Brain Research, 537 (1990) 355-358 Elsevier
355
BRES 24458
Temporal progression of cortical reorganization following nerve injury Catherine G. Cusick 1, John T. Wall 2, John H. Whiting Jr. 1 and Ronald G. Wiley3 1Department of Anatomy and Neurosciences Program, Tulane University Medical Center, New Orleans, LA 70112 (U.S.A.), 2Department of Anatomy, Medical College of Ohio, Toledo, OH 43699 (U.S.A.) and 3Neurology Service, Veterans Administration Medical Center, Nashville, TN 37212 (U.S.A.)
(Accepted 18 September 1990) Key words: Adult neural plasticity; Somatosensory cortex; Cortical reorganization; Nerve injury; Ricin; Sciatic nerve; Rodent
Damage to peripheral nerves of adult mammals causes reorganization of somatosensory maps in the cerebral cortex. An understanding of the temporal progression of cortical changes is important for understanding the underlying mechanisms. The present experiments utilized neurophysiological recordings to analyze the time course of reorganization in the S-I cortical hindpaw area in adult rats. Following loss of sciatic inputs, the cortical area responding to low threshold inputs from the hindpaw saphenous nerve expands. A brief, early onset period of rapid expansion is followed by a prolonged period of slow increase. The temporal progression suggests that early onset changes condition the central nervous system for later changes. Nerve injury in adult mammals produces some degree of cortical reorganization within hours to days 1'6'8A4' 16,20,26,27 Cortical neurons with receptive fields on the denervated skin either become unresponsive to low threshold somatic stimuli, or acquire 'new' receptive fields on skin innervated by adjacent, intact nerves. Although cortical changes remain evident weeks to years after injury 6-8'13-15'18'2°,24'26-28, it is not clear to what extent the alterations observed at long postinjury times represent a preservation of earlier changes. It is uncertain how long the reorganization can continue, and whether cortical changes take place at different rates at different times after injury. To address these questions, we examined somatosensory cortical reorganization as a function of time after sciatic nerve lesions in 45 adult rats, compared to 10 rats with intact nerves. Using procedures described previously26'27'3°, sciatic deafferentations were accomplished in two ways: by mid-thigh transection and ligation of the sciatic nerve (n = 27), or by application of the neurotoxin ricin to a similar level of the nerve (n = 18). Both treatments produce an irreversible loss of sciatic inputs from the hindpaw skin, thus leaving the hindpaw partially innervated by only saphenous nerve afferents 27. The deafferentation procedures differ, however, in that nerve transection results in death of about 8-30% of sciatic nerve sensory neurons, whereas ricin treatment produces a much higher sciatic cell death (about 95%) and degeneration of projections to the CNS 27'3°. At times
ranging from 1 day to more than 2 years after injury, rats were anesthetized with ketamine and grids of multiunit recording sites were systematically spaced across the S-I hindpaw representation using previously described procedures 26'27. For each animal, borders of the cortical hindpaw area were defined midway between adjacent recording sites that did and did not respond to low threshold mechanoreceptors in the hindpaw skin, and the resulting area was measured with a planimeter. Previous studies in normal rats have shown that the S-I hindpaw representation occupies a cortical area of about 0.94 mm 2, 15% of which is dominantly activated by low threshold tactile inputs from the saphenous skin territory, and 85% of which is dominantly activated by sciatic afferents 26 (Fig. 1A,H). After sciatic nerve transection and ligation, the saphenous representation shows the following temporal sequence of expansion (Figs. 1 and 2). First, within 1-3 days after injury the saphenous area increases rapidly from about 0.14 mm 2 to 0.36-0.48 mm 2. This equals an annexation of about an additional 23-36% of the normal hindpaw cortex (sciatic plus saphenous areas) by saphenous inputs. Second, after this brief period of rapid increase, there is little change over the next 1-6 months. As a result, 5-6 months after injury the saphenous representation remains significantly smaller than the normal hindpaw representation (t[ll] = 4.28, P < 0.01). Third, the saphenous area expands from about 0.47 mm 2 at 5-6 months to 0.83 mm 2 at about 7-8 months, or a further annexation of approximately 38% of
Correspondence: C.G. Cusick, Department of Anatomy, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, U.S.A.
