Reinnervation of mechanoreceptors in the human glabrous skin following peripheral nerve repair

Brain Research, 268 (1983) 49-65

49

Elsevier Biomedical Press

Reinnervation of Mechanoreceptors in the Human Glabrous Skin Following Peripheral Nerve Repair R. MACKEL, E. KUNESCH, F. WALDHOR and A. STRUPPLER

Department of Neurology, Technical University of Munich, Mi~hlstrasse28, D-8000 Munich 80 (F.R.G.) (Accepted November 9th, 1982)

Key words: microneurography - human skin - reinnervation - mechanoreceptors - adaptive behavior - receptive fields distribution density - sensory recovery

The technique of percutaneous microneurography was used to record single unit activity from 65 reinnervated and 24 normally innervated mechanoreceptors in the glabrous skin of the human hand. The results were obtained from 20 patients and 5 control subjects. The patients had suffered complete traumatic transsection, with subsequent repair, of the median or ulnar nerves. Three types of mechanoreceptors (RA, SAI, SAIl) and many unidentified units located in deep tissues were found to become reinnervated. No reinnervated PC units could be identified. Response thresholds, discharge characteristics and receptive field properties of reinnervated receptors were comparable to normal, with the exception that reinnervated SA I units had slower static discharge rates and smaller receptive fields. No evidence was found for multiple peripheral innervation by a single afferent fiber. The reinnervated mechanoreceptors were predominantly located in the palm and the proximal fingers with few in the finger tips, contrary to normal. The locations and frequency of occurrence of the different types of receptors could be correlated with the goodness of sensory recovery. It is suggested that these differences result from misguidance of regenerating fibers and from poor reinnervation, and that they account for reduced sensitivity and poor tactile discrimination in patients with peripheral nerve injuries. INTRODUCTION

Neurophysiological studies have identified 4 types of mechanoreceptors sensitive to touch and pressure in the glabrous skin of the h u m a n hand 33,37. As in studies on subhuman species 14'15"28'39"40-42'57, the receptors could be classified according to their adaptive behavior and receptive field characteristics 32.35,36. Two types of receptors were found to be rapidly adapting, RA (rapidly adapting) and PC (Pacinian corpuscles); and two types to be slowly adapting, SAI and SAIl. The cutaneous receptive fields of the RA and SAI types are small and well defined, those of the PC and SAIl types are large, difficult to delineate and sensitive to remote stimuli. The low threshold RA and SAI units are most heavily concentrated in the finger tips, their density decreasing towards the proximal finger and the palm 33. The PC and SAIl units are approximately evenly distributed over the glabrous skin area ~3.33.The density of RA and SAI units in the

distal finger tips as well as their receptive field properties stress their importance in tactile exploration and discrimination. These two systems of mechanosensitive units are said to be particularly suitable for tactile spatial analysis33. It is well known from clinical observations 47.56 that the tactile performance of the human hand is severely affected when the peripheral nerves innervating the cutaneous mechanoreceptors are severed, the disturbances always being more severe following nerve transsection than following nerve crush 420A7-56-58. Sensory disturbances resulting from nerve injuries, such as reduced sensitivity and abnormal sensations could be the consequences of peripheral as well as central changes (e.g. ref. 49). Peripheral changes known to occur include structural changes in regenerated fibers 22.23 or end organs s,:~-65, poor reinnervation of tactile end organs 7.38.5s.64,and the misguidance of regenerating fibers 7.27. It is also possible that target structures are morphologically reinnervated L65,

0006-8993/83/000ff0000/$03.00 © 1983 Elsevier Science Publishers

50 but function abnormally, and finally, that a mismatch in reinnervation occurs, such that regrowing axons reinnervate the wrong kind of receptors. In the present study the technique of percutaneous microneurography (MNG) was used to record from single mechanosensitive primary afferents following reinnervation, to see which receptors are reinnervated, how they function compared to normal, and whether any properties of the reinnervated receptors may be correlated with clinically observable deficits. The results show that certain differences in properties and distributions of receptors occur, that can be explained by different known peripheral changes, and which in turn can help to explain loss of tactile sensitivity. Some of the results were already reported earlie¢ 3.

were made in 20 subjects who had suffered complete transsection, with subsequent repair, of the median or ulnar nerves. The injuries were located at the wrist or in the forearm. Clinical details on the subjects and the surgery are listed in Table I. Recordings were also made in 5 normal subjects (2 males and 3 females, 24 31 years old) to obtain control information on normallyinnervated mechanoreceptors using the same procedure, The obtained observations agree with those reported earlie? 2.35 37 All examinations were performed with the consent of the subjects and according to the guidelines of the Declaration of Helsinki. Clinical examination

MATERIALS AND METHODS

Microneurographic recordings of mechanoreceptors innervating glabrous skin of the hand

The cutaneous sensibility was examined by applying light, non-noxious tactile stimuli to the skin with blunt probes, cotton sticks, v. Frey hairs and by gently stroking the skin with small brushes. Two point discrimination was also measured. The territories of various abnormal sensations were mapped. The definitions for

TABLE 1

List of subjects who had undergone nerve repair Age (years)

Graft Suture

Lesion N. med.

W.G. M.B. M.Br. B.F. S.H. H.A. A.J. Z.S. H.A. B.H. W.E. A.E. S.E. R.I. Z.L. W.F, R.,I.

m f 1' m m m m f m m m m f f f m m

43 23 17 27 17 29 60 34 24 31 50 50 32 38 27 27 22

S.J,

m

29

R.prox. L.dist. R.dist.

