Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct

Science

Volumn 272, Issue 5269, 1996, Pages 1791-1794

  Nudo, Randolph J ^a   Wise, Birute M ^a   SiFuentes, Frank ^a   Milliken, Garrett W ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL EXPERIMENT; ARTICLE; BRAIN INFARCTION; BRAIN ISCHEMIA; MOTOR ACTIVITY; MOTOR CORTEX; MUSCLE INNERVATION; NONHUMAN; PARALYSIS; PRIORITY JOURNAL; SQUIRREL MONKEY;

ANIMALIA; PRIMATES; SAIMIRI; SCIURIDAE;

EID: 0030017218     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.272.5269.1791     Document Type: Article

References (43)

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14. A recent study with ICMS techniques in rats suggests that the region adjacent to a damaged portion of the motor cortex reorganizes after behavioraliy contingent electrical stimulation of the ventral tegmentum [M. A Castro-Alamancos, L M. Garcia-Sequia, J. Borrell, Eur. J. Neurosci. 4, 853 (1992)].
15. R J. Nudo, G. W Milliken, W M Jenkins, M. M. Merzenich, J. Neurosci. 16, 785 (1996).
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17. P. L. Strick and J. B. Preston, J. Neurophysiol. 48, 139 (1982); H. J. I. Gould, C. G. Cusick, T P Pons, J. H. Kaas. J. Comp. Neurol 247, 297 (1986); J. P Donoghue, S. Leibovic, J N. Sanes, Exp. Brain Res. 89, 1 (1992); R. J. Nudo, W. M. Jenkins, M. M. Merzenich, T. Prejean, R. Gedela, J. Neurosci 12, 2918 (1992)
18. P. L. Strick and J. B. Preston, J. Neurophysiol. 48, 139 (1982); H. J. I. Gould, C. G. Cusick, T P Pons, J. H. Kaas. J. Comp. Neurol 247, 297 (1986); J. P Donoghue, S. Leibovic, J N. Sanes, Exp. Brain Res. 89, 1 (1992); R. J. Nudo, W. M. Jenkins, M. M. Merzenich, T. Prejean, R. Gedela, J. Neurosci 12, 2918 (1992)
19. P. L. Strick and J. B. Preston, J. Neurophysiol. 48, 139 (1982); H. J. I. Gould, C. G. Cusick, T P Pons, J. H. Kaas. J. Comp. Neurol 247, 297 (1986); J. P Donoghue, S. Leibovic, J N. Sanes, Exp. Brain Res. 89, 1 (1992); R. J. Nudo, W. M. Jenkins, M. M. Merzenich, T. Prejean, R. Gedela, J. Neurosci 12, 2918 (1992)
20. R J. Nudo and G. W Milliken, J. Neurophysiol. 75, 2144 (1996). Average losses for digit and wristforearm representational areas were 57 and 25%, respectively.
21. Eight adult male squirrel monkeys (Saimiri boliviensis spp.) were used in the present study Four monkeys were randomly assigned to a training group and four to a control group (no infarct, no training). The control group served to assess the relative stability of ICMS-derived motor maps in the absence of any manipulation other than the mapping procedure itself. After determination of hand preference (8), a jacket was placed on each monkey with a sleeve that extended the length of the nonpreferred forelimb, covering the hand. The monkey wore the jacket for the remainder of the experiment (both pre- and postinfarct periods), except during surgical procedures In normal monkeys, this jacket does not markedly impair pellet retrieval. Training was conducted with a rectangular Plexiglas board containing five food wells of different diameters, ranging from 9.5 to 25 mm. Two 30-min sessions were conducted per day. The target well size was gradually titrated to produce progressively more retrievals from the smaller wells, until all training trials were conducted on the smallest well Preinfarct training continued until 600 pellets were retrieved from the smallest well on each of two consecutive days (criterion performance) On the two subsequent preinfarct days, sessions consisted of 25 probe trials followed by training trials During probe trials, a single 45-mg banana-flavored food pellet was placed randomly into one of the five wells, and the animal was allowed to retrieve it. During training trials, a single food pellet was placed into the target well. Sessions consisting of a combination of probe and training trials were continued during the postinfarct period to track recovery.
22. Under sterile conditions and halothane-nitrous oxide anesthesia, the primary motor cortex was exposed. A small cylinder was fitted over the opening and filled with warm, sterile silicone oil. Halothane was withdrawn, ketamine-acepromazine was administered, and vital signs were monitored throughout the remainder of the experiment A glass micropipette filled with 3.5 M NaCl served as the microelectrode It was introduced on a fine grid pattern, sited with reference to the surface vasculature (interpenetration distances of ∼250 μm), and then advanced perpendicular to the cortical surface to a depth of 1700 to 1800 μm (layer V). Movement fields were defined by determining movements evoked by ICMS with near-threshold current levels (maximum current, 30 μA). For further details of these procedures and a discussion of the possible sources of variation in ICMS-defined motor maps, see (8, 9).
