Pharmacological profile of vestibular inhibitory inputs to superior oblique motoneurons.

Vestibulo-ocular reflexes (VOR) are mediated by three-neuronal brainstem pathways that transform semicircular canal and otolith sensory signals into motor commands for the contraction of spatially specific sets of eye muscles. The vestibular excitation and inhibition of extraocular motoneurons underlying this reflex is reciprocally organized and allows coordinated activation of particular eye muscles and concurrent relaxation of their antagonistic counterparts. Here, we demonstrate in isolated preparations of Xenopus laevis tadpoles that the discharge modulation of superior oblique motoneurons during cyclic head motion derives from an alternating excitation and inhibition. The latter component is mediated exclusively by GABA, at variance with the glycinergic inhibitory component in lateral rectus motoneurons. The different pharmacological profile of the inhibition correlates with rhombomere-specific origins of vestibulo-ocular projection neurons and the complementary segmental abundance of GABAergic and glycinergic vestibular neurons. The evolutionary conserved rhombomeric topography of vestibulo-ocular projections makes it likely that a similar pharmacological organization of inhibitory VOR neurons as reported here for anurans is also implemented in mammalian species including humans.

Isolated pseudoabducens palsy in acute thalamic stroke.

Oculomotor abnormalities are rarely noted in thalamic strokes. We describe isolated right pseudoabducens palsy in a young patient with acute left thalamic infarction revealed by diffusion-weighted magnetic resonance imaging. The patient's horizontal diplopia and oculomotor palsy resolved within 3days. This case supports the hypothesis that a lesion can cause isolated esotropia by interrupting descending inhibitory convergence pathways that traverse the paramedian thalamus and decussate in the subthalamic region to innervate the contralateral third oculomotor nucleus. Esotropia contralateral to the thalamic lesion results from tonic activation of the medial rectus, producing pseudoabducens palsy.

Ascending vestibular drive is asymmetrically distributed to the inferior oblique motoneuron pools in a subset of hemispheric stroke survivors.

OBJECTIVE: Aberrant vestibular nuclear function is proposed to be a principle driver of limb muscle spasticity after stroke. Although spasticity does not manifest in ocular muscles, we sought to determine whether altered cortical modulation of ascending vestibuloocular pathways post-stroke could impact the excitability of ocular motoneurons. METHODS: Nineteen chronic stroke survivors, aged 49-68 yrs. were enrolled. Vestibular evoked myogenic potentials (VEMPs) were recorded from the inferior oblique muscles of the eye using surface EMG electrodes. We assessed the impact of ascending otolith pathways on eye muscle activity and evaluated the relationship between otolith-ocular function and the severity of spasticity. RESULTS: VEMP responses were recorded bilaterally in 14/19 subjects. Response magnitude on the affected side was significantly larger than on the spared side. In a subset of subjects, there was a strong relationship between affected response amplitude and the severity of limb spasticity, as estimated using a standard clinical scale. CONCLUSIONS: This study suggests that alterations in ascending vestibular drive to ocular motoneurons contribute to post-stroke spasticity in a subset of spastic stroke subjects. We speculate this imbalance is a consequence of the unilateral disruption of inhibitory corticobulbar projections to the vestibular nuclei. SIGNIFICANCE: This study potentially sheds light on the underlying mechanisms of post-stroke spasticity.

Nonclassical innervation patterns in mammalian extraocular muscles.

PURPOSE: The abducens (CN6) and oculomotor (CN3) nerves (nn) enter target extraocular muscles (EOMs) via their global surfaces; the trochlear (CN4) nerve enters the superior oblique (SO) muscle on its orbital surface. Motor nn are classically described as entering the EOMs in their middle thirds. We investigated EOM innervation that does not follow the classic pattern. METHODS: Intact, whole orbits of two humans and one each monkey, cow, and rabbit were paraffin embedded, serially sectioned in coronal plane, and prepared with Masson's trichrome and by choline acetyltransferase (ChAT) immunohistochemistry. Nerves innervating EOMs were traced from the orbital apex toward the scleral insertion, and some were reconstructed in three dimensions. RESULTS: Classical motor nn positive for ChAT entered rectus and SO EOMs and coursed anteriorly, without usually exhibiting recurrent branches. In every orbit, nonclassical (NC) nn entered each EOM well posterior to classical motor nn. These NC nn entered and arborized in the posterior EOMs, mainly within the orbital layer (OL), but often traveled into the global layer or entered an adjacent EOM. Other NC nn originated in the orbital apex and entered each EOM through its orbital surface, ultimately anastomosing with classical motor nn. Mixed sensory and motor nn interconnected EOM spindles. CONCLUSIONS: EOMs exhibit a previously undescribed pattern of NC innervation originating in the proximal orbit that partially joins branches of the classical motor nn. This NC innervation appears preferential for the OL, and may have mixed supplemental motor and/or proprioceptive functions, perhaps depending upon species. The origin of the NC innervation is currently unknown.

