Influence of static magnetic fields on pain perception and sympathetic nerve activity in humans.

Static and pulsed magnetic fields have been reported to have a variety of physiological effects. However, the effect of static magnetic fields on pain perception and sympathetic function is equivocal. To address this question, we measured pain perception during reproducible noxious stimuli during acute exposure to static magnets. Pain perception, muscle sympathetic nerve activity, mean arterial pressure, heart rate, and forearm blood velocity were measured during rest, isometric handgrip, postexercise muscle ischemia, and cold pressor test during magnet and placebo exposure in 15 subjects (25 +/- 1 yr; 8 men and 7 women) following 1 h of exposure. During magnet exposure, subjects were placed on a mattress with 95 evenly spaced 0.06-T magnets imbedded in it. During placebo exposure, subjects were placed on an identical mattress without magnets. The order of the two exposure conditions was randomized. At rest, no significant differences were noted in muscle sympathetic nerve activity (8 +/- 1 and 7 +/- 1 bursts/min for magnet and placebo, respectively), mean arterial pressure (91 +/- 3 and 93 +/- 3 mmHg), heart rate (63 +/- 2 and 62 +/- 2 beats/min), and forearm blood velocity (3.0 +/- 0.3 and 2.6 +/- 0.3 cm/s). Magnets did not alter pain perception during the three stimuli. During all interventions, no significant differences between exposure conditions were found in muscle sympathetic nerve activity and hemodynamic measurements. These results indicate that acute exposure to static magnetic fields does not alter pain perception, sympathetic function, and hemodynamics at rest or during noxious stimuli.     

Modulation of skin sensitivity by dynamic and isometric exercise in man

The effect of dynamic cycle ergometer exercise and isometric leg exercise on skin sensitivity was studied in man. Exercise was performed at different loads. Cutaneous sensitivity to innocuous and noxious thermal stimuli was tested using a contact thermostimulator and sensitivity to tactile stimuli was tested using electrical stimuli. During isometric exercise a segmental (the exercising limb), but not a multisegmental, phasic decrease of cutaneous thermal sensitivity to innocuous stimuli was found. At the isometric forces used the effect on tactile and heat pain sensitivity was not significant. During dynamic exercise a multisegmental, load-dependent decrease of sensitivity in all tested sensory modalities was found and this attenuation disappeared gradually after the end of exercise. In contrast to isometric exercise, the decrease of sensitivity produced by dynamic exercise was most evident in tactile sensitivity. The size of the stimulus area (7.9 vs 11.8 cm2) did not have a significant effect on the magnitude of the exercise-induced decrease of cutaneous thermal sensitivity to innocuous stimuli. It was concluded that underlying the modulation of skin sensitivity by dynamic and isometric exercise were mechanisms that were different, at least to a small extent. Isometric exercise produced a segmental modulation of skin sensitivity due to central neuronal mechanisms, independent of exercise-induced stress. Exercise-induced stress could have caused the modulation of skin sensitivity by dynamic exercise.     

An evaluation of analgesia associated with the immobility response in laboratory rabbits

The immobility response (IR) was studied in rabbits to evaluate its analgesic properties and reliability as a method of restraint. The participation of the endogenous opioid system in IR was studied indirectly by evaluating the effects of the narcotic antagonist naloxone on this phenomenon. Twenty-four adult New Zealand White rabbits were subjected to six noxious stimuli while restrained by IR and while restrained under control conditions. Testing on each animal was repeated under both conditions following the administration of naloxone. The noxious stimuli consisted of three levels of electric shock (10 volts, 30 volts, and 50 volts) applied to the shaved forearm, and mechanical pressure applied to the pinna, front toe, and hind toe. Withdrawal and changes in blood pressure, heart rate, and respiration were used as indicators of pain perception. Distress associated with noxious electrical and pressure stimulation was significantly reduced by IR, which suggested that the phenomenon does have a significant analgesic component. However, the rabbits showed wide variability in their susceptibility to IR induction, and even animals which did not withdraw in response to noxious stimulation under IR sometimes exhibited physiological changes suggestive of distress. Therefore, IR should not be considered as a reliable or humane alternative to analgesic/anesthetic drugs for laboratory rabbits. Naloxone had little effect on IR or IR-associated analgesia.     

