ANOMALOUS DOUBLE SENSATIONS AFTER DAMAGE TO THE CORTICAL SOMATOSENSORY REPRESENTATION OF THE HAND IN HUMANS

Salvatore Aglioti1,2, Alberto Beltramello3, Andrea Peru2, Nicola Smania4, Michele Tinazzi5

1 Dipartimento di Psicologia, Universit La Sapienza, Roma, Italy2 Dipartimento di Scienze Neurologiche e della Visione, Sezione di Fisiologia Umana, Universit di Verona, Verona, Italy3 Servizio di Neuroradiologia, Ospedale Maggiore, Borgo Trento, Verona, Italy4 Servizio di Rieducazione Funzionale, Policlinico Borgo Roma, Verona, Italy5 Dipartimento di Scienze Neurologiche e della Visione, Sezione di Neurologia, Universit di Verona, Verona, Italy

Address for correspondence and reprint requests:Salvatore M. Aglioti, Universit di Verona, Dipartimento di Scienze Neurologiche e della Visione, Sezione di Fisiologia Umana, Strada Le Grazie 8, 37134 Verona, ItalyVoice ++39-45-8098134; Facsimile ++39-45-580881; E-mail: smagli@borgoroma.univr.it

Running Head: ANOMALOUS SENSATIONS AND NEUROPLASTICITY

ABSTRACT

Hand amputees may report that a tactile stimulus delivered to the stump region or the face ipsilateral to the amputation induces the sensation of being touched on the phantom. Given the representational contiguity between hand and face, this phenomenon has been related to electrophysiologically demonstrated orderly remappings occurring in deafferented somatosensory areas. Here we report for the first time double sensations evoked by tactile stimuli delivered to the contralesional hypoesthesic hand in a patient with a lesion involving the hand representation in the primary somatosensory cortex. These double sensations were very precise and consistent over a 4-months period and were clustered on the contralesional scalp and bilaterally on the nape. The distribution of the referred sensations did not conform to any orderly topographic relation with the known somatosensory hand representation. Since in our patient the lesion left unaffected the nervous pathway from the skin to the thalamus, the selective cortical perturbation may have induced a thalamic reactivity eventually leading to the expression of latent thalamic inputs to intact cortical targets. The non-topographic distribution of the areas inducing double sensations is likely to reflect a noisy rearrangement process.

KEY WORDS: SOMATOSENSORY CORTEX - BRAIN DAMAGE - ADULT HUMAN BRAIN - NEURAL REARRANGEMENT- BRAIN PLASTICITY - SENSORY DISORGANIZATIONINTRODUCTION

