The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter.

Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with the spinal network; a parallel corticobulbar system projects to the cranial motor network and to brainstem motor pathways. The primate corticospinal system has a widespread cortical origin and an extensive range of different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand alpha motoneurons are a recent evolutionary feature, that is well developed in dexterous primates and particularly in humans. Many of these projections originate from the caudal subdivision of area 4 ('new' M1: primary motor cortex). They arise from corticospinal neurons of varied soma size, including those with fast- and relatively slow-conducting axons. This CM system has been shown to be involved in the control of skilled movements, carried out with fractionation of the distal extremities and at low force levels. During movement, corticospinal neurons are activated quite differently from 'lower' motoneurons, and there is no simple or fixed functional relationship between a so-called 'upper' motoneuron and its target lower motoneuron. There are key differences in the organisation and function of the corticospinal and CM system in primates versus non-primates, such as rodents. These differences need to be recognized when making the choice of animal model for understanding disorders such as amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease there is a selective loss of fast-conducting corticospinal axons, and their synaptic connections, and this is reflected in responses to non-invasive cortical stimuli and measures of cortico-muscular coherence. The loss of CM connections influencing distal limb muscles results in a differential loss of muscle strength or 'split-hand' phenotype. Importantly, there is also a unique impairment in the coordination of skilled hand tasks that require fractionation of digit movement. Scores on validated tests of skilled hand function could be used to assess disease progression.

Terminal organization of the corticospinal projection from the arm/hand region of the rostral primary motor cortex (M1r or old M1) to the cervical enlargement (C5-T1) in rhesus monkey.

High-resolution anterograde tracers and stereology were used to study the terminal organization of the corticospinal projection (CSP) from the rostral portion of the primary motor cortex (M1r) to spinal levels C5-T1. Most of this projection (90%) terminated contralaterally within laminae V-IX, with the densest distribution in lamina VII. Moderate bouton numbers occurred in laminae VI, VIII, and IX with few in lamina V. Within lamina VII, labeling occurred over the distal-related dorsolateral subsectors and proximal-related ventromedial subsectors. Within motoneuron lamina IX, most terminations occurred in the proximal-related dorsomedial quadrant, followed by the distal-related dorsolateral quadrant. Segmentally, the contralateral lamina VII CSP gradually declined from C5-T1 but was consistently distributed at C5-C7 in lamina IX. The ipsilateral CSP ended in axial-related lamina VIII and adjacent ventromedial region of lamina VII. These findings demonstrate the M1r CSP influences distal and proximal/axial-related spinal targets. Thus, the M1r CSP represents a transitional CSP, positioned between the caudal M1 (M1c) CSP, which is 98% contralateral and optimally organized to mediate distal upper extremity movements (Morecraft et al., 2013), and dorsolateral premotor (LPMCd) CSP being 79% contralateral and optimally organized to mediate proximal/axial movements (Morecraft et al., 2019). This distal to proximal CSP gradient corresponds to the clinical deficits accompanying caudal to rostral motor cortex injury. The lamina IX CSP is considered in the light of anatomical and neurophysiological evidence which suggests M1c gives rise to the major proportion of the cortico-motoneuronal (CM) projection, while there is a limited M1r CM projection.

The evidence against somatotopic organization of function in the primate corticospinal tract.

