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Department of Bioengineering, University of Utah, Salt Lake City, Utah
Submitted 30 October 2006; accepted in final form 9 January 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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in the early 1920s, benign paroxysmal positional vertigo (BPPV) is the most common vestibular disorder leading to vertigo (Froehling et al. 1991; Mizukoshi et al. 1988). Patients suffering from BPPV experience debilitating symptoms of impaired vision, dizziness, and imbalance. These vestibular symptoms are precipitated when the orientation of the head is changed relative to gravity. Posterior semicircular canal positional vertigo (PC-BPPV) is the most commonly occurring form of the disorder. Although not as common, positional vertigo can afflict the lateral canal (LC) and/or anterior canal (AC) as well (Baloh et al. 1993; Honrubia et al. 1999; McClure 1985). In PC-BPPV, vestibular symptoms are provoked when the head is tipped back relative to gravity—for example, when a subject looks up to view an object on a high shelf or when the head is tipped back as the result of lying down. Dix and Hallpike (1952) identified the semicircular canals as the origin of gravity-sensitive afferent neural inputs to the brain during BPPV and introduced the most widely used clinical test popularly referred to as the Dix–Hallpike maneuver. The test involves a reorientation of the head to align the posterior canal (at its entrance to the ampulla) with the direction of gravity. This test stimulus is effective in provoking the symptoms in subjects suffering from archetypal PC-BPPV.
Two distinct pathological conditions were previously identified as possible causes of the symptoms: cupulolithiasis (Schuknecht 1962) and canalithiasis (Brandt and Steddin 1993; Epley 1992; Hall et al. 1979). Cupulolithiasis describes a condition where otoconial debris adheres to a semicircular canal cupula rendering it "heavy" relative to the surrounding endolymphatic fluid. When the head is reoriented relative to gravity, the cupula is weighted down by the dense particles, thereby inducing an immediate and maintained excitation (or inhibition) of semicircular canal afferents. It is well established that afferent inputs from the semicircular canals are reflected in the slow-phase eye movements (Suzuki et al. 1969; Wilson and Jones 1979) and, as a result, pathological afferent inputs arising from cupulolithiasis would be expected to generate short-latency and tonic nystagmus. Rapid-onset tonic nystagmus indeed has been observed in a small subset of subjects suffering from BPPV (Smouha and Roussos 1995), observations that are consistent with pathological cupulolithiasis in these subjects. Unlike cupulolithiasis, in most cases the nystagmus decreases over time and typically reverses direction when the head is returned to its original position. The symptoms begin after the head has been reoriented with an onset latency of 
1 s and the eye movements are phasic with a duration ranging from 5 s to more than 1 min (Brandt and Daroff 1980; Epley 1980; Herdman 1990). These long-latency phasic eye movements are consistent with a canalithiasis diagnosis—a condition characterized by the presence of free-moving dense particles (e.g., otoconial debris) within the lumen of the afflicted semicircular canal. Free-moving particles have indeed been directly observed in the lumen of the semicircular canal in patients suffering from BPPV (Parnes and McClure 1992).
To provide orientation, Fig. 1 illustrates canalithiasis of the human posterior canal (Rajguru et al. 2004, 2005). The orientation of head and the vestibular labyrinth in the initial upright position (Fig. 1A) and in the supine head-hanging Dix–Hallpike position (Fig. 1B) commonly used to provoke PC-BPPV symptoms are shown (see movie, online Supplement 1, showing dynamic movement of particles).1 The head-hanging position causes dense particles to fall from the PC ampulla (Fig. 1A), under the action of gravity, in the direction indicated by the dotted arrow. In human canalithiasis, the dense particles are suspected to be displaced otoconia calcium carbonate crystals (Parnes and McClure 1992) with a density of about 2.7 g/cm3 (Carmichael 1984; Lim 1984). Because the endolymphdensity is near that of water (1.0 g/cm3) (Steer et al. 1967), dense particles would sink in the endolymph and move along the long arm of the canal. A portion of the drag force acting between the moving particles and the endolymph would be transmitted by fluid pressure to the semicircular canal cupula (Rajguru et al. 2004, 2005; Squires et al. 2004). This pressure would deflect the cupula and hair bundles and ultimately lead to modulation of afferent spike trains and pathological signals sent to the brain that underlie symptoms of the disorder.
