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1.  The Influence of Pain on Masseter Spindle Afferent Discharge 
Archives of oral biology  2006;52(4):387-390.
Muscle spindles provide proprioceptive feedback supporting normal patterns of motor activity and kinesthetic sensibility. During mastication, jaw muscle spindles play an important role in monitoring and regulating the chewing cycle and the bite forces generated during mastication. Both acute and chronic orofacial pain disorders are associated with changes in proprioceptive feedback and motor function. Experimental jaw muscle pain also alters the normal response of masseter spindle afferents to ramp and hold jaw movements [1]. It has been proposed that altered motor function and proprioceptive input results from group III muscle afferent modulation of the fusimotor system which alters spindle afferent sensitivity in limb muscles[2]. The response to nociceptive stimuli may enhance or reduce the response of spindle afferents to proprioceptive stimuli. Several experimental observations suggesting the possibility that a similar mechanism also functions in jaw muscles are presented in this report. First, evidence is provided to show that nociceptive stimulation of the masseter muscle primarily influences the amplitude sensitivity of spindle afferents with relatively little effect on the dynamic sensitivity [3]. Second, reversible inactivation of the caudal trigeminal nuclei attenuates the nociceptive modulation of spindle afferents. Finally, functionally identified gamma-motoneurons in the trigeminal motor nucleus are modulated by intramuscular injection with algesic substances. Taken together, these results suggest that pain-induced modulation of spindle afferent responses are mediated by small diameter muscle afferents and that this modulation is dependent, in part, on the relay of muscle nociceptive information from trigeminal subnucleus caudalis onto trigeminal gamma-motoneurons. The implication of these results will be considered in light of current theories on the relationship between jaw muscle pain and oral motor function.
PMCID: PMC1868482  PMID: 17126284
Muscle spindle afferents; Masseter muscle; Pain; Proprioception; Rats
Background Context
Spinal manipulation (SM) is a form of manual therapy used clinically to treat patients with low back and neck pain. The most common form of this maneuver is characterized as a high velocity (duration < 150ms), low amplitude (segmental translation < 2mm, rotation < 4°, and applied force 220-889N) impulse thrust (HVLA-SM). Clinical skill in applying an HVLA-SM lies in the practitioner's ability to control the duration and magnitude of the load (i.e., the rate of loading), the direction in which the load is applied, and the contact point at which the load is applied. Control over its mechanical delivery presumably related to its clinical effects. Biomechanical changes evoked by an HVLA-SM are thought to have physiological consequences caused, at least in part, by changes in sensory signaling from paraspinal tissues.
If activation of afferent pathways does contribute to the effects of an HVLA-SM, it seems reasonable to anticipate that neural discharge might increase or decrease in a non-linear fashion as the thrust duration thrust approaches a threshold value. We hypothesized that the relationship between the duration of an impulsive thrust to a vertebra and paraspinal muscle spindle discharge would be non-linear with an inflection near the duration of an HVLA-SM delivered clinically (<150ms). In addition, we anticipated that muscle spindle discharge would be more sensitive to larger amplitude thrusts.
Study Design/Setting
A neurophysiological study of spinal manipulation using the lumbar spine of a feline model.
Impulse thrusts (duration: 12.5, 25, 50, 100, 200, and 400 ms; amplitude 1 or 2mm posterior to anterior) were applied to the spinous process of the L6 vertebra of deeply anesthetized cats while recording single unit activity from dorsal root filaments of muscle spindle afferents innervating the lumbar paraspinal muscles. A feedback motor was used in displacement control mode to deliver the impulse thrusts. The motor's drive arm was securely attached to the L6 spinous process via a forceps.
As thrust duration became shorter the discharge of the lumbar paraspinal muscle spindles increased in a curvilinear fashion. A concave up inflection occurred near the 100ms duration eliciting both a higher frequency discharge compared to the longer durations and a substantially faster rate of change as thrust duration was shortened. This pattern was evident in paraspinal afferents with receptive fields both close and far from the midline. Paradoxically, spindle afferents were almost twice as sensitive to the 1mm compared to the 2mm amplitude thrust (6.2 vs 3.3 spikes/s/mm/s). This latter finding may be related to the small vs large signal range properties of muscle spindles.
. The results indicate that the duration and amplitude of a spinal manipulation elicits a pattern of discharge from paraspinal muscle spindles different from slower mechanical inputs. Clinically, these parameters may be important determinants of an HVLA-SM's therapeutic benefit.
PMCID: PMC2075482  PMID: 17905321
lumbar spine; spinal manipulation; chiropractic; osteopathy; paraspinal muscles; muscle spindle
3.  Muscle afferent potential (`A-wave') in the surface electromyogram of a phasic stretch reflex in normal humans 
The experiments reported in this paper tested the hypothesis that the afferent potential elicited by a tendon tap in an isometrically recorded phasic stretch reflex can be detected in the surface EMG of normal humans when appropriate techniques are used. These techniques involved (1) training the subjects to relax mentally and physically so that the EMG was silent before and immediately after the diphasic MAP which reflects a highly synchronous discharge of afferent impulses from low threshold muscle stretch receptors after a tendon tap, and (2) using a data retrieval computer to summate stimulus-locked potentials in the EMG over a series of 16 samples using taps of uniform peak force and duration on the Achilles tendon to elicit the tendon jerk in the calf muscles. A discrete, diphasic potential (`A-wave') was recorded from EMG electrodes placed on the surface of the skin over the medial gastrocnemius muscle. The `A-wave' afferent potential had the opposite polarity to the corresponding efferent MAP. Under control conditions of relaxation the `A-wave' had a latency after the onset of the tap of 2 msec, the peak to peak amplitude was of the order of 5 μV and the duration was in the range of 6 to 10 msec. Further experiments were conducted to show that the `A-wave' (1) was not an artefact of the instrumentation used, (2) had a threshold at low intensities of stimulation, and (3) could be reliably augmented by using a Jendrassik manoeuvre compared with the potential observed during control (relaxation) conditions. The results support the conclusion that the `A-wave' emanates from the pool of muscle spindles which discharges impulses along group Ia nerve fibres in response to the phasic stretch stimulus because the primary ending of the spindles is known to initiate the stretch reflex and the spindles can be sensitized by fusimotor impulses so that their threshold is lowered as a result of a Jendrassik manoeuvre. The finding has important implications for the investigation of the fusimotor system in intact man.
