The experiment was devised, inter alia, to test the statements of

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1 THE PERMANENT RESULTS OF DENERVATION OF A CUTANEOUS AREA. By E. SHARPEY-SCHAFER. From the Department of Physiology, Edinburgh University. (Received for publication, 21st January 1930.) IT is just three years since Mr NORMAN DOTT cut the branch of the ulnar nerve distributed to the radial side of the little finger of my left hand. The immediate results of the operation have been given by me in this Journal.' The reader is referred to that article for the details of the operation and its more immediate effects, as well as for a comparison between this and previous experiments involving section of cutaneous nerves. The experiment was devised, inter alia, to test the statements of HEAD and RIVERS in " A human experiment in nerve-division," published in Brain, vol. xxxi. in 1908, statements that were elaborated in subsequent writings by HEAD and his fellow-workers. The gist of their results was that section of a cutaneous nerve is followed by complete ansesthesia and analgesia in the area of distribution of the cut nerve, and that during recovery the first sensation to appear is different from any kind of sensation present before the operation. This special kind of sensation is distinguished by HEAD under the name " protopathic sensibility " from all previously recognised forms of cutaneous sensation, such as touch, warmth, cold, and pain, which are grouped together by him under the term " epicritic sensibility." I had already repeated HEAD and RIVERS' experiment upon a nerve of the forearm and had signally failed-as had others-to obtain the ancesthesia described by those authors. I was therefore forced to the conclusion that they had drawn wrong inferences from their experiment owing to failure to take into consideration that no area on the forearm is wholly supplied by a single branch of a cutaneous nerve, but that the supply is invariably multiple by reason of the fact that there is always a perceptible overlap or accessory supply from neighbouring nerves. The cutaneous area in such a case is therefore never wholly denervated, and to speak of complete loss of sensibility as the result of severance of only one of the nerves distributed to it is obviously erroneous. For even if any diminution of sensibility is temporarily produced, the 1 Quart. Journ. Exper. Physiol., 192w, xix The literature of the subject is to be found in this paper.

2 96 Sharpey-Schafer interpretation of the results is complicated by the presence of intact fibres from the overlapping nerve-supply. Indeed, in the experiment recorded by HEAD and RIVERS, SO far from the area supplied by the severed nerve exhibiting the complete anaesthesia they described, the surgeon who performed the operation, and who carefully examined the case nine days after, remarked that he would have thought sensation to touch was intact if he had not known the nerves were divided. It was obviously hopeless to expect a definite result unless this complication of overlap could be eliminated. On talking over the matter with Mr DOTT, we came to the conclusion that the only cutaneous nerves which could be easily cut and of which the area of supply was unlikely to be subject to overlap were the nerves supplying the fingers, especially the branches of the ulnar nerve distributed to the palmar surface and sides of the little finger. Accordingly, as I have related in the article already referred to, Mr DOTT cut, on February 22nd, 1927, under local aneesthesia, the cutaneous branch of the ulnar nerve distributed to the radial side of the little finger of my left hand, and nine weeks later severed the corresponding branch of the ulnar nerve distributed to the ulnar side of the same finger: the severance in this case being made not by cutting the nerve across but by compressing it firmly with hawmostatic forceps. The result of the experiment showed that our conjecture was right, for there were no signs of overlap: the area of distr-ibution of the nerves was rendered functionally inert. The effect of the first or cutting operation was to render the radial side of the little finger, the radial half of its palmar surface, and almost the whole of both dorsal C nd ventral surfaces of its ungual phalanx completely anaesthetic and analgesic; the area in question responding to no kind of stimulus. The effect of the second operation was to produce an equally complete paralysis of sensation on the ulnar side of the finger and the ulnar side of the palmar aspect of the proximal and middle phalanges. So that now the whole of the palmar and lateral aspects of the finger and the dorsum of the ungual phalanx were paralysed for every kind of sensation. A primary object of the experiment was to determine what difference, if any, was to be met with in the symptoms of recovery of the two sides, the paralysis of the nerve supplying the ulnar side having been produced by crushing, that on the radial side by cutting. For it was to be expected that there would be differences, at least in the rate of recovery, because on the ulnar side the nerve was not cut through, the neurolemmal sheaths being left intact, so that the regenerating axis cylinders could be guided along them to the original terminations of the severed fibres. This expectation was fulfilled, and within four months there was complete recovery of all forms of sensation on the ulnar side, that of pain being the first to be manifested, and this being followed by recovery of sensibility to warmth and cold and to touch. But on the radial side, that on which the nerve was entirely cut through and not