0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
356 SECTION & LIGATION
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Fig. l. Maps of the S-I cortical representation of the hindpaw at different times after nerve injuries in adults rats. In A - G , shading indicates the region of S-I cortex responding to saphenous nerve inputs from the hindpaw. Part A shows the area activated by the saphenous nerve in a normal animal, B - D show the expanded saphenous areas determined at increasing times after nerve transection and ligation, E - G show expanded saphenous areas at similar times following ablation of the sciatic nerve by ricin, and H shows the total saphenous plus sciatic hindpaw area in a normal animal. Each map illustrates data from an individual rat whose saphenous area is near the mean for that time interval. Thus, maps from individual animals show expansion of the saphenous area within the first week after injury (B,E), followed by little additional increase 4-5 months after injury (C,F). At 7-9 months postinjury (D,G), the enlarged saphenous area approaches the size of the normal hindpaw representation (H, sciatic plus saphenous areas). Large dots indicate recording sites where neurons responded to low threshold mechanical stimuli, whereas small dots denote sites unresponsive to these stimuli. ANT., anterior; FL, forelimb; FP, forepaw; HL, hindlimb; MED., medial; TR, trunk.
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Fig. 2. Temporal progression of enlargement of the saphenous representation after sciatic nerve transection or ricin ablation. Some of the data used to compile time course curves were used in previous descriptions of other aspects of cortical reorganization in this system2 '26'27. The dosed circles indicate mean areas for animals that had undergone nerve transection and ligation, and the open circles indicate means for the ricin-treated group. The circled stars to the left and right of the curves indicate normal area measures for the saphenous and total hindpaw representations, respectively. The development of saphenous expansion is tracked from the day of injury to a time 7-8 months later when the saphenous area is statistically indistinguishable from the normal total hindpaw area. Standard deviations for groups in the first 3 days after injury, omitted on the figure for clarity, are 0.18, 0.16 and 0.04 mm 2 respectively.
357
the normal hindpaw area. Fourth, at 7-8 months and longer, the saphenous representation is not significantly different from the size of the normal total hindpaw representation (Fig. 2; t[ll] = 1.258, P > 0.05 and t[12] = 0.281, P > 0.05). This sequence of change is evident whether the data are expressed in 60- (e.g. Fig. 2), 30-, 50- or 90-day intervals. It is important to note that the time course curve does not describe the sequence of cortical reactivation in individual rats, although it is consistent with individual maps at different times (e.g. Fig. 1). Given the variability in the data from 3-6 months after injury, one possible explanation is that, after the initial rapid reorganization, the recovery of cortical responsiveness occurs slowly and at different rates in different animals. By 7-8 months after injury, almost all animals have fully reactivated the S-I hindpaw area. The temporal progression of cortical reactivation after ablation of the sciatic nerve with ricin resembles that following nerve transection in several respects. As shown previously27, the saphenous expansion by the end of the first week is similar. During the subsequent 1-4 months after ricin application, the rate of expansion is attenuated (Fig. 2), as in the nerve transection group. By 5-6 months after ricin treatment, the mean saphenous representation is about 57% above normal, but remains significantly smaller than the total hindpaw area in normal rats (t[13] = 3.43, P < 0.01). Over the interval 5-8 months postinjury, the saphenous area undergoes slow expansion similar to that in the transection group. Finally, by 7-8 months after ricin treatment, the saphenous area is not significantly different in size from the normal hindpaw area (t[13] = 0.11, P > 0.05). Nerve transection produces only modest loss of sciatic dorsal root ganglion cells, whereas ablation by ricin leads to massive death of sciatic neurons 27'3°. The similar time course of cortical reactivation after these two treatments indicates that surviving primary afferent neurons are not required for either phase of remodeling to occur. In contrast to these