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introduced a treatment for PC-BPPV designed to reposition particles from the canal lumen to the utricular vestibule through a series of timed head rotations. Once within the large cross-sectional area of the vestibule, the free-moving particles would no longer be expected to evoke vestibular symptoms (Rajguru et al. 2004). Canalith repositioning procedures (CRPs) are now routinely applied in the clinic and have good efficacy for treatment of PC-BPPV.
Theoretical investigations of the etiology of BPPV focused on the biofluid mechanics of canalithiasis and generally support the hypothesis that free-moving dense particles could account for the symptoms of BPPV (House and Honrubia 2003; Rajguru et al. 2004, 2005; Squires et al. 2004). Experimental investigations have thus far focused on changes in whole nerve compound action potentials during canalithiasis (Inagaki et al. 2006; Suzuki et al. 1996a,b). These studies indeed confirm that gravity-driven particle movements within the lumen of the canal can evoke significant afferent responses. In the present work, we induced canalithiasis in an animal model in vivo and recorded afferent nerve responses to explicitly define the relationship between canalithiasis and the equivalent (pathological) angular velocity inputs to the brain. Afferent responses were calibrated using mechanical stimuli and recorded during gravity-driven particle movements to estimate the equivalent head velocity that would be present in BPPV. Results quantify the neural sensory signals evoked by canalithiasis and show that these afferent signals account for the common symptoms of BPPV.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Rajguru et al. 2004) and because the cartilaginous anatomy facilitated simultaneous recordings of canal afferent discharge and particle movements in vivo (Rabbitt et al. 2005). It is also a well-established animal model for the vestibular semicircular canal system (Boyle and Highstein 1990; Highstein et al. 1996; Rabbitt et al. 1995). Physiological preparation followed methods described previously (Boyle and Highstein 1990). Briefly, fish were anesthetized with MS222 (25 mg/mL in seawater, 3-aminobenzoic acid ethyl ester, Sigma), partially immobilized through intramuscular injection of pancuronium bromide (0.05 mg/kg) in the tail, and secured in an experimental tank with two thirds of its body and gills immersed in bubbled seawater (Instant Ocean, at 10–15°C). The eyes and remainder of the body were covered with moist tissue papers. A small craniotomy (3–4 mm in diameter) was performed lateral to the dorsal course of the anterior canal and rostral to the common crus (CC) to expose the LC and nerve. This surgical approach allowed direct access to the LC nerve without disturbing the membranous labyrinth structures. During surgery, the perilymph within the upper region of the cavity was replaced with fluorocarbon (FC-75, 3M) to improve optical access to the nerve and canal structures and provide a water-immiscible encapsulation of the section of the labyrinth under study.
Canalithiasis was induced by surgical introduction of glass microbeads (density about 2.5 g/cm3; diameters between 15 and 25 µm) into the canal lumen. The glass beads mimic the mammalian otoconia because they have a similar density and fall within the size range between 0.1 and 30 µm (Lim 1984). To facilitate introduction of microbeads, a small endolymphatic fenestra was made by brief delivery of 4- to 8-W cutting waveform by a 76-µm-diameter tungsten electrode (SSE4, Valleylab). This allowed access to the endolymph from a 25- to 75-µm-diameter hole in the membranous wall (Fig. 2A, arrow a). The use of electrically insulating fluorocarbon covering the membranous duct was key to success of the electrosurgical fenestration technique. Fluorocarbon is immiscible with endolymph and thereby prevented any fluid or ionic movement through the hole. It is important to note that the pressure required to overcome the fluorocarbon/water interface surface tension (about 0.015 N/m) and push endolymph though a 50-µm-diameter fenestration in the membranous labyrinth is about 600 Pa, a value that exceeds the endolymph pressure known to be generated during indentation by three orders of magnitude (Yamauchi et al. 2001). Because of this, normal fluid mechanics of the canal is maintained even after fenestration. In addition to preventing translabyrinthine pressure loss, the fluorocarbon also prevented tissue dehydration during the experimental procedure. Neural responses to calibrated mechanical indentation (see following text) were recorded for the same units both before and after generation of the fenestration to ensure that the procedure did not disrupt normal function. An endolymph-filled pressure-balanced micropipette containing beads was inserted into the fenestration, allowing the beads to fall out of the pipette tip and into the lumen of the canal under the action of gravity. The animal was oriented with the plane of the canal tilted roughly 21° relative to the horizontal, such that the slippery beads introduced into the canal moved under the action of gravity, down the canal lumen, and toward the ampulla (Fig. 2B, dotted arrow).
