Clin Auton Res (2004) 14 : 107–112 DOI 10.1007/s10286-004-0170-6
Bruno Estañol Marco Vinicio Corona Yolanda Elías José Francisco Téllez-Zenteno Oscar Infante Guillermo García-Ramos
■ Abstract Skin blood vessels and sweat glands are both innervated by sympathetic C fibers. We investigated whether during diverse respiratory maneuvers the vasomotor responses (VRs) and the sympaReceived: 25 June 2003 Accepted: 14 November 2003 B. Estañol · M. V. Corona · J. F. Téllez-Zenteno · G. García-Ramos Clinical Neurophysiology Laboratory Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán México City, México B. Estañol, M.D. () Cerro Chinaco 139 Colonia Campestre Churubusco, México City, 04200, México Tel.: +52-55/683450 Fax: +52-55/688460 E-Mail:
[email protected] O. Infante Dept. of Medical Instrumentation National Institute of Cardiology México City, México Y. Elías National Institute of Communication Disorders México City, México
RESEARCH ARTICLE
Sympathetic co-activation of skin blood vessels and sweat glands
thetic skin responses (SSRs) were frequently or occasionally co-activated. We simultaneously recorded the amplitude of the vasomotor responses and the sympathetic skin responses, the ECG and the respiratory movements in 30 healthy subjects during natural breathing at rest, rhythmic respirations at 6 per minute, sudden deep inspiration and Valsalva maneuver. We found: 1) The SSR habituates with all respiratory maneuvers whereas the VRs do not habituate. 2) There was slight co-activation between the SSRs and VRs during natural default breathing (56 percent). 3) During rhythmic breathing at 6 per minute the VRs and the SSRs were frequently co-activated (97 percent). The SSR appeared at the end of the inspiration coinciding with the end of the decreased blood flow. However the SSR habituated after few rhythmic respirations. 4) During sudden deep inspiration one hundred percent of co-activations were between the initial phase of the VRs and the SSR. The SSR is large in amplitude and
Introduction
■ Key words vasomotor responses (VRs) · sympathetic skin response (SSR) · co-activation · skin blood flow (SBF) · respiratory frequencies · nonrespiratory frequencies
transfer of heat, whereas the sweat production controls evaporative heat [12]. The innervation of the sweat glands, however, is cholinergic, whereas the innervation of the blood vessels is noradrenergic [7]. Thus the innervation to these structures appears to be differentiated. The conduction velocity of the postganglionic sympathetic nerves in humans has been calculated to be
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The sympathetic efferent system innervates different skin structures including the eccrine sweat glands, the skin blood vessels and the piloerector muscles [14]. The skin blood flow (SBF) mainly regulates the convective
longer in duration than during rhythmic breathing. 5) During the Valsalva maneuver there was a strong co-activation (100 percent) particularly during the phases II and III that are characterized by vaso-constriction but also during phase IV. The SSR is the longest of duration in all of the maneuvers. The sympathetic innervation to the sweat glands of the palm of the hand and to the skin blood vessels of the fingertips is differentiated. Under normothermic conditions sudden deep inspiration and Valsalva maneuver induced a large sympathetic simultaneous outflow to the skin blood vessels and sweat glands. The simultaneous recording of skin blood flow and the SSRs provides a more complete assessment of the sympathetic outflow to the skin than either one alone.
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0.7 to 1 m/s for cutaneous vasoconstrictor axons and 1.2 to 1.4 m/s for sudomotor axons [12]. It has been known for several years that sudden inspiration and the Valsalva maneuver induce skin vasoconstriction [1, 5, 8, 9] and at the same time they may elicit a sympathetic skin response (SSR) due to activation of the sweat glands [2, 3]. It has been possible to record selectively with microneurographic recordings the sympathetic nerve discharges to the sweat glands and the sympathetic nerve discharges to the skin blood vessels [22]. The sweat glands of the palm of the hands may discharge selectively to emotional changes [4], whereas the skin blood flow has been mostly related to temperature changes and arousal but also to emotional changes and respiratory movements [4]. One important difference is that the SSR has been known to habituate [10, 15, 19]. We were interested in finding out whether the SBF and the SSR are co-activated and under what circumstances. As several respiratory maneuvers are known to induce synchronous sympathetic nerve discharges to both structures we studied simultaneously the SBF and the SSR to determine their relationship. We decided to study the coactivation of the skin blood vessels and eccrine sweat glands because we were looking for non-invasive approaches to the study of the skin sympathetic unmyelinated C fibers. These methods may be potentially useful in the study of several central and peripheral central nervous system disorders including peripheral neuropathies and some microvascular skin disorders such as the Raynaud’s phenomenon [6].