similarities, the saphenous area in the ricin treatment group appears to be shifted above the level of the transection group at all time intervals (Fig. 2). Although there is no overall statistical difference between the ricin and transection groups (t[6] = 0.405, P > 0.05), the consistent offsetting of the curves suggests that the rate or magnitude of cortical reorganization may, to some degree, reflect peripheral cell loss. The present study provides the first quantitative description of cortical reorganization from the time of a peripheral injury to a time when deprived cortical areas appear completely reactivated. Cortical changes occur with both early (hours to days) and late (months) onset times, the rates of cortical reorganization differ at
different times after injury, and cortical reorganization is cumulative. The results imply that functional assessments at intermediate times after nerve injuries may not fully reveal the ability of the central nervous system to reorganize. These findings are consistent with previous studies of cortical reorganization that demonstrate acute changes, including both immediate shifting of receptive field locations and the appearance of unresponsive cortical regions, within hours or a few days after nerve injury 1' 6,8,14.16.20,26,27. Previous studies also show that somatotopic reorganization remains evident many months to years after injury6-8'13-15'1s'2°'24'26-28, but the qualitative nature of previous observations, combined with sampling at widely spaced times after injury, do not allow definition of the temporal progression of change. As a result it has been difficult to assess the relative contribution that early and late onset changes make to cortical reorganization at different postinjury times. From the present findings, it is clear that the reorganization observed at longer times is not due to a simple prolonged maintenance of acute changes. Late cortical expansion can approximately equal the early changes. It is widely thought that the rapid onset of postinjury shifts in central receptive fields is due to increased efficacy of pre-existing or latent connections which are unmasked following loss of dominant inputs 3"5'25'29. Putative mechanisms for rapidly developed changes include, for example, increases in the efficacy of excitatory synapses, and shifts in the balance of excitatory and inhibitory connections at cortical and subcortical levels of the neuraxis 1'3-5'9'12'16'17'2°'25'29. Explanations for cortical changes observed at longer times after nerve injury have not been possible because neither the onset nor the rate of late reorganization have been discriminated temporally from acute changes. Recent evidence indicates that peripheral injury in adults does not produce long distance anatomical sprouting along the ascending somatosensory neuraxis 1°'19'21'22. Given this view, it seems plausible that early and late cortical changes both involve local synaptic reorganization, but that late, slowly developing cortical changes do not occur unless neurons and synapses are appropriately conditioned by a 'priming' sequence of earlier changes. From the present findings it is clear that cortical reorganization continues long after nerve injury. This implies that amputation injuries that deprive large extents of somatosensory cortex of inputs also lead to prolonged reorganization. Thus, late onset changes may underlie such temporally related phenomena as telescoping of perceived sensations from phantom limbs which can occur at long times after injury 11'23.
358 We thank Tim Murphy for technical assistance, and Dr. Preston Garraghty for comments on an earlier version of the manuscript.
Supported by NIH Grant DE07695.
1 Calford, M.B. and Tweedale, R., Immediate and chronic changes in responses of somatosensory cortex in adult flying-fox after digit amputation, Nature, 332 (1988) 446-448. 2 Cusick, C.G., Whiting, J. and Wall, J.T., Rapid and slow cortical reorganization after nerve injury, Anat. Rec., 223 (1989) 30A. 3 Devor, M., On mechanisms of somatotopic plasticity. In L.M. Pubols and B.J. Sessle (Eds.), Effects of Injury on Trigeminal and Spinal Somatosensory Systems, Alan R. Liss, New York, 1987, pp. 215-225. 4 Devor, M. and Wall, J.T., Plasticity in the spinal cord sensory map following peripheral nerve injury in rats, J. Neurosci., 1 (1981) 679-684. 5 Dostrovsky, J.O., Miilar, J. and Wall, P.D., The immediate shift of afferent drive of dorsal column nucleus cells following deafferentation: a comparison of acute and chronic deafferentation in gracile nucleus and spinal cord, Exp. Neurol., 52 (1976) 480-495. 