Resting discharge patterns of macular primary afferents in otoconia-deficient mice.

Vestibular primary afferents in the normal mammal are spontaneously active. The consensus hypothesis states that such discharge patterns are independent of stimulation and depend instead on excitation by vestibular hair cells due to background release of synaptic neurotransmitter. In the case of otoconial sensory receptors, it is difficult to test the independence of resting discharge from natural tonic stimulation by gravity. We examined this question by studying discharge patterns of single vestibular primary afferent neurons in the absence of gravity stimulation using two mutant strains of mice that lack otoconia (OTO-; head tilt, het-Nox3, and tilted, tlt-Otop1). Our findings demonstrated that macular primary afferent neurons exhibit robust resting discharge activity in OTO- mice. Spike interval coefficient of variation (CV = SD/mean spike interval) values reflected both regular and irregular discharge patterns in OTO- mice, and the range of values for rate-normalized CV was similar to mice and other mammals with intact otoconia although there were proportionately fewer irregular fibers. Mean discharge rates were slightly higher in otoconia-deficient strains even after accounting for proportionately fewer irregular fibers [OTO- = 75.4 +/- 31.1(113) vs OTO+ = 68.1 +/- 28.5(143) in sp/s]. These results confirm the hypothesis that resting activity in macular primary afferents occurs in the absence of ambient stimulation. The robust discharge rates are interesting in that they may reflect the presence of a functionally 'up-regulated' tonic excitatory process in the absence of natural sensory stimulation.

Optimal firing rate estimation.

We define a measure for evaluating the quality of a predictive model of the behavior of a spiking neuron. This measure, information gain per spike (Is), indicates how much more information is provided by the model than if the prediction were made by specifying the neuron's average firing rate over the same time period. We apply a maximum Is criterion to optimize the performance of Gaussian smoothing filters for estimating neural firing rates. With data from bullfrog vestibular semicircular canal neurons and data from simulated integrate-and-fire neurons, the optimal bandwidth for firing rate estimation is typically similar to the average firing rate. Precise timing and average rate models are limiting cases that perform poorly. We estimate that bullfrog semicircular canal sensory neurons transmit in the order of 1 bit of stimulus-related information per spike.

State-space receptive fields of semicircular canal afferent neurons in the bullfrog.

Receptive fields are commonly used to describe spatial characteristics of sensory neuron responses. They can be extended to characterize temporal or dynamical aspects by mapping neural responses in dynamical state spaces. The state-space receptive field of a neuron is the probability distribution of the dynamical state of the stimulus-generating system conditioned upon the occurrence of a spike. We have computed state-space receptive fields for semicircular canal afferent neurons in the bullfrog (Rana catesbeiana). We recorded spike times during broad-band Gaussian noise rotational velocity stimuli, computed the frequency distribution of head states at spike times, and normalized these to obtain conditional pdfs for the state. These state-space receptive fields quantify what the brain can deduce about the dynamical state of the head when a single spike arrives from the periphery.

A model of cerebellar computations for dynamical state estimation.

The cerebellum is a neural structure that is essential for agility in vertebrate movements. Its contribution to motor control appears to be due to a fundamental role in dynamical state estimation, which also underlies its role in various non-motor tasks. Single spikes in vestibular sensory neurons carry information about head state. We show how computations for optimal dynamical state estimation may be accomplished when signals are encoded in spikes. This provides a novel way to design dynamical state estimators, and a novel way to interpret the structure and function of the cerebellum.

Modelling the firing pattern of bullfrog vestibular neurons responding to naturalistic stimuli.

We have developed a neural system identification method for fitting models to stimulus-response data, where the response is a spike train. The method involves using a general nonlinear optimisation procedure to fit models in the time domain. We have applied the method to model bullfrog semicircular canal afferent neuron responses during naturalistic, broad-band head rotations. These neurons respond in diverse ways, but a simple four parameter class of models elegantly accounts for the various types of responses observed.

Vestibular nerve regeneration in the bullfrog, Rana catesbeiana: peripheral dendrites.

