Recovery of motor control after cortical lesion and polysensory integration in the primate
Stroke is the third most frequent cause of death in industrialized countries and is the most frequent one causing permanent acquired intellectual and physical impairment in adult human subjects. In particular, stroke is the leading cause of motor disability in adult human subjects. Despite recent progress, motor functional recovery remains largely incomplete after stroke.
In the preliminary steps of this study, we found that monkeys treated with an antibody neutralizing Nogo-A, a neurite growth inhibitor, recovered substantially better manual dexterity following unilateral lesion of the opposite primary motor cortex, as compared to monkeys subjected to the same lesion, but not treated with anti-Nogo-A.
These findings are new and of interest because it is the first evidence in adult primates that such anti-Nogo-A treatment may enhance functional recovery of motor control after a lesion of the cerebral cortex located in the primary motor area. The present study thus represents an additional step towards the development of a treatment based on the neutralization of Nogo-A. Indeed, since the pioneering work of Dr. Martin Schwab and his collaborators demonstrating that Nogo-A, produced by oligodendrocytes, prevents regeneration of sectioned nerve fibers in the central nervous system of adult rats, a therapeutical strategy based on the neutralization of Nogo-A was found to be efficient in adult rats subjected to a lesion of the spinal cord (see Schwab, 2004, for review). In contrast to control lesioned rats, anti-Nogo-A treated rats exhibited a regeneration of transected corticospinal axons, correlated with a better recovery of motor function. In recent work, our team provided evidence that the anti-Nogo-A treatment also leads to enhancement of motor recovery in adult monkeys subjected to a lesion of the cervical cord. The present study thus extends these data from spinal cord lesion to cortical lesion, also in adult monkeys. Moreover, our findings also extend to the primates previous observations in the rat that anti-Nogo-A treatment enhanced motor recovery following cortical lesion (Papadopoulos et al., 2002; Emerick et al., 2003; Emerick and Kartje, 2004). The preliminary evidence that anti-Nogo-A strategy is also valid for cortical lesions is of great clinical relevance if one considers that such trauma are far more numerous than spinal lesions.
The present pilot study is conducted on adult monkeys (macaca fascicularis; 3-4 years old), trained in three behavioral tests consisting of reach and prehension tasks, to quantify their manual dexterity for each hand. Once they reach a stable performance (plateau), the hand representation in the primary motor cortex (M1) is precisely located in each hemisphere. To do so, chronic intracorticical microstimulation (ICMS) is applied daily during 3-4 months to map the left and right M1. Sites inM1 are thus identified where electrical stimulation produced movements of the fingers of the opposite hand, thus corresponding to the so-called “hand area”. The digit representation (hand area) of the left M1 is then lesioned by injecting the same volume of ibotenic acid (an excitotoxic drug). A subgroup of monkeys is treated with antibodies neutralizing Nogo-A during 2 weeks, whereas the other subgroup of monkeys is not treated. Following the lesion, the monkeys show a severe paralysis of the contralateral hand, which is reflected by low behavioral scores in the manual dexterity tests, whereas there is no impairment of the ipsilesional hand. The recovery of precision grip is generally nearly complete for the treated monkeys after couple of weeks post-lesion, but remained incomplete for the untreated monkeys, reaching a level of 65% below pre-lesion score.
To investigate if changes took place in the lesioned territory, ICMS sessions are repeated after the plateau of behavioral scores was reached.It is also proposed to assess the post-lesional plastic re-organization of the motor cortex using an optical imaging method (Laser Speckle Imaging).To test whether the re-organized territory in the treated monkey play a role in the functional recovery, it is reversibly inactivated pharmacologically by injecting the GABA agonist muscimol.
The present, preliminary data indicate that treatment with anti-Nogo leads to better and faster recovery after cortical lesion, extending to the primate previous results obtained in the rat. However, further experiments are needed to confirm this preliminary result on a larger number of monkeys.