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The effectors: the sweat glands and their innervation. Sweat glands are classified into apocrine and eccrine type, even if the mechanisms of sweat secretion are.
Clin Auton Res (2003) 13 : 256–270 DOI 10.1007/s10286-003-0107-5

Roberto Vetrugno Rocco Liguori Pietro Cortelli Pasquale Montagna

REVIEW ARTICLE

Sympathetic skin response Basic mechanisms and clinical applications

Received: 10 June 2002 Accepted: 9 June 2003

Dr. R. Vetrugno () Dipartimento di Scienze Neurologiche dell’Università di Bologna Via Ugo Foscolo 7 40123 Bologna, Italy Tel.: +39-051/6442-225 Fax: +39-051/6442-165 E-Mail: [email protected]

R. Vetrugno, MD · R. Liguori, MD · P. Montagna, MD Dept. of Neurological Sciences University of Bologna Bologna, Italy

■ Abstract Sympathetic skin response (SSR), defined as the momentary change of the electrical potential of the skin, may be spontaneous or reflexively evoked by a variety of internal or by externally applied arousal stimuli. Although the suprasegmental structures in-

P. Cortelli, MD Institute of Clinical Neurology University of Modena and Reggio Emilia Modena, Italy

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Introduction Electrodermal activity (EDA) reflects sympathetic cholinergic sudomotor function which induces changes in skin resistance to electrical conduction. EDA, assessed by the Sympathetic Skin Response (SSR), has been proposed as an easily obtainable index of sudomotor function [88, 154] and as a sensitive index of bodily arousal related to emotion and attention [15, 41, 60, 184]. SSR was first noted by Tarchanoff [170] who assigned the potential change to modification in the secretory activity of sweat glands independent of the vascular reaction. Shahani et al. [154] first described applications of SSR in clinical neurophysiology. Subsequently skin potentials have been studied in peripheral as well as central autonomic nervous system dysfunctions. SSR is one of the most frequently used measures in psychophysiological studies. We review here the basic mechanisms of sweat production and the functional regulation of

fluencing the SSR in humans are not well known, SSR has been proposed as a non-invasive approach to investigate the function of the sympathetic system. SSR is easy to apply but current procedures are not sufficiently reliable for diagnostic purposes, and show imperfect correlations both with clinical features and other measurements of autonomic, in particular, sudomotor dysfunction. ■ Key words sympathetic skin response · autonomic system · sweating · sudomotor response · neurophysiology

sweating, and the spinal and supraspinal control of the SSR as an introduction to the methods used for recording and the applications of the SSR in the different clinical conditions. Finally we offer some views on the usefulness and limitations of SSR and suggestions for improved procedures.

Basic mechanisms of sweat production ■ The effectors: the sweat glands and their innervation Sweat glands are classified into apocrine and eccrine type, even if the mechanisms of sweat secretion are probably the same [34, 91]. The eccrine gland consists of a tightly coiled corkscrew secretory coil, which secretes an isotonic primary fluid, and a duct which by reabsorbing NaCl, produces a hypotonic sweat onto the skin surface.The secretory part of the apocrine glands is similar but wider and opens on the surface of the skin after

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passage through the epidermis as a straight channel. Apocrine glands arise from hair follicles (epitrichial glands), whereas eccrine glands arise from the epidermis proper (atrichial glands). The eccrine glands are densely distributed over almost the entire body, whereas the apocrine glands are found mainly in the axillae, around the nipples and the pubic area, and in some races, also on the skin of the lower abdomen [147, 148]. Contrary to the eccrine glands, the apocrine glands do not function in neonates [91]. Sweat gland secretion is normally activated by nerve impulses from the sympathetic nervous system [95, 96, 135] although, paradoxically, acetylcholine (Ach) is the transmitter at the neuroeffector junction [38]. Efferent sweat fibers originate in the hypothalamic preoptic sweat center, and descend through the ipsilateral brainstem and medulla to synapse with the intermediolateral cell column neurons. The preganglionic fibers emerge from the anterior roots to reach (via the white rami communicantes) the chain ganglia. Unmyelinated postganglionic sympathetic class C fibers arise from the sympathetic ganglia to join the major peripheral nerves to reach the sweat glands, providing them with cholinergic innervation (Fig. 1). The 2nd to 9th thoracic segments give rise to preganglionic fibers supplying the skin of the upper limbs, the 1st to 4th thoracic segments supply the face and eyelids, the 4th to 12th thoracic segments the trunk and the 10th thoracic to 3rd lumbar segments the skin of the lower extremities, with a significant overlap of innervation in the sympathetic dermatomes. Catecholamines (norepinephrine) [177, 178], vasoactive intestinal polypeptide [103, 179], atrial natriuretic peptide, calcitonin gene-related pep-

