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Repetitive passive movement (RPM) activates afferent Ia fibers. The input of afferent Ia fibers from antagonist muscle may modulate the extent of spinal reciprocal inhibition (RI). However, effects of RPM on RI remain unknown. We aimed to clarify these effects in 20 healthy adults. Four RPM tasks (40°/s, 80°/s, 120°/s, and 160°/s), with the range of ankle joint movement set to 40°, ranging from 10° in dorsiflexion to 30° in plantar flexion, were performed for 10 min. For measuring RI, a deep peroneal nerve as a conditioning stimulus, tibial nerve as a test stimulus, and three condition-test stimulus intervals (CTIs; single, 2 ms, and 20 ms) were used. The stimulation frequency was 0.3 Hz for 36 times (3 stimulation conditions × 12 sets). RI was measured before, immediately after, and 5, 10, 15, and 20 min (Pre, Post 5, 10, 15, and 20, respectively) after the task. The extent of reciprocal Ia inhibition (CTI 2 ms) significantly increased in Post 5 and 10 at RPM speed of ≥ 120°/s. The extent of D1 inhibition (CTI 20 ms) significantly increased in Post 5 and 10 at RPM speed of ≥ 80°/s, and continued to increase until Post 15 at RPM speed of 160°/s. The extent of RI was the highest at RPM speed of 160°/s for both Ia and D1. Therefore, high RPM may increase the extent of reciprocal Ia inhibition and D1 inhibition, suggesting that rapid movements affect RI by increasing the firing frequency from the muscle spindle to afferent Ia fibers.

Although spatial summation of pain (SSP) is central to the processing of pain intensity and quality, its mechanism is not fully understood. We previously found greater heat SSP in hairy than in glabrous skin, suggesting that perhaps A-mechano-heat II (AMH-II) nociceptors are the dominant subserving system. In order to further explore the role of A-delta fibers in heat-induced SSP, we analyzed the electrophysiological correlates of SSP under conditions that minimize the influence of skin thicknesses. Among 17 subjects, fast rate of rise (70 °C/sec) heat stimuli that induced a pre-fixed, similar, SSP magnitude for hairy and glabrous skin were repeatedly administered using large and small probes, during which time the contact heat-evoked potentials (CHEPs) and pain ratings were recorded. Both N2 and P2 amplitudes were larger in hairy than in glabrous skin, but a differential effect of SSP was found on the CHEPs. Despite similar psychophysical SSP in hairy and glabrous skin, the electrophysiological SSP reflected in N2 but not P2 amplitude was larger in hairy skin. Nevertheless, regardless of skin type, SSP was manifested by an increase in P2 amplitudes. Considering the uniform psychophysical SSP for the two skin types, the fast stimulation rate and lower activity of AMH-II in glabrous skin, a greater electrophysiological SSP in hairy than in glabrous skin may suggest that SSP is mainly subserved by AMH nociceptors. The overall SSP effect, manifested in greater P2 amplitude, may reflect specific brain responses aimed to prepare the individual to an increased potential tissue damage.

Sensitization is an example of malfunctioning of the nociceptive pathway in either the peripheral or central nervous system. Using quantitative sensory testing, one can only infer sensitization, but not determine the defective subsystem. The states of the subsystems may be characterized using computational modeling together with experimental data. Here, we develop a neurophysiologically plausible model replicating experimental observations from a psychophysical human subject study. We study the effects of single temporal stimulus parameters on detection thresholds corresponding to a 0.5 detection probability. To model peripheral activation and central processing, we adapt a stochastic drift-diffusion model and a probabilistic hazard model to our experimental setting without reaction times. We retain six lumped parameters in both models characterizing peripheral and central mechanisms. Both models have similar psychophysical functions, but the hazard model is computationally more efficient. The model-based effects of temporal stimulus parameters on detection thresholds are consistent with those from human subject data.

Mediterranean Kaposi's sarcoma (MKS), HIV-related KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p < 0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p < 0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence.

Functional magnetic resonance imaging (fMRI) is an important and novel neuroimaging modality for patients with brain tumors. By non-invasive measurement, localization and lateralization of brain activiation, most importantly of motor and speech function, fMRI facilitates the selection of the most appropriate and sparing treatment and function-preserving surgery. Prerequisites for the diagnostic use of fMRI are the application of dedicated clinical imaging protocols and standardization of the respective imaging procedures. The combination with diffusion tensor imaging (DTI) also enables tracking and visualization of important fiber bundles such as the pyramidal tract and the arcuate fascicle. These multimodal MR data can be implemented in computer systems for functional neuronavigation or radiation treatment. The practicability, accuracy and reliability of presurgical fMRI have been validated by large numbers of published data. However, fMRI cannot be considered as a fully established modality of diagnostic neuroimaging due to the lack of guidelines of the responsible medical associations as well as the lack of medical certification of important hardware and software components. This article reviews the current research in the field and provides practical information relevant for presurgical fMRI.

The objective of this study was to determine if a recently developed human Ranvier node model, which is based on a modified version of the Hodgkin-Huxley model, could predict the excitability behaviour in human peripheral sensory nerve fibres with diameters ranging from 5.0 to 15.0 microm. The Ranvier node model was extended to include a persistent sodium current and was incorporated into a generalised single cable nerve fibre model. Parameter temperature dependence was included. All calculations were performed in Matlab. Sensory nerve fibre excitability behaviour characteristics predicted by the new nerve fibre model at different temperatures and fibre diameters compared well with measured data. Absolute refractory periods deviated from measured data, while relative refractory periods were similar to measured data. Conduction velocities showed both fibre diameter and temperature dependence and were underestimated in fibres thinner than 12.5 microm. Calculated strength-duration time constants ranged from 128.5 to 183.0 micros at 37 degrees C over the studied nerve fibre diameter range, with chronaxie times about 30% shorter than strength-duration time constants. Chronaxie times exhibited temperature dependence, with values overestimated by a factor 5 at temperatures lower than body temperature. Possible explanations include the deviated absolute refractory period trend and inclusion of a nodal strangulation relationship.

We have investigated the effect of intravaginal application of capsaicin on micturition reflex in female rats. Urinary bladder contractility was measured by transurethral pressure recording at isovolumetric and subthreshold conditions in anaesthetized rats. The intravaginal application of capsaicin (15 microg/50 microl rat) induced reproducible bladder phasic contractions, without desensitization upon repeated applications, that were blocked by intravenous atropine (1 mg/kg) or hexamethonium (5 mg/kg) and prevented by removal of paracervical ganglia or systemic capsaicin pretreatment (125 mg/kg, s.c.). The inhibition of sympathetic transmission by guanethidine (30 mg/kg, s.c.) produced significant increase of the bladder reflex contractions activated by intravaginal capsaicin. Intravenous administration of the TRPV1 antagonist, capsazepine (3 mg/kg), significantly reduced the excitatory reflex response to capsaicin. Intravaginal administration of capsaicin (15 microg/50 microl), during distension-induced reflex bladder contractions, produced a transient block of reflexes, unaffected by guanethidine pretreatment. In conclusion, the stimulation of capsaicin-sensitive sensory nerve endings in the rat cervix-vagina induced a dual excitatory or inhibitory bladder response in anaesthetized female rats depending on the degree of bladder distension.

The objective of this study was to determine whether the Hodgkin-Huxley model for unmyelinated nerve fibres could be modified to predict excitability behaviour at Ranvier nodes. Only the model parameters were modified to those of human, with the equations left unaltered. A model of a single Ranvier node has been developed as part of a larger model to describe excitation behaviour in a generalised human peripheral sensory nerve fibre. Parameter values describing the ionic and leakage conductances, corresponding equilibrium potentials, resting membrane potential and membrane capacitance of the original Hodgkin-Huxley model were modified to reflect the corresponding parameter values for human. Parameter temperature dependence was included. The fast activating potassium current kinetics were slowed down to represent those of a slow activating and deactivating potassium current, which do not inactivate. All calculations were performed in MATLAB. Action potential shape and amplitude were satisfactorily predicted at 20, 25 and 37 degrees C, and were not influenced by activation or deactivation of the slow potassium current. The calculated chronaxie time constant was 65.5 micros at 37 degrees C. However, chronaxie times were overestimated at temperatures lower than body temperature.