We review the spatial organization of corticospinal outputs from different cortical areas and how this reflects the varied functions mediated by the corticospinal tract. A long-standing question is whether the primate corticospinal tract shows somatotopical organization. Although this has been clearly demonstrated for corticofugal outputs passing through the internal capsule and cerebral peduncle, there is accumulating evidence against somatotopy in the pyramidal tract in the lower brainstem and in the spinal course of the corticospinal tract. Answering the question on somatotopy has important consequences for understanding the effects of incomplete spinal cord injury. Our recent study in the macaque monkey, using high-resolution dextran tracers, demonstrated a great deal of intermingling of fibres originating from primary motor cortex arm/hand, shoulder and leg areas. We quantified the distribution of fibres belonging to these different projections and found no significant difference in their distribution across different subsectors of the pyramidal tract or lateral corticospinal tract, arguing against somatotopy. We further demonstrated intermingling with corticospinal outputs derived from premotor and supplementary motor arm areas. We present new evidence against somatotopy for corticospinal projections from rostral and caudal cingulate motor areas and from somatosensory areas of the parietal cortex. In the pyramidal tract and lateral corticospinal tract, fibres from the cingulate motor areas overlap with each other. Fibres from the primary somatosensory cortex arm area completely overlap those from the leg area. There is also substantial overlap of both these outputs with those from posterior parietal sensorimotor areas. We argue that the extensive intermingling of corticospinal outputs from so many different cortical regions must represent an organizational principle, closely related to its mediation of many different functions and its large range of fibre diameters. The motor sequelae of incomplete spinal injury, such as central cord syndrome and 'cruciate paralysis', include much greater deficits in upper than in lower limb movement. Current teaching and text book explanations of these symptoms are still based on a supposed corticospinal somatotopy or 'lamination', with greater vulnerability of arm and hand versus leg fibres. We suggest that such explanations should now be finally abandoned. Instead, the clinical and neurobiological implications of the complex organization of the corticospinal tract need now to be taken into consideration. This leads us to consider the evidence for a greater relative influence of the corticospinal tract on upper versus lower limb movements, the former best characterized by skilled hand and digit movements.

Lack of somatotopy among corticospinal tract fibers passing through the primate craniovertebral junction and cervical spinal cord: pathoanatomical substrate of central cord syndrome and cruciate paralysis.

OBJECTIVE: In some cases of incomplete cervical spinal cord injury (iSCI) there is marked paresis and dysfunction of upper-extremity movement but not lower-extremity movement. A continued explanation of such symptoms is a somatotopic organization of corticospinal tract (CST) fibers passing through the decussation at the craniovertebral junction (CVJ) and lateral CST (LCST). In central cord syndrome, it has been suggested that injury to the core of the cervical cord may include selective damage to medially located arm/hand LCST fibers, without compromising laterally located leg fibers. Because such somatotopic organization in the primate CST might contribute to the disproportionate motor deficits after some forms of iSCI, the authors made a systematic investigation of CST organization in the CVJ and LCST using modern neuroanatomical techniques. METHODS: High-resolution anterograde tracers were used in 11 rhesus macaque monkeys to define the course of the corticospinal projection (CSP) through the CVJ and LCST from the arm/hand, shoulder, and leg areas of the primary motor cortex (M1). This approach labels CST fibers of all sizes, large and small, arising in these areas. The CSP from the dorsolateral and ventrolateral premotor cortex and supplementary motor area were also studied. A stereological approach was adapted to quantify labeled fiber distribution in 8 cases. RESULTS: There was no evidence for somatotopic organization of CST fibers passing through the CVJ or contralateral LCST. Fiber labeling from each cortical representation was widespread throughout the CST at the CVJ and LCST and overlapped extensively with fibers from other representations. This study demonstrated no significant difference between medial versus lateral subsectors of the LCST in terms of number of fibers labeled from the M1 arm/hand area. CONCLUSIONS: This investigation firmly rejects the concept of somatotopy among CST fibers passing through the CVJ and LCST, in contrast with the somatotopy in the cortex, corona radiata, and internal capsule. All CST fibers in the CVJ and LCST would thus appear to be equally susceptible to focal or diffuse injury, regardless of their cortical origin. The disproportionate impairment of arm/hand movement after iSCI must therefore be due to other factors, including greater dependence of hand/arm movements on the CST compared with the lower limb. The dispersed and intermingled nature of frontomotor fibers may be important in motor recovery after cervical iSCI.

The motor deficit of ALS reflects failure to generate muscle synergies for complex motor tasks, not just muscle strength.