Subjects and methods ■ Subjects We studied 30 normal subjects without a history of peripheral or central neurological disease, 18 were females (60 %) and 12 were males (40 %); ages ranged from 18 to 45 years. Inclusion criteria Inclusion criteria required that patients have no history of peripheral or central nervous system disease. On the day of the study, the subjects had no coffee, tobacco and had a light breakfast. The studies were performed between 8 and 11 a. m. They did not ingest any medications, in particular anticholinergics or adrenergic agents.
We measured the following variables: 1) heart rate (HR); 2) respiratory frequency (RF); 3) skin blood flow (SBF); 4) sympathetic skin response (SSR). The SBF was measured with a high resolution infrared photoplethysmograph that had one LED in the band of 640 ± 20 nM, an infrared LED in the band of 960 ± 20 nM and, in the middle, a phototransitor to capture the signal of the hemoglobin and deoxihemoglobin. The whole recording system is 2.1 cm in length and 0.7 cm wide. The photoplethysmograph is run with a 9 V battery to avoid the A. C. 60 Hz current artifact. We have previously used the system in studies with more than 50 normal subjects at rest [11], during several respiratory maneuvers [16] and during muscle contraction [17]. The response appeared to be linear in relationship to a respiratory stimulus. The signal response could be reduced by decreasing the sensitivity in such a way that the response does not saturate in amplitude. The photoplethysmograph was placed on the pad of the forefinger that was kept at the heart level. The signal of the photoplethysmograph was fed into the amplifier of the digital polygraph. The systolic amplitude of the signal was measured in µV. The amplitude was measured before, during and after the maneuvers. The signal was filtered at 75 Hz and we used a time constant of 0.032 seconds. The signal we obtained was of high quality. The impedance was kept below 5 K Ohms. The ECG signal was obtained with two electrodes located over the sternum. The respiratory movements were measured with a pneumograph adapted with a piezo-electric crystal that was placed on the thoraco-abdominal junction. The time constant was kept at 1 second. The SSR was recorded on the palm of the hand on the same side we measured the SBF. The active electrode was a 10 mm diameter gold electrode that was placed on the palm of the hand; the reference electrode was placed on the dorsum of the hand. The ground electrode was placed on the forearm. The time constant was set at 1 second and the high frequency filter at 35 to 15 Hz. The gain was adjusted at 50 to 100 µV. The impedance was kept below 5 K Ohms. In general, we followed the technique of Shahani [19] and Uncini [20] to obtain the SSR. The responses we obtained were of good quality. A basal recording was obtained during 5 to 10 minutes of rest. After this time the subjects were asked to make a sudden deep inspiration of 3 seconds duration. This maneuver was repeated three times with an interval of two minutes between each inspiration. A period of three minutes of rest was followed by rhythmic breathing at 6 cycles per minute (0.1 Hz, 5 seconds inspiration, 5 seconds expiration) during one minute. The maneuver was repeated three times with an interval of rest of 2 minutes between each. After a period of 5 minutes rest, three Valsalva maneuvers were performed. The subjects were asked to make a deep inspiration and thereafter through a mouth piece to elevate the column of a sphigmomanometer to 40 mmHg during 15 seconds. A period of 2 minutes rest was allowed between each maneuver. We measured: 1) the presence of the SSR during breathing at rest and during each respiratory maneuver; 2) the duration of the SSR; 3) the amplitude of the SBF in µV at rest, and before, during and after each maneuver; 4) amplitude of the photoplethysmographic signal at which the maximum decrease of the SBF was obtained; 5) time of recovery of the decrease SBF; 6) percentage of decrease of the SBF with the following formula: basal SBF-minimum SBF/basal SBF x 100; 7) the relationship of the SSR to the respiratory movement.
■ Methods The subjects were reclined in an armchair. They were asked to be alert to the indications and not to move. The temperature of the fingers was monitored and kept between 30 and 35 °C. The room was semidarkened and quiet. The temperature of the room was kept between 24 and 27 °C. The temperatures of the extremities and the ambient temperature were recorded at the onset and the end of each maneuver. For recording we used a digital polygraph machine of 32 bytes (Cadwell, Easy Lab V1.5, USA) with a sampling rate of 400 Hz. The records were stored on the hard disk for further analysis. The sweep speed was adjusted at 30 mm/s but sometimes we also used 10 mm/s.