S.Jo. R.J.

m m

41 49

R.dist.

N. uln.

L.dist. R.prox. L.dist.

X X X X

L.dist. L.prox.

X X X

R.dist. R.prox. R.dist. R.dist. R.dist.

X X X X X

L.dist. R.prox. R.prox.

X X X X X X

R.dist. L.prox.

R.dist.

X X

L = left: R = right: dist. = distal (wrist): prox. = proximal (forearm). good: dysaesthesia. mediocre: hyperpathia / hyperaesthesia/dysaesthesia. poor: anaesthesia/hypoaesthesia.

Recovery

Time (months) Injury-repair

Repair-examin.

29 4 12 3 13 13 2 5 4 1 0 1 18 0 0 0 0 0 12 20

15 34 98 79 107 60 100 36 72 96 52 56 28 25 30 45 14 40 89 115

mediocre mediocre good mediocre good mediocre poor poor poor mediocre mediocre poor mediocre good good mediocre good good mediocre poor

51 these sensory p h e n o m e n a were adopted from the recommendation by the International Association for the Study of Pain, IASP, Subcommittee on Taxonomy 3°. Briefly, by dysaesthesia we understand an unpleasant abnormal experience to light tactile stimuli. The experiences should not have the sensory qualities of pain. Hyperand hypoaesthesia mean, respectively, an increased and a decreased sensitivity to stimulation, although the stimulus and locus can be defined. Hyperpathia is a painful sensation to a non-noxious stimulus. The stimulus is usually faultily localized and identified, and the sensation usually outlasts the stimulation. Anaesthesia is an absence of sensation to an non-noxious stimulus. The clinical recovery was considered poor, mediocre or good according to the following criteria: recovery was poor when the projection zone of the repaired nerve was anaesthetic and severely hypoaesthetic to light mechanical stimuli. Recovery was mediocre when anaesthesia and hypoaesthesia were present to a lesser degree and sensations such as dysaesthesia, hyperaesthesia and hyperpathia prevailed. The sensory recovery was considered good when only moderate dysaesthesia and hypoaesthesia were encountered in the territory of the injured nerve.

Recording The technique of percutaneous microneurography has been described in detail elsewher~ .6°-62. Briefly, sterilized, lacquer-coated tungsten electrodes electrolytically sharpened to a tip diameter of 5-10 ~m and with resistance between 200 and 500 k~2, were inserted manually, under aseptic conditions, into the nerve fascicles. Once the electrodes were intrafascicularly placed, they were removed until activity of single afferent fibers was isolated. The nerve signals were amplified, displayed on the oscilloscope, fed into an audiomonitor, and stored, together with an analog signal of the mechanical stimulus, on magnetic tape for later analysis. On reproduction the signal-to-noise ratio was improved by non-linear suppression of background activity ('noise-cutter').

Procedure During the experiment the subjects lay supine with their arms extended laterally and resting in an arm-holder and with the volar aspect of the hands faced upward to allow easy access for mechanical exploration. The median or ulnar nerves were impaled in the forearm or in the axilia, depending on the location of the injury. Nerve impalement was always proximal to the site of nerve repair. Mechanosensitive afferents were identifed according to the criteria of discharge characteristics35 37 and receptive field properties 32.37 used in the studies on the normally innervated mechanoreceptors in the h u m a n glabrous skin. The units responding to light mechanical stimuli and having definable receptive fields were considered to be cutaneous receptors. In normally innervated skin, the search for cutaneous afferents is aided by the occurrence of superficial paraesthesiae when the electrode penetrates the epineurium or when it is moved in the fascicle. Then, activity can usually be recorded from skin mechanoreceptors in the region where the paraesthesiae are referred. It may be pointed out that this is usually not useful for reinnervated skin, because subjects with repaired nerves typically experience paraesthesiae in the projection zone of the repaired nerve, in the absence of mechanical stimulation. When a single unit was encountered in the median or ulnar nerves, the receptor site was first determined with a blunt probe. Secondly, the absolute threshold (in force units) to mechanical stimulation was determined using calibrated v. Frey hairs (Stoelting, Chicago). The diameter of the calibrated v. Frey hairs ranged between 0.05 m m and 0.36 mm, the forces they provided were 0.1, 0.2, 0.3, 0.6, 1.6, 4, 6.7, 9.8, 14.7, 19.6, 35.3, 53.9, 83.3 and 1 17.6 mN. The rise times of typical stimuli were measured by applying stimuli to an electromagnetic force transducer. The values ranged from 7 to 11.5 ms for a hair (6.7 raN) that was often threshold, indicating that while velocities of v. Frey hairs applied could not be precisely controlled, the range of variation was fairly restricted. The threshold for a mechanoreceptor was defined as the stimulus which pro-

52 duced one or, in some cases, two impulses. The latter was also accepted as threshold since the v. Fret hairs provided stepwise rather than continuous increments of stimuli. Although, the v. Fret method has the drawbacks that the velocity is uncontrolled and the stimuli are discontinuous and of unequal steps, there is a good correlation between measurements of thresholds obtained with this and with a more precise technique ~4. Thirdly, adaptive properties (slowly or rapidly adapting) and static or dynamic sensitivities of the receptors were studied using a handheld electromechanical force transducer, the probe of which had a tip diameter of 2 ram. This transducer provided an analog signal of the stimulus so that the velocities could be determined. Fourthly, the receptive fields were mapped, using 10x v. Frey threshold stimuli. The borders of the receptive fields were drawn under a magnifying glass (6 × ) on the skin surface, as well as redrawn to scale on paper, and the long and short axes measured. Sensitivity profiles of the receptive fields were also established. For this, the extent of the most sensitive area was determined by stimulating with the threshold stimulus. Then, moving outward from the sensitive areas, the boundaries were determined where successively higher stimuli (5 x , 10x) were necessary to evoke at least one discharge in the afferent. Sensitivity profiles were plotted along the long axis of the receptive fields, which were roughly oval or round (e.g. Fig. 6). RESULTS

