Brain, Vol. 123, No. 9, 1883-1895,
September 2000
© 2000 Oxford University Press
Investigation of the functional correlates of reorganization within the human somatosensory cortex
1 Departments of Clinical Neurophysiology and 2 Neurology, The Royal Infirmary, Manchester, UK
Correspondence to:
Dr C. E. G. Moore, Department of Clinical Neurophysiology, The Royal Infirmary, Oxford Road, Manchester M13 9WL, UK E-mail: chris.moore{at}man.ac.uk
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Abstract |
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Much work in animals and humans has demonstrated the existence of changes in topographic organization within the somatosensory cortex (SSC) after amputation or nerve injury. Afferent inputs from one area of skin are able to activate novel areas of cortex after amputation of an adjacent body part. We have investigated the functional consequences of this reorganization in a group of patients with nerve injury. Using the microneurographic technique of intraneural microstimulation (INMS) we stimulated groups of nerve fibres, within individual fascicles proximal to the nerve transection, with small electrical pulses. This enabled us to activate the deafferented cortex that had presumably undergone remodelling and study the conscious percepts described by the subjects. In 39 fascicles from 10 subjects, we found that the sensations evoked on INMS were no different from those reported previously by subjects with intact nerves. This finding suggests that such reorganization within the SSC has little effect on the function of deafferented cortical neurones or subcortical relay stations. In a separate set of experiments, INMS was performed in 16 nerve fascicles from an adjacent non-injured nerve or uninjured fascicle within a partially injured nerve. The sensations evoked by INMS in these experiments were also comparable to those obtained in normal subjects. This indicates that the expanded cortical representation of adjacent non-anaesthetic skin does not influence the cortical processing of afferent information. Taken together, these findings lead us to question the notion that reorganization of connections within the somatosensory cortex equates to a change in function. Whilst it may be advantageous that the human brain is not `hard-wired', neurophysiological proof of functional plasticity in the adult somatosensory system as a result of deafferentation is elusive.
plasticity; somatosensory; human; microneurography
FPT = fascicular projection territory; INMS = intraneural microstimulation; SSC = somatosensory cortex
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Traditionally, the adult CNS was thought to be fixed in its connections and function. With the exception of the changes needed for learning and memory, the majority of the CNS was considered `hard-wired'. This was thought to be the reason for the observation that damage to specific parts of the CNS resulted in predictable clinical syndromes and that recovery after brain injury was generally poor. However, during the 1970s and 1980s many papers were published that questioned the concept of a fixed adult nervous system. They reported alterations in the shape and size of somatosensory maps after amputation, nerve ligation and whisker removal in adult animals of several species. It was shown that cortical neurones activated at one time by inputs from a certain body part are capable of activation by stimulation of a different body part as a result of such an intervention. For instance, after amputation of the middle finger the cortical representation of digits 2 and 4 in area 3b of adult owl monkeys expands to occupy the cortical domain that previously represented the amputated digit. Similar patterns of reorganization have been observed within the visual, auditory and motor cortices after alterations to their afferent inputs (Wiesel, 1965; Rasmusson, 1982
; Merzenich et al., 1983, 1984; Doetsch et al., 1992).
If a peripheral nerve is crushed or sectioned and repaired, its cortical representation falls silent before becoming responsive to inputs from skin supplied by adjacent peripheral nerves. When the crushed or resutured nerve reinnervates its target skin, the cortical maps revert towards normal and inputs from adjacent nerves no longer excite cells in the previously deafferented area. The degree of restoration of normal somatotopy is better for crushed than for transected nerves, because in the former case regenerating fibres are more likely to reach their original target skin. The failure of resutured nerves to redevelop a normal pattern of activity is due to the more random regrowth of nerve fibres (Merzenich et al., 1983; Wall, 1986, 1988; Clark et al., 1988; Kaas, 1991; Garraghty and Kaas, 1992).
