar surface observed. Habituation of the response to a repeatable stimulus, even when applied at random intervals, is a well known feature of the SSR with the degree of habituation varying between individuals (Hoeldtke et al., 1992; Aramaki et al., 1997; Cariga et al., 2001). Habituation of the SSR in the present study was evident for all subjects exhibiting biphasic responses and most frequently consisted of a reduction in the amplitude of the second, positive-going component of the potential. The habituation could also result in the form of the SSR changing from a biphasic potential to an essentially monophasic, negative peak during the series of stimuli. Habituation of the SSR was accompanied by a decrease in the SSwR, i.e. sweat release itself also habituated, and the habituation of both SSR and SSwR were observed to occur symmetrically across the left and right palms. In conclusion, the strong linear correlation between the positive element of the biphasic potential of the SSR and the SSwR leads us to propose that the former may itself provide a quantitative functional measure of sudomotor activity, i.e. the amount of sweat produced in
response to a startle stimulus. Thus, in situations where it is impractical to measure the amount of sweat produced in the startle response, the positive component of the biphasic SSR may be employed to assess the functional efficacy of the sympathetic sudomotor system. Acknowledgement The work was supported by the International Spinal Research Trust. References Alexander, M.S., Anderson, K.D., Biering-Sorensen, F., Blight, A.R., Brannon, R., Bryce, T.N., Creasey, G., Catz, A., Curt, A., Donovan, W., Ditunno, J., Ellaway, P., Finnerup, N.B., Graves, D.E., Haynes, B.A., Heinemann, A.W., Jackson, A.B., Johnston, M.V., Kalpakjian, C.Z., Kleitman, N., Krassioukov, A., Krogh, K., Lammertse, D., Magasi, S., Mulcahey, M.J., Schurch, B., Sherwood, A., Steeves, J.D., Stiens, S., Tulsky, D.S., van Hedel, H.J., Whiteneck, G., 2009. Outcome measures in spinal cord injury: recent assessments and recommendations for future directions. Spinal Cord 47, 582–591. Andary, M.T., Stolov, W.C., Nutter, P.B., 1993. Sympathetic skin response in fifth lumbar and first sacral radiculopathies. Electromyogr. Clin. Neurophysiol. 33, 91–99. Aramaki, S., Kira, Y., Hirasawa, Y., 1997. A study of the normal values and habituation phenomenon of sympathetic skin response. Am. J. Phys. Med. Rehabil. 76, 2–7. Asahina, M., Kuwabara, S., Suzuki, A., Hattori, T., 2002. Autonomic function in demyelinating and axonal subtypes of Guillain–Barré syndrome. Acta Neurol. Scand. 105, 44–50. Baba, M., Watahiki, Y., Matsunaga, M., Takebe, K., 1988. Sympathetic skin response in healthy man. Electromyogr. Clin. Neurophysiol. 28, 277–283. Cariga, P., Catley, M., Mathias, C.J., Ellaway, P.H., 2001. Characteristics of habituation of the sympathetic skin response to repeated electrical stimuli in man. Clin. Neurophysiol. 112, 1875–1880. Critchley, H.D., Elliott, R., Mathias, C.J., Dolan, R.J., 2000. Neural activity relating to generation and representation of galvanic skin conductance responses: a functional magnetic resonance imaging study. J. Neurosci. 20, 3033–3040. Curt, A., Dietz, V., 1999. Electrophysiological recordings in patients with spinal cord injury: significance for predicting outcome. Spinal Cord 37, 157–165. Freedman, R.R., Woodward, S., Mayes, M.M., 1994. Non-neural mediation of digital vasodilation during menopausal hot flushes. Gynecol. Obstet. Invest. 38, 206–209.
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Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t n e u
Sweat production and the sympathetic skin response: Improving the clinical assessment of autonomic function P.H. Ellaway ⁎, A. Kuppuswamy, A. Nicotra, C.J. Mathias Division of Neuroscience and Mental Health, Imperial College, London W6 8RP, UK
a r t i c l e
i n f o
Article history: Received 14 October 2009 Received in revised form 4 January 2010 Accepted 11 January 2010 Keywords: Sympathetic skin response Sweat Electrodermal potential Spinal cord injury
a b s t r a c t The aim of this project was to establish the relationship between sweat production and the electrodermal events comprising the sympathetic skin response to arousal stimuli. A series of randomly timed magnetic stimuli were applied to the neck of healthy human volunteers. Sympathetic skin responses and the associated sweat responses were recorded from the palms of both hands. Sympathetic skin responses typically had a biphasic shape consisting of a negative initial potential (palm relative to dorsum of hand) followed by a positive deflection. Sweat production was positively correlated with amplitude of the second positive deflection of the sympathetic skin response and negatively correlated with the amplitude of the initial negative deflection. For subjects showing only an initial negative sympathetic skin response, sweat release was low or not detectable. During habituation, the negative initial wave increased relative to the second positive wave, and sweat production fell. The strong correlation between the positive wave of the sympathetic skin response and sweat production suggests that the former may provide a quantitative functional measure of sudomotor activity in situations when it is impractical to measure the amount of sweat produced in the startle response. Thus, the positive component of the biphasic sympathetic skin response may be employed in clinical assessment of the functional efficacy of the sympathetic sudomotor system. © 2010 Elsevier B.V. All rights reserved.
