Andrew J Fuglevand

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• Martin, A. B., Cardenas, M. A., Andersen, R. K., Bowman, A. I., Hillier, E. A., Bensmaia, S., Fuglevand, A. J., & Gothard, K. M. (2023). A context-dependent switch from sensing to feeling in the primate amygdala. Cell reports, 42(2), 112056.
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  The skin transmits affective signals that integrate into our social vocabulary. As the socio-affective aspects of touch are likely processed in the amygdala, we compare neural responses to social grooming and gentle airflow recorded from the amygdala and the primary somatosensory cortex of non-human primates. Neurons in the somatosensory cortex respond to both types of tactile stimuli. In the amygdala, however, neurons do not respond to individual grooming sweeps even though grooming elicits autonomic states indicative of positive affect. Instead, many show changes in baseline firing rates that persist throughout the grooming bout. Such baseline fluctuations are attributed to social context because the presence of the groomer alone can account for the observed changes in baseline activity. It appears, therefore, that during grooming, the amygdala stops responding to external inputs on a short timescale but remains responsive to social context (or the associated affective states) on longer time scales.
• Sundman, M. H., Avila De Vault, B. E., Chen, A. Y., Madhavan, L., Fuglevand, A. J., & Chou, Y. H. (2023). The (hyper)excitable brain: what can a ubiquitous TMS measure reveal about cognitive aging?. Neurobiology of aging, 132, 250-252.
• Gothard, K. M., & Fuglevand, A. J. (2022). The role of the amygdala in processing social and affective touch. Current opinion in behavioral sciences, 43, 46-53.
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  The amygdala plays a central role in emotion and social behavior, yet its role in processing social and affective touch is not well established. Longitudinal studies reveal that touch-deprived infants show later in life exaggerated emotional reactivity related to structural and functional changes in the amygdala and other brain structures. The internal organization and connectivity of the amygdala is well-suited to process the sensory features of tactile stimuli and also the socio-cognitive dimensions of the received touch. The convergent processing of bottom-up and top-down pathways that carry information about touch results in the elaboration of context appropriate autonomic responses. Indeed, the positive value of affective touch in humans and social grooming in non-human primates is correlated with vagal tone and the release of oxytocin and endogenous opioids. Grooming, the non-human primate equivalent of affective touch in humans, reduces vigilance, that depends on the amygdala. During touch-induced vagal tone and low vigilance, neural activity in the amygdala is substantially different from activity corresponding to the attentive processing of tactile stimuli. Under these circumstances neurons no longer respond phasically to each touch stimulus, rather they signal a sustained functional state in which the amygdala appears decoupled from monitoring the external environment.
• Hasse, B. A., Sheets, D. E., Holly, N. L., Gothard, K. M., & Fuglevand, A. J. (2022). Restoration of complex movement in the paralyzed upper limb. Journal of neural engineering, 19(4).
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  Functional electrical stimulation (FES) involves artificial activation of skeletal muscles to reinstate motor function in paralyzed individuals. While FES applied to the upper limb has improved the ability of tetraplegics to perform activities of daily living, there are key shortcomings impeding its widespread use. One major limitation is that the range of motor behaviors that can be generated is restricted to a small set of simple, preprogrammed movements. This limitation stems from the substantial difficulty in determining the patterns of stimulation across many muscles required to produce more complex movements. Therefore, the objective of this study was to use machine learning to flexibly identify patterns of muscle stimulation needed to evoke a wide array of multi-joint arm movements.. Arm kinematics and electromyographic (EMG) activity from 29 muscles were recorded while a 'trainer' monkey made an extensive range of arm movements. Those data were used to train an artificial neural network that predicted patterns of muscle activity associated with a new set of movements. Those patterns were converted into trains of stimulus pulses that were delivered to upper limb muscles in two other temporarily paralyzed monkeys.. Machine-learning based prediction of EMG was good for within-subject predictions but appreciably poorer for across-subject predictions. Evoked responses matched the desired movements with good fidelity only in some cases. Means to mitigate errors associated with FES-evoked movements are discussed.. Because the range of movements that can be produced with our approach is virtually unlimited, this system could greatly expand the repertoire of movements available to individuals with high level paralysis.
• Holly, N. L., Hasse, B. A., Gothard, K. M., & Fuglevand, A. J. (2022). Large-scale intramuscular electrode system for chronic electromyography and functional electrical stimulation. Journal of neurophysiology, 128(4), 1011-1024.
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  To understand how the central nervous system (CNS) enacts movements, it seems important to monitor the activities of the many muscles involved. Likewise, to restore complex movements to paralyzed limbs with electrical stimulation requires access to most limb muscles. Intramuscular electrodes are needed to obtain isolated recordings or stimulation of individual muscles. As such, we developed and tested the stability of large arrays of implanted intramuscular electrodes. We implanted 58 electrodes in 29 upper limb muscles in each of three macaques. Electrode connectors were protected within a skull-mounted chamber. During surgery, wires were tunneled subcutaneously to target muscles, where gold anchors were crimped onto the leads. The anchors were then deployed with an insertion device. In two monkeys, the chamber was fixed to the skull with a titanium baseplate rather than acrylic cement. In multiple sessions up to 15 wk after surgery, electromyographic (EMG) signals were recorded while monkeys made the same reaching movement. EMG signals were stable, with an average (SD) coefficient of variation across sessions of 0.24 ± 0.15. In addition, at 4, 8, and 16 wk after surgery, forces to incrementing stimulus pulses were measured for each electrode. The threshold current needed to evoke a response at 16 wk was not different from that at 4 wk. Likewise, peak force evoked by 16 mA of current at 16 wk was not different from 4 wk. The stability of this system implies it could be effectively used to monitor and stimulate large numbers of muscles needed to understand the control of natural and evoked movements. A new method was developed to enable long-lasting recording and stimulation of large numbers of muscles with intramuscular electrodes. Electromyographic signals and evoked force responses in 29 upper limb muscles remained stable over several months when tested in nonhuman primates. This system could be used effectively to monitor and stimulate numerous muscles needed to more fully understand the control of natural and evoked movements.