Over the past 10–15 years, similar physiological changes have been demonstrated in the adult human brain. Functional MRI (fMRI), focal magnetic stimulation, PET and somatosensory evoked potentials and fields have proved useful non-invasive techniques for demonstrating alterations in cortical function. Amputation (McComas et al., 1978; Sica et al., 1984, 1988; Cohen et al., 1991a; Kew et al., 1994; Elbert et al., 1994), reading Braille (Pascual-Leone and Torres, 1993; Pascual-Leone et al., 1993), playing string instruments (Elbert et al., 1995), carpal tunnel syndrome (Weerasinghe et al., 1994, Tinazzi et al., 1998), the separation of syndactyly (Mogilner et al., 1993), acute anaesthesia of the fingers (Rossini et al., 1994), facial palsy (Rijntjes et al., 1997), motor skill learning (Karni et al., 1995) and peripheral nerve anastomosis (Mano et al., 1995) have all been shown to cause changes in sensory or motor cortical activity, as measured by the above methods. Whilst there is an obvious advantage in developing a larger cortical representation as a result of skill acquisition, the significance of the reorganization that results from deafferentation alone is not known.
From a functional perspective, it is evidently important to establish whether this alteration in map topography within the somatosensory cortex (SSC) is associated with changes in cognitive or perceptual performance. In a recent review, Ramachandran suggested that, in arm amputees, the development of a phantom limb and, more specifically, the misreferral of sensations from the face to the phantom are at least partly determined by `massive cortical reorganization' (Ramachandran, 1998). On the other hand, it is not clear whether central remodelling represents a true change in cortical function or is merely an epiphenomenon that results from deafferentation.
We have addressed these questions in a series of experiments in a hitherto unreported group of patients with traumatic peripheral nerve injury and repair. They correspond to the primate model of nerve injury studied by many animal researchers, in which reorganization of the somatosensory topographic maps is seen (Wall et al., 1986). Our methods allowed us to investigate changes in perception that may occur as a result of such plasticity. The following questions were posed. (i) How does the deafferented cortex respond to a sudden influx of activity from silent skin? Is it able to generate normal perceptions or does it develop some novel function? (ii) How does this response alter with time? (iii) Would stimulation of fascicles within a normal nerve adjacent to the injured nerve evoke sensations in the denervated area akin to the facial remapping described above?
We used the methods of microneurography (Valbo and Hagbarth, 1967) and intraneural microstimulation (INMS) (Torebjork and Ochoa, 1980; Torebjork et al., 1987) in order to activate peripheral nerve fibres in subjects with traumatic transection of an upper limb nerve. Two sets of experiments were carried out. In the first, an intraneural microelectrode was placed within the proximal portion of the transected nerve, and in the second the electrode was placed within a normal nerve adjacent to the injured nerve or a normal fascicle within a partially injured nerve.
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Subjects
Subjects were recruited from the department of plastic surgery at Withington Hospital, Manchester. They received a full explanation of the experimental methods and gave informed consent in accordance with the hospital (Royal Infirmary, Manchester) ethics committee recommendations. The committee approved the study. In total, 16 subjects, aged 17–47 years, with complete or partial peripheral nerve transection and repair (within 24 h of injury) were studied.
Clinical examination and nerve conduction studies
The upper limbs were examined in detail. The extent of the injury, scars, muscle wasting and trophic changes were noted and the area of anaesthesia and any areas of hyperaesthesia were mapped onto a drawing of the hand. Points of mislocalization were noted on these figures, along with the descriptions of feelings that had returned if reinnervation had occurred. Subjects were asked to describe the sensations evoked by touch and pinprick, especially over the reinnervated skin. Specific enquiry was made about any percepts evoked within the anaesthetic area when the normal adjacent skin was stimulated. Tinel's sign was looked for by gently tapping over the nerve anastomosis or the reinnervated skin, and the character and radiation of any evoked sensations were noted. Other lesions or diseases that might cause misinterpretation of the results were looked for. Standard median, ulnar and radial motor and sensory nerve conduction studies were carried out in both upper limbs in all patients.
