Influence of anti-Nogo-A antibody treatment on the reorganization of callosal connectivity of the premotor cortical areas following unilateral lesion of primary motor cortex (M1) in adult macaque monkeys

Following unilateral lesion of the primary motor cortex, the reorganization of callosal projections from the intact hemisphere to the ipsilesional premotor cortex (PM) was investigated in 7 adult macaque monkeys, in absence of treatment (control; n=4) or treated with function blocking antibodies against the neurite growth inhibitory protein Nogo-A (n=3). After functional recovery, though incomplete, the tracer biotinylated dextran amine (BDA) was injected in the ipsilesional PM. Retrogradely labelled neurons were plotted in the intact hemisphere and their number was normalized with respect to the volume of the core of BDA injection sites. (1) The callosal projections to PM in the controls originate mainly from homotypic PM areas and, but to a somewhat lesser extent, from the mesial cortex (cingulate and supplementary motor areas). (2) In the lesioned anti-Nogo-A antibody-treated monkeys, the normalized number of callosal retrogradely labelled neurons was up to several folds higher than in controls, especially in the homotypic PM areas. (3) Except one control with a small lesion and a limited, transient deficit, the anti-Nogo-A antibody-treated monkeys recovered to nearly baseline levels of performance (73-90%), in contrast to persistent deficits in the control monkeys. These results are consistent with a sprouting and/or sparing of callosal axons promoted by the anti-Nogo-A antibody treatment after lesion of the primary motor cortex, as compared to untreated monkey

Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys

Although the arrangement of the corticospinal projection in primates is consistent with a more prominent role of the ipsilateral motor cortex on proximal muscles, rather than on distal muscles involved in manual dexterity, the role played by the primary motor cortex on the control of manual dexterity for the ipsilateral hand remains a matter a debate, either in the normal function or after a lesion. We, therefore, tested the impact of permanent unilateral motor cortex lesion on the manual dexterity of the ipsilateral hand in 11 macaque monkeys, within a time window of 60days post-lesion. For comparison, unilateral reversible pharmacological inactivation of the motor cortex was produced in an additional monkey. Manual dexterity was assessed quantitatively based on three motor parameters derived from two reach and grasp manual tasks. In contrast to the expected dramatic, complete deficit of manual dexterity of the contralesional hand that persists for several weeks, the impact on the manual dexterity of the ipsilesional hand was generally moderate (but statistically significant) and, when present, lasted less than 20days. Out of the 11 monkeys, only 3 showed a deficit of the ipsilesional hand for 2 of the 3 motor parameters, and 4 animals had a deficit for only one motor parameter. Four monkeys did not show any deficit. The reversible inactivation experiment yielded results consistent with the permanent lesion data. In conclusion, the primary motor cortex exerts a modest role on ipsilateral manual dexterity, most likely in the form of indirect hand postural contro

Catalytical performance of heteroatom doped and undoped carbon-based materials

Developing cost-effective, eco-friendly, efficient, stable, and unique catalytic systems remains a crucial issue in catalysis. Due to their superior physicochemical and electrochemical properties, exceptional structural characteristics, environmental friendliness, economic productivity, minimal energy demand, and abundant supply, a significant amount of research has been devoted to the development of various doped carbon materials as efficient catalysts. In addition, carbon-based materials (CBMs) with specified doping have lately become significant members of the carbon group, showing promise for a broad range of uses (e.g., catalysis, environmental remediation, critical chemical production, and energy conversion and storage). This study will, therefore, pay attention to the function of heteroatom-based doped and undoped CBMs for catalytical applications and discuss the underlying chemistries of catalysis. According to the findings, doping CBMs may greatly improve their catalytic activity, and heteroatom-doped CBMs may be a promising option for further metal doping to attach them to an appropriate place. This paper also covers the potential applications of both doped and undoped CBMs in the future

Behavioral Assessment of Manual Dexterity in Non-Human Primates

The corticospinal (CS) tract is the anatomical support of the exquisite motor ability to skillfully manipulate small objects, a prerogative mainly of primates1. In case of lesion affecting the CS projection system at its origin (lesion of motor cortical areas) or along its trajectory (cervical cord lesion), there is a dramatic loss of manual dexterity (hand paralysis), as seen in some tetraplegic or hemiplegic patients. Although there is some spontaneous functional recovery after such lesion, it remains very limited in the adult. Various therapeutic strategies are presently proposed (e.g. cell therapy, neutralization of inhibitory axonal growth molecules, application of growth factors, etc), which are mostly developed in rodents. However, before clinical application, it is often recommended to test the feasibility, efficacy, and security of the treatment in non-human primates. This is especially true when the goal is to restore manual dexterity after a lesion of the central nervous system, as the organization of the motor system of rodents is different from that of primates1,2. Macaque monkeys are illustrated here as a suitable behavioral model to quantify manual dexterity in primates, to reflect the deficits resulting from lesion of the motor cortex or cervical cord for instance, measure the extent of spontaneous functional recovery and, when a treatment is applied, evaluate how much it can enhance the functional recovery

Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys

Although the arrangement of the corticospinal projection in primates is consistent with a more prominent role of the ipsilateral motor cortex on proximal muscles, rather than on distal muscles involved in manual dexterity, the role played by the primary motor cortex on the control of manual dexterity for the ipsilateral hand remains a matter a debate, either in the normal function or after a lesion. We, therefore, tested the impact of permanent unilateral motor cortex lesion on the manual dexterity of the ipsilateral hand in 11 macaque monkeys, within a time window of 60 days post-lesion. For comparison, unilateral reversible pharmacological inactivation of the motor cortex was produced in an additional monkey. Manual dexterity was assessed quantitatively based on three motor parameters derived from two reach and grasp manual tasks. In contrast to the expected dramatic, complete deficit of manual dexterity of the contralesional hand that persists for several weeks, the impact on the manual dexterity of the ipsilesional hand was generally moderate (but statistically significant) and, when present, lasted less than 20 days. Out of the 11 monkeys, only 3 showed a deficit of the ipsilesional hand for 2 of the 3 motor parameters, and 4 animals had a deficit for only one motor parameter. Four monkeys did not show any deficit. The reversible inactivation experiment yielded results consistent with the permanent lesion data. In conclusion, the primary motor cortex exerts a modest role on ipsilateral manual dexterity, most likely in the form of indirect hand postural control

Autologous adult cortical cell transplantation enhances functional recovery following unilateral lesion of motor cortex in primates: a pilot study

BACKGROUND: Although cell therapy is a promising approach after cerebral cortex lesion, few studies assess quantitatively its behavioral gain in nonhuman primates. Furthermore, implantations of fetal grafts of exogenous stem cells are limited by safety and ethical issues.OBJECTIVE: To test in nonhuman primates the transplantation of autologous adult neural progenitor cortical cells with assessment of functional outcome.METHODS: Seven adult macaque monkeys were trained to perform a manual dexterity task, before the hand representation in motor cortex was chemically lesioned unilaterally. Five monkeys were used as control, compared with 2 monkeys subjected to different autologous cells transplantation protocols performed at different time intervals.RESULTS: After lesion, there was a complete loss of manual dexterity in the contralesional hand. The 5 "control" monkeys recovered progressively and spontaneously part of their manual dexterity, reaching a unique and definitive plateau of recovery, ranging from 38% to 98% of prelesion score after 10 to 120 days. The 2 "treated" monkeys reached a first spontaneous recovery plateau at about 25 and 40 days postlesion, representing 35% and 61% of the prelesion performance, respectively. In contrast to the controls, a second recovery plateau took place 2 to 3 months after cell transplantation, corresponding to an additional enhancement of functional recovery, representing 24% and 37% improvement, respectively.CONCLUSIONS: These pilot data, derived from 2 monkeys treated differently, suggest that, in the present experimental conditions, autologous adult brain progenitor cell transplantation in a nonhuman primate is safe and promotes enhancement of functional recovery

Refined methodology for implantation of a head fixation device and chronic recording chambers in non-human primates

The present study was aimed at developing a new strategy to design and anchor custom-fitted implants, consisting of a head fixation device and a chronic recording chamber, on the skull of adult macaque monkeys. This was done without the use of dental resin or orthopedic cement, as these modes of fixation exert a detrimental effect on the bone. The implants were made of titanium or tekapeek and anchored to the skull with titanium screws. Two adult macaque monkeys were initially implanted with the head fixation device several months previous to electrophysiological investigation, to allow optimal osseous-integration, including growth of the bone above the implant's footplate. In a second step, the chronic recording chamber was implanted above the brain region of interest. The present study proposes two original approaches for both implants. First, based on a CT scan of the monkey, a plastic replicate of the skull was obtained in the form of a 3D print, used to accurately shape and position the two implants. This would ensure a perfect match with the skull surface. Second, the part of the implants in contact with the bone was coated with hydroxyapatite, presenting chemical similarity to natural bone, thus promoting excellent osseous-integration. The longevity of the implants used here was 4 years for the head fixation device and 1.5 years for the chronic chamber. There were no adverse events and daily care was easy. This is clear evidence that the present implanting strategy was successful and provokes less discomfort to the animals

