The basic connectivity from the vestibular labyrinth to the eye muscles (vestibular ocular reflex, VOR) has been elucidated in the past decade, and we summarise this in graphic format. We also review the concept of ‘velocity storage’, a brainstem integrator that prolongs vestibular responses. Finally, we present new discoveries of how complex visual stimuli, such as binocular rivalry, influence VOR processing. In contrast to the basic brainstem circuits, cortical vestibular circuits are far from being understood, but parietal-vestibular nuclei projections are likely to be involved.
In this contribution we will discuss a few clinical and scientific topics of potential interest relating to the present understanding of the vestibular ocular reflex (VOR). The vestibular system is connected to virtually all levels of the CNS. Simple introspection of your own reactions to spinning round or clinical observation of a patient with an acute vestibular episode will let you conclude that the vestibular system is connected to (1) the eye muscles (responsible for the nystagmus), (2) the spinal cord (responsible for the lateropulsion observed), (3) autonomic centres (responsible for the nausea), and (4) to the cortex (which mediates the conscious perception of turning and vertigo). Finally, the cerebellum, in particular the flocculo-nodular portion known as archi-cerebellum, is in overall modulatory control of these multisegmental vestibular projections.1
Of all the vestibular connections, the vestibular ocular is the best known and this is good news for clinicians given that the standard way to investigate patients with visuo-vestibular symptoms is via the VOR. The VOR, has a well-defined function—to maintain gaze stability and hence preserve visual acuity during head movements. It does so by generating slow-phase eye movements in exactly the opposite direction and of almost equal velocity to the head movement. Ophthalmologists are aware that apart from a variable degree of imbalance, the typical presentation in patients with bilateral vestibular failure is oscillopsia. As dictated by the physiology of the VOR, the oscillopsia in patients with bilateral vestibular failure presents only during head and body movements such as, walking, running, or driving on a bumpy road. Further details and the differential diagnosis of oscillopsia can be found in the article vision and vertigo.2
Basic clinical anatomy of the VOR
The basic neural connectivity of the VOR is provided by the ‘3-neuron arc’, namely, a primary sensory afferent neuron whose body sits in the Scarpa’s ganglion (the vestibular nerve), a vestibular nucleus neuron in the ponto-medullary region, and an oculomotor neuron in the III, IV, or VI nuclei in the brainstem. As the vestibular labyrinth consists of three semicircular canals (angular acceleration) and two otolith organs (utricle and sacculus, linear and gravitational acceleration sensors) the best way of describing the complete 3-neuron arc connectivity is by schematic figures, as shown in Figure 1. The general organisation comprises the vestibular nuclei on the same side of the labyrinth sending excitatory projections to the oculomotor nuclei on the opposite side and inhibitory projections to antagonistic oculomotor neurons on the same side of the brainstem. This scheme, easy to remember for the horizontal VOR (eg, contralateral abducens nucleus neurons and ipsilateral medial rectus motoneurons), is also preserved for vertically acting muscles (see Figure 1).
Up to a few years ago, the only way to assess the VOR was with rotating chairs or by caloric ear stimulation. Recently, advances in understanding of vestibulo-ocular physiology, largely by Curthoys and Halmagyi in Sydney, have led to the development of, first, a bed-side clinical head thrust or impulse test (HIT)3 and subsequently video–image-based versions of the test that are now available commercially for clinical use (vHIT, or videoHIT).4
The principle of this procedure is that the VOR is capable of generating slow-phase eye movements of high velocity (to preserve gaze stability) in response to high acceleration head movements or impulses. Figure 2a shows how to conduct this test in the clinic. For examination of the horizontal semicircular canals (and accordingly the lateral and medial recti eye muscles) the head impulses are delivered in the horizontal (yaw) plane. Figure 2b also illustrates how to deliver oblique head acceleration impulses in the clinic so that right anterior–left posterior canals (hence the right superior rectus and the left inferior oblique muscles are activated during a nose-down oblique VOR). In vestibular jargon, this plane is called RALP and the plane of action of the left anterior–right posterior canals is called LARP (which recruits the left superior rectus and right inferior oblique during a nose-down VOR, see Figure 2c).