PMCID: PMC494040  PMID: 4260958
4.  Feasibility of dual Doppler velocity measurements to estimate volume pulsations of an arterial segment 
Ultrasound in medicine & biology  2010;36(7):1169-1175.
If volume flow was measured at each end of an arterial segment with no branches, any instantaneous differences would indicate that volume was increasing or decreasing transiently within the segment. This concept could provide an alternative method to assess the mechanical properties or distensibility of an artery noninvasively using ultrasound. The goal of this study was to determine the feasibility of using Doppler measurements of pulsatile velocity (as opposed to flow) at two sites to estimate the volume pulsations of the intervening arterial segment. To test the concept over a wide range of dimensions, we made simultaneous measurements of velocity in a short 5 mm segment of a mouse common carotid artery and in a longer 20 cm segment of a human brachial-radial artery using a two-channel 20 MHz pulsed Doppler, and calculated the waveforms and magnitudes of the volume pulsations during the cardiac cycle. We also estimated pulse wave velocity from the velocity upstroke arrival times and measured artery wall motion using tissue Doppler methods for comparison of magnitudes and waveforms. Volume pulsations estimated from Doppler velocity measurements were 16% for the mouse carotid artery and 4% for the human brachial artery. These values are consistent with the measured pulse wave velocities of 4.2 m/s and 10 m/s respectively and with the mouse carotid diameter pulsation. In addition, the segmental volume waveforms resemble diameter and pressure waveforms as expected. We conclude that with proper application and further validation, dual Doppler velocity measurements can be used to estimate the magnitude and waveform of volume pulsations of an arterial segment and to provide an alternative noninvasive index of arterial mechanical properties.
PMCID: PMC2904320  PMID: 20620703
blood flow velocity; Doppler ultrasound; vascular compliance; pulse wave velocity
5.  Contrasting phenotypes of putative proprioceptive and nociceptive trigeminal neurons innervating jaw muscle in rat 
Molecular Pain  2005;1:31.
Despite the clinical significance of muscle pain, and the extensive investigation of the properties of muscle afferent fibers, there has been little study of the ion channels on sensory neurons that innervate muscle. In this study, we have fluorescently tagged sensory neurons that innervate the masseter muscle, which is unique because cell bodies for its muscle spindles are in a brainstem nucleus (mesencephalic nucleus of the 5th cranial nerve, MeV) while all its other sensory afferents are in the trigeminal ganglion (TG). We examine the hypothesis that certain molecules proposed to be used selectively by nociceptors fail to express on muscle spindles afferents but appear on other afferents from the same muscle.
MeV muscle afferents perfectly fit expectations of cells with a non-nociceptive sensory modality: Opiates failed to inhibit calcium channel currents (ICa) in 90% of MeV neurons, although ICa were inhibited by GABAB receptor activation. All MeV afferents had brief (1 msec) action potentials driven solely by tetrodotoxin (TTX)-sensitive Na channels and no MeV afferent expressed either of three ion channels (TRPV1, P2X3, and ASIC3) thought to be transducers for nociceptive stimuli, although they did express other ATP and acid-sensing channels. Trigeminal masseter afferents were much more diverse. Virtually all of them expressed at least one, and often several, of the three putative nociceptive transducer channels, but the mix varied from cell to cell. Calcium currents in 80% of the neurons were measurably inhibited by μ-opioids, but the extent of inhibition varied greatly. Almost all TG masseter afferents expressed some TTX-insensitive sodium currents, but the amount compared to TTX sensitive sodium current varied, as did the duration of action potentials.
Most masseter muscle afferents that are not muscle spindle afferents express molecules that are considered characteristic of nociceptors, but these putative muscle nociceptors are molecularly diverse. This heterogeneity may reflect the mixture of metabosensitive afferents which can also signal noxious stimuli and purely nociceptive afferents characteristic of muscle.
PMCID: PMC1283980  PMID: 16242047
Background Context
In neutral spinal postures with low loading moments the lumbar spine is not inherently stable. Small compromises in paraspinal muscle activity may affect lumbar spinal biomechanics. Proprioceptive feedback from muscle spindles is considered important for control of muscle activity. Because skeletal muscle and muscle spindles are thixotropic, their length history changes their physical properties. The present study explores a mechanism that can affect the responsiveness of paraspinal muscle spindles in the lumbar spine.
This study had two aims: to extend our previous findings demonstrating the history dependent effects of vertebral position on the responsiveness of lumbar paraspinal muscle spindles; and to determine the time course for these effects. Based upon previous studies, if a crossbridge mechanism underlies these thixotropic effects, then the relationship between the magnitude of spindle discharge and the duration of the vertebral position will be one of exponential decay or growth.
Study Design/Setting
A neurophysiological study using the lumbar spine of a feline model.