We have induced H-reflex responses in human tibialis anterior motor units and analysed the results using the classical technique, peristimulus time histogram (PSTH), and a new technique, peristimulus frequencygram (PSF). The PSF has recently been shown to be more reliable than the PSTH for indicating the synaptic connections on motoneurones, and therefore we wished to examine the differences between the two analysis methods. Experiments were conducted on eleven healthy subjects (7 males and 4 females) who did not have any known neurological disorder. The subject sat comfortably on a dental chair and the common peroneal nerve was stimulated. In each experiment, about 600 electrical stimuli were applied to the nerve randomly between 1 and 2 s. The recordings were taken with both by surface electromyogram (SEMG) and as single motor unit potentials. We found that, when a stimulus induces an H-reflex, it also generates a period of reduced activity (silent period) and a long latency excitation in the PSTH. However, the PSF records in general do not match the indications of the PSTH records. For example, when the PSTH indicated existence of a silent period immediately following the H-reflex response, the discharge rate of the unit was in fact higher than the prestimulus rate. On the contrary, during the PSTH illustrated long latency excitatory response, the discharge rate was lower than the prestimulus rate. Our findings suggest that PSF gives significantly different results compared with the PSTH in determining the synaptic connection of the low threshold muscle afferents to the motoneurones. While PSTH indicated that there was a silent period immediately after the H-reflex, the PSF demonstrated that the silent period was actually a continuation of the net excitatory effect and not a genuine inhibition since the small number of action potentials occured during this period displayed higher discharge rates than the prestimulus level. Furthermore, the long latency excitation, as it was indicated in the PSTH; was actually a net inhibitory effect since the large number of spikes that occured during that period had lower discharge rates than the prestimulus average. In the lights of the recent brain slice findings and completely different results obtained using the two analysis techniques, we suggest that the PSF analysis should be used along with the PSTH to illustrate the net synaptic connection between peripheral receptors and motoneurones in the human nervous system.

In previous studies, the effect of tenotomy had been focused mainly on muscle properties (typology, capillarity, force, etc.). Little attention was paid to the metabosensitive fibers from groups III and IV (also called 'ergoreceptors' or 'exercise receptors'). In the current study, we assessed the metabosensitive responses in a rat model with tenotomized muscle. Two groups of animals were included: a control group (C, no tenotomy) and a tenotomized group (Tn, transection of the distal tendon of the left tibialis anterior). After 10 weeks, we observed in the Tn group a significant decrease in the metabosensitive afferent responses to electrically induced fatigue and to chemical agents (KCl and lactic acid), known to activate the metabosensitive fibers. These data indicate that (1) tenotomy induces an alteration in the metabosensitive response and consequently modifies the sensory-motor loop; (2) metabosensitive fibers may have a secondary role in tenotomy-induced muscle properties alterations. Additional studies are required to improve our understanding of the metabosensitive responses after tendon or nerve injury.

Inter-hemispheric modulation has been extensively studied, as it is critical for human behavior and could be involved in the development of neuropsychiatric disorders, such as major depression, epilepsy and stroke. Malnutrition early in life can alter brain processes such as inter-hemispheric modulation and these alterations can persist into adulthood. Here, we used cortical spreading depression (CSD) as a neurophysiological parameter to investigate inter-hemispheric modulation in 19 well-nourished and 18 early-malnourished male adult rats. CSD was evoked on the right frontal region and monitored at two parietal points on the same hemisphere. After a 2 h baseline recording, fibers projecting from the left to the right hemisphere via the corpus callosum were cut with a longitudinal lesion in the contralateral cortex and recording continued for two more hours. The results show that (1) baseline CSD propagation velocities were higher in the malnourished rats, as compared to the respective well-nourished controls; (2) post-lesion velocities increased in both nutritional groups, as compared with the baseline values; (3) this CSD increase persisted 3-7 days after lesion, suggesting a lasting effect and (4) in the malnourished group the post-lesion CSD enhancement was of smaller amplitude. Furthermore, a midline lesion (callosotomy) in eight well-nourished rats similarly facilitated CSD, suggesting the involvement of callosal fibers on this effect. No differences were found in sham-operated rats (21 well-nourished and 21 malnourished), as well as in a superficial (1 mm deep) contralateral lesion group (8 well-nourished). Results support the hypothesis of a lasting inhibitory contralateral influence on CSD propagation, which is attenuated, but not abolished, by early malnutrition.

Nerve growth studies in adults usually rely upon nerve regeneration that follows axon disruption. In this study elongation of the epidermal nerve fibers occurred in human and pig epidermis stimulated to hypertrophy by removing the stratum corneum with repetitive applications of tape (tape stripping). Epidermal thickening was accompanied by elongation of the epidermal nerve fibers. This study demonstrates that changing the cellular and chemical environment of nerves by tape stripping is a feasible method to study nerve fiber growth in a physiological manner.

The present study was designed to explore whether a discharge of a certain type of frog retinal ganglion cell [likely changing contrast (third) detector] can evoke NMDA response in frog tectum neurons and higher level of activity of tectal neuron network. Discharge of a single retinal ganglion cell was elicited by electrical stimulation of the retina. Evoked electrical activity of the tectum was recorded by the carbon-fiber microelectrode brought into the optic fiber layer F. We show that: (1) strong discharge of a frog individual retinal ganglion cell (third detector) has evoked NMDA response of tectal neurons and higher level of tectal neuron network activity characterized by prominent suprathreshold excitation of efferent neurons. Consequently, the firing of only one retinal ganglion cell (third detector) could lead to the activation of the tectobulbospinal tract and motor reaction. (2) The excitation of a retinotectal fiber of the first kind (axon of third detector) gave rise to the same effects as activation of a retinotectal fiber of the second kind (axon of fifth detector): the suprathreshold excitation of recurrent and efferent tectal neurons, the slow depolarizing potential (seen as the sNW), and the NMDA receptor activation were observed. However, stronger excitation (longer bursts of action potentials) was needed to evoke those effects in the considered case of the retinotectal input of the first kind. This difference could be attributed to the lower quantal size of neurotransmitter release in synapses of the retinotectal input of the first than second kind.

Two distinct areas of cerebellar cortex, vermal lobule VII and the dorsal paraflocculus (DPFl) receive visual input. To help understand the visuomotor functions of these two regions, we compared their afferent and efferent connections using the tracers wheatgerm agglutinin horseradish peroxidase (WGA-HRP) and biotinilated dextran amine (BDA). The sources of both mossy fibre and climbing fibre input to the two areas are different. The main mossy fibre input to lobule VII is from the nucleus reticularis tegmenti pontis (NRTP), which relays visual information from the superior colliculus, while the main mossy fibre input to the DPFl is from the pontine nuclei, relaying information from cortical visual areas. The DPFl and lobule VII both also receive mossy fibre input from several common brainstem regions, but from different subsets of cells. These include visual input from the dorsolateral pons, and vestibular-oculomotor input from the medial vestibular nucleus (MVe) and the nucleus prepositus hypoglossi (Nph). The climbing fibre input to the two cerebellar regions is from different subdivisions of the inferior olivary nuclei. Climbing fibres from the caudal medial accessory olive (cMAO) project to lobule VII, while the rostral MAO (rMAO) and the principal olive (PO) project to the DPFl. The efferent projections from lobule VII and the DPF1 are to all of the recognised oculomotor and visual areas within the deep cerebellar nuclei, but to separate territories. Both regions play a role in eye movement control. The DPFl may also have a role in visually guided reaching.

