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L E Miller

Publications and source records attributed to L E Miller.

At least 19 recordsLinked to original sources

Direct comparison of the task-dependent discharge of M1 in hand space and muscle space.

Since its introduction in the early 1980s, the concept of a "preferred direction" for neuronal discharge has proven to be a powerful means of studying motor areas of the brain. In the current paper, we introduce the concept of a "muscle-space"-preferred direction (PD(M)) that is analogous to the familiar hand-space-preferred direction (PD(H)). PD(M) reflects the similarity between the discharge of a given neuron and the activity of each muscle in much the way that PD(H) reflects the similarity of discharge with motion along each of the three Cartesian coordinate axes. We used PD(M) to analyze the data recorded from neurons in the primary motor cortex (M1) of three different monkeys. The monkeys performed center-out movements within two different cubical workspaces centered either to the left or right of the monkey's shoulder while we simultaneously recorded neuronal discharge, muscle activity, and limb orientation. We calculated preferred directions in both hand space and muscle space, and computed the angles between these vectors under a variety of conditions. PDs for different neurons were broadly distributed throughout both hand space and muscle space, but the muscle-space vectors appeared to form clusters of functionally similar neurons. In general, repeated estimates of PD(M) were more stable over time than were similar estimates of PD(H). Likewise, there was less change in PD(M) than in PD(H) for data recorded from the two different workspaces. However, although a majority of neurons had this muscle-like property, a significant minority was more stable in Cartesian hand space, reflecting a heterogeneity of function within M1.

Algorithms↗

Movement-related discharge in the cerebellar nuclei persists after local injections of GABA(A) antagonists.

Limb movement-related neurons in the cerebellar nuclei (CN) typically produce bursts of discharge in association with movement. Consequently, given the inhibitory nature of the Purkinje cell (PC) projection to CN, it is puzzling that only a minority of movement-related PCs pause; the majority burst. Some of the movement-related CN activity may be the result of excitation from collaterals of mossy and climbing fiber projections to the cerebellar cortex. The only other input to CN is diffuse and neuromodulatory, from locus ceruleus and raphe nuclei. To investigate the role of the excitatory mossy fiber input, single units in CN were recorded in macaque monkeys during the performance of reaching and manipulation tasks, before and after blocking the PC input with local microinjections of GABA(A) antagonists (bicuculline or SR95531). After these injections, the movement-related modulation of CN discharge was greater and began earlier, compared with the modulation in the preinjection group of neurons. These observations indicate that an important excitatory drive is provided by extracerebellar inputs to CN, most likely from collaterals of mossy fibers. PCs may serve primarily to regulate this activity, by either pausing or bursting as necessary.

Action Potentials↗

Relationships among bone mineral density, body composition, and isokinetic strength in young women.

The purpose of this study was to examine the relationships among bone mineral density (BMD), body composition, and isokinetic strength in young women. Subjects were 76 women (age: 20 +/- 2 yr, height: 164 +/- 6 cm, weight: 57 +/- 6 kg, body fat: 27 +/- 4%) with a normal body mass index (18-25 kg/m(2)). Total body, nondominant proximal femur, and nondominant distal forearm BMD were measured with dual-energy x-ray absorptiometry. Isokinetic concentric (CON) and eccentric (ECC) strength of the nondominant thigh and upper arm were measured at 60 deg/sec. Fat-free mass (FFM) correlated (P < 0.001) with BMD of the total body (r = 0.56) and femoral neck (r = 0.52), whereas fat mass (FM) did not relate to BMD at any site. Leg FFM, but not FM, correlated with BMD in all regions of interest at the proximal femur. Weak associations were observed between arm FFM and forearm BMD. Isokinetic strength did not relate to BMD at any site after correcting for regional FFM. In conclusion, strong, independent associations exist between BMD and FFM, but not FM or isokinetic strength, in young women.

Absorptiometry, Photon↗

The effect of urethral instrumentation on uroflowmetry.

