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1Departments of Otolaryngology and 2 Neuroscience, University of Texas Medical Branch, Galveston, Texas; and 3Yerkes National Primate Research Center and 4Department of Neurology, Emory University, Atlanta, Georgia
Submitted 21 July 2004; accepted in final form 19 February 2005
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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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; Miles and Lisberger 1981 for review). Plasticity in the VOR allows adaptation to changes in vestibular-ocular function that occur over the lifetime of the individual, and this plasticity also allows for adaptation to pathological changes that affect the vestibular apparatus. The mechanisms supporting VOR plasticity that occur after injury to the peripheral vestibular system are incompletely understood. It is known that considerable compensation occurs during a recovery period after damage to the vestibular periphery and that interaction between the visual and vestibular systems is important (see Zee 2000 for review).
The most direct demonstration of the role of the visual system in vestibular compensation was conducted by Fetter and colleagues (1988), who showed that both development and maintenance of vestibular compensation were dependent on visual processing mediated by the occipital cortices. They assessed vestibular function by examining horizontal, angular VOR (hVOR). The development of vestibular compensation was delayed and was deficient in high velocity horizontal rotation (300°/s) when bilateral occipital lobectomy preceded hemilabyrinthectomy (HL). In addition, similar deficiencies in functional recovery occurred in complete darkness in centrally intact animals that recovered from HL surgery. These findings implicate visual experience in general, and visual processing mediated by the occipital cortices in particular, in the development of vestibular compensation. Our goal was to more precisely define potential sources of visual information that are specifically related to compensation.
There are two primary pathways by which the visual input might influence vestibular compensation. Anatomic and physiologic relations between the visual and vestibular systems have been identified in several CNS structures including the middle temporal (MT), medial superior temporal (MST), posterior parietal cortical regions, and subcortical areas such as the dorsolateral pontine nucleus (DLPN), the NOT, and the accessory optic system (AOS) (see Fuchs and Mustari 1993; Wurtz 1996 for review). The preceding cortical areas all project to the DLPN, which projects to the vestibulo-cerebellum including the flocculus and ventral paraflocculus, structures implicated by lesion studies to participate in optokinetic nystagmus, smooth pursuit, and visual and vestibular interactions (Belton and McCrea 2000; Lisberger 1994; Lisberger et al. 1994b; Ono et al. 2003; Rambold et al. 2002; Waespe and Cohen 1983; Zee et al. 1981). Thus the cortico-DLPN-floccular complex pathway is one potential route for visual signals to effect visual-vestibular interaction.
The other potential source involves the NOT. Primate NOT units predominantly respond preferentially to horizontal visual motion directed ipsilaterally (Hoffman and Distler 1986; Inoue et al. 2000; Mustari and Fuchs 1990). NOT units evince strong relationships between discharge rate and stimulus velocity between 1 and 200°/s (Das et al. 2001; Inoue et al. 2000; Mustari and Fuchs 1990). In addition, all NOT receptive fields examined include representation of the fovea. NOT unit velocity sensitivity and full-field visual representation are well suited to support the horizontal optokinetic response and may play an important role in the optokinetic support of the VOR during head movement (Fuchs and Mustari 1993; Schiff et al. 1990 for review). In the primate, neurons with sensitivity to vertical large-field visual motion are found in the lateral terminal nucleus (LTN), a member of the AOS (Mustari and Fuchs 1989). NOT and LTN neurons have appropriate visual response properties including direction and speed sensitivity to provide error signals to adjust the VOR behavior. For example, recent studies by Yakushin and colleagues (2000) reported that VOR gain could not be reduced in a short-term visual-vestibular mismatch paradigm in NOT lesioned monkeys. Specifically, NOT lesioned animals were unable to adapt the gain of contraversive VOR-induced eye velocities.