If the VOR is working normally, high acceleration impulses to the head are perfectly counteracted by compensatory slow-phase movements. Thus, fixation of the visual target (eg, the examiner’s nose) is seamlessly preserved. However, if the VOR is substantially reduced (>50%) slow-phase vestibular eye movements are incapable of preserving fixation and therefore a small ‘catch-up’ saccade is generated towards the visual target. With minimal practice, ophthalmologists are able to see the catch-up saccade by naked eye and hence establish that individual semicircular canals are dysfunctional. Figure 3 shows a photographic representation of a positive (ie, abnormal) head impulse test and Figure 4 shows two examples of abnormalities in the vHIT following either unilateral or bilateral loss of vestibular function.
The capacity of the HIT to detect substantial functional reduction of the semicircular canals, particularly the horizontal canal as this is the easiest to do, has given this procedure a prominent role in the diagnosis of acute vertigo in emergency rooms and stroke units. If a patient presents with acute vertigo and nystagmus, even in the absence of additional neurological features such as speech disorder, diplopia, or face numbness, the presence of a normal (negative) HIT raises a ‘red flag’. The normal HIT suggests that the vertigo may not be of peripheral labyrinthine origin and, therefore, an urgent MRI scan is warranted. Other ocular-motor signs are also becoming increasingly popular to help in the important distinction between acute peripheral vs central (‘stroke’) origin of vertigo. In addition to the HIT (if positive, more likely peripheral), this includes testing for skew deviation (if present, more likely central) and whether the nystagmus is unidirectional (more likely vestibular) or not (more likely central). This forms the basis of the ‘HINTS’ protocol (Head-impulse, Nystagmus, Test-skew) which has at least as much sensitivity to rule out posterior fossa stroke as MRI does.5, 6
Additional brainstem VOR mechanisms
The VOR is under powerful cerebellar control and this is reviewed by Zee in this issue. Indeed many ‘cerebellar’ eye signs are actually vestibulo-cerebellar signs, including the common syndrome of downbeat nystagmus.7, 8 The cerebellum and interconnected brainstem nuclei, prominently the perihypoglosal nuclei in the medulla (Figure 1), are also part of a polysynaptic vestibular ocular network generally termed the ‘velocity storage system’. Essentially, this ‘velocity storage’ integrator extends the duration of the horizontal vestibular ocular response, which allows for a better compensatory VOR response to rotational stimuli of low frequency (long duration). This function is exemplified by the fact that the time constant of decay (TC) following a post-rotational stimulus is 4–7 s but the TC of vestibular nystagmus is approximately 15–18 s.9, 10 It is in these additional cerebellar and brainstem circuits that a profound interaction between vestibular ocular-motor and visual-ocular-motor mechanisms, such as optokinetic nystagmic responses, takes place.
Visual input has profound influences on vestibular function. Up until recently, however, it was difficult to assess this interaction in patients with visual-motor disorders because the loss of visual input (blindness), excessive nystagmus, or reduced eye movements (ophthalmoplegia) interfered with obtaining reliable eye movement recordings, as required to measure the VOR. On the basis of the assumption that VOR and vestibulo-perceptual function (presumably mediated by the vestibulo-cortical projection) must be matched in normal man, we developed a technique to measure vestibular perception (Figure 5). Given that the latter technique does not rely on eye movement recordings we investigated vestibular function in three groups, patients with congenital nystagmus,9 severely reduced eye movements (chronic progressive external ophthalmoplegia,11) and congenital blindness who have no structured eye movements.12 On the basis of the measurement of the TC of the vestibulo-perceptual function we observed that in these patients perceptual TCs were shorter, that is, vestibulo-perceptual function was reduced. This somewhat suppressed vestibulo-perceptual function could be expected, given that long duration vestibular responses could create additional problems of disorientation in these patients when they move about in the environment. In any case, the findings testify to the interdependence of the two major motion processing systems of the brain, vestibular and visual, but whether this interaction takes place at lower (brainstem) or higher (cortical) levels is not fully understood.