Myoelectric signals of levator palpebrae superioris as a trigger for FES to restore the paralyzed eyelid.

Some closed loop FES systems have been designed to restore the blinking function of facial paralysis patients. All of them used myoelectric signal of orbicularis oculi at the normal side as the trigger to stimulate the paralyzed side. They were limited to the one side facial paralysis. Here we proposed that the myoelectric signal of levator palpebrae superioris could be used as the trigger to stimulate the paralyzed orbicularis oculi. Because the levator palpebrae superioris and the innervating nerve are intact, the myoelectric signal of the paralyzed side still could be used as the trigger. It will be more acceptable for the patients and have the potential to resolve the bilateral facial paralysis.

The basis for using bone-conducted vibration or air-conducted sound to test otolithic function.

Extracellular single neuron recordings of primary vestibular neurons in Scarpa's ganglion in guinea pigs show that low-intensity 500 Hz bone-conducted vibration (BCV) or 500 Hz air-conducted sound (ACS) activate a high proportion of otolith irregular neurons from the utricular and saccular maculae but few semicircular canal neurons. In alert guinea pigs, and humans, 500 Hz BCV elicits otolith-evoked eye movements. In humans, it also elicits a myogenic potential on tensed sternocleidomastoid muscles. Although BCV and ACS activate both utricular and saccular maculae, it is possible to probe the functional status of these two sense organs separately because of their differential neural projections. Saccular neurons have a strong projection to neck muscles and a weak projection to the oculomotor system. Utricular afferents have a strong projection to eye muscles. So measuring oculomotor responses to ACS and BCV predominantly probes utricular function, while measuring neck muscle responses to these stimuli predominantly probes saccular function.

Coupling between spontaneous (resting state) fMRI fluctuations and human oculo-motor activity.

The recent discovery of incessant spontaneous fluctuations in human brain activity (also termed resting state fMRI) has been a focus of intense research in brain imaging. The spontaneous BOLD activity shows organized anatomical specialization as well as disruption in a number of brain pathologies. The link between the spontaneous fMRI fluctuations and human behavior is therefore of acute interest and importance. Here we report that a highly significant correlation exists between spontaneous BOLD fluctuations and eye movements which occur subliminally and spontaneously in the absence of any visual stimulation. Of the various eye movement parameters tested, we found robust and anatomically consistent correlations with both the amplitude and velocity of spontaneous eye movements. Control experiments ruled out a contribution of spatial and visual attention as well as smooth pursuit eye movements to the effect. The consistent anatomical specificity of the correlation patterns and their tight temporal link at the proper hemodynamic delay argues against a non-neuronal explanation of the effect, such as cardiac or respiratory cycles. Our results thus demonstrate a link between resting state and spontaneously emerging subconscious oculo-motor behavior.

The optic nerve head in congenital fibrosis of the extraocular muscles.

OBJECTIVE: Optic nerve head abnormalities have been reported in some patients with congenital fibrosis of the extraocular muscles (CFEOM). This study prospectively assesses optic nerve head appearance in a consecutive CFEOM cohort. METHODS: All patients with CFEOM referred between 2006 and 2010 and who were mature enough to cooperate with fundus photography were included. Fundus photographs were reviewed with attention to optic nerve head features (eg, cupping >0.6, asymmetric cupping >0.3, optic nerve hypoplasia). Interested participants had CFEOM candidate gene analysis (KIF21A, TUBB3, PHOX2A) for genetic counseling purposes. RESULTS: Ten CFEOM patients (five CFEOM1, five CFEOM3, age range 5-23 years) from eight families (all consanguineous but one) participated. All 10 patients had notable disc excavation (5) or optic nerve hypoplasia (5). CFEOM candidate gene analysis was performed in all patients and revealed a heterozygous p.R954W KIF21A mutation only in the patient who was not from a consanguineous family. CONCLUSIONS: Our observations suggest the optic nerve head can be affected by the orbital dysinnervation that occurs in CFEOM. Because careful clinical optic nerve head assessment is difficult in young patients with CFEOM and associated large angle incomitant strabismus, optic nerve head abnormalities may be under-diagnosed. The absence of mutations in known CFEOM genes in our cohort of consanguineous families suggests further genetic heterogeneity of this group of conditions.