We have examined in the anesthetized cat the threshold changes produced by sensory and supraspinal stimuli on intraspinal collaterals of single afferents from the posterior articular nerve (PAN). Forty-eight fibers were tested in the L3 segment, in or close to Clarke's column, and 70 fibers in the L6-L7 segments within the intermediate zone. Of these, 15 pairs of L3 and L6-L7 collaterals were from the same afferent. Antidromically activated fibers had conduction velocities between 23 and 74 m/s and peripheral thresholds between 1.1 and 4.7 times the threshold of the most excitable fibers (xT), most of them below 3 xT. PAN afferents were strongly depolarized by stimulation of muscle afferents and by cutaneous afferents, as well as by stimulation of the bulbar reticular formation and the midline raphe nuclei. Stimulation of muscle nerves (posterior biceps and semitendinosus, quadriceps) produced a larger PAD (primary afferent depolarization) in the L6-L7 than in the L3 terminations. Group II were more effective than group I muscle afferents. As with group I muscle afferents, the PAD elicited in PAN afferents by stimulation of muscle nerves could be inhibited by conditioning stimulation of cutaneous afferents. Stimulation of the cutaneous sural and superficial peroneal nerves increased the threshold of few terminations (i.e., produced primary afferent hyperpolarization, PAH) and reduced the threshold of many others, particularly of those tested in the L6-L7 segments. Yet, there was a substantial number of terminals where these conditioning stimuli had minor or no effects. Autogenetic stimulation of the PAN with trains of pulses increased the intraspinal threshold in 46% and reduced the threshold in 26% of fibers tested in the L6-L7 segments (no tests were made with trains of pulses on fibers ending in L3). These observations indicate that PAN afferents have a rather small autogenetic PAD, particularly if this is compared with the effects of heterogenetic stimulation. Therefore, the depression of the PAN intraspinal fields produced by autogenetic stimulation described by Rudomin et al. (Exp Brain Res DOI 10.1007/s00221-006-0600-x, 2006) may be ascribed to other mechanisms besides a GABAa PAD. It is suggested that the small or no autogenetic PAD displayed by the examined joint afferents prevents presynaptic filtering of their synaptic actions and preserves the original information generated in the periphery. This could be important for proper adjustment of limb position.

Aims/hypothesis: The support of distal regenerating axons and epidermal nerve fibres through growth factor delivery may depend on the site of delivery. While low-dose systemic insulin provides trophic support for regenerating axons or axons from diabetic animals, its potential action upon the most distal neurites within the epidermis is unknown. In diabetic neuropathy, distal loss of axons is an important clinical and pathological feature. We hypothesised that insulin and IGF-1 delivered intrathecally could support the most distal epidermal nerve fibres., Materials and Methods: As insulin and IGF-1 receptors are present upon sensory ganglion perikarya, we studied the impact of intrathecal delivery of low-dose insulin and equimolar IGF-1 on the density of epidermal axons expressing protein gene product 9.5 in experimental diabetic rats. After 2 months of diabetes induced by streptozotocin injection, intrathecal delivery of low-dose insulin or IGF-1 or saline was provided for 1 month, with comparison to compatible doses of subcutaneous insulin delivery., Results: Diabetes, in itself, was associated with a decline in epidermal nerve fibre density. Delivery of both intrathecal IGF-1 and insulin was associated with significant improvement in epidermal fibre density (greatest with IGF-1) and length relative to placebo., Conclusions/interpretation: Central intrathecal delivery of IGF-1 and insulin offers remote support for epidermal nerve fibres, subjected to 'dying-back' in early diabetic polyneuropathy.

It has been established that coincident inputs from multiple presynaptic axons are required to achieve a suprathreshold level of excitation for the most of central neurons. The present study, however, was designed to determine whether a train of spikes of an individual retinal ganglion cell (that is, input from a single presynaptic axon) targeting a frog tectum layer F could evoke suprathreshold excitation of tectal neurons. The lungs of immobilized frog were artificially ventilated during experiments. An individual ganglion cell was electrically stimulated in the retina through a multi-channel electrode. Responses evoked in the tectum by the stimulation were recorded extracellularly from a terminal arborization of the retinotectal fiber using the carbon-fiber microelectrode. Negative and negative-positive spikes (referred to as first type population responses) and polyphasic spikes followed by excitatory synaptic potentials (referred to as second type population responses) were observed in the recordings of retinotectal activity. Usually, the population responses have ensued after the frequency facilitated first and/or second testing individual retinotectal synaptic potential and disappeared in a threshold manner with a reduction of retinotectal transmission by an application of kynurenic acid. These observations have suggested that the population responses were a consequence of a suprathreshold excitation of tectal neurons and, therefore, could serve as the sign for such an excitation. Recordings have also demonstrated that sources of the first type population responses (likely, the hillocks of axons or somas of postsynaptic neurons) lie deeper than the optic fiber layer F of the tectum, whereas sources of the second type population responses (likely, axon terminal arborizations of these postsynaptic neurons) are scattered throughout the optic fiber layers. The findings have suggested: 1) a short train of action potentials of an individual retinal ganglion cell (likely darkness, also known as 5th, detector) can excite tectal neurons to suprathreshold level; 2) tectal and perhaps, nucleus isthmi neurons that make up recurrent connection circuits to the optic fiber layers of the tectum are also activated; 3) a suprathreshold level for an individual retinotectal input is achieved primarily due to the frequency facilitation of synaptic potentials; and 4) an artificial ventilation of the lungs of immobilized frog favors the eliciting of a suprathreshold excitation of tectal neurons, demonstrating that the ventilation certainly improves the physiological condition of a frog.

This study is an extension of the experimental research of Nalçaci et al., who presented 16 subjects with a reversal of checkerboard pattern as stimuli in the right visual field or left visual field and recorded EEG at O1, O2, P3, and P4. They applied the chosen bandpass filters (4-8, 8-15, 15-20, 20-32 Hz) to the VEPs of subjects and obtained four different components for each VEP. The first aim of this study is to improve the previous report using some methods in time-frequency domain to estimate interhemispheric delays and amplitudes in a time window. Using the improved estimates of interhemispheric delays, the second aim is to estimate the proportion of callosal fibers of different diameters that are activated by visual stimuli by comparing amplitudes of VEPs in different frequency bands. If the relation between frequency components of VEP and delays for callosal fibers of different dimension were reliable, it would give us an opportunity to deal with amplitude of bandpass-filtered VEPs in order to see approximately the proportion of these fibers activated by a certain stimulus. By using frequency-dependent shifts in time and maximizing the cross correlation of direct VEP (DVEP-VEP obtained from contralateral hemisphere)-indirect VEP (IVEP-VEP obtained from ipsilateral hemisphere) pairs in the time-frequency domain, we examined the delay not only at P100 and N160 peaks but along a meaningful time interval as well. Furthermore, by shifting back the IVEP according to the delay estimated at each time window, both the amplitudes and energies of the synchronized DVEP-IVEP pairs were compared at the chosen frequency bands. The percentages of IVEPs at each band was then examined further in conjunction with the distribution of axon diameters in the posterior pole of the CC, questioning the relation between the distributions of the axon diameters and activations at each band. We established an energy definition to express the activation in the fibers. When the energy percentages of IVEPs in theta and alpha were totaled, they were found to be between 76.2% and 81.6%, which is close to the value 74-77% for fibers of 0.4-1 microm in diameter obtained from anatomical study of human CC. The sum of energy percentages in the beta1 and beta2 bands was between 20.1% and 24.2%, which probably reflects the proportion of activation of callosal fibers 1-3 microm in diameter.

