Recent advances in our understanding of the primate corticospinal system [version 1; referees: 2 approved]

The last few years have seen major advances in our understanding of the organisation and function of the corticospinal tract (CST). These have included studies highlighting important species-specific variations in the different functions mediated by the CST. In the primate, the most characteristic feature is direct cortico-motoneuronal (CM) control of muscles, particularly of hand and finger muscles. This system, which is unique to dexterous primates, is probably at its most advanced level in humans. We now know much more about the origin of the CM system within the cortical motor network, and its connectivity within the spinal cord has been quantified. We have learnt much more about how the CM system works in parallel with other spinal circuits receiving input from the CST and how the CST functions alongside other brainstem motor pathways. New work in the mouse has provided fascinating insights into the contribution of the CM system to dexterity. Finally, accumulating evidence for the involvement of CM projections in motor neuron disease has highlighted the importance of advances in basic neuroscience for our understanding and possible treatment of a devastating neurological disease

What drives corticospinal output?

Recent work has not only defined the origin of the direct cortico-motoneuronal output to the upper limb but has also identified some of the cortical networks that engage the corticospinal output during movement. A surprising finding is that some corticospinal neurons show ‘mirror-like’ properties and are actively modulated not only during self-movement but also during action observation

Cortical Plasticity and Behavioral Recovery Following Focal Lesion to Primary Motor Cortex in Adult Rats

Acquired brain injuries, such as ischemic stroke and traumatic brain injury, are the leading causes of physical disabilities. Previously, scientists have shown that damage of the primary motor cortex induced neural plasticity in the premotor area in human and non-human primate studies. Neural plasticity, particularly within the same hemisphere of the lesion (ipsilesional), is thought to contribute to and account for functional recovery. It is not yet known to what extent plasticity mediates recovery and how to take advantage of neural plasticity to maximize the functional outcome. Rodent models are most often used not only for studying the role of motor cortex in motor skill learning but also in neurodegenerative research. To further elucidate the role of adaptive plasticity in the ipsilesional hemisphere during the recovery of upper limb function, we aimed to establish the baseline neural changes after a focal cortical injury. Therefore, we took advantage of two separate cortical motor areas, in the Rattus norvegicus, from which the corticospinal tracts terminate in the motor nuclei of the cervical level spinal cord, controlling upper extremity musculature--the first, a more caudally located subregion of M1, often referred to as the caudal forelimb area (CFA), and the second, a more rostrally located non-primary area, referred to as the rostral forelimb area (RFA). The objective of this dissertation work was to characterize physiological changes in RFA during the complex and lengthy process of recovery using rat models of focal cortical trauma and cortical ischemia restricted to CFA. The results demonstrated that the post-injury cortical plasticity in RFA may play a role in functional recovery. Further, we showed differential effects of rehabilitative training on ipsilesional RFA plasticity after CFA ischemic injury. Extensive physiological changes were evident past rehabilitative training. Thus, neural plasticity in RFA appeared to be dependent both on post-lesion motor experience and time. The dissertation work supports the hypothesis that cortical plasticity within the spared RFA after restrictive damage to CFA mediates use-dependent physiological reorganization, which provides a substrate for sustaining rehabilitation-aided motor functional recovery

A computational model based on corticospinal functional MRI revealed asymmetrically organized motor corticospinal networks in humans

新規MRI技術で利き手の神経制御メカニズムを解明 --手指運動中の脳・脊髄機能結合パターンの左右差を世界で初めて計測--. 京都大学プレスリリース. 2022-08-08.Evolution of the direct, monosynaptic connection from the primary motor cortex to the spinal cord parallels acquisition of hand dexterity and lateralization of hand preference. In non-human mammals, the indirect, multi-synaptic connections between the bilateral primary motor cortices and the spinal cord also participates in controlling dexterous hand movement. However, it remains unknown how the direct and indirect corticospinal pathways work in concert to control unilateral hand movement with lateralized preference in humans. Here we demonstrated the asymmetric functional organization of the two corticospinal networks, by combining network modelling and simultaneous functional magnetic resonance imaging techniques of the brain and the spinal cord. Moreover, we also found that the degree of the involvement of the two corticospinal networks paralleled lateralization of hand preference. The present results pointed to the functionally lateralized motor nervous system that underlies the behavioral asymmetry of handedness in humans

Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.

Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge

Reticulospinal and corticospinal axon regeneration after complete spinal cord injury

Neuroprosthetic rehabilitation demonstrated that significant functional benefit could be achieved with lumbosacral neuromodulation in both human and animal models of spinal cord injury. It promoted the recovery of voluntary leg movements through the reorganization of residual reticulospinal and propriospinal projections pathways. However, in case of complete spinal cord injuries (SCI), which isolate the circuits under the lesion from any supraspinal control, the outcome of neuroprosthetic rehabilitation is still not sufficient. Indeed, it will require the restoration of robust regrowth and sprouting of several types of axons across the injury. Axons fail to regrow across spinal lesions because of different inhibitory mechanisms. It has been demonstrated that this spontaneous axon regeneration failure can be reversed by i) stimulating the neuronal intrinsic growth capacity using viral technology, ii) remodeling the lesion core with growth factors, in order to create a more permissive environment, and iii) guiding axons with chemo-attractive molecules across and beyond the SCI site. It was thus demonstrated that propriospinal axons are able to regrow and build a robust descending bridge across complete SCIs when the needed facilitators are provided. However, this robust propriospinal bridging failed to promote functional recovery by itself. It might be explained by an insufficient descending motor control partly supported by other systems such as the reticulospinal tract (RtST) and the corticospinal tract (CST). Therefore we wanted to study the regenerative potential of the RtST and CST pathways. The RtST arises from the brainstem and reaches for the spinal cord acting as relay for descending motor cortical commands. The CST is the main descending motor cortical command arising from the primary motor cortex. In the present study, we applied the same strategy to enhance sprouting and regrowth of reticulospinal and corticospinal neurons across anatomically complete SCI. We first activated the neuronal intrinsic growth capacity of both tracts using viral technology. The lesion environment was then remodeled with growth factors, delivered using a biocompatible hydrogel. Finally, we established chemical axon guidance using chemoattractant molecules. These interventions were delivered with a spatiotemporal profile corresponding to the axon growth sequence during development. We did not obtain any CST regeneration, due to the severe crush injury model inducing extensive CST axons degeneration probably caused by ischemic phenomenon. Regarding the RtST, we obtained significant reticulospinal regeneration into the lesion core with some fibers growing across the lesion reaching the healthy caudal tissue. This regeneration remained limited though as compared with the propriospinal results indicating the importance of identifying complementary strategies to increase the density of the regenerated tract and to attract the axons in the healthy tissue below the SCI. Our ultimate goal is to restore anatomical communications across complete SCI and promote their functional integration using neuroprosthetic rehabilitation program

Non-Human Primate Models in Neuroscience Research

Neuroscience is progressively increasing its comprehension of the normal functioning of the central and  peripheral nervous system. Such understanding is essential to challenge important neurodegenerative disorders  and clinical conditions such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, etc. The  aim of neuroscience research is to improve understanding of normal and pathological functions and to  develop therapeutic strategies and tools. Fundamental neuroscience utilizes a variety of techniques which  include: electrophysiology, imaging, and computational modelling and entails interactions with clinical  studies. Non-human primates are the closest species to humans in terms of biological, physiological, immunological  and neurological characteristics; their closeness has been, and is still, an important reason for  using them in biomedical studies. These animals have a vertebrate brain that is most like that of humans  in terms of neural circuitry and this, together with similarities with human physiological and behavioural  characteristics, makes them more valuable and accurate models of neurological and psychiatric diseases  than other animals. This article provides an overview of the contribution of non-human primate models in  fundamental neuroscience research and in generating clinically relevant findings and therapeutic developments.

Starting and stopping movement by the primate brain

We review the current knowledge about the part that motor cortex plays in the preparation and generation of movement, and we discuss the idea that corticospinal neurons, and particularly those with cortico-motoneuronal connections, act as ‘command’ neurons for skilled reach-to-grasp movements in the primate. We also review the increasing evidence that it is active during processes such as action observation and motor imagery. This leads to a discussion about how movement is inhibited and stopped, and the role in these for disfacilitation of the corticospinal output. We highlight the importance of the non-human primate as a model for the human motor system. Finally, we discuss the insights that recent research into the monkey motor system has provided for translational approaches to neurological diseases such as stroke, spinal injury and motor neuron disease

Red nucleus structure and function: from anatomy to clinical neurosciences

The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal cord, during its phylogenesis the RN shows a progressive segregation between a magnocellular part, involved in the rubrospinal system, and a parvocellular part, involved in the olivocerebellar system. Despite exhibiting distinct evolutionary trajectories, these two regions are strictly tied together and play a prominent role in motor and non-motor behavior in different animal species. However, little is known about their function in the human brain. This lack of knowledge may have been conditioned both by the notable differences between human and non-human RN and by inherent difficulties in studying this structure directly in the human brain, leading to a general decrease of interest in the last decades. In the present review, we identify the crucial issues in the current knowledge and summarize the results of several decades of research about the RN, ranging from animal models to human diseases. Connecting the dots between morphology, experimental physiology and neuroimaging, we try to draw a comprehensive overview on RN functional anatomy and bridge the gap between basic and translational research