The role of the contralateral cerebral cortical plasticity in functional recovery after cerebral infarction is controversial. To clarify this role, we made a second contralateral cortical infarction after recovery from the first cerebral infarction. To produce the first infarction, Wistar rats were intravenously injected with Rose Bengal to the sensorimotor area of the right hemisphere of the cerebral cortex under green-light irradiation. Two weeks after the first hemiplegia, a secondary infarction was induced in the left cerebral cortex. Functional recovery was evaluated in a beam-walking test. Hemiplegia observed 1 day after both the first and second infarctions was given a score of 1. At 14 days after the first infarction, the average recovery score (± standard error) was 6.8 ± 0.1. In contrast, functional recovery was slower after the second infarction, reaching an average score of only 3.5 ± 0.5 after 14 days. Therefore, recovery after the contralateral secondary infarction was slower than that from the first, and received a lower recovery score compared to the recovery after the first infarction. These results suggest that the undamaged contralateral cortex plays an important role in motor recovery after hemiplegia caused by
cerebral infarction

Harada, Katsuhiro

Ikeda, Satoshi

Kamikawa, Yurie

Ohwatashi, Akihiko

Yoshida, Akira

Eldorado - Ressourcen aus und für Lehre, Studium und Forschung

EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   641 Original article: CONTRALATERAL CORTICAL ROLE ON FUNCTIONAL RECOVERY IN A RAT MODEL OF HEMIPLEGIA  Satoshi Ikeda*, Katsuhiro Harada, Akihiko Ohwatashi, Yurie Kamikawa, Akira Yoshida  Department of Rehabilitation and Physical Medicine,  Graduate School of Medical and Dental Sciences, Kagoshima University  * Corresponding author: Satoshi Ikeda, Department of Rehabilitation and Physical Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University,  8-35-1 Sakuragaoka, Kagoshima-shi, Kagoshima 890-8520, Japan,  Tel.: +81-99-275-5339; Fax: +81-275-1273, E-mail: ikedas@m2.kufm.kagoshima-u.ac.jp  ABSTRACT The role of the contralateral cerebral cortical plasticity in functional recovery after cerebral in-farction is controversial. To clarify this role, we made a second contralateral cortical infarc-tion after recovery from the first cerebral infarction. To produce the first infarction, Wistar rats were intravenously injected with Rose Bengal to the sensorimotor area of the right hemi-sphere of the cerebral cortex under green-light irradiation. Two weeks after the first hemiple-gia, a secondary infarction was induced in the left cerebral cortex. Functional recovery was evaluated in a beam-walking test. Hemiplegia observed 1 day after both the first and second infarctions was given a score of 1. At 14 days after the first infarction, the average recovery score (± standard error) was 6.8 ± 0.1. In contrast, functional recovery was slower after the second infarction, reaching an average score of only 3.5 ± 0.5 after 14 days. Therefore, recov-ery after the contralateral secondary infarction was slower than that from the first, and re-ceived a lower recovery score compared to the recovery after the first infarction. These results suggest that the undamaged contralateral cortex plays an important role in motor recovery af-ter hemiplegia caused by cerebral infarction.  Keywords: Stroke, animal model, recovery, photochemical infarction   INTRODUCTION Plasticity on cerebral cortex has an im-portant role in functional recovery from dysfunction on cerebral infarction. Clinical-ly serious hemiplegia can be caused by re-current contralateral infarctions (Jorgensen et al., 1997; Kim, 1999; Alexander et al., 2010; Paciaroni and Bogousslavsky, 2010; Sterr and Conforto, 2012). Calautti and Baron (2003) reported that the contralateral cortex participates in functional recovery from cerebral infarction. Functional mag-netic resonance imaging (fMRI) studies of patients with hemiparetic stroke clearly demonstrate that bilateral activation occurs in contralesional premotor and motor corti-cal areas during movement of the affected hand (Johansen-Berg et al., 2002). Recovered forelimb function after MCA occlusion was impaired by Lidocaine injec-tion to the contralateral undamaged cortex (Biernaskie et al., 2005). Additionally, adaptive changes take place in the vicinity of the infarction (Frost et al., 2003). Few studies have investigated the role of the contralateral cortex in functional recovery EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   642 after bilateral cortical infarction. A report indicated that there is only relatively weak contralateral participation in an animal model of small infarction (Shanina et al., 2006). However, the role of functional recovery after a large, bilateral infarction has not been studied. Therefore, to clarify the role of contralateral participation after large cerebral infarctions, we studied the functional effects of contralateral secondary infarction after functional recovery from a primary infarction.  