6 Franck, J.I., Functional reorganization of cat somatic sensorymotor cortex (SmI) after selective dorsal root rhizotomies, Brain Research, 186 (1980) 458-462. 7 Kalaska, J. and Pomeranz, B., Chronic paw denervation causes an age-dependent appearance of novel responses from forearm in 'paw cortex' of kittens and adult cats, J. Neurophysiol., 42 (1979) 618-633. 8 Kelahan, A.M. and Doetsch, G.S., Time-dependent changes in the functional organization of somatosensory cerebral cortex following digit amputation in adult raccoons, Somatosens. Res., 2 (1984) 49-81. 9 Markus, H., Pomeranz, B. and Krushelnycky, D., Spread of saphenous somatotopic projection map in spinal cord and hypersensitivity of the foot after chronic sciatic denervation in adult rat, Brain Research, 296 (1984) 27-39. 10 McKinley, P.A. and Kruger, L., Non-overlapping thalamocortical connections to normal and deprived primary somatosensory cortex for similar forelimb receptive fields in chronic spinal cats, Somatosens. Motor Res., 5 (1988) 311-323. 11 Melzack, R., Phantom limbs and the concept of a neuromatrix, Trends Neurosci., 13 (1990) 88-92. 12 Mendell, L.M., Modifiability of spinal synapses, Physiol. Rev., 64 (1984) 260-324. 13 Merzenich, M.M., Kaas, J.H., Wall, J.T., Nelson, R.J., Sur, M. and Felleman, D.J., Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation, Neuroscience, 8 (1983) 33-55. 14 Merzenich, M.M., Kaas, J.H., Wall, J.T., Sur, M., Nelson, R.J. and Felleman, D.J., Progression of change following median nerve section in the cortical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys, Neuroscience, 10 (1983) 639-665. 15 Merzenich, M.M., Nelson, R.J., Stryker, M.P., Cynader, M.S., Schoppmann, A. and Zook, J.M., Somatosensory cortical map
changes following digit amputation in adult monkeys, J. Comp. Neurol., 224 (1984) 591-605. 16 Metzler, J. and Marks, P.S., Functional changes in cat somatic sensory-motor cortex during short-term reversible epidural blocks, Brain Research, 177 (1979) 379-383. 17 Pollin, B. and Albe-Fessard, D., Organization of somatic thalamic in monkeys with and without section of dorsal spinal tracts, Brain Research, 173 (1979) 431-449. 18 Rasmusson, D.D., Reorganization of raccoon somatosensory cortex following removal of the fifth digit, J. Comp. Neurol., 205 (1982) 313-326. 19 Rasmusson, D.D. and Nance, D.M., Non-overlapping thalamocortical projection for separate forepaw digits before and after cortical reorganization in the raccoon, Brain Res. Bull., 16 (1986) 399-406. 20 Rasmusson, D.D. and Turnbull, B.G., Immediate effects of digit amputation on SI cortex in the raccoon: unmasking of inhibitory fields, Brain Research, 288 (1983) 368-370. 21 Rodin, B.E., Sampogna, S.L. and Kruger, L., An examination of intraspinal sprouting in dorsal root axons with the tracer horseradish peroxidase, J. Comp, Neurol., 215 (1983) 187-198. 22 Seltzer, Z. and Devor, M., Effect of nerve section on the spinal distribution of neighboring nerves, Brain Research, 306 (1984) 31-44. 23 Solonen, K.A., The phantom phenomenon in amputated Finnish war veterans, Acta Orthopaed. Scand., Suppl. 54 (1962) 1-37. 24 Waite, P.M.E., Rearrangement of neuronal responses in the trigeminai system of the rat following peripheral nerve section, J. Physiol., 352 (1984) 425-445. 25 Wall, J.T., Variable organization in cortical maps of the skin as an indication of the lifelong adaptive capacities of circuits in the mammalian brain, Trends Neurosci., 11 (1988) 549-557. 26 Wall, J.T. and Cusick, C.G., Cutaneous responsiveness in primary somatosensory (S-I) hindpaw cortex before and after partial hindpaw deafferentation in adult rats, J. NeuroscL, 4 (1984) 1499-1515. 27 Wall, J.T., Cusick, C.G., Migani-Wall, S.A. and Wiley, R.G., Cortical organization after treatment of a peripheral nerve with ricin: an evaluation of the relationship between sensory neuron death and cortical adjustments after nerve injury, J. Comp. Neurol., 277 (1988) 578-592. 28 Wall, J.T. and Kaas, J.H., Long-term cortical consequences of reinnervation errors after nerve regeneration in monkeys, Brain Research, 372 (1976) 400-404. 29 Wall, P.D., The presence of ineffective synapses and the circumstances which unmask them, Philos. Trans. R. Soc. Lond. B., 278 (1977) 361-372. 30 Wiley, R.G. and Oeltmann, T.N., Anatomically selective peripheral nerve ablation using intraneural riein injection, J. Neurosci. Methods, 17 (1986) 43-53.