3 The Permanent Results of enervation of a Cutaneous Area merely crushed, recovery was not only much more slow but also incomplete. The first sign of recovery showed itself in the reappearance of painful sensation. This began, about three months after the operation, in the immediate neighbourhood of the cut, and as time passed could be gradually traced along the proximal and middle phalanges to the ungual phalanx, the apex of which did not show any form of returned sensation until seven months after the operation. The cutaneous area supplied by the cut nerve, which, as the result of the section, had been rendered completely aneesthetic and analgesic, was now distinctly hyperalgesic. There was no true tactile sensibility, but even a light touch caused a painful sensation; and, although warmth and cold could be distinguished, the touch of the warm or cold object was always accompanied by a quality of disagreeableness which modified the specific temperature-sensibility investigated. The cause of the hypersensitiveness of the pain-fibres is discussed in the original paper and need not be treated of here. This hypersensitiveness for pain is obviously the same as the sensation which HEAD and RIVERS described as a new kind of sensation, viz. "protopathic sensibility": the reason for its appearance before that of the special sensations for warmth, cold, and touch is also dealt with in the original paper. What now concerns us is the steady condition which remains in the original area denervated by section of its cutaneous nerve: this area having had three years for regeneration of fibres and recovery of sensibility. First, as to touch. There is still no recovery of this in the true sense of the word. The slightest touch, if sufficient to be felt at all, gives rise to a disagreeable feeling entirely different from that caused by a touch upon a normal cutaneous surface. A slight prick or pinch is sharply painful. Gently stroking the surface, which causes a pleasant tickling sensation on a corresponding normal part of the skin, gives rise to an unpleasant tingling, like "pins and needles." A touch with the blunt point of a heated or cooled metal rod, such as is used for determining differences of temperature-sensibility, gives the feeling of warmth or coolness, but the touch also brings into play the disagreeable feeling above referred to: this is associated by the mind with the warm or cold feeling caused by the high or low temperature of the metal rod. If warmed or cooled air is gently blown on to the affected part, or if a heated or cooled rod is brought near it without actually touching it, the warm or cold feeling is experienced without this unpleasantness. It is not easy to say whether the sensation of warmth or of cold is as distinct as on a normal surface: all that can be affirmed is that it is not more distinct, and is usually judged less so. The unpleasant quality of the sensation which has been described by others as felt when a warm or cold object is applied to the surface of the skin has nothing really to do with the specific temperature-sensation but is due to the contact of the solid object stimulating the hypersensitive pain-nerves. VOL. XX., NO