1. Introduction The clinical assessment of sudomotor function, as a component of autonomic sympathetic function, can be achieved using a number of techniques, including recently refined developments such as the quantitative sudomotor axon reflex test (QSART) for sweat production (Sletten et al., 2009a,b). Employed in combination, certain methods allow distinction between central nervous and peripheral components of sudomotor function (see Illigens and Gibbons, 2009) and may be used to monitor deterioration or recovery from trauma or disease. Of the techniques available, the sympathetic skin response (SSR) is widely regarded as being indicative of the integrity of the combined central and peripheral components of the sympathetic cholinergic sudomotor system. However, the relationship between the electrodermal events of the SSR and sweat production remains unclear (Freedman et al., 1994; Krogstad et al., 2004). In order to accept the SSR as a valid tool for the assessment of sudomotor function it would be of value if this relationship could be firmly established. The SSR is a slow change in electrical potential that can be recorded from the palmar and plantar surfaces when a human subject is presented with an unexpected stimulus, such as a loud noise or cutaneous electrical stimulus (Shahani et al., 1984). The presentation of
⁎ Corresponding author. E-mail address: [email protected] (P.H. Ellaway). 1566-0702/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.01.008
an unexpected stimulus is thought to give rise to sympathetic activation through afferent input via hypothalamic, brain stem and other central connections (Isamat, 1961; Yokota et al., 1991; Critchley et al., 2000) leading to excitation of elements of the sympathetic chain and, finally, sweat gland activation (Magnifico et al., 1998). When two surface electrodes are placed one each on the palm and the dorsum of the hand, a biphasic SSR response associated with the sweat gland activation is most often recorded with the palm initially becoming negative with respect to the dorsum of the hand and then reversing. The waveform can however be simpler (monophasic) or more complex (Shahani et al., 1984; Baba et al., 1988; Andary et al., 1993) with variation in form within subjects (Hoeldtke et al., 1992; Levy et al., 1992; Toyokura and Murakami, 1996) and as a result of habituation (Toyokura, 1998; Cariga et al., 2001). Mitani et al. (2003) made monopolar recordings from several sites on both the palm and the dorsum of the hand against a ground electrode at a remote site. The initial potential change during an SSR was negative on the palm and positive on the dorsum of the hand. In none of the above studies was the amount of sweat recorded at the time of an SSR, so the relationship between the various components of the SSR waveform and sweat release is unknown. Others have recorded the sweat produced in response to arousal stimuli that would presumably have elicited an SSR (Asahina et al., 2002; Kuwabara et al., 2008). In the absence of an SSR recording, the profile of sweat production was insufficient to predict any relationship to electrodermal events.
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The SSR is disrupted in a variety of central and peripheral nervous system disorders with sweat disturbances (Vetrugno et al., 2003). Although SSR has been used as a routine test in a number of neurological conditions there is, as yet, no standardised method of measuring the SSR waveform or any direct relation between the SSR and sweat production. The need for improved evaluation of autonomic function has been recognised, at least in spinal cord injury (Krassioukov et al., 2007; Alexander et al., 2009). In order to improve on the usefulness of the SSR as a predictor of functional outcome or as an objective assessment of recovery of cholinergic sympathetic pathways, the precise relationship between the amount of sweat produced and the different components of SSR needs to be understood. In this study we attempt to study the relationship between the different components of palmar SSR and the volume of sweat produced in the palm in healthy subjects. The SSR has already been used (Curt and Dietz, 1999; Nicotra et al., 2005) to provide information about the extent and level of lesions of the spinal cord affecting the sympathetic nervous system. The SSR recordings were regarded as supplementary to the clinical examination (American Spinal Injuries Association — ASIA assessment) and would have the potential to provide additional guidance for the selection of appropriate therapy within a programme of rehabilitation. The present study aims to provide a functional element to the use of the SSR in assessing damage and disorders of the sympathetic sudomotor system particularly when access to direct recording of sweat production may be unavailable.
