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1.  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
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
3.  Modulatory Effects of α1-, α2-, and β-Receptor Agonists on Feline Spinal Interneurons with Monosynaptic Input from Group I Muscle Afferents 
Previous studies have shown that monoamines may modulate operation of spinal neuronal networks by depressing or facilitating responses of the involved neurons. Recently, activation of interneurons mediating reciprocal inhibition from muscle spindle (Ia) afferents and nonreciprocal inhibition from muscle spindle and tendon organ (Ia/Ib) afferents in the cat was found to be facilitated by noradrenaline (NA). However, which subclass membrane receptors are involved in mediating this facilitation was not established; the aim of the present experiments was to investigate this. Individual Ia- and Ia/Ib-inhibitory interneurons were identified in the cat lumbar spinal cord, and NA agonists were applied close to these neurons by ionophoresis. The agonists included the α1-receptor agonist phenylephrine, the α2-receptor agonists clonidine and tizanidine, and the β-receptor agonist isoproterenol. Effects were measured by comparing changes in the number of extracellularly recorded spike potentials evoked by electrical stimulation of muscle nerves and changes in the latency of these potentials before, during, and after application of the tested compounds. Results show that the facilitatory effect of phenylephrine is as strong as that of NA, whereas the facilitatory effect of isoproterenol is weaker. Clonidine depressed activity of both Ia- and Ia/Ib-inhibitory interneurons, whereas tizanidine had no effect. These findings lead to the conclusion that beneficial antispastic effects of clonidine and tizanidine in humans are unlikely to be associated with an enhancement of the actions of Ia- and Ia/Ib-inhibitory interneurons, and the findings also support previous proposals that these compounds exert their antispastic actions via effects on other neuronal populations.
PMCID: PMC1890035  PMID: 12514232
spinal cord; spinal reflexes; cat; group I afferents; spasticity; noradrenaline; clonidine; tizanidine; phenylephrine; isoproterenol
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.  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
6.  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
7.  Assessment of fusimotor contribution to reflex reinforcement in humans 1 
The contribution of the fusimotor system to reflex reinforcement such as the Jendrassik manoeuvre was investigated by recording single unit activity with tungsten electrodes from muscle spindle afferent nerves in unanaesthetized normal human subjects. Muscle spindle afferent activity was recorded before, during, and after the reinforcement test. When the leg muscles remained relaxed during the Jendrassik manoeuvre, spindle activity recorded in the tibial nerve was accelerated. Also in the median nerve, activity from muscle spindle afferent fibres was increased during a remote contraction of the ipsilateral quadriceps muscle. Comparing the time course of the phasic reflex reinforcement and the muscle spindle facilitation during the remote contraction, a marked after-effect was recorded in both responses. Present results show an increased spontaneous muscle spindle activity in relaxed muscles during a remote muscle contraction, and provide evidence for the contribution of the fusimotor system to the enhancement of phasic reflexes by reinforcement manoeuvres.
PMCID: PMC494832
8.  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
9.  Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans. 
Journal of Clinical Investigation  1987;79(2):508-516.
We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.
PMCID: PMC424115  PMID: 3805279
10.  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
11.  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
12.  Diffusing-wave spectroscopy with dynamic contrast variation: disentangling the effects of blood flow and extravascular tissue shearing on signals from deep tissue 
Biomedical Optics Express  2010;1(5):1502-1513.
We investigate the effects of blood flow and extravascular tissue shearing on diffusing-wave spectroscopy (DWS) signals from deep tissue, using an ex vivo porcine kidney model perfused artificially at controlled arterial pressure and flow. Temporal autocorrelation functions g(1)(τ) of the multiply scattered light field show a decay which is described by diffusion for constant flow, with a diffusion coefficient scaling linearly with volume flow rate. Replacing blood by a non-scattering fluid reveals a flow-independent background dynamics of the extravascular tissue. For a sinusoidally driven perfusion, field autocorrelation functions g(1)(τ, t′) depend on the phase t′ within the pulsation cycle and are approximately described by diffusion. The effective diffusion coefficient Deff(t′) is modulated at the driving frequency in the presence of blood, showing coupling with flow rate; in the absence of blood, Deff(t′) is modulated at twice the driving frequency, indicating shearing of extravascular tissue as the origin of the DWS signal. For both constant and pulsatile flow the contribution of extravascular tissue shearing to the DWS signal is small.