MATERIALS AND METHODS Ten eight-week-old male Wistar rats weighing 250 - 300 g were used in this study. The study protocol was carried out in accordance with the guide for animal exper-imentation of the faculty in the department of medicine of Kagoshima University and the guidelines of the US national institute of health. This study was approved by the an-imal experiment committee of Kagoshima University. These animals were housed alone in plastic cages in an environmentally controlled room with a 12/12-hour light-dark cycle ad libitum. Cerebral ischemia was produced via in-travascular thrombosis. This thrombosis was induced by an intravenous injection of Rose Bengal (20 mg/kg) and irradiation by green light (533 nm) for 20 min under deep anesthesia. To target the sensorimotor area of the cerebral cortex, green light of 10 mm diameter was irradiated on the exposed skull at 6 mm lateral to the midline and 4 mm posterior to bregma (Horinouchi et al., 2007). Two weeks after recovery from the first hemiplegia, a secondary infarction was induced in the left cerebral cortex. The postoperative locomotion of rats was evalu-ated using a beam-walking task on an ele-vated narrow beam (1,220 mm length  25 mm width). Performance was rated daily on a 7-point scale. The lowest score, 1, was given if the animal was unable to traverse the beam and could not place the affected hind limb onto the horizontal surface. A score of 2 was given if the animal was una-ble to traverse the beam but placed the af-fected hind limb on the horizontal surface of the beam and maintained balance. An an-imal received a score of 3 if it traversed the beam while dragging the affected hind limb. If an animal traversed the beam and placed the affected hind paw on the horizontal sur-face of the beam at least once, it was given a score of 4. A score of 5 was given if the animal used the affected limb in less than half of the steps along the beam. When an animal traversed the beam and used the af-fected limb to aid more than 50 % of its steps along the beam, it received a score of 6. The highest score, 7, was given if the an-imal traversed the beam normally with few-er than 2 independent foot slips (Feeney et al., 1982). Rats that were given a score of 1 the day after the operation were used in subsequent analysis. After perfusion fixa-tion, animal brains were removed and the infarction area was measured. Statistical analyses were carried out using the Wil-coxon signed-rank test (P < 0.01).   RESULTS Hemiparesis was observed after the first infarction since animals could not traverse the beam or position their affected hind limbs on the horizontal surface. The aver-age scores for left hemiplegia were 1.0, 3.5, 6.8, and 6.8 at 1, 3, 7, and 14 d after the first infarction, respectively. All animals had almost fully recovered from left hemi-plegia by day 14 after the first infarction. In contrast, after the second infarction, the av-erage scores for right hemiplegia were 1.0, 1.2, 2.7, and 3.5 after 1, 3, 7, and 14 d, re-spectively. A significant difference in the rate of recovery was observed only 2 days after the second infarction (Figure 1). On the second day after infarction, the average beam-walking score for the contra-lateral secondary infarction group remained at 1, compared to 3 for the unilateral prima-ry infarction group. After 3 days, animals from the secondary infarction group began EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   643 to recover. Seven days after the procedure, the average score for rats in the secondary infarction group had increased to 2.7, while the score for the unilateral primary infarc-tion group had improved to 6.2. After functional analysis, experimental animal brains were removed to measure the area of infarction. Scar of first infarction is seen on right hemisphere (Figure 2A, B) and subacute infarcted lesion is located on left hemisphere (Figure 2A, C). There was no significant difference between the aver-age area of the affected region in the right hemisphere after the first infarction and corresponding value in the left hemisphere after the second infarction (Table 1).    