355
BRES 24458
Temporal progression of cortical reorganization following nerve injury Catherine G. Cusick 1, John T. Wall 2, John H. Whiting Jr. 1 and Ronald G. Wiley3 1Department of Anatomy and Neurosciences Program, Tulane University Medical Center, New Orleans, LA 70112 (U.S.A.), 2Department of Anatomy, Medical College of Ohio, Toledo, OH 43699 (U.S.A.) and 3Neurology Service, Veterans Administration Medical Center, Nashville, TN 37212 (U.S.A.)
(Accepted 18 September 1990) Key words: Adult neural plasticity; Somatosensory cortex; Cortical reorganization; Nerve injury; Ricin; Sciatic nerve; Rodent
Damage to peripheral nerves of adult mammals causes reorganization of somatosensory maps in the cerebral cortex. An understanding of the temporal progression of cortical changes is important for understanding the underlying mechanisms. The present experiments utilized neurophysiological recordings to analyze the time course of reorganization in the S-I cortical hindpaw area in adult rats. Following loss of sciatic inputs, the cortical area responding to low threshold inputs from the hindpaw saphenous nerve expands. A brief, early onset period of rapid expansion is followed by a prolonged period of slow increase. The temporal progression suggests that early onset changes condition the central nervous system for later changes. Nerve injury in adult mammals produces some degree of cortical reorganization within hours to days 1'6'8A4' 16,20,26,27 Cortical neurons with receptive fields on the denervated skin either become unresponsive to low threshold somatic stimuli, or acquire 'new' receptive fields on skin innervated by adjacent, intact nerves. Although cortical changes remain evident weeks to years after injury 6-8'13-15'18'2°,24'26-28, it is not clear to what extent the alterations observed at long postinjury times represent a preservation of earlier changes. It is uncertain how long the reorganization can continue, and whether cortical changes take place at different rates at different times after injury. To address these questions, we examined somatosensory cortical reorganization as a function of time after sciatic nerve lesions in 45 adult rats, compared to 10 rats with intact nerves. Using procedures described previously26'27'3°, sciatic deafferentations were accomplished in two ways: by mid-thigh transection and ligation of the sciatic nerve (n = 27), or by application of the neurotoxin ricin to a similar level of the nerve (n = 18). Both treatments produce an irreversible loss of sciatic inputs from the hindpaw skin, thus leaving the hindpaw partially innervated by only saphenous nerve afferents 27. The deafferentation procedures differ, however, in that nerve transection results in death of about 8-30% of sciatic nerve sensory neurons, whereas ricin treatment produces a much higher sciatic cell death (about 95%) and degeneration of projections to the CNS 27'3°. At times
ranging from 1 day to more than 2 years after injury, rats were anesthetized with ketamine and grids of multiunit recording sites were systematically spaced across the S-I hindpaw representation using previously described procedures 26'27. For each animal, borders of the cortical hindpaw area were defined midway between adjacent recording sites that did and did not respond to low threshold mechanoreceptors in the hindpaw skin, and the resulting area was measured with a planimeter. Previous studies in normal rats have shown that the S-I hindpaw representation occupies a cortical area of about 0.94 mm 2, 15% of which is dominantly activated by low threshold tactile inputs from the saphenous skin territory, and 85% of which is dominantly activated by sciatic afferents 26 (Fig. 1A,H). After sciatic nerve transection and ligation, the saphenous representation shows the following temporal sequence of expansion (Figs. 1 and 2). First, within 1-3 days after injury the saphenous area increases rapidly from about 0.14 mm 2 to 0.36-0.48 mm 2. This equals an annexation of about an additional 23-36% of the normal hindpaw cortex (sciatic plus saphenous areas) by saphenous inputs. Second, after this brief period of rapid increase, there is little change over the next 1-6 months. As a result, 5-6 months after injury the saphenous representation remains significantly smaller than the normal hindpaw representation (t[ll] = 4.28, P < 0.01). Third, the saphenous area expands from about 0.47 mm 2 at 5-6 months to 0.83 mm 2 at about 7-8 months, or a further annexation of approximately 38% of
Correspondence: C.G. Cusick, Department of Anatomy, Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112, U.S.A.
0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
356 SECTION & LIGATION
NORMAL SAPHENOUS
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TI~
•
•
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•
NORMAL SAPHENOUS ÷ SCIATIC
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FL
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1 6 DAYS
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MONTHS
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F TR, ,
FP
•
HL
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•
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.