Microneurography and intraneural microstimulation: experimental procedure
The ulnar or median nerve was identified along a 10–15 cm segment above the elbow by palpation. Two electrodes were inserted into the skin, namely the active stimulating/recording electrode and a reference electrode 2–3 cm away. The electrodes were made of 0.2 mm diameter tungsten wire, the tip of which had been electrolytically sharpened to 1–15 µm. Electrical pulses of 0.5 V, 0.2 ms were delivered at 3 Hz by a constant-voltage stimulator through the active electrode, whilst the electrode was advanced gently towards the nerve. Entry into the nerve led to perception of pulses in the skin of the hand or muscle twitching. When this occurred, the electrical stimulation was stopped immediately. INMS was then restarted and the voltage was increased slowly from zero until the subject perceived a sensation. The position and quality of this sensation were recorded on a life-size drawing of the patient's hand, as were those of further sensations that arose when intraneural stimulation was increased. Eventually, the projections merged. The stimulus intensity was increased until the area of the projected sensation failed to enlarge, which was taken to represent a fascicular projection territory (FPT) (Schady et al., 1983a).
After the FPT had been mapped, the preamplifier was switched to recording mode to look for any afferent activity within that fascicle. The skin of the whole hand (not just the area corresponding to the FPT) was probed with a pointed stick, which is known to excite cutaneous mechanoreceptors and evoke afferent discharges. The cutaneous receptive fields for such recordable activity were drawn. Activity was expected in normal nerve fascicles and in those where some reinnervation had taken place.
Facial stimulation
The side of the face ipsilateral to the nerve injury was stimulated by applying firm pressure with a blunted stick, and subjects were asked to describe any feelings this evoked. Stimulation of the face was repeated after the subject had been asked to concentrate on possible evoked sensations in his injured hand. These tests were designed specifically to look for any `remapping' of facial stimuli to the anaesthetic areas of the hand, akin to the projection of facial stimuli to a phantom hand in upper-limb amputees observed by Ramachandran and colleagues (Ramachandran et al., 1992a, b).
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Clinical findings and nerve conduction studies
Clinical examination showed an area of total anaesthesia corresponding to the territory of the damaged nerve in all patients, with the exception of Subjects VI and IX. Subject VI had complete transection of the median and superficial radial nerves in the right forearm; however, hyperaesthesia of the middle finger together with a small (0.5 µV) but reproducible SNAP (sensory nerve action potential) recorded from the ulnar nerve at the wrist after stimulation of digit 3 suggested that some of the fibres from this finger travelled in the ulnar nerve at the wrist. Subject IX was reported by the surgeon to have a 50% injury to the ulnar nerve, which was grafted using the superficial radial nerve. However, the majority of ulnar innervated skin was clinically normal, which suggests that the injured fascicles contained mostly motor fibres. This was subsequently confirmed by nerve conduction studies. Tinel's phenomenon was demonstrated clinically in all subjects by tapping over the nerve anastomosis.
At the time of initial testing, 3–14 weeks after injury, no evidence of reinnervation was seen in any subject. The demarcation between the normal and anaesthetic areas of the hand was always clear, with the exception of Subject VI. Wasting was not evident in the early stages despite complete nerve transection, though muscle atrophy was noted in most patients during the follow-up period. All subjects showed progressive recovery of sensory function. Upon reinnervation, hypersensitivity to pinprick, and later touch, was reported. This excessive response diminished slowly until pinprick was felt as pinprick, whilst touch continued to evoke unpleasant sensations. Later, touch was recognized as touch, with a progressively lower tactile threshold.
In all cases, nerve conduction studies confirmed the operative findings of nerve injury, i.e. when complete nerve injury was reported by the surgeon no sensory or motor action potential was obtained from that nerve. Conduction data for the uninjured adjacent nerves were always within the normal reference limits for this laboratory.
Facial stimulation
No subject reported reproducible sensations in the anaesthetic hand on tactile stimulation of the ipsilateral face, nor had any patient noticed feelings within the anaesthetic area when washing or shaving. There was thus no evidence of remapping of sensation from the face to the anaesthetic area, as seen in some patients with upper limb amputation (Ramachandran et al., 1992a, b; Halligan et al., 1993; Ramachandran, 1993).
