Roger M. Enoka, Ph.D. - US grants

One of the most striking features of the aging process is the associated decline in physical capabilities, including the slowing of movements, a decrease in strength, and a loss of fine motor coordination. Although the entire motor system seems to be involved in these age-related changes, more attention has been directed toward muscle architecture than to the properties of motor units. A thorough understanding of changes in motoneuron function with aging is critical. For example, as we age the number of motoneurons innerving a muscle decreases while the average size of each surviving motor unit increases. These changes undoubtedly influence the way in which the nervous system varies the force that a muscle exerts. The purpose of this project is to determine if the known age-related changes in motor unit number are associated with specific alterations in motor unit behavior during acute exercise, and whether chronic exercise (training) has a beneficial effect on these behavioral changes. It is hypothesized that the pattern of motor unit activation during simple exercises is different in older, compared to younger, subjects but that these differences can be lessened with training. Although the ultimate goal is to correlate changes in motor unit behavior with performance capabilities, this proposal consists of three specific aims that address the intermediate step of characterizing the effects of age on motor unit behavior. [unreadable]he dependent variable will be motor unit activity, as characterized by the forces at which the units are activated and inactivated and the pattern of action potential discharge. The experiments are designed to examine the effect of age on these properties as exhibited during a simple isometric exercise. In order to explore the functional implications of any age-related effects, motor unit activity during this exercise will be examined under three conditions:(1) tests will be conducted on a small hand muscle (first dorsal interosseus) and on an arm muscle (biceps brachii) to see if motor unit behavior, as it does in young subjects, varies across muscles:(2) since muscle fatigue is known to alter motor unit behavior during subsequent exercise in young subjects: we propose to contrast the ability of older subjects to perform the exercise before and after a fatiguing contraction;(3) in order to test whether rehabilitative interventions might attenuate the ge-related changes in motor unit behavior, we plan to examine the effects of a physical training program on motor unit activity during the isometric exercise. The single motor unit potentials will be measured with a new technique, which utilizes a subcutaneous, branched, bipolar electrode, and a unique waveform discrimination procedure. Preliminary studies have indicated that these procedures are appropriate for the proposed project and that motor unit behavior in older subjects is substantially different from that seen in younger subjects. It is anticipated that these studies will contribute new and useful information on fundamental issues in aging and motor control.

DESCRIPTION: (Adapted from investigator's abstract) It has been clearly demonstrated that limb immobilization affects muscle and the force that it can exert. This effect can have significant functional consequences. Although the precise control of muscle force is achieved by varying motor-unit activity, little is known about the influence of immobilization on motor-unit properties. In order to address this issue, the investigator proposes to examine the effects of immobilization on the properties and segmental interactions of motor neurons, motor units, and muscle receptors. The applicant's approach to this topic has two unique features: (1)the studies have been designed to use both an experimental animal paradigm and a conscious human paradigm so that behavior and invasive, mechanistic observations can be integrated; and (2) the studies will focus on the unexpected effects of immobilization since they represent some of the boundary conditions that determine various characteristics of the segmental motor system. In conscious human, the effects of immobilization on the contributions of motor unit recruitment and discharge rate to the gradation of muscle force will be examined (Aim 1) and on the fatigue related changes in discharge variability (Aim 2a). These effects will be quantified in terms of the upper limit of motor-unit recruitment, modulation of discharge rate (range, variability, and pattern), change in endurance time, and impairment of performance. Since afferent feedback has been implicated as a mechanism underlying the change in motor-unit discharge with fatigue, the applicants propose to determine the effect of an anesthetic block of small-diameter axons in humans (Aim 2b) and changes in the coupling between muscle receptors and motor units in anesthetized cats (Aim 2c) during fatiguing activity. Furthermore, because the remodeling of neuromuscular junctions may contribute to the absence of a decrease in fatigability with immobilization and in the appearance of "no-force" units, the applicants plan to measure neuromuscular propagation to determine the susceptibility of neuromuscular junctions to failure in both anesthetized cats and conscious humans (Aim 3). The observation of no-force units provides further evidence that immobilization affects muscle, perhaps even in the transmission of force from the active muscle fibers to the tendon. Selected mechanical effects on motor units in anesthetized cats will be quantified by measuring the nonlinear summation of the force exerted by pairs of motor units and the stiffness of homogeneous groups of motor units (Aim 4). Centrally, the effects of immobilization on motor neurons will be examined by measuring the post-synaptic response of neurons to feedback from muscle receptors and by measuring various intrinsic biophysical properties (Aim 5). It is anticipated that these studies will contribute new and useful information on fundamental issues related to the adaptive properties of the segmental motor system and on the functional consequences of limb immobilization, particularly after an orthopedic injury.