To investigate the excitability of Adelta nociceptive pathways and the nature of the vertex laser evoked potentials (LEPs), we studied the recovery cycle of the P2-LEP component and compared it with that of the P200 of the somatosensory evoked potential (SEP). Using two identical CO(2)-laser stimulators, we delivered paired stimuli to two adjacent skin spots on the hand at interstimulus intervals ranging from 250 ms to 2 s. The test P2-LEP was strongly inhibited at the 250-ms interstimulus interval ( P<0.01) and progressively recovered by the 2-s interval. The P200-SEP, after paired stimuli to the median nerve, showed a time course even slower than the P2-LEP ( P<0.01). Besides providing the LEP recovery curve in normal subjects, our findings indicate that the P2-LEP relays through a number of synapses similar to (or even lower than) that for the P200-SEP, thus lending further support to the view that the nociceptive P2-LEP is not an endogenous potential equivalent to the P300.

We present a method based on information-theoretic distances for measuring the information transfer efficiency of voltage to impulse encoders. In response to light pulses, we simultaneously recorded the EPSP and spiking output of crayfish sustaining fibers. To measure the distance between analog EPSP responses, we developed a membrane noise model that accurately captures stimulus-induced nonstationarities. By comparing the EPSP and spike responses, we found encoding efficiencies on the order of 10(-4), with interesting dynamics occurring during initial transients. A simple analog to point-process converter predicted the small information transfer efficiencies and dynamic properties we measured.

The brainstem projection of the saccular nerve was investigated by transganglionic tracing with horseradish peroxidase in the cat. The labeled fibers were located most caudally and laterally (dorsolaterally) in the vestibular nerve root. This was unique when compared with the locations of the fibers from the nerves of the other vestibular-end organs that were studied by the present authors by the same approach previously. In addition, such a comparison revealed a specific location, from lateral to medial, for the fibers from each of the five divisions of the vestibular nerve. In the present study, labeled fibers from the sacculus, of fine caliber, were found close to the restiform body, both medially and laterally, some even penetrating through this structure. Labeled terminals were present in cell group "y". This was unique, compared with the nerves from the other end organs. Such terminals were also found in the four main vestibular nuclei, except for the medial vestibular nucleus, where no labeled terminals could be detected. No labeled terminals were found in the interstitial nucleus of the vestibular nerve. Together with the findings from our previous studies, this suggests that, in contrast to the ampullar nerves, the nerves from the maculae do not project to this structure. This study confirms, but also extends, findings reported from a previous investigation in the cat, using an experimental degeneration technique.

The epidermis is innervated by fine nerve endings that are thought to have important sensory functions including nociception. Their role in neuropathic pain is as yet unclear. We used rats with a chronic constriction injury (CCI) of the sciatic nerve, a model of painful partial nerve injury, to examine the temporal course of the epidermal innervation density in correlation with corresponding nerve fiber numbers in the sciatic nerve and with pain-related behavior of the rats. A significant reduction of protein gene product 9.5 (PGP 9.5)-immunoreactive (ir) fibers and a nearly complete loss of calcitonin gene-related peptide (CGRP)-ir fibers was found after CCI in the epidermis as well as in the sciatic nerve. Reappearance of epidermal fibers was delayed compared to the regeneration of nerve fibers in the sciatic nerve. The maximum of pain-related behavior occurred at the time of maximal reduction of epidermal nerve fiber density. Possible explanations for this apparent discrepancy could be the presence of abnormal electrophysiological properties in the few remaining epidermal fibers, the lack of inhibition by intact fibers, or the generation of hyperalgesia in deeper layers of the skin. The number of PGP 9.5-ir Langerhans cells was increased after CCI, and this increase also temporally correlated with the presence of thermal hyperalgesia and mechanical allodynia, supporting a role of Langerhans cells in the generation of pain.

The aim of the present study was to simulate the input system and the motoneuron (MN) pool of the MN pool-muscle complex (MNPMC). Input fibers, which can originate from command centers in the central nervous system or from sensory organs, activate the MN pool. They generate sequences of action potentials, the frequency of which is proportional to a time-dependent activation factor (which is an input to the model). Different connection patterns between the input fibers and motor units (MUs) are allowed. For simplicity and since no precise experimental data are available, 70 input fibers and 4 boutons per fiber and MN are simulated (this corresponds approximately to the monosynaptic group-Ia input of the cat medial gastrocnemius muscle). Each bouton generates the same conductance change in the postsynaptic membrane. The MNs are modeled with a single compartment and a homogeneous membrane. According to experimental data, the membrane leakage conductance and capacitance are MU dependent. Since the precise relation is unknown: (a) the computed relation between MU contraction force and the MN leakage conductance was taken from a steady-state MNPMC model, and (b) the capacitance was assumed to be proportional to the leakage conductance. The MN membrane includes time- and voltage-dependent ionic channels (fast and slow K(+) and low- and high-threshold Ca(2+) channels). The density and time constant of the slow K(+) channels and the density of the Ca(2+) channels were fitted to approximate afterhyperpolarization characteristics and frequency-injected current relations of type-identified cat MNs. If the membrane reaches a voltage threshold the MNs generate action potentials, which were simulated by voltage pulses. The activation of the MN pool of the human first dorsal interosseus muscle was simulated with injected and synaptic currents in order to illustrate the size principle, synaptic noise, and other features of muscle activation. It is concluded that the present model reproduces the main properties of the input-output relations of different MN types within a muscle. Together with the simulation of the muscle force and the surface EMG, which will be published in subsequent papers, it will be a powerful tool for reproducing experiments on the motor system and investigating functional mechanisms of motor control.

Topical treatment with capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatic diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treatment (18.3+/-3.2 vs. 14.3+/-3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7+/-0.4 degrees C vs. 11.4+/-0.7 degrees C: p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9+/-5.8 pg/ml vs. 81.7+/-5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4+/-8.3 pg/ml: n.s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control.

Previous studies in the inferior colliculus have shown that spatial separation of signal and noise sources improves signal detection. In this study, we investigated the free-field unmasking response properties of single fibers in the auditory nerve--these were compared to those of inferior colliculus neurons under the same experimental conditions to test the hypothesis that central processing confers advantages for signal detection in the presence of spatially separated noise. For each neuron, we determined the detection threshold for a probe at the unit's best azimuth under three conditions: (1) by itself, (2) when a masker at a constant level was also presented at the unit's best azimuth, and (3) when the masker was positioned at different azimuths. We found that, on average, maskers presented at a unit's best azimuth elevated the probe detection threshold by 4.22 dB in the auditory nerve and 10.97 dB in the inferior colliculus. Angular separation of probe and masker sources systematically reduced the masking effect. The maximum masking release was on average 2.90 dB for auditory nerve fibers and 9.40 dB for inferior colliculus units. These results support the working hypothesis, suggesting that central processing contributes to the stronger free-field unmasking in the inferior colliculus.

The unipolar brush cell (UBC) is an excitatory glutamatergic interneuron, situated in the cerebellar granular layer, that itself receives excitatory synaptic input on its dendritic brush from a single mossy fiber terminal in the form of a giant glutamatergic synapse. The UBC axon branches within the granular layer, giving rise to large terminals that synapse with both granule cell and UBC dendrites within glomeruli and resemble in morphological and functional terms those formed by extrinsic mossy fibers. So far, the only demonstrated extrinsic afferents to the UBC are the choline acetyltransferase (ChAT)-positive mossy fibers, some of which originate from the medial and descending vestibular nuclei. To ascertain whether UBCs are innervated by primary vestibular fibers, we performed a tract-tracing light and electron microscopic study of the vestibulocerebellum in gerbils. Macular and canal vestibular end-organs were individually labeled by injection of biotinylated dextran amine. After an appropriate survival time, gerbils were then processed for light and electron microscopic analysis of central vestibular projections. In the nodulus and uvula, labeled primary vestibular fibers formed mossy terminals synapsing with both granule cells and UBCs in all of the injected gerbils. Thus, innervation of UBCs by extrinsic mossy fibers carrying static and dynamic vestibular signals represents the first synapse of networks that contribute a powerful form of distributed excitation in the granular layer.

