Treatment of spasticity with botulinum toxin.
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Botulinum Toxins↗
Biomedical subjects
A W Wiegner
Publications and source records attributed to A W Wiegner.
Effects of weak antagonist on fast elbow flexion movements in man.
By using a mathematical model and experiments involving electrical simulation of antagonistic muscles, we have formed the hypothesis (Wierzbicka et al. 1986) that in one-joint movements the antagonist muscle not only provides braking torque but also controls movement time. To get additional experimental support for this hypothesis, we studied elbow flexion movements performed by patients with spinal cord injury at the C5-6 level who had relatively normal strength in their biceps muscle and little or no voluntary control of the triceps. Seven quadriplegic patients and six control subjects performed elbow flexion movements of 10 degrees, 20 degrees, and 30 degrees "as fast and accurately as possible". Despite the lack of antagonist, patients used the same "pulse height" strategy as control subjects to scale their responses with movement amplitude. However, patients' movement time was on average twice that of control subjects, and durations of both accelerative and decelerative phases of movement were increased. Movement speed and acceleration were reduced to 20-50% of the corresponding values of control subjects. Patients tended to overshoot the target to a larger extent than control subjects, particularly 10 degrees targets, with nearly twice the error. We performed the same experiments using an external torque motor to assist the weak triceps. When a constant extensor torque of 2.5 or 5 Nm was provided by the motor, patients were able to move faster, and movement accuracy improved to within the normal range. These results provide direct evidence that the lack of an antagonist has an important effect on completion time and accuracy of fast goal-directed movements.
Adult↗
Kinematic models and human elbow flexion movements: quantitative analysis.
The smoothness with which movements are customarily performed has led Hogan (1984) to formulate a model for trajectory planning by the central nervous system in which the goal is to maximize smoothness, one measure of which is the integrated mean squared magnitude of jerk (jerk cost). We tested the applicability of this minimum-jerk model to one-joint goal directed movements performed by human subjects at different speeds and amplitudes, by comparing kinematic parameters and the jerk cost predicted by the mathematical model with values calculated from experimental data. We also tested a higher order, minimum-snap kinematic model. Normal subjects performed elbow flexions of 5 to 50 degrees "as rapidly and accurately as possible" and also at slower speeds. The boundary conditions of both models were adjusted to account for the failure of subjects to produce movements which reached equilibrium precisely at the target (so that acceleration and velocity reached zero together). Typically, fast movements (less than 300 ms duration) were fairly symmetric in that the durations and amplitudes of acceleration and deceleration were approximately equal; slower movements (greater than 300 ms) were asymmetric with strong, brief acceleration peaks and broad, slow deceleration peaks. In fast movements, the calculated jerk cost was consistently higher than predicted by the minimum-jerk model; a good fit to all kinematic parameters was provided by the minimum-snap model (a seventh-order polynomial). Neither model consistently predicted the trajectories of slower movements. We conclude that muscle/limb dynamics can account for the success of the minimum-snap model with fast movements, and that there is no evidence of planning for maximal smoothness in slower movements.
Brain↗
Innervation zone of orbicularis oculi muscle and implications for botulinum A toxin therapy.
Motor points (areas of maximal sensitivity to electrical stimulation) were found in constant locations over orbicularis oculi when measured in both eyes of six normal subjects. All subjects had a motor point at the lateral terminus of the upper lid crease and the medial extent of the lower lid crease. A study of the innervation zone [distribution of neuromuscular junctions (NMJ)] was conducted on strips of pretarsal and preseptal portions of the upper eyelid orbicularis that had been removed routinely during involutional ptosis surgery. There was no significant difference in NMJ concentration between the medial and lateral sections, as determined by cholinesterase staining. Therefore, we concluded that the innervation zone is diffuse for the orbicularis muscle within this portion of the upper eyelid. Single-point injections of botulinum toxin were then compared to the conventional multiple injection sites on separate eyes in 10 patients with benign essential blepharospasm. Eight of the 10 patients reported greater relief on the side given injections into multiple points; the other two patients experienced no difference between the two methods. Both histologic data and clinical observation of response to botulinum toxin injection suggest the innervation zone for the upper orbicularis is diffuse. Thus, we conclude that multiple injections are superior to the injection of a single motor point.