Clinical observations As reported earlier, subjects with repaired nerves showed reduced sensibility to light mechanical stimuli, decreased two point discrimination and abnormal sensations, when comparing the reinnervated hands to the non-injured opposite sidea5.47.5°. It was often difficult for the subjects to specify the exact location of a tactile stimulus within a restricted area. They were asked to describe the locus of the punctate stimulus (v. Frey hair or blunt probe) on the investi-

gator's hand. Usually they could only refer to large areas: for example, the entire volar surface of the finger tip, and not to small areas even when specifically pointed out by the experimenter. Fig. I A, B and C illustrates some examples of poor, mediocre and good sensory recovery. Outside anaesthetic areas, all subjects perceived dysaesthesiae and hypoaesthesiae of varying degrees to mechanical stimulation. The dysaesthesiae typically covered the whole projection zone of the repaired nerves and the other sensations were usually distributed in a patchy fashion over the affected region, as described earlie? °. Moving stimuli were usually the most effective for eliciting dysaesthesia, hyperaesthesia or hyperpathia. Another phenomenon commonly encountered following peripheral nerve lesions is perceptual mislocalization of tactile stimuli24,25. When the subjects were requested to describe with their eyes closed the location of a tactile stimulus, they felt the stimulus both at the actual spot of stimulation and in other skin areas within the projection zone of the repaired nerve (Fig. I D). These secondary areas were sometimes quite circumscribed, with the sensation being that of touch (Fig. I D: W.G.), but more often they were large areas over which a diffuse and difficult to define sensation was perceived (Fig. 1D: M.Br.). The mislocalization occurred only in one direction. For example, when the tip of the thumb was stimulated and the stimulus was also perceived in the index finger (Fig. ID: W.G.), then conversely stimulation of the index finger did not lead to a perception in the thumb.

Sample of reinnervatedmechanoreceptors Recordings were obtained from 65 mechanosensitive afferents, of which 42 were identified as cutaneous and 23 as located in deeper tissues of the hand (Table II). The cutaneous receptors were identifiable as the types RA, SAI, SAII that occur in the normally innervated skin; there were no apparent differences in receptor properties associated with the goodness of clinical recovery or with the location of the receptors. No receptors with properties of PC corpuscles, the fourth type of normally occurring mechanore-

53 A

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Fig. i. Typical sensory deficits as they occur following nerve transsection with subsequent repair. In each pair of hands the left shows the volar side and the right the dorsal side. Clinical recovery was considered poor in A, mediocre in B and good in C. Note in B that the boundary between ulnar and median nerves is on the llIrd digit, which occasionally occurs56. The dots were the points which were mechanically stimulated and the arrows point to the areas where the sensations were mislocalized. Dark regions refer to circumscribed areas of mislocalization and hatched to diffuse, wider areas ofmislocalizations.

ceptors, were encountered. Comparing the present sample to the sample of Johansson and Vallbo33 of normally innervated receptors, similar percentages of slowly adapting receptors, fewer rapidly adapting receptors, and more receptors innervating deep tissues were found among the reinnervated receptors. These differences are considered in the discussion. In the 5 control subjects, all 4 types of mechanoreceptors were encountered, with the sample distributed as follows: RA (n = 6), PC (n = 2), SAI (n = 8), SAIl (n = 6), deep (n = 2). Discharge characteristics of reinnervated mechanoreceptors SA I units These respond to punctate, well-defined stim-

uli, they may discharge either regularly or irregularly during sustained skin identation, they are not spontaneously active, and they have sharply-delineated receptive fields. As described for normal units 36"39,the reinnervated receptors display both dynamic and static sensitivity, with a greater dynamic discharge on faster rate of skin displacement (Fig. 2). The separation of dynamic and static responsiveness is illustrated in the stimulus-response curves of Fig. 3, which were obtained by applying and holding v. Frey hairs to the most sensitive site of the receptive fields, then counting separately the discharges occurring in the first and second seconds. The latter indicates static sensitivity alone and while the former includes both dynamic and static responses, the difference between the two reflects the dynamic component. For both reinnervated

54 TABLE

11

not be well controlled, discharge frequencies of reinnervated and normal SAI units during the dynamic phase were not compared. However, it was possible to compare the static discharge frequencies since the electromechanical transducer provided a standard amplitude (1.0 N) of indentation. The frequencies were measured over a period of several seconds starting one second after maximal indentation had been reached. Static discharge frequencies of reinnervated units were lower than normal. The mean static discharge frequency of the reinnervated SAI receptors was 22.8 ___ 8 (S.D.) impulses/s (range: 13 34 imp/s; n = 10); that of the normally innervated receptors was 34.9 _+ 5 (S.D.) imp/s (range: 26-40 imp/s, n = 6) (comparable to frequencies of SAI units, illustrated by Knibest61

Sampled reinnervated units in the glabrous skin

Number of units (Med. + Uln.)

%

%in normal skin

(afterJohansson and Vallbo, 1979)

RA SA I SA II PC Deep

17(11 16 10 9 4 0 23 12

+ ll)

26 25 14 0 35

Total

65 (37 + 28)

100

+ + +

6) 6) 5)

40.4 24 18 12 5.6 100

(left side) and normal (right side) SAI units, thresholds for the dynamic and static components are separable, the dynamic threshold being lower. Since the velocity of the stimuli could SAI

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and Vallbo 37, to similar stimuli). The difference in discharge rates between the reinnervated and normal SAI units in the present study is statistically significant (P < 0.01, two-tailed, using a ttest with correction for small sample size and not assuming homogeneity of variance26). An example of a very low discharge rate o f a reinnervated SAI unit is shown in Fig. 2A and B. For comparison, Fig. 2C and D show a normally innervated SAI unit. The absolute thresholds (v. Frey hairs eliciting 1-2 impulses) of reinnervated SAI units ranged from 4 to 19.6 mN with a median of 6.7 mN (n = 5). These were comparable to thresholds measured for normal SAI units (median: 4 mN; range: 0.66-19.6 mN; n = 5). The values for normal units are within range, although the median is higher than those reported by others34; perhaps the correspondence between the two studies would be better, were the present sample larger, and were the same steps ofv. Frey hair stimuli used in the two studies. RA units

These units can be distinguished from the other type of rapidly adapting receptors, the PC units, because, in contrast to the PC units, they have restricted receptive fields and do not respond to high frequency vibration. The reinner-

vated as well as the normal RA units respond to low threshold stimulation, are velocity sensitive, adapt rapidly, and sometimes discharge again on removal of the stimulus from the receptive field35,37"

Fig. 4 shows the dynamic responsiveness of a reinnervated RA unit (4A), and of a normally innervated RA unit (4B). In both cases the units respond with a slow discharge rate to slow skin displacement and then stop firing. Both units respond more strongly (faster rate of discharge a n d / o r greater total number of discharges) when the velocity of skin indentation is increased. Another example of the adaptive behavior is shown in Fig. 5A, where the unit (indicated by the dots) is recorded simultaneously with an SAII-type unit. The top record shows that the unit discharges to very slight skin contact (arrow in force trace of 5A) with the hand-held probe. The units do not discharge further during the slow rising phase of the stimulus, but discharges once more when the stimulus is removed from the skin. The same RA unit responds faster upon rapid skin indentation in the second set of traces in Fig. 5A. Here, the unit also discharges a few times prior to stimulus removal: this is undoubtedly due to minimal movements of the hand held probe as RA units are exquisitely sensitive to moving stimuli35.39-57.

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The absolute thresholds for reinnervated RA units ranged from 1.6 to 14.7 mN (n = 5), with a median of 9.8 mN, similar to reinnervated SAI units. Thresholds of reinnervated RA units were similar to those measured for normally innervated RA units (median: 6.7 mN; range: 0.6& 9.8 mN; n --- 5). (As for the SAI units, the present values for normal RA units are also within range but with a higher median than those reported by other authors 34. Again, this discrepancy is probably due to small sample size and methodological differences.) SA H units Reinnervated SAIl units were less frequently encountered than SAI or RA units. They discharged in a regular fashion in response to mechanical stimulation, were often spontaneously active and had large receptive fields with unclear boundaries. Only one SAIl unit was located at the base of the nail of the thumb and responded to pressure on the finger nail, as is characteristic for 'nail units '36. The other SAIl units were found in the glabrous skin and could be recognized by their responsiveness to skin stretch. The SAIl units did not respond dynamically to a mechanical stimulus. An example of the discharge behavior of a reinnervated SAIl

unit is shown in Fig. 5A. The unit responds to skin indentation regardless of whether the skin displacement is slow or fast, as do normal SAIl units (Fig. 5B). The reinnervated unit, which is spontaneously active, stops firing for a short while when the stimulus is removed from the receptive field and then resumes its spontaneous activity. The mean discharge rates of SAIl units are usually difficult to determine because of the spontaneous activity. When calculated for nonspontaneous units it was, however, found that the mean discharge rates were not significantly different (t-test for small samples 26) between reinnervated (mean: 23.5 _ 6 (S.D.); range: 1331; n = 7) and normally innervated SAIl units (mean: 31.6 ___ 10 (S.D.); range: 25-50; n = 5). The absolute thresholds of reinnervated and normally innervated SAIl units were also not different from each other (median: 19.6 mN; range: 9.8-35.3 mN; n = 5 versus median: 14.7 mN; range: 6.7-35.3 mN; n = 5). The absolute thresholds of reinnervated SAIl units were higher than those of RA and SAI units, as in the normal case34. Deep units Many units were encountered which were located in deeper tissues of the hand (see Table II).

57

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The units did not respond to squeeze of the skin but only to strong manual pressure (beyond the maximal force (117.6 mN) provided by the v. Frey hairs), and it was difficult to define a point of maximal sensitivity. The units were slowlyadapting, displayed only static sensitivity, and were often spontaneously active. Some of the

spontaneous active units (4 out of 12) displayed regular, grouped, burst-like spontaneous discharges. Since these deep receptors are probably not involved in tactile discrimination33.3v,which is the interest of this study, they were not further classified as any particular receptor type or their origin determined. They could arise from mus-

58 cle, ligaments or joints among other tissues. However, some (n = 3) may have been joint receptors as they could be best activated by passive movements of the interphalangeal joints, and not easily by local pressure. Their response to thermal stimuli was not measured nor were conduction velocities.