Effects of unilateral motor cortex lesion on ipsilesional hand's reach and grasp performance in monkeys: relationship with recovery in the contralesional hand

Manual dexterity, a prerogative of primates, is under the control of the corticospinal (CS) tract. As 90-95% of CS axons decussate, it is assumed that this control is exerted essentially on the contralateral hand. Consistently, unilateral lesion of the hand representation in the motor cortex is followed by a complete loss of dexterity of the contralesional hand. During the months following lesion, spontaneous recovery of manual dexterity takes place to a highly variable extent across subjects, although largely incomplete. In the present study, we tested the hypothesis that after a significant post-lesion period, manual performance in the ipsilesional hand is correlated with the extent of functional recovery in the contralesional hand. To this aim, ten adult macaque monkeys were subjected to permanent unilateral motor cortex lesion. Monkeys' manual performance was assessed for each hand during several months post-lesion, using our standard behavioral test (modified Brinkman board task) that provides a quantitative measure of reach and grasp ability. The ipsilesional hand's performance was found to be significantly enhanced on the long-term (100-300 days post-lesion) in 6 out of 10 monkeys, with the six exhibiting the best, though incomplete, recovery of the contralesional hand. There was a statistically significant correlation (r=0.932; p0.001) between performance in the ipsilesional hand after significant post-lesion period and the extent of recovery of the contralesional hand. This observation is interpreted in terms of different possible mechanisms of recovery, dependent on the recruitment of motor areas in the lesioned and/or intact hemispheres

Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates

The nonhuman primate model is suitable to study mechanisms of functional recovery following lesion of the cerebral cortex (motor cortex), on which therapeutic strategies can be tested. To interpret behavioral data (time course and extent of functional recovery), it is crucial to monitor the properties of the experimental cortical lesion, induced by infusion of the excitotoxin ibotenic acid. In two adult macaque monkeys, ibotenic acid infusions produced a restricted, permanent lesion of the motor cortex. In one monkey, the lesion was monitored over 3.5 weeks, combining laser speckle imaging (LSI) as metabolic readout (cerebral blood flow) and anatomical assessment with magnetic resonance imaging (T2-weighted MRI). The cerebral blood flow, measured online during subsequent injections of the ibotenic acid in the motor cortex, exhibited a dramatic increase, still present after one week, in parallel to a MRI hypersignal. After 3.5 weeks, the cerebral blood flow was strongly reduced (below reference level) and the hypersignal disappeared from the MRI scan, although the lesion was permanent as histologically assessed post-mortem. The MRI data were similar in the second monkey. Our experiments suggest that LSI and MRI, although they reflect different features, vary in parallel during a few weeks following an excitotoxic cortical lesion

Influence of anti-Nogo-A antibody treatment on the reorganization of callosal connectivity of the premotor cortical areas following unilateral lesion of primary motor cortex (M1) in adult macaque monkeys

Following unilateral lesion of the primary motor cortex, the reorganization of callosal projections from the intact hemisphere to the ipsilesional premotor cortex (PM) was investigated in 7 adult macaque monkeys, in absence of treatment (control; n = 4) or treated with function blocking antibodies against the neurite growth inhibitory protein Nogo-A (n = 3). After functional recovery, though incomplete, the tracer biotinylated dextran amine (BDA) was injected in the ipsilesional PM. Retrogradely labelled neurons were plotted in the intact hemisphere and their number was normalized with respect to the volume of the core of BDA injection sites. (1) The callosal projections to PM in the controls originate mainly from homotypic PM areas and, but to a somewhat lesser extent, from the mesial cortex (cingulate and supplementary motor areas). (2) In the lesioned anti-Nogo-A antibody-treated monkeys, the normalized number of callosal retrogradely labelled neurons was up to several folds higher than in controls, especially in the homotypic PM areas. (3) Except one control with a small lesion and a limited, transient deficit, the anti-Nogo-A antibody-treated monkeys recovered to nearly baseline levels of performance (73-90 %), in contrast to persistent deficits in the control monkeys. These results are consistent with a sprouting and/or sparing of callosal axons promoted by the anti-Nogo-A antibody treatment after lesion of the primary motor cortex, as compared to untreated monkeys