Fig. 1 Functional anatomy of sudomotor pathways

tide, galanin [166], and adenosine 5’-triphosphate [27] are present in the periglandular nerves with still unclear functions [75, 102]. These peptides increase sweating when administered locally.Ach action on sweat glands is mediated by intracellular Ca2+ increase. After Ach release and muscarinic receptor binding, an influx of extracellular Ca2+, by activation of receptor-coupled Ca2+ channels, stimulates Cl– and K+ channels, causing a net efflux of potassium, chloride and water. This produces cellular shrinkage with activation of cotransporters that return Na+, K+, and 2Cl– intracellularly, creating an isotonic solution that in turn stimulates Na+K+-ATPase in the sweat duct, resulting in a final hypotonic sweat solution [35, 146, 151]. There is little evidence for noradrenergic innervation of sweat glands yet the glands do respond to intradermal injection of adrenaline; the vasoconstriction accompanying catecholamine-induced sweating is probably of little thermoregulatory significance, the possible role of the adrenergic component being the metabolic control of glandular growth and plasticity [34, 178].

■ Functional regulation of sweating Two types of sweating are generally recognized: thermoregulatory sweating, which occurs over the whole body in response to changes in environment, and emotional sweating (palmar and plantar) which is confined to the palms, axillae and soles of the feet. The two have different and independent rhythmicity due to two different central drives [12, 125, 129]. Eccrine sweat glands are basically thermoregulatory organs, one of the most important effectors of the central autonomic network (CAN) during spontaneous visceral changes associated with homeostatic adjustments. Several lesional and stimulation studies indicate that the preoptic hypothalamic area is an important neural structure in the regulation of body temperature and that there exists a hierarchy of structures extending through the hypothalamus, brainstem, and spinal cord [16, 17, 20, 76]. Preoptic cooling produces shivering, increases heat production [18, 26, 71, 81], and gives rise to a variety of behavioral responses that conserve body heat, including vasoconstriction [16, 18, 63]. Preoptic cooling can also elicit non-shivering thermogenesis [26] by increased metabolic activity in brown adipose tissue [78] and by increased levels of plasma metabolic hormones, including thyroxine [3, 58], catecholamines, and glucocorticoids [4, 65]. Conversely, preoptic warming elicits cutaneous vasodilatation, sweating, panting, and various behavioral responses that enhance heat loss [16, 18, 63, 66, 85, 86]. Within the brain hierarchical structures, the lower brainstem may be viewed as a separate effector controlling thermoregulatory responses [158]. In addition to its great thermosensitivity to changes in core

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temperature, the preoptic region also receives afferent sensory inputs from thermoreceptors throughout the body, including warm and cold receptors in the skin, after spinal cord, trigeminal nucleus, thalamus and midbrain “first-step processing” of afferent impulses [19, 85, 86]. In this way, preoptic neurons compare and integrate central and peripheral thermal information, and orchestrate the most appropriate thermoregulatory final outputs, i. e., skin blood flow variations, shivering, nonshivering, sweat secretion, piloerection, panting, salivation, endocrine responses, seeking shelter, postural changes, use of clothing, etc. Central drive to sweat eccrine glands is synchronous over the general body surface and sweat expulsion is highly related to both the ambient temperature [128] and body temperature [164]. The secretory rhythm is irregular, the rate ranging from several to more than twenty expulsions per minute. Sweat expulsions on the palm and sole may be largely or partly synchronous with those on the general body surface [127]. Microneurographic recordings of skin sympathetic activity reveal that burst discharges coincide with sweat expulsion [165]. Thermoregulatory sweating is also regulated at a segmental spinal level. Sweat reflex inhibition due to pressure on the body surface (hemihydrosis) consists of a remarkable sweating-rate reduction of the side of the body on which the subject lies [168], probably via reflex pathways involving spinal segments [126]. Pressure applied to a peculiar region (axillae or adjacent pectoral region; iliac crest, trochanter and sole) is effective to start the reflex suppression of sweating over the ipsilateral upper or lower body surface, usually with a contralateral increase in sweating. These hemihydrotic reactions have to be kept in mind during experimental studies in man and by considering unilateral hyperhydrosis in patients long confined to bed. Hydromeiosis refers to a local effect due to the constant wetting of the epidermis exposed in a hot and humid environment, when the rate of sweat drippage first increases but then starts to decline after about an hour, until it stops, without changes in the rate of evaporation [28, 130]. In fact, osmosis of water causes swelling of the horny layer and, especially, of the keratin ring in the intraepidermal duct with consequent narrowing and occlusion of the orifices of the sweat glands, subsequent drying restoring sweating in the local area [145]. Emotional (or mental) sweating, especially evident at the palma and planta, is at least in part functionally independent from thermoregulatory sweating. Its control is integrated with emotional, cognitive and neuroendocrine functions and effected at multiple levels within the central nervous system (CNS). At the cortical level, the anterior cingulate cortex (ACC) is prominently implicated in the control of emotional sweating [120]. The ACC has a dorsal and a ventral portion [203]. The dorsal