Receptive field properties of reinnervated mechanoreceptors Receptive fields of SAI and RA units were plotted in detail since they show defined boundaries while those of SAII units are diffuse and therefore difficult to delineate. It is important to emphasize that each afferent fiber innervated only one peripheral receptive field. There was thus no evidence for multiple peripheral innervation by a single fiber, at least not 2 8 years following nerve repair, when the process of regeneration can be considered completed. The receptive fields ofreinnervated SAI and RA units had one point of maximal sensitivity, away from which the response threshold increased abruptly. This is also the case for normally innervated RA and SAI units when plotting fields with v. FreT hairs, although occasionally some normal units show several points of maximal sensitivity. (Note that when a more sensitive mapping procedure is used, normal units quite usually show several points of maximal sensitivity32.) For reinnervated as for normal SAII units there was one point of maximal sensitivity away from which the threshold to stimulation slowly increased in contrast to the abrupt increase in threshold for RA and SAI units. For each afferent fiber the mean diameter of the receptive field was calculated as the average of the long and short axis. Mean surface area of round receptive fields was calculated as the area of a circle (~ r2) and of oval fields as the area of an ellipse ((~'/4)D.d). The mean diameter of the receptive fields of reinnervated SAI units (n = 9) was 3.1 i ram, and the mean surface area was 9.52 mm 2. Thus the fields were smaller than those of normally innervated SAI units (n -- 4) which had a mean diameter of 6 mm and a mean surface area of 27.4 ram-'. The mean diameter of

the receptive fields of reinnervated RA units (n = 6) was 4.58 mm and the mean surface area was 19 mm 2. These values are more comparable to those obtained from normally innervated RA units (n = 3~ mean diameter: 5.2 ram: mean surface area 22.8 mm2). Thus although the sizes of the receptive fields of normally innervated SAi and RA units are similar, those of reinnervated SAI units are smaller than those of reinnervated RA units. That the receptive fields of SAI units after reinnervation are smaller than normal is illustrated by the receptive field maps and corresponding sensitivity profiles of Fig. 6, The discharges of the reinnervated unit at the successive boundaries are shown to the right of the profiles. The stimuli are suprathreshold for the dynamic response (initial burst), but are about threshold for the static response (rate after initial burst, given in Fig. 6),

Location and distribution of reinnervated mechanoreceptors As shown in Fig. 7, all reinnervated mechanoreceptors were located in the normal projection zones of the median or ulnar nerves, the apparent exceptions may be explained by individual differences in the borders between the ulnar or median nerves 56. The units were located on the volar side of the hand except one SAI unit which was located laterally on the IIIrd digit. Most of the reinnervated RA, SAI and SAII mechanoreceptors, as well as the deep units, were found in the palm and proximal regions of the fingers. This differs from the distribution found in normally-innervated skin (Fig. 7), where the RA and SAI units are concentrated in the finger tips and the remaining parts of the fingers. (In the present small sample of normally innervated units most RA and SAI, 9/14 units were also found in the finger tips.) Thus comparing the reinnervated distribution to the normal, there is a shifting away from the finger tips of RA and SAI receptors, the receptor types which are considered to be important for spatial discrimination 33. Although there were no differences in receptor properties associated with goodness ofsenso-

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117.6

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1

0

( S Jo

2

{ms)

Distance

Reinnerveted

1

.............

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( L. D ~ )

.............

Johennson

(1978)

Fig. 6. Sensitivity profiles ofa reinnervated and a normally innervated SAI unit. Receptive field boundaries of the normal and reinnervated units are to the left of the profiles. Sensitivity profiles were plotted from left to right along the longitudinal axes, as indicated. In the sensitivity profiles are shown the points where v. Fray hairs of 1.5, 5 and 10 times absolute response thresholds (T) elicited near threshold responses at varying distances from the most sensitive point in the receptive field. Discharges of the reinnervated unit at static threshold are to the right of the profiles. Static threshold is defined as the stimulus strength which caused at least one discharge following the rising phase of the stimulus (i.e. during the plateau of the prolonged indentation). The unit discharges at least once following the early burst of activity (dynamic response). The discharge is slightly higher at 10 T because no continuous steps ofv. Fray stimuli were available. When the skin just beyond the boundary was stimulated with the same v. Frey hair, it did not respond. Included in the sensitivity profiles is a reconstructed profile of a typical SAI unit (3/5) from an independent study32. It can be seen that there is good correspondence between field sizes plotted with the v. Frey ethod and with a more precise method. N uln

N.

mecl a

b C

~1 RA SAt SATI Deep

Reinnervated

a

,e

b c RA

b

c

I

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a

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Normal

ifttr Johinimon • VmlmO 1 9 r 9 )

(Moallit a

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I

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ry recovery, there were differences both in the distribution of the receptors and in the frequency of occurrence of the different types of receptors. In Fig. 8 the location of the reinnervated receptors has been replotied according to whether the sensory recovery was poor (5 patients), mediocre (9 patients), or good (6 patients). Additionally, the sampling distributions for each category of recovery are presented, together with one from a study of normal receptors 33. The sample distributions per patient were comparable to the total sample distribution. In cases of poor sensory recovery it can be seen that few cuFig. 7. Location and distribution of all sampled reinnervated mechanoreceptors from the ulnar and median nerves. The hands are subdivided into finger tips (a), remaining part of the finger (b) and palm (c). The symbols do not indicate receptive fields size. The histograms illustrate the distribution relative to these subdivisions of each type of reinnervated receptor. On the ordinate are expressed the percentage of total number of a given type of receptor within the subdivisions of the hand (a + b + c = 100%). For comparison the distributions in the normally innervated skin are also shown (after Johansson and Vallbo33). These histograms were obtained by counting the receptors in areas corresponding to a, b, and c in Johansson and Vallbo's Fig. 3.