Three experiments were conducted on healthy adult bullfrogs (Rana catesbeiana) for the purpose of investigating three characteristics of centrifugal vestibular afferent regeneration after complete transection of the anterior division of the vestibular nerve (AVN). In experiment 1 total fiber count and axon diameter measurements were obtained from the anterior canal nerve at three different time periods and compared with normal. The normal group (n = 3) demonstrated a total fiber count of 1001 +/- 76 (SEM). The early time period (1 to 2 weeks, n = 3) did not completely regenerate as demonstrated by a total fiber count of 282 +/- 23. The intermediate (4 to 6 weeks, n = 3) and late (8 to 16 weeks, n = 3) groups exhibited total fiber counts of 907 +/- 29 and 946 +/- 50, respectively, which were not different from normal (Mann-Whitney U, p > 0.2). Evaluation of fiber diameter distribution of the intermediate and late regenerated nerves revealed a reduction in axon diameter caliber compared with normal (analysis of variance, p < 0.0001). Thus transection of the AVN results in regeneration of all afferents that exhibit a reduction in axon diameter. In experiment 2 fibers innervating the anterior canal crista (ACC) were prelabeled before nerve transection. After the labeling procedure the AVN (n = 3) was sectioned at a location that resulted in denervation of three vestibular receptors: the ACC, horizontal canal cristae (HCC), and utricular macula. After 4 weeks of regeneration the ACC fibers that were prelabeled were observed innervating all three denervated vestibular receptors. This result demonstrated that reinnervation of the peripheral vestibular end organs after AVN transection is a nonspecific process. In experiment 3, 167 regenerated canal afferents were evaluated for functional recovery 16 weeks after transection. Both spontaneous and rotation-induced discharge characteristics were obtained and compared with those obtained from a sample of 254 normal afferents in a previous study (Hoffman LF. Factors affecting the response dynamics of canalicular primary afferent neurons in the bullfrog. St. Petersburg (FL): Association for Research in Otolaryngology; 1989). The mean spontaneous discharge coefficient of variation (CV) +/- standard deviation was 0.60 +/- 0.32 and 0.49 +/- 0.33 for ACC and HCC regenerated afferents, respectively, which did not differ from the normal means of 0.63 +/- 0.33 and 0.54 +/- 0.36 (Mann-Whitney, p > 0.2). Response gains and phases obtained during 0.05 Hz sinusoid rotations at 15 degrees/second maximum horizontal table velocity also demonstrated normal discharge characteristics. The mean phases were -28.2 +/- 25.2 degrees and -55.9 +/- 21.5 degrees for regenerated ACC and HCC afferents, respectively, which were not different from the normal means of -33.77 +/- 24.31 degrees and -58.0 +/- 23.3 degrees (Mann-Whitney U). Furthermore, regenerated afferents exhibited a positive association between phase and CV, which was also true for normal afferents (correlation analysis, p > 0.001). Although the mean gains for regenerated ACC and HCC (7.13 +/- 5.5 and 3.3 +/- 2.4 spikes x sec(-1)/degrees x sec(-2), respectively) afferents were reduced from normal ACC and HCC (14.8 +/- 12.52 and 7.76 +/- 6.58 spikes x sec(-1)/degrees x sec(-2), respectively) afferents (Mann-Whitney U, p > 0.0001), a positive association between gain and CV was also demonstrated by regenerated afferents, as was the case for normal afferents (correlation analysis, p < 0.001). Thus the overall response discharges of regenerated afferents were comparable with normal afferents. Normally, large fibers innervate central regions of the receptor, and smaller fibers innervate the peripheral regions. However, the data from experiments 1 and 2 demonstrate that vestibular nerve regeneration results in a dissociation between the normal topographic organization of fiber size and regional innervation of the receptor epithelium. (ABSTRACT TRUNCATED)

Vestibular and optokinetic function in the normal guinea pig.

Vestibular and optokinetic function was quantitatively studied in the normal guinea pig through investigation of the vestibulo-ocular reflex (VOR), optokinetic nystagmus (OKN), and the visual vestibulo-ocular reflex (VVOR) by means of sinusoidal stimulation with a computer-controlled rate table (VOR and VVOR) or an optokinetic drum. The VOR exhibited high-pass filter characteristics with steady state gain achieved at 0.125 Hz. The maximum gain was 0.55 at a velocity of 60 degrees/s. The VOR was modeled by a transfer function with best fits obtained with an adaptation time constant of 12.5 seconds. The OKN showed low-pass filter characteristics with a decrease in gain for increase in stimulus amplitude. The maximum gain measured was 0.64. A fractional pole model provided a fit of these data. The VVOR exhibited a mean gain of between 0.6 and 0.7 across the stimulus bandwidth and peak velocities. A model based on a linear combination of the actual OKN and VOR gains provided an estimate of the VVOR gain.