For at least 20 years, it has been known that the number of functioning motor units declines with age. Although there is some compensation for the decline in motor unit number in the form of collateral sprouting and reinnervation, the net effect is a decrease in motor unit number and in muscle mass but an increase in motor unit size. Little is known about the contribution of this motor unit reorganization to the age-related reduction in manipulative capabilities, the increased hesitancy of goal- directed movements, and the greater kinematic variability of simple movements. The hypothesis of this project is that motor unit reorganization during aging contributes significantly to the age-related decline in some movement capabilities. To test this hypothesis, we propose to identify differences in motor performance between young and elderly subjects that can be attributed to differences in motor unit properties and behavior. We have found evidence of motor unit reorganization in a hand muscle of healthy elderly subjects and a reduced ability to sustain constant submaximal forces. This impairment, which corresponds to an increase in the amplitude of the force fluctuations, appears to be adaptable and can be alleviated with the type of strengthening exercises used in rehabilitation (physical therapy). The current application proposes descriptive and mechanistic experiments that continue to explore a role for motor unit reorganization (decrease in number but increase in size) in the change in motor performance with aging. The specific aims are: (l) to determine the mechanisms mediating the training-induced reductions in the force fluctuations of constant- force contractions; (2) to characterize motor unit behavior during non- isometric contractions; and (3) to identify the adaptability of neural strategies used during isometric and non-isometric tasks. The experiments will involve single joint tasks performed by one hand muscle and by one arm muscle of human volunteers. The subjects will execute simple isometric and non-isometric contractions that will be characterized by electrophysiological and mechanical measures of muscle activity. The discharge of single motor units will be recorded with intramuscular electrodes so that motor unit behavior can be correlated to the surface- recorded EMG of synergist and antagonist muscles, and to the net muscle force. In addition, images from MRI scans will be used to quantify changes in the activation pattern of muscles following strength training. The data acquired by testing these aims will indicate the extent to which neural activation strategies and muscle function are influenced by the age-related reorganization of motor units. The proposed studies represent novel attempts to characterize the effects of aging on the relationship between neural strategies, motor unit behavior, and motor performance, albeit for simplified motor tasks. The knowledge gained from these studies will have relevance for geriatric, neurologic, and rehabilitation medicine.

DESCRIPTION (Adapted from the Applicant;s Abstracts): Older adults experience a marked decline in muscle mass (sarcopenia) and strength that can have a significant effect on the activities of daily living. As a countermeasure, a number of groups have shown that these individuals can experience a substantial increase in strength after participation in short-duration, strength training programs. Although most of these programs have involved heavy-load protocols, the investigators recent observations suggest that comparable gains in strength can be achieved with light loads if the participant focuses on exerting a steady force during each exercise. The investigators propose to test the hypothesis that older adults can increase muscle strength and achieve functional benefits with a strength-training program based on the use of steady contractions to lift light loads. The specific aims will be: (1) to compare the effects of training load on the changes in muscle strength; (2) to assess the functional consequences of the training-induced increase in muscle strength; and (3) to characterize the types of neural adaptations that underlie the increase in strength. These aims will be examined by recruiting older adults (65-80 years) to participate in a 16-week strength-training program. The predictor variables will be muscle group (knee-extensor or hand-forearm muscles), training load (30 or 80% of maximum), and degree of control (regular or steady muscle contractions). The outcome variables will be muscle strength, performance on functional tests, and the adaptations underlying the increase in strength. The investigators expect to find that older adults will be able to increase muscle strength in a program that uses light training and steady muscle contractions and that such a program will have a greater transfer to functional activities. This finding will underscore the critical role of neural adaptations in the strength gains experienced by older adults with short-duration training and will provide the foundation for an alternative therapeutic strategy for strengthening exercises in this population.