Experiment I: INMS of the injured nerve proximal to the site of trauma
Ten subjects took part in 19 separate experiments between 3 and 61 weeks after injury, in which 39 suitable fascicles were studied. A further 12 fascicles were discarded because of excessive motor unit content. Movement of the fingers induced by INMS in such fascicles and muscle cramp within the contracting muscle invariably interfered with the subject's awareness of cutaneous sensation. For each of the 39 fascicles suitable for study, a hand showing the location of the threshold sensation (yellow shading), the area corresponding to the FPT (green shading) and the anaesthetic area of skin (grey shading) were drawn (hands 1–39, Figs 1–3). For the subjects who had a degree of reinnervation at the time of the experiment, as judged by clinical examination, the areas of sensory recovery are shown in pink.
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Sensations evoked by INMS were referred to the territory of the injured nerve, which was anaesthetic. The first sensation on INMS was evoked at a mean stimulus voltage of 0.38 V (SD 0.09), most often described as a tingle or buzzing. The projection of this sensation was smaller at the fingertips than over the palm, consistent with previous observations during INMS (Schady and Torebjork, 1983
; Schady et al., 1983b, c). As the stimulus intensity was increased, there was an expansion of the initial projection or the appearance of other small areas of sensation. These sensations then increased in size until the areas merged and a larger area of skin was covered. The voltage that induced the maximal projection ranged from 0.5 to 9.0 V. (median 3.0 V).
The FPT was not scattered haphazardly across the hand. It was confluent, and was usually confined to the territory of one or two digital nerves and the adjoining web-space, as seen on INMS of normal nerves in healthy subjects. Some fascicles projected to the palm as an extension of the above pattern or, rarely, in isolation. Two FPTs (hands 7 and 20) showed discontinuities, though in both cases the outline of the multiple projections was within what would normally be considered a typical FPT (Schady et al., 1983a, b).
The FPTs included the tip of the digit in all but eight fascicles, in which the maximum projection fell short of the most distal part of the finger. In six of these (hands 9, 17, 31, 34, 37 and 38) the reduced projection occurred in only one of the two adjacent digits incorporated in an FPT. The other two hands (10 and 13) contained fibres from just one digital nerve. In five of these eight fascicles the FPT was mapped at a potentially submaximal stimulus strength because of the onset of muscle twitching at higher stimulus intensities.
All FPTs were perceived within the area of anaesthetic skin or a combination of reinnervated and anaesthetic skin. Five of the FPTs (hands 18, 24, 26, 27 and 30) extended onto a small area of clinically normal skin. The amount of overlap was up to 2 cm, which is within the margin of error for localization in the hand (Hamburger, 1980). It is worth noting that, in several patients with complete median nerve lesions, the normal superficial radial nerve territory extended well into the thenar eminence (Figs 1–3
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The projection of sensations on INMS was compared with the known innervation territories of the palmar digital nerves (Table 1). In 18 cases the FPT covered the cutaneous domain of a single digital nerve; in four there was a palmar extension. Thirteen FPTs covered the area of two digital nerves on adjacent fingers together with the palmar interspace (double-digit FPTs); two of them had a palmar extension. Four FPTs projected solely to the palm.
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In subjects in whom reinnervation had taken place, multiunit activity was recordable microneurographically. Cutaneous stimulation of the reinnervated skin evoked reproducible activity on the mass neurogram. Compared with multiunit activity in normal nerves, there were far fewer recordable potentials, indicating a decreased number of fibres or a decreased amplitude of the responses.
Longitudinal study
Nine subjects underwent repeated INMS of the injured nerve proximal to the injury (6 on two occasions and 3 three times) up to 61 weeks after injury, using identical experimental methods. During the follow-up period there was no significant change in the pattern of FPTs induced by INMS. The relative numbers of single-digit and double-digit FPTs remained the same. There was no increase in the number of discontinuous FPTs with time, and FPTs that failed to reach the fingertip were not confined to any one period.
As reinnervation progressed distally, the area of anaesthesia diminished, so that FPTs that originally projected onto anaesthetic skin overlapped reinnervated and denervated skin. Despite this, the shapes of the FPTs remained stable, i.e. they were similar to those obtained in the first experiment, before any demonstrable regeneration had taken place. Evidently, it is very unlikely that the same fascicles were accessed on both occasions, but the general shape and size of FPTs were not altered by the presence of regrowing fibres in the second or third experiment.