PMCID: PMC3018123  PMID: 21258565
(030.6140) Speckle; (170.0170) Medical optics and biotechnology; (170.1470) Blood or tissue constituent monitoring; (170.5280) Photon migration; (290.1990) Diffusion; (290.1350) Backscattering; (290.4210) Multiple Scattering; (290.7050) Turbid media
13.  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
14.  Functionally reduced sensorimotor connections form with normal specificity despite abnormal muscle spindle development: the role of spindle-derived NT3 
The mechanisms controlling the formation of synaptic connections between muscle spindle afferents and spinal motor neurons are believed to be regulated by factors originating from muscle spindles. Here, we find that the connections form with appropriate specificity in mice with abnormal spindle development caused by the conditional elimination of the neuregulin1 receptor ErbB2 from muscle precursors. However, despite a modest (~30%) decrease in the number of afferent terminals on motor neuron somata, the amplitude of afferent-evoked synaptic potentials recorded in motor neurons was reduced by ~80%, suggesting that many of the connections that form are functionally silent. The selective elimination of neurotrophin 3 (NT3) from muscle spindles had no effect on the amplitude of afferent-evoked ventral root potentials until the second postnatal week, revealing a late role for spindle-derived NT3 in the functional maintenance of the connections. These findings indicate that spindle-derived factors regulate the strength of the connections, but not their initial formation or their specificity.
PMCID: PMC2739048  PMID: 19369542
Muscle Spindle; Sensorimotor; Development; Glutamate transporters; knockout mice; Motoneuron [Motor Neuron]
15.  Point-Process Analysis of Neural Spiking Activity of Muscle Spindles Recorded from Thin-Film Longitudinal Intrafascicular Electrodes 
Conference Proceedings  2011;2011:2311-2314.
Recordings from thin-film Longitudinal Intra-Fascicular Electrodes (tfLIFE) together with a wavelet-based de-noising and a correlation-based spike sorting algorithm, give access to firing patterns of muscle spindle afferents. In this study we use a point process probability structure to assess mechanical stimulus-response characteristics of muscle spindle spike trains. We assume that the stimulus intensity is primarily a linear combination of the spontaneous firing rate, the muscle extension, and the stretch velocity.
By using the ability of the point process framework to provide an objective goodness of fit analysis, we were able to distinguish two classes of spike clusters with different statistical structure. We found that spike clusters with higher SNR have a temporal structure that can be fitted by an inverse Gaussian distribution while lower SNR clusters follow a Poisson-like distribution. The point process algorithm is further able to provide the instantaneous intensity function associated with the stimulus-response model with the best goodness of fit.
This important result is a first step towards a point process decoding algorithm to estimate the muscle length and possibly provide closed loop Functional Electrical Stimulation (FES) systems with natural sensory feedback information.
PMCID: PMC3275426  PMID: 22254803
16.  Mechanical Complications of Myocardial Infarction—Radiologic Aspects 
California Medicine  1970;113(3):11-15.
Left ventricular aneurysm, interventricular septal defect and acute mitral valve incompetence due to papillary muscle damage are three mechanical complications which cause intractable heart failure following myocardial infarction. In each case surgical intervention can result in dramatic improvement of congestive heart failure.
A hemodynamically significant left ventricular aneurysm enlarges the cardiac silhouette and frequently causes a localized protrusion as seen radiographically. Cardiac fluoroscopy will disclose an abnormal pulsation of the left ventricular border. The left ventricular angiogram establishes the diagnosis, reveals the extent of the aneurysm and may disclose a filling defect in the aneurysmal sac due to the presence of mural thrombus. Coronary arteriography shows occlusion of a major vessel, most commonly the anterior descending branch of the left coronary artery.