Acetylcholinesterase↗
Abnormal most-rapid isometric contractions in patients with Parkinson's disease.
Fast isometric elbow flexor muscle contractions of specified amplitude in six normal subjects were compared with those of 11 patients with Parkinson's disease. Despite treatment, all patients exhibited deficits in this motor task. Three patients were able to produce rapid force pulses with normal contraction times, but the variability of their force responses was increased in comparison with the highly stereotyped responses produced by normal subjects. The other eight patients had prolonged contraction times and segmentation of the force profiles. The integrated area of the first agonist EMG burst and the rate of development of force (dF/dt) were less at any target level than what was needed to produce a fast response. The area of the EMG burst, however, did increase with target amplitude, and the relative increase of dF/dt, with target amplitude, was normal. It is concluded that the motor program subserving fast muscle contraction is preserved in Parkinson's disease, but its execution is characterised by improper scaling of motor output.
Adult↗
Effects of muscle thixotropy on afferent activity in the hindlimb of the rat.
The increase with time of the stiffness of resting muscle and its effect on afferent nerve activity arising within the muscle were investigated in the leg of the anaesthetized rat. Nerve activity was recorded from the branch of the tibial nerve innervating the gastrocnemius muscle. A sinusoidal torque from a motor coaxial with the ankle produced small (less than 0.25 deg) oscillations of the resting foot that were interrupted by several cycles of a much larger amplitude displacement. After the perturbation, the same small torque caused larger (greater than 0.40 deg) oscillations, demonstrating a reduction in the resting or short-range stiffness of muscles acting at the joint. Turning off the torque for 30 s allowed the stiffness to return to its enhanced level. Afferent nerve activity in response to the small torque was greater following the perturbation, reflecting the larger oscillations. We conclude that thixotropic stiffening of muscles at rest reduces postural displacements produced by small torques as well as the quantity of afferent signals converging on the central nervous system from these events.
Afferent Pathways↗
Motor unit synchronization in physiologic, enhanced physiologic, and voluntary tremor in man.
Synchronization between pairs of single motor units simultaneously recorded from wrist extensor muscles was quantitated in 3 normal subjects during physiologic tremor (PT), beta-adrenergically enhanced physiologic tremor (EPT), and fast voluntary wrist flexion-extension movements mimicking tremor (VT). Cross-correlation histograms generated from the two spike trains of each motor unit pair demonstrated central or paracentral peaks in 13/19 recordings during PT, 22/36 during EPT, and 6/7 during VT. Relative peak area was used as a quantitative index of synchronization between the two motor units of each pair. It was lowest in PT, progressively increased in EPT as tremor amplitude increased, and highest in VT. In PT and lower amplitude EPT, the synchronization indexes were higher between motor units that discharged at the same or nearly the same frequency. In contrast, in higher amplitude EPT and VT, motor units with different firing frequencies were sometimes strongly synchronized as a consequence of double discharges in faster-firing motor units that had burst repetition rates in the range of slower-firing motor units discharging as singlets. Greater motor unit synchronization with increasing tremor amplitude in EPT may be secondary to a simultaneous increase in muscle spindle afferent activity from the tremulous muscle. Greatest synchronization in VT presumably reflects near maximal supraspinal and segmental common synaptic input onto motoneurons that generate VT. These results support a longstanding hypothesis that synchronization of motor units is the physiological basis for higher amplitude tremor.
Electromyography↗
Papillary muscle structure-function relations in the aging spontaneously hypertensive rat.
Isolated left ventricle papillary muscle mechanics and structure were studied in male spontaneously hypertensive (SHR) rats and two control groups of animals, the normotensive Wistar (NR) and the Wistar-Kyoto rat (WKY). Active tension and its first derivative (dT/dtmax) normalized for muscle cross-sectional area were increased in preparations from the SHR at all ages studied relative to control groups (P less than 0.01). However, when these parameters were normalized for myofibrillar cross-sectional area determined from electronmicroscopic point counting data, differences between groups were no longer significant. Force-velocity relations provided no evidence for a depression of shortening velocity at any load in the SHR at any age relative to the two control groups. The duration of mechanical activity, as determined by time-to-peak isometric tension and analysis of muscle force-velocity-time relations, was prolonged only in the 18 month old SHR (P less than 0.01). Thus, while changes in isolated muscle performance occur at a time when hemodynamic impairment is reported in the intact animal (male 18 month SHR), no evidence for depression of isolated muscle function is seen in the SHR at 6, 12 or 18 months of age.