DESCRIPTION (provided by applicant): Many older adults are less steady when exerting low forces and lifting light loads. The greater fluctuations in force exhibited by older adults can be caused either by increased discharge rate variability or by altered amounts of correlated activity among the motor units. Based on prior experimental and computational studies, we hypothesize that the greater fluctuations experienced by older adults during voluntary contractions are due to direct and indirect effects of correlated motor unit discharge. Aim 1 will extend our current model of the electromyogram (EMG) to simulate the reorganization of the neuromuscular system that occurs with advancing age. The simulations will assess the effect of cancellation of motor unit potentials on the amplitude of the surface EMG and will evaluate the validity of estimating common modulation of motor unit discharge from the EMG signal. Aim 2 will evaluate the fluctuations in force and acceleration during isometric and anisometric contractions performed with the first dorsal interosseus muscle by young and old adults. The time- and frequency-domain characteristics will be compared with prior experimental measurements and modeling results for young adults. Aim 3 will compare the contributions of the two candidate neural mechanisms (discharge rate variability and correlated discharge) to the differences between young and old adults in index finger acceleration when performing isometric and anisometric contractions with the first dorsal interosseus muscle. Aim 4 will examine the role of coactivation at the level of the motor unit by measuring the amount and timing of correlated discharge between motor units in the agonist and antagonist muscles. These studies will provide novel information on the neural mechanisms that contribute to the reduced ability of older adults to perform steady contractions.

The properties and function of the neuromuscular system change with advancing age. The effects on the performance capabilities of older adults are profound. We have found, for example, that finger movements are less steady in older adults compared with young adults. More recently, we have also demonstrated the impact of emotional state on neuromuscular function. We found that a stressor increased cognitive and physiological measures of arousal and impaired the ability of young men and women to exert a constant force during a submaximal pinch grip. It is likely that the same effect occurs in older adults. This led us to ask the question, does an increase in arousal further impair the steadiness of a submaximal pinch grip in older adults? Because baseline differences in steadiness are due to changes in the activation of muscle by nervous system, we hypothesize that an increase in arousal produces a greater deterioration of pinch-grip steadiness in older adults compared with young adults due the changes in motor unit function that occur with advancing age. We propose three specific aims to test this hypothesis: (1) to quantify the level of arousal evoked in young, middle-aged, and older adults in response to noxious stimulus using physiological and psychological measures; (2) to assess the fluctuations in force during a submaximal pinch grip performed by young, middle-aged, and older adults in the presence and absence of a noxious stimulus; (3) to examine the association between the changes in arousal fluctuations in pinch-grip force. We will quantify the moment-to-moment effect of the stressor on men and women with cognitive and physiological measures of arousal. The outcome variable will be the coefficient of variation for force during a submaximal pinch grip. We expect to find that the stress proposal will increase arousal to the same extent in all three groups of adults and that the impairment in steadiness will be proportional to the increase in arousal. These outcomes will result in a constant difference in steadiness between young and old adults, which will produce a much greater impairment in the simple motor task with an increase in arousal for the older adults. The findings will expand our understanding of the daily challenges experienced by older adults and will provide the foundation for a more extensive R01 application.

