Vibration-evoked sensory nerve action pontentials derived from Pacinian corpuscles

Electroencephalography and clinicalNeurophysiology, 89 (1993) 278-286 © 1993 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/93/$06.00

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Vibration-evoked sensory nerve action potentials derived from Pacinian corpuscles Toshiaki Hamano a, Ryuji Kaji a, Alejandro F. Diaz b Nobuo Kohara ", Nobuyuki Takamatsu c, Tatsumi Uchiyama c, Hiroshi Shibasaki d and Jun Kimura Department of Neurology, Faculty of Medicine, Kyoto University, h Department of Neurology, Unit,,ersity of Santo Tomas, ' NEC San-ei Instruments, Ltd., and a Department of Brain Pathophysiology, Faculty of Medicine, Kyoto University, Kyoto (Japan) (Accepted for publication: 5 February 1993) Summary

To evaluate sensory response to natural stimuli, we developed a method to record sensory nerve action potentials evoked by high-frequency vibratory stimulation. Trains of 250 Hz sinusoidal indentations with a duration of 100 msec were applied to the finger tip at a rate of 3 Hz. The responses were obtained with surface electrodes placed over the median and ulnar nerves at the wrist. Averaged wave forms consisted of two components: an initial diphasic or triphasic potential and the following low amplitude trains of discharges phase-locked to vibratory stimuli. Anesthesia of the skin at the stimulation site or tourniquet-induced ischemia of the limb eventually diminished both components. Neither of them therefore represented artifacts from electrode movement or electromagnetic field intrinsic to the stimulator. Various kinds of mechanoreceptors may contribute to the first component. Pacinian corpuscles probably give rise to the second component as the only skin receptors that can respond to high-frequency vibratory stimuli of 250 Hz. This method helps examine neural coding of the receptor and the peripheral nerve fiber mediating vibration sense. Key words: Mechanoreceptor; Neural coding; Sensory nerve action potential; Pacinian corpuscle: Vibration sense; Vibratory stimulation

Electrical stimulation of the peripheral nerve is one of the most useful tools in the diagnosis of neurological disorders. This method, however, differs from physiological stimulation such as pain, cold and touch in stimulating all the nerve fibers irrespective of the modalities of receptors, and it provides no information about the most distal branches of the nerve and their connection to the receptors, which are actually the first to be affected in dying-back neuropathies (Sumner 1978). With this method, therefore, early manifestations of such neuropathies may escape detection. In addition, electric shocks do not allow high-frequency stimulation because of the associated pain, although the frequency-related conduction block is an important finding in demyelinating lesions (Kaji et al. 1988). To overcome these technical constraints in electrical stimulation, mechanical stimulation of the skin receptors with electromagnetic transducers was employed (Sears 1959; Bannister and Sears 1962; McLeod 1966; Pratt et al. 1979; Buchthal 1980), although some of the

Correspondence to: Ryuji Kaji, M.D., Ph.D., D e p a r t m e n t of Neurology, Kyoto University Hospital, 54 Shogoin, Sakyoku, Kyoto 606 (Japan). Tel.: 075-751-3772; Fax: 075-761-9780.

responses recorded in earlier studies were regarded as artifacts (Pratt et al. 1979). Recently air-jet has also been used for selective stimulation of the mechanoreceptors (Schieppati and Ducati 1984; Hashimoto et al. 1989). These methods, however, do not allow the analysis of the specific sensory information from a single class of receptors, because they activate various kinds of mechanoreceptors simultaneously. Among the modalities of mechanoreception, vibration sense is unique in that information on the stimulus frequency is exactly encoded as the discharge frequency of the receptor and the nerve fiber (Hunt 1961; Talbot et al. 1968; Schmidt 1986). Therefore vibratory stimulation may provide an ideal tool to investigate the physiological mechanism underlying the neural coding of sensory information. Previous recordings of the electric activities induced by the mechanical stimuli used microelectrodes inserted into peripheral nerves (Talbot et al. 1968; Knibest61 and Vallbo 1970; Knibest61 1973; Johansson and Vallbo 1979), the spinal cord (Douglas et al. 1978) or the brain (Mountcastle et al. 1969; Herron and Dykes 1986), but their clinical application has been limited. In this article, we report a non-invasive method to record the sensory nerve action potentials evoked by high-frequency vibratory stimuli, which provides an electrophysiological tool to evaluate vibration sense

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quantitatively and to investigate the neural coding by the receptor and the peripheral nerve.