Experiment II: INMS of normal nerve fascicles adjacent to injured nerve fascicles
Three of the patients studied in Experiment I and a further six subjects with complete or partial nerve injury underwent INMS of non-injured nerve fascicles, either within a completely normal nerve (e.g. the median nerve after ulnar nerve injury) or in the normal part of a partially injured nerve. Microneurography helped to confirm the clinical impression that the fascicle under study was `normal', i.e. non-injured.
Sixteen fascicles were studied during 10 experimental sessions between 3.5 and 78 weeks after nerve injury. Predominantly motor fascicles were excluded. The mean stimulus voltage for the perception of a threshold sensation was 0.23 V (range 0.16–0.36 V). The fascicular projection territory was mapped at a voltage ranging from 0.7 to 8.0 V (Table 2). Six of the FPTs (hands 40, 43, 46, 48, 50 and 53) mapped to normal skin immediately adjacent to a clinically denervated area. Figure 3 (hands 39a–55) shows the position and relative size of the threshold sensation and the FPT on INMS at maximum tolerated intensity for each of the 16 fascicles suitable for study.
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The shape of these FPTs resembled the normal cutaneous domain of a single digital nerve or a pair of digital nerves with a palmar component, as described previously in healthy subjects (Schady et al., 1983a
). In all fascicles the threshold sensation and the fascicular projection were perceived within normally innervated skin, regardless of whether the experiment was carried out on a healthy nerve adjacent to the injured one or a healthy fascicle in a partially injured nerve. The FPTs never extended into the clinically anaesthetic area, even when the FPT was immediately adjacent to the denervated skin.
A clear example of this can be seen in hand 40. The subject had sustained partial damage (estimated by the surgeon at 90%) to the median nerve in the mid-forearm. At the time of investigation there was a clear demarcation of clinically normal (in the second interspace) and anaesthetic skin elsewhere in the cutaneous domain of the median nerve (Fig. 3). Microneurography of the median nerve above the elbow revealed normal levels of recordable multiunit activity for a fascicle covering the lateral side of digit 3 and the medial side of digit 2 (hand 39a). With the recording needle in the same position, INMS evoked sensations referred to the same area (hand 40). There was no spread of the projection into the anaesthetic skin supplied by neighbouring digital nerves.
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Discussion |
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Animal studies have shown that, when cells within the SSC are disconnected from their peripheral receptors, they fall silent before later becoming responsive to new inputs from adjacent skin (for reviews, see Wall, 1988; Kaas, 1991). Given the likelihood that the human SSC undergoes similar reorganization, we studied the conscious percepts evoked by INMS of peripheral nerves in subjects who had suffered traumatic transection of an upper limb nerve. This allowed us to examine the efficacy of afferent input, as it is not known whether a transected nerve which has been `silent' for some time is capable of activating cortical cells and generating a conscious percept akin to normal. It could be that the deafferented cortex is unable to process such information; sensations may be distorted or may appear only at high stimulus intensities because of a general decrease in synaptic efficiency. Also, changes in the orderly somatotopic organization as a result of cortical plasticity may result in the excitation of a novel population of cortical columns on peripheral stimulation. This could lead to a change in the quality or location of projected sensations when compared with those reported in normal skin.
In this context, INMS has the advantage over percutaneous nerve stimulation because it allows stimulation of small groups of nerve fibres without the simultaneous activation of neighbouring structures. Examination of these percepts allowed us to investigate the cognitive correlates of cortical plasticity in awake subjects, which is not possible in animals.
Broadly speaking, the cortical reorganization that follows deafferentation may have four cognitive effects: (i) expression of the `old construct', i.e. a phantom sensation (if neurones activated by novel pathways retain their old function, their excitation should evoke the same conscious sensation as was experienced when the anaesthetic area was normally innervated); (ii) expression of a `new construct', e.g. phantom pain (central neurones that have lost their normal peripheral receptive fields may generate new percepts different in quality, location or both, as a result of altered inputs); (iii) enhanced function in the normal skin surrounding the anaesthetic area (such skin would have an increased cortical representation and might thus be expected to have an improved sensory acuity); (iv) diminished function in the skin around the anaesthetic area (if the wider projection of inputs from adjacent skin is disorganized, sensory processing may be disrupted and acuity may worsen).