Psychophysical testing in amputees who experience phantom perceptions has shown that specific sensations referred to the amputated body parts can be evoked by tactile stimuli delivered to select cutaneous regions (Cronholm, 1951). In some cases the skin areas from which veridical and referred sensations can be evoked are represented in the brain in an orderly relation with the representation of the amputated part. For example, following amputation of a hand, stimulation of the lower hemiface or neck ipsilateral to the amputation may elicit, in addition to the local sensation, the feeling of being touched on the phantom fingers or index or palm (Ramachandran et al., 1992; Halligan et al 1993; Aglioti et al., 1997; Doetsch, 1997). It is known that the face and the hand are represented close to each other in the somatosensory system at both cortical and subcortical levels (Penfield and Rasmussen, 1950; Woolsey et al., 1978). The anomalous double sensations may indicate the extent to which sensory inputs from the face and neck have occupied somatosensory regions formerly representing the amputated hand; thus, this phenomenon may represent a possible perceptual correlate of the remapping phenomena observed following peripheral denervation in somatosensory and motor systems of human and other primates with electrophysiological, brain imaging and magnetic stimulation techniques (Pons et al., 1991; Yang et al., 1994; Kew et al.; 1994,1997; Boorsook et al., 1998). Recent magnetoencephalography studies, however, found that indices of reorganization in primary somatosensory areas are positively correlated with phantom pain but not with non-painful phantom sensations (Flor et al., 1995; Knecht et al., 1996; 1998). Moreover, the distribution of skin regions evoking phantom sensations may be quite variable and inconsistent with a strictly topographic remapping. However, although the phenomenon of evoked phantom sensations may not be a precise landmark of the amount of neural remapping, it has to do with changes in the adult nervous system induced by perturbations of the peripheral inputs.So far, psychophysical studies of anomalous sensations possibly related to reorganizational changes in the adult brain have been mainly carried out in amputee patients who do not have any damage to the central nervous system. The extremely important issue of reorganizational changes after brain lesions has been addressed recently in both animal (Nudo et al., 1996a, 1996b; Xerri et al., 1998) and human studies (Chollet and Weiller, 1994; Seitz and Freund, 1997). It may be relevant for rehabilitation to try and see if the simple psychophysical approach used in amputees may be helpful in revealing anomalous evoked sensations also in patients with lesions of the central nervous system. A potentially interesting model for testing this hypothesis in humans is the assessment of brain damaged patients with small cortical lesions involving selectively parts of a given representation, for example the hand. Since in these patients the nervous pathway from the skin to the thalamus is intact, one may wonder whether thalamic fibers disconnected from the lesioned cortex are able to express their relation with other cortical targets. This hypothesis is supported by the notion that cortical neurons may receive dominant and latent inputs from different body parts (Schroeder et al., 1995; Xing and Gerstein, 1996). Were this the case, should it be possible that somatic stimuli delivered to the hypoesthesic (or even the anaesthesic) skin regions (e.g., the hand) are mislocated to skin regions mapped contiguously in the cortex (e.g., the face ipsilateral to the lesion) just like in amputee patients? Indeed, in these brain-damaged patients not only the nervous pathway from the skin to the thalamus is intact, but also specific parts of the thalamo-cortical sensory pathway may be unaffected by the lesion. A major problem with this model is related to the possibility of finding in humans select and quite small cortical somatosensory lesions. Nevertheless, we report here the presence of anomalous double sensations evoked by somatic stimuli in a patient with a small lesion involving the S1 hand representation.