• Sundman, M. H., Lim, K., Ton That, V., Mizell, J. M., Ugonna, C., Rodriguez, R., Chen, N. K., Fuglevand, A. J., Liu, Y., Wilson, R. C., Fellous, J. M., Rapcsak, S., & Chou, Y. H. (2020). Transcranial magnetic stimulation reveals diminished homoeostatic metaplasticity in cognitively impaired adults. Brain communications, 2(2), fcaa203.
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  Homoeostatic metaplasticity is a neuroprotective physiological feature that counterbalances Hebbian forms of plasticity to prevent network destabilization and hyperexcitability. Recent animal models highlight dysfunctional homoeostatic metaplasticity in the pathogenesis of Alzheimer's disease. However, the association between homoeostatic metaplasticity and cognitive status has not been systematically characterized in either demented or non-demented human populations, and the potential value of homoeostatic metaplasticity as an early biomarker of cognitive impairment has not been explored in humans. Here, we report that, through pre-conditioning the synaptic activity prior to non-invasive brain stimulation, the association between homoeostatic metaplasticity and cognitive status could be established in a population of non-demented human subjects (older adults across cognitive spectrums; all within the non-demented range). All participants ( = 40; age range, 65-74, 47.5% female) underwent a standardized neuropsychological battery, magnetic resonance imaging and a transcranial magnetic stimulation protocol. Specifically, we sampled motor-evoked potentials with an input/output curve immediately before and after repetitive transcranial magnetic stimulation to assess neural plasticity with two experimental paradigms: one with voluntary muscle contraction (i.e. modulated synaptic activity history) to deliberately introduce homoeostatic interference, and one without to serve as a control condition. From comparing neuroplastic responses across these experimental paradigms and across cohorts grouped by cognitive status, we found that (i) homoeostatic metaplasticity is diminished in our cohort of cognitively impaired older adults and (ii) this neuroprotective feature remains intact in cognitively normal participants. This novel finding suggests that (i) future studies should expand their scope beyond just Hebbian forms of plasticity that are traditionally assessed when using non-invasive brain stimulation to investigate cognitive ageing and (ii) the potential value of homoeostatic metaplasticity in serving as a biomarker for cognitive impairment should be further explored.
• Fuglevand, A. J. (2019). The brain can make you stronger. The Journal of physiology, 597(7), 1779-1780.
• Arakeri, T. J., Hasse, B. A., & Fuglevand, A. J. (2018). Object discrimination using electrotactile feedback. Journal of neural engineering, 15(4), 046007.
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  A variety of bioengineering systems are being developed to restore tactile sensations in individuals who have lost somatosensory feedback because of spinal cord injury, stroke, or amputation. These systems typically detect tactile force with sensors placed on an insensate hand (or prosthetic hand in the case of amputees) and deliver touch information by electrically or mechanically stimulating sensate skin above the site of injury. Successful object manipulation, however, also requires proprioceptive feedback representing the configuration and movements of the hand and digits.
• Buckmire, A. B., Lockwood, D. L., Doane, C. J., & Fuglevand, A. J. (2018). Distributed stimulation increases force elicited with functional electrical stimulation. J Neural Engineering, 15(2).
• Buckmire, A. J., Arakeri, T. J., Reinhard, J. P., & Fuglevand, A. J. (2018). Mitigation of excessive fatigue associated with functional electrical stimulation. Journal of neural engineering, 15(6), 066004.
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  Restoration of motor function in paralyzed limbs using functional electrical stimulation (FES) is undermined by rapid fatigue associated with artificial stimulation. Typically, single electrodes are used to activate muscles with FES. However, due to the highly distributed branching of muscle nerves, a single electrode may not be able to activate the entire array of motor axons supplying a muscle. Therefore, stimulating muscle with multiple electrodes might enable access to a larger volume of muscle and thereby reduce fatigue.
• Buckmire, A. J., Lockwood, D. R., Doane, C. J., & Fuglevand, A. J. (2018). Distributed stimulation increases force elicited with functional electrical stimulation. Journal of neural engineering.
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  The maximum muscle forces that can be evoked using functional electrical stimulation (FES) are relatively modest. The reason for this weakness is not fully understood but could be partly related to the widespread distribution of motor nerve branches within muscle. As such, a single stimulating electrode (as is conventionally used) may be incapable of activating the entire array of motor axons supplying a muscle. Therefore, the objective of this study was to determine whether stimulating a muscle with more than one source of current could boost force above that achievable with a single source. Approach: We compared the maximum isometric forces that could be evoked in anterior deltoid of anesthetized monkeys using one or two intramuscular electrodes. We also evaluated whether temporally interleaved stimulation between two electrodes might reduce fatigue during prolonged activity compared to synchronized stimulation through two electrodes. Main Results: We found that dual electrode stimulation consistently produced greater force (~50% greater on average) than maximal stimulation with single electrodes. No differences, however, were found in the fatigue responses using interleaved versus synchronized stimulation. Significance: It seems reasonable to consider using multi-electrode stimulation to augment the force-generating capacity of muscles and thereby increase the utility of FES systems..
• Gothard, K. M., Mosher, C. P., Zimmerman, P. E., Putnam, P. T., Morrow, J. K., & Fuglevand, A. J. (2018). New perspectives on the neurophysiology of primate amygdala emerging from the study of naturalistic social behaviors. Wiley interdisciplinary reviews. Cognitive science, 9(1).
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  A major challenge of primate neurophysiology, particularly in the domain of social neuroscience, is to adopt more natural behaviors without compromising the ability to relate patterns of neural activity to specific actions or sensory inputs. Traditional approaches have identified neural activity patterns in the amygdala in response to simplified versions of social stimuli such as static images of faces. As a departure from this reduced approach, single images of faces were replaced with arrays of images or videos of conspecifics. These stimuli elicited more natural behaviors and new types of neural responses: (1) attention-gated responses to faces, (2) selective responses to eye contact, and (3) selective responses to touch and somatosensory feedback during the production of facial expressions. An additional advance toward more natural social behaviors in the laboratory was the implementation of dyadic social interactions. Under these conditions, neurons encoded similarly rewards that monkeys delivered to self and to their social partner. These findings reinforce the value of bringing natural, ethologically valid, behavioral tasks under neurophysiological scrutiny. WIREs Cogn Sci 2018, 9:e1449. doi: 10.1002/wcs.1449 This article is categorized under: Psychology > Emotion and Motivation Neuroscience > Cognition Neuroscience > Physiology.
• Pham, T. T., Moore, S. T., Lewis, S. J., Nguyen, D. N., Dutkiewicz, E., Fuglevand, A. J., McEwan, A. L., & Leong, P. H. (2017). Freezing of Gait Detection in Parkinson's Disease: A Subject-Independent Detector Using Anomaly Scores. IEEE transactions on bio-medical engineering, 64(11), 2719-2728.
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  Freezing of gait (FoG) is common in Parkinsonian gait and strongly relates to falls. Current clinical FoG assessments are patients' self-report diaries and experts' manual video analysis. Both are subjective and yield moderate reliability. Existing detection algorithms have been predominantly designed in subject-dependent settings. In this paper, we aim to develop an automated FoG detector for subject independent. After extracting highly relevant features, we apply anomaly detection techniques to detect FoG events. Specifically, feature selection is performed using correlation and clusterability metrics. From a list of 244 feature candidates, 36 candidates were selected using saliency and robustness criteria. We develop an anomaly score detector with adaptive thresholding to identify FoG events. Then, using accuracy metrics, we reduce the feature list to seven candidates. Our novel multichannel freezing index was the most selective across all window sizes, achieving sensitivity (specificity) of (). On the other hand, freezing index from the vertical axis was the best choice for a single input, achieving sensitivity (specificity) of () for ankle and () for back sensors. Our subject-independent method is not only significantly more accurate than those previously reported, but also uses a much smaller window (e.g., versus ) and/or lower tolerance (e.g., versus ).Freezing of gait (FoG) is common in Parkinsonian gait and strongly relates to falls. Current clinical FoG assessments are patients' self-report diaries and experts' manual video analysis. Both are subjective and yield moderate reliability. Existing detection algorithms have been predominantly designed in subject-dependent settings. In this paper, we aim to develop an automated FoG detector for subject independent. After extracting highly relevant features, we apply anomaly detection techniques to detect FoG events. Specifically, feature selection is performed using correlation and clusterability metrics. From a list of 244 feature candidates, 36 candidates were selected using saliency and robustness criteria. We develop an anomaly score detector with adaptive thresholding to identify FoG events. Then, using accuracy metrics, we reduce the feature list to seven candidates. Our novel multichannel freezing index was the most selective across all window sizes, achieving sensitivity (specificity) of (). On the other hand, freezing index from the vertical axis was the best choice for a single input, achieving sensitivity (specificity) of () for ankle and () for back sensors. Our subject-independent method is not only significantly more accurate than those previously reported, but also uses a much smaller window (e.g., versus ) and/or lower tolerance (e.g., versus ).
• Potvin, J. R., & Fuglevand, A. J. (2017). A motor unit-based model of muscle fatigue. PLoS computational biology, 13(6), e1005581.
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  Muscle fatigue is a temporary decline in the force and power capacity of skeletal muscle resulting from muscle activity. Because control of muscle is realized at the level of the motor unit (MU), it seems important to consider the physiological properties of motor units when attempting to understand and predict muscle fatigue. Therefore, we developed a phenomenological model of motor unit fatigue as a tractable means to predict muscle fatigue for a variety of tasks and to illustrate the individual contractile responses of MUs whose collective action determines the trajectory of changes in muscle force capacity during prolonged activity. An existing MU population model was used to simulate MU firing rates and isometric muscle forces and, to that model, we added fatigue-related changes in MU force, contraction time, and firing rate associated with sustained voluntary contractions. The model accurately estimated endurance times for sustained isometric contractions across a wide range of target levels. In addition, simulations were run for situations that have little experimental precedent to demonstrate the potential utility of the model to predict motor unit fatigue for more complicated, real-world applications. Moreover, the model provided insight into the complex orchestration of MU force contributions during fatigue, that would be unattainable with current experimental approaches.
• Revill, A. L., & Fuglevand, A. J. (2017). Inhibition linearizes firing rate responses in human motor units: implications for the role of persistent inward currents. The Journal of physiology, 595(1), 179-191.
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  Motor neurons are the output neurons of the central nervous system and are responsible for controlling muscle contraction. When initially activated during voluntary contraction, firing rates of motor neurons increase steeply but then level out at modest rates. Activation of an intrinsic source of excitatory current at recruitment onset may underlie the initial steep increase in firing rate in motor neurons. We attempted to disable this intrinsic excitatory current by artificially activating an inhibitory reflex. When motor neuron activity was recorded while the inhibitory reflex was engaged, firing rates no longer increased steeply, suggesting that the intrinsic excitatory current was probably responsible for the initial sharp rise in motor neuron firing rate.
• Mosher, C. P., Zimmerman, P. E., Fuglevand, A. J., & Gothard, K. M. (2016). Tactile Stimulation of the Face and the Production of Facial Expressions Activate Neurons in the Primate Amygdala. eNeuro, 3(5).
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  The majority of neurophysiological studies that have explored the role of the primate amygdala in the evaluation of social signals have relied on visual stimuli such as images of facial expressions. Vision, however, is not the only sensory modality that carries social signals. Both humans and nonhuman primates exchange emotionally meaningful social signals through touch. Indeed, social grooming in nonhuman primates and caressing touch in humans is critical for building lasting and reassuring social bonds. To determine the role of the amygdala in processing touch, we recorded the responses of single neurons in the macaque amygdala while we applied tactile stimuli to the face. We found that one-third of the recorded neurons responded to tactile stimulation. Although we recorded exclusively from the right amygdala, the receptive fields of 98% of the neurons were bilateral. A fraction of these tactile neurons were monitored during the production of facial expressions and during facial movements elicited occasionally by touch stimuli. Firing rates arising during the production of facial expressions were similar to those elicited by tactile stimulation. In a subset of cells, combining tactile stimulation with facial movement further augmented the firing rates. This suggests that tactile neurons in the amygdala receive input from skin mechanoceptors that are activated by touch and by compressions and stretches of the facial skin during the contraction of the underlying muscles. Tactile neurons in the amygdala may play a role in extracting the valence of touch stimuli and/or monitoring the facial expressions of self during social interactions.
• Tadros, M. A., Fuglevand, A. J., Brichta, A. M., & Callister, R. J. (2016). Intrinsic excitability differs between murine hypoglossal and spinal motoneurons. Journal of neurophysiology, 115(5), 2672-80.
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  Motoneurons differ in the behaviors they control and their vulnerability to disease and aging. For example, brain stem motoneurons such as hypoglossal motoneurons (HMs) are involved in licking, suckling, swallowing, respiration, and vocalization. In contrast, spinal motoneurons (SMs) innervating the limbs are involved in postural and locomotor tasks requiring higher loads and lower movement velocities. Surprisingly, the properties of these two motoneuron pools have not been directly compared, even though studies on HMs predominate in the literature compared with SMs, especially for adult animals. Here we used whole cell patch-clamp recording to compare the electrophysiological properties of HMs and SMs in age-matched neonatal mice (P7-P10). Passive membrane properties were remarkably similar in HMs and SMs, and afterhyperpolarization properties did not differ markedly between the two populations. HMs had narrower action potentials (APs) and a faster upstroke on their APs compared with SMs. Furthermore, HMs discharged APs at higher frequencies in response to both step and ramp current injection than SMs. Therefore, while HMs and SMs have similar passive properties, they differ in their response to similar levels of depolarizing current. This suggests that each population possesses differing suites of ion channels that allow them to discharge at rates matched to the different mechanical properties of the muscle fibers that drive their distinct motor functions.
• Wakefield, H. E., Fregosi, R. F., & Fuglevand, A. J. (2016). Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons. Journal of neurophysiology, 115(3), 1307-13.
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  The maximum firing rates of motoneurons (MNs), activated in response to synaptic drive, appear to be much lower than that elicited by current injection. It could be that the decrease in input resistance associated with increased synaptic activity (but not current injection) might blunt overall changes in membrane depolarization and thereby limit spike-frequency output. To test this idea, we recorded, in the same cells, maximal firing responses to current injection and to synaptic activation. We prepared 300 μm medullary slices in neonatal rats that contained hypoglossal MNs and used whole-cell patch-clamp electrophysiology to record their maximum firing rates in response to triangular-ramp current injections and to glutamate receptor-mediated excitation. Brief pressure pulses of high-concentration glutamate led to significant depolarization, high firing rates, and temporary cessation of spiking due to spike inactivation. In the same cells, we applied current clamp protocols that approximated the time course of membrane potential change associated with glutamate application and with peak current levels large enough to cause spike inactivation. Means (SD) of maximum firing rates obtained in response to glutamate application were nearly identical to those obtained in response to ramp current injection [glutamate 47.1 ± 12.0 impulses (imp)/s, current injection 47.5 ± 11.2 imp/s], even though input resistance was 40% less during glutamate application compared with current injection. Therefore, these data suggest that the reduction in input resistance associated with receptor-mediated excitation does not, by itself, limit the maximal firing rate responses in MNs.
• Fuglevand, A. J., Lester, R. A., & Johns, R. K. (2015). Distinguishing intrinsic from extrinsic factors underlying firing rate saturation in human motor units. Journal of neurophysiology, 113(5), 1310-22.
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  During voluntary contraction, firing rates of individual motor units (MUs) increase modestly over a narrow force range beyond which little additional increase in firing rate is seen. Such saturation of MU discharge may be a consequence of extrinsic factors that limit net synaptic excitation acting on motor neurons (MNs) or may be due to intrinsic properties of the MNs. Two sets of experiments involving recording of human biceps brachii MUs were carried out to evaluate saturation. In the first set, the extent of saturation was quantified for 136 low-threshold MUs during isometric ramp contractions. Firing rate-force data were best fit by a saturating function for 90% of MUs recorded with a maximum rate of 14.8 ± 2.0 impulses/s. In the second set of experiments, to distinguish extrinsic from intrinsic factors underlying saturation, we artificially augmented descending excitatory drive to biceps MNs by activation of muscle spindle afferents through tendon vibration. We examined the change in firing rate caused by tendon vibration in 96 MUs that were voluntarily activated at rates below and at saturation. Vibration had little effect on the discharge of MUs that were firing at saturation frequencies but strongly increased firing rates of the same units when active at lower frequencies. These results indicate that saturation is likely caused by intrinsic mechanisms that prevent further increases in firing rate in the presence of increasing synaptic excitation. Possible intrinsic cellular mechanisms that limit firing rates of motor units during voluntary effort are discussed.
• Tibold, R., & Fuglevand, A. J. (2015). Prediction of muscle activity during loaded movements of the upper limb. Journal of neuroengineering and rehabilitation, 12(1), 6.
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  Accurate prediction of electromyographic (EMG) signals associated with a variety of motor behaviors could, in theory, serve as activity templates needed to evoke movements in paralyzed individuals using functional electrical stimulation. Such predictions should encompass complex multi-joint movements and include interactions with objects in the environment.
• Pham, T. T., Fuglevand, A. J., McEwan, A. L., & Leong, P. H. (2014). Unsupervised discrimination of motor unit action potentials using spectrograms. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014, 1-4.
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  Single motor unit activity study is a major research interest because changes of MUAP morphology, MU activation, and MU recruitment provide the most informative part in diagnosis and treatment of neuromuscular disorders. Intramuscular recordings often provide a more than one motor unit activities, thus MUAP discrimination is a crucial task to study single unit activities. Most neurology laboratories worldwide still need specialists who spend hours to classify MUAPs. In this study, we present a new real-time unsupervised method for MUAP discrimination. After automatically detect MUAPs, we extract features of spectrogram images from the wavelet coefficients of MUAPs. Unlike benchmark methods, we do not calculate Euclidean distances which assumes a spherical distribution of data. Instead, we measure correlation between spectrogram images. Then MUAPs are automatically discriminated without any prior knowledge of the number of clusters as in previous works. MUAP were detected on a real data set with a precision PPV of 94% (tolerance of 2 ms). We obtained a similar result in MUAP classification to the reference. The difference in percentages of MU proportions between our method and the reference were 3% for MU1, 0.4% for MU2, and 12% for MU3. In contrast, F1-score for MU3 reached the highest level at 91% (PPV at the highest of 96.64% as well).
• Tadros, M. A., Farrell, K. E., Schofield, P. R., Brichta, A. M., Graham, B. A., Fuglevand, A. J., & Callister, R. J. (2014). Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations. Journal of neurophysiology, 111(7), 1487-98.
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  Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type (wt), spasmodic (spd), spastic (spa), and oscillator (ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by "gain" in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., ΔI) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot.
• Keen, D. A., Chou, L. W., Nordstrom, M. A., & Fuglevand, A. J. (2012). Short-term synchrony in diverse motor nuclei presumed to receive different extents of direct cortical input. Journal of neurophysiology, 108(12), 3264-75.
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  Motor units within human muscles usually exhibit a significant degree of short-term synchronization. Such coincident spiking typically has been attributed to last-order projections that provide common synaptic input across motor neurons. The extent of branched input arising directly from cortical neurons has often been suggested as a critical factor determining the magnitude of short-term synchrony. The purpose of this study, therefore, was to quantify motor unit synchrony in a variety of human muscles differing in the presumed extent of cortical input to their respective motor nuclei. Cross-correlation histograms were generated from the firing times of 551 pairs of motor units in 16 human muscles. Motor unit synchrony tended to be weakest for proximal muscles and strongest for more distal muscles. Previous work in monkeys and humans has shown that the strength of cortical inputs to motor neurons also exhibits a similar proximal-to-distal gradient. However, in the present study, proximal-distal location was not an exclusive predictor of synchrony magnitude. The muscle that exhibited the least synchrony was an elbow flexor, whereas the greatest synchrony was most often found in intrinsic foot muscles. Furthermore, the strength of corticospinal inputs to the abductor hallucis muscle, an intrinsic foot muscle, as assessed through transcranial magnetic stimulation, was weaker than that projecting to the tibialis anterior muscle, even though the abductor hallucis muscle had higher synchrony values compared with the tibialis anterior muscle. We argue, therefore, that factors other than the potency of cortical inputs to motor neurons, such as the number of motor neurons innervating a muscle, significantly affects motor unit synchrony.
• Pilarski, J. Q., Wakefield, H. E., Fuglevand, A. J., Levine, R. B., & Fregosi, R. F. (2012). Increased nicotinic receptor desensitization in hypoglossal motor neurons following chronic developmental nicotine exposure. Journal of neurophysiology, 107(1), 257-64.
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  Neuronal nicotinic acetylcholine receptors (nAChRs) are expressed on hypoglossal motor neurons (XII MNs) that innervate muscles of the tongue. Activation of XII MN nAChRs evokes depolarizing currents, which are important for regulating the size and stiffness of the upper airway. Although data show that chronic developmental nicotine exposure (DNE) blunts cholinergic neurotransmission in the XII motor nucleus, it is unclear how nAChRs are involved. Therefore, XII MN nAChR desensitization and recovery were examined in tissues from DNE or control pups using a medullary slice preparation and tight-seal whole cell patch-clamp recordings. nAChR-mediated inward currents were evoked by brief pressure pulses of nicotine or the α4β2 nAChR agonist RJR-2403. We found that, regardless of treatment, activatable nAChRs underwent desensitization, but, following DNE, nAChRs exhibited increased desensitization and delayed recovery. Similar results were produced using RJR-2403, showing that DNE influences primarily the α4β2 nAChR subtype. These results show that while some nAChRs preserve their responsiveness to acute nicotine following DNE, they more readily desensitize and recover more slowly from the desensitized state. These data provide new evidence that chronic DNE modulates XII MN nAChR function, and suggests an explanation for the association between DNE and the incidence of central and obstructive apneas.
• Fuglevand, A. J. (2011). Mechanical properties and neural control of human hand motor units. The Journal of physiology, 589(Pt 23), 5595-602.
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  Motor units serve both as the mechanical apparatus and the final stage of neural processing through which motor behaviours are enacted. Therefore, knowledge about the contractile properties and organization of the neural inputs to motor units supplying finger muscles is essential for understanding the control strategies underlying the diverse motor functions of the human hand. In this brief review, basic contractile properties of motor units residing in human hand muscles are described. Hand motor units are not readily categorized into the classical physiological types as established in the cat gastrocnemius muscle. In addition, the distribution of descending synaptic inputs to motor nuclei supplying different hand muscles is outlined. Motor neurons innervating intrinsic muscles appear to have relatively independent lines of input from supraspinal centres whereas substantial divergence of descending input is seen across motor nuclei supplying extrinsic hand muscles. The functional significance of such differential organizations of descending inputs for the control of hand movements is discussed.
• Johns, R. K., & Fuglevand, A. J. (2011). Number of motor units in human abductor hallucis. Muscle & nerve, 43(6), 895-6.
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  Motor unit number was estimated for the human abductor hallucis (AH) muscle in 11 subjects by counting the number of increments in surface electromyographic responses to progressive increases in current-pulse amplitude applied to the muscle-nerve. The average motor unit count for AH (43) was substantially smaller than that estimated for other human muscles. Consequently, motor unit activity should be readily recordable up to high forces in AH, making it well suited for studies of recruitment and rate coding.
• Johnson, L. A., & Fuglevand, A. J. (2011). Mimicking muscle activity with electrical stimulation. Journal of neural engineering, 8(1), 016009.
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  Functional electrical stimulation is a rehabilitation technology that can restore some degree of motor function in individuals who have sustained a spinal cord injury or stroke. One way to identify the spatio-temporal patterns of muscle stimulation needed to elicit complex upper limb movements is to use electromyographic (EMG) activity recorded from able-bodied subjects as a template for electrical stimulation. However, this requires a transfer function to convert the recorded (or predicted) EMG signals into an appropriate pattern of electrical stimulation. Here we develop a generalized transfer function that maps EMG activity into a stimulation pattern that modulates muscle output by varying both the pulse frequency and the pulse amplitude. We show that the stimulation patterns produced by this transfer function mimic the active state measured by EMG insofar as they reproduce with good fidelity the complex patterns of joint torque and joint displacement.
• Pilarski, J. Q., Wakefield, H. E., Fuglevand, A. J., Levine, R. B., & Fregosi, R. F. (2011). Developmental nicotine exposure alters neurotransmission and excitability in hypoglossal motoneurons. Journal of neurophysiology, 105(1), 423-33.
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  Hypoglossal motoneurons (XII MNs) control muscles of the mammalian tongue and are rhythmically active during breathing. Acetylcholine (ACh) modulates XII MN activity by promoting the release of glutamate from neurons that express nicotinic ACh receptors (nAChRs). Chronic nicotine exposure alters nAChRs on neurons throughout the brain, including brain stem respiratory neurons. Here we test the hypothesis that developmental nicotine exposure (DNE) reduces excitatory synaptic input to XII MNs. Voltage-clamp experiments in rhythmically active medullary slices showed that the frequency of excitatory postsynaptic currents (EPSCs) onto XII MNs from DNE animals is reduced by 61% (DNE = 1.7 ± 0.4 events/s; control = 4.4 ± 0.6 events/s; P < 0.002). We also examine the intrinsic excitability of XII MNs to test whether cells from DNE animals have altered membrane properties. Current-clamp experiments showed XII MNs from DNE animals had higher intrinsic excitability, as evaluated by measuring their response to injected current. DNE cells had high-input resistances (DNE = 131.9 ± 13.7 MΩ, control = 78.6 ± 9.7 MΩ, P < 0.008), began firing at lower current levels (DNE = 144 ± 22 pA, control = 351 ± 45 pA, P < 0.003), and exhibited higher frequency-current gain values (DNE = 0.087 ± 0.012 Hz/pA, control = 0.050 ± 0.004 Hz/pA, P < 0.02). Taken together, our data show previously unreported effects of DNE on XII MN function and may also help to explain the association between DNE and the incidence of central and obstructive apneas.
• Revill, A. L., & Fuglevand, A. J. (2011). Effects of persistent inward currents, accommodation, and adaptation on motor unit behavior: a simulation study. Journal of neurophysiology, 106(3), 1467-79.
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  Motor neurons are often assumed to generate spikes in proportion to the excitatory synaptic input received. There are, however, many intrinsic properties of motor neurons that might affect this relationship, such as persistent inward currents (PICs), spike-threshold accommodation, or spike-frequency adaptation. These nonlinear properties have been investigated in reduced animal preparation but have not been well studied during natural motor behaviors because of the difficulty in characterizing synaptic input in intact animals. Therefore, we studied the influence of each of these intrinsic properties on spiking responses and muscle force using a population model of motor units that simulates voluntary contractions in human subjects. In particular, we focused on the difference in firing rate of low-threshold motor units when higher threshold motor units were recruited and subsequently derecruited, referred to as ΔF. Others have used ΔF to evaluate the extent of PIC activation during voluntary behavior. Our results showed that positive ΔF values could arise when any one of these nonlinear properties was included in the simulations. Therefore, a positive ΔF should not be considered as exclusive evidence for PIC activation. Furthermore, by systematically varying contraction duration and speed in our simulations, we identified a means that might be used experimentally to distinguish among PICs, accommodation, and adaptation as contributors to ΔF.
• Rice, A., Fuglevand, A. J., Laine, C. M., & Fregosi, R. F. (2011). Synchronization of presynaptic input to motor units of tongue, inspiratory intercostal, and diaphragm muscles. Journal of neurophysiology, 105(5), 2330-6.
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  The respiratory central pattern generator distributes rhythmic excitatory input to phrenic, intercostal, and hypoglossal premotor neurons. The degree to which this input shapes motor neuron activity can vary across respiratory muscles and motor neuron pools. We evaluated the extent to which respiratory drive synchronizes the activation of motor unit pairs in tongue (genioglossus, hyoglossus) and chest-wall (diaphragm, external intercostals) muscles using coherence analysis. This is a frequency domain technique, which characterizes the frequency and relative strength of neural inputs that are common to each of the recorded motor units. We also examined coherence across the two tongue muscles, as our previous work shows that, despite being antagonists, they are strongly coactivated during the inspiratory phase, suggesting that excitatory input from the premotor neurons is distributed broadly throughout the hypoglossal motoneuron pool. All motor unit pairs showed highly correlated activity in the low-frequency range (1-8 Hz), reflecting the fundamental respiratory frequency and its harmonics. Coherence of motor unit pairs recorded either within or across the tongue muscles was similar, consistent with broadly distributed premotor input to the hypoglossal motoneuron pool. Interestingly, motor units from diaphragm and external intercostal muscles showed significantly higher coherence across the 10-20-Hz bandwidth than tongue-muscle units. We propose that the lower coherence in tongue-muscle motor units over this range reflects a larger constellation of presynaptic inputs, which collectively lead to a reduction in the coherence between hypoglossal motoneurons in this frequency band. This, in turn, may reflect the relative simplicity of the respiratory drive to the diaphragm and intercostal muscles, compared with the greater diversity of functions fulfilled by muscles of the tongue.
• Johnson, L. A., & Fuglevand, A. J. (2009). Evaluation of probabilistic methods to predict muscle activity: implications for neuroprosthetics. Journal of neural engineering, 6(5), 055008.
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  Functional electrical stimulation (FES) involves artificial activation of muscles with surface or implanted electrodes to restore motor function in paralyzed individuals. Currently, FES-based prostheses produce only a limited range of movements due to the difficulty associated with identifying patterns of muscle activity needed to evoke more complex behaviour. Here we test three probability-based models (Bayesian density estimation, polynomial curve fitting and dynamic neural network) that use the trajectory of the hand to predict the electromyographic (EMG) activities of 12 arm muscles during complex two- and three-dimensional movements. Across most conditions, the neural network model yielded the best predictions of muscle activity. For three-dimensional movements, the predicted patterns of muscle activity using the neural network accounted for 40% of the variance in the actual EMG signals and were associated with an average root-mean-squared error of 6%. These results suggest that such probabilistic models could be used effectively to predict patterns of muscle stimulation needed to produce complex movements with an FES-based neuroprosthetic.
• Marcus, P. L., & Fuglevand, A. J. (2009). Perception of electrical and mechanical stimulation of the skin: implications for electrotactile feedback. Journal of neural engineering, 6(6), 066008.
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  Spinal cord injury is often accompanied by impaired tactile and proprioceptive sensations. Normally, somatosensensory information derived from such sensations is important in the formation of voluntary motor commands. Therefore, as a preliminary step toward the development of an electrotactile feedback system to restore somatosensation, psychophysical methods were used to characterize perceptual attributes associated with electrical stimulation of the skin on the back of the neck in human subjects. These data were compared to mechanical stimulation of the skin on the back of neck and on the distal pad of the index finger. Spatial acuity of the neck, evaluated using two-point thresholds, was not significantly different for electrical (37 +/- 14 mm) or mechanical stimulation (39 +/- 10 mm). The exponent (beta) of the best fitting power function relating perceived intensity to applied stimulus strength was used to characterize perceptual sensitivity to mechanical and electrical stimuli. For electrical stimuli, both current amplitude-modulated and frequency-modulated trains of pulses were tested. Perceptual sensitivity was significantly greater for current amplitude modulation (beta = 1.14 +/- 0.37) compared to frequency modulation (beta = 0.57 +/- 0.24) and mechanical stimulation (0.51 +/- 0.12). Finally, based on the data gathered here, we derive a transfer function that could be used in the future to convert mechanical stimuli detected with artificial sensors placed on the fingers into electrotactile signals that evoke perceptions similar to those arising from normal mechanical stimulation of the skin.
• Anderson, C. V., & Fuglevand, A. J. (2008). Probability-based prediction of activity in multiple arm muscles: implications for functional electrical stimulation. Journal of neurophysiology, 100(1), 482-94.
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  Functional electrical stimulation (FES) involves artificial activation of muscles with implanted electrodes to restore motor function in paralyzed individuals. The range of motor behaviors that can be generated by FES, however, is limited to a small set of preprogrammed movements such as hand grasp and release. A broader range of movements has not been implemented because of the substantial difficulty associated with identifying the patterns of muscle stimulation needed to elicit specified movements. To overcome this limitation in controlling FES systems, we used probabilistic methods to estimate the levels of muscle activity in the human arm during a wide range of free movements based on kinematic information of the upper limb. Conditional probability distributions were generated based on hand kinematics and associated surface electromyographic (EMG) signals from 12 arm muscles recorded during a training task involving random movements of the arm in one subject. These distributions were then used to predict in four other subjects the patterns of muscle activity associated with eight different movement tasks. On average, about 40% of the variance in the actual EMG signals could be accounted for in the predicted EMG signals. These results suggest that probabilistic methods ultimately might be used to predict the patterns of muscle stimulation needed to produce a wide array of desired movements in paralyzed individuals with FES.
• McIsaac, T. L., & Fuglevand, A. J. (2008). Common synaptic input across motor nuclei supplying intrinsic muscles involved in the precision grip. Experimental brain research, 188(1), 159-64.
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  To gain insight into the mechanism by which the nervous system orchestrates the activities of multiple muscles during voluntary motor behaviors, we measured the degree of synchrony in the discharge times across pairs of motor units recorded from two intrinsic hand muscles, the adductor pollicis (AdP) and first dorsal interosseous (FDI), in human subjects performing a precision grip. The magnitude of synchrony measured across muscles is thought to reflect the extent of divergent synaptic input delivered in common to the motor nuclei supplying the two muscles. Unlike the pronounced motor-unit synchrony observed across comparable extrinsic hand muscles during the precision grip, little synchrony was detected across these two intrinsic muscles. These results suggest that extrinsic and intrinsic muscles of the hand are controlled by descending pathways with distinctly different patterns of spinal connectivity--more widespread terminations across motor nuclei supplying extrinsic muscles whereas more focal input to individual motor nuclei innervating intrinsic muscles.
• Waller, B. M., Parr, L. A., Gothard, K. M., Burrows, A. M., & Fuglevand, A. J. (2008). Mapping the contribution of single muscles to facial movements in the rhesus macaque. Physiology & behavior, 95(1-2), 93-100.
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  The rhesus macaque (Macaca mulatta) is the most utilized primate model in the biomedical and psychological sciences. Expressive behavior is of interest to scientists studying these animals, both as a direct variable (modeling neuropsychiatric disease, where expressivity is a primary deficit), as an indirect measure of health and welfare, and also in order to understand the evolution of communication. Here, intramuscular electrical stimulation of facial muscles was conducted in the rhesus macaque in order to document the relative contribution of each muscle to the range of facial movements and to compare the expressive function of homologous muscles in humans, chimpanzees and macaques. Despite published accounts that monkeys possess less differentiated and less complex facial musculature, the majority of muscles previously identified in humans and chimpanzees were stimulated successfully in the rhesus macaque and caused similar appearance changes. These observations suggest that the facial muscular apparatus of the monkey has extensive homology to the human face. The muscles of the human face, therefore, do not represent a significant evolutionary departure from those of a monkey species. Thus, facial expressions can be compared between humans and rhesus macaques at the level of the facial musculature, facilitating the systematic investigation of comparative facial communication.
• Bailey, E. F., Rice, A. D., & Fuglevand, A. J. (2007). Firing patterns of human genioglossus motor units during voluntary tongue movement. Journal of neurophysiology, 97(1), 933-6.
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  The tongue participates in a range of complex oromotor behaviors, including mastication, swallowing, respiration, and speech. Previous electromyographic studies of the human tongue have focused on respiratory-related tongue muscle activities and their role in maintaining upper airway patency. Remarkably, the activities of human hypoglossal motor units have not been studied during the execution of voluntary maneuvers. We recorded single motor unit activity using tungsten microelectrodes in the genioglossus muscle of 10 healthy human subjects performing both slow tongue protrusions and a static holding maneuver. Displacement of the tongue was detected by an isotonic transducer coupled to the lingual surface through a customized lever arm. For protrusion trials, the firing rate at recruitment was 13.1 +/- 3 Hz and increased steeply to an average of 24 +/- 6 Hz, often with very modest increases in tongue protrusion. For the static holding task, the average firing rate was 16.1 +/- 4 Hz, which is surprisingly high relative to limb motor units. The average coefficient of variation of interspike intervals was approximately 20% (range, 10-28%). These are the first recordings of their type obtained in human subjects and provide an initial glimpse into the voluntary control of hypoglossal motoneurons during tongue movements presumably instigated by activity in the motor cortex.
• McIsaac, T. L., & Fuglevand, A. J. (2007). Motor-unit synchrony within and across compartments of the human flexor digitorum superficialis. Journal of neurophysiology, 97(1), 550-6.
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  An interesting feature of the muscular organization of the human hand is that the main flexors and extensors of the fingers are compartmentalized and give rise to multiple parallel tendons that insert onto all the fingers. Previous studies of motor-unit synchrony in extensor digitorum and flexor digitorum profundus indicated that synaptic input to motor neurons supplying these multitendoned muscles is not uniformly distributed across the entire pool of motor neurons but instead appears to be partially segregated to supply subsets of motor neurons that innervate different muscular compartments. Little is known, however, about the organization of the synaptic inputs to the motor neurons supplying another multitendoned finger muscle, the flexor digitorum superficialis (FDS). Therefore in this study, we estimated the extent of divergence of last-order inputs to FDS motor neurons by measuring the degree of short-term synchrony among motor units within and across compartments of FDS. The degree of synchrony for motor-unit pairs within the same digit compartment was nearly twofold that of pairs of motor units in adjacent compartments and more than fourfold that of pairs in nonadjacent compartments. Therefore like other multitendoned muscles of the hand, last-order synaptic inputs to motor neurons supplying the FDS appear to primarily supply subsets of motor neurons innervating specific finger compartments. Such an organization presumably enables differential activation of separate compartments to facilitate independent movements of the fingers.
• McIsaac, T. L., & Fuglevand, A. J. (2006). Influence of tactile afferents on the coordination of muscles during a simulated precision grip. Experimental brain research, 174(4), 769-74.
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  The mechanisms by which the nervous system coordinates multiple muscles for the control of finger movements are not well understood. One possibility is that groups of muscles may be enlisted into synergies by last-order inputs that project across multiple motor nuclei. In this study we investigated the role that tactile input might play in coupling together the activities of motor units in two muscles involved in generating the precision grip. Cross-correlation analysis was used to assess the degree of synchrony in the discharge times of pairs of motor units recorded from index-finger and thumb flexor muscles while human subjects performed an isometric task that mimicked a precision grip. The magnitude of synchrony is thought to reflect the extent to which divergent last order inputs provide common synaptic input across motor neurons. Synchrony was evaluated under two simulated-gripping conditions: gripping with normal tactile input and gripping when tactile input from the digit pads was eliminated by applying flexion forces to fittings glued to the finger nails. Synchrony between motor units of index finger flexor and thumb flexor muscles, while substantial, was not significantly different across the two tactile-input conditions. These findings suggest that tactile input is not required to activate the divergent last-order inputs that couple together the activities of the index finger and thumb flexor muscles during the precision grip.
• Waller, B. M., Vick, S. J., Parr, L. A., Bard, K. A., Pasqualini, M. C., Gothard, K. M., & Fuglevand, A. J. (2006). Intramuscular electrical stimulation of facial muscles in humans and chimpanzees: Duchenne revisited and extended. Emotion (Washington, D.C.), 6(3), 367-82.
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  The pioneering work of Duchenne (1862/1990) was replicated in humans using intramuscular electrical stimulation and extended to another species (Pan troglodytes: chimpanzees) to facilitate comparative facial expression research. Intramuscular electrical stimulation, in contrast to the original surface stimulation, offers the opportunity to activate individual muscles as opposed to groups of muscles. In humans, stimulation resulted in appearance changes in line with Facial Action Coding System (FACS) action units (AUs), and chimpanzee facial musculature displayed functional similarity to human facial musculature. The present results provide objective identification of the muscle substrate of human and chimpanzee facial expressions- data that will be useful in providing a common language to compare the units of human and chimpanzee facial expression.