./
'
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Fig. l. Maps of the S-I cortical representation of the hindpaw at different times after nerve injuries in adults rats. In A - G , shading indicates the region of S-I cortex responding to saphenous nerve inputs from the hindpaw. Part A shows the area activated by the saphenous nerve in a normal animal, B - D show the expanded saphenous areas determined at increasing times after nerve transection and ligation, E - G show expanded saphenous areas at similar times following ablation of the sciatic nerve by ricin, and H shows the total saphenous plus sciatic hindpaw area in a normal animal. Each map illustrates data from an individual rat whose saphenous area is near the mean for that time interval. Thus, maps from individual animals show expansion of the saphenous area within the first week after injury (B,E), followed by little additional increase 4-5 months after injury (C,F). At 7-9 months postinjury (D,G), the enlarged saphenous area approaches the size of the normal hindpaw representation (H, sciatic plus saphenous areas). Large dots indicate recording sites where neurons responded to low threshold mechanical stimuli, whereas small dots denote sites unresponsive to these stimuli. ANT., anterior; FL, forelimb; FP, forepaw; HL, hindlimb; MED., medial; TR, trunk.
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Fig. 2. Temporal progression of enlargement of the saphenous representation after sciatic nerve transection or ricin ablation. Some of the data used to compile time course curves were used in previous descriptions of other aspects of cortical reorganization in this system2 '26'27. The dosed circles indicate mean areas for animals that had undergone nerve transection and ligation, and the open circles indicate means for the ricin-treated group. The circled stars to the left and right of the curves indicate normal area measures for the saphenous and total hindpaw representations, respectively. The development of saphenous expansion is tracked from the day of injury to a time 7-8 months later when the saphenous area is statistically indistinguishable from the normal total hindpaw area. Standard deviations for groups in the first 3 days after injury, omitted on the figure for clarity, are 0.18, 0.16 and 0.04 mm 2 respectively.
357
the normal hindpaw area. Fourth, at 7-8 months and longer, the saphenous representation is not significantly different from the size of the normal total hindpaw representation (Fig. 2; t[ll] = 1.258, P > 0.05 and t[12] = 0.281, P > 0.05). This sequence of change is evident whether the data are expressed in 60- (e.g. Fig. 2), 30-, 50- or 90-day intervals. It is important to note that the time course curve does not describe the sequence of cortical reactivation in individual rats, although it is consistent with individual maps at different times (e.g. Fig. 1). Given the variability in the data from 3-6 months after injury, one possible explanation is that, after the initial rapid reorganization, the recovery of cortical responsiveness occurs slowly and at different rates in different animals. By 7-8 months after injury, almost all animals have fully reactivated the S-I hindpaw area. The temporal progression of cortical reactivation after ablation of the sciatic nerve with ricin resembles that following nerve transection in several respects. As shown previously27, the saphenous expansion by the end of the first week is similar. During the subsequent 1-4 months after ricin application, the rate of expansion is attenuated (Fig. 2), as in the nerve transection group. By 5-6 months after ricin treatment, the mean saphenous representation is about 57% above normal, but remains significantly smaller than the total hindpaw area in normal rats (t[13] = 3.43, P < 0.01). Over the interval 5-8 months postinjury, the saphenous area undergoes slow expansion similar to that in the transection group. Finally, by 7-8 months after ricin treatment, the saphenous area is not significantly different in size from the normal hindpaw area (t[13] = 0.11, P > 0.05). Nerve transection produces only modest loss of sciatic dorsal root ganglion cells, whereas ablation by ricin leads to massive death of sciatic neurons 27'3°. The similar time course of cortical reactivation after these two treatments indicates that surviving primary afferent neurons are not required for either phase of remodeling to occur. In contrast to these similarities, the saphenous area in the ricin