Convergence of nociceptive information from temporomandibular joint and tooth pulp afferents on C1 spinal neurons in the rat

The aim of the present study was to test the hypothesis that there is a convergence of afferent inputs from the temporomandibular joint (TMJ) on C1 spinal neurons responding to electrical stimulation of the tooth pulp (TP). In 14 pentobarbital anesthetized rats, the extracellular single unit activity of 31 C1 spinal neurons and the amplitude in a digastric muscle electromyogram (n = 31) increased proportionally during 1.0-3.5 times the threshold for the jaw-opening reflex (JOR). Of 31 C1 spinal neurons responsive to TP afferents, 28 (approximately 90%) were also excited by electrical stimulation of the ipsilateral TMJ capsule. All neurons tested were divided into three categories of nociceptive specific, wide dynamic range and non-responsive as to their responsiveness to mechanical stimuli (pin prick and touch) of the somatic receptive field (skin of the face, neck, jaw and upper forearm) and TMJ capsule. Nineteen (68%) of 28 C1 spinal neurons received nociceptive information from C fibers of the TMJ capsule. These results suggest that there is a convergence of noxious information from the TMJ and TP afferents on the same C1 spinal neurons, which importantly contribute to pain perception from the TMJ region.     

Isoflurane anesthesia blunts cerebral responses to noxious and innocuous stimuli: a fMRI study

We used functional magnetic resonance imaging to determine how isoflurane affected cerebral neuronal activation resulting from noxious and innocuous stimuli. Five male volunteers were subjected to mild electrical shock and tactile stimuli applied to the hand. During low (0.7%) and moderate (1.3%) isoflurane anesthesia the stimuli were repeated and a supramaximal electrical shock was also applied. Tactile stimulation activated bilateral SI and SII, but resulted in no significant activation at low or moderate anesthesia. Electrical shock activated contralateral SI and bilateral SII; low anesthesia completely abolished this response. The supramaximal stimulus activated the caudate nucleus and bilateral thalamus at low anesthesia; these responses were diminished at moderate anesthesia. Isoflurane anesthesia blunts cerebral responses to somatosensory stimuli, and the absence of cortical activation during supramaximal stimulation suggests that noxious-induced movement is generated in lower CNS structures.     

The Sensory Effects of l-Menthol on Human Skin

Psychophysical measurements were made of the sensory effects of l-menthol applied topically to the forearm under controlled thermal conditions. In the first experiment, subjects judged the intensity and quality of sensations produced by warming or cooling the skin in the presence of menthol or the vehicle. During cooling, menthol intensified cutaneous sensations and increased reports of burning. During warming, menthol intensified sensations transiently at low temperatures and weakened them lastingly at higher temperatures; the frequency of reports of burning varied with intensity. A second experiment tested the hypothesis that menthol would lower the threshold for warmth and raise the threshold for heat pain. No change in either threshold was observed. The primary sensory effects of l-menthol on hairy skin are therefore to heighten the perception of cooling and to attenuate the perception of moderate warming. In contrast with other common chemical irritants, menthol's pungent qualities appear to be enhanced by cooling and suppressed by warming; this suggests that its sensory irritancy may be attributable to the stimulation of a population of high-threshold cold fibers or cold-sensitive nociceptors.     

Does EEG activity during painful stimulation mirror more closely the noxious stimulus intensity or the subjective pain sensation?

Abstract

Background: Many researchers have tried to investigate pain by studying brain responses. One method used to investigate pain-related brain responses is continuous electroencephalography (EEG). The objective of the current study is to add on to our understanding of EEG responses during pain, by differentiation between EEG patterns indicative of (i) the noxious stimulus intensity and (ii) the subjective pain sensation.

Methods: EEG was recorded during the administration of tonic experimental pain, consisting of six minutes of contact heat applied to the leg via a thermode. Two stimuli above pain threshold, one at pain threshold and two non-painful stimuli were administered. Thirty-six healthy participants provided a subjective pain rating during thermal stimulation. Relative EEG power was calculated for the frequency bands alpha1, alpha2, beta1, beta2, delta, and theta.