4 98 "ISharpey-Scha,fer The cutaneous area supplied by the branch of Inerve oin the uilnar side which had been denervated by crushing instead of by cutting is normal. All kinds of sensations are felt in exactly the same manner and, so far as can be determined, to the same degree as over a correspoinding area which has not been the subject of experiment. The inference is that the down-growinig nerve-fibres which had been severed by cruslhing have been able to find their way without difficulty to their original terminations, having been guided by the intact neurolemmal sheaths to the special terminations adapted to receive the particular sensation subserved by each fibre. It was further noted in the paper referred to that there is evidence of an alteration in growth and nutrition of the denervated part as shownl by a change in the shape of the finger-nail, which is more flattened than that on the normal side, and by a difference in rate of growth, which is (listinetly slower on the operated finger as compared with that on the right hand. In order to determine whether this difference in rate is maintained, I marked on May 1st, 1929, the nails of both little fingers at their base. Each inail measured from base to free edge 10 mnm. The nails were pared at regular intervals. On September 1st (i.e. exactly four calendar months or 122 days later) the mark on the nail of the right or normal little finger was pared off; but it was not until October 16th (i.e. five and a half calendar months or 168 days) that the mark on the nail of the left or operated finger was removed. This gives a rate for the (lenervated nail distinctly slower than that of the normal nail, and shows that there still remains a trophic disturbance as the result of the nerve-section-in other words, that the nerves which subserve the growth and nutrition of the area are not functionally regenerated. Control observations are in progress to determine whether there are constant differences between the rate of growth of the nails on the two hands, and whether the time of year influences the rate, but as these will take some months to complete, the publication of the results must be deferred. The above statements regard what may be termed the steady residuary effects, observed after three years, of total denervatioin of a cutaneous area, and the fuiictional regeneration which has become stabilised withini the area. The residuary effects seen after partial denervation of a cutaneous area may now be briefly referred to. It will be remembered that in my first experiments oin this subject I followed the course which had been pursued by my predecessors (HEAD, TROTTER and DAVIES, BORING), studying the subject by severing a nerve supplied to a cutaneous area in the forearm or in the lower limb. "The result of the section was to produce hardly any appreciable loss of sensibility. Pain sensation, warmth, cold, and touch were all felt: touch was slightly diminished, but so slightly it was not easy to be sure of the fact.. There was also produced a peculiar feeling of

5 The Permanent Results of Denervation of a Cutaneous Area numbness to the touch.... No form of sensation was lost over any part of the area supplied by the cut nerve.... After about two months hypersensitiveness to pain began to show itself.... This hypersensitiveness still persists," twenty months after section. Most of this description still applies although an interval of four years has now elapsed since the operation. The conditions may therefore be regarded as stabilised. There is no appreciable loss of sensibility to touch, warmth or cold, but an increase of sensibility to pain. If a blunt object is drawn lightly over the area the tickling sensation produced, as elsewhere, is here accompanied by a peculiar tingling due no doubt to this hypersensitivity. The effect is small but appreciable, and by its means it is still possible to map out the cutaneous area affected by section of the nerve. The slight cedema which was noted as characterising the area is also still evident. The condition which was described in June 1928 is therefore to all appearance permanent. SUMMARY. In a cutaneous area which has been completely denervated by section of all the nerve fibres distributed to it, i.e. an area in which there is no overlapping or accessory supply of uncut nerve-fibres and in which sufficient time has elapsed for regeneration of the cut nerves to take place, those fibres which subserve pain are permanently hypersensitive and confer a disagreeable character upon any sensation evoked by mechanical stimuli. The ordinary sensation of touch is not properly appreciated, being obscured by this hypersensitiveness to pain. A stimulation such as would produce a pleasant sensation of tickling on a normal cutaneous surface causes an unpleasant sensation of tingling over the denervated area. If the blunt point of a heated or cooled metal rod is allowed to come in contact with the area, the warm or cold feeling is complicated by the concomitant disagreeable sensation caused by contact of the rod with the skin. But if the rod is not allowed to touch the skin, the sensations of warmth or cold are felt without such concomitant disagreeable sensation. Stated briefly, the following is the permanent condition of the original denervated area, as tested three years after section of the nerve supplying the area:- The sensation of touch is abolished or is at any rate obscured by a concomitant sensation of pain. Appreciation of warmth and cold has returned but in a somewhat diminished degree as compared with a normal area. Sensation of pain is increased over the originally denervated area as compared with that felt over a normal area. Trophic conditions are less favourable than in parts where the nervesupply has not been interfered with. 99