Distribution of calcitonin gene-related peptide immunoreactivity in vestibular efferent neurons of the chinchilla.

The distribution of calcitonin gene-related peptide immunoreactivity (CGRPi) within efferent vestibular neurons in the chinchilla was investigated using fluorescent retrograde labeling combined with immunohistochemistry. Efferent vestibular neurons were found bilaterally in clusters: dorsolateral (group E1) and medial (group E2) to the genu of CN VII, as well as ventromedial to the descending CN VII fibers in the parvicellular reticular formation (PCR). The percentage of retrogradely labeled cells containing CGRPi was 77.1 +/- 5.7 for group E1 neurons, 90.3 +/- 3.8 in the E2 region. Among the PCR efferents more then half of the neurons (61.4 +/- 19.9%) expressed CGRP peptide or message. The wide distribution of CGRP among vestibular efferent neurons suggests that CGRP plays an important role in vestibular efferent function. In addition, the differential distribution among the groups of vestibular efferent neurons suggests that efferent modulation of vestibular function is different between the E cell group efferent neurons and the PCR efferent neurons.

Characterization of vestibular potentials evoked by linear acceleration pulses in the chinchilla.

The objective of this study was to improve vestibular evoked potentials as a qualitative parameter for vestibular function in small laboratory animals. Linear upward acceleration pulses (up to 8 g within 1 ms) were applied to the head of anesthetized chinchillas. Electrophysiologic responses recorded by a chronically implanted electrode within the facial nerve canal consisted of an initial negative potential, labeled N1, within the first millisecond following the onset of acceleration. This potential was followed by a series of positive and negative potentials found to be highly labile to acoustic masking. The initial negative potential was only minimally sensitive to acoustic masking and persisted following surgical cochlear ablation, but completely disappeared following administration of potassium chloride into the inner ear. Recorded from the contralateral ear, N1 was unaffected by these procedures. Amplitudes of N1 decreased with attenuating stimulus intensity (1.45 microV/dB), whereby N1 latencies slightly increased (-0.015 ms/dB). These data, when coupled with the ability to completely abolish N1 with potassium intoxication while the contralateral ear remained intact, indicate that this potential represents electrophysiologic activity resulting from activation of the ipsilateral vestibular labyrinth.

Correlation of compound action potential and electromyography with facial muscle tension.

Functional electric stimulation is a new method for dynamic rehabilitation of paralyzed muscles. The output of such prosthetic devices needs to be modulated by some index of the muscle movement. In facial paralysis a measure of the muscle contractions of the normal contralateral side seems to be an appropriate input. In the rabbit, we simultaneously measured the compound action potential of the buccal branch of the facial nerve, the electromyogram of the zygomaticus major muscle, and the muscle twitch tension through strain gauge. The compound action potential, electromyogram, and strain gauge each had a sigmoidal relationship to stimulus intensity. The compound action potential peak-to-peak amplitude was found to have a linear correlation to the peak twitch tension of the corresponding facial muscle. The electromyogram response, although more variable, also had a linear correlation with muscle contraction. The possibility of predicting the contraction of facial muscles before they actually occur is discussed in the context of available and future functional electric rehabilitation models.

The effect of nifedipine on skin flap survival in rats.

Maintaining the viability of an extended skin flap remains one of the continuing challenges in reconstructive surgery. As flaps lengthen, viability becomes more unpredictable and necrosis of distal segments can occur. The specific mechanisms involved in determining flap survival remain unclear, but vasoconstriction within the flap microcirculation appears to play a significant role in regulating flap viability. Vasodilators have been used, with limited success, in an attempt to improve survival of ischemic skin flaps in rats. One such agent, nifedipine, a calcium channel blocker, demonstrated conflicting results when used to improve rat skin flap survival, despite its potent vasodilating properties. A standard rat flap model was used to help clarify the potential of nifedipine to salvage ischemic skin flaps. Alterations in flap perfusion were assessed using a laser Doppler flowmeter and dermofluorometry in an attempt to characterize nifedipine's mechanism of action on flap preservation. Increased flap survival was demonstrated in treatment animals when compared to controls. Despite significant improvement in flap viability, perfusion measurements failed to confirm increased flow within the flap microcirculation. Although the mechanisms of action remain speculative, nifedipine may have important therapeutic potential in improving skin flap survival in a clinical setting.

The galvanically-induced vestibulo-ocular reflex in the cat.