ACC receives visual sensory inputs from the superior colliculus and directs output to brainstem regions controlling the eye and head movements essential for attentional mechanisms and subserving the orienting response (see later). The ventral ACC has visceral sensory inputs from the nucleus of the solitary tract, dorsal and median raphe nuclei, and parabrachial nucleus (via relays with the mediodorsal and midline parataenial and paraventricular thalamic nuclei) and directs output to brainstem visceral control areas (nucleus of the solitary tract, dorsal motor nucleus of the vagus, nucleus ambiguus) and to sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (visceral pyramidal tract system) [77]. The ACC thus integrates the visceral and somatic responses that are essential both for emotional experience and for the arousal mechanisms involved in attention. The ACC also contributes to emotional sensation: failure to normally differentiate between somatic and visceral responses may cause loss of emotive dynamics [39, 56, 134], as happens in sociopaths or psychopaths [70], a pathological condition called interoceptive agnosia [104, 118]. Arousals, as shown by PET studies, induce metabolic activation of the cingulate gyrus [67], and deficits in selective attention follow anterior cingulotomy [82]. Electrical stimulation of the amygdala, hippocampus, anterior cingulate and frontal cortex modulate the SSR, and functional imaging studies have shown a positive correlation of neural activity in motor and mid-cingulate cortex with SSR in subjects experiencing emotive stimuli [62]. In addition, the cingulate cortex can inhibit attention to nonnovel reverberating stimuli, thus, mediating the socalled “habituation” to monotonous stimuli, and recognizing as relevant only those stimuli necessary for survival [93]. Arousal and emotion govern the so-called orienting response, which consists of rapid eye-head movements directed toward a novel stimulus associated with EEG signs of arousal (desynchronization) and autonomic variations (tachycardia, midriasis) [162]. Emotional (mental) sweating and SSR constitute important autonomic components of the orienting response, occurring any time attention is directed to a novel and significant stimulus. An integrative level below the ACC is represented by the thalamus, which participates in the orienting response by a transition from the rhythmic burst discharges, typical of sleep or drowsiness, to the singlespike firing of thalamo-cortical projections during alert states [163]. Serotonin and norepinephrine systems mediate such thalamic switch of firing from one mode to another [109]. Thus, thalamo-limbic circuits controlling degree of alertness, significance of stimuli and habituation are implicated in the control of emotional (mental) sweating and therefore of SSR. Their physiological state should always be taken into careful consideration any time an SSR is obtained.

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Even though they have distinct basic neuroregulatory mechanisms, thermal and emotional sweating however interact [127].At normal ambient temperature sudomotion is generally present only in palmar and plantar skin sites (emotional sweating). Increasing ambient temperature leads to an orderly recruitment of sweating in nonpalmar and non-plantar skin sites (e. g., thigh and forearm) but emotional and thermoregulatory sweating now coexist, since spontaneous palmar and plantar sweating at an ambient temperature of 40 °C increases even more when the subject is asked to perform stressful mental mathematical calculations [11, 46]. Conversely, palmar (emotional) sweating is influenced by thermal conditions and does not occur when the temperature is low. Recognition of the interaction between thermal and emotional sweating is essential when studying SSR in both physiological and pathological conditions.

The sympathetic response ■ Spinal and supraspinal control of SSR The SSR is a somato-sympathetic reflex with a spinal, a bulbar, and a suprabulbar component, the precise pathways in humans being not yet precisely defined [161, 187, 188]. Many of the localization studies have been performed on the experimental animal, especially the cat. Since the cat’s sweat glands do not participate in thermoregulation [13, 40, 187, 188], these studies are especially interesting for the control of emotional sweating. In 1928, Wang and Richter recorded skin potential changes from the cat’s footpad during hypothalamic stimulation [191]. Subsequent studies showed that several brain regions were involved, including the sensorimotor [190, 196], the limbic cortex [79], the anterior hypothalamus and the brainstem facilitatory reticular system [187, 188, 192, 193]. Reactive sites for evoked SSR extend from the posterior hypothalamus through the ventrolateral reticular formation of the pons and medulla, to the spinal cord. Stimulation of this apparently single continuous efferent pathway elicits bilateral electrodermal response. Crossing most likely occurs at multiple levels, including the brainstem and spinal cord. SSR obtained after lower brainstem stimulation in decerebrate preparations suggests that the reactive loci for eliciting the sudomotor response are self-generating and, at the same time, part of a primarily efferent pathway [40]. Orbitofrontal cortex ablation enhances while removal of the striatum desynchronizes spontaneous SSR [116]. SSR progressively disappears after transection caudal to the superior colliculus [189]. The presence of spontaneous SSR in chronic spinal animals and its absence in animals with transection caudal to the inferior colliculus suggest the existence of a bulbar tonic in-

