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Physiological investigation of the motor output from motor cortex after transient and permanent inactivation in sub-human primate treated with an antibody enhancing functional recovery of function, assessed by chronically implanted electrodes.

English title Physiological investigation of the motor output from motor cortex after transient and permanent inactivation in sub-human primate treated with an antibody enhancing functional recovery of function, assessed by chronically implanted electrodes.
Applicant Schmidlin Eric
Number 121646
Funding scheme Ambizione
Research institution Division de Physiologie Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Neurophysiology and Brain Research
Start/End 01.03.2009 - 31.07.2012
Approved amount 589'387.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Pathophysiology

Keywords (4)

cortical lesion; primate; motor system; functional plasticity

Lay Summary (French)

Lead
Lay summary
En neurologie clinique, les lésions cérébrales chez des patients adultes résultent le plus souvent par des déficits moteurs persistants. Ce projet tend à quantifier les changements physiologiques dans la zone cérébrale lésée chez des primates non-humains soumis à un traitement favorisant la régénération neuronale. Les déficits moteurs résultants d’accidents vasculaires cérébraux ou de traumatismes crâniens sont la plupart du temps permanents, le système nerveux central des mammifères adultes (cerveau, moelle épinière) n’ayant pas la possibilité de se régénérer. Un des facteurs responsable a été identifié sur le modèle du rongeur et neutralisé par un anticorps spécifique. Dans une étude faite sur des primates non-humains dont la moelle épinière a été partiellement lésée, la neutralisation de ce facteur a montré une amélioration de la fonction motrice après la lésion en comparaison avec des animaux non-traités. Lors d’une étude faite sur des lésions du cortex sensori-moteur du rongeur, ce traitement a démontré une augmentation significative de la réorganisation fonctionnelle du système moteur. L’effet exact sur la fonction corticale d’un tel traitement nécessite de passer sur le modèle du primate non-humain avant de pouvoir faire l’objet d’une éventuelle étude sur des patients. Nous allons d’abord déterminer dans quelle mesure la fonction du cortex moteur est affectée par la lésion, si les régions motrices secondaires jouent un rôle dans les mécanismes de récupération et ensuite si les changements observés sont influencés par l’application du traitement mentionné. Cette fonction peut être quantifiée grâce aux propriétés excitables des neurones localisés dans le cortex moteur: une stimulation faite par des microélectrodes produit une activité musculaire dans les doigts, mesurable par des enregistrements électromyographiques. On peut ensuite inactiver artificiellement cette portion de cortex et en mesurer les conséquences sur l’activité musculaire. Enfin, on compare les résultats obtenus chez les animaux traités et non-traités. D’autres méthodes sont inclues dans ce projet, à savoir différents tests de dextérité manuelle et l’analyse des changements anatomiques dans le cortex cérébral au moyen de l’imagerie par résonnance magnétique. Les résultats obtenus peuvent avoir une incidence sur une éventuelle application clinique dans une étude plus large, soit directement en utilisant la même base de traitement en cas de lésion corticale, soit en ciblant une réhabilitation sur les régions motrices corticales secondaires.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Behavioral assessment of manual dexterity in non-human primates.
Schmidlin Eric, Kaeser Mélanie, Gindrat Anne-Dominique, Savidan Julie, Chatagny Pauline, Badoud Simon, Hamadjida Adjia, Beaud Marie-Laure, Wannier Thierry, Belhaj-Saif Abderraouf, Rouiller Eric M (2011), Behavioral assessment of manual dexterity in non-human primates., in Journal of visualized experiments : JoVE, (57), 1-16.
Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates.
Peuser Jörn, Belhaj-Saif Abderraouf, Hamadjida Adjia, Schmidlin Eric, Gindrat Anne-Dominique, Völker Andreas Charles, Zakharov Pavel, Hoogewoud Henri-Marcel, Rouiller Eric M, Scheffold Frank (2011), Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates., in Journal of biomedical optics, 16(9), 096011-096011.

Collaboration

Group / person Country
Types of collaboration
Hirnforschung Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Newcastle Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Sobell Dept. of Neurophysiology UCL London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Awards

Title Year
Venia Legendi 2011

Associated projects

Number Title Start Funding scheme
142258 Physiological investigation of the motor output from motor cortex after transient and permanent inactivation in sub-human primate treated with an antibody enhancing functional recovery of function, assessed by chronically implanted electrodes. 01.02.2013 Ambizione
118157 Indicateurs de mesure de la politique culturelle 01.10.2007 DORE project funding
110005 Recovery of motor control after cortical lesion and polysensory-motor integration in the primate 01.10.2005 Project funding