DESCRIPTION (provided by applicant): The correlated discharge of action potentials by motor neurons is caused by common synaptic input that is delivered either by branched neurons or by rhythmic drive from supraspinal sources. The effect on motor unit activity is quantified as motor unit synchronization. Although technically challenging, the measurement of motor unit synchronization is a powerful technique that provides information about connections in the human CNS during voluntary muscle contractions. The two sources of common input can be distinguished by time-and frequency-domain analyses of the discharge times of pairs of motor units. This proposal focuses on the emerging concept that motor unit synchronization is a consequence of common rhythmic activity in the sensorimotor cortex. The presence of this rhythmicity in the descending drive onto motor neurons may enhance physiological tremor. We hypothesize that motor unit synchronization is caused by common oscillations present in the synaptic input received by motor neurons and that these increase with excitatory drive and impair the ability to perform steady contractions. Aim 1 is a modeling study that extends our existing motor unit model to include a current-based, threshold-crossing model of neuronal membrane potential coupled to a multi-compartment dendritic tree. With this model, we will explicitly control the synaptic inputs to the motor neurons with computer simulations and thereby determine the effects of common branched and rhythmic synaptic input on the correlated discharges of motor units. Interpretation of the experimental results (Aims 2 and 3) will be based on the outcomes of the simulations. Aim 2 will determine why the amount of motor unit synchronization is less at low forces compared with high forces. The correlated discharge of pairs of motor units will be measured at several discharge rates to distinguish among three possible factors: variation in the proportion of common synaptic input with the level of excitatory drive, greater synchronization for high threshold motor units, and changes in the source of common synaptic input. Aim 3 will examine the effect of motor unit synchronization on physiological tremor by comparing changes in the time- and frequency-domain measures of motor unit synchronization with the steadiness of performance across different types of muscle contractions. We expect to find that motor unit synchronization is largely due to common oscillations in the synaptic input onto motor neurons, that the proportion of common input changes both with the level of excitatory drive and the type of muscle contraction, and that this influences the steadiness of performance. The outcomes of this project will have direct application to the measurement and interpretation of motor unit synchronization in neurological patients.

DESCRIPTION (provided by applicant): The time to task failure for an isometric contraction with the elbow flexor muscles is twice as long when an individual sustains a submaximal force (force task) compared with maintaining a constant limb position while supporting an equivalent inertial load (position task). Although the net muscle torque generated by each subject is identical for the two tasks, indirect measurements indicate that central neural activity increases more rapidly during the position task. Furthermore, work completed in the initial cycle of this award has suggested that a difference in the time to task failure can exist without significant differences in inhibitory inputs, but that these inputs augment the difference in time to failure for the two tasks. Our model is that the position task involves reduced activation of the interneurons that are responsible for presynaptic inhibition of the feedback transmitted by group la afferents. Such suppression of presynaptic inhibition, which is modulated by both descending drive and feedback from peripheral afferents, will result in heightened excitation of the spinal motor neurons during the position task. We hypothesize that the position task is associated with greater net excitation from spinal and supraspinal sources, resulting in earlier recruitment of a finite pool of motor units and premature task failure. According to this hypothesis, the difference in the time to task failure is attributable to differences in the input received by the spinal motor neurons. We propose a research plan that will quantify the change in excitability of single motor units (Aim 1), compare the inputs that the spinal motor neurons receive from corticospinal neurons (Aim 2) and group la afferents of muscle spindles (Aims 3-4). and determine the level of activity in accessory muscles (Aim 5) during the two tasks. The experiments on the corticospinal neurons and the group la reflex pathway will involve evoked responses and will be performed in collaboration with Prof. Duchateau in Brussels. The outcomes will provide novel information on the physiological adjustments that occur during isometric contractions, which are the most common form of muscle activity, and will have direct application to the design of work tasks in ergonomics and the prescription of physical activities in rehabilitation.