There is empirical evidence to support the first three possibilities.
(i) Expression of the old construct
Tactile stimulation of the amputation stump or the face ipsilateral to an upper limb amputation may induce sensations in a phantom limb. This observation, termed remapping, has been reported by several groups (Cronholm, 1951; Ramachandran et al., 1992a, b; Halligan et al., 1993; Elbert et al., 1994; Yang et al., 1994). In some of these patients there was detailed point-to-point correspondence of sensations such that stimulation of one part of the face always induced a sensation at the same point on the phantom hand. However, facial remapping is not a universal phenomenon and is thought to occur in fewer than 5% of amputees. In the patients with nerve injury reported here, referral of facial stimuli to the anaesthetic areas of the hand was not seen. It may be that the extent of remapping depends on time (Jain et al., 1997; Kaas and Ebner, 1998), but whether it is functionally relevant remains questionable.
Ramachandran also reported a patient who mislocalized stimuli from a digit adjacent to the amputated one to the phantom finger (Ramachandran et al., 1992a). These findings were interpreted as the direct correlate of the animal observation of cortical reorganization after digit amputation (Rasmusson, 1982; Merzenich et al., 1983; Doetsch et al., 1992). Both these sets of results suggest that the cells in the deafferented, `invaded' cortex retain the ability to evoke the perception of `hand' or `finger' even though they have been activated along new pathways. The implication is that cortical remodelling after loss of peripheral input involves, rather than `functional plasticity', plasticity of connections, perhaps due to altered synaptic thresholds (Wall, 1977). The function of an individual cell or a group of cortical cells, when activated, remains stable. Indeed, magnetic brain stimulation of the deafferented sensory cortex in patients with thoracic spinal cord injury induced leg paraesthesiae (Cohen et al., 1991b).
Similarly, Knecht and colleagues (Knecht et al., 1995) demonstrated that stimuli delivered to normal skin both ipsilateral and contralateral to an upper limb amputation evoked sensations in the phantom limb of five subjects. This mislocalization suggested that central reorganization was more extensive than a simple expansion into neighbouring cortical representation zones and involved bilateral pathways. Nevertheless, the old construct of sensation in the phantom limb was retained.
The mere existence of phantom sensations lends weight to the argument that the deafferented SSC retains its ability to generate a conscious percept of the amputated body part. In our patients with nerve injury, INMS induced sensations projected to anaesthetic skin. The fact that they were similar to those in normal subjects suggests that they were old constructs. We shall return to a discussion of our results below.
(ii) Expression of a new construct
Phantom non-painful sensations are almost universally experienced after limb amputation, whereas phantom pain is seen less frequently. Pain may be generated peripherally by spontaneous discharges in the stump neuroma, the dorsal root ganglia or centrally. It is a new construct that arises from an abnormal pattern of activation, perhaps in relation to the magnitude of reorganization, as suggested by Flor and colleagues (Flor et al., 1995), or from other ill-understood factors involving central pain pathways. Despite extensive work in this field, the mechanisms of phantom pain remain elusive (Coderre et al., 1993; Melzack, 1995; Ramachandran, 1998). In our own patients with nerve injury we found no evidence of new constructs, i.e. none of the patients developed painful phantom sensations. It may be that the amount of deafferentation was too small, compared with limb amputation, or that the reinnervation that followed nerve repair restricted the scope of reorganization.
(iii) Enhanced function
Increased sensory acuity on the stump adjacent to an amputation has been reported. Katz and Teuber and colleagues showed that two-point discrimination was better on the amputation stump than in the corresponding area of the contralateral limb (Katz, 1920; Teuber et al., 1949). Haber demonstrated lower tactile thresholds, decreased two-point discrimination and better point localization in such patients (Haber, 1958). These improvements in sensory acuity have since been attributed to the increased mass of cortical neurones activated after central reorganization. However, another explanation is that an amputee is able to focus his attention on a smaller area of skin when the stump is tested, thereby improving his sensory acuity. We know that this phenomenon, which may be termed cortical focusing, occurs in humans (Moore et al., 1999).