Rotatory vestibular input is processed by receptor organs and relayed along the vestibular nerves to a central processor, whence the vestibulo-ocular reflex (VOR) is generated. Electrical stimuli applied to the labyrinth can bypass receptors and stimulate the nerve directly, thereby generating horizontal eye movements (EVOR). It was our purpose to mathematically relate the EVOR to the VOR in an effort to generate a parameter by which the experimental effects of ototoxins on the inner ear can be evaluated. A feline preparation was created in which the VOR and EVOR were measured in response to various sinusoidal stimuli. A detailed comparison between VOR and EVOR with respect to gain and phase was performed. From analysis of the data, the differential sensitivity to rotatory amplitude with respect to electrical amplitude was proposed as this parameter.

The measurement and manipulation of intralabyrinthine pressure in experimental endolymphatic hydrops.

Three to four months after unilateral surgical ablation of the endolymphatic duct and sac, endolymphatic and perilymphatic pressures were measured in both the normal and hydropic ears of 11 guinea pigs. In normal ears, endolymphatic pressure always approximated perilymphatic pressure. Endolymphatic pressure exceeded perilymphatic pressure in all ears with hydrops, except one in which these pressures were equal. The effect of postural inversion on inner ear pressures were studied in both normal and hydropic inner ears. Normal ears showed endolymphatic and perilymphatic pressure to rise equally during this maneuver. In hydropic ears, the difference between endolymphatic and perilymphatic pressure was notably reduced from measurements obtained in the prone position. This study indicates that an alteration in pressure regulation within the inner ear may be important in the pathogenesis and manifestation of experimental endolymphatic hydrops in the guinea pig. Physiologic mechanisms and clinical implications of these results are described.

The electrically evoked vestibulo-ocular reflex: I. Normal subjects.

Recent animal studies indicate that electric currents applied through perilymphatic-space electrodes stimulate vestibular primary afferent neurons directly. These findings suggest that electrical stimulation may provide a testing method by which the vestibular nerve and central pathways could be evaluated separately from the vestibular end-organ. The goal of this study was to obtain normative data on human beings for an electrically evoked vestibulo-ocular reflex (EVOR). Sinusoidal electrical stimuli (0.0125 to 0.8 Hz, 4 mA peak intensity) were applied along the interaural axis through mastoid electrodes in 10 subjects. Horizontal eye movements were recorded by an infrared limbus-tracking device. The subjects also underwent rotational stimulation at the same frequencies so that their horizontal vestibulo-ocular reflex (VOR) could be evaluated. Nystagmus was observed in the EVOR at lower stimulus frequencies, whereas purely sinusoidal eye deviations occurred at higher frequencies. The phase of the EVOR slow-component eye velocity consistently lagged the stimulus. This contrasts with the phase measurements of the VOR in the same subjects, which exhibited a lead relative to head velocity. These findings suggest that currents applied to human beings may activate vestibular primary afferents independent of peripheral receptor mechanisms and thereby provide a "site-of-lesion" testing method by which the vestibular nerve and central pathways can be evaluated separately from the vestibular end-organ.

Anatomic and physiological correlates in bullfrog vestibular nerve.

1. The correlations between anatomic and physiological characteristics of primary afferent neurons innervating the anterior semicircular canal in the bullfrog were investigated. These characteristics were examined separately in large groups of neurons, and the direct correlations between them were established in a subset of neurons by means of intraaxonal recording and labeling. 2. Anatomic features of the anterior canalicular nerve that were related with fiber diameter were studied. This nerve was composed of an average of 1,142 fibers (standard deviation of 171 in 5 samples), of which 42% were less than 2 microns in diameter and 8% were greater than 7 microns. The nerve branched into 6 clearly defined bundles, whose fiber diameter-dependent composition could be determined in 5 samples. In the 2 center bundles, 32% of the fibers had diameters greater than 7 microns. In contrast, these thick fibers comprised only 4% of the fiber population in the 2 lateralmost bundles, in which 44% of the fibers had diameters less than 2 microns. The projections of labeled afferent fibers were traced into the neuroepithelium, and it was demonstrated that all thick fibers, even those of the lateral bundles, turned toward more central regions of the crista. Consequently, in the bullfrog, there is a clear predominance of thick afferent fibers innervating the anterior crista's central region and thin fibers in the peripheral region. 3. The dendritic morphology of the broad classes of afferent fibers (i.e., thick and thin) was elucidated. Individually labeled thick afferents possessed dendrites forming short, thick, clawlike extensions to contact a few hair cells. The thinnest afferents were labeled through extracellular horseradish peroxidase (HRP) injections. In contrast to the thick fibers, thin afferents were characterized by an unbranched trajectory with serially located bouton-like structures that were apposed to successive hair cells. 4. The characteristics of spontaneous firing and the responses to rotational stimuli were determined for 138 anterior canalicular neurons. Spontaneous firing rates ranged from 0 to 95 spikes.s-1. The coefficient of variation (CV) of spontaneous firing ranged from 0.12 to 2.5. Response gains to high- (0.5 and 0.4 Hz) and medium- (0.05 Hz) frequency sinusoidal acceleration stimuli were positively correlated with CV (P less than 0.001) for neurons with a CV value less than or equal to 0.5. The gain of neurons characterized by more irregular spontaneous firing (CV values greater than 0.5) was uncorrelated with CV.(ABSTRACT TRUNCATED AT 400 WORDS)