Following the application of SSR electrodes and sudorometer probes on the hands, the subjects were instructed to close their eyes and relax for approximately 10 min before the start of any recordings. 2.3. Magnetic stimulation SSR and SSwR were elicited in subjects by applying an unexpected magnetic stimulus to the back of the neck. Magnetic stimuli have previously been shown to reliably evoke an SSR (Uozumi et al., 1993; Toyokura, 2003). Such magnetic stimuli are, in our experience, as consistent as other means of stimulation (electrical, acoustic, and inspiratory gasp) at evoking an SSR. A circular coil attached to a MagStim 200 magnetic stimulator (MagStim Co, Dyfed, Wales) was charged up to 65% maximum stimulator output and 15 to 20 stimuli were given at random intervals with the coil positioned over the back of the neck of a subject. To minimise habituation of the responses (Cariga et al., 2001), the stimuli were separated by at least a minute. 2.4. Analysis and statistics Individual, stimulus-triggered SSR and SSwR traces were visually inspected and any anomalous records were discarded. Anomalous records were defined as shifts in the electrodermal signal with a
2. Materials and methods 2.1. Subjects With the approval of the local ethics committee 12 healthy and neurologically normal individuals (21–65 years, 6 females) gave informed consent to participate in the study. 2.2. Recordings Subjects were seated comfortably in a chair with the room temperature maintained at 24 ± 1 °C. The SSR was recorded using surface electrodes placed on the hands. The volar and dorsal surfaces of both hands were cleaned using alcohol swabs. Two Ag–AgCl surface electrodes (2 × 3 cm Arbo neonatal ECG electrodes, Henley's medical) were deployed, one on the palm and the other on the dorsum of the hand. A reference electrode was placed at a remote site on the wrist. A differential isolated biological amplifier (IsoDam 7 — World Precision Instruments, USA) was used to record the potential difference between the palm and the dorsum of the hand. The signal was amplified 100 times and high and low pass filters were set at 0.1 Hz and 100 Hz respectively. Signals were sampled at 1 kHz using a data acquisition interface, host PC and software (Cambridge Electronic Design 1401+ and Signal version 3.1). A sudorometer (Skinos Ltd., Japan) was used to record the sweat response from the palms. Each sudorometer probe consisted of an air chamber (1 cm2 contact area) attached to the palm using adhesive stickers to make an air-tight seal. Two air hoses connected the chamber with the sudorometer, one that delivered dry air by pump action and the other that retrieved air moistened by any sweat. The difference in humidity between the air delivered and the air retrieved was measured by the sudorometer and the signal expressed in mg/ cm2/min. The humidity recording is a measure of the amount of sweat produced and, in response to an arousal stimulus, has been termed the sympathetic skin sweat response (SSwR) by Asahina et al. (2002). The SSwR was sampled at 1 kHz by the data acquisition interface (Cambridge Electronic Design 1401+ and Signal version 3.1) and stored on a computer, with the simultaneously recorded SSR signal, for offline analysis. SSR and SSwR were recorded from both palms.
Fig. 1. The SSR (A) and SSwR (B) recorded from the palm. The responses were elicited by a magnetic stimulus to the neck of the subject at time zero. Polarity of the differential recording of the SSR refers to the voltage recorded from an electrode on the volar surface of the hand (palm) with respect to a second electrode on the back of the hand. A: Horizontal arrows represent measures made for analysis of SSR records. Absolute magnitudes of the first peak (typically negative) and of the second peak (typically positive going) are indicated. B. Vertical arrow represents magnitude of the maximum sweat production (from baseline) immediately following the SSR.