OBJECTIVE: To evaluate in a prospective study the effect of urethral instrumentation (flexible cystoscopy) on uroflowmetry, and in particular the peak urinary flow rate (Qmax). PATIENTS AND METHODS: Thirty-two consecutive patients (median age 61.8 years, range 24-80) undergoing flexible cystoscopy were included in the analysis. Patients with active urethral stricture disease or urinary infection were excluded. The indications for cystoscopy included haematuria (44%), voiding symptoms (66%), history of bladder cancer (19%), and history of perineal trauma (3%). Patients underwent uroflowmetry immediately before instrumentation. The postvoid residual volume (PVR) was measured by bladder catheterization. After cystoscopy the bladder was completely emptied and then filled with the same volume of sterile normal saline (bladder volume = voided volume + PVR), and the patient underwent a second uroflowmetry. RESULTS: Patients with voiding symptoms (21, 66%) had a median (range) American Urological Association symptom score of 17 (4-34), a Bother score of 16 (1-23), and Quality of Life score of 3 (1-6). The mean Qmax was 16.9 (4.5-36.9) and 13.3 (4.5-39.4) mL/s before and after cystoscopy, respectively (P = 0.029). The mean percentage difference in Qmax was + 27 (- 23 to 139)% higher before than after cystoscopy. After cystoscopy, up to 25% (eight) and 21% (seven) patients had a lower Qmax, from > 15 to < 15 mL/s and from > 12 to < 12 mL/s, respectively. There were no significant differences in the bladder volume and PVR (P = 0.914 and 0.984, respectively). CONCLUSIONS: Urethral instrumentation by flexible cystoscopy significantly alters Qmax. A 'false' mean change in Qmax (favouring improvement) of +27% would result if uroflowmetry data after instrumentation were used at baseline. Therefore, study protocols for benign prostatic obstruction should exclude uroflowmetry data obtained after urethral instrumentation; failure to exclude such data will lead to disproportionately greater improvements in Qmax that are independent of the therapy delivered.

Adult↗

Prediction of muscle activity by populations of sequentially recorded primary motor cortex neurons.

We have adopted an analysis that produces a post hoc prediction of the time course of electromyogram (EMG) activity from the discharge of ensembles of neurons recorded sequentially from the primary motor cortex (M1) of a monkey. Over several recording sessions, we collected data from 50 M1 neurons and several distal forelimb muscles during a stereotyped precision grip task. Ensemble averages were constructed from 5 to 10 trials for each neuron and EMG signal. We used multiple linear regression on randomly chosen subsets of these neurons to find the best fit between the neuronal and EMG data. The fixed delay between neuronal and EMG signals that yielded the largest coefficient of determination (R(2)) between predicted and actual EMG was 50 ms. R(2) averaged 0.83 for ensembles composed of 15 neurons. If, instead, each neuronal signal was delayed by the time of its peak cross-correlation with the EMG signal, R(2) increased to 0.88. Using all 50 neurons, R(2) under these conditions averaged nearly 0.97. A similar analysis was conducted with signals recorded during both a power grip and a precision grip task. Quality of the fit dropped dramatically when parameters from the precision grip for a given set of neurons were used to fit data recorded during the power grip. However, when a single set of regression parameters was used to fit a combination of the two tasks, the quality of the fits decreased by <10% from that of a single task.

Animals↗

Features of motor performance that drive adaptation in rapid hand movements.

In order to explore how subjects correct for errors in movement and adapt their motor programs, we studied rapid hand movements. Subjects grasped a grooved knob and made brisk turning movements to various targets, similar to tuning a radio dial. A motor attached to the knob shaft was configured to apply a destabilizing negative viscous perturbation. Following a period of practice with no perturbations, the negative viscosity was engaged, which caused a large change in overall kinematics: the peak velocity increased, the movement amplitude was too large, and discrete corrective submovements were generated to bring the pointer back onto the target. After about an hour and nearly 1000 trials, subjects learned to move accurately in the new dynamic environment, returning their overall kinematics near to previous levels. Measures of performance included the endpoint error of the primary movement (the initial movement segment), the frequency and amplitude of corrective submovements, task success rate, mean squared jerk, and deviation from a "normal" angular velocity temporal profile. Both the amplitude and frequency of corrective submovements decreased progressively during adaptation as the subjects made fewer target overshoot errors. These results are consistent with motor learning schemes in which adaptation of the motor controller is driven by an attempt to reduce the endpoint error of the primary movement. While there have been many theories regarding what is being optimized in motor control, in general, biologically plausible mechanisms for implementing these schemes have not been described. A biologically plausible optimization criterion is the minimization of the occurrence and amplitude of corrective submovements, since the latter have been proposed as realistic climbing fiber training signals for adaptive changes in the cerebellum. We postulate that the other criteria that have been proposed are instead secondary to an increased accuracy of the primary movement and a corresponding decrease in the occurrence and amplitude of corrective submovements.