The discharge from individual muscle spindles afferents innervating lumbar paraspinal muscles in response to the duration and direction of vertebral position were obtained from teased filaments in the L6 dorsal roots of 30 Nembutal-anesthetized cats. The L6 vertebra was controlled using a displacement-controlled feedback motor and was held in each of 3 different conditioning positions for durations of 0, 0.5, 1, 1.5, and 2 seconds. Two of the conditioning positions stretched or shortened the lumbar muscles relative to an intermediate conditioning position. Conditioning positions for all cats ranged from 0.9 – 2.0 mm dorsal and ventralward relative to the intermediate position. These magnitudes were determined based upon the displacement that loaded the L6 vertebra to 50–60% of the cat’s body weight. Conditioning was thought to simulate a motion segment’s position that might be passively maintained due to fixation, external load, a prolonged posture, or structural change. Following conditioning positions that stretched (hold-long) and shortened (hold-short) the spindle, the vertebra was repositioned identically and muscle spindle discharge at rest and to movement was compared with conditioning at the intermediate position.
Lumbar vertebral positions maintained for less than 2 seconds were capable of evoking different discharge rates from lumbar paraspinal muscle spindles despite the vertebra having been returned to identical locations. Both resting spindle discharge and their responsiveness to movement were altered. Conditioning vertebral positions that stretched the spindles decreased spindle activity and positions that unloaded the spindles increased spindle activity upon returning the vertebra to identical original (intermediate) positions. The magnitude of these effects increased as conditioning duration increased to 2 seconds. These effects developed with a time course following a first order exponential reaching a maximal value after approximately 4 seconds of history. The time constant for a hold-short history was 2.6 seconds and for a hold-long history was approximately half of that at 1.1 seconds.
Thixotropic contributions to the responsiveness of muscles spindles in the low back are caused by the rapid, spontaneous formation of stable crossbridges. These sensory alterations due to vertebral history would represent a proprioceptive input not necessarily representative of the current state of intersegmental positioning. As such, they would constitute a source of inaccurate sensory feedback. Examples are presented suggesting ways in which this novel finding may affect spinal physiology.
PMCID: PMC2366132  PMID: 17938002
7.  Fusimotor control of spindle sensitivity regulates central and peripheral coding of joint angles 
Proprioceptive afferents from muscle spindles encode information about peripheral joint movements for the central nervous system (CNS). The sensitivity of muscle spindle is nonlinearly dependent on the activation of gamma (γ) motoneurons in the spinal cord that receives inputs from the motor cortex. How fusimotor control of spindle sensitivity affects proprioceptive coding of joint position is not clear. Furthermore, what information is carried in the fusimotor signal from the motor cortex to the muscle spindle is largely unknown. In this study, we addressed the issue of communication between the central and peripheral sensorimotor systems using a computational approach based on the virtual arm (VA) model. In simulation experiments within the operational range of joint movements, the gamma static commands (γs) to the spindles of both mono-articular and bi-articular muscles were hypothesized (1) to remain constant, (2) to be modulated with joint angles linearly, and (3) to be modulated with joint angles nonlinearly. Simulation results revealed a nonlinear landscape of Ia afferent with respect to both γs activation and joint angle. Among the three hypotheses, the constant and linear strategies did not yield Ia responses that matched the experimental data, and therefore, were rejected as plausible strategies of spindle sensitivity control. However, if γs commands were quadratically modulated with joint angles, a robust linear relation between Ia afferents and joint angles could be obtained in both mono-articular and bi-articular muscles. With the quadratic strategy of spindle sensitivity control, γs commands may serve as the CNS outputs that inform the periphery of central coding of joint angles. The results suggest that the information of joint angles may be communicated between the CNS and muscles via the descending γs efferent and Ia afferent signals.
PMCID: PMC3431011  PMID: 22969720
muscle spindle; γs control; spindle sensitivity; Ia afferents; joint angle; central and peripheral coding
8.  On the temporal relationship between throbbing migraine pain and arterial pulse 
Headache  2010;50(9):1507-1510.
Objective and Background
The characteristic throbbing quality of migraine pain is often attributed to the periodic activation of trigeminovascular sensory afferents triggered by the distension of cranial arteries during systole, but direct evidence for this model has been elusive.
Design and Methods
Patients with throbbing migrainous pain were asked to signal in real time the occurrences of their subjective experience of pulsating pain, during which time their arterial pulse was independently monitored.
Overall, the throbbing pain rate (61.7 ± 5.5 SEM) was substantially slower than the arterial pulse rate (80 ± 2.6 SEM, p < .02), and among the few individuals in whom the two rates were the same or nearly the same, the occurrences of throbbing and arterial pulsations fell in and out of phase with each other.
The lack of a simple correspondence between the subjective experience of throbbing pain and the arterial pulse would at the very least require extensive refinement of the prevailing view that the subjective experience of throbbing migraine pain is directly related to the distension of cranial arteries and activation of associated sensory afferents.
PMCID: PMC2965597  PMID: 20976872
9.  Characterization of Muscle Spindle Afferents in the Adult Mouse Using an In Vitro Muscle-Nerve Preparation 
PLoS ONE  2012;7(6):e39140.
