Htr2a-Expressing Cells in the Central Amygdala Control the Hierarchy between Innate and Learned Fear.

Fear is induced by innate and learned mechanisms involving separate pathways. Here, we used an olfactory-mediated innate-fear versus learned-fear paradigm to investigate how these pathways are integrated. Notably, prior presentation of innate-fear stimuli inhibited learned-freezing response, but not vice versa. Whole-brain mapping and pharmacological screening indicated that serotonin-2A receptor (Htr2a)-expressing cells in the central amygdala (CeA) control both innate and learned freezing, but in opposing directions. In vivo fiber photometry analyses in freely moving mice indicated that innate but not learned-fear stimuli suppressed the activity of Htr2a-expressing CeA cells. Artificial inactivation of these cells upregulated innate-freezing response and downregulated learned-freezing response. Thus, Htr2a-expressing CeA cells serve as a hierarchy generator, prioritizing innate fear over learned fear.

Long-latency optical responses from the dorsal inferior colliculus of Seba's fruit bat.

We used a novel microendoscope system to record simultaneously optical activity (fluorescence of a calcium indicator dye) and electrical activity (multi-unit activity and local field potentials) from the dorsal inferior colliculus of the echolocating bat, Carollia perspicillata. Optically recorded calcium responses to wide-band noise and to frequency-modulated bursts were recorded at probe depths down to 1300 µm, with the majority of active sites encountered at more shallow depths down to 800 µm. Calcium activity exhibited long latencies, within the time span of 50-100 ms after stimulus onset, significantly longer than onset latencies of either multi-unit activity or local field potentials. Latencies and amplitude/latency trading of these electrical responses were consistent with those seen in standard electrophysiological recordings, confirming that the microendoscope was able to record both neural and optical activity successfully. Optically recorded calcium responses rose and decayed slowly and were correlated in time with long-latency negative deflections in local field potentials. These data suggest that calcium-evoked responses may reflect known, sustained inhibitory interactions in the inferior colliculus.

Contribution of action potentials to the extracellular field potential in the nucleus laminaris of barn owl.

Extracellular field potentials (EFP) are widely used to evaluate in vivo neural activity, but identification of multiple sources and their relative contributions is often ambiguous, making the interpretation of the EFP difficult. We have therefore analyzed a model EFP from a simple brainstem circuit with separable pre- and postsynaptic components to determine whether we could isolate its sources. Our previous papers had shown that the barn owl neurophonic largely originates with spikes from input axons and synapses that terminate on the neurons in the nucleus laminaris (NL) (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274-2290, 2010; Kuokkanen PT, Ashida G, Carr CE, Wagner H, Kempter R. J Neurophysiol 110: 117-130, 2013; McColgan T, Liu J, Kuokkanen PT, Carr CE, Wagner H, Kempter R. eLife 6: e26106, 2017). To determine how much the postsynaptic NL neurons contributed to the neurophonic, we recorded EFP responses in NL in vivo. Power spectral analyses showed that a small spectral component of the evoked response, between 200 and 700 Hz, could be attributed to the NL neurons' spikes, while nucleus magnocellularis (NM) spikes dominate the EFP at frequencies ≳1 kHz. Thus, spikes of NL neurons and NM axons contribute to the EFP in NL in distinct frequency bands. We conclude that if the spectral components of source types are different and if their activities can be selectively modulated, the identification of EFP sources is possible. NEW & NOTEWORTHY Extracellular field potentials (EFPs) generate clinically important signals, but their sources are incompletely understood. As a model, we have analyzed the auditory neurophonic in the barn owl's nucleus laminaris. There the EFP originates predominantly from spiking in the afferent axons, with spectral power ≳1 kHz, while postsynaptic laminaris neurons contribute little. In conclusion, the identification of EFP sources is possible if they have different spectral components and if their activities can be modulated selectively.

Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning.

The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention.

Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice.

The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.

Role of granule-cell transmission in memory trace of cerebellum-dependent optokinetic motor learning.