hibitory center impinging upon sympathetic spinal circuits [142]. Stimulation of the orbitofrontal cortex, caudate nucleus, anterior lobe of the cerebellum and particularly the ventromedial brainstem reticular formation inhibits the SSR [44, 187, 188], while the lack of supraspinal synchronized inputs makes the spontaneous SSR desynchronized and of low intensity in body sites below a thoracic cord lesion [189]. Finally, SSR basically generated by “simple intraspinal circuits” was demonstrated by studies on electrodermal reflexes evoked in acute spinal cats [80]. In humans, studies have shown that SSR occurs independently from sympathetic muscular activity: there is no obvious cardiac rhythmicity and no obvious baroreceptor influence on SSR; on the other hand an arousing stimulus or a deep breath elicit a strong sympathetic skin burst, but sympathetic muscle activity remains unchanged. The same effects can be observed after emotional reactions [11, 45, 46, 69]. Striking variations in SSR are provoked by physiological modifications in vigilance levels, in particular drowsiness and sleep. Broughton et al. [25] noted a progressive increase in spontaneous SSR during NREM sleep (from stage 2, to 3, to 4) compared to wakefulness: SSR could be associated with K complexes, an EEG marker of abortive arousal [84]. REM sleep was instead characterized by minimal spontaneous SSR, often only during bursts of rapid eye movements. During sleep, SSR could be evoked by various stimuli, with the highest threshold during REM sleep. In another study, frequency of spontaneous SSR again increased progressively during NREM sleep with the highest value during stage 4, and diminished during REM sleep. Evoked SSR was possible during light sleep only by electrical stimuli which induced EEG arousal, but not during deep NREM and REM sleep in spite of high intensity and long duration stimuli (Fig. 2) [100]. Functional changes in cortical excitability could explain these findings, since during deep NREM sleep, activity decreases in the centroencephalic regions, cortical paralimbic structures and even more in the heteromodal regions, i. e., the prefrontal cortex and the inferior parietal lobule, severing the limbic areas from other brain regions [22]. In partial contrast,microneurographic investigations during sleep in humans found suppressed skin sympathetic nerve activity during light sleep, with some increase in such activity during slow-wave sleep [169], and Noll et al. [122] showed that intraneurally recorded sympathetic nerve activity did not change significantly during NREM sleep but that K-complexes as well as REM sleep periods were associated with sympathetic bursts followed by transient sympathetic effector responses; in particular, K complexes were associated with increasing blood pressure and vasomotor and sudomotor responses. Thus, the two sympathetic subdivisions, muscular and skin sympathetic nerve activity, seemed to op-

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Fig. 2 Polygraphic recording of SSR from the palm during Wake (A), NREM (B) and REM sleep (C). Unaspected acoustic bruit (marked by ) elicited repetitive SSR (A). K-complex-related SSR during NREM (B) and rapid eye movement-related SSR during REM sleep (C)

erate transiently and simultaneously as in a more primitive type of state-related defence-alarm reaction, not exhibited in the awake state [59].

Recording the SSR: methods and procedures The SSR is easily recorded on most standard EMG equipment. The active silver/silver electrodes are placed

in the palm or sole with the reference over the dorsum of the respective body part, after cleaning the skin surfaces and using electrolyte gels. SSR may also be recorded from the forehead [183], the axilla [7] or the genitalia [55]. The temperature of a quiet dimly lit room is normally kept at 22–24 °C or higher [94, 98, 137, 154, 175, 194], with the subject supine and relaxed. Most laboratories keep the skin temperature at > 32–36 °C [48, 68, 88, 113, 121, 159, 160].

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The low frequency content of the electrodermal potential makes it necessary to set the low-frequency (high pass) filter to as low as possible, 0.1 or 0.5 Hz, with a high-frequency (low pass) filter of 500 Hz (or 1000) Hz being sufficient. Many modalities of stimulation exist (Fig. 3). The stimulus may be an inspiratory gasp, a cough, a loud noise, an electrical shock, or a stroke of the skin; flash or cold pressor test [94], hypodermic “injection” [114] and other forms of somatic or psychic stress can also elicit the SSR. Deep breathing [154] or mixed stimuli (electric and acoustic) [52] may enhance the amplitude of the response. SSR can also be elicited by magnetic stimulation [141]. The most common type of stimulus is an electrical shock delivered at a peripheral nerve, most commonly the median nerve (but electrical stimulation of glabella is also effective [111]), usually on the side opposite the recorded site. The electrical stimulus applied is generally a single square pulse, 0.1–0.2 ms in duration, delivered randomly and at a minimal interstimulus interval > 30 s. The stimulus intensity is normally between 10 and 30 mA, but patients can be asked to indicate when the stimuli are strong and tolerable, or by looking for blinking or slight withdrawal. Individual responses are