The ocular vestibular-evoked myogenic potential to air-conducted sound; probable superior vestibular nerve origin.

OBJECTIVE: Intense air-conducted sound (ACS) elicits an ocular vestibular-evoked myogenic potential (oVEMP), and it has been suggested that it does so by stimulating saccular receptors and afferents in the inferior vestibular nerve and so activating a crossed sacculo-ocular pathway. Bone conducted vibration (BCV) also elicits an oVEMP probably by activating utricular receptors and a crossed utriculo-ocular pathway. Are there two separate pathways mediating oVEMPs for ACS and BCV? If saccular receptors and afferents are primarily responsible for the oVEMP to ACS, then the oVEMP to ACS should be normal in patients with reduced or absent utricular function--unilateral superior vestibular neuritis (SVN). If utricular receptors and afferents are primarily responsible for oVEMP n10, then oVEMP to ACS should be reduced or absent in SVN patients, and in these patients there should be a close relationship between the size of the oVEMP n10 to BCV and to ACS. METHODS: The n10 component of the oVEMP to 500 Hz BCV and to 500 Hz ACS was recorded in 10 patients with unilateral SVN but who had saccular and inferior vestibular nerve function preserved, as shown by their normal cVEMP responses to ACS. RESULTS: In SVN patients with normal saccular and inferior vestibular nerve function, the oVEMP n10 in response to ACS was reduced or absent. Across SVN patients there was a very close correspondence between the size of oVEMP n10 for ACS and for BCV. CONCLUSIONS: The n10 component of the oVEMP to ACS is probably mediated predominantly by the superior vestibular nerve and so most likely by utricular receptors and afferents. SIGNIFICANCE: The n10 component of the oVEMP to either ACS or BCV probably indicates mainly superior vestibular nerve function.

Scalp-recorded induced γ-band responses to auditory stimulation and its correlations with saccadic muscle-activity.

We previously showed that the transient broadband induced gamma-band response in EEG (iGBRtb) appearing around 200-300 ms following a visual stimulus reflects the contraction of extra-ocular muscles involved in the execution of saccades, rather than neural oscillations. Several previous studies reported induced gamma-band responses also following auditory stimulation. It is still an open question whether, similarly to visual paradigms, such auditory paradigms are also sensitive to the saccadic confound. In the current study we address this question using simultaneous eye-tracking and EEG recordings during an auditory oddball paradigm. Subjects were instructed to respond to a rare target defined by sound source location, while fixating on a central screen. Results show that, similar to what was found in visual paradigms, saccadic rate displayed typical temporal dynamics including a post-stimulus decrease followed by an increase. This increase was more moderate, had a longer latency, and was less consistent across subjects than was found in the visual case. Crucially, the temporal dynamics of the induced gamma response were similar to those of saccadic-rate modulation. This suggests that the auditory induced gamma-band responses recorded on the scalp may also be affected by saccadic muscle activity.

Is there any difference in human pupillary reaction when different acupuncture points are stimulated?

OBJECTIVES: To determine if there is any difference in pupillary response among different acupuncture stimulation sites. METHODS: The subjects were 14 healthy males who had no known eye diseases or abnormality in their pupils. They received five different interventions: no acupuncture stimulation (hereinafter 'no-stimulation') and acupuncture stimulation at four sites (TE5, ST7, CV12 and ST36). The Latin square design was used to allocate stimulation order. For all acupuncture stimulation interventions, a disposable acupuncture needle was inserted superficially at the acupuncture point. Gentle repetitive tapping stimulation was applied manually during the subject's exhalation phase of respiration, for 90 s. The pupil diameter was continuously measured for 2 min before stimulation, during stimulation and for 2 min after stimulation. Statistical analysis was conducted on serial changes in pupil diameter during acupuncture stimulation on each respective site and during non-stimulation session by analysis of variance and Fisher (least significant difference) multiple comparison, with linear analysis using a mixed model. RESULTS: Pupil diameter reduction occurred at 30 s after stimulation on ST7 (p=0.008) and 60 s after stimulation (p=0.014) compared with pre-stimulation. The decrease of pupillary diameter occurred 60 s after stimulation on TE5 (p=0.028) compared with pre-stimulation. On ST36, CV12 and during the non-stimulation intervention, no significant change in the pupil diameter was observed. CONCLUSIONS: Pupillary reaction varies depending on the different stimulation sites.