We utilized an in vitro adult mouse extensor digitorum longus (EDL) nerve-attached preparation to characterize the responses of muscle spindle afferents to ramp-and-hold stretch and sinusoidal vibratory stimuli. Responses were measured at both room (24°C) and muscle body temperature (34°C). Muscle spindle afferent static firing frequencies increased linearly in response to increasing stretch lengths to accurately encode the magnitude of muscle stretch (tested at 2.5%, 5% and 7.5% of resting length [Lo]). Peak firing frequency increased with ramp speeds (20% Lo/sec, 40% Lo/sec, and 60% Lo/sec). As a population, muscle spindle afferents could entrain 1:1 to sinusoidal vibrations throughout the frequency (10–100 Hz) and amplitude ranges tested (5–100 µm). Most units preferentially entrained to vibration frequencies close to their baseline steady-state firing frequencies. Cooling the muscle to 24°C decreased baseline firing frequency and units correspondingly entrained to slower frequency vibrations. The ramp component of stretch generated dynamic firing responses. These responses and related measures of dynamic sensitivity were not able to categorize units as primary (group Ia) or secondary (group II) even when tested with more extreme length changes (10% Lo). We conclude that the population of spindle afferents combines to encode stretch in a smoothly graded manner over the physiological range of lengths and speeds tested. Overall, spindle afferent response properties were comparable to those seen in other species, supporting subsequent use of the mouse genetic model system for studies on spindle function and dysfunction in an isolated muscle-nerve preparation.
PMCID: PMC3380032  PMID: 22745708
10.  The transduction properties of intercostal muscle mechanoreceptors 
BMC Physiology  2002;2:16.
Intercostal muscles are richly innervated by mechanoreceptors. In vivo studies of cat intercostal muscle have shown that there are 3 populations of intercostal muscle mechanoreceptors: primary muscle spindles (1°), secondary muscle spindles (2°) and Golgi tendon organs (GTO). The purpose of this study was to determine the mechanical transduction properties of intercostal muscle mechanoreceptors in response to controlled length and velocity displacements of the intercostal space. Mechanoreceptors, recorded from dorsal root fibers, were localized within an isolated intercostal muscle space (ICS). Changes in ICS displacement and the velocity of ICS displacement were independently controlled with an electromagnetic motor. ICS velocity (0.5 – 100 μm/msec to a displacement of 2,000 μm) and displacement (50–2,000 μm at a constant velocity of 10 μm/msec) parameters encompassed the full range of rib motion.
Both 1° and 2° muscle spindles were found evenly distributed within the ICS. GTOs were localized along the rib borders. The 1° spindles had the greatest discharge frequency in response to displacement amplitude followed by the 2° afferents and GTOs. The 1° muscle spindles also possessed the greatest discharge frequency in response to graded velocity changes, 3.0 spikes·sec-1/μm·msec-1. GTOs had a velocity response of 2.4 spikes·sec-1/μm·msec-1 followed by 2° muscle spindles at 0.6 spikes·sec-1/μm·msec-1.
The results of this study provide a systematic description of the mechanosenitivity of the 3 types of intercostal muscle mechanoreceptors. These mechanoreceptors have discharge properties that transduce the magnitude and velocity of intercostal muscle length.
PMCID: PMC137590  PMID: 12392601
11.  Phantoms in the brain: Ambiguous representations of stimulus amplitude and timing in weakly electric fish 
Journal of physiology, Paris  2008;102(4-6):209-222.
In wave-type weakly electric fish, two distinct types of primary afferent fibers are specialized for separately encoding modulations in the amplitude and phase (timing) of electrosensory stimuli. Time-coding afferents phase lock to periodic stimuli and respond to changes in stimulus phase with shifts in spike timing. Amplitude-coding afferents fire sporadically to periodic stimuli. Their probability of firing in a given cycle, and therefore their firing rate, is proportional to stimulus amplitude. However, the spike times of time-coding afferents are also affected by changes in amplitude; similarly, the firing rates of amplitude-coding afferents are also affected by changes in phase. Because identical changes in the activity of an individual primary afferent can be caused by modulations in either the amplitude or phase of stimuli, there is ambiguity regarding the information content of primary afferent responses that can result in ‘phantom’ modulations not present in an actual stimulus. Central electrosensory neurons in the hindbrain and midbrain respond to these phantom modulations. Phantom modulations can also elicit behavioral responses, indicating that ambiguity in the encoding of amplitude and timing information ultimately distorts electrosensory perception. A lack of independence in the encoding of multiple stimulus attributes can therefore result in perceptual illusions. Similar effects may occur in other sensory systems as well. In particular, the vertebrate auditory system is thought to be phylogenetically related to the electrosensory system and it encodes information about amplitude and timing in similar ways. It has been well established that pitch perception and loudness perception are both affected by the frequency and intensity of sounds, raising the intriguing possibility that auditory perception may also be affected by ambiguity in the encoding of sound amplitude and timing.
PMCID: PMC2669179  PMID: 18984041
electrosensory; electric organ discharge; jamming avoidance response; sensory integration; perception; illusion
12.  Lumbar position sense acuity during an electrical shock stressor 
Optimal motor control of the spine depends on proprioceptive input as a prerequisite for co-ordination and the stability of the spine. Muscle spindles are known to play an important role in proprioception. Animal experiments suggest that an increase in sympathetic outflow can depress muscle spindle sensitivity. As the muscle spindle may be influenced by sympathetic modulation, we hypothesized that a state of high sympathetic activity as during mental stress would affect the proprioceptive output from the muscle spindles in the back muscles leading to alterations in proprioception and position sense acuity. The aim was to investigate the effect of mental stress, in this study the response to an electrical shock stressor, on position sense acuity in the rotational axis of the lumbar spine.