Adaptation of the optokinetic response (OKR) is an eye movement enhanced by repeated motion of a surrounding visual field and represents a prototype of cerebellum-dependent motor learning. Purkinje cells and vestibular nuclei (VN) receive optokinetic and retinal slip signals via the mossy fiber-granule cell pathway and climbing-fiber projections, respectively. To explore the neural circuits and mechanisms responsible for OKR adaptation, we adopted the reversible neurotransmission-blocking (RNB) technique, in which granule-cell transmission to Purkinje cells was selectively and reversibly blocked by doxycycline-dependent expression of transmission-blocking tetanus toxin in granule cells. Blockade of granule-cell inputs abolished both short-term and long-term OKR adaptation induced by repeated OKR training, but normal levels of both responses were immediately evoked in the pretrained RNB mice by OKR retraining once granule-cell transmission had recovered. Importantly, eye movement elicited by electrical stimulation of the cerebellar focculus was elevated by long-term but not by short-term OKR training in adaptive OKR-negative RNB mice. Furthermore, when the flocculus of adaptive OKR-negative RNB mice was electrically excited in-phase with OKR stimulation, these mice exhibited long-term adaptive OKR. These results indicate that convergent information to the VN was critical for acquisition and storage of long-term OKR adaptation with conjunctive action of Purkinje cells for OKR expression. Interestingly, in contrast to conditioned eyeblink memory, the expression of once acquired adaptive long-term OKR was not abrogated by blockade of granule-cell transmission, suggesting that distinct forms of neural plasticity would operate in different forms of cerebellum-dependent motor learning.

Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens.

Dopamine (DA) transmission from the ventral tegmental area (VTA) is critical for controlling both rewarding and aversive behaviors. The transient silencing of DA neurons is one of the responses to aversive stimuli, but its consequences and neural mechanisms regarding aversive responses and learning have largely remained elusive. Here, we report that optogenetic inactivation of VTA DA neurons promptly down-regulated DA levels and induced up-regulation of the neural activity in the nucleus accumbens (NAc) as evaluated by Fos expression. This optogenetic suppression of DA neuron firing immediately evoked aversive responses to the previously preferred dark room and led to aversive learning toward the optogenetically conditioned place. Importantly, this place aversion was abolished by knockdown of dopamine D2 receptors but not by that of D1 receptors in the NAc. Silencing of DA neurons in the VTA was thus indispensable for inducing aversive responses and learning through dopamine D2 receptors in the NAc.

TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade.

An essential step in intricate visual processing is the segregation of visual signals into ON and OFF pathways by retinal bipolar cells (BCs). Glutamate released from photoreceptors modulates the photoresponse of ON BCs via metabotropic glutamate receptor 6 (mGluR6) and G protein (Go) that regulates a cation channel. However, the cation channel has not yet been unequivocally identified. Here, we report a mouse TRPM1 long form (TRPM1-L) as the cation channel. We found that TRPM1-L localization is developmentally restricted to the dendritic tips of ON BCs in colocalization with mGluR6. TRPM1 null mutant mice completely lose the photoresponse of ON BCs but not that of OFF BCs. In the TRPM1-L-expressing cells, TRPM1-L functions as a constitutively active nonselective cation channel and its activity is negatively regulated by Go in the mGluR6 cascade. These results demonstrate that TRPM1-L is a component of the ON BC transduction channel downstream of mGluR6 in ON BCs.

Computation of interaural time difference in the owl's coincidence detector neurons.

Both the mammalian and avian auditory systems localize sound sources by computing the interaural time difference (ITD) with submillisecond accuracy. The neural circuits for this computation in birds consist of axonal delay lines and coincidence detector neurons. Here, we report the first in vivo intracellular recordings from coincidence detectors in the nucleus laminaris of barn owls. Binaural tonal stimuli induced sustained depolarizations (DC) and oscillating potentials whose waveforms reflected the stimulus. The amplitude of this sound analog potential (SAP) varied with ITD, whereas DC potentials did not. The amplitude of the SAP was correlated with firing rate in a linear fashion. Spike shape, synaptic noise, the amplitude of SAP, and responsiveness to current pulses differed between cells at different frequencies, suggesting an optimization strategy for sensing sound signals in neurons tuned to different frequencies.