The AOS and NOT can influence smooth eye movements of foveal, optokinetic, or vestibular origin by at least three pathways. First, the NOT and LTN (AOS) project to the dorsal cap of the inferior olive (Buttner-Ennever et al. 1996; Hoffmann and Distler 1986; Maekawa and Simpson 1973; Mustari et al. 1994), the sole source of visual climbing fiber input to the flocculus (Langer et al. 1985; Maekawa and Simpson 1973). The climbing fiber driven complex spikes of floccular complex Purkinje cells have been shown to carry necessary and sufficient information for visual modification of the VOR (see Raymond and Lisberger 1996 for review). Second, the NOT projects to the nucleus reticularis tegmenti pontis (NRTP), a source of visual mossy fiber input to the vestibulo-cerebellum. This input could effect moment to moment changes in smooth eye movements (Benevento et al. 1977; Mustari et al. 1994; Ono et al. 2004). Third, both the AOS and NOT have been shown to project to the nucleus prepositus hypoglossi (NPH) and parts of the vestibular nuclear complex (VNC) (Belknap and McCrea 1986; Buettner-Ennever et al. 1996; Cooper and Magnin 1987; Mustari et al. 1994). These structures are known to contain neurons with vestibular, smooth pursuit, and visual sensitivity, some of which project directly to oculomotor neurons. In summary, both the AOS and NOT receive appropriate signals and project to relevant target structures to participate in all types of slow eye movements and might therefore be the likely sources of visual signals supporting visual/vestibular interactions and vestibular compensation.
In this study, we have recorded the changes in oculomotor behavior, in trained primates, during compensation after HL. We have compared the quality of vestibular compensation in monkeys with intact NOTs with analogous recordings obtained from monkeys with bilateral, excitotoxic lesions of the NOT performed prior to and after HL surgery. These comparisons allowed us to test our hypotheses that the NOT is a crucial source of visual input for vestibular compensation after HL. We have combined this information with previous results on the response characteristics of neurons in visual centers related to the vestibular nuclear complex to identify what types of visual stimulation are implicated in the development and maintenance of vestibular compensation.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Three juvenile male rhesus monkeys (Macaca mulatta) were used. One animal, C1, received only the hemilabyrinthectomy surgery. Two animals, A1 and A2, received bilateral lesions of the NOT before HL surgery. All experimental and animal care procedures were in strict adherence with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the University of Texas Medical Branch Institutional Animal Care and Use Committee. The animals were prepared by implantation of skull-mounted, stainless steel chambers fitted delrin guide platforms drilled with 1-mm grids. Eye movements were measured with an implanted scleral search coil (Judge et al. 1980) and electromagnetic induction method (Fuchs and Robinson 1966). The animals were painlessly head-restrained in a primate chair so that the horizontal semicircular canals were oriented in the earth horizontal plane. HL surgeries were performed using a retroauricular approach through the left mastoid. Each canal lumen was dissected to reveal and remove all three semicircular canal cristae. The utricular and saccular maculae were visualized and aspirated. All soft tissue and bony aspects of the labyrinth were scraped with a curette. The mastoid was packed with gel-foam and muscular fascia and closed. All surgical procedures were performed under aseptic conditions with the monkey under deep anesthesia (isoflurane 1–2%, or ketamine and xylazine).
Visual and vestibular stimulation
Smooth pursuit and fixation stimuli were presented using paired X and Y mirror galvanometers (General Scanning) to project a reflected laser beam on a tangent screen that served as the tracking target. Smooth pursuit protocols were sinusoidal motions of the target that ranged from 0.1 to 1.0 Hz with peak excursions of 10–20°. Large-field visual background stimulation was provided with another set of galvanometers that reflected a large-field, random-dot pattern from a projector. This system was used to provide sinusoidal, triangular, and sawtooth waveform background motion at 0.1–6 Hz, peak velocities of 2–50°/s. Large-field background stimulation was used to map NOT sites prior to ibotenic acid injections.
Vestibular stimuli in the form of sinusoidal and constant velocity angular rotations were provided by an apparatus consisting of a primate chair with attached magnetic search coil frame (CNC Engineering, Seattle), a mechanical interface between a 23-ft.-lb servo-controlled DC torque motor, a slip-ring system, and hardware for interfacing with the air bearings of a horizontal, linear track. The chair was mounted to the rotator interface with the vertical axis of rotation perpendicular to and bisecting the interaural axis. Angular accelerations were computer controlled (Acroloop 8000, Manufacture Location) with sinusoidal stimuli ranging from 0.1 to 5 Hz with peak angular velocities 
150°/s. Constant velocity rotations were performed using accelerations of 400°/s2 to constant velocities from 30 to 120°/s.