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latency of less than 1 s to the stimulus. The expected latency for palmar SSR in normal subjects is 1473 ± 82 ms (mean ± SD) at the start and 1550 ± 90 ms at the end of 20 consecutive randomly delivered stimuli (Cariga et al., 2001). Thus, an event with a latency of less than 1 s was likely to be a spontaneous shift in electrodermal potential and not a response to the stimulus. The SSR and SSwR illustrated in Fig. 1 are typical for the majority of subjects. The SSR and SSwR have latencies of 1.4 s and 3.3 s respectively with a time to peak SSwR of 5.5 s. Offline analysis of SSR and SSwR records was performed using Signal software (CED, version 3.1). Fig. 1 illustrates the methods used to measure the amplitudes of the SSR and SSwR recordings. Typically the form of the SSR was a biphasic potential change but, less frequently, could present simply as a monophasic potential. The amplitude from baseline of the first peak of each biphasic SSR (a negative deflection) and the absolute amplitude of the second peak (positive going from an initial negative peak) were measured, as was the peak to peak (negative to positive) amplitude. The absolute amplitude (negative) from baseline was also measured for monophasic SSRs. The amplitude of the SSwR was measured from the sudorometer recordings as the change from baseline to the peak of the deflection following the magnetic stimulus. Statistics (regression analysis) were performed using Sigmastat (Systat software, version 3.1) and the graphs were plotted using Sigmaplot (Systat software, version 10.0). 3. Results An SSR was elicited in response to magnetic stimulation of the back of the neck in all twelve subjects. In one subject it was possible to elicit an SSR only from one palm (left) and not the other. The SSR
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varied in form between subjects and even within a subject in response to repeated stimuli. Most frequently (9 of 12 subjects), the SSR in response to a stimulus had a predominantly biphasic shape with the initial peak representing increased negativity of the volar aspect of the hand with respect to the dorsum of the hand. The second peak was either positive or positive going with respect to the first peak. In several of these nine subjects a biphasic response was observed in response to the stimuli occurring early during the series but the SSR changed to a monophasic response as the series progressed. Monophasic responses consisted solely of a negative potential, the palm being negative with respect to the dorsum of the hand. For three subjects (2 female and one male), including the one subject with no detectable SSR in the right hand, no biphasic waveforms were recorded and the SSR consisted solely of a monophasic peak (palm negative with respect to the dorsum of the hand). The absence of a biphasic peak was not age-related. The main finding of this study is that sweat production in response to stimulation appeared to be associated with the second (positive) peak of the SSR and not with the first (negative) peak. Fig. 2 shows the SSR and associated SSwR records for two subjects. Recordings have been selected from the start of the series of twenty randomly timed stimuli, towards the middle of the run and at the end of the run for both subjects. For subject 1, the SSR was consistently biphasic (negative followed by a positive peak) and each SSR was accompanied by a substantial SSwR. In the case of subject 2, the SSwR habituated during the series of stimuli. The biphasic SSR at the start of the series of stimuli is accompanied by a substantial SSwR whereas at the end of the series the SSR is monophasic (negative) and the SSwR is greatly attenuated. In the middle of the series, the SSR is complex with an initially large negative deflection followed by a smaller positive-going component. The associated SSwR is intermediate in size compared to
Fig. 2. Relationship between components of the SSR and sweat production. For both subjects the left column shows the SSR and the right column the related SSwR response with stimuli having been applied at the start of all traces. The responses in the first row were recorded at the beginning of a series of twenty stimuli, randomly timed with a minimum separation of 1 min. The responses in the second row were recorded in the middle of the sequence and the bottom row towards the end of the sequence of stimuli. Note the lack of habituation of the SSR and SSwR in subject 1. In subject 2, the SSR changes from a biphasic wave with a dominant positive second peak and large SSwR at the start of the sequence to a monophasic negative peak with a small SSwR towards the end of the sequence. Calibrations at left for the SSR and at right for SSwR are the same for all traces.
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the responses at the start and end of the series. It is also noticeable that whereas the latency of the negative wave is relatively constant, the latency of the second, positive-going potential becomes progressively later as the positive wave diminishes in amplitude. Some degree of habituation was observed for all nine subjects in whom biphasic responses were observed at the start of a series of stimuli. However, it varied from minimal reductions in the size of the SSR and SSwR to a substantial reduction in the SSwR accompanied by a change from a biphasic to a monophasic SSR. Occasionally, the process of habituation was not uniform and a transient increase in the SSwR accompanied by an increase in the second (positive) peak of the SSR was observed. Habituation was not clearly evident either for the weak SSwR or the negative peak of the SSR in the three subjects lacking a biphasic SSR. Regression plots were constructed to examine further the relationship between the components of the SSR and the magnitude of the SSwR. Fig. 3 shows plots of the amplitude of the SSwR against the amplitude of the first peak of the SSR (Fig. 3A) and against the second peak (Fig. 3B) for the same subject. Linear regression analysis showed positive and statistically significant correlations for both plots, but with a greater r2 value for the relation between the SSwR and the second peak of the SSR (r2 = 0.87, P < 0.0001) than for the first peak (r2 = 0.43, P = 0.002). Interpreting the plots in Fig. 3, it is evident that a large negative first peak in an SSR is associated with little or no SSwR (Fig. 3C) whereas a large positive second peak is associated with a large SSwR (Fig. 3E). All nine subjects with a biphasic SSR showed significant positive correlations between the amount of sweat (SSwR) and the second positive-going peak of the SSR whereas only six showed correlation between the SSwR and the first negative-going SSR peak and five with the peak to peak SSR measure. A high level of correlation existed for SSR and SSwR measures between the two hands of subjects. The example in Fig. 4 shows plots of the data measured for the train of stimuli presented to one subject.