Age Factors↗
A method for assessing significance of peaks in cross-correlation histograms.
Cross-correlation histograms have been widely used to analyze the interdependence of two simultaneously observed trains of neuronal spikes or muscle motor unit discharges. Here, a formula is presented for calculating a synchronization index from such a histogram to reliably detect subtle correlations such as short-term synchronization, even in the case of relatively sparse data, as well as allowing comparison of the degree of synchronization of grouped or correlated motor unit discharges. The index takes into account the number of counts in the histogram, number of bins, and width of the histogram peak. A table of critical values of the index, at several levels of statistical significance, is included.
Animals↗
Mechanism of thixotropic behavior at relaxed joints in the rat.
When a relaxed joint is subjected to a small sinusoidal torque, the amplitude of the steady-state displacement response is increased up to severalfold by a transient larger perturbation. The original state, in which the relaxed joint is unexpectedly stiff, is restored by several seconds of inactivity. This thixotropic phenomenon has previously been observed in a variety of human joints. We have now investigated the mechanism of thixotropic behavior at relaxed joints in rats anesthetized with pentobarbital sodium, by using a series of preparations including the intact ankle joint, a blood-perfused soleus muscle preparation, an isolated soleus muscle, and ankle joint isolated by severing all muscular attachments. Thixotropic behavior was observed in all intact, isolated muscle, and isolated joint preparations. The contribution of the joint to thixotropic behavior was comparable to, and at times exceeded, the contribution of muscle. We also analyzed the short-range stiffness properties of relaxed, blood-perfused soleus muscles and found them to be similar to thixotropy with respect to range of action (0.2-0.3% of muscle length), elastic modulus (approximately 4 kg/cm2), and time course for redevelopment (time constant = 2.5 s at 34 degrees C). Thus thixotropic behavior at a relaxed joint may be attributed both to the joint structures and to short-range stiffness of muscles acting at the joint.
Animals↗
Mechanical determinants of maximum isotonic lengthening rate in rat left ventricular myocardium.
The effects of changing loading conditions and inotropic state on maximum isotonic lengthening rate (+dL/dt, muscle lengths/sec) were examined in isolated rat myocardium. Physiologically sequenced contractions were studied in 18 left ventricular papillary muscle preparations (stimulation rate, 12/min). To study the effects of changing loading conditions, only one loading variable (preload, total load, or late load) was changed during each contraction, while the others were held constant. To study the effects of isoproterenol (10(-6) M) and temperature (28 vs. 33 degrees C) on maximum isotonic lengthening rate, preload and late load were held constant and +dL/dt was examined at a common total load. When preload was increased from 0.7 +/- 0.1 to 1.4 +/- 0.1 g/mm2, muscle length increased from 0.98 +/- 0.003 to 1.01 +/- 0.002 muscle lengths, the extent of shortening increased from 0.05 +/- 0.003 to 0.08 +/- 0.003 muscle lengths, but minimum length (0.93 +/- 0.01 muscle lengths) and +dL/dt (1.1 +/- 0.1 muscle lengths/sec) were unchanged. When total load was increased from 1.5 to 4.5 g/mm2, minimum length increased from 0.91 +/- 0.05 to 0.97 +/- 0.05 muscle lengths and +dL/dt fell from 1.4 +/- 0.1 to 0.5 +/- 0.1 muscle lengths/sec. Late load (the load borne by or applied to the muscle during isotonic lengthening) was altered by changing its magnitude (g/mm2) or time (milliseconds after stimulation) of application. As late load was increased from 1.4 +/- 0.02 to 2.1 +/- 0.3 g/mm2, +dL/dt increased from 1.3 +/- 0.2 to 2.1 +/- 0.3 muscle lengths/sec.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Spasticity.