Fig. 3 Multiple modalities evoked SSR in the right palm in the same subject. Beginning of the traces is simultaneous with: onset of diaphragm EMG activity (not shown) for cough and gasp; acoustic burst (beep); electrical stimulation (E. S.) at left wrist and Glabella; magnetic stimulation (M. S.) with the center of coil positioned about C3 position of the 10–20 international system

normally studied choosing the best potentials for measurement. Averaging should not be performed, since latency and morphology vary from one recording to the next with a possible phase cancellation. SSR shape consists usually of negative and positive phases [6, 7]. The source of the negative component of SSR is the sweat gland itself [155, 167] and depends directly on its neuronal innervation [173]. The source of the positive component is not fully established [140, 155, 198]. Negative potentials with the same latency as the SSR, without any positive component, have been recorded with microelectrodes placed in the lumen of individual sweat glands during peripheral nerve stimulation or intra-arterial injection of metacholine [155, 167]. This supports the conjecture that the sweat glands generate the SSR negative component. Positive potentials have been recorded in congenital absence of sweat glands [140], and from microelectrodes applied to the epidermal surface of the skin post-mortem, when negative sweat gland potentials were no longer recordable [155]. Furthermore, in an anhydrotic Fabry’s disease female carrier, SSR with negative and positive components were recorded in response to skin sympathetic nerve activity bursts despite complete absence of sweating [197]. This latter observation also begs the question whether SSR reflects the production and migration of sweat towards the lumen of the excretory duct or the sweat expulsion and excretion from the skin. Edelberg proposed the two-effector model, i. e., epidermis-sweat gland unit, like an individual generator-resistance connected in parallel [50, 51]. Response shape is most often either biphasic or triphasic in the hands, and biphasic in the feet; it is seldom monophasic. At the hand, a low amplitude initially negative (upward) deflection is followed by a higher amplitude positive (downward) deflection in > 40 % of healthy adults [7], but an initial high amplitude negative deflection and, rarely, an initial positive deflection are also possible. The amplitude of the SSR is age dependent. SSR is normally present in both hands and feet under the age of 60 years, but in subjects older than 60 years it is found in only 50 % of feet and in 73 % of hands [49]. The SSR potential is susceptible to wide inter- and intra-individual variability [6, 7], environmental influences such as ambient temperature [198], skin potential level [61], skin temperature [64, 98], stimulus strength [6, 74, 198], mental or emotional state [88], arousing stimuli (surprise effect) [52], habituation of response with repeated stimulations and R-C/D-C coupled preamplifier “distortion” [6, 15, 52, 74]. SSR characteristics depend highly on habituation; in particular, the surprise effect and the excitability level of sympathetic neurons are important influencing factors determining the progressive and irregular variability of the responses during long-term experimental evaluations. This is highly

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correlated with the attention level of the subject [13]. Temporal and spatial facilitation are important determinants, which when decreasing (i. e., low attentional level) cause the SSR to fluctuate and vanish. But cognitive adaptation by reducing levels of selective attention [5] is not the only demonstrated mechanism of SSR adaptation. Peripheral components such as low metabolic turnover or a lack of a complete metabolic restoration between stimuli of the sweat glands [29, 90], might also be involved in the progressive modification of the SSR to repeated electrical stimuli, as microneurographic investigation of sympathetic nerve activity indicates [11]. The excitability state of the multisynaptic somatosympathetic circuit involved with sweating can be studied by means of the excitability recovery curve of the SSR, which evaluates at which interstimulus interval applied pairs of stimuli can enhance or suppress the SSR. Manca et al. proposed a procedure consisting of applying pairs of stimuli separated by increasing interstimulus intervals (ISI), i. e., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5 s, and delivered at random intervals never shorter than 30 s to prevent habituation. The amplitude of the SSR evoked by the second (conditioned) stimulus expressed as the percentage of that evoked by the first (conditioning) stimulus (SSR%) is then plotted against the ISIs, giving the SSR excitability recovery curve. In normal subjects, the second stimulus gives no response when the ISI is between 0.5 and 1.5 s, excitability of the SSR being fully recovered at ISIs of 3.5 s. That the onset of excitability recovery takes longer than the duration of the action potential itself was taken as an indication that an active process of inhibition takes place at the level of the CNS. The conditioning stimulus would thus cause initial excitation followed by a period of active inhibition, in the SSR circuit [106].The SSR excitability recovery curve has been proposed as a useful indicator of excitability changes at the level of the CNS structures which integrate the response. A systematic variability in the SSR latency in a circadian fashion has also been reported. The mean latency of SSR obtained in the morning (7:30) was shorter than those obtained at noon and in the evening (18:30), the difference in the latencies between noon and early evening not being statistically significant [21].

SSR: clinical applications Testing and quantifying autonomic nervous system function is an important but difficult area of clinical neurophysiology. SSR is simple, fast, and readily obtainable on most electrophysiological equipment, but it may be difficult to reproduce and obtain consistently. Therefore controversy still surrounds the principal markers of abnormality for SSR. Overall, latency measurements of SSR are of little value, the efferent un-

myelinated fibers accounting for most of the latency, although a slow conduction in the afferent branch of the reflex arc, or central delay in activation of sympathetic neurons, may cause relevant changes. Latency and amplitude normative data of hands and feet SSR should be available in EMG laboratories, but the main clinical consideration remains the presence/absence of the response.