Signal-to-noise ratio in the membrane potential of the owl's auditory coincidence detectors.

Owls use interaural time differences (ITDs) to locate a sound source. They compute ITD in a specialized neural circuit that consists of axonal delay lines from the cochlear nucleus magnocellularis (NM) and coincidence detectors in the nucleus laminaris (NL). Recent physiological recordings have shown that tonal stimuli induce oscillatory membrane potentials in NL neurons (Funabiki K, Ashida G, Konishi M. J Neurosci 31: 15245-15256, 2011). The amplitude of these oscillations varies with ITD and is strongly correlated to the firing rate. The oscillation, termed the sound analog potential, has the same frequency as the stimulus tone and is presumed to originate from phase-locked synaptic inputs from NM fibers. To investigate how these oscillatory membrane potentials are generated, we applied recently developed signal-to-noise ratio (SNR) analysis techniques (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274-2290, 2010) to the intracellular waveforms obtained in vivo. Our theoretical prediction of the band-limited SNRs agreed with experimental data for mid- to high-frequency (>2 kHz) NL neurons. For low-frequency (≤2 kHz) NL neurons, however, measured SNRs were lower than theoretical predictions. These results suggest that the number of independent NM fibers converging onto each NL neuron and/or the population-averaged degree of phase-locking of the NM fibers could be significantly smaller in the low-frequency NL region than estimated for higher best-frequency NL.

Spatio-temporal control of neural activity in vivo using fluorescence microendoscopy.

Controlling neural activity with high spatio-temporal resolution is desired for studying how neural circuit dynamics control animal behavior. Conventional methods for manipulating neural activity, such as electrical microstimulation or pharmacological blockade, have poor spatial and/or temporal resolution. Algal protein channelrhodopsin-2 (ChR2) enables millisecond-precision control of neural activity. However, a photostimulation method for high spatial resolution mapping in vivo is yet to be established. Here, we report a novel optical/electrical probe, consisting of optical fiber bundles and metal electrodes. Optical fiber bundles were used as a brain-insertable endoscope for image transfer and stimulating light delivery. Light-induced activity from ChR2-expressing neurons was detected with electrodes bundled to the endoscope, enabling verification of light-evoked action potentials. Photostimulation through optical fiber bundles of transgenic mice expressing ChR2 in layer 5 cortical neurons resulted in single-whisker movement, indicating spatially restricted activation of neurons in vivo. The probe system described here and a combination of various photoactive molecules will facilitate studies on the causal link between specific neural activity patterns and behavior.

Variants of benign paroxysmal positional vertigo in relation to head position during sleep.

BACKGROUND: Patients with posterior- and lateral-(canal)-benign paroxysmal positional vertigo (BPPV)-canalolithiasis sleep in the affected-ear-down head position. Posterior-BPPV-canalolithiasis typically affects the right than left ear; sleeping in the right-ear-down head position may be causal. OBJECTIVE: To investigate the relationship between habitual head position during sleep and the onset of BPPV variants. METHODS: Among 1,170 cases of BPPV variants with unknown etiology, the affected ears, habitual head positions during sleep based on interviews, and relationships among them were investigated. RESULTS: Posterior-BPPV-canalolithiasis and lateral-BPPV-canalolithiasis-geotropic affected the right ear significantly more often. Significantly more patients with posterior-BPPV-canalolithiasis and lateral-BPPV-canalolithiasis-apogeotropic habitually slept in the right-ear-down head position. Patients with posterior- and lateral-BPPV-canalolithiasis and light cupula were more likely to sleep habitually in the affected-ear-down position than in the healthy-ear-down head position; no relationship was observed in patients with posterior- and lateral-BPPV-cupulolithiasis. In patients with posterior-BPPV-canalolithiasis and lateral-BPPV-canalolithiasis-geotropic, the proportion of right-affected ears in those sleeping habitually in the right-ear-down head position was significantly greater than that for the left-affected ear. CONCLUSIONS: A habitual affected-ear-down head position during sleep may contribute to BPPV-canalolithiasis and light cupula onset, but not BPPV-cupulolithiasis onset. However, habitual sleeping in the right-ear-down head position cannot explain the predominance of right-affected ears.