Results: Whereas EEG activity could not be predicted by stimulus intensity (except in one frequency band), subjective pain sensation could significantly predict differences in EEG activity in several frequency bands. An increase in the subjective pain sensation was associated with a decrease in alpha2, beta1, beta2 as well as in theta activity across the midline electrodes.

Conclusion: The subjective experience of pain seems to capture unique variance in EEG activity above and beyond what is captured by noxious stimulus intensity.     

Transcranial Direct Current Stimulation Improves Ipsilateral Selective Muscle Activation in a Frequency Dependent Manner

Failure to suppress antagonist muscles can lead to movement dysfunction, such as the abnormal muscle synergies often seen in the upper limb after stroke. A neurophysiological surrogate of upper limb synergies, the selectivity ratio (SR), can be determined from the ratio of biceps brachii (BB) motor evoked potentials to transcranial magnetic stimulation prior to forearm pronation versus elbow flexion. Surprisingly, cathodal transcranial direct current stimulation (c-TDCS) over ipsilateral primary motor cortex (M1) reduces (i.e. improves) the SR in healthy adults, and chronic stroke patients. The ability to suppress antagonist muscles may be exacerbated at high movement rates. The aim of the present study was to investigate whether the selective muscle activation of the biceps brachii (BB) is dependent on altering frequency demands, and whether the c-tDCS improvement of SR is dependent on task frequency. Seventeen healthy participants performed repetitive isometric elbow flexion and forearm pronation at three rates, before and after c-tDCS or sham delivered to ipsilateral left M1. Ipsilateral c-tDCS improved the SR in a frequency dependent manner by selectively suppressing BB antagonist excitability. Our findings confirm that c-tDCS is an effective tool for improving selective muscle activation, and provide novel evidence for its efficacy at rates of movement where it is most likely to benefit task performance.     

Theta Burst Stimulation Applied over Primary Motor and Somatosensory Cortices Produces Analgesia Unrelated to the Changes in Nociceptive Event-Related Potentials

Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO₂ laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.     

Convergence of nociceptive information on the parabrachio-amygdala neurons in the rat

Neurones were recorded with extracellular micropipettes, in the parabrachial area located in the dorsolateral region of the pons of anaesthetized rats. All the neurones were identified by antidromic stimulation from the nucleus centralis of the amygdala. Numerous parabrachio-amygdala neurones (70%) were exclusively affected by noxious stimuli applied to several areas of the body. The rest of the neurones (30%) were not activated by any of these stimuli. The "nociceptive" neurones were classified in two groups: the neurones in the first group ("specific nociceptive", 55% of the whole population), responded to mechanical nociceptive and thermal nociceptive stimulation (threshold greater than 44 degrees C), with a strong and sustained activation. The neurones in the second group (15% of the whole population) responded by a strong inhibition to the nociceptive stimulation. Transcutaneous electrical stimulation demonstrated that the specific nociceptive parabrachial neurones received messages from A delta and C fibres. These results demonstrate that a spino-(trigemino)-ponto-amygdala nociceptive pathway exists which could be implicated in the emotional responses to noxious events.     