Ocular vestibular-evoked myogenic potentials (oVEMPs) require extraocular muscles but not facial or cochlear nerve activity.

OBJECTIVES: Cervical vestibular evoked myogenic potentials (cVEMPs) have been found to be useful for clinical testing of vestibular function. Recently, investigators showed that short-latency, initially negative surface EMG potentials can be recorded around the extraocular muscles (oVEMPs) in response to air-conducted sound (ACS), bone-conducted vibration (BCV), and head taps. Although these evoked potentials, which are located around the eyes, most likely originate primarily from the otolith-ocular pathway, the possibility of contamination by other nerve activities cannot be completely eliminated. The purpose of the present study was to clarify the origin of oVEMPs by examining these possibilities using clinical findings. METHODS: Twelve healthy subjects and 15 patients were enrolled. Of the 15 patients, 3 patients had undergone exenteration of the unilateral intraorbital contents, one had undergone exenteration of the right eyeball with preservation of extraocular muscles, 5 had facial palsy, and 6 had profound hearing loss. ACS and/or BCV were used in these subjects. RESULTS: Exenteration of the unilateral intraorbital contents resulted in absence of myogenic potentials on the affected side. On the other hand, exenteration of the eyeball with preservation of extraocular muscles did not have a major impact on the responses. There were no significant differences in the waveforms between healthy subjects and patients with facial palsy or profound hearing loss. CONCLUSIONS: The results suggested that short-latency, initially negative evoked potentials recorded below the eyes are not affected by cochlear or facial nerve activities and are dependent on the presence of extraocular muscles. SIGNIFICANCE: This study provides the evidence that oVEMPs originate from exraocular muscles activated through the vestibulo-ocular pathway.

Ocular vestibular evoked myogenic potentials to bone conducted vibration of the midline forehead at Fz in healthy subjects.

OBJECTIVE: To provide the empirical basis for using ocular vestibular evoked myogenic potentials (oVEMPS) in response to Fz bone conducted vibration (BCV) stimulation to indicate vestibular function in human subjects. To show the generality of the response by testing a large number of unselected healthy subjects across a wide age range and the repeatability of the response within subjects. To provide evidence that the response depends on otolithic function. METHODS: The early negative component (n10) of the oVEMP to brief BCV of the forehead, in the midline at the hairline (Fz) is recorded by surface EMG electrodes just beneath the eyes. We used a Bruel and Kjaer 4810 Mini-Shaker or a light tap with a tendon hammer to provide adequate BCV stimuli to test a large number (67) of unselected healthy people to quantify the individual differences in n10 magnitude, latency and symmetry to Fz BCV. A Radioear B-71 bone oscillator at Fz is not adequate to elicit a reliable n10 response. RESULTS: The n10 oVEMP response showed substantial differences in amplitude between subjects, but is repeatable within subjects. n10 is of equal magnitude in both eyes with an average asymmetry around 11%. The average n10 amplitude for Mini Tone Burst BCV is 8.47microV+/-4.02 (sd), the average latency is 10.35ms+/-0.63 (sd). The amplitude of n10 decreases and its latency increases with age. CONCLUSIONS: oVEMPs are a new reliable, repeatable test to indicate vestibular and probably otolithic function. SIGNIFICANCE: This study shows the optimum conditions for recording oVEMPs and provides baseline values for individual differences and asymmetry. oVEMPs can be measured in senior subjects without difficulty.

Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis.