■ Excessive and defective sweating Focal hyperhydrosis is defined as an excessive socially and occupationally disabling sweating, mostly located at the palms and soles, axillae, and face [149, 150]. No consistent results have been reported in this condition with SSR, with occasionally absent palmar response [32], or instead enhanced amplitude and sometimes doublepeak responses to single median nerve stimuli [97]. Excitability recovery curves in palmar hyperhydrosis patients showed an interstimulus interval of SSR recovery onset of 1.5 s, compared to 2.5 s in control subjects [106], suggesting enhanced excitability of the sweating circuit. Botulinum toxin (BTX) blocks the release of Ach in the neuromuscular junction and inhibits cholinergic transmission in postganglionic sympathetic cholinergic fibers to sweat glands [1]. BTX is the first care effective treatment of enhanced sudomotor pathway excitability in palmar hyperhydrosis [117] and its intradermal injection significantly decreases palmar hyperhydrosis, as revealed by image analysis of the iodine starch test and by reduction in amplitude until disappearance of the SSR [143]. It is still uncertain which factor has the most important role in anhydrosis: dysfunction of neuronal elements or abnormal sweat glands. Histopathologic examination showed degenerated eccrine glands associated with surrounding inflammatory cellular infiltration in a patient with acquired idiopathic generalized anhydrosis in whom skin sympathetic nerve activity microneurographically recorded was preserved [115]. Hypothalamic sudomotor center dysfunction may be accompanied by anhydrosis, despite normal eccrine gland histology [157]. A definite SSR has also been obtained despite reduced skin sympathetic nerve activity and complete absence of sweating in an anhydrotic female carrier of Fabry’s disease [197]. Overall, on the basis of current data, recording the SSR in pathological conditions characterized by excessive or defective sweating seems helpful in localizing the lesion to the effector glands or peripheral nerve fibers only when associated with microneurographic recordings in skin nerves.

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■ Peripheral neuropathies (Table 1)

only probably unequivocal abnormality being absent SSR in the palms.

SSR abnormalities have been reported in 66–83 % of diabetic patients, frequency of abnormalities increasing as disease progresses from asymptomatic through symptomatic polyneuropathy to symptomatic autonomic neuropathy [88, 121, 154, 160]. Familial Amyloid Polyneuropathy including carriers of the mutation with normal motor and sensory conduction velocities [112], patients with distal small fiber peripheral neuropathy [57], Hereditary Motor and Sensory Neuropathy type I (HMSN I) [159], Hereditary Sensory Autonomic Neuropathy type IV (HSAN IV) [72], entrapment neuropathies [2, 92, 185], alcoholic subjects [180], scleroderma [138], Sjogren’s disease [119], and other clinical conditions in which there exists a peripheral autonomic nervous system impairment may show abnormal SSR. SSR is abnormal in 45–67 % of patients with chronic renal failure and autonomic dysfunction (hypohydrosis, xerosis, orthostatic hypotension, constipation, hyperhydrosis, diarrhea) [133, 195, 201]. Critical evaluation of the literature on SSR changes in peripheral neuropathies raises several doubts as to its utility. An abnormal SSR could indeed result from abnormal autonomic efferents but also from atrophy of effector sweat glands after chronic denervation and from altered perception (afferent sensory fibers of the arc), all of which are often simultaneously present in peripheral neuropathy. SSR, when obtained alone, cannot discriminate among these different sites of lesions. Moreover, due to the variability inherent in the SSR, only large and well-defined samples of patients in carefully controlled recording conditions may often afford valuable conclusions; in the single neuropathic patient, SSR is unlikely to be of diagnostic value, the

Table 1 SSR in peripheral neuropathy (HMSN I hereditary motor and sensory neuropathy type 1; HSAN IV hereditary sensory autonomic neuropathy type IV)

■ Central nervous system diseases In humans, lesions to the amygdala impair skin conductance responses during aversive conditioning and reward-related feedback [10], but not in response to unconditioned aversive stimuli [171]. Impaired SSR has been reported in patients with discrete lesions of the right hemisphere [132, 204], the ventromedial prefrontal bilateral cortex, bilateral anterior cingulate gyrus, and right inferior parietal lobe [172]: these data imply a sympathetic brain lateralization prevailing in the right hemisphere [73, 131, 202]. In this regard, functional magnetic resonance imaging showed an association between arousal-induced sympathetically mediated SSR and activity predominantly localized in the right orbitofrontal cortex and right anterior insula, confirming a right hemisphere sympathetic lateralization [36]. Studies on Parkinson disease (PD) have shown qualitative and quantitative SSR abnormalities, including loss of response [14, 194]. SSR alterations seem to correlate with severity of motor disability [14, 23] and the side of the lower amplitude SSR corresponds to the side more affected by disease [83]. Indeed, in patients with asymmetrical PD, a significant increase in SSR latency and decrease in SSR amplitude was found on the more severely affected side, regardless of the side of stimulation, and only SSR values from the side with more severe motor symptoms differentiated PD patients from control subjects [42]. Absent or abnormal SSR has been found in multiple system atrophy (MSA) [14, 139, 200], with longer latency and smaller amplitude of the responses

Familial amyloid polyneuropathy HMSN I HSAN IV Diabetic neuropathy

Alcoholic neuropathy Chronic renal failure Small fiber peripheral neuropathy Scleroderma