MATERIALS AND METHODS Subjects. We tested two right-handed women (CG and GT) with an ischemic lesion mainly involving the somatosensory cortices and one right-handed man (GV) with an haemorrhagic lesion centred upon the posterior part of the right thalamus. Manual preference was assessed in all patients by using the Briggs and Nebes' (1975) laterality inventory. The patients were selected because they presented with clear somatosensory deficits but their elementary motor functions (e.g., muscle strength and tone) were practically unimpaired. Patient CG: is a 51-year old housewife with 5 years of schooling. On October 3, 1995 she suddenly suffered from paresthesias to the right hand and a great difficulty in feeling and holding objects with that hand. No other neurological or neuropsychological signs were detected. A MRI exam performed on November 27, 1995 documented a small ischemic lesion involving the left primary somatosensory cortex (Figures 1 and 2).________________________________________________PLEASE INSERT FIGURES 1 AND 2 NEAR HERE_______________________________________________When we first met this patient, 18 days after the stroke, she exhibited a severe somatosensory deficit in the right hand with which she was unable not only to recognise but also, in several trials, to detect the presence of common objects put there by the examiner. We found only minimal sensory deficits in the right forearm and no deficit at all in the right arm and shoulder. Deep tendon reflexes were normal. Active movements of the hand appeared normal under visual guidance, but were awkward and imprecise when the patient was blindfolded. The sensory deficit, confined to the right hand and wrist, was clearly expressed in the patient's inability to localise tactile stimuli delivered to those regions. Pinpricks delivered to the right fingers were perceived but not localised correctly. Unlike the other two patients, CG was able to detect the movement of tactile stimuli sliding on her right hand, but was inaccurate in reporting the direction of the movement. Position sense was impaired at the fingers and wrist but it was comparable to the other side at the elbow and shoulder. Vibratory stimuli to the right fingers were perceived but not localised. The perceived duration of vibratory stimuli was longer on the intact side by 8.5 sec at the thumb, 8 sec at the index finger, 8 sec at the middle finger, 7 sec at the ring finger, and 8 sec at the little finger. Smaller left-right differences of 4 and 2 sec were recorded at the wrist and the elbow, while no side differences for vibratory stimuli were observed at the cheekbone. Patient GT was 68 year-old at the time of the present study. She had suffered (when she was 59) from a lesion centred upon the right primary somatosensory area but involving in part the posterior parietal cortex and a small part of the right temporal superior gyrus. Detailed information on this patient is reported elsewhere (Aglioti et al., 1996). A clinical examination showed somatosensory deficits particularly severe at hand and wrist. No tactile stimulus delivered to the hand was localised correctly and only intense pinpricks were detected.Patient GV is a 51-year-old street-cleaner with 5 years of schooling who suddenly suffered from motor weakness and loss of sensibility to the right hemisoma. A MRI examination showed a hyperdense, haemorrhagic lesion involving the left thalamus and the overlying white matter. When we met the patient, 12 days after the stroke, there was no residual motor impairment. By contrast, he showed a clear hemianesthesia which was particularly severe at the right hand where only vibratory stimuli and very intense pinpricks could be detected. The perceived duration of vibratory stimuli was longer on the intact side. The right-left difference was 9.5 sec. at the basis of the index finger, 8.5 at the wrist and 7 at the elbow. A marked difference (6.5 sec) emerged also for stimuli to the cheekbone. No stimuli to the upper right limb were localised correctly. All patients badly failed a hatpic test of object recognition by scoring 0 hits out of 20 trials. None of them was able to judge whether objects held in the two hands were the same or different. During standard procedures for examining tactile functions, we serendipitously noticed that patient CG was puzzled by the occurrence of anomalous double sensations when touched on the hypoesthesic skin regions. With the aim of investigating this phenomenon systematically, we tested all the three patients as follows: In a preliminary interview, they were questioned about any anomalous sensations that may had occurred after their stroke (how long they had lasted, when they had started and whether or not they were still present at the testing period). During the testing sessions, patients were required to report on the sensations elicited by somatic stimuli delivered to several skin points both ipsilateral and contralateral to the lesion. In the first testing session at least five stimuli were delivered to each of the following points: dorsal and ventral surfaces of foot, leg, thigh, forearm, arm, shoulder; anterior and posterior surface of the neck, four points on the face, dorsal and ventral surfaces of the hand, fingers and wrist. Stimuli could be delivered both within and outside the hypo/anaesthetic areas. Different kinds of somatic stimuli were used: light touch and sliding stimuli were delivered by using the examiners fingertips, deep pressure through the handle of a knee hammer, pinpricks through the tip of an esthesiometer. Patients were instructed to keep their eyes closed during stimulations. Accuracy of response was recommended. The possible presence of a response bias was checked by introducing catch-trials, i.e. trials where no stimulus was delivered after the examiners warning. Patient CG spontaneously reported anomalous double sensations contingent upon stimulation of the hypoesthesic hand. Patients GT and GV, who never reported evoked double sensations, were explicitly encouraged to pay attention about any possible double sensation evoked by stimuli delivered by the experimenter. All patients consented to participate in the testing. While all patients were informed that the test was not part of any rehabilitation programme, none of them was informed about the aims of the experiment. A different number of trials were delivered in the different experimental sessions. This was mainly due to the patients fatigue and other controls or exams scheduled for the session. The interval between stroke and first testing session was 73 and 40 days in patients CG and GV and about 8 years in patient GT.