Customarily the motor deficits that develop in ALS are considered in terms of muscle weakness. Functional rating scales used to assess ALS in terms of functional decline do not measure the deficits when performing complex motor tasks, that make up the human skilled motor repertoire, best exemplified by tasks requiring skilled hand and finger movement. This repertoire depends primarily upon the strength of direct corticomotoneuronal (CM) connectivity from primary motor cortex to the motor units subserving skilled movements. Our review prompts the question: if accumulating evidence suggests involvement of the CM system in the early stages of ALS, what kinds of motor deficit might be expected to result, and is current methodology able to identify such deficits? We point out that the CM system is organized not in "commands" to individual muscles, but rather encodes the building blocks of complex and intricate movements, which depend upon synergy between not only the prime mover muscles, but other muscles that stabilize the limb during skilled movement. Our knowledge of the functional organization of the CM system has come both from invasive studies in non-human primates and from advanced imaging and neurophysiological techniques in humans, some of which are now being applied in ALS. CM pathology in ALS has consequences not only for muscle strength, but importantly in the failure to generate complex motor tasks, often involving elaborate muscle synergies. Our aim is to encourage innovative methodology specifically directed to assessing complex motor tasks, failure of which is likely a very early clinical deficit in ALS.

The Cortical "Upper Motoneuron" in Health and Disease.

Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre diameters, including large diameter fibres which are unique to humans and other large primates. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand motoneurons are a late evolutionary feature only present in dexterous primates and best developed in humans. CM projections are derived from a more restricted cortical territory ('new' M1, area 3a) and arise not only from corticospinal neurons with large, fast axons but also from those with relatively slow-conducting axons. During movement, corticospinal neurons are organised and recruited quite differently from 'lower' motoneurons. Accumulating evidence strongly implicates the corticospinal system in the early stages of ALS, with particular involvement of CM projections to distal limb muscles, but also to other muscle groups influenced by the CM system. There are important species differences in the organisation and function of the corticospinal system, and appropriate animal models are needed to understand disorders involving the human corticospinal system.

Classification of Cortical Neurons by Spike Shape and the Identification of Pyramidal Neurons.

Many investigators who make extracellular recordings from populations of cortical neurons are now using spike shape parameters, and particularly spike duration, as a means of classifying different neuronal sub-types. Because of the nature of the experimental approach, particularly that involving nonhuman primates, it is very difficult to validate directly which spike characteristics belong to particular types of pyramidal neurons and interneurons, as defined by modern histological approaches. This commentary looks at the way antidromic identification of pyramidal cells projecting to different targets, and in particular, pyramidal tract neurons (PTN), can inform the utility of spike width classification. Spike duration may provide clues to a diversity of function across the pyramidal cell population, and also highlights important differences that exist across species. Our studies suggest that further electrophysiological and optogenetic approaches are needed to validate spike duration as a means of cell classification and to relate this to well-established histological differences in neocortical cell types.

Pattern of paresis in ALS is consistent with the physiology of the corticomotoneuronal projections to different muscle groups.

OBJECTIVE: A recent neuroanatomical staging scheme of amyotrophic lateral sclerosis (ALS) indicates that a cortical lesion may spread, as a network disorder, both at the cortical level and via corticofugal tracts, including corticospinal projections providing direct monosynaptic input to α-motoneurons. These projections are involved preferentially and early in ALS. If these findings are clinically relevant, the pattern of paresis in ALS should primarily involve those muscle groups that receive the strongest direct corticomotoneuronal (CM) innervation. METHODS: In a large cohort (N=436), we analysed retrospectively the pattern of muscle paresis in patients with ALS using the UK Medical Research Council (MRC) scoring system; we subsequently carried out two independent prospective studies in two smaller groups (N=92 and N=54). RESULTS: The results indicated that a characteristic pattern of paresis exists. When pairs of muscle groups were compared within patients, the group known to receive the more pronounced CM connections was significantly weaker. Within patients, there was greater relative weakness (lower MRC score) in thumb abductors versus elbow extensors, for hand extensors versus hand flexors and for elbow flexors versus elbow extensors. In the lower limb, knee flexors were relatively weaker than extensors, and plantar extensors were weaker than plantar flexors. CONCLUSIONS: These findings were mostly significant (p<0.01) for all six pairs of muscles tested and provide indirect support for the concept that ALS may specifically affect muscle groups with strong CM connections. This specific pattern could help to refine clinical and electrophysiological ALS diagnostic criteria and complement prospective clinicopathological correlation studies.

Differential neural coordination of bilateral hand and finger movements.

Cooperative hand movements (e.g., opening a bottle) require a close coordination of the hands. This is reflected in a neural coupling between the two sides. The aim of this study was to investigate in how far neural coupling is present not only during bilateral hand but also during bilateral finger movements. For this purpose unilateral mechanical and electrical nerve stimuli were delivered during bilateral sequentially and synchronously performed finger movements on a keyboard and, for comparison, during bilateral hand flexion movements. Electromyographic (EMG) activity and reflex responses in forearm flexor and extensor muscles of both sides were recorded and analyzed. Confounding EMG activity related to hand movements during the finger task was limited by wrist fixating braces. During the hand flexion task, complex reflex responses appeared in the forearm muscles of both sides to unilateral stimulation of the ulnar nerve (mean latency 57 ms), reflecting neural coupling between the two hands. In contrast, during the bilateral finger movement task, unilateral electrical nerve or mechanical stimulation of the right index finger was followed by dominant ipsilateral reflex responses (latency 45 and 58 ms, respectively). The results indicate that in contrast to the coupled hand movements, finger movements may not be coupled but can move independently on each side. Functionally this makes sense because during most activities of daily living, a close cooperation of the hands but not of individual fingers is needed. This independence of individual finger movements may rely on strong, specific, contralateral cortico-motoneuronal control.

Recent advances in our understanding of the primate corticospinal system.

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.

The Corticospinal Discrepancy: Where are all the Slow Pyramidal Tract Neurons?

This feature article focuses on the discrepancy between the distribution of axon diameters within the primate corticospinal tract, determined neuroanatomically, and the distribution of axonal conduction velocities within the same tract, determined electrophysiologically. We point out the importance of resolving this discrepancy for a complete understanding of corticospinal functions, and discuss the various explanations for the mismatch between anatomy and physiology.

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.

Continued need for non-human primate neuroscience research.

Neuroscience research in non-human primates (NHPs) has delivered fundamental knowledge about human brain function as well as some valuable therapies that have improved the lives of human patients with a variety of brain disorders. Research using NHPs, although it is facing serious challenges, continues to complement studies in human volunteers and patients, and will continue to be needed as the burdens of mental health problems and neurodegenerative diseases increase. At the same time, research into the 3Rs is helping to ameliorate the harms experienced by NHPs in experimental procedures, allowing the effective combination of optimal welfare conditions for the NHPs and high quality research.

Applying the 3Rs to neuroscience research involving nonhuman primates.

This Feature focuses on UK neuroscience research using nonhuman primates (NHPs), and the application of the 3Rs, in the light of the recent EU SCHEER report and subsequent article by Prescott et al. (2017). The challenge of understanding the human brain and its disorders means that NHP research is still very much needed, although it is essential that this research is complemented by studies using other approaches, such as human volunteers and patients, and other alternatives to NHP use. Analysis of recent publications shows that these complementary approaches are already being actively exploited by NHP researchers in the UK. Application of the 3Rs has been led by the UK National Centre for the 3Rs (NC3Rs), with active participation of UK NHP researchers, who are constantly refining research methodology. However, not all refinements work, and those that do succeed need to be fully validated before they can be introduced more widely into current practice. More generally, the 3Rs have helped to ameliorate harm experienced by NHPs in procedures, although there is still more to do. Accumulating evidence from recent UK Home Office statistics suggests that most monkeys used in scientific procedures experience a moderate rather than a severe level of harm.

Cortical influences drive amyotrophic lateral sclerosis.

The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia.

Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque.

There are substantial differences across species in the organization and function of the motor pathways. These differences extend to basic electrophysiological properties. Thus, in rat motor cortex, pyramidal cells have long duration action potentials, while in the macaque, some pyramidal neurons exhibit short duration "thin" spikes. These differences may be related to the expression of the fast potassium channel Kv3.1b, which in rat interneurons is associated with generation of thin spikes. Rat pyramidal cells typically lack these channels, while there are reports that they are present in macaque pyramids. Here we made a systematic, quantitative comparison of the Kv3.1b expression in sections from macaque and rat motor cortex, using two different antibodies (NeuroMab, Millipore). As our standard reference, we examined, in the same sections, Kv3.1b staining in parvalbumin-positive interneurons, which show strong Kv3.1b immunoreactivity. In macaque motor cortex, a large sample of pyramidal neurons were nearly all found to express Kv3.1b in their soma membranes. These labeled neurons were identified as pyramidal based either by expression of SMI32 (a pyramidal marker), or by their shape and size, and lack of expression of parvalbumin (a marker for some classes of interneuron). Large (Betz cells), medium, and small pyramidal neurons all expressed Kv3.1b. In rat motor cortex, SMI32-postive pyramidal neurons expressing Kv3.1b were very rare and weakly stained. Thus, there is a marked species difference in the immunoreactivity of Kv3.1b in pyramidal neurons, and this may be one of the factors explaining the pronounced electrophysiological differences between rat and macaque pyramidal neurons.

Functional Strength Training and Movement Performance Therapy for Upper Limb Recovery Early Poststroke-Efficacy, Neural Correlates, Predictive Markers, and Cost-Effectiveness: FAST-INdiCATE Trial.

BACKGROUND: Variation in physiological deficits underlying upper limb paresis after stroke could influence how people recover and to which physical therapy they best respond. OBJECTIVES: To determine whether functional strength training (FST) improves upper limb recovery more than movement performance therapy (MPT). To identify: (a) neural correlates of response and (b) whether pre-intervention neural characteristics predict response. DESIGN: Explanatory investigations within a randomised, controlled, observer-blind, and multicentre trial. Randomisation was computer-generated and concealed by an independent facility until baseline measures were completed. Primary time point was outcome, after the 6-week intervention phase. Follow-up was at 6 months after stroke. PARTICIPANTS: With some voluntary muscle contraction in the paretic upper limb, not full dexterity, when recruited up to 60 days after an anterior cerebral circulation territory stroke. INTERVENTIONS: Conventional physical therapy (CPT) plus either MPT or FST for up to 90 min-a-day, 5 days-a-week for 6 weeks. FST was "hands-off" progressive resistive exercise cemented into functional task training. MPT was "hands-on" sensory/facilitation techniques for smooth and accurate movement. OUTCOMES: The primary efficacy measure was the Action Research Arm Test (ARAT). Neural measures: fractional anisotropy (FA) corpus callosum midline; asymmetry of corticospinal tracts FA; and resting motor threshold (RMT) of motor-evoked potentials. ANALYSIS: Covariance models tested ARAT change from baseline. At outcome: correlation coefficients assessed relationship between change in ARAT and neural measures; an interaction term assessed whether baseline neural characteristics predicted response. RESULTS: 288 Participants had: mean age of 72.2 (SD 12.5) years and mean ARAT 25.5 (18.2). For 240 participants with ARAT at baseline and outcome the mean change was 9.70 (11.72) for FST + CPT and 7.90 (9.18) for MPT + CPT, which did not differ statistically (p = 0.298). Correlations between ARAT change scores and baseline neural values were between 0.199, p = 0.320 for MPT + CPT RMT (n = 27) and -0.147, p = 0.385 for asymmetry of corticospinal tracts FA (n = 37). Interaction effects between neural values and ARAT change between baseline and outcome were not statistically significant. CONCLUSIONS: There was no significant difference in upper limb improvement between FST and MPT. Baseline neural measures did not correlate with upper limb recovery or predict therapy response. TRIAL REGISTRATION: Current Controlled Trials: ISRCT 19090862, http://www.controlled-trials.com.

Grasp-specific motor resonance is influenced by the visibility of the observed actor.

Motor resonance is the modulation of M1 corticospinal excitability induced by observation of others' actions. Recent brain imaging studies have revealed that viewing videos of grasping actions led to a differential activation of the ventral premotor cortex depending on whether the entire person is viewed versus only their disembodied hand. Here we used transcranial magnetic stimulation (TMS) to examine motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) during observation of videos or static images in which a whole person or merely the hand was seen reaching and grasping a peanut (precision grip) or an apple (whole hand grasp). Participants were presented with six visual conditions in which visual stimuli (video vs static image), view (whole person vs hand) and grasp (precision grip vs whole hand grasp) were varied in a 2 × 2 × 2 factorial design. Observing videos, but not static images, of a hand grasping different objects resulted in a grasp-specific interaction, such that FDI and ADM MEPs were differentially modulated depending on the type of grasp being observed (precision grip vs whole hand grasp). This interaction was present when observing the hand acting, but not when observing the whole person acting. Additional experiments revealed that these results were unlikely to be due to the relative size of the hand being observed. Our results suggest that observation of videos rather than static images is critical for motor resonance. Importantly, observing the whole person performing the action abolished the grasp-specific effect, which could be due to a variety of PMv inputs converging on M1.

Cortical projections to the red nucleus and the brain stem in the rhesus monkey.

The 1967 paper from Hans Kuypers and Don Lawrence provided the first complete description of the projections from every major cortical area to the red nucleus and brainstem in the monkey. The study includes descriptions of some of the major cortical influences on sensory and motor circuits subserving vision, hearing and proprioception, as well as movements of the eyes, head and limbs. It also describes the detailed anatomy of the red nucleus in the monkey, and highlights species differences in this structure. It also postulates that cortical projections to the parvicellular component of the red nucleus provide a recurrent loop returning via the thalamus to the motor cortex. The findings reported in this paper helped to substantiate Kuypers' new theory on the organisation of the descending motor pathways by showing that the primary motor cortex, as well as providing a direct crossed corticospinal input to spinal circuits controlling movements of the distal extremities (hand and foot), also influenced these same circuits through ipsilateral projections to the cells of origin of the rubrospinal tract. In contrast, projections from more rostral motor, premotor and prefrontal regions terminated bilaterally in the parvicellular red nucleus, and influenced ventromedial descending pathways controlling movements of the head, neck, trunk and proximal limbs. The paper has proved of lasting value to our understanding of sensorimotor control and the contribution of different pathways to it. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Modulation of the Intracortical LFP during Action Execution and Observation.

The activity of mirror neurons in macaque ventral premotor cortex (PMv) and primary motor cortex (M1) is modulated by the observation of another's movements. This modulation could underpin well documented changes in EEG/MEG activity indicating the existence of a mirror neuron system in humans. Because the local field potential (LFP) represents an important link between macaque single neuron and human noninvasive studies, we focused on mirror properties of intracortical LFPs recorded in the PMv and M1 hand regions in two macaques while they reached, grasped and held different objects, or observed the same actions performed by an experimenter. Upper limb EMGs were recorded to control for covert muscle activity during observation.The movement-related potential (MRP), investigated as intracortical low-frequency LFP activity (<9 Hz), was modulated in both M1 and PMv, not only during action execution but also during action observation. Moreover, the temporal LFP modulations during execution and observation were highly correlated in both cortical areas. Beta power in both PMv and M1 was clearly modulated in both conditions. Although the MRP was detected only during dynamic periods of the task (reach/grasp/release), beta decreased during dynamic and increased during static periods (hold).Comparison of LFPs for different grasps provided evidence for partially nonoverlapping networks being active during execution and observation, which might be related to different inputs to motor areas during these conditions. We found substantial information about grasp in the MRP corroborating its suitability for brain-machine interfaces, although information about grasp was generally low during action observation.