Saccades were removed off-line using an acceleration filter. Corrections for spontaneous nystagmus prior to constant velocity rotations were made by averaging slow phase eye velocity across a large number (>30) of trials to summarize nystagmus speeds and added or subtracted this spontaneous nystagmus offset. Sinusoidal rotation after HL surgery leads to asymmetric responses and a dynamic bias offset of eye velocity. We used half-cycle analysis to calculate VOR gains for head movements directed to different sides of the head. We solved for the dynamic bias offset and added or subtracted it from the eye velocity trace (see Fig. 6, inset). VOR gain (eye velocity/head velocity) was measured in complete darkness.
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Extracellular single-unit potentials were recorded using 0.005-in epoxy-insulated tungsten wire microelectrodes manufactured in-house or purchased (Frederich-Haer). Target-, large-field-, eye-, and head-position signals, and other analog signals (room lights, motor tachometer) were digitized at 5 kHz for quantitative off-line analysis. Unit recording signals were digitized at 40 kHz. Insulated tungsten microelectrodes were used for microelectrical stimulation. Unit responses were analyzed off-line using feature analysis techniques as already described (Stewart et al. 2004). We used electrical stimulation [200-Hz square wave, 100-µs impulse duration (2% duty cycle), 40–80 µA] to produce electrically elicited horizontal nystagmus that resembled horizontal OKN for verifying localization of the NOT (Mustari and Fuchs 1990; Schiff et al. 1988). Microelectrode position was controlled by an r-theta device rigidly coupled to the recording chamber. The r-theta device carried a stepper motor microdrive system (Frederich-Haer) that allowed precise movement of the electrode in depth.
NOT lesion placement
NOT lesions were placed using ibotenic acid (Sigma), 15 µg/µl, dissolved in phosphate buffered saline, pH 7.4. Ibotenic acid was delivered to NOT sites using cannulae constructed from 33-gauge stainless steel tubing adapted to calibrated polyethylene tubing (40 nl/mm). The filled cannula was placed inside a 26-gauge stainless steel guide tube and acutely placed into the brain above the NOT target and advanced to target using the microdrive. The injection apparatus was coupled to a pressure injection device (Picospritzer, General Valve). Injection volumes of 200–460 nl were delivered slowly over the course of 
2 min by applying short impulses (10–60 ms) of low pressure (10–60 psi). Animal A1 received a total of five injections: right NOT, three injections totaling 800 nl; and left NOT, two injections totaling 860 nl. Animal A2 received a total of two injections: right NOT, one injection of 320 nl; and left NOT, one injection of 200 nl. We chose to use multiple injections distributed in the NOT to remove as much of the NOT as possible without significant involvement of neighboring structures.
At the conclusion of the experimental series, each animal was given a lethal dose of barbiturate and perfused transcardially with heparinized saline (10,000 IU/l) followed by 4% paraformaldehye-lysine-phosphate (PLP), final solution 4% PLP with 25% sucrose. The pretectum was embedded in paraffin and cut coronally every 8 µm, mounted on microscope slides, and stained with cresyl violet. Some sections underwent immunohistological staining for antibodies directed against glial acidic fibrillary protein (GFAP; Vector) to detect ibotenic acid injection sites (e.g., Kaneko 1997).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The location of each NOT was determined by electrical stimulation that evoked nystagmus with slow phases directed toward the side of stimulation (Mustari and Fuchs 1990; Schiff et al. 1988). Figure 1 shows rightward slow-phase eye movements evoked by stimulation of the right NOT. Precise mapping of the NOT was achieved during electrophysiological recording experiments by recording of unit responses with preference for ipsilateral, full-field background motion (e.g., Mustari and Fuchs 1990). We have already shown that such ipsiversive visual neurons are restricted in medial-lateral, anterior-posterior, and dorsoventral extent to the NOT (Mustari and Fuchs 1990). Figure 2 displays discriminated unit activity related to ipsiversive full-field background motion. The position of the center of the large-field visual stimulus is plotted on the ordinate. This NOT neuron responds when visual motion direction is toward the side of recording (leftward).