Methods and materials

(1) Subjects The experiments were conducted in 8 healthy volunteers (7 men, 1 woman), aged 28-37 years (mean 32 years). Informed consent was obtained from every subject after the study was explained in full.

(2) Mechanical stimulation (Fig. 1) A mechanical stimulator described by Brown et al. (1973) was adopted in a modified form. A loudspeaker was used to drive a stimulating probe. One end of the probe was glued to the center of the speaker cone, and a plastic disk (10 mm in diameter) was attached to the other end of the probe. A flag which was fixed to the probe shaft cut off a variable amount of light as a function of the cone movement. Detecting the amount of light passing through the flag by a photocell served as a monitor of the probe displacement. To generate sinusoidal movement of the probe, a train of square electric pulses was fed to the loudspeaker using a pulse train generator (SEN-3301, Nihon Kohden, Tokyo, Japan). As the vibratory stimuli, a train of 25 cycles of 250 Hz sinusoidal indentations (total duration 100 msec) was delivered to the finger tip via the plastic disk at a rate of 3 Hz. The stimulus intensity was measured as the probe displacement with a microscope. Unless otherwise specified, the intensity of 40 p~m was used, which was the maximum displacement that could be attained at 250 Hz with the stimulator.

hand of the subject was put on a urethane pad attached to the edge of the table with the digit to be stimulated projecting out of the pad. A pair of disk electrodes, 9 mm in diameter, was placed 3 cm apart over the median or the ulnar nerve at the wrist. A ground strap was wound around the hand. Electrode impedance was kept below 5 k J2. For recording responses and data analysis, an E M G machine (Neuropack 8, Nihon Kohden, Tokyo, Japan) was used. Signals were amplified with a bandpass of 20-1000 Hz. The sampling rate for averaging was 5 kHz. The analysis time was 200 msec, including 20 msec preceding the onset of each stimulus train. The subject was instructed to adjust the position of the hands and digits to minimize the contamination by muscle potentials with the aid of E M G monitoring and speaker sound. The stimulating probe was applied to the pad of the distal phalanx from under the table. The position of the probe was adjusted to the most sensitive spot for vibration. In each recording, 500-1000 responses were averaged.

(4) Local anesthesia and ischemia To confirm that the obtained responses were not artifacts but nerve potentials, the following two experiments were performed. (1) The skin around the site of stimulation was anesthetized by injecting 0.1 ml of 2% lidocaine subcutaneously in two subjects. Serial recordings were performed before and after local anesthesia. (2) Ischemia was induced in the hand by a tourniquet around the forearm in 4 subjects. The cuff was kept inflated above the systolic pressure for 15 min, and responses were recorded before, during and after that procedure.

(3) Recording of sensory nerve action potentials The subject was seated comfortably in a reclining chair with the arm extended laterally on a wooden table in an air-conditioned room. Room temperature was kept constant during the recording procedure. The

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Results

Typical responses obtained after the vibratory stimulation of the first digit are shown in Fig. 2 (2nd trace). The response consisted of two components: a diphasic or triphasic potential (asterisk) and a train of discharges which began just after the first component and lasted a few milliseconds after the termination of the vibratory stimulus (underlined). When the digit was detached from the probe, with the distance from the stimulator to the electrodes being kept constant, those responses were lost (3rd trace). When the hand was positioned closer to the speaker with the finger detached from the probe, artifacts from the electromagnetic field were recorded with the distance between the electrodes and the speaker being about 1 cm (bottom trace). Fig. 3 shows the responses recorded after stimulating each digit. In the top 3 traces are shown the

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Fig. 2. Typical responses recorded from the median nerve after the vibratory stimulation of the first digit in a 31-year-old m a n (top trace). Movement of the probe monitored by the photocell. The arrow indicates the onset of the probe movement (2nd trace). Responses obtained at the wrist. Two components were identified (asterisk and underlined). Two records are superimposed (3rd trace). No responses were obtained when the digit was detached from the stimulating probe (bottom trace). Artifacts due to electromagnetic field recorded in the vicinity of the stimulator. Time scale is the same for all traces. The vertical bar indicates 0.5 ttV for the middle two traces and 5/zV for the bottom trace.