Results Under normothermic conditions the SSR appears apparently at random during normal default breathing at 0.2–0.3 Hz (12–18 cycles per minute). We found the response at least once during breathing at rest for 5 minutes in 57 percent of the subjects (Table 1, Fig. 1). However on close inspection of the records we found it frequently related to a respiratory change either in fre-
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Table 1 Presence of sympathetic skin responses with various respiratory maneuvers (n = 30)
Presence SSR (%) Duration SSR (sec)
Natural Breathing (NB)
Forced Breathing (FB)
Sudden deep inspiration (SDI)
Valsalva maneuver (VM)
57
93
100
100
6.3±1.0*
6.4±1.5
7.8±2.4*
8±2.5*
P
0.009
* Difference significant using Tukey’s test
Fig. 2 The duration of the SSRs during the four respiratory maneuvers are shown. There is a tendency to increase the duration of the response with each successive maneuver. The greatest difference was found between the SSR during natural breathing (6.4 ± 1.5 s) with the duration during SDI and VM (8 ± 2.5 s) (NB natural breathing; FB forced breathing; SDI sudden deep inspiration; VM Valsalva maneuver)
Fig. 1 Spontaneous breathing. First trace the ECG, second trace the photoplethysmographic signal of the SBF (PLET), third trace respiratory movements (RESP), fourth trace the sympathetic skin response (SSR). There is no coupling of the SSR and the VMrs with normal breathing at 18 cycles per minute (0.3 Hz)
quency or in depth such as a sigh or cough. Other times it could not be related to any physiological event. When it could be related to a respiratory movement it had a mean duration of 6.3 ± 1 s (Fig. 2). During rhythmic breathing at 6 cycles per minute (0.1Hz), the SSR was present in 97 percent of the subjects (Table 1, Fig. 3). The SSR appears at the end of the inspiration coinciding with the end of the decreased SBF.However we found that the SSR habituates decreasing in amplitude with each cycle whereas the VRs do not habituate. In general the largest amplitude is seen with the first respiratory cycle and it tends to decrease in size gradually and disappear. We found a SSR under this condition to have a duration of 6.4 ± 1.5 s (Fig. 2). The SBF decreased with the inspiration and increased with expiration. During sudden deep inspiration there was a constant co-activation (100 percent) between the initial phase of the vasomotor responses and the SSR (Table 1). The SSR was longer in duration with sudden deep inspiration than during rhythmic breathing (Fig. 4, Table 1). The mean duration of the SSR was 7.8 ± 1.5 s (Fig. 2). During the Valsalva maneuver there was a strong coactivation (100 percent) particularly during the phases II and II that are characterized by vasoconstriction (Table 1). The SSRs have the largest amplitudes under
Fig. 3 Forced breathing at 6 cycles per minute. First trace the ECG, second trace the photoplethysmographic signal of the SBF (PLET), third trace respiratory movements (RESP), fourth trace the sympathetic skin response SSR. It shows the presence of the SSR during each cycle of respiration coupled to the changes in skin blood flow
this condition. They frequently lasted during the whole period of the maneuver including phase IV (Fig. 5). The mean duration was 8 ± 2.5 s (Table 2, Fig. 2). When we compared the duration of the SSR between the four maneuvers with ANOVA, we found a statistically significant difference between the duration and amplitude of the responses during natural breathing (6.7 ± 0.7 s) vs. sudden deep inspiration (7.8 ± 2.4 s) and Valsalva maneuver (8 ± 2.5 s). The SBF was decreased 36 percent during natural breathing at rest, 56 percent during rhythmic breathing, 60 percent during sudden deep inspiration and 73 percent during the phase II and III of the Valsalva maneu-
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ver (Table 2). The decrease in the SBF coincided with the appearance of the SSR (Table 2).
The maximum decrease of the SBF was seen 8 beats after the onset of the sudden deep inspiration and 14 beats after the onset of the Valsalva maneuver (Table 3). The recovery of the SBF was observed 17 beats after the onset of the deep inspiration and 6 beats after the termination of the Valsalva maneuver (Table 3). When we compared the maximum decrease of the SBF during sudden deep inspiration vs. the maximum decrease during the Valsalva maneuver, a statistically significant difference was found (p < 0.001). Finally, there was a striking decrease of the SBF during phases II and III of the Valsalva maneuver and an increase of the SBF during phase IV. The Valsalva maneuver index was found to have a mean 1.8 ± 0.3. The SSR habituated with rhythmic breathing while the SBF did not.