Figure 1: Changes in functional recovery be-tween first and second contralateral infarctions. The average score for the beam-walking test is shown (n = 10). Circles denote the average score after the first infarction. Squares denote the average scores after the second infarction. Asterisk (*) indicates significant difference (P < 0.01) between first and second infarctions ac-cording to the Wilcoxon signed-rank test.   Table 1: Infarction sizes across all experimental animals. The infarction area (mean ± standard error) for all 10 animals of first and second  infarctions  First  Infarction Second Infarction  Infarcted area (mm2) 39.9 ± 3.3 41.4 ± 4.9 n.s.    Figure 2: Representative brain removed 2 weeks after the second infarction (A) and pho-tomicrograph of sliced section (B, C). The first infarction is located in the right hemisphere (A, B), while the second infarction is located in the left hemisphere (A, C). C B A EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   644 DISCUSSION Previous clinical reports suggest that patients with a contralateral recurrence after their first stroke showed more severe func-tional disability after rehabilitation than did patients with an ipsilateral recurrence (Jor-gensen et al., 1997; Kim, 1999; Alexander et al., 2010; Paciaroni and Bogousslavsky, 2010; Sterr and Conforto, 2012). The pho-tothrombotic ischemic model has been used in recent years (Abo et al., 2001; Horinou-chi et al., 2007; Zheng et al., 2010; Diede-rich et al., 2012) to induce different sized strokes, while decreasing surgical stress in experimental rats. In this study, serious pa-ralysis was shown to result from a series of bilateral secondary infarctions, and this finding mirrors previous clinical reports. Similarly, a study of motor cortical excita-bility in the non-lesioned hemispheres of patients with large cortical infarctions showed that intracortical inhibition was re-duced (Liepert et al., 2000). In a recent clin-ical study using transcranial magnetic stim-ulation, some patients were able to recover upper limb function, suggesting an altera-tion in the cortical representation to the ip-silateral target muscle in the non-affected hemisphere (Summers et al., 2007). Similar-ly, in patients with an infarction of the pos-terior limb of the right internal capsule, the bilateral primary sensorimotor cortices are activated by movements of the affected (left) hand, and ipsilateral motor-evoked potentials are found in the affected muscle after stimulation of the unaffected (left) motor cortex (Kim et al., 2004). Further-more, an fMRI study measuring recovery from infarction in rats showed that electri-cal stimulation of the previously paretic hindlimb activated both the non-damaged contralateral sensorimotor cortex and the region lateral to the damaged area (Abo et al., 2001). Immunohistochemical analysis of brain sections of animal models of in-farction showed that gamma-aminobutyric acid (A)-receptor subunits were observed in the contralateral cortex homotopic to the in-farct (Redecker et al., 2002). These findings suggest that the plasticity of contralateral undamaged cortex plays an important role in cerebral damage. However, in a study of contralateral secondary infarction, Shanina et al. (2006) induced small ischemic cortical infarcts in the sensorimotor cortex and demonstrated that the contralateral cortex homotopic to the lesion plays only a minor role in func-tional recovery. In contrast, this study de-monstrates that recovery from hemiplegia caused by a secondary infarction was relati-vely slow (the average beam-walking score remained at only 3.5 after 2 weeks), sug-gesting participation of the contralateral cortex in functional recovery.  These results suggest that both the con-tralateral cortex and the region surrounding the infarction participate in the functional recovery process. In the present study, the infarct size after the first procedure was rel-atively large leaving only a comparatively small area of intact cortex remaining on the ipsilateral side. Therefore, we consider par-ticipation of the contralateral cortex to be necessary for functional recovery from large cortical lesions. In previous studies on animal models of cerebral infarction, almost all rats recovered from functional disability within 2 weeks (Feeney et al., 1982; Horinouchi et al., 2007). Alternatively, in our bilateral infarc-tion model, functional disability lasted for more than 2 weeks. These findings suggest that our infarction model is more useful for understanding lasting disability.  