Interneuronal convergence of corticospinal and segmental pathways involved with the generation of extensor activities during locomotion was investigated in decerebrate and partially spinalized cats. L-dihydroxyphenylalanine (L-DOPA) was slowly injected until long-latency, long-lasting discharges could be evoked by the stimulation of contralateral flexor reflex afferents (coFRA) and the group I autogenetic inhibition was reversed to polysynaptic excitation in extensor motoneurons. Under these conditions, we stimulated in alternation the contralateral pyramidal tract (PT), group I afferents from knee and ankle extensor muscles, and both stimuli together. We did the same for the stimulation of PT and of coFRA. Clear polysynaptic EPSPs could be evoked from all three sources in 32 extensor motoneurons. Convergence was inferred from spatial facilitation, which occurred when the amplitude of the EPSPs evoked by the combined stimuli was notably larger than the algebraic sum of the EPSPs evoked by individual stimulation. Spatial facilitation was found between PT and extensor group I inputs in 30/59 tests (51%) in 20 motoneurons and in all cases (6/6) between PT and coFRA in six motoneurons. When fictive locomotion was induced with further injection of L-DOPA, PT descending volleys from the same stimulating site could reset the stepping rhythm by initiating bursts of activity in all extensors. These results indicate that at least some of the corticospinal fibers project onto interneurons shared by the coFRA and the polysynaptic excitatory group I pathways to extensors. The implications of such convergence patterns on the organization of the extensor "half-center" for locomotion are discussed.

Mean firing rates (MFRs), with analogue values, have thus far been used as information carriers of neurons in most brain theories of learning. However, the neurons transmit the signal by spikes, which are discrete events. The climbing fibers (CFs), which are known to be essential for cerebellar motor learning, fire at the ultra-low firing rates (around 1 Hz), and it is not yet understood theoretically how high-frequency information can be conveyed and how learning of smooth and fast movements can be achieved. Here we address whether cerebellar learning can be achieved by CF spikes instead of conventional MFR in an eye movement task, such as the ocular following response (OFR), and an arm movement task. There are two major afferents into cerebellar Purkinje cells: parallel fiber (PF) and CF, and the synaptic weights between PFs and Purkinje cells have been shown to be modulated by the stimulation of both types of fiber. The modulation of the synaptic weights is regulated by the cerebellar synaptic plasticity. In this study we simulated cerebellar learning using CF signals as spikes instead of conventional MFR. To generate the spikes we used the following four spike generation models: (1) a Poisson model in which the spike interval probability follows a Poisson distribution, (2) a gamma model in which the spike interval probability follows the gamma distribution, (3) a max model in which a spike is generated when a synaptic input reaches maximum, and (4) a threshold model in which a spike is generated when the input crosses a certain small threshold. We found that, in an OFR task with a constant visual velocity, learning was successful with stochastic models, such as Poisson and gamma models, but not in the deterministic models, such as max and threshold models. In an OFR with a stepwise velocity change and an arm movement task, learning could be achieved only in the Poisson model. In addition, for efficient cerebellar learning, the distribution of CF spike-occurrence time after stimulus onset must capture at least the first, second and third moments of the temporal distribution of error signals.

Second-order vestibular neurons of frogs receive converging monosynaptic excitatory and disynaptic excitatory and inhibitory inputs following electrical pulse stimulation of an individual semicircular canal nerve on the ipsilateral side. Here we revealed, in the in vitro frog brain, disynaptic inhibitory postsynaptic potentials (IPSPs) by bath application of antagonists specific for glycine or gamma-aminobutyric acid-A (GABA(A)) receptors. Differences in the response parameters between disynaptic IPSPs and excitatory postsynaptic potentials (EPSPs) suggested that disynaptic IPSPs originated from a more homogeneous subpopulation of thicker vestibular nerve afferent fibers than mono- or disynaptic EPSPs. To investigate a possible size-related organization of these canal-specific, parallel pathways, we combined long-lasting anodal currents of variable intensities with strong cathodal test pulses, to block pulse-evoked responses reversibly in a graded manner according to the size-related sensitivity of vestibular nerve afferent fibers. The anodal current intensity required to block a particular response component was about 15 times lower than the strength of the cathodal test pulse that activated this response component. These large threshold differences were exploited for a selective anodal suppression of the responses from thick vestibular nerve afferent fibers. In fact, response components known to originate exclusively from thick-caliber afferent fibers such as the electrically transmitted monosynaptic EPSP component exhibited the lowest thresholds for cathodal test pulses and were the first to disappear in the presence of small anodal polarization steps. Thresholds for the activation/inactivation of responses and current intensities required for response saturation/blockade were used to assess the fiber spectrum that evoked the different response components. Mono- and disynaptic EPSPs appeared to originate from a broad spectrum of thick and thin vestibular nerve afferent fibers. The spectrum of afferent fibers that activated disynaptic IPSPs on the other hand was more homogeneous and consisted of thick and intermediate fibers. Such a canal-specific and fiber type-related organization of converging inputs of second-order vestibular neurons via feedforward projections was shown for the first time by this study in frogs, but might also prevail in mammals. Similar differences in these feedforward pathways have been proposed earlier in a vestibular side-loop model. Our results are consistent with the basic assumptions of this model and relate to the processing and tuning of dynamic vestibular signals.

Long-term changes in the synaptic efficacy of corticostriatal synapses are believed to be important for regulating the excitatory input to the basal ganglia, and hence for motor learning and certain forms of cognition. Previous reports have suggested that long-term depression (LTD) is the predominant form of plasticity at corticostriatal synapses. However, we report here that tetanic stimulation of the white matter can readily induce long-term potentiation (LTP) at corticostriatal synapses in a sagittal slice preparation. Furthermore, we find that corticostriatal LTP is obtained in the absence of pharmacological manipulation, and is dependent on NMDA receptor activation. In contrast, LTD is rarely observed following tetanic stimulation of the white matter, but in fact requires direct stimulation within the striatum. This striatally induced depression is blocked by both D1 and D2 dopamine receptor antagonists and by NMDA receptor blockade. Pairing of striatal stimulation with tetanic stimulation of the white matter does not prevent the induction, but significantly enhances the magnitude of LTP at corticostriatal synapses. We suggest that the corticostriatal depression reported here most likely involves the recruitment of local striatal circuits and dopaminergic inputs, and thus might explain the predominance of LTD previously reported. Our observation that it is indeed possible to induce LTP at corticostriatal synapses under physiological conditions in vitro has implications for the normal function and control of the basal ganglia in motor learning and cognition.

The dentatovestibular connections were investigated using anterograde and retrograde tracing methods. All parts of the cerebellar nucleus lateralis (NL) or dentate nucleus sent fibers onto the ipsilateral vestibular nuclear complex. In spite of their apparently widespread area of termination, dentatovestibular fibers were distributed differentially, according to the subregion of the NL they arose from. Fibers from the main, magnocellular region and the dorsolateral hump (dlh) reached the four main vestibular nuclei, but preferentially the superior (SV) and inferior (IV) vestibular nuclei. The projections to the lateral and the medial vestibular nuclei, which were less abundant, essentially originated from neurons located in the dlh. Fibers arising from the parvocellular subregion of Flood and Jansen terminated within the SV and IV only. Some rare reciprocal vestibulodentate projections were observed. These observations suggest highly integrated activities of dentatovestibular connections related to postural, but also vestibulo-oculomotor functions.