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). Slow phase velocities were apparent in light within 10 min of injection and increased to saturation levels (
100°/s) within the hour. The initial excitatory effect of ibotenic acid was present after all seven injections of ibotenic acid. The initial values decreased over time. Histological confirmation of bilateral NOT lesion placement for animal A2 is presented in Fig. 3. The pretectal olivary nucleus (PON) serves as a useful landmark for establishing the location of the NOT in both single-unit recording and anatomical studies (e.g., Buettner-Ennever et al. 1996; Mustari and Fuchs 1990; Mustari et al. 1994). Even after the relatively long postlesion survival, we were able to confirm that our injections were well placed in the center of the NOT as indicated by GFAP staining and loss of NOT neurons at least in some GFAP-rich patches. Because there are no clear nuclear divisions between the NOT and surrounding regions, we could not be sure what proportion of NOT neurons were actually lost after lesions.
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RECOVERY OF DYNAMIC SYMPTOMS, CONSTANT VELOCITY ROTATIONS, PER-ROTATORY RESPONSES.
Figure 4 shows the peak, per-rotatory, slow phase velocity values, measured in response to constant velocity stimuli performed in darkness. Figure 4 displays responses to rotations directed toward the labyrinth intact (LI) and HL sides of the head (top and bottom) at speeds of 30, 60, 90, and 120°/s. The HL-only animal C1, had nearly identical slow phase velocities on post HL day 3 and 30 (Fig. 4, 
and 
), for LI rotations of 30, 60, and 90°/s. These gains measured on post-HL days 3 and 30 were: 0.68 and 0.70 for 30°/s, 0.79 and 0.76 for 60°/s, and 0.79 and 0.78 for 90°/s. At the highest head velocity, 120°/s, C1 had a post-HL day 3 gain of 0.80. This decreased to 0.59 on post-HL day 30. Gain recovery for this rotation rose to 0.82 by post-HL day 55, and was 0.92 on post-HL day 472. This pattern of initially high values of gain recovery, followed by a transient decreases, and finally, asymptotic increases was evident for LI rotations at all velocities.
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and 
) exhibited small, and in some cases no, responses for constant velocity rotations performed in the dark. To characterize these responses, the data plotted in Fig. 4 have been divided into two categories for animal A1: early and late. Early responses range from post-HL day 3–61; late responses are from post-HL day 124 and 210. The actual post-HL days used for each point are given in the legend of Fig. 4. Both the initial and final gains for LI rotation were low for animal A1. The early and late compensation gains for LI rotation for A1 were: 0.27 and 0.39 for 30°/s, 0.23 and 0.16 for 60°/s, 0.14 and 0.09 for 90°/s; and 0.09 and 0.09 for 120°/s.
Figure 4 plots post-HL day 3 and day 90 data for A2 (Fig. 4, 
and 
). Data were chosen from that obtained on post-HL day 90 for comparison to post-HL day 30 data of the control animal C1. Animal A2 had intermediate responses compared with C1 and A1. The HL day 3 and 90 gains for LI rotation for A2 were: 0.41 and 1.11 for 30°/s, 0.42 and 0.80 for 60°/s, 0.40 and 0.65 for 90°/s, and 0.35 and 0.69 for 120°/s. In comparison, Fetter and Zee (1988) described VOR gain recovery to constant velocity rotation as essentially completed by day 94. For example, for rotations of 120°/s, the six monkeys in that study had average LI and HL gains of 0.92 and 0.75.