Passive and active position sense acuity in the rotational plane of the lumbar spine was investigated in the presence and absence of an electrical shock stressor in 14 healthy participants. An electrical shock-threat stressor lasting for approximately 12 minutes was used as imposed stressor to build up a strong anticipatory arousal: The participants were told that they were going to receive 8 painful electrical shocks however the participants never received the shocks. To quantify the level of physiological arousal and the level of sympathetic outflow continuous beat-to-beat changes in heart rate (beats*min-1) and systolic, diastolic and mean arterial blood pressure (mmHg) were measured. To quantify position sense acuity absolute error (AE) expressed in degrees was measured. Two-way analysis of variance with repeated measurements (subjects as random factor and treatments as fixed factors) was used to compare the different treatments.
Significant increases were observed in systolic blood pressure, diastolic blood pressure, and heart rate during the stress sessions indicating elevated sympathetic activity (15, 14 and 10%, respectively). Despite pronounced changes in the sympathetic activity and subjective experiences of stress no changes were found in position sense acuity in the rotational plane of the lumbar spine in the presence of the electrical shock stressor compared to the control period.
The present findings indicate that position sense acuity in the rotational plane of the spine was unaffected by the electrical shock stressor.
PMCID: PMC1185546  PMID: 15992402
13.  Delayed Depolarization and Slow Sodium Currents in Cutaneous Afferents 
Journal of neurophysiology  1994;71(5):1627-1637.
Intraaxonal recordings were obtained in vitro from the sural nerve (SN), the muscle branch of the anterior tibial nerve (ATN), or the deefferented ATN (dATN) in 5- to 7-wk-old rats. Whole-nerve sucrose gap recordings were obtained from the SN and the ATN. This allowed study of cutaneous (SN), mixed motor and muscle afferent (ATN), and isolated muscle afferent (dATN) axons.Application of the potassium channel blocking agent 4-aminopyridine (4-AP) to ATN or dATN resulted in a slight prolongation of the action potential. In contrast, a distinct delayed depolarization followed the axonal action potential in cutaneous afferents (SN) exposed to 4-AP. The delayed depolarization could be induced by a single whole-nerve stimulus or by injection of constant-current depolarizing pulses into individual axons. The delayed depolarization often gave rise to bursts of action potentials and was followed by a prominent afterhyperpolarization (AHP).In paired-pulse experiments on single SN axons, the recovery time (half-amplitude of the action potential) was 3.06 ± 1.82 (SE) ms (n = 12). After exposure to 4-AP the recovery time of the delayed depolarization was considerably longer (half-recovery time: 99.0 ± 28.3 ms; n = 15) than that of the action potential (18.8 ± 9.1 ms; n = 16).Application of tetraethylammonium (TEA) to cutaneous or muscle afferents alone had little effect on single action potential waveform. However, TEA reduced the amplitude of the AHP elicited by a single stimulus in cutaneous afferent axons after exposure to 4-AP and resulted in repetitive spike discharge.The delayed depolarization and spike burst activity induced by 4-AP in SN was present in Ca2+ -free solutions containing 1 mM ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid and was not blocked by Cd2+ (1.0 mM).We obtained whole-cell patch-clamp recordings to study Na+ currents from either randomly selected dorsal root ganglion neurons or cutaneous afferent neurons identified by retrograde labeling with Fluoro-Gold. The majority of the randomly selected neurons had a singular kinetically fast Na+ current. In contrast, no identified cutaneous afferent neurons had a singular fast Na+ current. Rather, they had a combination of kinetically separable fast and slow currents or a singular relatively slow Na+ current.These results demonstrate a difference in the sensitivity of myelinated cutaneous and muscle afferent axons to blockade of a 4-AP-sensitive K+ channel. Cutaneous afferent axons give rise to a prominent depolarizing potential after the action potential, which is not present in the muscle afferent or motor axons. We propose that cutaneous afferent axons have kinetically slow Na+ channels not present in muscle afferent and efferent fibers, whose activation underlies the delayed depolarization and multiple spike discharge. The results indicate a difference in the Na+ channel organization of myelinated cutaneous versus muscle afferent axons and their cell bodies.
PMCID: PMC2605949  PMID: 8064338
14.  Sleep spindles in humans: insights from intracranial EEG and unit recordings 
The Journal of Neuroscience  2011;31(49):17821-17834.
Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we utilized a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13-15Hz) centroparietal spindles often occurring with slow wave up-states, and slow (9-12Hz) frontal spindles occurring 200ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency.
PMCID: PMC3270580  PMID: 22159098
15.  Effects of the Jendrassik manoeuvre on muscle spindle activity in man. 
Twenty-eight mechanoreceptive units identified as primary or secondary spindle afferents were sampled from muscle nerve fascicles in the median, peroneal, and tibial nerves of healthy adult subjects. The responses of these units to sustained passive muscle stretch, to passive stretching movements, to tendon taps, and electrically-induced muscle twitches were studied while the subject performed repeated Jendrassik manoeuvres involving strong voluntary contractions in distant muscle groups. The manoeuvres had no effect upon the afferent spindle discharges as long as there were no EMG signs of unintentional contractions occurring in the receptor-bearing muscle and no mechanotransducer signs of unintentional positional changes altering the load on that muscle. Unintentional contractions in the receptor-bearing muscle frequently occurred during the manoeuvres, however, and then coactivation of the spindle afferents was observed. Multiunit afferent responses to Achilles tendon taps, led off from tibial nerve fascicles, were in a similar way uninfluenced by the Jendrassik manoeuvres, even when these resulted in marked reinforcement of the calf muscle tendon jerk. The results provide no evidence for fusimotor sensitization of spindles in muscles remaining relaxed during the Jendrassik manoeuvre, and reflex reinforcement occurring without concomitant signs of active tension rise in the muscles tested is presumed to depend upon altered processing of the afferent volleys within the cord.