Protein kinase G dynamically modulates TASK1-mediated leak K+ currents in cholinergic neurons of the basal forebrain.

Leak K(+) conductance generated by TASK1/3 channels is crucial for neuronal excitability. However, endogenous modulators activating TASK channels in neurons remained unknown. We previously reported that in the presumed cholinergic neurons of the basal forebrain (BF), activation of NO-cGMP-PKG (protein kinase G) pathway enhanced the TASK1-like leak K(+) current (I-K(leak)). As 8-Br-cGMP enhanced the I-K(leak) mainly at pH 7.3 as if changing the I-K(leak) from TASK1-like to TASK3-like current, such an enhancement of the I-K(leak) would result either from an enhancement of hidden TASK3 component or from an acidic shift in the pH sensitivity profile of TASK1 component. In view of the report that protonation of TASK channel decreases its open probability, the present study was designed to examine whether the activation of PKG increases the conductance of TASK1 channels by reducing their binding affinity for H(+), i.e., by increasing K(d) for protonation, or not. We here demonstrate that PKG activation and inhibition respectively upregulate and downregulate TASK1 channels heterologously expressed in PKG-loaded HEK293 cells at physiological pH, by causing shifts in the K(d) in the acidic and basic directions, respectively. Such PKG modulations of TASK1 channels were largely abolished by mutating pH sensor H98. In the BF neurons that were identified to express ChAT and TASK1 channels, similar dynamic modulations of TASK1-like pH sensitivity of I-K(leak) were caused by PKG. It is strongly suggested that PKG activation and inhibition dynamically modulate TASK1 currents at physiological pH by bidirectionally changing K(d) values for protonation of the extracellular pH sensors of TASK1 channels in cholinergic BF neurons.

Real-time imaging of head and neck squamous cell carcinomas using confocal micro-endoscopy and applicable dye: A preliminary study.

OBJECTIVES: Confocal laser endomicroscopy (CLE) is a technology that enables microscopic visualization of lesions in real-time (optical biopsy) and has been successfully applied for clinical use in gastroenterology. Recently, it was also introduced for head and neck squamous cell carcinoma (HNSCC) diagnostics. We previously designed a self-made CLE, which can provide bichrome images, with topical contrast agents that are safe for use in patients. Herein, we report findings of a pilot study using our self-made CLE to image pairs of normal and cancerous tissues. This study aimed to characterize the features of HNSCC compared with normal mucosa and to establish a methodology of in vivo real-time optical biopsy of HNSCCs. METHODS: HNSCC tissues were acquired from 10 patients who underwent surgical resection. Dissected specimens were first evaluated for their auto-fluorescence spectral profiles with 473 nm laser excitation and further optical observation. While obtaining the image, auto-fluorescence spectrum and intensity of the reflectance fluorescent signals were measured in real-time by a spectrometer. Subsequently, acriflavine was applied to the specimen to fluorescently label the nuclei and observe the difference between normal and cancerous tissues with 473 nm laser excitation. Finally, double staining with acriflavine and edible Food Red No.106 was performed to observe both nuclei and the cytoplasm of normal and cancerous tissues at 473 nm and 561 nm laser excitation. RESULTS: Lower signals were detected from auto-fluorescence images of cancer tissues than normal tissues with 473 nm laser excitation. After acriflavine application, there was a clear difference between cancer and normal mucosa in the uniformity of nuclear size and shape. In normal mucosa, cells were arranged in an orderly manner, with each cell resembling a frog's egg. By contrast, in cancer tissues, the cell density was higher, and the cellular arrangement was less orderly. Using both acriflavine and Food Red No.106, images became more vivid, but more complicated because red dye staining of the cytoplasm emerged as fluorescence at different wavelengths. CONCLUSIONS: Real-time in vivo imaging using the newly developed CLE and conditions may be used to distinguish cancer tissue from normal mucosa without invasive biopsy.