Sjögren disease Entrapment neuropathies

SSR absent in symptomatic patients; significantly reduced amplitude in asymptomatic mutation carriers [112] Delayed latency, reduced amplitude; SSR absent in 5/15 patients [159] Reduced amplitude; thermal SSR absent [72] SSR usually absent [154] or significantly reduced in amplitude [88] in axonal diabetic neuropathy; absent at foot in 66 % and hand in 28 % of patients [160]. No correlation with clinical dysautonomia [154] or with EMG or clinical dysautonomia, but correlation with abnormal R-R expiratory/inspiratory ratio and pupil cycle [160] SSR absent in the fingertips (but not palma) in 18/70, and in feet in 37/70 patients [180] SSR abnormal in 45 % of patients [201] Reduced amplitude [57] SSR abnormal in 22/32 patients; no correlation with localization, degree and character of skin changes, duration of disease, clinical dysautonomia and changes in capillaroscopy [138] SSR absent in either hand and foot, even with normal autonomic cardiovascular tests and pupillary cycle [119] SSR absent only in 3/76 carpal tunnels [185]

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when compared to PD and control subjects [14, 42]. Sympathetic cholinergic dysfunction on the side with more severe motor symptoms in PD, as well as in MSA, supports the hypothesis of a preganglionic sympathetic dysfunction [47]. Nevertheless, in patients with autonomic failure syndromes such as MSA and progressive autonomic failure, abnormalities are detected in only 88 % of patients and SSR is not useful alone in distinguishing between clinical subtypes [9, 105, 139]. In dopamine-beta-hydroxylase deficiency patients, who have intact sudomotor function, SSR is normal [105]. Thus, SSR should be used only as an additional test for the evaluation of sympathetic degeneration in patients with MSA and PD, and although motor symptom asymmetries correlate with interside asymmetries of SSR [23, 42], the latter does not evaluate the site of lesions in sympathetic efferent pathways. Thermoregulatory sweating in patients with multiple sclerosis (MS) corresponds to some extent to MS severity [31, 123] with a direct relationship between sweating dysfunction and the presence or absence of impaired sexual potency [31, 182]. In 28 patients with definite MS, 75 % had abnormal SSR, more in the soles than palms [199]. The prevalence of SSR abnormalities was as high as those of somatosensory (79 %) and visual evoked potentials (75 %). Out of 70 MS patients, SSR was abnormal in 94 % [53]. Autonomic dysfunctions, including abnormal SSR, in MS appeared to be more closely related to axonal loss, i. e., spinal cord atrophy, as correlation with spinal cord MRI findings demonstrated [43]. Tetraplegic patients and patients with a thoracic spinal cord injury (higher than T6) are prone to autonomic dysreflexia below the level of the lesion due to the loss of supraspinal control of spinal sympathetic centers [108]. SSR has been found abnormal in the lower limbs of humans after spinal cord injury [199] and abolished in the hands or feet of tetraplegic patients with traumatic spinal cord lesions, with a close correspondence, for paraplegic patients, between SSR abolition and the level of the dorsal spinal cord lesion [54]. Moreover, among patients with spinal cord lesions no patients with complete tetraplegia displayed normal SSR potentials in the hands and feet and no patients with preserved SSR potentials showed symptoms of autonomic dysreflexia either clinically or during urodynamic examination [37], supporting the hypothesis that the spinal cord completely isolated from the brainstem cannot generate an SSR in humans [30]. Patients with lateral medullary syndrome showed heterogeneous SSR abnormalities, poorly related to the clinical sensory manifestations and MRI findings [33, 87, 124, 144, 181]. A case study reported reduced amplitude of the SSR in one patient with amyotrophic lateral sclerosis (ALS) [8], but this finding is inconclusive due to age-related variations and the fact that the plantar response may be

absent in up to 50 % of normal subjects over 60 years of age [49]. Current opinions hold that in ALS SSR can become altered in the last phase of the degenerative process and does not indicate the presence of a “primary” autonomic dysfunction [110]. Absent SSR in patients with fatal familial insomnia, a prion disease with prominent abnormalities of sleep and severe loss of neurons and gliosis of anterior and dorsomedial thalamic nuclei (thalamus limbicus) [113] confirmed the relevance of the vigilance status for SSR. Likewise, studies performed in stroke patients have shown the importance of the integrity of the cerebral cortex for the SSR, and of brainstem structures, with a correlation between patients’ level of consciousness and the absence or presence of evoked SSR [89, 136, 176]. In comatose patients with stroke, SSR may disappear bilaterally after stimulation of the hemiplegic side and persist bilaterally after stimulation of the normal side, suggesting an involvement of central afferent pathways or temporary suppression of suprasegmental excitatory influences. Nevertheless deep inspiration ability to elicit SSR in stroke patients indicates that reticular structures remain functional, since evoked SSR require the integrity of neural mechanisms underlying arousal but not a functioning cerebral cortex. Indeed, SSR has been related to the outcome from post-traumatic vegetative state, with early greater SSRs associated with better potential recovery [174]. In 11 patients with chronic coma and normal hypothalamus and brainstem MRI, normal SSR were found in all six patients with brainstem arousability, i.e., persistent vegetative state, whereas no response was elicited in all five patients without brainstem arousability, evoked SSR supporting preservation of brainstem arousability in the assessment of unconsciousness state. It was acknowledged, however, that the prognostic value of SSR in coma must await further larger studies [99]. From a critical review of the literature, it appears that it is difficult to judge the diagnostic and prognostic significance of the SSR in the single patient with CNS lesions due to the vagaries of lesion localization, interference from associated medications and other confounding technical factors. Again, SSR changes usually became significant only when large cohorts of patients were compared to control populations. SSR must still remain more a research than a diagnostic tool in the assessment of CNS lesions, even though it shows some promise in the definition of disturbances of vigilance.