Abstract

The general aim of this project is to investigate the physiological changes of the primary motor cortex (M1) in sub-human primate before and after a permanent lesion, treated with an antibody enhancing the cortical plasticity to restore motor function: the anti-Nogo-A antibody. This approach is based on the stimulation of the hand area of M1 with chronically implanted electrodes and the measurement of the electromyographic (EMG) activity elicited by trains of stimulation in the cortex in the hand muscles. Another point to be investigated is the compensatory mechanisms involved in a permanent lesion, compared to a transient loss of function. As stimulation in the chronically implanted electrodes produces a stable EMG response during several weeks, the effect of the lesions and the treatment can be thus directly compared, including a chronic implantation of EMG electrodes in the targeted muscles. With these permanently fixed electrodes, other cortical mechanisms can be investigated, such as intrahemispheric facilitation and/or inhibition and interhemispheric interactions. In addition, we will try to establish a correlation between electrophysiological changes and the time course of behavioral readouts such as manual dexterity. The behavioral assessment will be twofold: the monkey will perform a Brinkman board task, consisting in emptying 50 wells randomly distributed and the drawer task, consisting simply in opening a drawer and withdrawing the contained food reward. The central nervous system of adult mammals is not capable of spontaneous regeneration in case of lesion, due to two main mechanisms: absence of effective neurotrophic factors and growth inhibitory environment. Nevertheless, the latter has been shown to be blocked by a monoclonal antibody: the anti-Nogo-A antibody. This factor can though promote regeneration and compensatory sprouting in adult mammals suffering from spinal cord or cortical lesion. Personal state of research in the field:The aim of my PhD thesis was to investigate the anatomical, behavioral and electrophysiological consequences of a hemisection of the cervical cord in two groups of non-human primates: one group treated with an antibody directed against growth inhibitory factors normally present in the central nervous system of adult mammals and in a control group subjected to the same lesion, treated with a control antibody. It appeared that the anti-Nogo-A antibody significantly promoted functional recovery of manual dexterity after cervical hemisection. During my post-doctoral fellowship in Prof. Lemon’s lab in London, I developed a new technical tool to access to the cortex with chronically implanted microelectrodes, in order to inactivate the primary motor cortex hand area and to control the function of the motor cortex by recording EMG activity in the hand muscles elicited by cortical stimulation. The aim of the present research proposal is to combine the technique of chronically implanted electrodes in the M1 hand area and chronic EMG electrodes in the contralateral hand muscles, to permanently inactivate this cortical region and to treat the lesioned M1 with the same antibody, that has already shown to improve the functional recovery in rat models of cortical lesion. A microelectrode fixed in M1 hand area did produce stable EMG effect during several months, allowing us to continuously assess the electrophysiological properties of M1 hand area affected by a permanent lesion and treated with the antiNogo-A antibody.The unfolding of this experiment is the following: we will first perform an MRI analysis of the cortical topography to localize the M1 hand area and the arcuate sulcus, landmark for the premotor cortex. We will then train the animal to perform two behavioral tasks requiring high level of manual dexterity: the modified Brinkman board and the so-called “reach and grasp” task, the drawer test. Once the animal has reached a plateau of performance, two chronic chambers will be implanted over the M1 hand area of both hemispheres. IN the same surgery, a polymer grid, made of 64 holes to allow access to the cortex with tungsten microelectrodes that can be let in place, will be fixed inside the chamber. Electrophysiological mapping of M1 hand area will be made with stimulation paradigm consisting in train of 9 to 12 pulses at a maximum of 90 microamps. When a stimulation train elicits single joint movement in the hand muscles, at a threshold of less than 10 microamps, the microelectrode will be fixed in place. In a second surgery, we will then implant chronic EMG electrodes in the targeted muscles of the forelimb. After the acquisition of control data, we will permanently inactivate the M1 hand area by microinfusion of ibotenic acid. Chronic stimulation of the cortex and EMG activity recordings during this recovery period will allow us to observe pathophysiological mechanisms taking place in two animals affected by a permanent lesion of primary motor cortex and in two animals affected by the same lesion but treated with the anti-Nogo-A antibody. Preliminary data:A pilot study tends to show an enhanced functional recovery of manual dexterity in these two behavioral tasks after antiNogo-A antibody treatment of the cortical lesion, compared to the untreated group of animals. The MRI analysis shows a fast disappearance of the hypersignal generated by the cortical lesion. Electrophysiological mapping show several months after the cortical lesion a shrinkage of the hand area of M1 and an extension of region of M1 responsible for more proximal movements. Behavioral data show a dramatic loss of manual dexterity immediately after the cortical lesion, followed by an almost complete functional recovery.Predicted results: The experimental paradigm proposed here, based on an original double chronic implantation approach (in cerebral cortex and in hand muscles), will permit for the first time to precisely and directly compare motor control properties pre- and post-lesion, in order to test several scenarios of recovery from unilateral cortical lesion in primates. We expect that the following mechanisms are likely to be verified (in the hypothetic following order of likelihood):i) The re-appearance of a few microexcitable sites in the lesioned M1 territory (in parallel to the functional recovery), enhanced by anti-Nogo-A treatment, represents the anatomical and functional support for re-establishing the capability of M1 in the lesioned hemisphere to address contralesional hand muscles.ii) As a result of stimulation of the premotor cortex (F5) spared by the lesion in M1, in relation to the anti-Nogo-A treatment, more prominent movements of the hand can be elicited post-lesion than pre-lesion. If verified, such an observation supports the notion of a rewiring (sprouting) of F5 efferents in the cerebral cortex and/or in the spinal cord. iii) The same as ii) may apply for the primary somatosensory cortex (S1). Indeed, a possible role played by S1 in recovery from M1 lesion has been suggested by transient, reversible inactivation of M1 experiments iv) Possibly, F5 and S1 may cooperate to the post-lesional recovery of manual dexterity, to an extent larger in anti-Nogo-A treated monkeys than in control antibody treated monkeys. Such observation would be in line with the post-lesion enhanced connectivity between F5 and S1 observed in squirrel monkeys, an effect that may even be amplified as a result of the anti-Nogo-A treatment.v) The intact hemisphere may exert a stronger influence post- than pre-lesion on the hand affected by the lesion of M1 in the opposite hemisphere. This effect, enhanced in anti-Nogo-A treated monkeys, may be mediated via a re-arrangement and/or functional refinement of the uncrossed corticospinal projection from the intact M1 onto the contralesional hand.
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