Spasticity has been defined as velocity-dependent hyperactivity of stretch reflexes; it is therefore only one aspect of the complex syndrome produced by a lesion of the upper motoneuron. Although spasticity may be partially responsible for joint contractures, it does not produce most of the functional disability experienced by patients with upper motoneuron lesions. Paresis, fatigability, lack of dexterity, etc., account for most of these patients' complaints. The pathophysiology of spasticity is poorly understood but appears to be related to an increased excitatory state at the segmental spinal level; there is no evidence for increased sensitivity of muscle spindles in spastic patients. Several mechanisms for this increased excitability within the spinal cord have been proposed. There are different types as well as degrees of spasticity. Clinical neurophysiologic recordings of reflex activity in patients with spasticity provide the means to differentiate among the various types of spasticity, to select the therapy most likely to be effective in a particular patient, and to see the results of its employment objectively. The latter will prove whether a specific therapy is useful or not. Ablative treatment at the level of the peripheral nerve or dorsal root may be useful, particularly when spasticity is severe. Drugs such as baclofen or diazepam relieve flexor spasms but are not particularly effective against spasticity itself. Dantrolene acts to weaken muscles, but that is not often helpful. Rarely do any of these therapies increase function; there are no effective cures for paresis or related negative manifestations of chronic spasticity.
Combined Modality Therapy↗
Role of agonist and antagonist muscles in fast arm movements in man.
Fast goal-directed voluntary movements of the human upper extremity are known to be associated with three distinct bursts of EMG activity in antagonistic muscles. The role of each burst (AG1, ANT, AG2) in controlling motion is not fully understood, largely because overall limb response is a complex function of the entire sequence of bursts recorded during experimental trials. In order to investigate the role of each burst of muscle activity in controlling motion, we studied fast voluntary arm movements and also developed two simulation techniques, one employing a mathematical model of the limb and the other using electrical stimulation of human arm muscles. These techniques show that two important movement parameters (peak displacement, time to reach peak displacement) are non-linear functions of the magnitude of the antagonist input (torque and stimulation voltage, respectively, in our two simulations). In the fastest movements, the agonist muscle is primarily responsible for the distance moved, while the antagonist muscle provides an effective means of reducing movement time. The third component of the triphasic pattern moderates the antagonist braking forces and redirects the movement back to the target.
Arm↗
Measurement of relaxation in isolated rat ventricular myocardium during hypoxia and reoxygenation.
The effects of hypoxia and subsequent reoxygenation were examined in isolated left ventricular papillary muscles from the rat at 28 degrees C and 33 degrees C. Studies of relaxation were carried out in isometric and physiologically sequenced contractions. In studies of isometric contractions, the following variables were determined: active tension (AT), maximum rate of tension increase (+dT/dt), time to peak tension (TPT), time for tension to fall from peak to 50% of peak tension (RT1/2), maximum rate of tension decline (-dT/dt), isometric peak (-dT/dt/T), and isometric maximum (-dT/dt per T). Variables measured in physiologically sequenced contractions were the slopes of the relation between -dT/dtmax and end systolic length (SIM) and maximum rate of isotonic muscle lengthening (+dL/dtmax) and end systolic length (SIT). Tau, the exponential time constant for isometric relaxation, was also examined. Pronounced changes in active tension and +dT/dt were seen during hypoxia at both temperatures, whereas changes in measured relaxation variables were less prominent and inconsistent. At neither 28 degrees C nor 33 degrees C did TPT or RT1/2 indicate impaired relaxation during hypoxia. Isometric peak -dT/dt declined with hypoxia at both temperatures but the normalised indices, isometric peak -dT/dt/T, peak (-dT/dt per T), and tau showed consistent impairment of relaxation only at 33 degrees C. In physiologically sequenced contractions, SIM suggested impaired relaxation during hypoxia at 28 degrees C but not at 33 degrees C. SIT showed impaired relaxation at both 28 degrees C and 33 degrees C. These findings are consistent with data suggesting impairment of the cardiac relaxing system during hypoxia. Nevertheless, relaxation appears less affected than contraction, and impairment is best seen late in the cardiac cycle.
Animals↗
Elastic properties of muscles measured at the elbow in man: I. Normal controls.