Rotations directed toward the HL side of the head are plotted in Fig. 4, bottom, using the same days as described in the preceding text. Animal A1 early and late gains for post-HL rotation were: 0.14 and 0.23 for 30°/s, 0.06 and no response for 60 °/s, 0.26 and 0.13 for 90°/s, and 0.15 and 0.11 for 120°/s. Animal C1 also had much lower gains compared with LI rotation. The post-HL day 3 and 30 gains for C1 were: 0.52 and 0.37 for 30°/s, 0.30 and 0.50 for 60°/s, 0.31 and 0.66 for 90°/s, and 0.36 and 0.50 for 120°/s. Responses for rotations toward the HL side recovered at a slower rate than LI rotations, which reached final values after 3 days. The post-HL day 294 gains improved to 0.61 for 30°/s, 0.75 for 60°/s, 0.59 for 90°/s, and 0.81 for 120°/s. Animal A2 had variable results that were delayed compared with C1. The post-HL day 3 and 90 gains for A2 were: 0.16 and 0.56 for 30°/s, no response and 0.65 for 60°/s, 0.17 and 0.49 for 90°/s, and 0.21 and 0.58 for 120°/s. Animal A2 had much greater recovery than A1. Nevertheless those responses were initially much lower and recovered more slowly than C1. Rotations of 30, 60, and 120°/s led to gains that were higher at post-HL day 90 for A2 than post-HL day 30 gains for C1. In all cases, the final HL gain values for C1 exceeded the post-HL day 90 gain levels of A2.
In summary, per-rotatory responses for C1 were similar to findings of a previous study (Fetter and Zee 1988) for both LI and HL rotations. Responses for both LI and HL rotations were absent or very low for animal A1, the animal that received five ibotenic acid lesions. Responses for animal A2, the animal that received two ibotenic acid lesions, were intermediate between A1 and C1. In all cases of HL rotation, final C1 gains exceeded A2 responses at post-HL day 90. Post-HL day 3 responses of C1 always exceeded day 3 responses of animals A1 and A2.
RECOVERY OF DYNAMIC SIGNS, CONSTANT VELOCITY ROTATIONS, POSTROTATORY RESPONSES. Postrotatory responses were examined for eight protocols of rotations performed in darkness. Postrotatory responses are related to per-rotatory responses in several ways. Both responses consisted of eye motions evoked by passive head rotation and both demonstrated velocity storage. We examine postrotatory responses because, in the HL animal, LI accelerations that evoke postrotatory responses may only utilize compensatory mechanisms. Postrotatory responses are generated when the head and body are stationary. The stimulation arises from utriculo-fugal motion of the cupula of the contralesional (LI) horizontal semicircular canal.
Figure 5 (top) plots the postrotatory responses after LI-directed rotations for all three animals using the same days detailed in Figs. 4. Animal A1 only generated five responses for the eight early and eight late rotations. The HL-only control, C1, had post-HL day 3 and 30 gains that were: 0.47 and 0.32 for 30°/s, 0.40 and 0.53 for 60°/s, 0.43 and 0.49 for 90°/s, and 0.45 and 0.48 for 120°/s. Animal A2 had post-HL day 90 responses to 30 and 60°/s that exceeded post-HL day 30 values. In contrast, for the higher velocities of 90 and 120°/s, the post-HL day 90 responses were less that the post-HL day 3 values of C1. The post-HL day 3 and day 90 gains for A2 were no response and 0.81 for 30°/s, 0.30 and 0.70 for 60°/s, 0.21 and 0.38 for 90°/s, and 0.12 and 0.43 for 120°/s. In all cases, the post-HL day 3, postrotatory, LI responses of A2 were lower that C1.
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In summary, postrotatory responses for C1 were similar to those reported in other studies (Fetter and Zee 1988) for both LI and HL rotations. Early responses of C1 were always higher than A1 and A2. At lower velocities, A2 and C1 generated similar responses. At higher velocities, A2 recovery was 50% lower than C1.