Adaptation, Physiological↗

Primary motor cortical neurons encode functional muscle synergies.

Many different kinematic and kinetic signals have been proposed as possible variables under the control of the primary motor cortex. Despite the presence of direct projections to motor neurons, muscle activation has received less attention as a controlled variable. Furthermore, although it is well known that descending fibers project to multiple motor pools, an objective, quantitative study of the relation between neuronal modulation and the activity of groups of muscles has not previously been reported. We have recorded the discharge of 310 neurons located in the primary motor cortex of two monkeys, along with the activity of a variety of arm and hand muscles. Data were recorded while the monkey reached to and pressed a series of illuminated buttons. The similarity of a given neuron's discharge with respect to each muscle was determined by calculating the linear cross-correlation between its discharge rate and each rectified, filtered electromyogram. A "functional linkage vector" was then constructed, which expressed the similarity of that neuron's discharge to the entire set of muscles. We discovered discrete groups of functional linkage vectors within the high order muscle space for both monkeys which corresponded to functional properties of the neurons measured by other methods. Several of these groups appeared to represent a functional synergy of muscles, such as those required to extend the limb, press a button, or open the hand in preparation for the press. When the dimensionality of this space was reduced by a principal components analysis, the originally identified clusters of neurons remained well separated. These results are consistent with the hypothesis that the discharge of individual neurons in the primary motor cortex encodes the activity of a relatively small number of functionally relevant groups of muscles. It will be important to determine whether these results will also apply to more complex behavior, and to what extent these functional muscle synergy representations remain fixed across behaviors.

Action Potentials↗

The use of overlapping submovements in the control of rapid hand movements.

Rapid targeted movements are subject to special control considerations, since there may be inadequate time available for either visual or somatosensory feedback to be effective. In our experiments, subjects rapidly rotated a knob to align a pointer to one of several targets. We recognized three different types of movement segments: the primary movement, and two types of submovement, which frequently followed. The submovements were initiated either before or after the end of the primary movement. The former, or "overlapping" type of submovement altered the kinematics of the overall movement and was consequently difficult to detect. We used a direct, objective test of movement regularity to detect overlapping submovements, namely, examining the number of jerk and snap zero crossings during the second half of a movement. Any overlapping submovements were parsed from the overall movement by subtracting the velocity profile of the primary movement. The velocity profiles of the extracted submovements had near-symmetric bell shapes, similar to the shapes of both pure primary movements and nonoverlapping submovements. This suggests that the same neural control mechanisms may be responsible for producing all three types of movement segments. Overlapping submovements corrected for errors in the amplitude of the primary movement. Furthermore, they may account for the previously observed, speed-dependent asymmetry of the velocity profile. We used a nonlinear model of the musculoskeletal system to explain most of the kinematic features of these rapid hand movements, including how discrete submovements are superimposed on a primary movement. Finally, we present a plausible scheme for how the central nervous system may generate the commands to control these rapid hand movements.

Adult↗

The role of the cerebellum in modulating voluntary limb movement commands.