PMCID: PMC492180  PMID: 130466
16.  Pathophysiology of persistent syringomyelia after decompressive craniocervical surgery 
Journal of neurosurgery. Spine  2010;13(6):10.3171/2010.6.SPINE10200.
Craniocervical decompression for Chiari malformation Type I (CM-I) and syringomyelia has been reported to fail in 10%–40% of patients. The present prospective clinical study was designed to test the hypothesis that in cases in which syringomyelia persists after surgery, craniocervical decompression relieves neither the physiological block at the foramen magnum nor the mechanism of syringomyelia progression.
The authors prospectively evaluated and treated 16 patients with CM-I who had persistent syringomyelia despite previous craniocervical decompression. Testing before surgery included the following: 1) clinical examination; 2) evaluation of the anatomy using T1-weighted MR imaging; 3) assessment of the syrinx and CSF velocity and flow using cine phase-contrast MR imaging; and 4) appraisal of the lumbar and cervical subarachnoid pressures at rest, during a Valsalva maneuver, during jugular compression, and following the removal of CSF (CSF compliance measurement). During surgery, ultrasonography was performed to observe the motion of the cerebellar tonsils and syrinx walls; pressure measurements were obtained from the intracranial and lumbar intrathecal spaces. The surgical procedure involved enlarging the previous craniectomy and performing an expansile duraplasty with autologous pericranium. Three to 6 months after surgery, clinical examination, MR imaging, and CSF pressure recordings were repeated. Clinical examination and MR imaging studies were then repeated annually.
Before reexploration, patients had a decreased size of the CSF pathways and a partial blockage in CSF transmission at the foramen magnum. Cervical subarachnoid pressure and pulse pressure were abnormally elevated. During surgery, ultrasonographic imaging demonstrated active pulsation of the cerebellar tonsils, with the tonsils descending during cardiac systole and concomitant narrowing of the upper pole of the syrinx. Three months after reoperation, patency of the CSF pathways was restored and pressure transmission was improved. The flow of syrinx fluid and the diameter of the syrinx decreased after surgery in 15 of 16 patients.
Persistent blockage of the CSF pathways at the foramen magnum resulted in increased pulsation of the cerebellar tonsils, which acted on a partially enclosed cervical subarachnoid space to create elevated cervical CSF pressure waves, which in turn affected the external surface of the spinal cord to force CSF into the spinal cord through the Virchow-Robin spaces and to propel the syrinx fluid caudally, leading to syrinx progression. A surgical procedure that reestablished the CSF pathways at the foramen magnum reversed this pathophysiological mechanism and resolved syringomyelia. Elucidating the pathophysiology of persistent syringomyelia has implications for its primary and secondary treatment.
PMCID: PMC3822767  PMID: 21121751
syringomyelia; therapeutics; radiography; physiology; Arnold-Chiari malformation, Type I
17.  Studying the Spatial Distribution of Physiological Effects on BOLD Signals Using Ultrafast fMRI 
The blood-oxygen-level dependent (BOLD) signal in functional MRI (fMRI) reflects both neuronal activations and global physiological fluctuations. These physiological fluctuations can be attributed to physiological low frequency oscillations (pLFOs), respiration, and cardiac pulsation. With typical TR values, i.e., 2 s or longer, the high frequency physiological signals (i.e., from respiration and cardiac pulsation) are aliased into the low frequency band, making it hard to study the individual effect of these physiological processes on BOLD. Recently developed multiband EPI sequences, which offer full brain coverage with extremely short TR values (400 ms or less) allow these physiological signals to be spectrally separated. In this study, we applied multiband resting state scans on nine healthy participants with TR = 0.4 s. The spatial distribution of each physiological process on BOLD fMRI was explored using their spectral features and independent component analysis (ICA). We found that the spatial distributions of different physiological processes are distinct. First, cardiac pulsation affects mostly the base of the brain, where high density of arteries exists. Second, respiration affects prefrontal and occipital areas, suggesting the motion associated with breathing might contribute to the noise. Finally, and most importantly, we found that the effects of pLFOs dominated many prominent ICA components, which suggests that, contrary to the popular belief that aliased cardiac and respiration signals are the main physiological noise source in BOLD fMRI, pLFOs may be the most influential physiological signals. Understanding and measuring these pLFOs are important for denoising and accurately modeling BOLD signals.
PMCID: PMC3978361  PMID: 24744722
BOLD fMRI; multiband EPI; physiological noise; independent component analysis; low frequency oscillations
18.  Emulated muscle spindle and spiking afferents validates VLSI neuromorphic hardware as a testbed for sensorimotor function and disease 
The lack of multi-scale empirical measurements (e.g., recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a synthetic platform for emulating multi-scale activity of the vertebrate sensorimotor system. Our design benefits from Very Large Scale Integrated-circuit (VLSI) technology to provide considerable scalability and high-speed, as much as 365× faster than real-time. An essential component of our design is the proprioceptive sensor, or muscle spindle. Here we demonstrate an accurate and extremely fast emulation of a muscle spindle and its spiking afferents, which are computationally expensive but fundamental for reflex functions. We implemented a well-known rate-based model of the spindle (Mileusnic et al., 2006) and a simplified spiking sensory neuron model using the Izhikevich approximation to the Hodgkin–Huxley model. The resulting behavior of our afferent sensory system is qualitatively compatible with classic cat soleus recording (Crowe and Matthews, 1964b; Matthews, 1964, 1972). Our results suggest that this simplified structure of the spindle and afferent neuron is sufficient to produce physiologically-realistic behavior. The VLSI technology allows us to accelerate this behavior beyond 365× real-time. Our goal is to use this testbed for predicting years of disease progression with only a few days of emulation. This is the first hardware emulation of the spindle afferent system, and it may have application not only for emulation of human health and disease, but also for the construction of compliant neuromorphic robotic systems.