treatment group appears to be shifted above the level of the transection group at all time intervals (Fig. 2). Although there is no overall statistical difference between the ricin and transection groups (t[6] = 0.405, P > 0.05), the consistent offsetting of the curves suggests that the rate or magnitude of cortical reorganization may, to some degree, reflect peripheral cell loss. The present study provides the first quantitative description of cortical reorganization from the time of a peripheral injury to a time when deprived cortical areas appear completely reactivated. Cortical changes occur with both early (hours to days) and late (months) onset times, the rates of cortical reorganization differ at
different times after injury, and cortical reorganization is cumulative. The results imply that functional assessments at intermediate times after nerve injuries may not fully reveal the ability of the central nervous system to reorganize. These findings are consistent with previous studies of cortical reorganization that demonstrate acute changes, including both immediate shifting of receptive field locations and the appearance of unresponsive cortical regions, within hours or a few days after nerve injury 1' 6,8,14.16.20,26,27. Previous studies also show that somatotopic reorganization remains evident many months to years after injury6-8'13-15'1s'2°'24'26-28, but the qualitative nature of previous observations, combined with sampling at widely spaced times after injury, do not allow definition of the temporal progression of change. As a result it has been difficult to assess the relative contribution that early and late onset changes make to cortical reorganization at different postinjury times. From the present findings, it is clear that the reorganization observed at longer times is not due to a simple prolonged maintenance of acute changes. Late cortical expansion can approximately equal the early changes. It is widely thought that the rapid onset of postinjury shifts in central receptive fields is due to increased efficacy of pre-existing or latent connections which are unmasked following loss of dominant inputs 3"5'25'29. Putative mechanisms for rapidly developed changes include, for example, increases in the efficacy of excitatory synapses, and shifts in the balance of excitatory and inhibitory connections at cortical and subcortical levels of the neuraxis 1'3-5'9'12'16'17'2°'25'29. Explanations for cortical changes observed at longer times after nerve injury have not been possible because neither the onset nor the rate of late reorganization have been discriminated temporally from acute changes. Recent evidence indicates that peripheral injury in adults does not produce long distance anatomical sprouting along the ascending somatosensory neuraxis 1°'19'21'22. Given this view, it seems plausible that early and late cortical changes both involve local synaptic reorganization, but that late, slowly developing cortical changes do not occur unless neurons and synapses are appropriately conditioned by a 'priming' sequence of earlier changes. From the present findings it is clear that cortical reorganization continues long after nerve injury. This implies that amputation injuries that deprive large extents of somatosensory cortex of inputs also lead to prolonged reorganization. Thus, late onset changes may underlie such temporally related phenomena as telescoping of perceived sensations from phantom limbs which can occur at long times after injury 11'23.
358 We thank Tim Murphy for technical assistance, and Dr. Preston Garraghty for comments on an earlier version of the manuscript.
Supported by NIH Grant DE07695.
1 Calford, M.B. and Tweedale, R., Immediate and chronic changes in responses of somatosensory cortex in adult flying-fox after digit amputation, Nature, 332 (1988) 446-448. 2 Cusick, C.G., Whiting, J. and Wall, J.T., Rapid and slow cortical reorganization after nerve injury, Anat. Rec., 223 (1989) 30A. 3 Devor, M., On mechanisms of somatotopic plasticity. In L.M. Pubols and B.J. Sessle (Eds.), Effects of Injury on Trigeminal and Spinal Somatosensory Systems, Alan R. Liss, New York, 1987, pp. 215-225. 4 Devor, M. and Wall, J.T., Plasticity in the spinal cord sensory map following peripheral nerve injury in rats, J. Neurosci., 1 (1981) 679-684. 5 Dostrovsky, J.O., Miilar, J. and Wall, P.D., The immediate shift of afferent drive of dorsal column nucleus cells following deafferentation: a comparison of acute and chronic deafferentation in gracile nucleus and spinal cord, Exp. Neurol., 52 (1976) 480-495. 