Effects of dorsolateral prefrontal cortex lesion on motor habit and performance assessed with manual grasping and control of force in macaque monkeys.

In the context of an autologous adult neural cell ecosystem (ANCE) transplantation study, four intact adult female macaque monkeys underwent a unilateral biopsy of the dorsolateral prefrontal cortex (dlPFC) to provide the cellular material needed to obtain the ANCE. Monkeys were previously trained to perform quantitative motor (manual dexterity) tasks, namely, the "modified-Brinkman board" task and the "reach and grasp drawer" task. The aim of the present study was to extend preliminary data on the role of the prefrontal cortex in motor habit and test the hypothesis that dlPFC contributes to predict the grip force required when a precise level of force to be generated is known beforehand. As expected for a small dlPFC biopsy, neither the motor performance (score) nor the spatiotemporal motor sequences were affected in the "modified-Brinkman board" task, whereas significant changes (mainly decreases) in the maximal grip force (force applied on the drawer knob) were observed in the "reach and grasp drawer" task. The present data in the macaque monkey related to the prediction of grip force are well in line with the previous fMRI data reported for human subjects. Moreover, the ANCE transplantation strategy (in the case of stroke or Parkinson's disease) based on biopsy in dlPFC does not generate unwanted motor consequences, at least as far as motor habit and motor performance are concerned in the context of a sequential grasping a small objects, which does not require the development of significant force levels

Changes of motor corticobulbar projections following different lesion types affecting the central nervous system in adult macaque monkeys.

Functional recovery from central nervous system injury is likely to be partly due to a rearrangement of neural circuits. In this context, the corticobulbar (corticoreticular) motor projections onto different nuclei of the ponto-medullary reticular formation (PMRF) were investigated in 13 adult macaque monkeys after either, primary motor cortex injury (MCI) in the hand area, or spinal cord injury (SCI) or Parkinson's disease-like lesions of the nigro-striatal dopaminergic system (PD). A subgroup of animals in both MCI and SCI groups was treated with neurite growth promoting anti-Nogo-A antibodies, whereas all PD animals were treated with autologous neural cell ecosystems (ANCE). The anterograde tracer BDA was injected either in the premotor cortex (PM) or in the primary motor cortex (M1) to label and quantify corticobulbar axonal boutons terminaux and en passant in PMRF. As compared to intact animals, after MCI the density of corticobulbar projections from PM was strongly reduced but maintained their laterality dominance (ipsilateral), both in the presence or absence of anti-Nogo-A antibody treatment. In contrast, the density of corticobulbar projections from M1 was increased following opposite hemi-section of the cervical cord (at C7 level) and anti-Nogo-A antibody treatment, with maintenance of contralateral laterality bias. In PD monkeys, the density of corticobulbar projections from PM was strongly reduced, as well as that from M1, but to a lesser extent. In conclusion, the densities of corticobulbar projections from PM or M1 were affected in a variable manner, depending on the type of lesion/pathology and the treatment aimed to enhance functional recovery

Cortical Projection From the Premotor or Primary Motor Cortex to the Subthalamic Nucleus in Intact and Parkinsonian Adult Macaque Monkeys: A Pilot Tracing Study.

Besides the main cortical inputs to the basal ganglia, via the corticostriatal projection, there is another input via the corticosubthalamic projection (CSTP), terminating in the subthalamic nucleus (STN). The present study investigated and compared the CSTPs originating from the premotor cortex (PM) or the primary motor cortex (M1) in two groups of adult macaque monkeys. The first group includes six intact monkeys, whereas the second group was made up of four monkeys subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication producing Parkinson's disease (PD)-like symptoms and subsequently treated with an autologous neural cell ecosystem (ANCE) therapy. The CSTPs were labeled with the anterograde tracer biotinylated dextran amine (BDA), injected either in PM or in M1. BDA-labeled axonal terminal boutons in STN were charted, counted, and then normalized based on the number of labeled corticospinal axons in each monkey. In intact monkeys, the CSTP from PM was denser than that originating from M1. In two PD monkeys, the CSTP originating from PM or M1 were substantially increased, as compared to intact monkeys. In one other PD monkey, there was no obvious change, whereas the last PD monkey showed a decrease of the CSTP originating from M1. Interestingly, the linear relationship between CSTP density and PD symptoms yielded a possible dependence of the CSTP re-organization with the severity of the MPTP lesion. The higher the PD symptoms, the larger the CSTP densities, irrespective of the origin (from both M1 or PM). Plasticity of the CSTP in PD monkeys may be related to PD itself and/or to the ANCE treatment

Recruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord.

Epidural electrical stimulation (EES) of lumbosacral sensorimotor circuits improves leg motor control in animals and humans with spinal cord injury (SCI). Upper-limb motor control involves similar circuits, located in the cervical spinal cord, suggesting that EES could also improve arm and hand movements after quadriplegia. However, the ability of cervical EES to selectively modulate specific upper-limb motor nuclei remains unclear. Here, we combined a computational model of the cervical spinal cord with experiments in macaque monkeys to explore the mechanisms of upper-limb motoneuron recruitment with EES and characterize the selectivity of cervical interfaces. We show that lateral electrodes produce a segmental recruitment of arm motoneurons mediated by the direct activation of sensory afferents, and that muscle responses to EES are modulated during movement. Intraoperative recordings suggested similar properties in humans at rest. These modelling and experimental results can be applied for the development of neurotechnologies designed for the improvement of arm and hand control in humans with quadriplegia

Bayesian optimization of peripheral intraneural stimulation protocols to evoke distal limb movements.