We recorded the activity of cerebellar Purkinje cells (PCs), primary motor cortical (M1) neurons, and limb EMG signals while monkeys executed a sequential reaching and button pressing task. PC simple spike discharge generally correlated well with the activity of one or more forelimb muscles. Surprisingly, given the inhibitory projection of PCs, only about one quarter of the correlations were negative. The largest group of neurons burst during movement and were positively correlated with EMG signals, while another significant group burst and were negatively correlated. Among the PCs that paused during movement most were negatively correlated with EMG. The strength of these various correlations was somewhat weaker, on average, than equivalent correlations between M1 neurons and EMG signals. On the other hand, there were no significant differences in the timing of the onset of movement related discharge among these groups of PCs, or between the PCs and M1 neurons. PC discharge was modulated largely in phase, or directly out of phase, with muscle activity. The nearly synchronous activation of PCs and muscles yielded positive correlations, despite the fact that the synaptic effect of the PC discharge is inhibitory. The apparent function of this inhibition is to restrain activity in the limb premotor network, shaping it into a spatiotemporal pattern that is appropriate for controlling the many muscles that participate in this task. The observed timing suggests that the cerebellar cortex learns to modulate PC discharge predictively. Through the cerebellar nucleus, this PC signal is combined with an underlying cerebral cortical signal. In this manner the cerebellum refines the descending command as compared with the relatively crude version generated when the cerebellum is damaged.

Action Potentials↗

A possible role of the superior colliculus in eye-hand coordination.

Reaching with the arm to a newly appearing target is usually preceded by a saccadic eye movement. Neurons in the superior colliculus (SC) constitute one important brain structure controlling saccades. Yet, the SC also contains reach neurons activated during arm movements, whose location extends also deeper into the underlying mesencephalic reticular formation. Reach neurons can be divided into two classes based on their different modulation with respect to gaze position. For the first class, the gaze-independent reach neurons, the activity does not depend on which location is currently fixated, but solely on the position and movement of the (usually contralateral) arm. There is a correlation of the activity of these neurons with the activity of shoulder muscles. The second class, the gaze-related reach neurons, are active for reaches into a specific area relative to the current point of gaze. This means the target has to project on a certain part of the retina, while it is not important which arm is used or by which trajectory the target will be reached. Many fixation neurons in the rostral pole of the SC discharge tonically during fixation and pause during saccades. For some fixation neurons, the activity can be increased during simultaneous arm movements, for others decreased. Two psychophysical experiments with healthy human subjects show possible behavioral correlates of an interaction between these reach neurons and visuomotor neurons within the SC.

Animals↗

Verification of good production practices that reduce the risk of exposure of pigs to Trichinella.

Control of Trichinella infection in swine has traditionally been accomplished by inspection of individual carcasses or by post-slaughter processing to inactivate parasites. Recent declines in prevalence of this parasite in domestic swine, coupled with improvements in swine management systems, offer the opportunity to document pork safety during the production phase. We report here on a certification pilot study using an audit to document good production practices for swine relative to the risk of exposure to trichinae. Based on the results, improvements in the program have been made and further studies will be undertaken prior to launching a voluntary trichinae herd certification program in the United States.

Abattoirs↗

Context dependency in the globus pallidus internal segment during targeted arm movements.

Extracellular discharges from single neurons in the internal segment of the globus pallidus (GPi) were recorded and analyzed for rate changes associated with visually guided forearm rotations to four different targets. We sought to examine how GPi neurons contribute to movement preparation and execution. Unit discharge from 108 GPi neurons recorded in 35 electrode penetrations was aligned to the time of various behavioral events, including the onset of cued and return movements. In total, 39 of 108 GPi neurons (36%) were task-modulated, demonstrating statistically significant changes in discharge rate at various times between the presentation of visual cues and movement generation. Most often, strong modulation in discharge rate occurred selectively during either the cued (n = 32) or return (n = 2) phases of the task, although a few neurons (n = 5) were well-modulated during both movement phases. Of the 34 neurons that were modulated exclusively during cued or return movements, 50% (n = 17) were modulated similarly in association with movements to any target. The remaining 17 neurons exhibited considerable diversity in their discharge properties associated with movements to each target. Cued phases of behavior were always rewarded if executed correctly, whereas return phases were never rewarded. Overall, these data reveal that many GPi neurons discharged in a context-dependent manner, being modulated during cued, rewarded movements, but not during similar self-paced, unrewarded movements. When considered in the light of other observations, the context-dependence we have observed seems likely to be influenced by the animal's expectation of reward.

Acoustic Stimulation↗

Cytokines and hormones as possible links between endocrinosenescence and immunosenescence.