OBJECTIVE: The goal of this investigation was to demonstrate that internuclear ophthalmoparesis (INO) can be utilized to model the effects of body temperature-induced changes on the fidelity of axonal conduction in multiple sclerosis (Uhthoff's phenomenon). METHODS: Ocular motor function was measured using infrared oculography at 10-minute intervals in patients with multiple sclerosis (MS) with INO (MS-INO; n = 8), patients with MS without INO (MS-CON; n = 8), and matched healthy controls (CON; n = 8) at normothermic baseline, during whole-body heating (increase in core temperature 0.8 degrees C as measured by an ingestible temperature probe and transabdominal telemetry), and after whole-body cooling. The versional disconjugacy index (velocity-VDI), the ratio of abducting/adducting eye movements for velocity, was calculated to assess changes in interocular disconjugacy. The first pass amplitude (FPA), the position of the adducting eye when the abducting eye achieves a centrifugal fixation target, was also computed. RESULTS: Velocity-VDI and FPA in MS-INO patients was elevated (p < 0.001) following whole body heating with respect to baseline measures, confirming a compromise in axonal electrical impulse transmission properties. Velocity-VDI and FPA in MS-INO patients was then restored to baseline values following whole-body cooling, confirming the reversible and stereotyped nature of this characteristic feature of demyelination. CONCLUSIONS: We have developed a neurophysiologic model for objectively understanding temperature-related reversible changes in axonal conduction in multiple sclerosis. Our observations corroborate the hypothesis that changes in core body temperature (heating and cooling) are associated with stereotypic decay and restoration in axonal conduction mechanisms.

Vestibular-evoked extraocular potentials by air-conducted sound: another clinical test for vestibular function.

OBJECTIVE: The purpose of this study was to identify an appropriate way to detect vestibular-evoked extraocular potentials (oVEMPs) produced by air-conducted sound stimulation in healthy subjects and to apply this test clinically in patients with various vestibular disorders. METHODS: Ten healthy subjects were included in this study. Surface electromyographic (EMG) activity was recorded from active electrodes placed on the face just inferior to each eye. Stimulation with 0.1 ms clicks and 500 Hz short tone bursts was used to activate the vestibular end-organs in healthy subjects. We also tested 12 patients with unilateral vestibular disorders using 500 Hz short tone bursts. RESULTS: In healthy subjects, negative-positive biphasic responses with short latency by air-conducted click (the first negative peak latency=8.8 ms and the following positive peak latency=14.5 ms on the average) (oVEMP) were only identified beneath the eye contralateral to the stimulating ear. On the other hand, stimulation with 500 Hz short tone bursts evoked negative-positive biphasic responses (the first negative peak latency=10.5 ms and the following positive peak latency=15.9 ms on the average) on both ipsilateral and contralateral eyes, while responses were contralateral eye-dominant. Contralateral eye responses by 500 Hz short tone bursts had higher response prevalence and larger amplitudes than clicks. In patients, oVEMPs evoked by the affected side stimulation tended to decrease or lacked a response. The presence of oVEMPs and cVEMPs coincided well in patients when 500 Hz short tone bursts were presented. CONCLUSIONS: oVEMPs can be evoked using air-conducted 500 Hz tone burst and are best recorded contralaterally on upgaze. SIGNIFICANCE: oVEMPs by air-conducted sounds could be a useful alternative clinical test for patients with vestibular lesions.

Regional nerve block of the upper eyelid in oculoplastic surgery.

PURPOSE: To establish the efficacy of a regional nerve block of the upper eyelid and its effect on levator motor function. METHODS: Forty-one patients underwent surgery on 54 upper eyelids by one surgeon, after administration of a regional nerve block at the supraorbital notch. The amount of pain experienced by patients due to the local anesthetic injection and surgery was determined by using visual analogue scores. The effect of the local anesthetic injection on levator function was determined by comparing the measured levator function prior to and following administration. Any complications attributable to the regional sensory nerve block were recorded. RESULTS: Ninety-two percent of patients found the injection painless, and the rest reported negligible pain. The mean pain score for the injection was 2 (SD 1.3, range 0-6). The mean pain score for the surgery was 0.3 (SD 0.6, range 0-3). No significant difference was found in levator function prior to and following the injection (pre-function: 14.4 mm, post-function: 13.4 mm, p=0.01). One patient had hematoma formation at the site of injection. CONCLUSIONS: A regional nerve block of the upper eyelid achieves effective sensory anesthesia,without compromising motor function. This helps in an accurate assessment of intraoperative height during upper lid surgery.