RECOVERY OF DYNAMIC SYMPTOMS, SINUSOIDAL ROTATIONS, VOR GAIN RECOVERY. All three animals were tested with the following six protocols of passive, horizontal, sinusoidal rotations: 60°/s peak velocity at 0.2, 1.0, and 2.0 Hz and 30, 60, and 90°/s peak velocity at 0.5 Hz. HL surgery led to permanent, asymmetric hVOR responses in all animals for all stimuli tested, requiring the use of half-cycle analysis to calculate gains for HL- and LI-directed motion. In addition, spontaneous nystagmus after HL leads to an offset of eye velocity during sinusoidal motion, over- and underestimating the two half-cycle gains (Fig. 6, open points, and inset). This was corrected by subtracting the offset from the eye velocity traces (Fig. 6, filled points). Half-cycle gains of corrected and uncorrected eye responses have been determined for animals A1, A2, and C1 (Table 1). Figure 6 illustrates the corrected and uncorrected responses of all three animals to sinusoidal stimulation at 0.5 Hz, peak velocity 30°/s.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The HL-only control animal C1 had per-rotatory VOR gain recovery patterns that closely matched the results of Fetter and Zee (1988). In particular, LI- directed rotations demonstrated nearly complete recovery after 3 days. In contrast, both A1 and A2 had much lower gain values three days after HL (Fig. 4). Animal A2 demonstrated slow and consistent gain recovery. These responses are similar to the lower velocities studied by Fetter and Zee (1988), 30, 60, and 120°/s. Their occipital lobectomized monkeys demonstrated 50–75% increases in gain from day 3 to 93. In contrast, our animal A1 had very poor gain recovery for all rotations indicating a more potent effect of NOT lesions then that found after lesion of the occipital lobes (see following text). This more potent effect compared with the occipital lobectomy results of Fetter and colleagues (1988) may be due to the afferent and efferent connections of the NOT per se. As schematized in Fig. 8, the NOT receives visual inputs not only from the contralateral retina but also from the ipsilateral middle temporal visual area (MT) (see Distler et al. 2002 for review). Hoffmann and colleagues (1992) have demonstrated that NOT projecting MT neurons carry ipsiversive visual signals. Occipital lobectomy would have interrupted the flow of MT signals to the NOT. However, direct retinal inputs from the contralateral retina would remain. It is possible that this source of visual motion still could play a role in vestibular compensation in the occipital lobectomy cases. The strong efferent projection of the NOT to the dorsal cap of Kooy may also explain the more dramatic results we obtained with NOT lesions compared with occipital lobectomy. Our anatomical results (Mustari et al. 1994) and the work of Buettner-Ennever and colleagues (1996) show that the primate NOT is a major source of input to the dorsal cap of Kooy of the inferior olive.
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demonstrated a slower pattern of recovery for HL-directed rotations. These animals recovered only 50% of the final gain values after 4 days compared with the final values at 93 days. Monkey C1 exhibited similar findings and in fact continued to achieve even larger gains over the final 7 mo. The early responses of A1 and A2 were always much lower than those of C1, demonstrating that vestibular compensation was delayed. In addition, the degree of compensation was always less, despite longer post lesion recovery times. Vestibular compensation, measured by per-rotatory responses to constant velocity rotation, was clearly impaired by prior NOT lesions. Postrotatory analysis of LI-directed constant velocity rotations provides special insight into vestibular compensation (Fig. 5). At the higher velocities of 90 and 120°/s, control animal C1 always had higher postrotatory gains than A1 and A2. At lower velocities, C1 had higher final gains, but these differences were smaller. Higher velocities cause larger postrotatory, utriculo-fugal deflections of the contralesional cupula in the horizontal ampulla. As a consequence, up to the point of inhibitory cutoff, higher velocities provide more sensory information about head acceleration in the compensated animal. In this special case of vestibular stimulation in the absence of head motion, NOT lesions were associated with attenuated vestibular compensation compared with control.
Sinusoidal rotation: VOR gain recovery
HL in the normal monkey leads to a dynamic bias of eye movements during sinusoidal rotation. This differs from the spontaneous nystagmus present acutely after HL surgery. Spontaneous nystagmus occurs in the absence of head motion. Dynamic bias occurs during head motion but may not be VOR mediated. This bias must be subtracted or added to assess the VOR-mediated contribution of the actual eye movements. The uncorrected signal, however, serves as an indicator of overall, or absolute gain, i.e., the actual response of the animal. Because spontaneous nystagmus generated slow phases directed toward the HL side at rest, the dynamic bias is additive for LI rotation and subtractive for HL rotation, see Fig. 6, inset.
Half-cycle gains remain asymmetric after correction for dynamic bias offset. HL surgery alone and HL combined with NOT lesions induces a permanent, asymmetric difference in VOR performance. Based on the different patterns of recovery of VOR gain for constant velocity and sinusoidal rotations, we conclude that the visual motion processing provided by the pretectal nucleus of the optic tract is essential for the development of compensation of dynamic VOR responses.