Cortical processing and the VOR
Cortical modulation of the VOR has been known at least since the days of Charles Hallpike. In a series of experiments in the 1940s in London, Hallpike and colleagues provided arguably the first insights into the neurology of vertigo. In a series of patients with temporal lobe lesions, they found that the vestibular nystagmus elicited during caloric stimulation exhibited a strong directional preponderance, a phenomenon termed, ‘nystagmusberietschaft’.13
Much of the work conducted by the vestibular community since the above report has focussed primarily upon establishing the neural correlates using functional imaging techniques.14, 15, 16, 17 These data have implicated a widespread distributed network in the frontal and tempo-parietal areas that strongly overlaps with the neural networks found for spatial attention,18 with a right hemisphere dominance.19, 20
Behavioural observations in patients with posterior parietal cortical lesions provide further support for the suggested overlapping neural networks. Posterior parietal cortical lesions (particularly on the right) typically result in spatial neglect, a disorder of spatial attention.21 That is, despite having normal visual fields, patients typically tend to ignore salient visual stimuli presented to the contralateral side of space.22 Firstly, it was shown that this spatial bias can be temporally alleviated via the application of a caloric stimulus23 and secondly that these lesions result in an asymmetrical modulation of the VOR in response to velocity step rotations.21
Furthermore, based on the premise that overlapping neural networks subserve spatial attention and vestibular processing, we developed a novel paradigm in normal subjects to see if this induced modulation of the VOR.24 During velocity step rotations, subjects viewed bi-stable percepts (ie, binocular rivalry or motion induced blindness), or performed complex attention tasks. Upon stopping, the VOR was measured in darkness. It was found that following concurrent vestibular activation and either viewing bi-stable percepts that contained a spatial component (ie, motion rivalry but not colour rivalry) or performance of a visuospatial working memory task, the VOR was asymmetrically supressed. Intriguingly, the direction of the modulation was determined by the subject’s handedness, strongly implicating the role of higher-order mechanisms for the modulation.24 As shown in Figure 6, in right-handed subjects the VOR was supressed following rightward rotations and conversely following leftward rotations in left-handed subjects.
To understand the neural mechanisms of the above VOR modulation, we applied non-invasive trans-cranial direct current stimulation (tDCS) over the posterior parietal cortex to directly modulate cortical excitability. The VOR was assessed using caloric stimulation before and after tDCS. Excitation of the right hemisphere (ie, anodal stimulation) and concurrent inhibition of the left hemisphere (ie, cathodal stimulation) induced an asymmetrical VOR response with suppression of left beating nystagmus in response to right cold (30 °C) irrigations. No effect of tDCS was found for the processing of right-beating nystagmus elicited via left cold irrigations25 as shown in Figure 7. To elucidate the ‘active’ electrode we applied unipolar tDCS and found that the modulation was specifically attributable to the suppression of the left hemisphere.25 Further, to ascertain whether the tDCS was impacting upon pursuit and/or VOR suppression mechanisms, that in turn might mediate VOR modulation, we performed a follow-up study and ruled out such an explanation.26 Hence, we tentatively conclude that cortical modulations of the VOR that we have reported both in behavioural and electrical stimulation studies are subject to dynamic inter-hemispheric competition. Moreover, such a mechanism can also explain the asymmetrical VOR observed following parietal lesions. Anatomically, such top-down modulation is proposed to be mediated by descending projections identified in primates connecting the parietal cortex and the vestibular nuclei.27
Taken together, our findings in neurologically intact individuals and reports in the literature from brain damaged patients imply that the vestibular cortex is able to down-regulate the VOR and specifically influence the ‘low frequency’ component of the horizontal velocity storage mechanism.25 However, much remains unknown; for example, what are the exact anatomical pathways in man, what functionality does such top-down modulation serve, and why is there such a close relationship with spatial attention mechanisms? To conclude, in contrast to the extensive and well-defined knowledge regarding low-level control of the VOR, much is unknown and remains to be elucidated regarding the higher-order mechanisms that govern central modulation of the VOR.
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We thank Otometrics, UK, for the Video Head Impulse Test equipment.
The authors declare no conflict of interest.
Contributed at the Cambridge Ophthalmological symposium
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Bronstein, A., Patel, M. & Arshad, Q. A brief review of the clinical anatomy of the vestibular-ocular connections—how much do we know?. Eye 29, 163–170 (2015). https://doi.org/10.1038/eye.2014.262
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