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; Rabbitt et al. 1995). Afferent responses to indentation and rotation were within the range reported previously in this species (Rabbitt et al. 1995), thus providing experimental evidence that the surgical approach and introduction of beads did not significantly alter canal responses to angular rotation. Knowing the afferent responses for angular rotation stimuli also allowed us to estimate the equivalent head velocity that would reproduce the pathological afferent discharge observed during canalithiasis while the head was stationary. This equivalent head velocity is the pathological signal that was transmitted to the brain during experimentally induced canalithiasis BPPV. Preparation of glass beads
The glass microbead (Mo-Sci) surfaces were cleaned with piranha solution (70% H2SO4:30% H2O2) for 15 min and subsequently rinsed thoroughly with deionized water. After drying in a vacuum dessicator, the surfaces were cleaned further with oxygen plasma (PLASMOD, Tegal) for 2 min. To obtain hydrophobic surfaces, the beads were soaked for 10 min in 10 vol % dimethyldichlorosilane (DMDCS, Sigma) in dry toluene (EM Science) (Lowe et al. 1986). The soak was followed by three rinses in absolute ethanol, one rinse in glass-distilled water, and a final ethanol rinse. The surfaces were then air-dried and cured in an 80°C oven with nitrogen flow for 3 h and stored in an airtight container. Beads were then soaked in bovine serum albumin solution (Sigma) in deionized water for 1 h. This treatment made the beads slippery and prevented adhesion of the beads to macromolecules in the endolymphatic space as well as adhesion to the membranous wall.
Afferent recording
Extracellular action potentials were recorded using saline-filled glass suction electrodes (tip diameter 
50 µm) that were brought in contact with the outside surface of the LC nerve near the ampulla. A small suction was applied until extracellular potentials were observed and maintained over the duration of the experiment. In most cases, individual single units could be identified using a simple window threshold (example Fig. 5). The extracellular potentials were conventionally amplified, filtered at 5 kHz, digitized at 10 kHz (National Instruments), and stored for subsequent analysis. Afferent responses were characterized in each animal using sinusoidal mechanical indentation (simulating head rotation) before, during, and after introduction of beads (Rabbitt et al. 1995).
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The afferent discharge modulations recorded in response to the sinusoidal stimuli allowed calculations of gain (spikes/s per deg/sec · s–1 of head rotation) and phase shift (degrees relative to the peak stimulus). The gain and phase were computed based on 10 consecutive sinusoidal stimulus cycles by manually selecting portions of the record. Using the zero crossing of the sinusoidal mechanical stimulus, response phase histograms of 25 bins per cycle were generated. Histograms were normalized by the number of cycles and displayed in the form of spike frequency (spikes/s). Histograms were fit with a sine wave to determine the magnitude and phase of the afferent response modulation. Bins containing no data were ignored and did not influence the curve fit. The phase was expressed as the difference in degrees between the peak amplitude of afferent response and the peak stimulus. The gain (sensitivity) was defined as the amplitude of sinusoidal afferent modulation over the amplitude of mechanical stimulus (spikes · s–1 · µm–1) and converted to the equivalent head rotation (spike/s per deg/s) by noting that a 1-µm LC indentation corresponds to about 4°/s of head angular velocity at the frequencies used (Rabbitt et al. 1995).