Discussion Fig. 4 Sudden deep inspiration (SDI). There is a simultaneous appearance of a decrease of the SBF and the SSR (co-activation). There is an initial tachycardia coinciding with the decrease SBF followed by a persistent decrease of SBF without a tachycardia. The SSR coincides with the tachycardia phase and the initial decrease of the SBF
The sympathetic innervation of the skin blood vessels and sweat glands is differentiated [7,12].Skin blood flow innervation is adrenergic with α–2 adrenergic receptors present [22], whereas the innervation of the sweat gland is cholinergic [10, 15, 19]. The conduction velocity is also slightly different [12]. However they have several things in common. Both are related to temperature homeostasis [2, 3, 12, 14, 21]. The skin blood vessels are highly sensitive to temperature changes and arousal [21]. The SSR
Table 3 Beats of maximum decrease and recovery of SBF with sudden deep inspiration and Valsalva maneuver (n = 30) Sudden deep inspiration
Fig. 5 Valsalva maneuver. The SSR is present at the onset of the maneuver and lasts during the whole phase II during the tachycardia phase. The SSR is large in amplitude and long in duration
Table 2 Skin blood flow during several respiratory maneuvers (n = 30)
Valsalva maneuver
P
Beat of maximum decrease of SBF after the beginning of the respiratory maneuver
8 (9–12)
14 (9–20)
< 0.001
Beat at which the recovery occurs after the beginning of the respiratory maneuver
17 (11–20)
6 (3–9)
< 0.001
We used beat 1 as the first beat after the maneuver
Natural Breathing (NB)
Forced Breathing (FB)
Sudden deep Inspiration (SDI)
Valsalva Maneuver (VM)
P
Basal SBF (mcV)
189.6±32.7
168.1±26.5
151.3±24
156.8±24
> 0.050
Maximal decrement of SBF (mcV)
121.4±34*
74.8±31.8
Percentage of decrease (%)
35*
56
62.2±21*
42.6±16.5*
< 0.001
60*
73*
< 0.001
* When we compared the maximum decrease of the SBF and the percentage of decrement with the Tukey test we found a highly significant statistical difference between natural breathing (NB) vs. sudden deep inspirations (SDI) and Valsalva maneuver (VM) (P < 0.001)
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is also sensitive to arousal and attention [10, 15, 19, 20]. Both, the VRs and SSRs are highly sensitive to several respiratory maneuvers [2–4, 7–10, 12, 15, 19–21]. We found that during natural breathing at rest and during normothermic conditions the SSR appears at random and infrequently. Its appearance may be related to changes in the frequency of breathing, cough, sighs, movements, noises, verbal instructions, and some other unknown factors. During forced paced breathing at 6 cycles per minute (0.1Hz) there is co-activation of the SSR and the vasomotor responses. The SSR usually appears during the tachycardia phase, that is during the inspiration. The fundamental difference between vasomotor responses and SSR is that the SSR habituates whereas the VRs do not seem to habituate. This suggests that both have a different central type of processing. The first SSR response is usually the largest in amplitude and the longest in duration. Sudden deep inspiration induced consistent co-activation of SSRs and VRs with each maneuver, provided it is done at least one minute apart. The SSR induced by sudden deep inspiration is larger in amplitude and duration than the one induced with rhythmic breathing. The SSR during sudden deep inspiration is time-locked with the phase of decreased skin blood flow. During the Valsalva maneuver the largest and longest SSR appears. It may last during the four phases or may be present only during phase I, II and III. In summary the simultaneous recording of the SBF and the VRs allows the non-invasive assessment of the co-activated sympathetic outflow to the skin. Under
normothermic conditions the SSR and the VRs are not associated while breathing at rest. During paced breathing there is a consistent co-activation of both responses but the SSR habituates while the VRs do not. Under this condition, the SSR appears frequently during the tachycardia phase of the sinus arrhythmia, which is also the time of the decrease of SBF. Sudden deep inspiration and Valsalva maneuver induce the most consistent co-activation of the SSR and the VRs and the largest and longest responses. Sudden deep inspiration and Valsalva maneuver induce a very strong sympathetic innervation to the skin blood vessels and sweat glands. These observations may be true only for glabrous skin under normothermic conditions. It has been shown that under a temperature rise from 25 °C to 34 °C both sudomotor and vasoconstrictor components in microneurographic recordings of the peroneal nerve are enhanced whereas both were suppressed in the tibial nerve (glabrous sole of the foot) [18]. The simultaneous recording of the skin blood flow and SSR may be useful for the assessment of diseases that have sympathetic damage to the extremities. However, the responses are differentiated. The simultaneous recording of SBF and the SSRs provides a more complete assessment of the sympathetic outflow to the skin than either one alone. A sudden deep inspiration is perhaps the simplest and most consistent maneuver that produces the co-activation of SBF and SSR provided it is given one minute apart to avoid habituation of the latter.
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