23. A computer algorithm was used to delineate functional boundaries of movement representations unambiguously. The hand representation, as defined here, comprises cortical regions in which ICMS evoked distal forelimb movements at near-threshold current levels. These distal forelimb movements include finger, thumb, wrist, and forearm (supiriation and pronation) movements but exclude elbow and shoulder movements. The mosaical representations of movements in the primary motor cortex have been noted in several mapping studies in primates, including humans (8, 22) [J. N. Sanes, J P. Donoghue, V. Thangaraj, R. R Edelman, S. Warach, Science 268, 1775 (1995)] After completion of these experiments, each animal was injected with a lethal dose of pentobarbital (100 mg per kilogram of body mass) and perfused for histological examination.
24. Monkeys were anesthetized with halothane-nitrous oxide A small functional zone was identified in the motor cortex contralateral to the preferred hand with the use of previously derived representational maps. This zone comprised 26.7 ± 8.5% (mean ± SD) of the total hand area and contained a larger proportion of digit than wrist-forearm representational area (31.5 and 16.6%, respectively) Blood vessels supplying this cortical zone were permanently occluded where they entered the cortical surface with the use of microforceps connected to a bipolar electrocoagulator. This technique consistently produced focal, columnar infarcts through all six layers of the cerebral neocortex that were of predictable size and did not extend into the underlying white matter (10) These procedures were approved by the University of Texas Institutional Animal Care and Use Committee.
25. The fourth monkey did not survive the postinfarct mapping session.
26. Because two monkeys made no retrievals from the smallest well on the first postinfarct training days, the number of flexions per retrieval was derived from the first 10 retrievals, spanning 1 to 3 days.
27. In a third monkey, relapse was not apparent because manual skill was much more variable In a fourth monkey, no attempts were made until postinfarct day 13, after which manual skill gradually improved.
28. Statistical analyses were performed with a factorial analysis of variance design to examine variation in the percentage change in each movement area among the three groups (P ≤ 0.05), Post hoc multiple comparisons (Bonferroni-Dunn) were then performed to determine which pairwise comparisons contributed to significant main effects. Pairwise comparisons were not significant unless the P-value was <0 0167 In both pre- and postinfarct maps, only representations in the cortex outside of the infarct zone were considered for analysis.
29. Alternatively, the differential changes observed in digit and wrist-forearm areas may be related to the location of the infarcts. In each instance, the infarct destroyed a greater proportion of digit, as opposed to wrist-forearm, area.
30. Infarct size and location were similar in the two groups (size: t = 0.37, P = 073) However, it is possible that changes in monkeys undergoing rehabilitation were attributable to the relatively short interval between pre- and postinfarct mapping procedures (4 to 5 weeks). Preliminary results from two additional monkeys indicate that the loss in the spared hand representational area after an infarct and spontaneous recovery are greater at 1 month than at 3 to 4 months [R. J Nudo, B. M Wise, F. SiFuentes, Soc. Neurosci. Abstr. 21, 517 (1995)]. Thus, if time after infarct had been matched, the difference between the spontaneous recovery group and the rehabilitation group would probably have been greater
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43. We thank K. Fnel, G. Gardner, R Grenda, C. Knox, and R Raiszadeh for technical assistance and P Kelly for critical comments on an earlier draft of the manuscript. Supported by grants from the National Institute of Neurological Diseases and Stroke (NS 27974 and NS 30853) and the American Heart Association. This research was done during the tenure of an Established Investigatorship award to R.J N. from the American Heart Association