DESCRIPTION (provided by applicant): In the classic view of spinal cord neurophysiology, the thousands of synaptic inputs that impinge on motor neurons are integrated and converted to action potentials. In recent years, however, it has become evident that he dendrites of motor neurons do not act as passive recipients of synaptic input; they contain voltage-sensitive onductances that are influenced by neuromodulatory input from monoaminergic axons originating in the brainstem: At high levels of monoaminergic input, the persistent inward currents that are generated in the dendrites become so large that the discharge rates required for maximal activation of muscle fibers can be achieved with relatively minor amounts of synaptic input. Thus, active dendritic currents rather than ionotropic synaptic currents may dominate integration by motor neurons during normal motor behavior. One consequence of this possibility is that it becomes difficult to infer patterns of synaptic input from recordings of motor unit activity made in human subjects and patients. The purpose of this R13 application is to request support for a 3-day meeting that will provide a forum for the exchange of information between investigators who study motor neuron properties in experimental animals and those who record motor unit activity in humans. The meeting, which is titled "'Active Dendrites in Motor Neurons: Mechanisms and Effects on Motor Output", will be held at the University of Colorado at Boulder on June 24-26, 2004. The meeting will involve about 75 participants: 26 invited speakers, approximately 30 trainees (graduate students and postdoctoral fellows), and a number of collaborators. The invited speakers, all of whom have agreed to participate in the meeting, are PIs who direct research programs that study either motor neuron properties in experimental animals or motor unit activity in humans. Nine of the 26 invited speakers are women. The meeting format will consist of podium presentations (30, 10, and 2 rain), poster sessions, and significant time for discussion. The meeting will also include three young investigator awards to encourage participation by trainees in the meeting. The abstracts submitted by each invited speaker will be posted on a publicized website. Our expectation is that the meeting will provide an opportunity to review current knowledge on motor neuron properties and motor unit behavior, to identify critical gaps in existing knowledge, and to formulate a research agenda that can address these issues.

DESCRIPTION (provided by applicant): The progressive decline in mobility that occurs with multiple sclerosis (MS) is attributable to two factors: a reduction in the ability of the nervous system to generate adequate muscle activation signals and a decrease in the level of physical conditioning that results from the development of a more sedentary lifestyle. Exercise programs can provide some relief by reducing the level of deconditioning, but only for individuals with low levels of disability. There are no effective countermeasures for persons with MS who are moderately disabled with limitations in walking performance. To address this knowledge gap, we will examine the effectiveness of an intervention that evokes involuntary contractions in leg muscles with a novel form of neuromuscular electrical stimulation (NMES). Conventional NMES mainly activates motor axons using narrow (0.2-0.5 ms) stimulus pulses, but does not improve the walking performance of persons with MS. As an alternative approach, we will use wide (1 ms) stimulus pulses to activate both motor and sensory axons and thereby modulate the excitability of spinal and cortical neurons to promote the recovery of motor function in the nervous system. The primary outcome will be walking endurance, which will be quantified as the distance walked in 6 min. The participants (n = 30, 18-55 yrs) will be individuals diagnosed with MS who exhibit a clinically defined moderate level of disability. The research design comprises a 6 week (18 sessions), randomized, evaluator-blinded comparison of narrow- and wide-pulse NMES treatment on walking performance and then retention of the gains in walking endurance during 6 months of follow-up. Based on the demonstrated acute effects of wide-pulse NMES in healthy volunteers, the intervention will comprise stimulation of each leg individually with 30 trains of stimulation (20 s on, 20 s off) with a well-tolerated current that elicits a submaximal force (~20% maximum). We will evaluate two hypotheses: H1: Treatment of moderately disabled MS patients with wide-pulse NMES will improve walking endurance more than treatment with narrow-pulse NMES. H2: Improvements in walking endurance will be associated with elevated levels of habitual physical activity that will be retained longer after the treatment ends for the wide-pulse NMES group compared with the narrow-pulse NMES group. We expect wide-pulse NMES to produce greater improvement in walking endurance than narrow-pulse NMES and the gains to be associated with: (1) sustained electromyographic (EMG) activity in leg muscles during walking; (2) improved walking economy; and (3) increases in stride length. If wide-pulse NMES can elicit clinically significant improvements in mobility and quality of life for persons with moderate disability, clinicians will be able to prescribe a meaningful strategy for this underserved group of MS patients. Moreover, the intervention may delay the development of disability in individuals who are less affected by the disease. The outcomes of this feasibility study will suggest directions for subsequent R01 projects.