Therapeutic strategies For vestibular rehabilitation
Several animal and human studies have determined that motion and exercise differences during recovery from labyrinthine injury may lead to different functional outcomes. Passively applied or voluntary motion of the eyes, head, and neck may lead to the generation of retinal slip signals and alters recovery (Miles and Eighmy 1980). Squirrel monkeys recovering from HL surgery in a rotating cage had less spontaneous nystagmus than monkeys recovering in static cages (Igarashi et al. 1975). In a separate study, Igarashi et al. (1981) found that the active group compensated for locomotion faster than static monkeys. Dynamic VOR gain recovery after HL does not occur for cats (Courjon et al. 1977) or monkeys (Fetter and Zee 1988) kept in darkness during recovery. The source of visual information was partially identified by showing that bilateral occipital lobectomy prior to HL surgery attenuates VOR gain in monkeys (Fetter and Zee 1988; Zee 2000). Visual motion was shown to play a role in adapting the VOR 3 days after HL surgery in cats (Maioli and Precht 1985). Consistent with these experimental results is the finding that patients receiving optokinetic stimulation increased VOR gain after HL surgery, compared with untreated patients (Pfaltz 1983). Patients assisted with specific vestibular adaptation exercises increased VOR gain more than those performing unsupervised, nonspecific vestibular exercises (Szturm et al. 1994). A prospective, double-blinded, human study compared combined vestibular and visual exercise paradigms with pursuit-only therapy and found increased locomotion and gaze control in the vestibular rehabilitation group (Herdman et al. 1995). Expanding postoperative therapy to include sustained rotation of the visual world with the head-fixed would lead to activation of the indirect pathway of the optokinetic nystagmus (discussed in the following text). Combined pre- and postoperative therapy could help to maximize the potential degree of recovery for different patient populations.
Schematic model for visual-vestibular interactions during compensation
The optokinetic response (OKR) is generated when the visual field moves relative to the retina (see Fuchs and Mustari 1993 for review). When the head is at rest, the response enables tracking of a target in motion with respect to the stationary background. OKR may also occur when the head is in motion and gaze is changed as the eye tracks stationary images. Finally, if both the head and the eye are at rest, motion of the visual world will move the image across a stationary retina. The second and third cases are closely related in that the eyes are at rest, and either the visual field rotates about the fixed head or the head rotates within a fixed visual field. Rotation of the head stimulates the vestibular system and generates VOR movements. OKR complements VOR responses to prevent visual blurring when VOR responses are less than the head motion that evoked them especially at slower head velocities.
Anatomical investigation of the NOT led to the development of a schematic model that unified the relevant visual and vestibular anatomy and proposed direct and indirect pathways that anatomically and functionally served as the neural mechanisms underlying the rapid and slow components of OKN, Fig. 8 (Buttener-Ennever et al. 1996; Mustari et al. 1994; Tusa et al. 2001). The NOT projects to anatomical groups from both pathways. There are connections to the dorsal cap of Kooy of the inferior olive that provides the sole source of visual climbing fibers to the flocculus. The NOT also has access to the dorsolateral pontine nucleus, which provides mossy fiber input the flocculus. In addition, the NOT provides projections directly to the vestibular brain stem including areas of the medial vestibular nuclei and prepositus nucleus that have been implicated in vestibuloocular functions (Mustari et al. 1994). Both cerebellar and brain stem projections of the NOT involve areas that have been implicated in visually induced VOR gain adaptation.
The climbing fiber input to the flocculus been implicated as providing input to floccular mechanisms for adaptation of ocular motor function (Belknap and McCrea 1988; Glickstein et al. 1994; Langer et al. 1985; Lisberger et al. 1994b; Raymond and Lisberger 1996). Dorsal cap of Kooy neurons also discharge during retinal slip, but this discharge changes only slightly for different retinal slip speeds (Fuchs et al. 1992). Thus the pretecto-olivary input to the flocculus could serve to indicate the presence of retinal slip to allow floccular/ventral parafloccular activation of VOR plasticity (Mustari et al. 1994). If NOT input was missing, or permanently impaired, then VOR adaptation to subsequent HL surgery might be delayed, deficient, or absent, see Fig. 8, A. The deficient vestibular compensation of our combined NOT and HL lesion experiments reported here support this conclusion.