Ischemic perforation of the interventricular septum and acute mitral incompetence due to severe papillary muscle damage both cause severe heart failure shortly after myocardial infarction. A similar pansystolic murmur accompanies both conditions, and differentiation between the two is rarely possible on the basis of the electrocardiogram or x-ray film of the chest. Ventricular cardiac catheterization and left ventricular angiocardiography are required for a correct diagnosis.
PMCID: PMC1501569  PMID: 5457510
17.  Asynchronicity of Facial Blood Perfusion in Migraine 
PLoS ONE  2013;8(12):e80189.
Asymmetrical changes in blood perfusion and asynchronous blood supply to head tissues likely contribute to migraine pathophysiology. Imaging was widely used in order to understand hemodynamic variations in migraine. However, mapping of blood pulsations in the face of migraineurs has not been performed so far. We used the Blood Pulsation Imaging (BPI) technique, which was recently developed in our group, to establish whether 2D-imaging of blood pulsations parameters can reveal new biomarkers of migraine. BPI characteristics were measured in migraineurs during the attack-free interval and compared to healthy subjects with and without a family history of migraine. We found a novel phenomenon of transverse waves of facial blood perfusion in migraineurs in contrast to healthy subjects who showed synchronous blood delivery to both sides of the face. Moreover, the amplitude of blood pulsations was symmetrically distributed over the face of healthy subjects, but asymmetrically in migraineurs and subjects with a family history of migraine. In the migraine patients we found a remarkable correlation between the side of unilateral headache and the direction of the blood perfusion wave. Our data suggest that migraine is associated with lateralization of blood perfusion and asynchronous blood pulsations in the facial area, which could be due to essential dysfunction of the autonomic vascular control in the face. These findings may further enhance our understanding of migraine pathophysiology and suggest new easily available biomarkers of this pathology.
PMCID: PMC3851171  PMID: 24324592
18.  Muscle spindle activity in alternating tremor of Parkinsonism and in clonus. 
Single unit activity in spindle afferent nerve fibres from the finger flexors, the anterior tibial muscle, and the calf muscles was recorded intraneurally with tungsten microelectrodes in patients with Parkinsonism with resting tremor and in spastic patients with clonus. During tremor of Parkinsonism, involving the receptor bearing muscles, the Ia afferent fibre discharge patterns were similar to those seen previously in healthy subjects during voluntary fast alternating finger or foot movements: besides the stretch discharges occurring during the relaxation phases, discharges also occurred during the contraction phases. Such contraction discharges, presumed to originate from intrafusal muscle fibre contractions, were not seen in the spastic patients during clonus. During the clonic oscillations each afferent stretch discharge was regularly followed by a stretch reflex contraction which on its falling phase elicited a new volley of impulses in the Ia afferent fibres. The findings are considered to support the notion that, like the contractions in normal voluntary alternating movements, the contractions in tremor of Parkinsonism are organized according to the principle of alpha-gamma coactivation, whereas the contractions in clonus are stretch reflexes causing pure alpha contractions.
PMCID: PMC1083240  PMID: 125783
19.  Staining of Human Thyroarytenoid Muscle with Myosin Antibodies Reveals Some Unique Extrafusal Fibers, but no Muscle Spindles 
This study describes the myosin composition of extrafusal and intrafusal muscle fibers found in the human thyroarytenoid (TA) and sternohyoid (control) muscles. We sought to determine the presence of muscle spindles in the TA muscle, and to identify unusual extrafusal fiber types, using the commonly accepted approach of tissue stainng with myosin isoform specific antibodies. Extrafusal fibers are organized into motor units, which subsequently produce muscle movement, whereas intrafusal fibers compose muscle spindles, the primary stretch receptor that provides afferent (feed back) information to the nervous system for regulation of motor unit length and tonicity. Immunohistochemical identification of muscle spindles was confirmed in sternohyoid, but not in TA samples; however, some extrafusal fibers contained tonic myosin. These results indicate that human TA muscle functions similar to some mammalian extraocular muscle, performing unloaded (non-weight bearing) contractions without afferent information from native muscle spindles.