Far-field brainstem responses evoked by vestibular and auditory stimuli exhibit increases in interpeak latency as brain temperature is decreased.

The effect of decreasing brain temperature upon the transmission of neural signals along the brainstem auditory pathway has been well documented in cats and mice. The increase in the absolute and interpeak latencies of components of the brainstem auditory evoked response (BAER) has indicated that a progressive slowing occurs along the pathway as the signals ascend toward higher brainstem areas. Therefore to fully describe BAERs, both peak latencies and temperature are measured, especially in anesthetized preparations when brain temperature can be labile. In comparison to the numerous studies on the auditory system there are few studies that relate far-field responses evoked by angular acceleration to the vestibular system. Moreover the temperature dependence of such responses has apparently not been investigated. In this study we performed experiments designed to examine whether interpeak latencies of the BAER in rats depended upon temperature. This led to experiments designed to examine whether interpeak latencies of responses evoked by an angular acceleration show a dependence on temperature.

Regional blood flow in the domestic fowl immediately following chronic acceleration.

In order to examine the effects of chronic low G acceleration on blood flow distribution and cardiac output, chickens (N=10) were centrifuged at +2Gz for 30-61 d. Controls (N=12) were not centrifuged. The animals were anesthetized with sodium pentobarbital after removal from the centrifuge and surgically prepared in order to measure cardiac output and regional blood flows by the reference sample method with 85Sr labeled microspheres (15 +/- 5 mum diam.). Both brachial arteries were cannulated to withdraw timed, paired blood samples at a known rate. The chest was opened and a cannula inserted into the left ventricle for administration of microspheres. Tissue samples were taken after completion of experimental procedures and their radioactivity was determined. The cardiac outputs in the two groups were not significantly different. Regional blood flows to the kidney, eyes, and skeletal muscle were significantly increased in the animals subjected to chronic +2Gz. While the mechanism by which these increases in blood flow occurred is not known, results indicate that chronic exposure to hyperdynamic gravitational fields can alter circulatory dynamics. We conclude that the cardiovascular system is directly involved in the process of adaptation to chronic positive acceleration.

The efffect of sustained +Gz acceleration on extravascular lung water content in domestic fowl.

In order to examine the effects of sustained acceleration on pulmonary fluid balance, chickens were centrifuged at low sustained +G acceleration (LSG) intensities of +3Gz or +4Gz or high sustained +G acceleration (HSG) at +6Gz for varying periods. Animals were exposed to acceleration on a hydraulic-driven centrifuge. Controls (Group I) were not centrifuged. The vascular lungs were rapidly excised after centrifugation, and the extravascular lung water content (EVLW) was measured. EVLW in Group I animals = 2.19 +/- 0.38 g/g. Results indicate that positive acceleration elevated in animals exposed to +4Gz for 60 min (Group III). In this group, EVLW = 3.01 +/- 1.07 g/g. This increase is largely attributable to an elevated EVLW in those animals which died as a result of centrifugation, in which EVLW = 3.90 +/- 1.04 g/g. Exposure to +3Gz for 120 min (Group II) or +6Gz for periods up to 50 min (Group IV) did not produce significant elevations in EVLW in either group as a whole, but EVLW in those Group II animals which died as a result of centrifugation was significantly elevated. EVLW in these animals = 2.87 +/- 0.21 g/g. We conclude that pulmonary edema caused by centrifugation is dependent on both magnitude and duration of G force.