RESULTSIn no trials did patients commit false alarm errors, as they never reported non-delivered stimuli. In two sessions separated by a two-week interval, GT and GV never reported any stimulus-induced double sensations or sensations mislocalized to body points different from that stimulated. By contrast, CG reported that single stimuli delivered to her affected hand evoked a sensation remote from the stimulated point in addition to a veridically localised sensation. Since CG is the only patient who showed this phenomenon we focus hereafter on her performance. The presence of anomalous double sensations in patient CG was tested systematically in 4 sessions (73 days, 106 days, 146 days and 9 months after the stroke). Double sensations were evoked only by stimuli on the hypoesthesic regions. The remote skin regions where the anomalous double sensation was referred to were clustered on the scalp contralesional to the hypoesthesic hand and on the posterior part of the neck, bilaterally. The distribution of these regions was consistent over the first three sessions. A schematic drawing of areas of mislocalization of stimuli delivered to the hypoesthesic regions is reported in figure 3. The testing sessions were videotaped and reconstruction of referral areas was checked against the film sequences. ______________________________________________PLEASE INSERT FIGURE 3 NEAR HERE_______________________________________________Quantitative results are reported in table 1. ______________________________________________PLEASE INSERT TABLE 1 NEAR HERE_______________________________________________Although the localisation was not as precise as in some amputee patients, the patient reported to be sure that the anomalous double sensation was identical to the sensation originating from the hypoesthesic region. For example, sliding stimuli were reported as slides on the scalp or nape, displacement of a finger evoked a sensation of movement also on the scalp. The patient stated the following: I know, you can hardly believe me; however, what I feel on the scalp is what I feel when you touch my hand. This pattern of response was also consistent over 3 testing sessions. According to the patients report strong stimuli evoked clear double sensations. The simultaneous stimulation of points on the hypoesthesic hand and scalp or nape did not modify the perceptual quality of the anomalous double sensations. Two simultaneous stimuli within the hypoesthesic area elicited double sensations on the scalp that were strong but less well localised. Anomalous double sensations were identical when evoked by a single stimulus on the hypoesthesic hand or by two stimuli delivered to symmetrical points on the two hands. The patient was able to evoke double sensations by auto-stimulating her affected hand with a pencil (in 5 out of 5 trials) and with her left index (in 2 out of 5 trials). In no case did stimuli delivered to the referral areas (scalp or neck) evoke any double sensations. No anomalous double sensation was evoked in the testing session carried out 9 months after the stroke when somatosensory deficits had only partially cleared-up. A schematic representation of somatosensory deficit and presence of referred sensations over the different sessions is reported in table 2.______________________________________________PLEASE INSERT TABLE 2 NEAR HERE_______________________________________________