6 Franck, J.I., Functional reorganization of cat somatic sensorymotor cortex (SmI) after selective dorsal root rhizotomies, Brain Research, 186 (1980) 458-462. 7 Kalaska, J. and Pomeranz, B., Chronic paw denervation causes an age-dependent appearance of novel responses from forearm in 'paw cortex' of kittens and adult cats, J. Neurophysiol., 42 (1979) 618-633. 8 Kelahan, A.M. and Doetsch, G.S., Time-dependent changes in the functional organization of somatosensory cerebral cortex following digit amputation in adult raccoons, Somatosens. Res., 2 (1984) 49-81. 9 Markus, H., Pomeranz, B. and Krushelnycky, D., Spread of saphenous somatotopic projection map in spinal cord and hypersensitivity of the foot after chronic sciatic denervation in adult rat, Brain Research, 296 (1984) 27-39. 10 McKinley, P.A. and Kruger, L., Non-overlapping thalamocortical connections to normal and deprived primary somatosensory cortex for similar forelimb receptive fields in chronic spinal cats, Somatosens. Motor Res., 5 (1988) 311-323. 11 Melzack, R., Phantom limbs and the concept of a neuromatrix, Trends Neurosci., 13 (1990) 88-92. 12 Mendell, L.M., Modifiability of spinal synapses, Physiol. Rev., 64 (1984) 260-324. 13 Merzenich, M.M., Kaas, J.H., Wall, J.T., Nelson, R.J., Sur, M. and Felleman, D.J., Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation, Neuroscience, 8 (1983) 33-55. 14 Merzenich, M.M., Kaas, J.H., Wall, J.T., Sur, M., Nelson, R.J. and Felleman, D.J., Progression of change following median nerve section in the cortical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys, Neuroscience, 10 (1983) 639-665. 15 Merzenich, M.M., Nelson, R.J., Stryker, M.P., Cynader, M.S., Schoppmann, A. and Zook, J.M., Somatosensory cortical map
changes following digit amputation in adult monkeys, J. Comp. Neurol., 224 (1984) 591-605. 16 Metzler, J. and Marks, P.S., Functional changes in cat somatic sensory-motor cortex during short-term reversible epidural blocks, Brain Research, 177 (1979) 379-383. 17 Pollin, B. and Albe-Fessard, D., Organization of somatic thalamic in monkeys with and without section of dorsal spinal tracts, Brain Research, 173 (1979) 431-449. 18 Rasmusson, D.D., Reorganization of raccoon somatosensory cortex following removal of the fifth digit, J. Comp. Neurol., 205 (1982) 313-326. 19 Rasmusson, D.D. and Nance, D.M., Non-overlapping thalamocortical projection for separate forepaw digits before and after cortical reorganization in the raccoon, Brain Res. Bull., 16 (1986) 399-406. 20 Rasmusson, D.D. and Turnbull, B.G., Immediate effects of digit amputation on SI cortex in the raccoon: unmasking of inhibitory fields, Brain Research, 288 (1983) 368-370. 21 Rodin, B.E., Sampogna, S.L. and Kruger, L., An examination of intraspinal sprouting in dorsal root axons with the tracer horseradish peroxidase, J. Comp, Neurol., 215 (1983) 187-198. 22 Seltzer, Z. and Devor, M., Effect of nerve section on the spinal distribution of neighboring nerves, Brain Research, 306 (1984) 31-44. 23 Solonen, K.A., The phantom phenomenon in amputated Finnish war veterans, Acta Orthopaed. Scand., Suppl. 54 (1962) 1-37. 24 Waite, P.M.E., Rearrangement of neuronal responses in the trigeminai system of the rat following peripheral nerve section, J. Physiol., 352 (1984) 425-445. 25 Wall, J.T., Variable organization in cortical maps of the skin as an indication of the lifelong adaptive capacities of circuits in the mammalian brain, Trends Neurosci., 11 (1988) 549-557. 26 Wall, J.T. and Cusick, C.G., Cutaneous responsiveness in primary somatosensory (S-I) hindpaw cortex before and after partial hindpaw deafferentation in adult rats, J. NeuroscL, 4 (1984) 1499-1515. 27 Wall, J.T., Cusick, C.G., Migani-Wall, S.A. and Wiley, R.G., Cortical organization after treatment of a peripheral nerve with ricin: an evaluation of the relationship between sensory neuron death and cortical adjustments after nerve injury, J. Comp. Neurol., 277 (1988) 578-592. 28 Wall, J.T. and Kaas, J.H., Long-term cortical consequences of reinnervation errors after nerve regeneration in monkeys, Brain Research, 372 (1976) 400-404. 29 Wall, P.D., The presence of ineffective synapses and the circumstances which unmask them, Philos. Trans. R. Soc. Lond. B., 278 (1977) 361-372. 30 Wiley, R.G. and Oeltmann, T.N., Anatomically selective peripheral nerve ablation using intraneural riein injection, J. Neurosci. Methods, 17 (1986) 43-53.