Fifteen patients with Charcot-Marie-Tooth type 1A (CMT1A) disease and 46 normal controls were studied. In the patients, leg muscle strength, touch-pressure, vibration and joint position sense were reduced; lower limb tendon reflexes were absent in 12 or markedly decreased. Motor and sensory conduction velocity (CV) of leg nerves was either reduced or not measurable. The Neurological Disability Score and the Neuropathy Score were obtained from clinical and electrophysiological examination, respectively. Tilt of a supporting platform elicited short- (SLR) and medium-latency (MLR) responses to stretch in the foot muscle flexor digitorum brevis (FDB) in controls. In the patients, the former response was absent and the latter delayed. These findings are in keeping with the known loss of large-diameter myelinated fibres, with relative sparing of the smaller fibres. The MLR delay was fully accounted for by the slowed CV of the motor fibres. The MLR afferent time was similar to that in normal subjects. Body sway area (SA) during quiet stance was recorded with eyes open or closed, and with feet apart or together. Under all postural and visual conditions, SA was within normal range in the less severely affected patients, but was moderately increased in the patients with a more severe neuropathy score. Across all patients, no correlation was found between SA and muscle force, motor CV, touch pressure, vibration and joint position sense, considered either separately or as an aggregate. We suggest that: (1) functional integrity of the largest afferent fibres is not necessary for appropriate equilibrium control during quiet stance and (2) any unsteadiness is related to additional functional alterations in smaller fibres, most likely group II spindle afferent fibres.

In anesthetized and paralyzed cats under artificial respiration, we examined the extent to which primary afferent depolarization (PAD) might affect invasion of action potentials in intraspinal axonal and/or terminal branches of single muscle afferents. To this end, one stimulating micropipette was placed at the L6 spinal level within the intermediate or motor nucleus, and another one at the L3 level, in or close to Clarke's column. Antidromically conducted responses produced in single muscle afferents by stimulation at these two spinal levels were recorded from fine lateral gastrocnemius nerve filaments. In all fibers examined, stimulation of one branch, with strengths producing action potentials, increased the intraspinal threshold of the other branch when applied at short conditioning testing stimulus intervals (<1.5-2.0 ms), because of the refractoriness produced by the action potentials invading the tested branch. Similar increases in the intraspinal threshold were found in branches showing tonic PAD and also during the PAD evoked by stimulation of group I afferent fibers in muscle nerves. It is concluded that during tonic or evoked PAD, axonal branches in the dorsal columns and myelinated terminals of muscle afferents ending deep in the L6 and L3 segmental levels continue to be invaded by action potentials. These findings strengthen the view that presynaptic inhibition of muscle afferents produced by activation of GABAergic mechanisms is more likely to result from changes in the synaptic effectiveness of the afferent terminals than from conduction failure because of PAD.

To evaluate occurrences of reinnervation and degeneration, the portio auricularis of the zygomatic muscle was reinnervated (either primary or secondary reinnervation) with an interval of 6 weeks, using a neuromuscular transplant of the sternohyoid muscle, which was left at the ansa hypoglossi. Histological examination was performed 6 and 12 weeks later. Enzymatic stains for myofibrillar ATPase were used for differentiation of muscle fibre types. Histomorphological features of denervation and reinnervation were analysed. Six weeks after denervation and primary neuromuscular transplantation, type grouping in regions close to the transplanted muscle were detectable as signs of reinnervation. After a period of 12 weeks, the progressing reinnervation was proved by type grouping in distal areas of the muscle far from the area of transplantation. At the same time, differentiation of fibre typing in the type grouping areas increased. All denervated and reinnervated muscles had pathological variations of fibre diameter. Primary reinnervated muscles showed tendency of normalization in variation of diameter. Compared with primary reinnervated muscles, secondary reinnervated muscles with an interval of 6 weeks showed pronounced polymorphology of fibres and a high pathological increase of the variation of fibre diameters. The interfascicular space was significantly spread. The tendency of reinnervation with incidence of fibre type grouping was comparable to primary reinnervated muscles and also occurred 6 weeks after transplantation.

Convergence of various afferent inputs onto brain-stem neurons may play an important role in the regulation of trigeminal motor function. The present study examined the efficacy of nociceptive and non-nociceptive perioral stimulation for the modulation of the two exteroceptive suppression periods (ES1 and ES2) in human jaw-closing muscles. The inhibitory jaw-reflexes, ES1 (10-15 ms onset) and ES2 (40-50 ms onset), were recorded as the surface electromyogram of masseter and temporalis muscles in 14 healthy subjects. Non-painful electrical stimuli were applied to the right mental nerve while the subject was biting at 50% of the maximal voluntary force. Five conditions were compared: baseline, repetitive tactile stimulation (1 Hz) on the right cheek, topical application of capsaicin (5%) on the right cheek, repetitive tactile stimulation plus capsaicin, and postbaseline. The perceived intensity of the electrical stimuli was evaluated by the subjects on a 0-10 rating scale. Capsaicin alone failed to induce significant changes of ES1 and ES2; tactile stimulation alone induced a significant delay in the onset of ES2 (P < 0.001). During repetitive tactile stimulation plus capsaicin, the duration of ES1 and ES2 was shortened (ES1 and ES2: P < 0.001) and the degree of suppression was reduced (ES1: P < 0.05; ES2: P < 0.005). Perceived intensity of the electrical stimuli was unchanged during the different experimental conditions. The present results suggest that summation of simultaneous nociceptive and non-nociceptive inputs plays an important role in the modulation of the neural pathways involved in the short-latency ES1 and long-latency ES2.

In seven alpha-chloralose anesthetized dogs we examined the contribution of lung afferents to the rapid, shallow breathing induced by inhalation of 10 breaths of histamine aerosol. In four spontaneously breathing dogs, the inhalation of histamine caused an increased respiratory frequency, decreased tidal volume, and decreased dynamic lung compliance. Selective blockade of pulmonary C-fibers abolished a reflex-induced increase in respiratory frequency but did not significantly affect the reductions in tidal volume or lung compliance. Terbutaline treatment in combination with C-fiber blockade abolished the reductions in tidal volume and lung compliance induced by histamine. In three separate alpha-chloralose anesthetized, open-chest, mechanically ventilated dogs, we recorded an increase in the inspiratory activity of rapidly adapting pulmonary stretch receptors (RARs) induced by the inhalation of histamine aerosol. Selective C-fiber blockade abolished histamine-induced increases in RAR activity while only partially attenuating reductions in lung compliance. We conclude that the increase in RAR activity induced by histamine depends on intact C-fibers and not on a direct effect of histamine on RARs or an indirect effect of histamine reducing lung compliance. In addition, our data illustrate the multiple interactions that occur between the various vagal afferents and their roles in the reflexes induced by histamine inhalation.

Peptidergic innervation of the human cerebral vasculature has not yet been described in detail and its role in the maintenance of cerebral autoregulation still needs to be established. Similarly, few data exist on the innervation of vascular malformations. The aim of this study was to clarify the peptidergic innervation patterns of human cerebral arteries of various sizes, and, for the first time, that of saccular aneurysms. Light microscopic study of whole-mount preparations of human cerebral arteries and aneurysm sacs resected either during tumor removal or after neck-clipping were carried out by means of silver-intensified light microscopic immunocytochemistry visualizing neuropeptide-Y, calcitonin gene-related peptide and substance P immunoreactivity. Systematic morphological investigations confirmed the presence of longitudinal fiber bundles on the adventitia and a network-like deeper peptidergic system at the adventitia-media border, while in smaller pial and intraparenchymal vessels, only sparse longitudinal immunopositive axons could be detected. The innervation pattern was totally absent in the wall of saccular aneurysms with the complete disappearance of peptidergic nerve fibers in some areas. To the best of our knowledge neither the disappearance of this network on small pial and intraparenchymal vessels, nor the absence of an innervation pattern in saccular aneurysms have been described before. Nonhomogeneous peptidergic innervation of the human cerebral vascular tree might be one of the factors responsible for the distinct autoregulatory properties of the capacitance and resistance vessels. Malfunction of this vasoregulatory system might lead to the impairment of autoregulation during pathological conditions such as subarachnoid hemorrhage.