PMCID: PMC3857100  PMID: 12825656
Muscle spindles; Human thyroarytenoid muscle; Myosin heavy chain; Intrafusal fibers
20.  Muscle spindle activity in man during voluntary fast alternating movements. 
Single unit activity in primary spindle afferent nerve fibres from finger and foot flexors was recorded with tungsten microelectrodes inserted into the median and peroneal nerves of healthy subjects. During voluntary fast alternating finger and foot movements, simulating the tremor of Parkinsonism, two types of discharges were seen in the Ia afferent fibres: (1) stretch responses occurring during the flexor relaxation phases, and (2) discharges occurring during the flexor contraction phases. Contrary to the stretch responses the spindle contraction discharges could be eliminated by a partial lidocaine block of the muscle nerve proximal to the recording site, indicating that they resulted from fusimotor activation of intrafusal fibres. On the basis of the temporal relations between the beginning and end of individual EMG-bursts, the start of the spindle contraction discharges and the latency of the stretch reflex in the muscles concerned, the following conclusions were drawn: the recurrent extrafusal contractions in movements of this type are initiated by the fast direct alpha route, but individual contraction phases generally last long enough to be influenced subsequently by the coactivated fusimotor loop through the spindles. It is postulated that this gamma loop influence during alternating movements helps to keep flexor and extensor muscles working in a regular reciprocal fashion with contractions adjusted in strength to the external loads.
PMCID: PMC1083239  PMID: 125782
21.  Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons 
Synaptic ribbons, found at the pre-synaptic membrane of sensory cells in both ear and eye, have been implicated in the vesicle-pool dynamics of synaptic transmission. To elucidate ribbon function, we characterized the response properties of single auditory nerve fibers in mice lacking Bassoon, a scaffolding protein involved in anchoring ribbons to the membrane. In Bassoon mutants, immunohistochemistry showed fewer than 3% of the hair cells’ afferent synapses retained anchored ribbons. Auditory nerve fibers from mutants had normal threshold, dynamic range and post-onset adaptation in response to tone bursts, and they were able to phase-lock with normal precision to amplitude-modulated tones. However, spontaneous and sound-evoked discharge rates were reduced, and the reliability of spikes, particularly at stimulus onset, was significantly degraded as shown by an increased variance of first-spike latencies. Modeling based on in vitro studies of normal and mutant hair cells links these findings to reduced release rates at the synapse. The degradation of response reliability in these mutants suggests that the ribbon and/or bassoon normally facilitate high rates of exocytosis and that its absence significantly compromises the temporal resolving power of the auditory system.
PMCID: PMC2901931  PMID: 20519533
synaptic ribbon; auditory nerve fiber; Bassoon; first spike latency
22.  Increased sensitivity of group III and group IV afferents from incised muscle in vitro 
Pain  2010;151(3):744-755.
Understanding deep muscle pain is of increasing importance for evaluating clinical pathologic pain states. Previously, a central role of deep muscle tissue in the development of ongoing pain behavior after incision was demonstrated. The underlying mechanisms, however, remain unclear. Using a new in vitro plantar flexor digitorum brevis (FDB) muscle-nerve preparation, we investigated properties of mechanosensitive group III and IV afferents innervating incised and unincised muscle, and explored potential mediators of afferent excitation after incision. Afferents of uninjured muscle had a low incidence (14.3%) of ongoing activity. A high proportion (65.8%) of afferents responded to heat and a minority, 20.8%, were activated by pH 6.0 lactic acid. Incision increased the prevalence of afferents with ongoing to 54.7%. A greater proportion of group III and IV afferents responded to pH 6.0 lactic acid after incision compared to control (55.4% vs. 20.8%). Sensitization of afferents to heat and mechanical stimulation was prominent in group IV afferents after incision; both heat (38.0 °C vs. 40.5 °C in control) and mechanical response threshold (median: 5.0 mN vs. 22.0 mN in control) were decreased. The finding that incision increased ongoing activity of muscle afferents is consistent with our previous in vivo studies and supports the idea that deep muscle tissue has a prominent role in the genesis of ongoing pain after incision. The enhanced chemosensitivity of muscle afferents to lactic acid after incision suggests an increased response to an ischemic mediator may contribute to pain and hyperalgesia caused by surgery in deep tissues.