Objective.Motor neuroprostheses require the identification of stimulation protocols that effectively produce desired movements. Manual search for these protocols can be very time-consuming and often leads to suboptimal solutions, as several stimulation parameters must be personalized for each subject for a variety of target motor functions. Here, we present an algorithm that efficiently tunes peripheral intraneural stimulation protocols to elicit functionally relevant distal limb movements.Approach.We developed the algorithm using Bayesian optimization (BO) with multi-output Gaussian Processes (GPs) and defined objective functions based on coordinated muscle recruitment. We applied the algorithm offline to data acquired in rats for walking control and in monkeys for hand grasping control and compared different GP models for these two systems. We then performed a preliminary online test in a monkey to experimentally validate the functionality of our method.Main results.Offline, optimal intraneural stimulation protocols for various target motor functions were rapidly identified in both experimental scenarios. Using the model that performed best, the algorithm converged to stimuli that evoked functionally consistent movements with an average number of actions equal to 20% of the search space size in both the rat and monkey animal models. Online, the algorithm quickly guided the observations to stimuli that elicited functional hand gestures, although more selective motor outputs could have been achieved by refining the objective function used.Significance.These results demonstrate that BO can reliably and efficiently automate the tuning of peripheral neurostimulation protocols, establishing a translational framework to configure peripheral motor neuroprostheses in clinical applications. The proposed method can also potentially be applied to optimize motor functions using other stimulation modalities

Corticotectal Projections From the Premotor or Primary Motor Cortex After Cortical Lesion or Parkinsonian Symptoms in Adult Macaque Monkeys: A Pilot Tracing Study.

The corticotectal projections, together with the corticobulbar (corticoreticular) projections, work in parallel with the corticospinal tract (CST) to influence motoneurons in the spinal cord both directly and indirectly via the brainstem descending pathways. The tectospinal tract (TST) originates in the deep layers of the superior colliculus. In the present study, we analyzed the corticotectal projections from two motor cortical areas, namely the premotor cortex (PM) and the primary motor cortex (M1) in eight macaque monkeys subjected to either a cortical lesion of the hand area in M1 (n = 4) or Parkinson's disease-like symptoms PD (n = 4). A subgroup of monkeys with cortical lesion was subjected to anti-Nogo-A antibody treatment whereas all PD monkeys were transplanted with Autologous Neural Cell Ecosystems (ANCEs). The anterograde tracer BDA was used to label the axonal boutons both en passant and terminaux in the ipsilateral superior colliculus. Individual axonal boutons were charted in the different layers of the superior colliculus. In intact animals, we previously observed that corticotectal projections were denser when originating from PM than from M1. In the present M1 lesioned monkeys, as compared to intact ones the corticotectal projection originating from PM was decreased when treated with anti-Nogo-A antibody but not in untreated monkeys. In PD-like symptoms' monkeys, on the other hand, there was no consistent change affecting the corticotectal projection as compared to intact monkeys. The present pilot study overall suggests that the corticotectal projection is less affected by M1 lesion or PD symptoms than the corticoreticular projection previously reported in the same animals

Fine Manual Dexterity Assessment After Autologous Neural Cell Ecosystem (ANCE) Transplantation in a Non-human Primate Model of Parkinson's Disease.

Background. Autologous neural cell ecosystem (ANCE) transplantation improves motor recovery in MPTP monkeys. These motor symptoms were assessed using semi-quantitative clinical rating scales, widely used in many studies. However, limitations in terms of sensitivity, combined with relatively subjective assessment of their different items, make inter-study comparisons difficult to achieve. Objective. The aim of this study was to quantify the impact of MPTP intoxication in macaque monkeys on manual dexterity and assess whether ANCE can contribute to functional recovery. Methods. Four animals were trained to perform 2 manual dexterity tasks. After reaching a motor performance plateau, the animals were subjected to an MPTP lesion. After the occurrence of a spontaneous functional recovery plateau, all 4 animals were subjected to ANCE transplantation. Results. Two of 4 animals underwent a full spontaneous recovery before the ANCE transplantation, whereas the 2 other animals (symptomatic) presented moderate to severe Parkinson's disease (PD)-like symptoms affecting manual dexterity. The time to grasp small objects using the precision grip increased in these 2 animals. After ANCE transplantation, the 2 symptomatic animals underwent a significant functional recovery, reflected by a decrease in time to execute the different tasks, as compared with the post-lesion phase. Conclusions. Manual dexterity is affected in symptomatic MPTP monkeys. The 2 manual dexterity tasks reported here as pilot are pertinent to quantify PD symptoms and reliably assess a treatment in MPTP monkeys, such as the present ANCE transplantation, to be confirmed in a larger cohort of animals before future clinical applications

Intrafascicular peripheral nerve stimulation produces fine functional hand movements in primates.

Restoring dexterous hand control is critical for people with paralysis. Approaches based on surface or intramuscular stimulation provide limited finger control, generate insufficient force to recover functional movements, and require numerous electrodes. Here, we show that intrafascicular peripheral electrodes could produce functional grasps and sustained forces in three monkeys. We designed an intrafascicular implantable electrode targeting the motor fibers of the median and radial nerves. Our interface selectively and reliably activated extrinsic and intrinsic hand muscles, generating multiple functional grips, hand opening, and sustained contraction forces for up to 2 months. We extended those results to a behaving monkey with transient hand paralysis and used intracortical signals to control simple stimulation protocols that enabled this animal to perform a functional grasping task. Our findings show that just two intrafascicular electrodes can generate a rich portfolio of dexterous and functional hand movements with important implications for clinical applicability

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD