Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study.

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Neural dysregulation in post-COVID fatigue.

Following infection with SARS-CoV-2, a substantial minority of people develop lingering after-effects known as 'long COVID'. Fatigue is a common complaint with a substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison with age- and sex-matched volunteers without fatigue (n = 52), we show underactivity in specific cortical circuits, dysregulation of autonomic function and myopathic change in skeletal muscle. Cluster analysis revealed no subgroupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis, we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control. These abnormalities on objective tests may aid in the development of novel approaches for disease monitoring.

Long COVID: mechanisms, risk factors and recovery.

NEW FINDINGS: What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. ABSTRACT: Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance - namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology - including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Long-latency Responses to a Mechanical Perturbation of the Index Finger Have a Spinal Component.

In an uncertain external environment, the motor system may need to respond rapidly to an unexpected stimulus. Limb displacement causes muscle stretch; the corrective response has multiple activity bursts, which are suggested to originate from different parts of the neuraxis. The earliest response is so fast, it can only be produced by spinal circuits; this is followed by slower components thought to arise from primary motor cortex (M1) and other supraspinal areas. Spinal cord (SC) contributions to the slower components are rarely considered. To address this, we recorded neural activity in M1 and the cervical SC during a visuomotor tracking task, in which 2 female macaque monkeys moved their index finger against a resisting motor to track an on-screen target. Following the behavioral trial, an increase in motor torque rapidly returned the finger to its starting position (lever velocity >200°/s). Many cells responded to this passive mechanical perturbation (M1: 148 of 211 cells, 70%; SC: 67 of 119 cells, 56%). The neural onset latency was faster for SC compared with M1 cells (21.7 ± 11.2 ms vs 25.5 ± 10.7 ms, respectively, mean ± SD). Using spike-triggered averaging, some cells in both regions were identified as likely premotor cells, with monosynaptic connections to motoneurons. Response latencies for these cells were compatible with a contribution to the muscle responses following the perturbation. Comparable fractions of responding neurons in both areas were active up to 100 ms after the perturbation, suggesting that both SC circuits and supraspinal centers could contribute to later response components.SIGNIFICANCE STATEMENT Following a limb perturbation, multiple reflexes help to restore limb position. Given conduction delays, the earliest part of these reflexes can only arise from spinal circuits. By contrast, long-latency reflex components are typically assumed to originate from supraspinal centers. We recorded from both spinal and motor cortical cells in monkeys responding to index finger perturbations. Many spinal interneurons, including those identified as projecting to motoneurons, responded to the perturbation; the timing of responses was compatible with a contribution to both short- and long-latency reflexes. We conclude that spinal circuits also contribute to long-latency reflexes in distal and forearm muscles, alongside supraspinal regions, such as the motor cortex and brainstem.

Postural control of arm and fingers through integration of movement commands.

Every movement ends in a period of stillness. Current models assume that commands that hold the limb at a target location do not depend on the commands that moved the limb to that location. Here, we report a surprising relationship between movement and posture in primates: on a within-trial basis, the commands that hold the arm and finger at a target location depend on the mathematical integration of the commands that moved the limb to that location. Following damage to the corticospinal tract, both the move and hold period commands become more variable. However, the hold period commands retain their dependence on the integral of the move period commands. Thus, our data suggest that the postural controller possesses a feedforward module that uses move commands to calculate a component of hold commands. This computation may arise within an unknown subcortical system that integrates cortical commands to stabilize limb posture.

Moving an arm requires the brain to send electrical signals to the arm's muscles, causing them to contract. Neuroscientists call these types of brain signals "move signals". The brain also sends so-called hold signals, which hold the arm still in a desired position. Part of the brain known as the primary motor cortex helps to calculate the move signals for the arm, but it was unclear how the brain produces the corresponding hold signals. Fortunately, the fact that the brain moves other things besides arms may help answer this question. Previous research has shown, for example, that a brain area called the "neural integrator" calculates the hold signals needed to hold the eye in a specific position. The neural integrator does this by using basic principles of physics, and details of the speed and duration of the eye's movements. Now, Albert et al. show a similar mechanism appears to control hold signals for arm movements. In one set of experiments, muscle activity was measured as monkeys moved their arms or fingers to different target positions. In other experiments, human volunteers held a robot arm, and Albert et al. measured the forces they produced while reaching and holding still. Both the human and monkey experiments revealed a relationship between move signals and hold signals. Like for eye movements, hold signals for the arm could be calculated from the move signals. In further experiments with stroke patients where the brain had been damaged, the move signals were found to be deteriorated, but the way hold signals were calculated stayed the same. This suggests that there is an unknown structure within the brain that calculates hold signals based on move signals. Investigating how the brain holds the arm still may help scientists understand why some neurological conditions like stroke or dystonia cause unwanted movements or unusual postures. This might also lead scientists to develop new ways to treat these conditions.

Rapid crossed responses in an intrinsic hand muscle during perturbed bimanual movements.

Mechanical perturbations in one upper limb often elicit corrective responses in both the perturbed as well as its contralateral and unperturbed counterpart. These crossed corrective responses have been shown to be sensitive to the bimanual requirements of the perturbation, but crossed responses (CRs) in hand muscles are far less well studied. Here, we investigate corrective CRs in an intrinsic hand muscle, the first dorsal interosseous (1DI), to clockwise and anticlockwise mechanical perturbations to the contralateral index finger while participants performed a bimanual finger abduction task. We found that the CRs in the unperturbed 1DI were sensitive to the direction of the perturbation of the contralateral index finger. However, the size of the CRs was not sensitive to the amplitude of the contralateral perturbation nor its context within the bimanual task. The onset latency of the CRs was too fast to be purely transcortical (<70 ms) in 12/12 participants. This confirms that during isolated bimanual finger movements, sensory feedback from one hand can influence the other, but the pathways mediating the earliest components of this interaction are likely to involve subcortical systems such as the brainstem or spinal cord, which may afford less flexibility to the task demands.NEW & NOTEWORTHY An intrinsic hand muscle shows a crossed response to a perturbation of the contralateral index finger. The crossed response is dependent on the direction of the contralateral perturbation but not on the amplitude or the bimanual requirements of the movement, suggesting a far less flexible control policy than those governing crossed responses in more proximal muscles. The crossed response is too fast to be purely mediated by transcortical pathways, suggesting subcortical contributions.

The mammalian spinal commissural system: properties and functions.

Commissural systems are essential components of motor circuits that coordinate left-right activity of the skeletomuscular system. Commissural systems are found at many levels of the neuraxis including the cortex, brainstem, and spinal cord. In this review we will discuss aspects of the mammalian spinal commissural system. We will focus on commissural interneurons, which project from one side of the cord to the other and form axonal terminations that are confined to the cord itself. Commissural interneurons form heterogeneous populations and influence a variety of spinal circuits. They can be defined according to a variety of criteria including, location in the spinal gray matter, axonal projections and targets, neurotransmitter phenotype, activation properties, and embryological origin. At present, we do not have a comprehensive classification of these cells, but it is clear that cells located within different areas of the gray matter have characteristic properties and make particular contributions to motor circuits. The contribution of commissural interneurons to locomotor function and posture is well established and briefly discussed. However, their role in other goal-orientated behaviors such as grasping, reaching, and bimanual tasks is less clear. This is partly because we only have limited information about the organization and functional properties of commissural interneurons in the cervical spinal cord of primates, including humans. In this review we shall discuss these various issues. First, we will consider the properties of commissural interneurons and subsequently examine what is known about their functions. We then discuss how they may contribute to restoration of function following spinal injury and stroke.

Classification of Neurons in the Primate Reticular Formation and Changes after Recovery from Pyramidal Tract Lesion.

The reticular formation is important in primate motor control, both in health and during recovery after brain damage. Little is known about the different neurons present in the reticular nuclei. Here we recorded extracellular spikes from the reticular formation in five healthy female awake behaving monkeys (193 cells), and in two female monkeys 1 year after recovery from a unilateral pyramidal tract lesion (125 cells). Analysis of spike shape and four measures derived from the interspike interval distribution identified four clusters of neurons in control animals. Cluster 1 cells had a slow firing rate. Cluster 2 cells had narrow spikes and irregular firing, which often included high-frequency bursts. Cluster 3 cells were highly rhythmic and fast firing. Cluster 4 cells showed negative spikes. A separate population of 42 cells was antidromically identified as reticulospinal neurons in five anesthetized female monkeys. The distribution of spike width in these cells closely overlaid the distribution for cluster 2, leading us tentatively to suggest that cluster 2 included neurons with reticulospinal projections. In animals after corticospinal lesion, cells could be identified in all four clusters. The firing rate of cells in clusters 1 and 2 was increased in lesioned animals relative to control animals (by 52% and 60%, respectively); cells in cluster 2 were also more regular and more bursting in the lesioned animals. We suggest that changes in both membrane properties and local circuits within the reticular formation occur following lesioning, potentially increasing reticulospinal output to help compensate for lost corticospinal descending drive.SIGNIFICANCE STATEMENT This work is the first to subclassify neurons in the reticular formation, providing insights into the local circuitry of this important but little understood structure. The approach developed can be applied to any extracellular recording from this region, allowing future studies to place their data within our current framework of four neural types. Changes in reticular neurons may be important to subserve functional recovery after damage in human patients, such as after stroke or spinal cord injury.

Corticospinal gating during action preparation and movement in the primate motor cortex.

During everyday actions there is a need to be able to withhold movements until the most appropriate time. This motor inhibition is likely to rely on multiple cortical and subcortical areas, but the primary motor cortex (M1) is a critical component of this process. However, the mechanisms behind this inhibition are unclear, particularly the role of the corticospinal system, which is most often associated with driving muscles and movement. To address this, recordings were made from identified corticospinal (PTN, n = 94) and corticomotoneuronal (CM, n = 16) cells from M1 during an instructed delay reach-to-grasp task. The task involved the animals withholding action for ~2 s until a GO cue, after which they were allowed to reach and perform the task for a food reward. Analysis of the firing of cells in M1 during the delay period revealed that, as a population, non-CM PTNs showed significant suppression in their activity during the cue and instructed delay periods, while CM cells instead showed a facilitation during the preparatory delay. Analysis of cell activity during movement also revealed that a substantial minority of PTNs (27%) showed suppressed activity during movement, a response pattern more suited to cells involved in withholding rather than driving movement. These results demonstrate the potential contributions of the M1 corticospinal system to withholding of actions and highlight that suppression of activity in M1 during movement preparation is not evenly distributed across different neural populations. NEW & NOTEWORTHY Recordings were made from identified corticospinal (PTN) and corticomotoneuronal (CM) cells during an instructed delay task. Activity of PTNs as a population was suppressed during the delay, in contrast to CM cells, which were facilitated. A minority of PTNs showed a rate profile that might be expected from inhibitory cells and could suggest that they play an active role in action suppression, most likely through downstream inhibitory circuits.

Interhemispheric connectivity during bimanual isometric force generation.

Interhemispheric interactions through the corpus callosum play an important role in the control of bimanual forces. However, the extent to which physiological connections between primary motor cortices are modulated during increasing levels of bimanual force generation in intact humans remains poorly understood. Here we studied coherence between electroencephalographic (EEG) signals and the ipsilateral cortical silent period (iSP), two well-known measures of interhemispheric connectivity between motor cortices, during unilateral and bilateral 10%, 40%, and 70% of maximal isometric voluntary contraction (MVC) into index finger abduction. We found that EEG-EEG coherence in the alpha frequency band decreased while the iSP area increased during bilateral compared with unilateral 40% and 70% but not 10% of MVC. Decreases in coherence in the alpha frequency band correlated with increases in the iSP area, and subjects who showed this inverse relation were able to maintain more steady bilateral muscle contractions. To further examine the relationship between the iSP and coherence we electrically stimulated the ulnar nerve at the wrist at the alpha frequency. Electrical stimulation increased coherence in the alpha frequency band and decreased the iSP area during bilateral 70% of MVC. Altogether, our findings demonstrate an inverse relation between alpha oscillations and the iSP during strong levels of bimanual force generation. We suggest that interactions between neural pathways mediating alpha oscillatory activity and transcallosal inhibition between motor cortices might contribute to the steadiness of strong bilateral isometric muscle contractions in intact humans.

Pathways mediating functional recovery.

Following damage to the motor system (e.g., after stroke or spinal cord injury), recovery of upper limb function exploits the multiple pathways which allow motor commands to be sent to the spinal cord. Corticospinal fibers originate from premotor as well as primary motor cortex. While some corticospinal fibers make direct monosynaptic connections to motoneurons, there are also many connections to interneurons which allow control of motoneurons indirectly. Such interneurons may be placed within the cervical enlargement, or more rostrally (propriospinal interneurons). In addition, connections from cortex to the reticular formation in the brainstem allow motor commands to be sent over the reticulospinal tract to these spinal centers. In this review, we consider the relative roles of these different routes for the control of hand function, both in healthy primates and after recovery from lesion.

Spinal commissural connections to motoneurons controlling the primate hand and wrist.

Left-right coordination is essential for locomotor movements and is partly mediated by spinal commissural systems. Such coordination is also essential for reaching and manipulation in primates, but the role of spinal commissural systems here has not been studied. We investigated commissural connectivity to motoneurons innervating forelimb muscles using intracellular recordings in acutely anesthetized macaque monkeys. In 57 of 81 motoneurons, synaptic responses (52 of 57 excitatory) were evoked after contralateral intraspinal microstimulation in the gray matter (cISMS; 300 µA maximum current intensity). Some responses (15 of 57) occurred at latencies compatible with a monosynaptic linkage, including in motoneurons projecting to intrinsic hand muscles (9 cells). Three pieces of evidence suggest that these effects reflected the action of commissural interneurons. In two cells, preceding cISMS with stimulation of the contralateral medial brainstem descending pathways facilitated the motoneuron responses, suggesting that cISMS acted on cell bodies whose excitability was increased by descending inputs. Pairing cISMS with stimulation of the contralateral corticospinal tract yielded no evidence of response occlusion in 16 cells tested, suggesting that the effects were not merely axon reflexes generated by stimulation of corticospinal axon branches, which cross the midline. Finally, stimulation of contralateral peripheral nerves evoked responses in 28 of 52 motoneurons (7 of 9 projecting to the hand). Our results demonstrate the existence of commissural neurons with access to spinal motoneurons in primate cervical spinal cord that receive inputs from the periphery as well as descending pathways. Most importantly, commissural neurons also innervate motoneurons of intrinsic hand muscles.

Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements.

Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion­extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke.

Changes in descending motor pathway connectivity after corticospinal tract lesion in macaque monkey.

Damage to the corticospinal tract is a leading cause of motor disability, for example in stroke or spinal cord injury. Some function usually recovers, but whether plasticity of undamaged ipsilaterally descending corticospinal axons and/or brainstem pathways such as the reticulospinal tract contributes to recovery is unknown. Here, we examined the connectivity in these pathways to motor neurons after recovery from corticospinal lesions. Extensive unilateral lesions of the medullary corticospinal fibres in the pyramidal tract were made in three adult macaque monkeys. After an initial contralateral flaccid paralysis, motor function rapidly recovered, after which all animals were capable of climbing and supporting their weight by gripping the cage bars with the contralesional hand. In one animal where experimental testing was carried out, there was (as expected) no recovery of fine independent finger movements. Around 6 months post-lesion, intracellular recordings were made from 167 motor neurons innervating hand and forearm muscles. Synaptic responses evoked by stimulating the unlesioned ipsilateral pyramidal tract and the medial longitudinal fasciculus were recorded and compared with control responses in 207 motor neurons from six unlesioned animals. Input from the ipsilateral pyramidal tract was rare and weak in both lesioned and control animals, suggesting a limited role for this pathway in functional recovery. In contrast, mono- and disynaptic excitatory post-synaptic potentials elicited from the medial longitudinal fasciculus significantly increased in average size after recovery, but only in motor neurons innervating forearm flexor and intrinsic hand muscles, not in forearm extensor motor neurons. We conclude that reticulospinal systems sub-serve some of the functional recovery after corticospinal lesions. The imbalanced strengthening of connections to flexor, but not extensor, motor neurons mirrors the extensor weakness and flexor spasm which in neurological experience is a common limitation to recovery in stroke survivors.

Corticomuscular coherence during bilateral isometric arm voluntary activity in healthy humans.

Bilateral voluntary contractions involve functional changes in both primary motor cortices. We investigated whether a voluntary contraction controlled by one hemisphere can influence oscillatory processes contralaterally. Corticomuscular coherence was calculated between EEG recorded over the motor cortex hand representation and electromyogram from the first dorsal interosseous muscle when the nondominant hand performed a precision grip task. The dominant arm remained at rest or performed a finger abduction or an elbow flexion task at 10, 40, and 70% of maximal isometric voluntary contraction (MVC). Mean coherence in the 15- to 30-Hz range in the hand performing a precision grip increased during 40% (by 72%) and 70% (by 73%) but not during 10% of MVC in the finger abduction task. Similarly, in the elbow flexion task, mean coherence increased during 40% (by 40%) and 70% (by 48%) but not during 10% of MVC. No differences were observed between the increments in coherence between the finger abduction and elbow flexion tasks at a given force level. We speculate that these results reflect the increased complexity of controlling a fine motor task with one hand while performing a strong contraction with the contralateral hand and suggest that increased oscillatory corticomuscular coupling may contribute to successful task performance.

Lack of evidence for direct corticospinal contributions to control of the ipsilateral forelimb in monkey.

Strong experimental evidence implicates the corticospinal tract in voluntary control of the contralateral forelimb. Its potential role in controlling the ipsilateral forelimb is less well understood, although anatomical projections to ipsilateral spinal circuits are identified. We investigated inputs to motoneurons innervating hand and forearm muscles from the ipsilateral corticospinal tract using multiple methods. Intracellular recordings from 62 motoneurons in three anesthetized monkeys revealed no monosynaptic and only one weak oligosynaptic EPSP after stimulation of the ipsilateral corticospinal tract. Single stimulus intracortical microstimulation of the primary motor cortex (M1) in awake animals failed to produce any responses in ipsilateral muscles. Strong stimulation (>500 µA, single stimulus) of the majority of corticospinal axons at the medullary pyramids revealed only weak suppressions in ipsilateral muscles at longer latencies than the robust facilitations seen contralaterally. Spike-triggered averaging of ipsilateral muscle activity from M1 neural discharge (184 cells) did not reveal any postspike effects consistent with monosynaptic corticomotoneuronal connections. We also examined the activity of 191 M1 neurons during ipsilateral or contralateral "reach to precision grip" movements. Many cells (67%) modulated their activity during ipsilateral limb movement trials (compared with 90% with contralateral trials), but the timing of this activity was best correlated with weak muscle activity in the contralateral nonmoving arm. We conclude that, in normal adults, any inputs to forelimb motoneurons from the ipsilateral corticospinal tract are weak and indirect and that modulation of M1 cell firing seems to be related primarily to control of the contralateral limb.

Physiological changes underlying bilateral isometric arm voluntary contractions in healthy humans.

Many bilateral motor tasks engage simultaneous activation of distal and proximal arm muscles, but little is known about their physiological interactions. Here, we used transcranial magnetic stimulation to examine motor-evoked potentials (MEPs), interhemispheric inhibition at a conditioning-test interval of 10 (IHI(10)) and 40 ms (IHI(40)), and short-interval intracortical inhibition (SICI) in the left first dorsal interosseous (FDI) muscle during isometric index finger abduction. The right side remained at rest or performed isometric voluntary contraction with the FDI, biceps or triceps brachii, or the tibialis anterior. Left FDI MEPs were suppressed to a similar extent during contraction of the right FDI and biceps and triceps brachii but remained unchanged during contraction of the right tibialis anterior. IHI(10) and IHI(40) were decreased during contraction of the right biceps and triceps brachii compared with contraction of the right FDI. SICI was increased during activation of the right biceps and triceps brachii and decreased during activation of the right FDI. The present results indicate that an isometric voluntary contraction with either a distal or a proximal arm muscle, but not a foot dorsiflexor, decreases corticospinal output in a contralateral active finger muscle. Transcallosal inhibitory effects were strong during bilateral activation of distal hand muscles and weak during simultaneous activation of a distal and a proximal arm muscle, whereas GABAergic intracortical activity was modulated in the opposite manner. These findings suggest that in intact humans crossed interactions at the level of the motor cortex involved different physiological mechanisms when bilateral distal hand muscles are active and when a distal and a proximal arm muscle are simultaneously active.