Deterioration of the immune system and the endocrine system during aging is thought to contribute to increased morbidity and mortality. Since bidirectional interrelations of both systems are present in the young and in the elderly, endocrinosenescence modulates the immune system and immunosenescence changes the endocrine system. This review focuses on age-related changes of the two systems and provides examples for the interaction of both systems during aging. It is demonstrated that both systems modulate each other in a probably unfavorable way which may be a cofactor in the aging process. Understanding of these bidirectional physiological mechanisms will help to define targets for therapeutical intervention to improve the health of aging people.

Aging↗

Modulation of IL-6 production during the menstrual cycle in vivo and in vitro.

During the menstrual cycle (MC), premenopausal women experience changes in basal temperature and their physical condition and well-being. Premenopausal female patients with chronic inflammatory diseases demonstrate changes in disease activity during the MC. The study was initiated to explore reasons for these phenomena. The sex hormone-modulated lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) secretion in a whole blood assay, serum IL-6 concentration, and serum sex hormone concentrations were studied throughout the MC in five healthy female subjects (median, 28 years; mean, 31.2+/-2.2 years, 26-38 years). Serum IL-6 concentration demonstrated a significant increase in the luteal phase of the MC and was elevated when serum dehydroepiandrosterone (DHEA) was low and vice versa. DHEA decreased LPS-induced IL-6 secretion at six of seven time points during the MC (DHEA, p = .047). In contrast, beta-estradiol and testosterone increased LPS-induced IL-6 secretion in six of seven time points during the MC (significant for testosterone, p = .005). The study demonstrates oscillation of serum IL-6 concentration during the MC and the marked MC-dependent modulation of IL-6 secretion by sex hormones. These mechanisms may be involved in the changes in the basal temperature, the general condition, and, in patients with chronic inflammatory diseases, of disease activity during the MC.

Adult↗

Kinematic properties of rapid hand movements in a knob turning task.

In order to understand how the central nervous system controls the kinematics of rapid finger and hand movements, we studied the motions of subjects turning a knob to light-emitting diode targets, similar to tuning a radio dial. On many trials, subjects turned the knob with a single, smooth, and regular motion as revealed by the angular position and velocity trajectories, but on others, subjects produced irregularities in the kinematics. Like many past studies, we interpreted these irregularities as discrete corrective submovements. Unlike other studies, we used a direct, objective algorithm to identify overlapping submovements, detecting appreciable inflections in the acceleration traces by examining zero crossings in their derivatives, jerk and snap. The movements without overlapping submovements on average had a near symmetric, bell-shaped velocity profile that was independent of speed, and which matched the theoretical minimum jerk velocity very closely. We proposed three plausible mechanisms for altering the shape of movement kinematics, and implemented a mass-spring model with nonlinear damping to explore the possibilities. Although there was relatively little variability in the shape and symmetry of movements across trials, there was a fair amount of variability in their amplitude. We show that subjects attempted to eliminate the need for corrective submovements by making more accurate primary movements with practice, but that the variability inherent in rapid movements dictated the need for corrective submovements. Subjects used corrective submovements to improve final endpoint accuracy while reducing endpoint variability, resulting in higher task success rates.

Adult↗

Neuropeptide Y cotransmission with norepinephrine in the sympathetic nerve-macrophage interplay.

The CNS modulates immune cells by direct synaptic-like contacts in the brain and at peripheral sites, such as lymphoid organs. To study the nerve-macrophage communication, a superfusion method was used to investigate cotransmission of neuropeptide Y (NPY) with norepinephrine (NE), with interleukin (IL)-6 secretion used as the macrophage read-out parameter. Spleen tissue slices spontaneously released NE, NPY, and IL-6 leading to a superfusate concentration at 3-4 h of 1 nM:, 10 pM:, and 120 pg/ml, respectively. Under these conditions, NPY dose-dependently inhibited IL-6 secretion with a maximum effect at 10(-10) M: (p = 0.012) and 10(-9) M: (p < 0.001). Simultaneous addition of NPY at 10(-9) M: and the alpha-2-adrenergic agonist p-aminoclonidine further inhibited IL-6 secretion (p < 0.05). However, simultaneous administration of NPY at 10(-9) M: and the beta-adrenergic agonist isoproterenol at 10(-6) M: or NE at 10(-6) M: significantly increased IL-6 secretion (p < 0.005). To objectify these differential effects of NPY, electrical field stimulation of spleen slices was applied to release endogenous NPY and NE. Electrical field stimulation markedly reduced IL-6 secretion, which was attenuated by the NPY Y1 receptor antagonist BIBP 3226 (10(-7) M, p = 0.039; 10(-8) M, p = 0.035). This indicates that NPY increases the inhibitory effect of endogenous NE, which is mediated at low NE concentrations via alpha-adrenoceptors. Blockade of alpha-adrenoceptors attenuated electrically induced inhibition of IL-6 secretion (p < 0.001), which was dose-dependently abrogated by BIBP 3226. This indicates that under blockade of alpha-adrenoceptors endogenous NPY supports the stimulating effect of endogenous NE via beta-adrenoceptors. These experiments demonstrate the ambiguity of NPY, which functions as a cotransmitter of NE in the nerve-macrophage interplay.