PMCID: PMC4255602  PMID: 25538613
spindle; motor control; afferents; emulation; neuromorphic
19.  Spinal Mechanisms May Provide a Combination of Intermittent and Continuous Control of Human Posture: Predictions from a Biologically Based Neuromusculoskeletal Model 
PLoS Computational Biology  2014;10(11):e1003944.
Several models have been employed to study human postural control during upright quiet stance. Most have adopted an inverted pendulum approximation to the standing human and theoretical models to account for the neural feedback necessary to keep balance. The present study adds to the previous efforts in focusing more closely on modelling the physiological mechanisms of important elements associated with the control of human posture. This paper studies neuromuscular mechanisms behind upright stance control by means of a biologically based large-scale neuromusculoskeletal (NMS) model. It encompasses: i) conductance-based spinal neuron models (motor neurons and interneurons); ii) muscle proprioceptor models (spindle and Golgi tendon organ) providing sensory afferent feedback; iii) Hill-type muscle models of the leg plantar and dorsiflexors; and iv) an inverted pendulum model for the body biomechanics during upright stance. The motor neuron pools are driven by stochastic spike trains. Simulation results showed that the neuromechanical outputs generated by the NMS model resemble experimental data from subjects standing on a stable surface. Interesting findings were that: i) an intermittent pattern of muscle activation emerged from this posture control model for two of the leg muscles (Medial and Lateral Gastrocnemius); and ii) the Soleus muscle was mostly activated in a continuous manner. These results suggest that the spinal cord anatomy and neurophysiology (e.g., motor unit types, synaptic connectivities, ordered recruitment), along with the modulation of afferent activity, may account for the mixture of intermittent and continuous control that has been a subject of debate in recent studies on postural control. Another finding was the occurrence of the so-called “paradoxical” behaviour of muscle fibre lengths as a function of postural sway. The simulations confirmed previous conjectures that reciprocal inhibition is possibly contributing to this effect, but on the other hand showed that this effect may arise without any anticipatory neural control mechanism.
Author Summary
The control of upright stance is a challenging task since the objective is to maintain the equilibrium of an intrinsically unstable biomechanical system. Somatosensory information is used by the central nervous system to modulate muscle contraction, which prevents the body from falling. While the visual and vestibular systems also provide important additional sensory information, a human being with only somatosensory inputs is able to maintain an upright stance. In this study, we used a biologically-based large-scale neuromusculoskeletal model driven only by somatosensory feedback to investigate human postural control from a neurophysiological point of view. No neural structures above the spinal cord were included in the model. The results showed that the model based on a spinal control of posture can reproduce several neuromechanical outcomes previously reported in the literature, including an intermittent muscle activation. Since this intermittent muscular recruitment is an emergent property of this spinal-like controller, we argue that the so-called intermittent control of upright stance might be produced by an interplay between spinal cord properties and modulated sensory inflow.
PMCID: PMC4230754  PMID: 25393548
Neuroscience  2007;146(2):822-832.
In the present study, the hypothesis that sex-related differences in glutamate-evoked rat masseter muscle afferent discharge may result from estrogen-related modulation of peripheral NMDA receptor activity and/or expression was tested by examining afferent fiber discharge in response to masseter injection of NMDA and the expression of NR2A/B subunits by masseter ganglion neurons in male and female rats. The results showed that injection of NMDA into the masseter muscle evoked discharges in putative mechanonociceptive afferent fibers and increased blood pressure that was concentration-dependent, however, a systemic action of NMDA appeared responsible for increased blood pressure. NMDA-evoked afferent discharge was significantly greater in female than in male rats, was positively correlated with plasma estrogen levels in females and was significantly greater in ovariectomized female rats treated with a high dose (5 μg/day) compared to a low dose (0.5 μg/day) of estrogen. Pre-treatment of high dose estrogen-treated-ovariectomized female rats with the Src tyrosine kinase inhibitor PP2 did not affect NMDA-evoked afferent discharge. NMDA-evoked afferent discharge was attenuated by the antagonists ketamine and ifenprodil, which is selective for NR2B containing NMDA receptors. Fewer masseter ganglion neurons expressed the NR2A (16%) subunit as compared with the NR2B subunit (38%), which was expressed at higher frequencies in intact female (46%) and high dose estrogen-treated ovariectomized female (60%) rats than in male (31%) rats. Taken together, these results suggest that sex-related differences in NMDA-evoked masseter afferent discharge are due, at least in part, to an estrogen-mediated increase in expression of peripheral NMDA receptors by masseter ganglion neurons in female rats.
PMCID: PMC1976542  PMID: 17382479
Nociception; Craniofacial; Estrogen; Temporomandibular; Sex; Trigeminal
21.  Does throbbing pain have a brain signature? 
Pain  2013;154(7):1150-1155.
Pain sometimes has a throbbing, pulsating quality, particularly when it is severe and disabling. We recently challenged the presumption that this throbbing quality is a sensory experience of arterial pulsations, but were unable to offer an alternative explanation for its rhythmic character. Here we report a case study of a woman with a history of daily headache consistent with the diagnosis of chronic migraine, but whose throbbing quality persisted long after the resolution of the headache. This chronic, daily, and persistent throbbing sensation, in the absence of headache pain, prompted closer examination for its neurophysiological correlate. By simultaneously recording the subjective report of the throbbing rhythm, arterial pulse, and high-density electroencephalogram (EEG), we found that the subjective throbbing rate (48 ± 1.7 bpm) and heart rate (68 ± 2 bpm) were distinct, in accord with our previous observations that the two are unrelated. On spectral analysis of the EEG we found that the overall amount of activity in the alpha range (8 to 12 Hz), or alpha power, increased in association with greater throbbing intensity. In addition, we also found that the rhythmic oscillations of overall alpha power, the so-called modulations of alpha power, coincided with the timing of the throbbing rhythm, and that this synchrony, or coherence, was proportional to the subjective intensity of the throbbing quality. This index case will motivate further studies whose aim is to determine whether modulations of alpha power could more generally represent a neurophysiological correlate of the throbbing quality of pain.