Linear regression analysis shows high degrees of correlation between the two hands for the amplitude of first peak of the SSR, the amplitude of the second peak of the SSR, peak to peak amplitude of the SSR and the maximum SSwR. 4. Discussion This study has shown that, in healthy subjects, the amount of sweat produced from the palm of the hand during an SSR is most closely related to a positive-going change in the electrodermal potential recorded from the volar surface of the hand with respect to the dorsum of the hand. The positive-going potential recorded from the palm usually follows an initial negative-going potential at the start of the SSR. In these instances, the SSR has an essentially biphasic waveform. When the SSR comprises simply a monophasic negative wave (volar surface negative with respect to the dorsum of the hand) little or no SSwR is produced. In contrast, the biphasic SSR is associated with SSwR production. The greater the SSwR, the larger the size of the positive-going potential of the biphasic SSR and the smaller it is, the larger the amplitude of the initial negative-going potential. The origins of the currents that cause the shifts in potential difference recorded during an SSR are uncertain. Using monopolar recording, Mitani et al. (2003) observed initial negativity of the palm (volar surface) of the hand, followed by a positive-going potential, during an acoustically elicited SSR in all normal subjects. They postulated that the source of the SSR was probably located in the sweat glands on the palm of the hand. The potential changes could be explained by an equivalent current dipole resulting from a Na+ concentration gradient in the fluid within the canals of sweat glands caused by intra-canal re-absorption of Na+. Mitani et al. (2003) also conjectured that the reversal of the potential from negative to positive could be explained by evaporation of water from sweat expressed on
Fig. 3. Correlations between the SSwR and the first (A) and second (B) peaks of the SSR for a sequence of twenty, randomly timed stimuli for the right hand of one subject. Note that sweat production decreases with an increase in the magnitude of the negative first peak of the SSR and increases in magnitude with the amplitude of the positive-going second peak of the SSR. The linear regression between SSR peak and the SSwR is stronger for the second peak (r2 = 0.87, P < 0.0001) than for the first peak (r2 = 0.43, P < 0.01). C, D and E: Sample tracings of the SSwR (above) and SSR (below). All traces have the same (arbitrary) calibrations for amplitude of the SSwR and SSR. Polarity of the SSR recording is indicated by the ± symbol. The duration of all traces is 8 s with stimulus presentation at time zero. The measurements for the three traces (C, D and E) are indicated on the regression plots A and B.
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Fig. 4. Correlations between responses from the left and right palms for one subject for a series of twenty randomly timed stimuli. A: The SSwR. B: The peak to peak amplitude of the SSR, i.e. between the maxima of the first and second peaks. C: The absolute value of the first peak of the SSR. D: The absolute value of the second peak of the SSR. All r2 values are significant at P < 0.001.
to the surface of the skin with a relative increase in sodium ion concentration. Our results are not in disagreement with this hypothesis in that it is the positivity at the palmar site that is associated with production of sweat that is released on to the surface of the palm. Other studies (Toyokura, 1998, 1999) have observed that the SSR may have predominantly negative, positive or mixed (biphasic) potential changes at the palmar surface. The mixed response was observed more frequently than the monophasic forms with negativity always preceding positivity. These findings appear to indicate that activation of the sweat glands first engages a process, likely to be sweat production within the sweat glands or secretion into the sweat ducts of the glands, that is associated with a negative shift in potential at the surface. Only when the negative potential is followed by a positive shift in potential is appreciable sweat expulsion on to the palmar surface observed. Habituation of the response to a repeatable stimulus, even when applied at random intervals, is a well known feature of the SSR with the degree of habituation varying between individuals (Hoeldtke et al., 1992; Aramaki et al., 1997; Cariga et al., 2001). Habituation of the SSR in the present study was evident for all subjects exhibiting biphasic responses and most frequently consisted of a reduction in the amplitude of the second, positive-going component of the potential. The habituation could also result in the form of the SSR changing from a biphasic potential to an essentially monophasic, negative peak during the series of stimuli. Habituation of the SSR was accompanied by a decrease in the SSwR, i.e. sweat release itself also habituated, and the habituation of both SSR and SSwR were observed to occur symmetrically across the left and right palms. In conclusion, the strong linear correlation between the positive element of the biphasic potential of the SSR and the SSwR leads us to propose that the former may itself provide a quantitative functional measure of sudomotor activity, i.e. the amount of sweat produced in
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