An attempt to measure the diametric relationship between slow and quick phases of nystagmus.

OBJECTIVE: To investigate whether our original method can precisely evaluate the angle between slow and quick phases of nystagmus (vector angle) and to determine whether vector angle analysis is helpful in differentiating between horizontal nystagmus and mixed nystagmus with horizontal and vertical components. METHODS: We included 20 healthy volunteers, 17 patients with horizontal nystagmus, and 15 patients with mixed nystagmus. Caloric nystagmus was recorded in healthy volunteers; positional nystagmus was recorded in each patient. We extracted the velocity of nystagmus from eye movement of each subject and analysed the vector angle. RESULTS: In caloric nystagmus, the vector angle approached 180 degrees as slow-phase velocity increased, suggesting that our vector angle measurement is more reliable with faster nystagmus. Importantly, in horizontal nystagmus from peripheral vestibular disease, the vector angle similarly approached 180 degrees as slow-phase velocity increased; in contrast, the vector angle in cases of mixed nystagmus from vertebrobasilar insufficiency or spinocerebellar degeneration significantly differed from the angle of caloric nystagmus. CONCLUSIONS: Vector angle analysis using our original algorithm can precisely evaluate the diametric relationship in vestibular nystagmus; it may be helpful in diagnosis of non-peripheral vestibular disorders.

The relationship between cerebral T2 hyperintensity and fixation suppression of vestibulo-ocular reflex in elderly patients with dysequilibrium symptoms.

OBJECTIVES: To evaluate the relationship between cerebral T2 hyperintensity on MRI and visual suppression of vestibulo-ocular reflex (VOR) in elderly patients with dysequilibrium symptoms. METHODS: Eighty-nine elderly patients with no MRI abnormalities in the infratentorial region aged 60-89 years complaining dysequilibrium symptoms were studied. Cases with whom a definitive diagnosis of peripheral or central disease could be established were not included. T2 hyperintense lesions in the cerebrum: basal ganglia, subcortical white matter and periventricular white matter were evaluated. VOR in darkness and fixation-suppressed VOR using pseudo-sinusoidal rotation stimuli were recorded to calculate visual suppression rate. Correlation between visual suppression rate and semi-quantitative scores for severity of T2 hyperintensity in the cerebrum was investigated. RESULTS: Patients with T2 hyperintensity in the cerebrum exhibited significantly lower visual suppression rate than those without lesions in the cerebrum. Multiple regression analysis showed that visual suppression rate was significantly and negatively correlated with severity of lesions in the basal ganglia, but not with patient age, severity of subcortical white matter lesions, or that of periventricular white matter lesions. CONCLUSIONS: In elderly patients with dizziness with a non-specific history and otoneurological findings, fixation suppression of vestibular nystagmus was associated with T2 hyperintensities in the basal ganglia.

In vivo calcium imaging from dentate granule cells with wide-field fluorescence microscopy.

A combination of genetically-encoded calcium indicators and micro-optics has enabled monitoring of large-scale dynamics of neuronal activity from behaving animals. In these studies, wide-field microscopy is often used to visualize neural activity. However, this method lacks optical sectioning capability, and therefore its axial resolution is generally poor. At present, it is unclear whether wide-field microscopy can visualize activity of densely packed small neurons at cellular resolution. To examine the applicability of wide-field microscopy for small-sized neurons, we recorded calcium activity of dentate granule cells having a small soma diameter of approximately 10 micrometers. Using a combination of high numerical aperture (0.8) objective lens and independent component analysis-based image segmentation technique, activity of putative single granule cell activity was separated from wide-field calcium imaging data. The result encourages wider application of wide-field microscopy in in vivo neurophysiology.

Micro-endoscopic system for functional assessment of neural circuits in deep brain regions: Simultaneous optical and electrical recordings of auditory responses in mouse's inferior colliculus.