responses recorded from the median nerve and elicited by the stimulation of the first, second and third digit in this order. The bottom trace shows the response obtained from the ulnar nerve after stimulation of the fifth digit. The latency and amplitude (measured from the negative peak to the positive peak) of the first component after stimulation of the first, second, third and fifth digit were 4.0 ___0.4 msec and 0.97 _+ 0.41 #zV, 4.6 + 0.5 msec and 0.76 _+ 0.3 #~V, 4.8 + 0.5 msec and 0.72 ± 0.24 #zV, 3.7 + 0.4 msec and 0.49 ± 0.31 ~V (mean ± standard deviation), respectively. Fig. 4 illustrates the responses recorded simultaneously from two pairs of electrodes, each pair overlying the median and ulnar nerves, respectively. When the first or the third digit was stimulated, typical responses were obtained only from the electrodes over the median nerve. No responses, except for small potentials which had almost the same latency as the first component of the responses recorded from the median nerve, were obtained from the electrodes over the ulnar nerve. On the right column of the figure, the sensory nerve action potentials recorded simultaneously from the same pairs of electrodes after electrical stimulation of the finger tip are shown. From the ulnar nerve, small volume-conducted potentials were recorded whose amplitudes are congruent with those after vibratory stimu-

lation. These findings suggest that the small potentials recorded from the ulnar nerve after the vibratory stimulation of the median nerve territory are likewise volume-conducted. When the fifth digit was stimulated, similar volume-conducted potentials were recorded from the median nerve. The second component consisted of a train of periodic discharges. Usually two peaks were generated per indentation cycle (Fig. 5, top trace). Responses with 3 peaks per cycle were recorded after the third digit stimulation in a subject (middle trace), and responses with 4 peaks were recorded after the third digit stimulation in another subject (bottom trace). In two subjects, the effect of the stimulus intensity on the response was examined (Fig. 6). At the threshold for subjective vibration sense, no responses were obtained. At the maximum intensity of 40 p~m, a train of distinct periodic discharge showing two peaks per indentation cycle was obtained. At an intermediate intensity (10-20 #zm), the discharges became smaller and less periodic. The number of peaks, however, was increased at this intensity.

Effects of local anesthesia (Fig. 7) The skin region around the site of lidocaine injection became insensitive to vibration after a few minutes, while limited sensation of touch and pressure still remained. At 5 rain when the amplitudes of both components were reduced and the periodicity of the discharges became less clear, the number of identifiable peaks increased conversely. The latency of the first component was slightly delayed. In spite of almost complete loss of vibration sense around the injected site, the response was not totally lost. Up to 30 rain, these changes remained the same. At 60 rain, the amplitude of the first response increased slightly. The response returned to normal after 120 rain, when the vibration sense was full with some persistent paresthesia.

Effects of ischemia (Fig. 8) At 5 min after the cuff inflation around the forearm, when the vibration sense was almost lost, the touch or pressure sense was still perceived. The first component reduced its amplitude slightly. The following discharges became smaller in amplitude and less periodic. At 10 min after the induced ischemia those changes became more apparent. Following the cuff deflation, the subject complained of paresthesia in the hand which continued for about 20 rain. At 5 min after deflation, the response began to recover when the vibration sense was still attenuated with intense paresthesia. At 20 rain, the vibration sense returned to normal and the response returned to the initial level. The latency of the first component showed transient delay during the ischemic procedure.

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Discussion The responses obtained in the present study are not artifacts due to either mechanical electrode movement or electromagnetic field, but are true nerve potentials evoked by high-frequency vibratory stimulation. This conclusion was drawn on the following grounds: (1) When the probe was detached from the finger tip, the responses were lost (Fig. 2). (2) The wave form of the responses was distinct from that of the artifacts originating from the electromagnetic field recorded in the vicinity of the stimulator (Fig. 2). (3) When the third digit was stimulated, the typical responses were recorded only from the median nerve. No responses except small v o l u m e - c o n d u c t e d potentials were recorded from the ulnar nerve (Fig. 4). (4) Local anesthesia as well as ischemia reduced the amplitude of the responses and disrupted the periodicity of the discharges (Figs. 7 and 8), although the possibility that the mechanical properties of the skin might change affecting the responses due to lidocaine injection or ischemic procedure cannot be excluded completely. (5) Transmitted mechanical waves are expected to arrive at the electrodes 2-2.5 msec after the stimulation of the third digit, because the estimated velocity of these waves