Adrenergic Agonists↗

The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages.

Our objective was to investigate sympathetic and sensory nerve fibers in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) in relation to histological inflammation and synovial cytokine and norepinephrine (NE) secretion. Immunohistochemistry was used to detect nerve fibers and inflammatory parameters. A superfusion technique of synovial tissue pieces was used to investigate cytokine and NE secretion. In RA, we detected 0.2 +/- 0.04 tyrosine hydroxylase-positive (TH-positive=sympathetic) nerve fibers/mm2 as compared to 4.4 +/- 0. 8 nerve fibers/mm2 in OA (P<0.001). In RA, there was a negative correlation between the number of TH-positive nerve fibers and inflammation index (RRank=-0.705, P=0.002) and synovial IL-6 secretion (RRank=-0.630, P=0.009), which was not found in OA. Substance P-positive (=sensory) nerve fibers were increased in RA as compared to OA (3.5+/-0.2 vs. 2.3+/-0.3/mm2, P=0.009). Despite lower numbers of sympathetic nerve fibers in RA than in OA, NE release was similar at baseline (RA vs. OA: 152+/-36 vs. 106+/-21 pg/ml, n.s.). Basal synovial NE secretions correlate with the number of TH-positive CD 163+ synovial macrophages (RA: RRank=0.622, P=0.031; OA: RRank=0.299, n.s.), and synovial macrophages have been shown to produce NE in vitro. Whereas sympathetic innervation is reduced, sensory innervation is increased in the synovium from patients with longstanding RA when compared to the synovium from OA patients. The differential patterns of innervation are dependent on the severity of the inflammation. However, NE secretion from the synovial tissue is maintained by synovial macrophages. This demonstrates a loss of the influence of the sympathetic nervous system on the inflammation, accompanied by an up-regulation of the sensory inputs into the joint, which may contribute to the maintenance of the disease.

Aged↗

Functional connectivity between cerebellum and primary motor cortex in the awake monkey.

Simultaneous single neuron and local field potential (LFP) recordings were made in arm-related areas of the cerebellar nuclei (CN) and primary motor cortex (M1) of two monkeys during a reaching and button pressing task. Microstimulation of focal sites in CN caused short latency (median = 3.0 ms) increases in discharge in 25% of 210 M1 neurons. Suppressive effects were less common (13%) and observed at longer latencies (median = 9.9 ms). Stimulation in CN also caused reciprocal facilitation and suppression in averages of antagonist muscle electromyograms (EMGs). The latency of these effects was approximately 8-11 ms. In contrast to the selectivity of unit and EMG effects, stimulation-evoked changes in LFP occurred over a broad range of sites. There were no significant short-latency effects detected in cross-correlation histograms between single neurons in CN and M1. However, CN spike-triggered averages of M1 LFPs were observed in a few cases (10% of 126 cases). In one-half of these, there were effects both before and after the CN spikes, which may reflect causal effects from M1 to CN, as well as from CN to M1. Overall, these results demonstrate a spatially specific, short latency, primarily excitatory pathway from CN to M1. The relatively rare effects at the single neuron level may have resulted from the difficulty in achieving optimal alignment between cerebellar and cerebral sites because of the specificity of these connections.

Action Potentials↗