Spinal interneuron circuits reduce approximately 10-Hz movement discontinuities by phase cancellation.

Tremor imposes an important limit to the accuracy of fine movements in healthy individuals and can be a disabling feature of neurological disease. Voluntary slow finger movements are not smooth but are characterized by large discontinuities (i.e., steps) in the tremor frequency range (approximately 10 Hz). Previous studies have shown that these discontinuities are coherent with activity in the primary motor cortex (M1), but that other brain areas are probably also involved. We investigated the contribution of three important subcortical areas in two macaque monkeys trained to perform slow finger movements. Local field potential and single-unit activity were recorded from the deep cerebellar nuclei (DCN), medial pontomedullary reticular formation, and the intermediate zone of the spinal cord (SC). Coherence between LFP and acceleration was significant at 6 to 13 Hz for all areas, confirming the highly distributed nature of the central network responsible for this activity. The coherence phase at 6 to 13 Hz for DCN and pontomedullary reticular formation was similar to our previous results in M1. By contrast, for SC the phase differed from M1 by approximately pi rad. Examination of single-unit discharge confirmed that this was a genuine difference in neural spiking and could not be explained by different properties of the local field potential. Convergence of antiphase oscillations from the SC with cortical and subcortical descending inputs will lead to cancellation of approximately 10 Hz oscillations at the motoneuronal level. This could appreciably limit drive to muscle at this frequency, thereby reducing tremor and improving movement precision.

Coherence between motor cortical activity and peripheral discontinuities during slow finger movements.

Slow finger movements in man are not smooth, but are characterized by 8- to 12-Hz discontinuities in finger acceleration thought to have a central source. We trained two macaque monkeys to track a moving target by performing index finger flexion/extension movements and recorded local field potentials (LFPs) and spike activity from the primary motor cortex (M1); some cells were identified as pyramidal tract neurons by antidromic activation or as corticomotoneuronal cells by spike-triggered averaging. There was significant coherence between finger acceleration in the approximately 10-Hz range and both LFPs and spikes. LFP-acceleration coherence was similar for flexion and extension movements (0.094 at 9.8 Hz and 0.11 at 6.8 Hz, respectively), but substantially smaller during steady holding (0.0067 at 9.35 Hz). The coherence phase showed a significant linear relationship with frequency over the 6- to 13-Hz range, as expected for a constant conduction delay, but the slope indicated that LFP lagged acceleration by 18 +/- 14 or 36 +/- 8 ms for flexion and extension movements, respectively. Directed coherence analysis supported the conclusion that the dominant interaction was in the acceleration to LFP (i.e., sensory) direction. The phase relationships between finger acceleration and both LFPs and spikes shifted by about pi radians in flexion compared with extension trials. However, for a given trial type the phase relationship with acceleration was similar for cells that increased their firing during flexion or during extension trials. We conclude that movement discontinuities during slow finger movements arise from a reciprocally coupled network, which includes M1 and the periphery.

Quantifying neural coding of event timing.

Single-neuron firing is often analyzed relative to an external event, such as successful task performance or the delivery of a stimulus. The perievent time histogram (PETH) examines how, on average, neural firing modulates before and after the alignment event. However, the PETH contains no information about the single-trial reliability of the neural response, which is important from the perspective of a target neuron. In this study, we propose the concept of using the neural activity to predict the timing of the occurrence of an event, as opposed to using the event to predict the neural response. We first estimate the likelihood of an observed spike train, under the assumption that it was generated by an inhomogeneous gamma process with rate profile similar to the PETH shifted by a small time. This is used to generate a probability distribution of the event occurrence, using Bayes' rule. By an information theoretic approach, this method yields a single value (in bits) that quantifies the reduction in uncertainty regarding the time of an external event following observation of the spike train. We show that the approach is sensitive to the amplitude of a response, to the level of baseline firing, and to the consistency of a response between trials, all of which are factors that will influence a neuron's ability to code for the time of the event. The technique can provide a useful means not only of determining which of several behavioral events a cell encodes best, but also of permitting objective comparison of different cell populations.