Although the experiments reported in this paper were undertaken in patients with nerve transections rather than amputations, they provide insights into the processing of information by deafferented somatosensory centres. In all our patients, INMS proximal to the point of nerve repair induced sensations within the anaesthetic skin that were similar in threshold, character and shape to those in healthy subjects. Stimulation at higher voltages led to an admixture of sensations referred to the projection territory of the fascicle under study (FPT). Generally, the shape of the FPTs was orderly and retained the features of fascicular projection territories seen during INMS of healthy nerves, i.e. they usually covered a confluent area of skin resembling the cutaneous domain of a single digital nerve, a digital nerve plus a palmar extension, or two digital nerves with the corresponding interspace. All subjects were able to define clearly the borders of the FPTs. INMS is therefore able to activate cortical cells that were originally devoted to the injured nerve, and this excitation results in sensations akin to normal.
One previous study employed electrical stimulation to evoke sensations in patients with peripheral nerve injury (Schady et al., 1994). Assessments were carried out 12 months after nerve transection and repair, by which time there was a degree of reinnervation resulting in recordable multiunit activity on microneurography, which may have contaminated the results. During the experiments reported here, most nerves were studied at a time when reinnervation could not have occurred (some as early as 2–3 weeks after repair), yet, judging from primate experiments, some cortical reorganization should already have taken place (Wall, 1988; Kaas, 1991). These early experiments produced results that were similar to those in patients with a longer interval since nerve injury. Indeed, when we studied the same subjects on more than one occasion there was no change in the pattern of sensory projections. These findings suggest that intraneurally evoked sensations are not dependent on time and are unrelated to the stage of denervation, reinnervation or central reorganization.
Out of the 39 fascicles studied in our patients, two were slightly broken up and eight failed to reach the fingertip. Discontinuous FPTs have not been reported previously in healthy subjects, but it is worth noting that the discontinuities in our two cases were, in fact, only minor gaps within boundaries corresponding to an FPT of otherwise normal shape. Of the eight FPTs that failed to reach the fingertip, five may not have been mapped at suprathreshold stimulus intensity. The other three may point to functional changes in central processing, but it should be remembered that even in healthy subjects a minority of FPTs evoked on INMS fail to reach the fingertip (Schady et al., 1983a).
Some FPTs overlapped small areas of normal skin adjacent to the anaesthetic area supplied by the injured nerve. However, the majority of these FPTs covered the anaesthetic domain of the injured nerve and thus presumably corresponded to activation of the deafferented cortex. It is likely that the small overlap with anaesthetic skin was a simple error of localization. There were no such errors at the fingertips, and it is precisely in the palm where locognosia is least accurate. At this location, errors of up to 3 cm have been reported in normal subjects (Hamburger, 1980).
The next step was to look at the cerebral representation of normal nerves adjacent to the one that had been injured. It might be expected that, bearing in mind the cortical remodelling referred to above, afferent input from a healthy adjacent nerve would result in the coactivation of its normal central representation and a new population of cells, thereby evoking sensations that might be unusual in character, projected to both normal and anaesthetic skin.
We studied 16 healthy fascicles in nine patients, and in all cases the projected sensations fell within the cutaneous domain of the normal nerve fascicle alone and matched the area of multiunit recordable activity. These experiments were carried out between 3.5 and 78 weeks after repair, encompassing various stages of deafferentation, central remodelling and peripheral reinnervation. Five of the FPTs mapped to normal skin immediately adjacent to denervated skin, and one healthy fascicle within a partially injured nerve projected to normal skin amidst a generally anaesthetic area. This is the scenario most likely to yield functional correlates of cortical plasticity, since one would expect the relevant cortical fields to be adjacent.
There are several possible explanations for our failure to demonstrate the spread of sensation from normal to anaesthetic skin in these experiments. First, it could be argued that the human cortex is not as plastic as that of other species. However, there is no reason to expect this, and indirect methods of assessing cortical maps in humans (EEG, PET, fMRI and magnetoencephalography) have shown shifts in sensory maps similar to those seen in animals (Rossini et al., 1994; Knecht et al., 1995). It could be that the pattern of activation by INMS is not suitable for evoking conscious perception from the deafferented cortex when it is activated indirectly via a healthy nerve. However, this seems unlikely, since our work has shown that activation of the deafferented cortex with identical electrical stimuli from its natural nerve does evoke a powerful percept. Lastly, it could be that activation of the homologous cortical zone inhibits firing within the `invaded' area. This seems a likely explanation in the light of the inhibitory cortical circuits that are known to exist (Mountcastle and Powell, 1959).