Afferent responses recorded during sinusoidal stimuli were used as a calibration to estimate the angular head velocity that would generate the same afferent discharge modulation as observed during pathological canalithiasis. For this, it was necessary to use a model of afferent discharge that was able to account for afferent discharge adaptation to maintained cupula displacements (Rabbitt et al. 2005) and capture gain and phase for sinusoidal stimui (Holstein et al. 2004). A fractional-order model was used because of its ability to fit both gain and phase of afferent discharge during sinusoidal stimuli and fit multi–time-constant adaptation to step stimuli. Responses for sinusoidal stimuli were first characterized using a simple fractional-order model of the form: S – 
= G
(dH/dt). Here S (spikes/s) is the afferent discharge rate as a function of time, (spikes/s) is the background discharge rate in the absence of a stimulus, H (deg/s) is the angular head velocity, t (s) is time, and G [spikes/s per deg/s (s)–1] is the fractional afferent gain. For sinusoidal stimuli, the fractional derivative power is related to the phase advance 
of afferent discharge relative to the stimulus by = x 90° (0 
1). The fractional order () and gain (G) were determined using responses to low-frequency sinusoidal stimuli by curve fitting the fractional-order model to bin histograms of the afferent modulation using least squares (Igor Pro, WaveMetrics, Lake Oswego, OR). We then used these same model parameters to estimate the equivalent head velocity that would need to occur to reproduce the afferent discharge patterns observed during BPPV when the head was stationary. This quantifies the pathological angular velocity signal transmitted to the brain. One complicating factor in the experiments was that introduction of the beads, because of their volume in the canal, caused excitation of the canal nerve even in the absence of gravity-driven bead movement. Afferent modulation caused by bead introduction followed the dynamic St = Gt(e–t/
1 – e–t/2), where Gt is the gain (spikes/s), 1 is the recovery time constant, and 2 is the rise time constant. These parameters were determined using untreated sticky beads that entered the canal but stuck to the wall and did not move under the action of gravity. Knowing the transient caused by introducing the beads St and the background discharge , we integrated the raw spike rate data S using the equation S – St – = G(dH/dt) numerically (Podlubny 1999) to estimate the equivalent head rotation H that would reproduce the same afferent discharge modulation observed experimentally during BPPV bead movement. Smoothing splines were used to interpolate the discharge rates to a continuous functions before numerical integration. In some cases, the background discharge rate at the end of the experiment differed slightly (up or down) from the rate before introducing beads. To account for this slow drift we used a straight-line interpolation of the background discharge from the pre- to the postbead data.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). The sticky beads did not move under the action of gravity toward the ampulla. Both adapting and nonadapting afferents (Rabbitt et al. 2005) responded with short-transient increases in discharge followed by a period of recovery to their resting discharge. Excitation occurred because the endolymph was displaced as the beads fell into the canal lumen. Part of the endolymph was directed toward the ampulla and this generated a transient excitatory response of afferents. In some cases (not shown), a small volume of endolymph was pulled out of the canal using the pipette, a manipulation that caused transient decreases in afferent discharge opposite of that caused by the introduction of beads. The small volume increase on introduction of the beads and the corresponding transient afferent response would not be present in human canalithiasis because the dense particles are already in the canal and are not suddenly introduced. Because of this, we focused our attention on experimental results obtained 1–4 s after the initial transient caused by introduction of the beads—a period when the dense particles were moving with nearly constant velocity toward the ampulla. On introduction into the canal lumen, the "slippery" beads fell to the bottom inside surface of the canal lumen and subsequently began to move downhill toward the ampulla. In most case, beads were introduced in groups of about eight to 20. The beads self-separated into a single-file line, spaced about 20–50 µm apart, and moved uniformly under the action of gravity toward the ampulla. Occasionally two or three beads moved together as a group, but in a vast majority of cases beads formed a single-file line as they moved along the canal (see online supplemental movie). Figure 4 shows the velocity of the beads recorded in a representative experiment. Because of the curved geometry of the canal, the beads reached a peak velocity of about 81 µm/s at a distance of about 5 mm from the ampulla and came to rest just before entering the ampulla after about 62–65 s of movement (see movie, online Supplement 2). In some animals, three to five beads fell into the ampulla, but in most cases the beads stopped moving just before entering the ampulla because of the presence of a small ledge in the anatomy adjacent to the ampulla (Fig. 1). The shaded region in Fig. 4 indicates the time range where afferent responses were dominated by transients associated with the introduction of the beads into the canal lumen (Fig. 3); after this initial period afferent responses observed were the result of bead movement along the canal lumen (see following text).
