chronic pain syndromes [35]. Our previous studies did not find any increase in static stretch sensitivity of muscle spindles; rather, the overall discharge rate actually decreased during muscle pain by 6%, but remained essentially the same during skin pain [16]. Irrespective of the type of pain, discharge variability parameters were not influenced. In that study, we concluded that, contrary to the ‘‘vicious cycle’’ hypothesis [35], acute activation of muscle or cutaneous nociceptors does not cause a reflex increase in static fusimotor drive in humans. Analyses of pulse wave modulation during acute experimental pain may provide valuable additional information: it would disclose any changes in dynamic fusimotor drive which were not specifically addressed in our previous study, partly because we wanted to avoid any subtle mechanical effects due to repetitive muscle stretching. Changes in fusimotor activity may have significant consequenc- es on proprioceptive acuity [36,37,38]. Similarly, changes in pulse wave modulation may have physiological consequences: firstly, it may be regarded as a change in noise level, and, secondly, such modulation may cause population-wide synchronised fluctuations of discharge rate, thereby affecting the excitability of, for example, the alpha motoneurone pool. Nevertheless, no changes were observed: pulse wave modulation of muscle spindle discharge did not change during nociceptive stimulation, indicating that the level of dynamic gamma-motor drive was not changed. We conclude that, while our previous study did not find any changes in muscle spindle static sensitivity, the current study indicates that dynamic sensitivity was also unchanged. Does pulse wave modulation influence muscle spindle function? Effects on muscle spindle population input. It was important to find out whether cardiac rhythmicity is also present during active contractions. One might expect this to be the case, given that gamma-motor activity increases the stretch sensitivity of muscle spindles. However, it should also be acknowledged that the profound variability of muscle spindle discharge during voluntary muscle contraction could mask this effect. We performed analyses on muscle spindle afferents that showed no spontaneous activity, but became activated during homonymous muscle contraction due to gamma-motor co-activation. Our results showed that arterial pulsations could be easily detected during voluntary muscle contraction and the size of the modulation relative to the mean discharge rate was comparable to that found during static stretch. Concurrent modulation of muscle spindle response by the same source in theory may be responsible for low-frequency oscillations in alpha motoneurone excitability. However, detailed analyses of the envelope of the modulatory effect revealed that there was a similar number of muscle spindles that were either excited or inhibited by the arterial pulse wave. This implies that, after signal integration at the population level, arterial pulsations of opposite polarity would largely cancel each other out. This important functional effect has been previously overlooked and therefore cardiac modulation was assumed to have a detrimental effect on the signalling capacity of muscle spindles. In contrast, our results indicate that the effect of cardiac pulsations on the population response of muscle spindles is rather limited. Detection thresholds of single muscle spindle afferents. Fusimotor activation is the key factor regulating the sensitivity and dynamic range of muscle spindle operation [39], however, for detection of very weak stimuli this mechanism may not be always efficient because weak activation and twitches of intrafusal muscle fibres below their fusion frequency generate twitch induced spiking activity that may mask the effects of very weak stimuli. However, more subtle fusimotor related Modulation of Human Muscle Spindle Discharge enhancement of muscle spindle afferent sensitivity, which is more likely to facilitate the detection of weak stimuli, are known as fusimotor after-effects [40–42]. The advantage of this mechanism is that it can increase sensitivity of muscle spindle endings in the absence of noise inducing fusimotor contraction. We would like to consider another hypothetical mechanisms as to how the detection of weak stimuli can be enhanced while avoiding the adverse effect of intrafusal muscle fibre twitches. The increase of the probability of spike generation around the peak of systolic blood pressure acts as source of fluctuations, or endogenous noise source, that may facilitate the detection of stimuli that are close to threshold [11]. The underlying principle that noise could be beneficial for signal detection bears some similarity with the mechanism of stochastic resonance, which has been described for muscle spindles [43] and other types of mechanoreceptors [44,45]. Sub-threshold signals in sensory afferents, by definition, have no effect on the output of the system, while noise can have an additive effect to the stimulus and cause subthreshold inputs to reach detection threshold. Obviously, the likelihood of this happening is higher the closer the inputs are to the threshold. Unlike high frequency stochastic noise, arterial pulsations have long well-defined period lengths that are synchronised across the whole muscle spindle population. Thus, any physiological effect mediated by arterial pulsations could be even more prominent because the probability of spike generation in response to subthreshold stimuli is increased in all excited afferents at the same time. Such a synchronised barrage of spikes generated in the population of afferents will significantly improve integration of weak inputs at the postsynaptic membrane of the 2nd order neurones. Input from muscle spindle afferents is known to converge in large numbers on the same motor neurone [46]; it has also been suggested that multiple simultaneous muscle spindle activation is required to evoke conscious sensation [47]. Thus, single spikes generated in a population of muscle spindles at random times may be too weak to be detected and to initiate any response, while spikes generated by a group of afferents at about the same time may depolarise the postsynaptic membrane and evoke a strong response also with relatively weak stimuli. To obtain physiological evidence for this, admittedly speculative, hypothesis is certainly beyond the scope of this study. We anticipate that this will give encouragement for future studies to assess the functional relevance of this hypothetical mechanism experimentally. Conclusions We have shown that arterial pulsations have a significant effect on the output of more than 60% of muscle spindle afferents by periodically changing the spike timing or discharge rate. The discharge of these afferents was either completely driven by, phase- locked to, or modulated by the arterial pulsation. It is not unreasonable to expect that such considerable modulatory effects (.10% of discharge rate at the peak) may influence proprioceptive accuracy and that those effects themselves may be influenced by physiological changes in blood pressure or blood flow. However, we found no evidence that the magnitude of the physiological noise induced by arterial pulsations was affected by any of the experimentally induced conditions affecting blood pressure and muscle sympathetic nerve activity. With respect to pain, this lack of effect on magnitude of modulation also indicates that there was no activation of dynamic fusimotor drive by nociceptive reflexes. That both positive and negative modulatory effects were observed in ongoing muscle spindle responses suggests that after signal integration at the population level the opposite sign effects of modulation may at least partly cancel each other out. On the other PLoS ONE | www.plosone.org 12 April 2012 | Volume 7 | Issue 4 | e35091