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after finger tap is 80-100 m / s e c (Gandevia et al. 1983). The first component of the present response had in fact a much longer latency (4.8 + 0.5 msec). Then what is the origin of these components? The mechanoreceptors of the human glabrous skin are divided into 3 groups according to the pattern of adaptation to ramp indentation of the skin. Slowly adapting receptors (SA) discharge at a frequency which rises in proportion to the skin displacement (J~inig et al. 1968; Iggo and Muir 1969; Knibest61 1975). Rapidly adapting receptors (RA), Meissner's corpuscles in the human glabrous skin, respond only during the ramp movement. The discharge rate is dependent on the velocity of the ramp movement (J~inig et al. 1968; Knibest61 1973; Iggo and Ogawa 1977; Schmidt 1986). Pacinian corpuscles (PCs), which also exist in the tendons, fascia, periosteum and joint capsules, generate only one impulse for each ramp indentation regardless of the skin displacement, thus adapting very rapidly (Schmidt 1986). The first diphasic or triphasic potential of the present response is probably derived from various kinds of mechanoreceptors, because all of them can respond to the first cycle of the vibratory stimuli. The latency of the first potential after stimulation of the second digit is coincident with that of the mechanically evoked

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Fig. 3. Responses recorded after the vibratory stimulation of each digit in a 30-year-old woman. Responses after stimulation of the first (I), second (II) and third (III) digits were recorded from the median nerve, and the response after the stimulation of the fifth (V) digit was recorded from the ulnar nerve. The top line indicates the duration of the vibratory stimulus.

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potentials in previous reports (Pratt et al. 1979; Schieppati and Ducati 1984; Hashimoto et al. 1989). The vibration sense is mainly mediated by RA and PC (Talbot et al. 1968). During the sinusoidal indentation, if its amplitude is set at an appropriate level, each indentation cycle elicits one action potential from each receptor. The discharges are in a fixed phase relationship, or phase-locked with respect to the sinusoid (Hunt 1961; J~inig et al. 1968; Iggo and Ogawa 1977). Thus the information on the vibration frequency is encoded exactly as the discharge frequency of the receptors. Talbot et al. (1968) reported that the quality of sensation to sinusoidal stimulation was dichotic: flutter and vibration. Sinusoidal indentations below 40 Hz evoked flutter sensation mainly through RA while those above 60-80 Hz provoked vibration sense through PC. The tuning threshold (the minimum amplitude of the indentation at which one nerve impulse is evoked per indentation cycle) is the lowest at 40 Hz for RA and at 250 Hz for PC. When the amplitude of indentation is larger than the tuning threshold, two or three discharges may be elicited per indentation cycle. The amplitude of indentation used in the present study (40 /xm) is larger than the tuning threshold of PC, but is

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smaller than that of RA. Therefore PC is the only mechanoreceptor that can respond to the vibration of 250 Hz used in the present study. After local anesthesia, the amplitude of the responses was reduced, but small discharges were still recordable in spite of the insensitiveness to vibration around the site of lidocaine injection. The origins of these persisting discharges may be the receptors distant from the site of stimulation which were not anesthetized. T h e receptive field of SA and RA is so small that the distant receptors located outside the area in contact with the stimulating probe are hardly activated (Johansson and Vallbo 1979). In contrast, PC has a large receptive field, sometimes extending over the entire digit, and is activated easily by the stimulation applied away from the receptors (Johansson and Vallbo 1979). These findings also favor PC as the origin of the second component of the present response. Another candidate for the origin of the second component is the muscle spindle. The vibration of 100-500 Hz applied to the muscle tendon selectively activates the primary endings of the muscle spindle to produce a single discharge for each vibration cycle (Brown et al. 1967). Since thenar muscles are inner-

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Fig. 4. R e s p o n s e s recorded simultaneously from the median and ulnar nerves in a 31-year-old man. Each of the first (I), third ( l i d and fifth (V) digits was stimulated. Typical responses were obtained from the electrodes over the median nerve after stimulation of the first or third digit, and from those over the ulnar nerve after stimulation of the fifth digit. Small volume-conducted potentials were recorded from the electrodes over the median nerve after stimulation of the fifth digit and from those over the ulnar nerve after stimulation of the first or third digit. The right column indicates the sensory nerve action potentials elicited by the electrical stimulation of the distal phalanx of each corresponding digit (aligned with respect to the negative peak latency).