Afferent Modulation of Warmth Sensation and Heat Pain in the Human Hand

The hands of 14 normal humans were used to determine the somatotopic organization of the modulation of warmth sensation and heat pain by different forms of cutaneous stimuli. Test stimuli were 5-sec heat pulses ranging from 36° to 51°C, delivered to the fingerpads of digits 1, 2, 4, and 5 with a contact thermode. Conditioning stimuli (15 sec) bracketed the test stimuli and included vibration, noxious and innocuous heat, cold, and electrical pulses delivered to the fingerpads of digits that were adjacent or nonadjacent to the tested digits. Noxious (48° ± 1.3°C), but not innocuous (43°C), heat stimuli increased the perceived magnitude estimation of innocuous test stimuli (36–43°C) by 20–37% when delivered to adjacent, but not to nonadjacent, digits. No other conditioning stimuli had any effect on the intensity of warmth perception. In contrast, both noxious and innocuous heat or electrical conditioning reduced the magnitude estimation of noxious (50–5°C), but not innocuous, test pulses by 12–22% when delivered to adjacent digits. Conditioning of nonadjacent digits was significantly less effective. The analgesic effects of noxious and innocuous conditioning were approximately equal. Vibratory (120 Hz, 3.5 μm) and cold (15°C) conditioning stimuli were ineffective. The results are consistent with a dermatomal somatotopic organization of tactile and heat modulatory influences on warmth sensation and heat pain. The results further suggest that the neural mechanisms subserving warmth mediate a negative feedback influence on heat pain intensity.     

Supraspinal fatigue during intermittent maximal voluntary contractions of the human elbow flexors.

Responses to transcranial magnetic stimulation in human subjects (n = 9) were studied during series of intermittent isometric maximal voluntary contractions (MVCs) of the elbow. Stimuli were given during MVCs in four fatigue protocols with different duty cycles. As maximal voluntary torque fell during each protocol, the torque increment evoked by cortical stimulation increased from approximately 1.5 to 7% of ongoing torque. Thus "supraspinal" fatigue developed in each protocol. The motor evoked potential (MEP) and silent period in the elbow flexor muscles also changed. The silent period lengthened by 20-75 ms (lowest to highest duty cycle protocol) and recovered significantly with a 5-s rest. The MEP increased in area by >50% in all protocols and recovered significantly with 10 s, but not 5 s, of rest. These changes are similar to those during sustained MVC. The central fatigue demonstrated by the torque increments evoked by the stimuli did not parallel the changes in the electromyogram responses. This suggests that part of the fatigue developed during intermittent exercise is "upstream" of the motor cortex.     

Anticipatory postural adjustment in bimanual unloading: role of the motor cortex in motor learning

The role of the motor cortex was investigated during learning unusual postural adjustment. Healthy subjects held their right (postural) forearm in a horizontal position while supporting a 1-kG load via an electromagnet. The postural forearm position was perturbed by the load release triggered by other elbow voluntary movement. Repetition of the imposed unloading test resulted in a progressive reduction of the maximal forearm rotation, accompanied by the anticipatory decrease in m. biceps brachii activity (learning). Control situation consisted of the voluntary forearm loading. Using the transcranial magnetic stimulation we examined changes in the motor evoked potential of the m. biceps brahii at the beginning and at the end of learning. The evoked potential amplitude did not significantly change in process of the decrease of m. biceps brachii activity. At the end of learning, motor evoked potential / baseline electromyogram ratio increased as compared to the beginning of learning and to the control situation. The results highlight the fundamental role of the motor cortex in suppression of synergies which interfere with formation of a new coordination during motor learning.     

急性神经损伤引起脊髓背角C-纤维诱发电位长时程增强

神经损伤引起神经病性疼痛,表现为持续性痛超敏和痛觉过敏。目前对神经病性疼痛的机制尚缺乏了解。我们以往的工作表明强直电刺激坐骨神经可引起脊髓背角C-纤维诱发电位的长时程增强(long-term potentiation,LTP),该LTP被认为是病理性疼痛的突触模型。本研究的目的在于探讨急性神经损伤是否能在完整动物的脊髓背角诱发出C-纤维诱发电位LTP。在以测试刺激(10～20V,0．5ms)电刺激坐骨神经的同时在脊髓背角用微电极记录C一纤维诱发电位。分别用强直刺激、剪断或夹捏坐骨神经诱导LTP。结果发现：(1)剪断或夹捏坐骨神经都可以诱导脊髓背角C-纤维诱发电位的LTP,该LTP可持续到实验结束(3～9h),在剪断神经前10min用利多卡因局部阻滞坐骨神经则可完全阻断LTP的产生;(2)神经损伤诱导的LTP可被NMDA受体阻断剂AP5所阻断;(3)用单次强直刺激引起LTP后,切断坐骨神经可使LTP的幅度进一步增大,而用多次强直电刺激使LTP饱和后,损伤神经则不能使LTP进一步增大。切断神经引起LTP后,强直电刺激也不能使LTP进一步增大。这些结果表明,急性神经损伤可以诱导脊髓背角C纤维诱发电位LTP,且切断神经能更有效地诱导LTP。该试验进一步支持我们的设想,即脊髓背角C-纤维诱发电位LTP可能在病理性疼痛的形成中起重要作用。     