Figure 5 shows multiunit afferent responses recorded using a single electrode in an example experiment. Simple voltage thresholding was used to separate the afferent nerve recording into three "units" shown separately in Fig. 5, B, C, and D (superimposed in A). The time course corresponds to the bead movement in Fig. 4. Beads were introduced at time 0 s (arrow 1), moved along the canal lumen according to the velocity shown in Fig. 4, and eventually can to rest after about 70 s (arrow 2). Note that the units shown in B and C exhibited tonic responses that lasted during the entire duration of bead movement, whereas the unit shown in D had a rapidly adapting component followed by a mild tonic response. It is important to note that all of these responses were recorded simultaneously during the same bead movement. Thus differences arose from interafferent response dynamics and not from the mechanical stimuli caused by canalithiasis. Figure 6 shows the average increase in afferent discharge rate during bead movement recorded in three fish reported as three groups—A: units with tonic increases in discharge rate during bead movement; B: units that responded vigorously during the first 15 s but then adapted by nearly 10-fold after 55 s; and C: units that responded vigorously during the first 15 s but then adapted by nearly 100-fold after 55 s. Error bars denote the SE based on the number of spikes within the time window and averaged over units and should be interpreted as the SE of the average unit. For the tonic units (A) and the modestly adapting units (B), the increase in discharge during bead movement was significantly different from zero over the entire period of bead movement (paired t-test, P << 0.01). However, for the highly adapting units (C) the increase in discharge rate 40–50 s after the introduction of the beads was not statistically significant (P > 0.8).
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; Honrubia and House 2001), with onset and duration consistent with the signals transmitted to the brain by afferents in the present experimental study. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The afferent responses evoked by canalithiasis arise because the falling beads induce cupula deflection. Once a bead reaches its terminal velocity of falling, its acceleration is zero and the entire bead weight is taken up by the fluid surrounding the bead. If the bead is in the exact center of the canal, all of the weight is transferred to the cupula, thereby deflecting the cupula and leading to the observed afferent responses. The terminal velocity of a 15-µm-diameter spherical bead (2.8 specific gravity) sedimenting along the centerline of a perfectly vertical canal is predicted by Stokes flow to be 245 µm/s. In our experiments, the canal was oriented at an angle of nearly 21° and thus the component of the gravitational acceleration acting in the direction of bead movement was only 3.51 m/s2 (vs. 9.8). For this angle, the terminal velocity of a 15-µm-diameter settling otoconia predicted by Stokes equation would be about 88 µm/s—a figure that compares well with the present experimental observation of 81 (±25) µm/s.
Interestingly, once introduced into the canal, the beads self-separated and moved in a single-file line toward the ampulla along the bottom inside surface of the canal. The fact that the beads were moving along the wall rather than along the centerline of the duct lumen would cause part of the bead weight to be lost to viscous interaction with the wall instead of being transferred to the cupula. This effect would reduce the cupula deflection for beads moving along the wall versus beads moving along the centerline. It was shown previously (Bungay and Brenner 1973) that the influence of a cylindrical tube wall on the pressure caused by a spherical particle moving in a tube the size of the canal duct is small for large particles (>1 µm), but becomes large for small particles (<<1 µm; e.g., zero-diameter Stokeslet limit). Particles in the present experiments were relatively large (about 15–20 µm), but still much smaller than the lumen. As expected from the work of Bungay and Brenner (1973) for straight tubes, experimental results in this study were consistent with an analysis of larger beads (Rajguru et al. 2004, 2005), but inconsistent with the zero-diameter Stokeslets moving along the duct wall (Squires et al. 2004). The Stokeslet limit might be appropriate for very small particles (<<1 µm), but such small particles would not generate large symptoms once moving along the wall because of the dominant viscous interaction with the duct wall. This implies that archetypical canalithiasis BPPV most likely involves larger particles on the order of 5–20 µm in diameter. The present experiments did not investigate the amplifying effect that occurs when particles move from the relatively large cross-sectional area ampulla into the smaller canal lumen—an effect that is likely to be a major contributor to the onset latency in posterior canal BPPV and is a direct result of the hydrodynamics (House and Honrubia 2003; Rajguru et al. 2004, 2005; Squires et al. 2004).