PMCID: PMC2972383  PMID: 20888124
incision; peripheral sensitization; chemosensitive; hyperalgesia
23.  Sensory Coding by Cerebellar Mossy Fibres through Inhibition-Driven Phase Resetting and Synchronisation 
PLoS ONE  2011;6(10):e26503.
Temporal coding of spike-times using oscillatory mechanisms allied to spike-time dependent plasticity could represent a powerful mechanism for neuronal communication. However, it is unclear how temporal coding is constructed at the single neuronal level. Here we investigate a novel class of highly regular, metronome-like neurones in the rat brainstem which form a major source of cerebellar afferents. Stimulation of sensory inputs evoked brief periods of inhibition that interrupted the regular firing of these cells leading to phase-shifted spike-time advancements and delays. Alongside phase-shifting, metronome cells also behaved as band-pass filters during rhythmic sensory stimulation, with maximal spike-stimulus synchronisation at frequencies close to the idiosyncratic firing frequency of each neurone. Phase-shifting and band-pass filtering serve to temporally align ensembles of metronome cells, leading to sustained volleys of near-coincident spike-times, thereby transmitting synchronised sensory information to downstream targets in the cerebellar cortex.
PMCID: PMC3202539  PMID: 22046297
24.  Human muscle afferent responses to tendon taps. 2. Effects of variations in fusimotor bias. 
The effect of varying the fusimotor bias on the muscle spindle responses to light tendon taps has been studied in normal human volunteers using surface electrodes at the wrist for recording whole nerve activity. Reinforcement manoeuvres were found to increase the sensitivity of the afferent responses to the mechanical stimulus. Such sensitisation was found to be exhibited more commonly as a decrease in the latency of the peak of the afferent waveform than as an increase in amplitude. Increase in amplitude of the response was seen in cases where the subject was well relaxed and the test muscle quiescent. A change in furimotor drive was also achieved by asking the subjects to close their eyes voluntarily during the test, thus depriving themselves of the visual feedback. The results under these conditions were found to be variable, though showing considerable changes from control recordings. The effect of reinforcement manoeuvres may perhaps result in increasing the dynamic fusimotor drive. Such an effect may be simulated on occluding the blood supply to the test muscle since ischaemia produces an immediate rise in the rate of afferent discharge. The method of recording is suggested as a convenient technique for clinical use.
PMCID: PMC493001  PMID: 147323
25.  Integrative Synaptic Mechanisms in the Caudal Ganglion of the Crayfish 
The Journal of General Physiology  1960;43(3):671-681.
A study of activity recorded with intracellular micropipettes was undertaken in the caudal abdominal ganglion of the crayfish in order to gain information about central fiber to fiber synaptic mechanisms. This synaptic system has well developed integrative properties. Excitatory post-synaptic potentials can be graded, and synaptic potentials from different inputs can sum to initiate spike discharge. In most impaled units, the spike discharge fails to destroy the synaptic potential, thereby allowing sustained depolarization and multiple spike discharge following single pulse stimulation to an afferent input. Some units had characteristics which suggest a graded threshold for spike generation along the post-synaptic fiber membrane. Other impaled units responded to afferent stimulation with spike discharges of two distinct amplitudes. The smaller or "abortive" spikes in such units may represent non-invading activity in branches of the post-synaptic axon. On a few occasions one afferent input was shown to inhibit the spike discharge initiated by another presynaptic input.
PMCID: PMC2195009  PMID: 14434789

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