The effects of repetitive contractions and ischemia on the ability to discriminate intramuscular sensation

In order to investigate whether repetitive, low-level, muscular contractions or ischemia affect the ability of subjects to discriminate electrical stimuli delivered to the forearm musculature, a total of 25 experiments was performed on a group of five healthy subjects utilizing signal detection methodology. EMG needle electrodes were inserted into the forearm extensor musculature and the discriminability of two different pairs of constant current electrical stimuli were measured for sequential blocks of 100 trials, before and after the experimental interventions. Repetitive muscular activity consisting of a 15-min typing intervention at a rate of 60-80 wpm using a numeric keypad led to a significant decrease in the ability to discriminate the non-noxious stimulus pair in the block of trials immediately following the typing intervention, which then returned to pre-intervention discrimination levels following a 5-min break. The forearm ischemia significantly impaired the ability to discriminate both the noxious and non-noxious stimulus pair in the blocks of trials during and immediately after ischemia, which then returned to pre-intervention discrimination levels following a 5-min break. These experiments demonstrate that both repetitive muscular activity and ischemia acutely decrease the ability to discriminate intramuscular sensation. The mechanism may be due to decreased cortical processing, spinal cord sensitization or peripheral ischemia of large diameter afferents. These findings may be relevant to the physiological mechanisms underlying the development of overuse injuries.     

Effect of chronic intermittent exposure to AM radiofrequency field on responses to various types of noxious stimuli in growing rats

There are several reports of altered pain sensation after exposure (from a few minutes to hours in single or repeated doses for 2-3 weeks) to electromagnetic fields (EMF) in adults. The commonly utilized noxious stimulus is radiant heat. The nociceptive responses are known to be influenced by characteristics of stimulus, organism, and environment. We studied the pattern of nociceptive responses to various noxious stimuli in growing rats exposed to radiofrequency field (73.5 MHz amplitude modulated, 16 Hz power density 1.33 mw/cm(2), SAR = 0.4 w/kg) for 45 d (2 h/d). Threshold current for stimulation of nociceptive afferents to mediate motor response of tail (TF), vocalization during stimulus (VD), and vocalization after discharge (VA); the withdrawal latency of tail (TFL) and hind paw (HPL) to thermal noxious stimulus and tonic pain responses were recorded in every rat. The TFL was not affected, HPL was decreased (p < 0.01), and the thresholds of TF and VD were not affected, while, that of VA was significantly decreased. The tonic pain rating was decreased (p < 0.01). A decrease in the threshold of VA (p < 0.01) is indicative of an increase in the emotional component of the response to the phasic pain, whereas a decrease in the pain rating indicates analgesia in response to the tonic pain. The results of our study suggest that chronic (45 d), intermittent (2 h/d) amplitude modulated RF field exposure to the peripubertal rat increases the emotional component of phasic pain over a basal eaualgesic state, while late response to tonic pain is decreased. The data suggest that amplitude modulated RF field differentially affects the mechanisms involved in the processing of various noxious stimuli.     

Sustained contraction at very low forces produces prominent supraspinal fatigue in human elbow flexor muscles.