■ SSR versus other measures of sudomotor activity Sudomotor activity may be measured by other tests, i. e., the thermoregulatory sweat test (TST), the quantitative sudomotor axon reflex test (QSART) and the silastic imprinting method (SIM) [101]. TST provides information on the distribution of sweat activity. SIM provides an

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evaluation of the single sweat glands with morphometric analysis, QSART a dynamic quantification of sweat output, and together evaluate the dynamic function of sweat gland units. SIM depends on the function of directly stimulated sweat glands, whereas QSART on the integrity of the axon reflex rather than sweat gland function since it evaluates a longer pathway (sympathetic C fiber – branch point – sympathetic C fiber) and often allows detection of sudomotor failure before SIM. Because of their different physiological meaning, there is often no correlation among all these laboratory measures, and no consistent data in the literature comparing these different methods and SSR. TST may be diagnostic, in spite of normal SIM and QSART, as happens in diabetic neuropathy and thoracic radiculopathy without distal anhydrosis. TST and QSART together may define the site of the lesion causing anhydrosis (pre- versus post-ganglionic). SSR may have a sensitivity comparable with the QSART [107] in patients with diabetic neuropathy. Nevertheless, the correlation between SSR and autonomic dysfunction in these patients is not as strong as for QSART, SSR depending on a polysynaptic reaction and reflecting dysfunction of many portions of the neuraxis, while QSART explores only the function of the postganglionic sudomotor nerve [24, 152, 153, 156].

Conclusions SSR as a diagnostic test used to evaluate sudomotor function presents several problems, some still unsolved: the pathway is still unclear; the response readily habituates and is unpredictably absent in normal and in neuropathic subjects; there may be incomplete reactions to inappropriate stimuli. In pathological conditions, there is often no relationship between SSR and symptoms of dysautonomia. Many centers use SSR to evaluate sympathetic cholinergic function but correlation with more generalized sympathetic denervation or deranged reflexive regulation of sympathetic outflow are often poor. A normal SSR cannot exclude a defective sympathetic noradrenergic function, and symptoms of dysautonomia frequently reflect dysfunction of autonomic nerves other than skin sympathetic nerves including sudomotor fibers. Unfortunately, small unmyelinated nerve fibers which control many autonomic functions are in-

accessible to direct neurophysiologic recording except by microneurographic techniques which are carried out only in specialized laboratories [186]. SSR, which is obtainable by simple techniques, may thus seem an easy short-cut. However, SSR is deceptively “simple”. There are at least two basic considerations that need to be taken into account any time SSR is employed in the diagnostic evaluation of sudomotor function. First that, since we are dealing with a sensory-autonomic reflex, the sensory branch of the arc must be assessed and optimally found normal. Indeed, in order to evoke SSR, a stimulus must be felt, and sensory thresholds should be analyzed or considered: a stimulus of intensity sufficient for a normal SSR in a normal person, could still evoke a normal SSR in a hyposensitive patient if the amplitude of the stimulus were corrected for the sensory loss. The same consideration applies to patients with sensory loss due to CNS lesions. A normal sensory branch would ensure that abnormal SSR reflects alteration in the efferent mainly unmyelinated axons or the central delay portion only of the reflex arc. As regards the latter, more attention should be paid to emotional and vigilance levels, by means of objective monitoring of the degree of alertness. We end this review, aimed at providing a schema of the different factors implicated in SSR variability and an assessment of its utility in clinical practice, with the following recommendations to be implemented whenever SSR is obtained in the neurophysiological laboratory for diagnostic purposes:  The sensory status of the patient, and in particular of the anatomical region stimulated, should be evaluated, and sensory thresholds for that particular technique and stimulation intensities for SSR reported;  Vigilance levels should be assessed by concurrent EEG or other reliable measurements of vigilance level. Moreover, as the SSR depends at least in part on the integrity of the peripheral effector, the sweat glands, some consideration should also be offered to the status of the local skin and the annexes, which are so easily affected in many and diverse neurological conditions. Together with strict control of body and ambient temperature, stimulus characteristics and habituation, observance of these recommendations could improve the reliability and clinical value of SSR.

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