CONCLUSION Here, we found that functional recovery after a large contralateral secondary infarc-tion was slow and unsatisfactory compared to recovery after a large primary infarction. Our results suggest that the undamaged contralateral cortex plays an important role in motor recovery after hemiplegia caused by large cerebral infarction. Furthermore, we believe that this experimental model ac-curately mirrors lasting disability in patients.  EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   645 CONFLICT OF INTEREST The authors declare no competing fi-nancial interests.  ACKNOWLEDGEMENTS The authors thank the staff of The Fron-tier Science Research Center Kagoshima University to manage animals.  REFERENCES Abo M, Chen Z, Lai LJ, Reese T, Bjelke B. Functional recovery after brain lesion-contralateral neuromodulation: an fMRI study. Neuroreport 2001;12:1543-7.  Alexander LD, Black SE, Gao F, Szilagyi G, Danells CJ, McIlroy WE. Correlating lesion size and location to deficits after ischemic stroke: the influence of accounting for altered peri-necrotic tissue and incident-al silent infarcts. Behav Brain Funct 2010; 6:6.  Biernaskie J, Szymanska A, Windle V, Corbett D. Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur J Neurosci 2005;21:989-99.  Calautti C, Baron JC. Functional neuro-imaging studies of motor recovery after stroke in adults: a review. Stroke 2003;34: 1553-66.  Diederich K, Quennet V, Bauer H, Müller HD, Wersching H, Schäbitz WR et al. Successful regeneration after experimental stroke by granulocyte-colony stimulating factor is not further enhanced by constraint-induced movement therapy either in concurrent or in sequential combination therapy. Stroke 2012;43:185-92.  Feeney DM, Gonzalez A, Law WA. Am-phetamine, haloperidol, and experience interact to affect rate of recovery after mo-tor cortex injury. Science 1982;217:855-7.  Frost SB, Barbay S, Friel KM, Plautz E, Nudo RJ. Reorganization of remote cortical regions after ischemic brain injury: a poten-tial substrate for stroke recovery. J Neuro-physiol 2003;89:3205-14.  Horinouchi K, Ikeda S, Harada K, Ohwatashi A, Kamikawa Y, Yoshida A et al. Functional recovery and expression of GDNF seen in photochemically induced cerebral infarction. Int J Neurosci 2007; 117:315-26.   Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci USA 2002;99: 14518-23.   Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Stroke recurrence: predictors, severity, and prognosis. The Co-penhagen Stroke Study. Neurology 1997; 48:891-5.   Kim JS. Aggravation of poststroke sensory symptoms after a second stroke on the opposite side. Eur Neurol 1999;42:200-4.   Kim YH, Jang SH, Byun WM, Han BS, Lee KH, Ahn SH. Ipsilateral motor path-way confirmed by combined brain mapping of a patient with hemiparetic stroke: a case report. Arch Phys Med Rehabil 2004;85: 1351-3.   Liepert J, Hamzei F, Weiller C. Motor cor-tex disinhibition of the unaffected hemi-sphere after acute stroke. Muscle Nerve 2000;23:1761-3.   EXCLI Journal 2013;12:641-646 – ISSN 1611-2156 Received: May 25, 2013, accepted: July 02, 2013, published: July 17, 2013   646 Paciaroni M, Bogousslavsky J. Primary and secondary prevention of ischemic stroke. Eur Neurol 2010;63:267-78.   Redecker C, Wang W, Fritschy JM, Witte OW. Widespread and long-lasting altera-tions in GABA(A)-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes. J Cereb Blood Flow Metab 2002;22:1463-75.   Shanina EV, Schallert T, Witte OW, Redecker C. Behavioral recovery from uni-lateral photothrombotic infarcts of the fore-limb sensorimotor cortex in rats: role of the contralateral cortex. Neuroscience 2006; 139:1495-506.   Sterr A, Conforto AB. Plasticity of adult sensorimotor system in severe brain in-farcts: challenges and opportunities. Neural Plast 2012;2012:970136 (doi: 10.1155/ 2012/970136).   Summers JJ, Kagerer FA, Garry MI, Hiraga CY, Loftus A, Cauraugh JH. Bilateral and unilateral movement training on upper limb function in chronic stroke patients: A TMS study. J Neurol Sci 2007;252:76-82.   Zheng W, Watts LT, Holstein DM, Prajapa-ti SI, Keller C, Grass EH et al. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mi-tochondria. PLoS One 2010;5:e14401 (doi: 10.1371/journal.pone.0014401).  

Contralateral cortical role on functional recovery in a rat model of hemiplegia

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Contralateral cortical role on functional recovery in a rat model of hemiplegia

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