During sustained maximal voluntary contractions (MVCs), most fatigue occurs within the muscle, but some occurs because voluntary activation of the muscle declines (central fatigue), and some of this reflects suboptimal output from the motor cortex (supraspinal fatigue). This study examines whether supraspinal fatigue occurs during a sustained submaximal contraction of 5% MVC. Eight subjects sustained an isometric elbow flexion of 5% MVC for 70 min. Brief MVCs were performed every 3 min, with stimulation of the motor point, motor cortex, and brachial plexus. Perceived effort and pain, elbow flexion torque, and surface EMGs from biceps and brachioradialis were recorded. During the sustained 5% contraction, perceived effort increased from 0.5 to 3.9 (out of 10), and elbow flexor EMG increased steadily by approximately 60-80%. Torque during brief MVCs fell to 72% of control values, while both the resting twitch and EMG declined progressively. Thus the sustained weak contraction caused fatigue, some of which was due to peripheral mechanisms. Voluntary activation measured by motor point and motor cortex stimulation methods fell to 90% and 80%, respectively. Thus some of the fatigue was central. Calculations based on the fall in voluntary activation measured with cortical stimulation indicate that about two-thirds of the fatigue was due to supraspinal mechanisms. Therefore, sustained performance of a very low-force contraction produces a progressive inability to drive the motor cortex optimally during brief MVCs. The effect of central fatigue on performance of the weak contraction is less clear, but it may contribute to the increase in perceived effort.     

Effect of experimental muscle pain on maximal voluntary activation of human biceps brachii muscle

Muscle pain has widespread effects on motor performance, but the effect of pain on voluntary activation, which is the level of neural drive to contracting muscle, is not known. To determine whether induced muscle pain reduces voluntary activation during maximal voluntary contractions, voluntary activation of elbow flexors was assessed with both motor-point stimulation and transcranial magnetic stimulation over the motor cortex. In addition, we performed a psychophysical experiment to investigate the effect of induced muscle pain across a wide range of submaximal efforts (5-75% maximum). In all studies, elbow flexion torque was recorded before, during, and after experimental muscle pain by injection of 1 ml of 5% hypertonic saline into biceps. Injection of hypertonic saline evoked deep pain in the muscle (pain rating ～5 on a scale from 0 to 10). Experimental muscle pain caused a small (～5%) but significant reduction of maximal voluntary torque in the motor-point and motor cortical studies (P < 0.001 and P = 0.045, respectively; n = 7). By contrast, experimental muscle pain had no significant effect on voluntary activation when assessed with motor-point and motor cortical stimulation although voluntary activation tested with motor-point stimulation was reduced by ～2% in contractions after pain had resolved (P = 0.003). Furthermore, induced muscle pain had no significant effect on torque output during submaximal efforts (P > 0.05; n = 6), which suggests that muscle pain did not alter the relationship between the sense of effort and production of voluntary torque. Hence, the present study suggests that transient experimental muscle pain in biceps brachii has a limited effect on central motor pathways.     

Skin potential and EMG changes induced by cutaneous electrical stimulation. I. Normal man in arousing and non-arousing environment.

Skin potential and EMG responses induced in normal man by electrical stimuli applied to the skin were recorded in the four limbs in order to study somato-sympathetic and somato-motor reflexes. Different patterns of responses were observed in different conditions: alarm, habituation, sensitization and arousal. During alarm, sensitization and arousal, the responses were present in the four limbs; during habituation, the responses were only present in the stimulated and in the contralateral limb. Three sensory thresholds to cutaneous electrical stimulation were identified in habituated subjects: tactile, tingling and pain. Cutaneous and EMG responses appeared at tingling threshold. A relationship between skin potential level and skin potential response was observed.     

Excessive reflexes in spinal cord injury triggered by electrical stimulation

Interaction of electrocutaneous stimulation with an impaired human motor control system may result in unstable reflex loops causing excessive spastic reactions. These contractions are usually excluded from analysis since the presence of spasm is one of the criteria commonly applied for discarding a contraction. They may, however, provide interesting information on the nature of spasticity. The dorsiflexor muscles of four SCI subjects were activated by means of surface electrical stimulation and the isometric ankle moment was measured. Short bursts of constant stimulation frequency at seven different frequencies (8, 12, 16, 20, 25, 33, 50 Hz) triggered spastic reactions in all subjects. The onset times of spastic activity during an electrically elicited contraction shortened with increased stimulation frequency. A stimulation burst may also have a spasticity reduction effect on a subsequent burst, indicating potential short term therapeutic effects of stimulation on spasticity in isometric conditions.