The limited work that has been carried out on human amputees also suggests that there is little functional adaptation to loss of peripheral input. In one case, projections to a phantom hand were mapped on intraneural stimulation in a subject 13 years after amputation at the wrist. The phantom fascicular projections in this subject, derived in the same way as in our patients, were normal except for the fact that they did not incorporate the fingertip (Schady et al., 1994). Projected sensations have also been evoked by stimulation of thalamic nuclei during neurosurgical procedures for pain relief in amputees (Davies et al., 1996). In patients with phantom pain, the thalamic neuronal population activated by cutaneous stimulation of the stump was larger than normal, and thalamic stimulation evoked sensations, sometimes painful, both in the stump and in the phantom limb. Changes in thalamic somatotopy have also been reported in human subjects after traumatic spinal transection (Lenz et al., 1994). These experiments provide direct evidence of reorganization in the human somatosensory system as a result of deafferentation. Enlargement of the stump's thalamic receptive field represents a change in synaptic efficiency. However, the fact that phantom sensations can be evoked by thalamic or peripheral nerve stimulation points to lack of functional plasticity.
It is tempting to assume that the opening up of new channels in the CNS after deafferentation must serve a useful purpose. Undoubtedly, the cortical changes described in Braille readers and skilled players of musical instruments represent a valuable functional adaptation, and the observation that the occipital cortex is used for tactile sensory processing in early-blind Braille readers shows a degree of plasticity that may have functional significance (Sadato et al., 1996; Cohen et al., 1997). However, it does not follow that the post hoc remodelling seen after amputation or nerve injury has the same significance. The large body of work in experimental animals demonstrating dynamic plasticity carries the implicit message that it confers biological advantage. But is this so? Could it be that the alteration in cortical somatosensory maps in response to loss of peripheral input is just another example of the adage that nature abhors a vacuum?
In some patients with limb amputations, touching specific regions of the face selectively evokes sensations in individual phantom digits, sometimes incorporating a surprising degree of topographic organization (Ramachandran et al., 1992a, b; Halligan et al., 1993; for review, see Ramachandran, 1998). Though this can be demonstrated in only a small proportion of patients, it is probably a reflection of the central remodelling that takes place in amputees, either by uncovering previously silent channels or creating new ones. On the other hand, there are descriptions of patients in whom remapping is not quite so orderly, for instance hand amputees whose phantom sensations are evoked from the contralateral face or hand, and below-knee amputees who experience phantom percepts in the foot during defaecation (Berlucchi and Aglioti, 1997). Knecht and colleagues (Knecht et al., 1995) found that painful phantom sensations in arm amputees could be elicited from multiple ipsilateral and contralateral sites. They concluded that `. . . after limb amputation the orderly cortical remapping demonstrated by magnetic source imaging is not translated into a similarly ordered set of perceptual changes'.
Two lines of reasoning argue against remapping being useful to the organism. First, it may be linked to the appearance of phantom pain, which is clearly not advantageous. Secondly, the perceptual correlates attributable to remapping are more in the nature of sensory anomalies, curiosities akin to the Mitempfindungen experienced by healthy subjects (Schott, 1988). The physiological substrate is an expansion into, but not an appropriation of, the original cortical representation of the lost or injured limb. Our study indicates that the deafferented somatosensory cortex remains able to process information from the limb, normally as far as we can tell, and it can generate sensations that are stable over time despite central reorganization. Neurones in the brain retain their original functions even when they have the opportunity to formulate new ones (Kaas and Ebner, 1998). They exhibit plasticity in their receptiveness but the body schema remains stable. This suggests that the somatosensory cortex and relay centres concerned have not altered their function significantly as a result of deafferentation, and the percepts generated by them remain faithful to those before the injury.
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C.E.G.M. was funded as a Medical Research Council training fellow.
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Received October 14, 1999. Revised March 9, 2000. Accepted May 18, 2000.
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