The direct pathway generates the rapid component of OKN. Because normal head motion in the light generates OKR contributions to VOR, the initial rapid component is present in normal head motion. In the HL state, the contribution of VOR responses to maintain a stable retinal image is greatly perturbed. As a result, OKR contributions become increasingly important. The NOT contributes to the direct pathway via the dorsolateral pontine nucleus, which in turn supplies fast mossy fiber input to the flocculus, see Fig. 8, B. The dorsolateral pontine nucleus, through projections to the floccular complex, has been implicated in the initiation of smooth pursuit, and ocular following, in addition to the initial rise component of OKN (May et al. 1988; Mustari et al. 1988; Ono et al. 2004; Suzuki and Keller 1988; Thier et al. 1988). Because the OKR increases in importance during normal function and vestibular hypofunction, this mechanism would be especially susceptible to NOT lesion prior to HL surgery.
The NOT has direct connections to the medial vestibular nucleus and the nucleus prepositus hypoglossi, both of which project to eye motoneurons, see Fig. 8, C. If vestibular compensation requires retinal slip information directly, bypassing the floccular pathways, or in addition to the floccular pathways, then the permanent NOT lesions in animals A1 and A2 would lead to deficient gain compensation after HL surgery.
Visual gain adaptation probably results from modifiable elements including both floccular and vestibular nuclear complex neurons (Lisberger 1994). Studies by Raymond and Lisberger (1996) have demonstrated that climbing fiber driven complex spike activity carry appropriate information for modification of VOR gain at low and high frequencies in a visual-vestibular mismatch paradigm. The source of these visual climbing fibers is at least in part from the NOT. The experiments of Yakushin et al. (2000) are complimentary to ours in showing that NOT-lesioned animals are unable to use visual motion information to modify the gain of the VOR in either short- or long-term paradigms. The vestibulo-cerebellum also receives visual information along mossy fiber pathways (e.g., Glickstein et al. 1994). The studies reported here did not specifically address the potential role of visual mossy fibers in vestibular plasticity. However, recent experiments have evaluated the role of visual mossy fibers in VOR adaptation. Ono and colleagues (2003) used unilateral muscimol injections to evaluate the potential role of the DLPN on short-term gain modifications (increase and decrease) of the VOR in a visual-vestibular mismatch paradigm. Unilateral DLPN inactivation did not affect visually guided motor learning in the VOR because appropriate gain increases and decreases were obtained in the visual-vestibular mismatch paradigm. Unilateral DPLN inactivation did produce deficits in ipsilesional smooth pursuit and cancellation of the VOR. Therefore experiments to date indicate that visual information carried along climbing fibers is required for all types of VOR plasticity. Perhaps visual information carried along mossy fibers is most important for moment-by-moment control of visual-vestibular, ocular following, and smooth pursuit behavior. The experiments described in this report involved bilateral chemical lesions of the NOT that could have affected multiple elements of direct and indirect OKN pathways, Fig. 8. In the indirect pathway, the most likely mechanism for deficient VOR gain compensation is the loss of climbing fiber input into the flocculus as reviewed in the preceding text. This signal conveys information indicating the presence of retinal image motion. Without this input from the NOT, gain adaptation strategies initiated in the floccular complex would be attenuated. Further studies would be required to evaluate the potential role of visual mossy fibers in the process of vestibular compensation following HL.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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Present address of C. M. Stewart: Johns Hopkins University, Dept. of Otolaryngology, Head and Neck Surgery, 601 N. Caroline St., Baltimore, MD 21287–6214.
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Address for reprint requests and other correspondence: A. A. Perachio, University of Texas Medical Branch, 301 University Blvd., Route 0130, Galveston, TX, 77555-0130 (E-mail: aperachi{at}utmb.edu)
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). A and B: low-power (x4) views of the left and right pretectal areas, scale bar = 500 µm. The approximate location of the NOT at each level is indicated (- - -). C and D: higher-power views (x10) of the left and right pretectal lesions indicating necrosis and gliosis, scale bar = 100 µm. The line drawing shows the approximate locations A and B above and the locations of the trochlear nucleus (IV), periaqueductal gray (PAG), pontine olivary nucleus (PON), and NOT.