60 taneous, but a number of deep receptors were encountered. In cases of mediocre recovery, all types of cutaneous receptors were encountered to about the same extent, but deep receptors were again most frequent. Almost all units were located in the palm. In contrast in the cases with good sensory recovery, the majority of receptors identified were of RA and SAI type, with most located towards the finger tips. This configuration of receptor density is more like that found in normal subjects and the sampling distribution of units is quite similar to the normal distribution. Thus, as recovery was clinically assessed as good, the relative numbers and the locations of reinnervated units approached normal.

Poor

10

5 m

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5A11

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Deep

Mediocre

lo

RA

DISCUSSION

Which types of mechanoreceptors are reinnerrated? The results show that three types of cutaneous mechanoreceptors subserved by RA, SAI and SAIl afferents are reinnervated in man, as also recently reported by Hallin et al.24. The morphological substrates of the units are Merkel cells for the SAI units, Meissner end organs for the RA units, and Ruffini endings for the SAIl units3.11.15.31.~t. Many deep receptor afferents were also found after reinnervation. The deep receptors might be a number of receptor types (e.g. Ruffini- or Pacini-type endings) including free nerve endings located in different tissues4455. No evidence was found for the reinnervation of PC units in the present study. It must be pointed out that the PC units ~3occur fairly infrequently in normal glabrous skin of the hand, where they account for 12% of the total mechanoreceptor population 33. It was, however, possible to find two PC units out of 24 units in the present sample of normally innervated receptors which suggests that inability to find reinnervated PC units was not simply the result of sampiing or technique. These findings on which receptors are reinnervated in man correlate with anatomical and physiological evidence obtained in animal studies. Following nerve transsections, Merkel cells of the cat's hairy skin6,7, and Meissner and

SAI

Good 10

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Normal

Johansson

&

[ Mod*fled

after

VaHbo

t979

Table I ) RA

Fig. 8. Location of the reinnervated receptors (left) and frequency of occurrence of receptor types (right) in relation to the goodness of clinical recovery. For comparison, the frequency with which these receptor types are encountered in normal skin are included. Note that in this histogram (from ref. 33) the counts of PC units (n = 43) have not been included as they were never encountered after reinnervation.

Ruffini endings in the primate glabrous skin 16.58.64have been found to be reinnervated. In contrast, there is contradictory evidence for reinnervation of Pacinian corpuscles. In a physiological study where the ulnar nerve of the monkey was immediately sutured following transsection at the wrist, probably one afferent and possible two others (out of 758 units) could be identified as having PC properties ~s. In anatomical studies38,64, Pacinian corpuscles persisted in the

61 skin but were not reinnervated up to one year following median nerve crush. The authors of the latter studies suggested that mechanical obstruction (fibrosis, myelin debris) at the point of nerve entry prevents the regrowing axon from reinnervating the corpuscle. However, Pacinian corpuscles in adult animals can be reinnervated, as shown in cross-innervation studies in the cat's mesentery 29.53, where 1/3 of the PC organs were reinnervated following reunion of the nerves close to the corpuscles. In view of the anatomical evidence, the regrowing axons were probably able to reach the corpuscles before sizeable obstruction occurred. The reinnervated corpuscles were able to generate action potentials, but their ability to function like normal was not assessed. Therefore, these findings may not in fact contradict the above study in the monkeySS: without normal function, any reinnervated corpuscles would not be identified as PC units.

Properties of reinnervated units Thresholds of the reinnervated mechanoreceptors were comparable to normal when studied long after nerve repair. This agrees with findings in animal studies6, v~here higher thresholds occur during the early stages of regeneration s.Ss, but return to normal during the later stages. Static sensitivity of the reinnervated receptors in man was similar to normal for SAII units, but was significantly reduced for the SAI units. Comparing animal work, there are conflicting reports. There is some evidence from the monkey glabrous skin5s that the sensitivity of slowly-adapting fibers is reduced following reinnervation, while no difference was found for reinnervated SAI units of the cat's hairy skin6. In agreement with animal work"6-5s, long after nerve reunion, all the afferents studied here in man reinnervated only one receptive field. From animal work multiple innervation may be seen during early stages of regeneration, but then subsides 5s. The disappearance of multiple receptive fields may result from retraction of peripheral sprouts as originally proposed by Cajal 9 a n d / or by coalescing 58 of individual fields, perhaps with progression and maturation of nerve terminal reconnections with receptors.