Passive elastic stiffness of muscle acting at the elbow was assessed in 19 normal subjects by measuring displacements produced by a torque motor acting at the joint. Stiffness ranged from 0.40 to 1.8 Nm/radian and was strongly correlated (r = 0.85) with upper arm volume, allowing us to define a "normal" range for stiffness when corrected for arm volume. In addition, the angle of the elbow with the arm fully relaxed and no external torque applied ("neutral" angle) was found to be 107 degrees +/- 10 degrees. Thus, we have quantified resting stiffness or "tone" in the arm and provided normal data for comparison with patients with pathophysiological conditions such as rigidity or spasticity.
Adult↗
Elastic properties of muscles measured at the elbow in man: II. Patients with parkinsonian rigidity.
A method is described to measure reproducibly stiffness, and therefore "tone", at the elbow of patients with Parkinson's disease using a torque motor. In Parkinsonian versus normal patients (previously reported) it was observed that: the neutral angle in Parkinson's disease patients was significantly smaller (92 degrees +/- 15 degrees) than in normals (107 degrees +/- 10 degrees), and in Parkinson's disease patients, even with relatively mild symptoms, the upper limb was stiffer than normals in the totally relaxed state with no electromyographic activity present. Our results suggest that changes in the passive mechanical properties of the upper limb affected by Parkinsonian rigidity may have taken place, accounting for the more flexed neutral elbow angle and greater passive stiffness. Using this technique, response to antirigidity therapy and natural progression of illness can be quantitatively assessed and followed.
Aged↗
Myocardial mechanics in allylamine-induced myocardial fibrosis.
To examine the effect of fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 18 rats given 0.1% allylamine, an agent known to cause myocardial fibrosis, in drinking water for 4-8 wk. Six control rats were given tap water. Left ventricular hydroxyproline concentration was higher in the allylamine-treated group [3.47 +/- 2.12 vs. 2.10 +/- 0.66 (SD) micrograms/mg dry wt; P less than 0.01]. Because of variable and heterogeneous involvement of the ventricle by fibrosis, preparations from allylamine-fed rats were divided into two subgroups; data from four papillary muscles with more than 25% fibrosis by point counting (AL-B group) were compared with eight control muscles from nonallylamine-treated rats. A third subgroup of nine muscles from allylamine-treated rats but with normal left ventricular hydroxyproline concentration and fibrosis as determined by point counting served as another control group (AL-A) for the evaluation of effects of allylamine not due to fibrosis. Myocardial fiber diameters of AL-B preparations were significantly larger than other groups (controls, 12.1 +/- 1.7 microns; AL-A group, 12.7 +/- 1.7 microns; AL-B group, 18.0 +/- 1.2 microns; P less than 0.01). Passive and active stiffness constants in AL-B muscles were significantly increased compared with control and AL-A preparations (P less than 0.05). Electromechanical delay plus time to peak tension and the time for tension to fall from its peak to one-half of that value at the peak of the length-tension curve were significantly prolonged in AL-B muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
Allylamine↗
Effects of hypertrophy and allylamine-induced fibrosis on mechanical properties of isolated rat heart muscles with references to the pumping function of the intact heart in the same models.
To examine the effects of hypertrophy and fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 6-month-old male SHR and allylamine-fed rats. In SHR, the peak developed tension (DT) and the maximum rate of tension development (dT/dt) were higher compared to control male Wistar-Kyoto rats (WKY). With 15 min of hypoxia, the DT and the dT/dt declined similarly in both groups and the ratios of DT and dT/dt to their prehypoxic values after 15 min of hypoxia were not different in the two groups. From allylamine-fed rats, only 4 papillary muscles had more than 25% interstitial fibrosis by point-counting (AL-B group), but 9 muscles had no fibrotic involvement and their left ventricular hydroxyproline concentration was normal (AL-A group). The myocardial diameters, the passive stiffness constant and the duration of isometric contractions at Lmax were increased in AL-B group, but the resting tension, the DT at Lmax and the force-velocity relations did not differ from controls. The mechanical properties of the AL-A group muscles were not different from controls. However, when pumping function was examined in the intact heart from the AL-A group, the LVEDP was increased and the peak cardiac output normalized by body weight was decreased. Thus, hypertrophied muscle from SHR shows hyperfunction without an increase in susceptibility to hypoxic stress. Even if fibrosis progresses, hypertrophy can compensate for the reduction in contractile component up to a certain degree.(ABSTRACT TRUNCATED AT 250 WORDS)
Allylamine↗