In vivo Ca2+ imaging is a powerful method for the functional assessment of neural circuits. Although multi-photon excitation fluorescence microscopy has been widely used, observation of circuits in deep brain regions remains challenging. Recently, observing these deep regions has become possible via an endoscope consisting of an optical fiber bundle or gradient-index lens. We have designed a micro-endoscope system that enables simultaneous optical recording of fluorescence and electrical recording of neural activity. Using this system, we recorded auditory responses by simultaneously detecting changes in the fluorescence intensity of a Ca2+ indicator dye, multi-unit activities (MUA), and local field potentials (LFP) in the mouse's inferior colliculus (IC). Such simultaneous optical and electrical recordings enabled detailed comparison of electrically recorded phenomena (MUA and LFP) and optically recorded Ca2+ response. By systematically changing sound frequency and intensity, we determined the frequency tuning of the recording site. The best frequency shifted higher as the probe advanced more deeply, demonstrating that the system is capable of optically measuring the dorso-ventral organization of IC (i.e., tonotopicity). Thus, our new micro-endoscope system will be useful in the neurophysiological studies of a wide range of brain circuits, including those within the auditory system.

Regenerative therapy for vestibular disorders using human induced pluripotent stem cells (iPSCs): neural differentiation of human iPSC-derived neural stem cells after in vitro transplantation into mouse vestibular epithelia.

OBJECTIVES: Vestibular ganglion cells, which convey sense of motion from vestibular hair cells to the brainstem, are known to degenerate with aging and after vestibular neuritis. Thus, regeneration of vestibular ganglion cells is important to aid in the recovery of balance for associated disorders. METHODS: The present study derived hNSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mouse utricle tissues. After a 7-day co-culture period, histological and electrophysiological examinations of transplanted hNSCs were performed. RESULTS: Injected hNSC-derived cells produced elongated axon-like structures within the utricle tissue that made contact with vestibular hair cells. A proportion of hNSC-derived cells showed spontaneous firing activities, similar to those observed in cultured mouse vestibular ganglion cells. However, hNSC-derived cells around the mouse utricle persisted as immature neurons or occasionally differentiated into putative astrocytes. Moreover, electrophysiological examination showed hNSC-derived cells around utricles did not exhibit any obvious spontaneous firing activities. CONCLUSIONS: Injected human neural stem cells (hNSCs) showed signs of morphological maturation including reconnection to denervated hair cells and partial physiological maturation, suggesting hNSC-derived cells possibly differentiated into neurons.

Validity and limitation of manual rotational test to detect impaired visual-vestibular interaction due to cerebellar disorders.

The aim of this study was to investigate validity and limitation of the novel infrared system to record and analyze horizontal visual-vestibular interaction using whole-body rotation rapidly and conveniently in the routine vestibular clinic. We examined 11 patients with cerebellar dysequilibrium and 25 patients with peripheral dysequilibrium for vestibulo-ocular reflex in darkness (DVOR), visually-enhanced vestibulo-ocular reflex (VEVOR), and fixation suppression of vestibulo-ocular reflex (FSVOR), and compared the results with those of examination for head-fixed smooth pursuit and fixation suppression during caloric stimulation. The manual rotation stimuli were 0.5-0.75 Hz in frequency and 60-90 degrees /s in maximal angular velocity. Gain of vestibulo-ocular reflex in darkness was not significantly correlated with maximal slow phase velocity (MSPV) of caloric-induced nystagmus at that stimulus condition either in patients with peripheral dysequilibrium or in those with cerebellar dysequilibrium. An index for fixation suppression of vestibulo-ocular reflex during rotation stimulus was significantly lower in patients with cerebellar dysequilibrium than in normal control subjects and those with peripheral dysequilibrium. On the other hand, there was no significant difference among the two disease groups and the normal control group in gain of visually-enhanced vestibulo-ocular reflex. In about a half of patients with cerebellar dysequilibrium, measured smooth pursuit gain was lower than estimated smooth pursuit gain calculated based on a simple superposition theory of vestibulo-ocular reflex and smooth pursuit. Testing fixation suppression using the present system is an unusually convenient tool for detection of cerebellar dysequilibrium.