While the receptive fields of reinnervated RA units in man were comparable to normal, those of reinnervated SAI units were smaller. In the monkey glabrous skin receptive fields of both types of units are initially smaller when individual fields are considered; however, the area circumscribing multiple fields innervated by a single axon appears to be about normal size or even bigger58 (see Fig. 3). During the later stages ofreinnervation in the monkey, when multiple fields are no longer present, the single receptive fields appear to have grown bigger, although by 10 months they are still smaller than normal. It is not known whether the fields might attain normal sizes after longer recovery times, i.e. comparable to those of the present study. Both the reduced receptive field size and the reduced static sensitivity of reinnervated SAI units might be explained by a reduced reinnervation density. Normally, many Merkel cells contribute to a single SAI afferent: 25-75 per morphological unit 44, and each afferent fiber usually branches several times (3-4 times) in the deep corial plexus or papillary layer of the skin before innervating groups of end organs ~~.12.Reduced reinnervation density could be due to a decrease of Merkel cells per morphological unit a n d / o r to reduction in the number of nerve branches innervating correct target organs 6. If the number of branches were decreased, then one would expect, contrary to the present findings, that the receptive fields ofreinnervated RA units would also be smaller, since the axons supplying Meissner end organs (1-8 end organs per morphological uni0 H2-64) branch as many times as those innervating Merkel cells ~t.~2.With a loss of Merkel cells per morphological unit, the receptive field per unit would be expected to shrink, leading to a reduction in overall receptive field size. With fewer end organs, there would of course be fewer spike generators available to respond to mechanical stimulation.

Location and frequency of occurrence of reinnervated receptors Most reinnervated receptors were loca,ed in the palm and proximal fingers, including the SAI and RA units. This is in contrast to nor-

62 ma133, where most SAI and RA are in the finger tips. The most likely explanation for this difference is that the regrowing afferents do not reach the finger tips as regrowth is more difficult with longer distances22.~6. The same idea could explain the differences in the sampling distributions. In the reinnervated case RA and SAI units make up less of the sample than they do normally. This could result if afferents failed to reach the region, i.e. the finger tips, where these receptors are most highly concentrated. This is supported by the observation that with better sensory recovery the location and sampling distribution approach normal. In the reinnervated sample a much greater percentage was made up by deep receptors. There are two possible explanations for this. In the first case, following reinnervation more of the afferents could terminate in deeper tissues than they do normally. Or, secondly, even if the numbers of deep afferents are the same after reinnervation as normally, reduction of numbers of SAI and RA afferents would bias sampling towards deep units. In either case, after reinnervation deep structures are over-represented when compared to normal. The first possible explanation is intriguing because it would question the specificity of reinnervation, which has been proposed from animal work6.27.~x. Some clinical observations might be explained by a lack of specificity, namely that patients have difficulties localizing and identifying punctuate stimuli in restricted skin areas. If one assumes that the central connections are the same after reinnervation, and that the mechanoreceptors are reinnervated by the wrong kind of afferent, the afferent would respond according to the mechanoreceptor, but the subject would report the centrally represented quality. There is no strong evidence in man one way or another for specificity of reinnervation: one way to study this might be to use microstimulation5~ of identified single afferents to see what sensations the subject reports. Functional considerations The present findings have shown that the properties of mechanoreceptors are not severely

altered following reinnervation. Instead, it appears that not all types of receptors become reinnervated and that the regrowing fibers predominantly end in deeper tissues and in the palm, and not in the finger tips where the highest density of touch-pressure sensitive RA and SAI units are normally found. Thus, misguidance of regrowing fibers and decreased innervation of end organs, particularly in the finger tips, most probably account for the reduced sensitivity and poor tactile performance encountered in patients suffering from peripheral nerve injuries. Misguidance of nerve fibers as they regrow towards the periphery has also been offered as an explanation for the occurrence of perceptual mislocalizations of tactile stimuli, with the assumption that central connections are the same as before reinnervation -'42-~. The patients would then report the location of the mechanical stimulus according to the central connections of the afferent fiber, which would no longer be correct. Impaired spatial resolution capacity of patients with repaired nerves, as indicated by poor performance in a two point discrimination test, is probably the combined effect of reduced numbers of RA and SAI units and reduced receptive fields of the SAI units. Together, these lead to decreased overlap of the responsive structures. The stimulus points of the compass encounter not only fewer but also smaller targets. While anaesthesia and hypoaesthesia are consequent to reduced innervation of tactile end organs, other sensations such as dysaesthesia, paraesthesia, hyperaesthesia and hyperpathia cannot be explained by the present findings, probably because they are generated by a different subset of the afferents fibers. It has been suggested that ephaptic cross-talk between mechanosensitive afferents-~2-~ or ectopic impulse generation ~°.46underlie dysaesthesia and paraesthesia, respectively. However, unusual or spontaneous impulse activity was not encountered when recording from the reinnervated afferents (with the exception that a few SAIl units showed spontaneous activity, as in the normal case). This suggests that abnormal impulse activity, if present, must occur in other afferent systems