Neurodegeneration of dopamine neurons in the ventral mesencephalon projecting to the dorsal striatum (meso-striatal system) plays a major role in Parkinson's disease. The aim of this study was to establish a simple organotypic, in vitro co-culture model for investigating the survival of dopamine neurons stimulated by the novel growth factor, glial-cell-line-derived neurotrophic factor. This model should allow investigation of the effects of the dopaminergic neurotoxin, 6-hydroxydopamine, on the expression of the transcription factor c-fos and on TUNEL staining in vitro. The dopaminotrophic factor, glial-cell-line-derived neurotrophic factor, markedly enhanced dopamine tissue levels and dopamine neuron number. Nerve-fiber ingrowth of dopamine neurons into its striatal target was found to be enhanced with glial-cell-line-derived neurotrophic factor. Using an optimized protocol, it was shown that the neurotoxin 6-hydroxydopamine selectively destructed dopamine neurons. C-fos-like immunoreactivity was enhanced in the mesencephalic part of the co-slices 3 h after application of the neurotoxin. The TUNEL staining occurred 2-5 days after the application of the neurotoxin, but did not seem to be related to dopamine neurons. In conclusion, the organotypic co-culture model provides a simple model for studying survival of dopamine neurons and for observing expression of genes and proteins that could be related to Parkinson's disease. This simple model is useful for screening novel drugs and growth factors and may markedly reduce severe animal experiments.

To further study the functional organisation of human peripheral nerves, the intrafascicular arrangement of afferent fibres supplying Pacinian corpuscles (PCs) was explored by percutaneous microneurography using thin-calibre, concentric needle electrodes. In normal adults, 20 PC afferents were identified in 13 recording sites. Low-amplitude (less than 30 microm) vibratory stimuli to the skin were applied with tuning forks oscillating at 128 Hz or 256 Hz and response patterns of individual PC units were studied. In many recording sites, two, sometimes even three, PC afferents with adjacent or overlapping receptive fields in the hand were clustered in the nerve. The observed incidence in the records containing a certain number of PC units was compared with the expected probability calculated according to the hypothesis that all nerve fibres are randomly organised in peripheral nerves. The results suggested that PC afferents are partially segregated in the nerve. In addition, PC afferents were neighbouring on slowly adapting type II (SAII) units and skin sympathetic activity in individual fascicles. SAII units often innervated the same skin area as PC units, but did not respond to vibration. The data provided additional information regarding the functional organisation of the human peripheral nerve and the mechanisms underlying the sense of vibration in man with special regard to population behaviour of neighbouring PC mechanoreceptors.

Effects of electrical stimulation of the ipsilateral tooth pulp (TP) on C1 spinal neurons were determined in 33 anesthetized rats. One hundred and seven neurons responded to TP stimulation. In 10 rats, the activity of 18 C1 spinal neurons and the amplitude of a digastric electromyogram (dEMG, n = 10) increased proportionally during the TP stimulation at an intensity of 1-3 times the threshold for jaw-opening reflex (JOR). Excitatory receptive somatic fields were examined in 61 neurons. Somatic field locations of many neurons (67.2%) involved the ipsilateral face, neck, and jaw. The activity of 45 neurons was increased by both noxious pinch and brushing hair. Of the 107 C1 spinal neurons responding to TP stimulation, 55 were tested to determine the effects of electrical stimulation of the ipsilateral phrenic nerve (PN) above the heart. Twenty-eight of 55 neurons tested were excited; no change in activity was seen for the remaining 27 neurons. The activity of six neurons increased as the intensity of PN stimulation was increased. Excitatory receptive somatic fields were determined in 28 neurons, and somatic field locations of 17 neurons (60.7%) included the ipsilateral face, neck, and jaw. Both noxious pinch and brushing hair excited all 28 neurons. These results suggest that there may be the convergence of face, neck, jaw, TP, and PN afferents on the same C1 spinal neurons in the rat.

The present model of the motoneuronal (MN) pool-muscle complex (MNPMC) is deterministic and designed for steady isometric muscle activation. Time-dependent quantities are treated as time-averages. The character of the model is continuous in the sense that the motor unit (MU) population is described by a continuous density function. In contrast to most already published models, the wiring (synaptic weight) between the input fibers to the MNPMC and the MNs (about which no detailed data are known) is deduced, whereas the input-force relation is given. As suggested by experimental data, this relation is assumed to be linear during MU recruitment, but the model allows other, nonlinear relations. The input to the MN pool is defined as the number of action potentials per second in all input fibers, and the excitatory postsynaptic potential (EPSP) conductance in MNs evoked by the input is assumed to be proportional to the input. A single compartment model with a homogeneous membrane is used for a MN. The MNs start firing after passing a constant voltage threshold. The synaptic current-frequency relation is described by a linear function and the frequency-force transformation of a MU by an exponential function. The sum of the MU contraction forces is the muscle force, and the activation of the MUs obeys the size principle. The model parameters were determined a priori, i.e., the model was not used for their estimation. The analysis of the model reveals special features of the activation curve which we define as the relation between the input normalized by the threshold input of the MN pool and the force normalized by the maximal muscle force. This curve for any muscle turned out to be completely determined by the activation factor, the slope of the linear part of the activation curve (during MU recruitment). This factor determines quantitatively the relation between MU recruitment and rate modulation. This property of the model (the only known model with this property) allows a quantification of the recruitment gain (Kernell and Hultborn 1990). The interest of the activation factor is illustrated using two human muscles, namely the first dorsal interosseus muscle, a small muscle with a relatively small force at the end of recruitment, and the medial gastrocnemius muscle, a strong muscle with a relatively large force at the end of recruitment. It is concluded that the present model allows us to reproduce the main features of muscle activation in the steady state. Its analytical character facilitates a deeper understanding of these features.

Effects of dopamine agonists and antagonists on the optical response of frontal cortical slices to stimulation of the subcortical white matter were examined using a voltage-sensitive dye and a high-speed image sensor. In the slices treated with bicuculline, stimulation of the white matter evoked optical responses propagating to the overlaying cortex. Bath application of the D1 agonist, chloro-APB (1 microM), consistently decreased the intensity of the early part of the response but increased the duration of the response occurring at the superficial layers of the cortex. Application of the D1 antagonist, SCH 23390 (1 microM), resulted in a small increase in both the intensity and the duration of the response. Bath application of the D2 agonist, quinpirole (1-10 microM), reduced the response occurring after 10 ms from stimulation. The effects of chloro-APB and quinpirole were additive. Application of the D2 antagonist, eticlopride, did not cause a significant change in the response but effectively blocked the quinpirole effects. This study suggests that although both D1 and D2 agonists reduced the peak optical response evoked in the slices of the frontal cortex, the two agonists exerted different temporal and spatial effects.