PMCID: PMC3679361  PMID: 23557747
22.  Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III 
Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley–Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1–10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.
•C-tactile afferents in hairy skin are believed to mediate affective touch.•They are sensitive to slow brushing stimuli, which are perceived as pleasant.•It is not known whether C-tactile afferents are affected in HSAN III.•Ratings of pleasantness were reduced in 15 HSAN III patients compared to controls.•We suggest that the density of C-tactile afferents is reduced in HSAN III.
PMCID: PMC4078239  PMID: 24726998
Affective touch; CT afferents; Pleasant touch; Tactile sensation
23.  Is there a relationship between throbbing pain and arterial pulsations? 
The Journal of Neuroscience  2012;32(22):7572-7576.
Pain can have a throbbing quality, especially when it is severe and disabling. It is widely held that this throbbing quality is a primary sensation of one's own arterial pulsations, arising directly from the activation of localized pain-sensory neurons by closely apposed blood vessels. We examined this presumption more closely by simultaneously recording the subjective report of the throbbing rhythm and the arterial pulse in human subjects of either sex with throbbing dental pain – a prevalent condition whose pulsatile quality is widely regarded a primary sensation. Contrary to the generally accepted view, which would predict a direct correspondence between the two, we found that the throbbing rate (44 bpm ± 3 SEM) was much slower than the arterial pulsation rate (73 bpm ± 2 SEM, p<0.001), and that the two rhythms exhibited no underlying synchrony. Moreover, the beat-to-beat variation in arterial and throbbing events observed distinct fractal properties, indicating that the physiological mechanisms underlying these rhythmic events are distinct. Confirmation of the generality of this observation in other pain conditions would support an alternative hypothesis, that the throbbing quality is not a primary sensation but rather an emergent property, or perception, whose “pacemaker” lies within the central nervous system. Future studies leading to an improved understanding of the neurobiological basis of clinically relevant pain qualities, such as throbbing, will also enhance our ability to measure and therapeutically target severe and disabling pain.
PMCID: PMC3376713  PMID: 22649235
24.  Neurotrophin-3 Ameliorates Sensory–Motor Deficits in Er81-Deficient Mice 
Two factors, the ETS transcription factor ER81 and skeletal muscle-derived neurotrophin-3 (NT3), are essential for the formation of muscle spindles and the function of spindle afferent–motoneuron synapses in the spinal cord. Spindles either degenerate completely or are abnormal, and spindle afferents fail to project to spinal motoneurons in Er81 null mice; however, the interactions between ER81 and NT3 during the processes of afferent neuron and muscle spindle development are poorly understood. To examine if overexpression of NT3 in muscle rescues spindles and afferent–motoneuron connectivity in the absence of ER81, we generated myoNT3;Er81−/− double-mutant mice that selectively overexpress NT3 in muscle in the absence of ER81. Spindle reflex arcs in myoNT3;Er81−/− mutants differed greatly from Er81 null mice. Muscle spindle densities were greater and more afferents projected into the ventral spinal cord in myoNT3;Er81−/− mice. Spindles of myoNT3;Er81−/− muscles responded normally to repetitive muscle taps, and the monosynaptic inputs from Ia afferents to motoneurons, grossly reduced in Er81−/− mutants, were restored to wild-type levels in myoNT3;Er81−/− mice. Thus, an excess of muscle-derived NT3 reverses deficits in spindle numbers and afferent function induced by the absence of ER81. We conclude that muscle-derived NT3 can modulate spindle density and afferent–motoneuron connectivity independently of ER81.
PMCID: PMC2587023  PMID: 17013886
muscle spindles; sensory neurons; motor neurons; neurotrophins; NT3; ETS transcription factors; ER81; mutant mice
25.  Are type III–IV muscle afferents required for a normal steady-state exercise hyperpnoea in humans? 
The Journal of Physiology  2013;592(Pt 3):463-474.
When tested in isolation, stimuli associated with respiratory CO2 exchange, feedforward central command and type III–IV muscle afferent feedback have each been shown to be capable of eliciting exercise-like cardio-ventilatory responses, but their relative contributions in a setting of physiological exercise remains controversial. We reasoned that in order to determine whether any of these regulators are obligatory to the exercise hyperpnoea each needs to be removed or significantly diminished in a setting of physiological steady-state exercise, during which all recognized stimuli (and other potential modulators) are normally operative. In the past few years we and others have used intrathecal fentanyl, a μ-opiate receptor agonist, in humans to reduce the input from type III–IV opiate-sensitive muscle afferents. During various types of intensities and durations of exercise a sustained hypoventilation, as well as reduced systemic pressure and cardioacceleration, were consistently observed with this blockade. These data provide the basis for the hypothesis that type III–IV muscle afferents are obligatory to the hyperpnoea of mild to moderate intensity rhythmic, large muscle, steady-state exercise. We discuss the limitations of these studies, the reasons for their disagreement with previous negative findings, the nature of the muscle afferent feedback stimulus and the need for future investigations.
PMCID: PMC3930433  PMID: 24000177

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