DISCUSSION Recent studies have shown a considerable reorganizational power in the adult brain as a consequence of learning (Recanzone et al., 1992; Merzenich and Sameshita, 1993) or deafferentation (Florence et al., 1997; Buonomano and Merzenich 1998). Even more novel is the notion of considerable neural rearrangements following lesions to the central nervous system in non-human (Nudo et al., 1996a, 1996b; Xerri et al., 1998) and human primates (Chollet and Weiller, 1994; Seitz and Freund, 1997).The present report shows for the first time that anomalous double sensations can be evoked systematically in a patient with a lesion of the primary somatosensory cortex. The phenomenon shows some limited analogies with the phantom sensations evoked by tactile stimulation of intact skin regions in limb or breast amputees (Cronholm, 1951; Aglioti et al.; 1994a; 1994b; 1997; Ramachandran et al., 1992; Halligan et al., 1994; Knecht et al., 1996; 1998). Anomalous double sensations evoked by electrical stimulation of the pinna have been reported in chronic low-back pain patients (Katz and Melzack, 1987). It is noteworthy that a recent magnetoencephalography study in low-back pain patients has shown clear signs of reorganization in the primary somatosensory cortex (Flor et al., 1997). Findings from our patient also present some analogies with data from neurologically intact subjects submitted to a prolonged vibratory stimulation of the volar surface of the forearm. After a 5-9 week period of repetitive stimulation, these subjects mislocalised tactile stimuli delivered within the previously vibrated skin area; moreover, they reported as double or triple, single stimuli delivered to the vibrated regions (Craig, 1993). These anomalous sensations disappeared within 15 weeks from the interruption of the repetitive stimulation. It appears that only the absent-minded wearing of vibrators can induce double sensations; indeed, people who wear vibrators as aid for blindness, and then attend the vibration stimuli, do not report any anomalous sensations (Craig, 1993). These results are in keeping with the notion that only plasticity effects linked to learning tasks are highly specific and probably require attention (Recanzone et al., 1992). Thus, stimuli not relevant for behaviour are not attended to and may simply introduce unwanted noise in the functioning of the system. Although it is hard to tell why anomalous double sensations are detected only in patient CG, some variables possibly involved in the phenomenon are to be discussed. The interval between stroke and testing may play a role because remote functional alterations after stroke may be maximal soon after the insult. However, this variable is unlikely to play a crucial role because both CG and GV have been tested in the acute post-stroke phase but only the former presented with referred double sensations. The severity of the somatosensory deficit and the type of lesion may be relevant variables. Patient CG not only presented with the mildest somatosensory defect but she also had the smallest cortical lesion and a complete sparing of the thalamus. These two conditions may leave room for reorganizational changes that may be linked to hyperactivity in perilesional areas, isles of spared neurons within the lesion, or the thalamus. The type of cortically induced thalamic plasticity recently described by Pons and co-workers may play a role in the above-described phenomenon. These authors (Ergenzinger, Glasier, Hahm and Pons, 1998) used a NMDA receptor antagonist to inactivate the hand representation into the area 3b and found a dramatic enlargement of the receptive field of thalamic neurons representing the hand. This is not to say that the thalamus is the source of double sensations in our patient but rather that an increased thalamic reactivity may allow the expression of thalamo-cortical connections kept silent under normal conditions. A long-term hyperexcitability consequent to an experimental induced ischemia has been documented in carefully controlled animal studies and put in relation to plastic processes following brain lesions (Eysel, 1997; Witte and Stoll, 1997). Such an hyperexcitability may be present not only ispilaterally and nearby the ischemic lesion, but also in brain areas remote from the lesion (Witte and Stoll, 1997). It is also noteworthy that this effect, perchance related to a dysregulation of the gabaergic system, may last from a few weeks to several months (Luhmann, Mudrick-Donnon, Mittman and Heinemann, 1995; Neumann-Haefelin, Staiger, Redecker, Zilles, Fritschy, Moheler, et al. 1998). This lapse of time suggests some analogies with the time of disappearance of evoked double sensations reported in our patient that may thus be expression of a post-lesional hyperactivity. In patient CG, the loci of mislocalized sensations turned out to be quite consistent over the experimental sessions but did not seem to bear any orderly topographic relation to the central representation of the hypoesthesic hand. In amputee patients, or at least in some of them, phantom sensations are evoked by stimulation of skin regions whose central representations border on those of the amputated body part. Doetsch (1997) reported a hand amputee patient in whom skin areas evoking phantom sensations changed size and site but remained topographically referred to specific fingers and other parts of the phantom hand, both soon and one year after the amputation. Other follow-up studies of limb amputees (Halligan et al., 1994; Aglioti et al., 1997) suggested that a topographic pattern of functional somatosensory rearrangement may be limited to an initial period following amputation and is related to sensations that are relevant for behavioural control. Thus, the fact that evoked double sensations in patient CG were no longer present nine months after the stroke also hints at a variability of reorganization processes with an eventual disappearance of sensations that are not used during daily life behaviour. This in keeping with the report in normal human observers that scratching a small excrescence on the skin may be referred to distant points as a prick or a tingle (Richter, 1977). Interestingly, this referral phenomenon appears to occur only during absent-minded scratching of the skin, i.e. when attention is not focused on the local sensation produced by the scratch. A more complex pattern of reorganization in amputees has been suggested by Knecht et al. (1998) who found that while the amount of cortical reorganization inferred from magnetoencephalography recording is rather stable, the topography of evoked sensations changes considerably over time perhaps because the alterations of sensory processing are mediated by extensive networks with fluctuating synaptic strengths. In conclusion, the application of the simple psychophysical paradigm used in amputees (Raamchandran et al., 1992; Aglioti et al., 1994a;1994b;1997) allowed us to find a perceptual phenomenon that may have to do with neural rearrangement processes consequent to a very small lesion affecting selectively the area of representation of the right hand. However, the finding does not imply that this type of anomalous evoked sensations have any functional relevance; it is noteworthy that no representational contiguity between hypoesthesic areas and areas of reference of stimuli has been reported. Thus, the phenomenon cannot be explained in terms of topographic rearrangement; however it speaks to the case that erratic changes in neural connectivity ensue from lesions of the central nervous system.