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T. HAMANOET AL.

vated by both the median and ulnar nerves, the vibration applied to the first digit would have activated the muscle spindles in both the median and ulnar innervated muscles. However, this was not the case in the present study. The fact that the second component was obtained from the median nerve but not from the ulnar nerve indicates little contribution from the muscle spindle. Then the question arises as to how many PCs are activated to make the second component of the present response. The innervation density of PC at the finger tip in man is estimated to be 2 0 / c m 2 (Johansson and Vallbo 1979). The probe of 10 mm diameter can stimulate much more than 15-20 PCs, because of their large receptive field. The second component usually comprises 2 peaks per indentation cycle. The number of peaks, however, does not serve as an estimate, because the indentation of 40 mm, which is much larger than the tuning threshold at 250 Hz, can fire PC more than twice (Talbot et al. 1968). In fact the peak number showed a paradoxical increase as the stimulus intensity was decreased to activate a smaller number of PCs (Fig. 6). At the sensory threshold, excitation of a single PC suffices to provoke vibration sense (Schmidt 1986). A single peak in the second component is derived from

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multiple PCs, because no peaks were identified at the sensory threshold (Fig. 6). The recorded wave forms are therefore considered to be envelopes in which more than 15-20 PCs discharge in harmonics. It was not technically feasible to rule out the possibility that the skin was not in contact with the probe during some fractions of the indentation cycle (Goodwin et al. 1989). If so, the skin motion might contain harmonics that were not present in the probe motion. This may generate 2 peaks per indentation cycle. The method presented here provides some advantages which have not been achieved with conventional electrical stimulation. First, high-frequency stimulation without painful sensation is possible. In central nervous system demyelination, transmission of highfrequency impulses is selectively disturbed with transmission of low-frequency impulses preserved (Kaji et al. 1988). The present method may be helpful to reveal whether this phenomenon is also seen in the peripheral nerve. Second, selective stimulation of PC is attained. Thus the function of the receptors and distal nerve branches can be evaluated electrophysiologically. The disturbance of vibration sense is often the initial symptom of some neuropathies. This method provides a unique opportunity not only to examine naturally stim-

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Fig. 7. Effects of local anesthesia on the responses obtained after the vibratory stimulation of the first digit in a 31-year-oldman. At 5 min when the amplitudes of both componentswere reduced and periodicity of the discharges became less clear, the number of identifiable peaks increased conversely. The response returned to normal after 120 rain. Latencies of the first component at 0, 5, 30, 60 and 120 min after lidocaine injection were 4.2, 4.8, 5.2, 4.4 and 4.3, respectively.

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286 Knibest61, M. Stimulus-response functions of slowly adapting mechanoreceptors in the human glabrous skin area. J. Physiol. (Lond.), 1975, 245: 63-80.o Knibest61, M. and Vallbo, A.B. Single unit analysis of mechanoreceptor activity from the human glabrous skin. Acta Physiol. Scand., 1970, 80: 178-195. McLeod, J.G. Digital nerve conduction in the carpal tunnel syndrome after mechanical stimulation of the finger. J. Neurol. Neurosurg. Psychiat., 1966, 29: 12-22. Mountcastle, V.B., Talbot, W.H., Sakata, H. and Hyv~irinen, J. Cortical neuronal mechanisms in flutter-vibration studied in unanesthetized monkeys. Neuronal periodicity and frequency discrimination. J. Neurophysiol., 1969, 32: 452-484. Pratt, H., Amlie, R.N. and Starr, A. Short latency mechanically evoked somatosensory potentials in humans. Electroenceph. clin. Neurophysiol., 1979, 47: 524-531.

T. HAMANO ET AL. Schieppati, M. and Ducati, A. Short-latency cortical potentials evoked by tactile air-jet stimulation of body and face in man. Electroenceph. clin. Neurophysiol., 1984, 58: 418-425. Schmidt, R.F. Somatovisceral sensibility. In: R.F. Schmidt (Ed.), Fundamentals of Sensory Physiology. Springer, Berlin, 1986: 3(167. Sears, T.A. Action potentials evoked in digital nerves by stimulation of mechanoreceptors in the human finger. J. Physiol. (Lond.), 1959, 148: 30P-31P. Sumner, A. Physiology of dying-back neuropathies. In: S.G. Waxman (Ed.), Physiology and Pathobiology of Axons. Raven Press, New York, 1978: 349-359. Talbot, W.H., Darian-Smith, I., Kornhuber, H.H. and Mountcastle, V.B. The sense of flutter-vibration: comparison of the human capacity with response patterns of mechanoreceptive afferents from the monkey hand. J. Neurophysiol., 1968, 31: 301-334.