Sources of mossy and climbing fiber inputs to the flocculus (FL), ventral paraflocculus (VP) and/or dorsal paraflocculus (DP) were identified in the vestibular ganglion, medulla oblongata and pons of 19 Wistar rats after 26 local injections of horseradish peroxidase, wheat-germ agglutinin-conjugated horseradish peroxidase, fast blue or diamidino yellow into the FL, VP and/or DP. There were large differences in the sources of mossy fibers to the FL and VP/DP. Labeled neurons after injections into the FL were observed mainly in the ipsilateral vestibular ganglion, bilaterally in the vestibular and prepositus hypoglossal nuclei, and in the caudal part of the nucleus reticularis tegmenti pontis. Labeled neurons were rarely observed in the pontine nuclei after localized injections into the FL. By contrast, after injections into the VP and/or DP, numerous labeled neurons were observed in the pontine nuclei with a contralateral predominance and in the rostral part of the nucleus reticularis tegmenti pontis bilaterally, but not in the vestibular nuclei in either side. Sources of climbing fibers to the FL and paraflocculus were completely contralateral to the injection side. After injection into the FL, labeled neurons were observed in the caudal dorsal cap and ventrolateral outgrowth of the inferior olivary nucleus. After injections into the VP, labeled neurons were observed mainly in the rostral dorsal cap, ventral medial accessory olivary nucleus (MAO) and caudal half of the ventral leaf of the principal olivary nucleus. After injections into the DP, labeled neurons were observed in the ventral MAO and caudal half of the ventral leaf of the principal olivary nucleus. These differences in the sources of mossy and climbing fiber inputs may suggest functional differences between the FL and VP/DP. The present results are consistent with our previous observations in monkey that the FL and VP/DP exhibit quite different mossy fiber input organizations.

Selective and dynamically co-ordinated functional electrical stimulation (FES) of paralysed/paretic limbs in upper motor neuron lesioned people depends on optimal contact at the neural interface. Implanted nerve cuff electrodes may form a stable electrical neural interface, but may also inflict nerve damage. In this study the immediate and long-term effects of cuff implantation on the number and sizes of myelinated and unmyelinated axons have been evaluated with unbiased stereological techniques. Cuff electrodes were implanted in rabbit tibial nerves just below the knee joint, and the stereological analyses were carried out 2 weeks and 16 months after implantation. Myelinated axons were analysed at standardised levels proximal to, underneath, and distal to the cuff; unmyelinated axons underneath the cuff. A 27% loss of myelinated axons was found underneath and distal to the nerve cuff 2 weeks post surgery. All axonal sizes were equally lost except for the very smallest. At 16 months post surgery the number of myelinated axons was restored to control values at both levels. Except for the presence of regenerative sprouts at 2 weeks post surgery, no changes in the number or sizes of unmyelinated axons were revealed at either 2 weeks or 16 months post surgery. Our study demonstrates that implanted cuff electrodes may cause an initial loss of myelinated axons but with subsequent regeneration.

Recordings were made in the peroneal nerve of healthy volunteer subjects from C-mechano-heat (CMH) nociceptors (n=25) with their receptive fields in the skin on the dorsum of the foot. The investigation focused on afferent single C-fiber activity induced by short (200 ms) high-intensity argon-laser light pulses projected to localized spots of the skin. Cutaneous heat stimulation with the argon laser, 2-3 times the activation threshold, induced inter-burst spike frequencies in the nerve, reaching 50 Hz, while mechanical stimulation 10-20 times threshold only evoked frequencies reaching 10 Hz. The decrease in conduction velocity of action potentials in the C-fiber afferents following mechanical and heat stimulation was closely related to the degree of activation. Following a laser pulse of 200 ms, a spike pattern with highly reproducible inter-spike intervals was evoked with a fast saturation. On the contrary, a high variability in the number of action potentials evoked by both heat and mechanical stimuli was found, depending on the location of stimuli within the receptive field. A relation between the conduction velocity and the peak firing within the spike train following laser stimulation was detected. Heat and mechanical stimulation activated single C-fibers in matching spots within the same skin areas, in line with the assumption that the two modalities in the CMH-fibers share matching morphological cutaneous substrates. No correlation was found in thresholds or excitability to mechanical and heat stimulation, respectively. This suggests that subsets of receptors exist within nerve endings of the cutaneous receptive fields, with the ability to generate action potentials independent of heat and mechanical stimuli. Unexpectedly, no signs of sensitization or other inflammatory responses were observed after repeated laser pulses; on the contrary, a rapidly developing fatigue was observed when single spots were repeatedly stimulated. However, no fatigue was observed if neighboring spots were stimulated, indicating a localized generator of the fatigue. In each subject, a good correlation was observed between the reported pain sensation and the activity evoked in the afferent C-fibers by the laser. However, the magnitude of the reported pain sensation to comparable degrees of C-fiber activation showed a high variability between different subjects. A fairly good subjective estimate of the afferent-fiber activation was observed when skin spots from 3- down to 1-mm diameter were stimulated. In a few individuals, no painful sensation was reported when the stimulated spots were reduced to 1-mm diameter, despite the occurrence of multiple spikes in single C-fiber afferents, amplifying the importance of spatial summation in the perception of pain.

Response of a nerve fiber of low excitability to periodic stimulus pulses is studied with computer simulation of the Hodgkin-Huxley model. The excitability of the Hodgkin-Huxley model is reduced by decreasing the equilibrium potential for the sodium ion and by increasing the temperature, so that the decremental propagation of spikes occurs in the refractory period. It is shown that, as the period of stimulus pulses is decreased, the propagation length of the spikes is continuously changed, and period-doubling bifurcations occur. The response of a nerve fiber of low excitability is then qualitatively different from that of a normal fiber.

Activity in single C-fiber afferents, whose cutaneous receptive fields were on the dorsal side of the foot (n=10), were recorded in the peroneal nerve of healthy voluntary subjects. Characterization of the fibers with respect to thresholds and field areas were made before and after cutaneous inflammation, which was induced with mustard oil. To test the nociceptive heat modality, a high-intensity argon laser was used and single 200-ms light pulses were focused onto the skin. The mechanical properties were tested with von Frey-type filaments. In the uninflamed skin, heat and mechanical stimulation activated single C-fibers in matching skin areas. The areas were all within the receptive field borders defined by electrical cutaneous stimulation. The mustard-oil-induced cutaneous inflammation was subjectively reported by the subjects as being moderately painful. In six of the units, a spontaneous activity was induced in the sample of ten previously non-active units. Before the inflammation, the 200-ms argon-laser pulse evoked a highly reproducible pattern of spike-trains. Following inflammation, this pattern was reproducible, but appeared with a significantly reduced activation rate despite the same energy being delivered to the skin both before and after the inflammation. A reduction in slope of the stimulus-response relationship was also observed after inflammation. Following inflammation, changes occurred with expansion both of the mechanical- and heat-receptive fields. The expansion was delineated by the areas defined by electrical stimulation. Following inflammation, the threshold to heat was decreased, but that to mechanical stimuli was not. No relation was detected between the threshold change and the degree of receptive-field expansion. The subjective pain reported changed following inflammation with an increase in the perceived pain in relation to the recorded action potentials, which emphasizes the importance of either an increase in sensitivity in the central nervous system or an increase in peripheral spatial summation after inflammation.

The components of the nervous system of rats that are most critically affected by methyl mercury are still a matter of debate. A recent stereological study of rats with typical symptoms resulting from methyl mercury intoxication demonstrated that the morphology of cerebellar granule cells and Purkinje cells were unchanged at the light microscopic level, even though there was pronounced degeneration of myelinated axons in dorsal nerve root nerves. In the present study, unbiased stereological methods were used to quantify morphological changes in the dorsal root ganglion, and dorsal and ventral nerve roots of the rats used in the previous study. The rats were treated with methyl mercury (2 mg daily/kg, per os) for a 19-day period that was followed by a 32-day period without treatment. The means of the total numbers of A-cell and B-cell perikarya in the dorsal root ganglion of the intoxicated rats were reduced by 60% and 24%, respectively. The mean volume of A-cell perikarya in rats of the experimental group was reduced by 22%, whereas the mean volume of B-cell perikarya was the same in the two groups. In the experimental group, the total number of myelinated axons in the dorsal nerve roots was reduced by 60%, whereas no difference was found in the ventral nerve roots. The areas of axon and myelin sheath, dorsal and ventral nerve roots were not affected. This study demonstrates that extensive loss of dorsal root ganglion cells and myelinated axons in dorsal nerve roots precedes light microscopical changes in the ventral nerve roots and the cerebellum of rats intoxicated with methyl mercury.