ACKNOWLEDGEMENTS Thanks are due to Prof. G. Berlucchi for his valuable comments and to Mr. Marco Veronese for preparing the figures. The financial support from the M.U.R.S.T. and the Consiglio Nazionale delle Ricerche, Italy to S. M. A. is gratefully acknowledged.

FIGURES AND TABLE CAPTIONS

Figure 1: Select MRI cuts (T2-weigthed coronal) in patient CG. Only slices in which the lesion was detected are reported. The upper left and the lower right pictures are the most anterior and the most posterior cuts respectively. It appears that the lesion (marked by arrows) is confined within a select portion of the post-central gyrus.

Figure 2: Select MRI cuts (T2-weigthed transverse) in patient CG. Only slices in which the lesion was detected are reported. The upper left and the lower right pictures are the most caudal and the most rostral cuts respectively. The lesion is marked by arrows.

Figure 3: Somatic stimuli applied to the hypoesthesic regions were referred to the regions of skin indicated as A and B. Stimuli were delivered to both palmar and dorsal surface of the hand and fingers.

Table 1: Number of somatic stimuli delivered to points within the hypoesthesic region in each experimental session. No stimuli delivered outside the hypoesthesic skin regions evoked double sensations. Stimuli delivered to the hypoesthesic areas evoked referred sensations in at least 95 % of trials. In a fourth testing session carried out 9 months after the stroke no anomalous double sensations could be evoked by stimuli on the hypoesthesic hand. Legend: Tr.= total number of stimuli; Ref. Scalp and Ref. Nape indicate the number of trials in which anomalous double sensations were referred to areas marked as A and B in figure 3. The difference between numbers under the heading Tr. and Ref. indicates trials in which no double sensation was evoked.

Table 2: Somatosensory deficit and presence of referred double sensations in the different testing sessions. Aspects of the deficit relevant for the assessment of double sensations are plotted. Legend: Refer. Sens.: referred double sensations, see also table 1 and figure 3. Stim. Det: detection of stimuli of 20 g; Stim. Loc: capability to localize the above stimuli; Stim. Dir: capability to judge the direction of sliding stimuli; Texture recog.: the patient was required to judge as same or different two different textures; Hap. Objec. Rec: capability to recognise objects held in the affected hand. It is noteworthy that in the first session only, the patient resulted unable to even feel the presence of the object in 4 out of 20 trials. Values represent the percentage of correct detections (out of 16 trials, except than in the haptic object recognition test) of stimuli delivered on the affected hand and wrist.

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Title: Anomalous double sensations after damage to the cortical somatosensory representation of the hand in humans

Authors: S Aglioti, A Beltramello , A Peru, N Smania, M Tinazzi

Abstract: Hand amputees may report that a tactile stimulus delivered to the stump region or the face ipsilateral to the amputation induces the sensation of being touched on the phantom. Given the representational contiguity between hand and face, this phenomenon has been related to electrophysiologically demonstrated orderly remappings occurring in deafferented somatosensory areas. Here we report for the first time double sensations evoked by tactile stimuli delivered to the contralesional hypoesthesic hand in a patient with a lesion involving the hand representation in the primary somatosensory cortex. These double sensations were very precise and consistent over a 4-months period and were clustered on the contralesional scalp and bilaterally on the nape. The distribution of the referred sensations did not conform to any orderly topographic relation with the known somatosensory hand representation. Since in our patient the lesion left unaffected the nervous pathway from the skin to the thalamus, the selective cortical perturbation may have induced a thalamic reactivity eventually leading to the expression of latent thalamic inputs to intact cortical targets. The non-topographic distribution of the areas inducing double sensations is likely to reflect a noisy rearrangement process.

Journal: NeurocaseNeurocase Reference Number: 239/98Primary Diagnosis of Interest: Somatosensory deficitsAuthors designation of the case: CGKey Theoretical issue: Post-lesional plasticityKey words: somatosensory cortex - brain damage - adult human brain - neural rearrangement- brain plasticity - sensory disorganizationScan, EEG and related measures MRI scanStandardized assessment: Clinical examination of somatosensory functions Other assessment: Assessment for double sensationsLesion location: left somatosensory cortexLesion type: ischemic stroke Language: English

Aglioti et al.