Because endolymph fluid mechanics is linear, it is possible to extrapolate present results to otoconia and to a different number of particles and to particles with larger or smaller Stokes diameters. Otoconia, although not completely spherical (Lim 1984), have an effective Stokes radius that allows the present results to be applied to otoconial particles. The magnitude of the afferent response reported here simply scales with the number of particles—doubling the number of particles will double the magnitude. Changing the diameter of the particles is more complex because it changes the latency to the peak response, the terminal velocity of the particles, and the magnitude of the response. For example, the Stokes terminal velocity increases as the square of the diameter, so doubling the diameter will quadruple the terminal velocity and will reduce the latency to peak response. At the same time, the weight will increase as the cube of the diameter, thus predicting a much larger cupula displacement at steady state. Offsetting this is the somewhat slow response of the cupula. If the particles are large and move too fast, the cupula will not have sufficient time to come to a steady-state deflection and the magnitude of the neural response will not reach the level expected from the full weight of the particle(s). In addition, the complex geometry and curvature of the labyrinth are also important. These mechanical factors are discussed in more detail by Rajguru et al. (2004) in the framework of a morphologically descriptive biomechanical model of canalithiasis.
The present work is focused on afferent responses to canalithiasis. It is important to note that not all semicircular canal afferents respond equally in response to step excitatory cupula displacements—some afferents respond with tonic increases in discharge rate whereas other afferents initially increase their discharge rate and then adapt back to prestimulus levels over time (Rabbitt et al. 2005). The same diversity was observed during canalithiasis bead movement (Figs. 5 and 6). Afferents with tonic increases in discharge during bead movements were identified as classic velocity-sensitive afferents that modulate their discharge rate in direct proportion to head angular velocity over a broad bandwidth. These are the well-studied velocity-sensitive units in the toadfish (Boyle and Highstein 1990) and are analogous to the regular-discharging units in mammals (Fernández and Goldberg 1971; Goldberg and Fernández 1971). Velocity-sensitive afferents are also known to be nonadapting (or very slowly adapting) for maintained stimuli (Goldberg and Fernández 1971; Rabbitt et al. 2005). Other afferents exhibited an initial increase in the discharge rate followed by a period of adaptation during the bead movement. The most rapidly adapting were representative of phasic acceleration-sensitive afferents in the toadfish (Boyle and Highstein 1990)—units that are also known to adapt to maintained cupula deflection (Rabbitt et al. 2005). Adapting afferents in the fish have some response characteristics similar to the irregularly discharging units in mammals (Fernández and Goldberg 1971; Goldberg and Fernández 1971). Within this broad diversity of afferent responses and adaptation times, it is known that the velocity-sensitive (Fig. 6A, very slowly adapting regularly discharging units in mammals) are the most critical to the low-frequency vestibuloocular reflex (Minor and Goldberg 1991) and therefore would be expected to be the most important afferent inputs to the brain underlying nystagmus of patients suffering from canalithiasis BPPV. With this understanding, present results show that canalithiasis indeed generates significant and long-lasting pathological inputs to the brain stem that are sufficient to explain the symptoms of archetypical BPPV.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 The online version of this article contains supplemental data. 
Address for reprint requests and other correspondence: R. D. Rabbitt, University of Utah, Department of Bioengineering, 20 South 2030 East, Rm. 506, Salt Lake City, UT 84112 (E-mail: r.rabbitt{at}utah.edu)
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t, component of gravity tangent to canal), beads fell in a single line along the bottom wall of LC toward the ampulla. Enlarged views of a small section of the canal illustrate the beads within the lumen. At the end of each experiment, most of the beads congregated near the entrance of the ampulla (arrow b), whereas some fell into the relatively large cross section of the ampulla. Mechanical indentation was used (point I) to simulate angular rotation (Rabbitt et al. 1995
