Pairing Transcranial Magnetic Stimulation and Loud Sounds Produces Plastic Changes in Motor Output.

Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50 ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30 min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms.SIGNIFICANCE STATEMENT Induction of plasticity by neurostimulation protocols may be promising to enhance functional recovery after damage such as following stroke, but current protocols mainly target cortical circuits. In this study, we developed a novel paradigm which may generate long-term changes in connections between cortex and brainstem. This could provide an additional tool to modulate and improve recovery.

Both Corticospinal and Reticulospinal Tracts Control Force of Contraction.

The control of contraction strength is a key part of movement control. In primates, both corticospinal and reticulospinal cells provide input to motoneurons. Corticospinal discharge is known to correlate with force, but there are no previous reports of how reticular formation (RF) activity modulates with different contractions. Here we trained two female macaque monkeys (body weight, 5.9-6.9 kg) to pull a handle that could be loaded with 0.5-6 kg weights and recorded from identified pyramidal tract neurons (PTNs) in primary motor cortex and RF cells during task performance. Population-averaged firing rate increased monotonically with higher force for the RF, but showed a complex profile with little net modulation for PTNs. This reflected a more heterogeneous profile of rate modulation across the PTN population, leading to cancellation in the average. Linear discriminant analysis classified the force based on the time course of rate modulation equally well for PTNs and RF cells. Peak firing rate had significant linear correlation with force for 43 of 92 PTNs (46.7%) and 21 of 46 RF cells (43.5%). For almost all RF cells (20 of 21), the correlation coefficient was positive; similar numbers of PTNs (22 vs 21) had positive versus negative coefficients. Considering the timing of force representation, similar fractions (PTNs: 61.2%; RF cells: 55.5%) commenced coding before the onset of muscle activity. We conclude that both corticospinal and reticulospinal tracts contribute to the control of contraction force; the reticulospinal tract seems to specify an overall signal simply related to force, whereas corticospinal cell activity would be better suited for fine-scale adjustments.SIGNIFICANCE STATEMENT For the first time, we compare the coding of force for corticospinal and reticular formation cells in awake behaving monkeys, over a wide range of contraction strengths likely to come close to maximum voluntary contraction. Both cortical and brainstem systems coded similarly well for force, but whereas reticular formation cells carried a simple uniform signal, corticospinal neurons were more heterogeneous. This may reflect a role in the gross specification of a coordinated movement, versus more fine-grained adjustments around individual joints.

The Existence of the StartReact Effect Implies Reticulospinal, Not Corticospinal, Inputs Dominate Drive to Motoneurons during Voluntary Movement.

Reaction time is accelerated if a loud (startling) sound accompanies the cue-the "StartReact" effect. Animal studies revealed a reticulospinal substrate for the startle reflex; StartReact may similarly involve the reticulospinal tract, but this is currently uncertain. Here we trained two female macaque monkeys to perform elbow flexion/extension movements following a visual cue. The cue was sometimes accompanied by a loud sound, generating a StartReact effect in electromyogram response latency, as seen in humans. Extracellular recordings were made from antidromically identified corticospinal neurons in primary motor cortex (M1), from the reticular formation (RF), and from the spinal cord (SC; C5-C8 segments). After loud sound, task-related activity was suppressed in M1 (latency, 70-200 ms after cue), but was initially enhanced (70-80 ms) and then suppressed (140-210 ms) in RF. SC activity was unchanged. In a computational model, we simulated a motoneuron pool receiving input from different proportions of the average M1 and RF activity recorded experimentally. Motoneuron firing generated simulated electromyogram, allowing reaction time measurements. Only if ≥60% of motoneuron drive came from RF (≤40% from M1) did loud sound shorten reaction time. The extent of shortening increased as more drive came from RF. If RF provided <60% of drive, loud sound lengthened the reaction time-the opposite of experimental findings. The majority of the drive for voluntary movements is thus likely to originate from the brainstem, not the cortex; changes in the magnitude of the StartReact effect can measure a shift in the relative importance of descending systems.SIGNIFICANCE STATEMENT Our results reveal that a loud sound has opposite effects on neural spiking in corticospinal cells from primary motor cortex, and in the reticular formation. We show that this fortuitously allows changes in reaction time produced by a loud sound to be used to assess the relative importance of reticulospinal versus corticospinal control of movement, validating previous noninvasive measurements in humans. Our findings suggest that the majority of the descending drive to motoneurons producing voluntary movement in primates comes from the reticulospinal tract, not the corticospinal tract.

Interfacing Motor Units in Non-Human Primates Identifies a Principal Neural Component for Force Control Constrained by the Size Principle.

Motor units convert the last neural code of movement into muscle forces. The classic view of motor unit control is that the central nervous system sends common synaptic inputs to motoneuron pools and that motoneurons respond in an orderly fashion dictated by the size principle. This view however is in contrast with the large number of dimensions observed in motor cortex which may allow individual and flexible control of motor units. Evidence for flexible control of motor units may be obtained by tracking motor units longitudinally during tasks with some level of behavioural variability. Here we identified and tracked populations of motor units in the brachioradialis muscle of two macaque monkeys during ten sessions spanning over one month with a broad range of rate of force development (1.8 - 38.6 N·m·s-1). We found a very stable recruitment order and discharge characteristics of the motor units over sessions and contraction trials. The small deviations from orderly recruitment were fully predicted by the motor unit recruitment intervals, so that small shifts in recruitment thresholds happened only during contractions at high rate of force development. Moreover, we also found that one component explained more than ∼50% of the motor unit discharge rate variance, and that the remaining components represented a time-shifted version of the first. In conclusion, our results show that motoneurons recruitment is determined by the interplay of the size principle and common input and that this recruitment scheme is not violated over time nor by the speed of the contractions.SIGNIFICANCE STATEMENT:With a new non-invasive high-density electromyographic framework we show the activity of motor unit ensembles in macaques during voluntary contractions. The discharge characteristics of brachioradialis motor units revealed a relatively fixed recruitment order and discharge characteristics across days and rate of force developments. These results were further confirmed through invasive axonal stimulation and recordings of intramuscular electromyographic activity from 16 arm muscles. The study shows for the first time the feasibility of longitudinal non-invasive motor unit interfacing and tracking of the same motor units in non-human primates.

Standard intensities of transcranial alternating current stimulation over the motor cortex do not entrain corticospinal inputs to motor neurons.

Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS-driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. KEY POINTS: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions. It is challenging to find direct evidence supporting TACS-driven neural entrainment due to the technical difficulties in recording brain activity during stimulation. Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment. Motor unit activity from human muscles does not support TACS-driven corticospinal entrainment.

Short-Latency Afferent Inhibition Correlates with Stage of Disease in Parkinson's Patients.

BACKGROUND: Sensory-motor decoupling at the cortical level involving cholinergic circuitry has also been reported in Parkinson's Disease (PD). Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been used previously to probe cortical cholinergic circuits in well-characterised subgroups of patients with PD. In the current study, we compared SAI in a cohort of PD patients at various stages of disease and explored correlations between SAI and various clinical measures of disease severity. METHODS: The modified Hoehn and Yahr (H&Y) scale was used to stage disease in 22 patients with PD. Motor and cognitive function were assessed using the MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale) part III and MoCA (Montreal Cognitive Assessment) score, respectively. Objective gait assessment was performed using an electronic walkway (GAITRite®). SAI was measured as the average percentage inhibition of test motor-evoked potentials (MEPs) conditioned by electrical stimulation of the contralateral median nerve at the wrist. RESULTS: SAI was significantly reduced in patients with advanced PD (H&Y stage 3) compared to early PD patients (H&Y stage 1) on pairwise comparison. The visuospatial executive function and orientation domains of cognition demonstrated significant negative associations with SAI. CONCLUSION: Cortical sensory-motor integration is progressively diminished as disease progresses. The observation that a reduction in SAI is associated with a reduction in cognitive function possibly reflects the progressive involvement of cortical cholinergic circuits in PD with increasing motor stage. Future longitudinal studies are necessary to confirm this preliminary result.

Evidence for Subcortical Plasticity after Paired Stimulation from a Wearable Device.

Existing non-invasive stimulation protocols can generate plasticity in the motor cortex and its corticospinal projections; techniques for inducing plasticity in subcortical circuits and alternative descending pathways such as the reticulospinal tract (RST) are less well developed. One possible approach developed by this laboratory pairs electrical muscle stimulation with auditory clicks, using a wearable device to deliver stimuli during normal daily activities. In this study, we applied a variety of electrophysiological assessments to male and female healthy human volunteers during a morning and evening laboratory visit. In the intervening time (∼6 h), subjects wore the stimulation device, receiving three different protocols, in which clicks and stimulation of the biceps muscle were paired at either low or high rate, or delivered at random. Paired stimulation: (1) increased the extent of reaction time shortening by a loud sound (the StartReact effect); (2) decreased the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; (3) enhanced muscle responses elicited by a TMS coil oriented to induce anterior-posterior (AP) current, but not posterior-anterior (PA) current, in the brain. These measurements have all been suggested to be sensitive to subcortical, possibly reticulospinal, activity. Changes were similar for either of the two paired stimulus rates tested, but absent after unpaired (control) stimulation. Taken together, these results suggest that pairing clicks and muscle stimulation for long periods does indeed induce plasticity in subcortical systems such as the RST.SIGNIFICANCE STATEMENT Subcortical systems such as the reticulospinal tract (RST) are important motor pathways, which can make a significant contribution to functional recovery after cortical damage such as stroke. Here, we measure changes produced after a novel non-invasive stimulation protocol, which uses a wearable device to stimulate for extended periods. We observed changes in electrophysiological measurements consistent with the induction of subcortical plasticity. This protocol may prove an important tool for enhancing motor rehabilitation, in situations where insufficient cortical tissue survives to be a plausible substrate for recovery of function.

Spatial and Temporal Arrangement of Recurrent Inhibition in the Primate Upper Limb.

Renshaw cells mediate recurrent inhibition between motoneurons within the spinal cord. The function of this circuit is not clear; we previously suggested based on computational modeling that it may cancel oscillations in muscle activity around 10 Hz, thereby reducing physiological tremor. Such tremor is especially problematic for dexterous hand movements, yet knowledge of recurrent inhibitory function is sparse for the control of the primate upper limb, where no direct measurements have been made to date. In this study, we made intracellular penetrations into 89 motoneurons in the cervical enlargement of four terminally anesthetized female macaque monkeys, and recorded recurrent IPSPs in response to antidromic stimulation of motor axons. Recurrent inhibition was strongest to motoneurons innervating shoulder muscles and elbow extensors, weak to wrist and digit extensors, and almost absent to the intrinsic muscles of the hand. Recurrent inhibitory connections often spanned joints, for example from motoneurons innervating wrist and digit muscles to those controlling the shoulder and elbow. Wrist and digit flexor motoneurons sometimes inhibited the corresponding extensors, and vice versa. This complex connectivity presumably reflects the flexible usage of the primate upper limb. Using trains of stimuli to motor nerves timed as a Poisson process and coherence analysis, we also examined the temporal properties of recurrent inhibition. The recurrent feedback loop effectively carried frequencies up to 100 Hz, with a coherence peak around 20 Hz. The coherence phase validated predictions from our previous computational model, supporting the idea that recurrent inhibition may function to reduce tremor.SIGNIFICANCE STATEMENT We present the first direct measurements of recurrent inhibition in primate upper limb motoneurons, revealing that it is more flexibly organized than previous observations in cat. Recurrent inhibitory connections were relatively common between motoneurons controlling muscles that act at different joints, and between flexors and extensors. As in the cat, connections were minimal for motoneurons innervating the most distal intrinsic hand muscles. Empirical data are consistent with previous modeling: temporal properties of the recurrent inhibitory feedback loop are compatible with a role in reducing physiological tremor by suppressing oscillations around 10 Hz.

Extensive Cortical Convergence to Primate Reticulospinal Pathways.

Early evolution of the motor cortex included development of connections to brainstem reticulospinal neurons; these projections persist in primates. In this study, we examined the organization of corticoreticular connections in five macaque monkeys (one male) using both intracellular and extracellular recordings from reticular formation neurons, including identified reticulospinal cells. Synaptic responses to stimulation of different parts of primary motor cortex (M1) and supplementary motor area (SMA) bilaterally were assessed. Widespread short latency excitation, compatible with monosynaptic transmission over fast-conducting pathways, was observed, as well as longer latency responses likely reflecting a mixture of slower monosynaptic and oligosynaptic pathways. There was a high degree of convergence: 56% of reticulospinal cells with input from M1 received projections from M1 in both hemispheres; for SMA, the equivalent figure was even higher (70%). Of reticulospinal neurons with input from the cortex, 78% received projections from both M1 and SMA (regardless of hemisphere); 83% of reticulospinal cells with input from M1 received projections from more than one of the tested M1 sites. This convergence at the single cell level allows reticulospinal neurons to integrate information from across the motor areas of the cortex, taking account of the bilateral motor context. Reticulospinal connections are known to strengthen following damage to the corticospinal tract, such as after stroke, partially contributing to functional recovery. Extensive corticoreticular convergence provides redundancy of control, which may allow the cortex to continue to exploit this descending pathway even after damage to one area.SIGNIFICANCE STATEMENT The reticulospinal tract (RST) provides a parallel pathway for motor control in primates, alongside the more sophisticated corticospinal system. We found extensive convergent inputs to primate reticulospinal cells from primary and supplementary motor cortex bilaterally. These redundant connections could maintain transmission of voluntary commands to the spinal cord after damage (e.g., after stroke or spinal cord injury), possibly assisting recovery of function.

Startling stimuli increase maximal motor unit discharge rate and rate of force development in humans.

Maximal rate of force development in adult humans is determined by the maximal motor unit discharge rate, however, the origin of the underlying synaptic inputs remains unclear. Here, we tested a hypothesis that the maximal motor unit discharge rate will increase in response to a startling cue, a stimulus that purportedly activates the pontomedullary reticular formation neurons that make mono- and disynaptic connections to motoneurons via fast-conducting axons. Twenty-two men were required to produce isometric knee extensor forces "as fast and as hard" as possible from rest to 75% of maximal voluntary force, in response to visual (VC), visual-auditory (VAC; 80 dB), or visual-startling cue (VSC; 110 dB). Motoneuron activity was estimated via decomposition of high-density surface electromyogram recordings over the vastus lateralis and medialis muscles. Reaction time was significantly shorter in response to VSC compared with VAC and VC. The VSC further elicited faster neuromechanical responses including a greater number of discharges per motor unit per second and greater maximal rate of force development, with no differences between VAC and VC. We provide evidence, for the first time, that the synaptic input to motoneurons increases in response to a startling cue, suggesting a contribution of subcortical pathways to maximal motoneuron output in humans.NEW & NOTEWORTHY Motor unit discharge characteristics are a key determinant of rate of force development in humans, but the neural substrate(s) underpinning such output remains unknown. Using decomposition of high-density electromyogram, we show greater number of discharges per motor unit per second and greater rate of force development after a startling auditory stimulus. These observations suggest a possible subcortical contribution to maximal in vivo motor unit discharge rate in adult humans.

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.

Comparing Stop Signal Reaction Times in Alzheimer's and Parkinson's Disease.

BACKGROUND: To investigate the relative contributions of cerebral cortex and basal ganglia to movement stopping, we tested the optimum combination Stop Signal Reaction Time (ocSSRT) and median visual reaction time (RT) in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and compared values with data from healthy controls. METHODS: Thirty-five PD patients, 22 AD patients, and 29 healthy controls were recruited to this study. RT and ocSSRT were measured using a hand-held battery-operated electronic box through a stop signal paradigm. RESULT: The mean ocSSRT was found to be 309 ms, 368 ms, and 265 ms in AD, PD, and healthy controls, respectively, and significantly prolonged in PD compared to healthy controls (p = 0.001). The ocSSRT but not RT could separate AD from PD patients (p = 0.022). CONCLUSION: Our data suggest that subcortical networks encompassing dopaminergic pathways in the basal ganglia play a more important role than cortical networks in movement-stopping. Combining ocSSRT with other putative indices or biomarkers of AD (and other dementias) could increase the accuracy of early diagnosis.

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.

Cortical, Corticospinal, and Reticulospinal Contributions to Strength Training.

Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in 2 female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor-evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST), and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6 kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a 2 week washout period without weights. After a further 3 months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared with the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.SIGNIFICANCE STATEMENT We provide the first report of a strength training intervention in nonhuman primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whereas corticospinal and motoneuronal adaptations are not dominant factors.

Plastic changes in primate motor cortex following paired peripheral nerve stimulation.

Repeated paired stimulation of two peripheral nerves can produce lasting changes in motor cortical excitability, but little is known of the underlying neuronal basis. Here, we trained two macaque monkeys to perform selective thumb and index finger abduction movements. Neural activity was recorded from the contralateral primary motor cortex during task performance, and following stimulation of the ulnar and median nerves, and the nerve supplying the extensor digitorum communis (EDC) muscle. Responses were compared before and after 1 h of synchronous or asynchronous paired ulnar/median nerve stimulation. Task performance was significantly enhanced after asynchronous and impaired after synchronous stimulation. The amplitude of short latency neural responses to median and ulnar nerve stimulation was increased after asynchronous stimulation; later components were reduced after synchronous stimulation. Synchronous stimulation increased neural activity during thumb movement and decreased it during index finger movement; asynchronous stimulation decreased activity during both movements. To assess how well neural activity could separate behavioral or sensory conditions, linear discriminant analysis was used to decode which nerve was stimulated, or which digit moved. Decoding accuracy for nerve stimulation was decreased after synchronous and increased after asynchronous paired stimulation. Decoding accuracy for task performance was decreased after synchronous but was unchanged after asynchronous paired stimulation. Paired stimulation produces changes in motor cortical circuits that outlast the stimulation. Some of these changes depend on precise stimulus timing.NEW & NOTEWORTHY Paired stimulation of peripheral nerves for 1 h induced lasting changes in neural responses within the motor cortex to nerve stimulation and to performance of a behavioral task. These changes were sufficient to alter the efficiency with which activity could encode stimulus type. Stimuli that can be easily applied noninvasively in human subjects can alter central motor circuits.

Induction of plasticity in the human motor system by motor imagery and transcranial magnetic stimulation.

KEY POINTS: Delivering transcranial magnetic brain stimulation over the motor cortex during motor imagination leads to enhanced motor output, which is selective for the muscles primarily involved in the imagined movement. This novel protocol may be useful to enhance function after damage to the motor system, such as after stroke. ABSTRACT: Several paired stimulation paradigms are known to induce plasticity in the motor cortex, reflected by changes in the motor evoked potential (MEP) following the paired stimulation. Motor imagery (MI) is capable of activating the motor system and affecting cortical excitability. We hypothesized that it might be possible to use MI in conjunction with transcranial magnetic stimulation (TMS) to induce plasticity in the human motor system. TMS was delivered to the motor cortex of healthy human subjects, and baseline MEPs recorded from forearm flexor, forearm extensor and intrinsic hand muscles. Subjects were then asked to imagine either wrist flexion or extension movements during TMS delivery (n = 90 trials). Immediately after this intervention, MEP measurement was repeated. Control protocols tested the impact of imagination or TMS alone. Flexion imagination with TMS increased MEPs in flexors and an intrinsic hand muscle. Extensor imagination with TMS increased MEPs in extensor muscles only. The control paradigms did not produce significant changes. We conclude that delivering TMS during MI is capable of inducing plastic changes in the motor system. This new protocol may find utility to enhance functional rehabilitation after brain injury.

Convergent Spinal Circuits Facilitating Human Wrist Flexors.

Noninvasive assessment of spinal circuitry in humans is limited, especially for Ib pathways in the upper limb. We developed a protocol in which we evoke the H-reflex in flexor carpi radialis (FCR) by median nerve stimulation and condition it with electrical stimulation above motor threshold over the extensor carpi radialis (ECR) muscle belly. Eighteen healthy adults (8 male, 10 female) took part in the study. There was a clear reflex facilitation at a 30 ms interstimulus interval (ISI) and suppression at a 70 ms ISI, which was highly consistent across subjects. We investigated the following two hypotheses of the possible source of the facilitation: (1) ECR Ib afferents from Golgi tendon organs, activated by the twitch following ECR stimulation; and (2) FCR afferents, from spindles and/or Golgi tendon organs, activated by the wrist extension movement that follows ECR stimulation. Several human and monkey experiments indicated a role for both of these sets of afferents. Our results provide evidence for a spinal circuit in which flexor motoneurons receive convergent excitatory input from flexor afferents as well as from extensor Ib afferents; this circuit can be straightforwardly assessed noninvasively in humans.SIGNIFICANCE STATEMENT Here we described a novel spinal circuit, which is easy to assess noninvasively in humans. Understanding this circuit in more detail could be beneficial for the design of clinical tests in neurological conditions.

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.

A hierarchy of corticospinal plasticity in human hand and forearm muscles.

KEY POINTS: Pairing stimulation of a finger flexor or extensor muscle at the motor point with transcranial magnetic stimulation (TMS) of the motor cortex generated plastic changes in motor output. Increases in output were greater in intrinsic hand muscles than in the finger flexor. No changes occurred in the finger extensor. This gradient was seen irrespective of which muscle was stimulated paired with transcranial magnetic stimulation. Intermittent theta-burst stimulation also produced increases in output, although these were similar across muscles. We suggest that intrinsic hand and flexor muscles have a higher potential to show plasticity than extensors, although only when plasticity is induced by sensory input. This may relate to differences seen in recovery of function in these muscles after injury, such as post-stroke. ABSTRACT: The ability of the motor system to show plastic change underlies skill learning and also permits recovery after injury. One puzzling observation is that, after stroke, upper limb flexor muscles show good recovery but extensors remain weak, with this being a major contributor to residual disability. We hypothesized that there might be differences in potential for plasticity across hand and forearm muscles. In the present study, we investigated this using two protocols based on transcranial magnetic brain stimulation (TMS) in healthy human subjects. Baseline TMS responses were recorded from two intrinsic hand muscles: flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC). In the first study, paired associative stimulation (PAS) was delivered by pairing motor point stimulation of FDS or EDC with TMS. Responses were then remeasured. Increases were greatest in the hand muscles, smaller in FDS and non-significant in EDC, irrespective of whether stimulation of FDS or EDC was used. In the second study, intermittent theta-burst rapid rate TMS was applied instead of PAS. In this case, all muscles showed similar increases in TMS responses. We conclude that the potential to show plastic changes in motor cortical output has the gradient: hand muscles > flexors > extensors. However, this was only seen in a protocol that requires integration of sensory input (PAS) and not when plasticity was induced purely by cortical stimulation (rapid rate TMS). This observation may relate to why functional recovery tends to favour flexor and hand muscles over extensors.

Multimodal stimuli modulate rapid visual responses during reaching.

The reticulospinal tract plays an important role in primate upper limb function, but methods for assessing its activity are limited. One promising approach is to measure rapid visual responses (RVRs) in arm muscle activity during a visually cued reaching task; these may arise from a tecto-reticulospinal pathway. We investigated whether changes in reticulospinal excitability can be assessed noninvasively using RVRs, by pairing the visual stimuli of the reaching task with electrical stimulation of the median nerve, galvanic vestibular stimulation, or loud sounds, all of which are known to activate the reticular formation. Surface electromyogram (EMG) recordings were made from the right deltoid of healthy human subjects as they performed fast reaching movements toward visual targets. Stimuli were delivered up to 200 ms before target appearance, and RVR was quantified as the EMG amplitude in a window 75-125 ms after visual target onset. Median nerve, vestibular, and auditory stimuli all consistently facilitated the RVRs, as well as reducing the latency of responses. We propose that this facilitation reflects modulation of tecto-reticulospinal excitability, which is consistent with the idea that the amplitude of RVRs can be used to assess changes in brain stem excitability noninvasively in humans.NEW & NOTEWORTHY Short-latency responses in arm muscles evoked during a visually driven reaching task have previously been proposed to be tecto-reticulospinal in origin. We demonstrate that these responses can be facilitated by pairing the appearance of a visual target with stimuli that activate the reticular formation: median nerve, vestibular, and auditory stimuli. We propose that this reflects noninvasive measurement and modulation of reticulospinal excitability.