63 (e.g. A-delta- or C-fibers). Hyperpathia and possibly hyperaesthesia, may be mediated by mechanosensitive unmyelinated afferents. Such afferents, which have been found in the cat2, although not normally in man, are effectively activated by light moving stimuli, which are also the most effective stimuli for evoking hyperpathia and hyperaesthesia. It is known that the unmyelinated and thinly myelinated fibers48.~3 regrow abundantly following nerve injury and possibly regenerated mechanosensitive afferents have abnormally low thresholds, as shown for heatsensitive C-nociceptoW 9. The patchy distribution of the abnormal sensations of hyperpathia and hyperaesthesia suggests that the responsible afferents reach the skin in bundles from the neighbouring intact nerve. Although extensive collateral sprouting has been reported to occur for afferents which respond to high threshold, nociceptive stimuli t7 and not for low threshold afferents t8, it is not known if mechanosensitive unmyelinated affeREFERENCES l Barker, D. and Boddy, A., Reinnervation of stretch receptors in the cat muscle after nerve crush. In J. Taxi (Ed.), Ontogenesis of Functional Mechanisms of Peripheral Synapses, Elsevier/North-Holland Biomedical Press, 1980, pp. 251-262. 2 Bessou, P., Burgess, P. R., Perl, E. R. and Taylor, C. B., Dynamic properties of mechanoreceptors with unmyelinated (C) fibers, J. Neurophysiol., 35 (1971) 116- 131. 3 Bolton, C. F., Winkelmann, R. K. and Dyck, P. J., A quantitative study of Meissner's corpuscles in man, Neurology, 16 (1966) 1-9. 4 Buchthal, F. and KGhl, V., Nerve conduction, tactile sensibility, and the electromyogram after suture or compression of peripheral nerve: a longitudinal study in man, J. Neurol. Neurosurg. Psychiatr., 47 (1979) 436- 451. 5 Burg, D., Szumski, A., Struppler, A. and Velho, F., Afferent and efferent activation of human muscle receptors involved in reflex and voluntary contraction, Exp. NeuroL, 41 (1973) 754- 768. 6 Burgess, P. R. and Horch, K. W., Specific regeneration of cutaneous fibers in the cat, J. NeurophysioL, 36 (1973) 101-114. 7 Burgess, P. R., English, K. B., Horch, K. W. and Stensaas, L. J., Patterning in the regeneration of type I cutaneous receptors, J. Physiol. (Lond.), 236 (1974) 57- 82. 8 Brown, A. G. and Iggo, A., The structure and function of cutaneous 'touch corpuscles' after nerve crush, J. PhysioL (Lond.), 165 (1963) 28-29P. 9 Cajal, Y Ramon, S., Degeneration and Regeneration of the Nervous System (transl. May. R.M.), Hafner, New York, 1968.

rents show sprouting or not. In any event, when the original nerve has regrown, the innervation from the neighbouring nerve recedes tT.tS. If substantial collateral sprouting had occurred and did mediate the abnormal sensations, one would expect the sensations to be reported along the border of the median and ulnar nerves and not in a patchy fashion over the denervated skin region. By the time regeneration is complete, collateral sprouting of intact axons probably does not contribute substantially to either the abnormal sensations or to tactile recovery tS, although it undoubtedly has a more important role if regeneration is blocked or poor. The sensory recovery depends primarily on a successful process of regeneration from the lesioned nerve. ACKNOWLEDGEMENTS

We wish to thank Dr. E. E. Brink for reading and commenting on the manuscript, and Mrs. N. Pahlke for valuable technical assistance. 10 Calvin, W. H., Devor, M. and Howe, J. F., Can neuralgias arise from minor demyelination? Spontaneous firing, mechanosensitivity, and afterdischarge from conducting axons, Exp. Neurol., 75 (1982) 755-763. 11 Cauna, N., Nerve supply and nerve endings in Meissner's corpuscles, A mer. J. A nat., 99 (1956) 315- 350. 12 Cauna, N., The mode and termination of the sensory nerves and its significance, J. comp. Neurol., 113 (1959) 169-199. 13 Cauna, N. and Mannan, G., The structure of human digital Pacinian corpuscles and its functional significance, J. Anat. (Lond.), 92 (1958) 1-20. 14 Chambers, M. R. and Iggo, A., Slowly adapting cutaneous receptors, J. Physiol. (Lond.), 198 (1968) 80- 81P. 15 Chambers, M. R., Andres, K. H., v. Duering, M. and Iggo, A., The structure and function of the slowly adapting type II mechanoreceptor in hairy skin, Quart. J. exp. Physiol., 57 (1972) 417-445. 16 Dellon, A. L., Reinnervation of denervated Meissner corpuscles: A sequential histologic study in the monkey following fascicular nerve repair, J. Hand Surg., 1 (1976) 98~ 109. 17 Devor, M., Schonfeld, D., Seltzer, Z. and Wall, P. D., Two modes of cutaneous reinnervation following peripheral nerve injury, J. comp. Neurol., 185 (1979) 211- 220. 18 Diamond, J., The recovery of sensory function in skin after peripheral nerve lesions. In A. Gorio, H. Millesi and S. Mingrino (Eds.), Posttraumatic Peripheral Nerve Re-

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64

20

21

22 23 24

25 26 27 28 29

30 31 32

33

34

35 36 37 38

39

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65 60 Vallbo. A. B., Single unit recording from human peripheral nerves: muscle receptor discharge in resting muscles and during voluntary contractions, in G. G. Somjen (Ed.), Neurophysiologv Studied in Man. Excerpta Medica, Amsterdam, 1972, pp. 283-297. 61 Vallbo, A. B. and Hagbarth, K.-E., Impulses recorded with microelectrodes in human muscle nerves during stimulation of mechanoreceptors and voluntary contractions, Electroenceph. clin. Neurophvsiol.. 23 (1967) 392. 62 Vallbo. A. B. and Hagbarth, K.-E., Activity from skin mechanoreceptors recorded percutaneously in awake

human subjects, Exp. Neurol., 21 (1968) 270--289. 63 Weddell, G., Guttman, L. and Gutman, E., The local extension of nerve fibers into denervated areas of skin, J. Neurol. Psvchiatr., 4 (1941) 206-225. 64 Wong, W. C. and Kanagasuntheram, R., Early and late effects of median nerve injury on Meissner's and Pacinian corpuscles of the hand of the macaque (M. fascieularis),J. Anat. (Lond.), 109 (1971) 135- 142. 65 Zelena, J., Multiple innervation of rat Pacinian corpuscles regenerated after neonatal axotomy, Neuroscience, 6 (1981) 1675- 1686.