The vestibular system detects motion of the head in space and in turn generates reflexes that are crucial for our daily activities, such as stabilizing the visual axis (gaze) and maintaining head and body posture. In addition, the vestibular system provides us with our subjective sense of movement and orientation in space. The vestibular sensory organs are located in the petrous part of the temporal bone in close proximity to the cochlea, the auditory sensory organ. Although the vestibular system was recognized as a separate entity from the auditory portion of the inner ear only in the middle of the 19th century, it is phylogenetically the oldest part of the inner ear. The vestibular system is comprised of two types of sensors: the two otolith organs (the saccule and utricle), which sense linear acceleration (i.e., gravity and translational movements), and the three semicircular canals, which sense angular acceleration in three planes. The receptor cells of the otoliths and semicircular canals send signals through the vestibular nerve fibers to the neural structures that control eye movements, posture, and balance (Figure 1).
In contrast to the senses of vision and audition which can easily be understood by simply shutting our eyes or plugging our ears, the significance of vestibular function in our daily lives is more difficult to appreciate. When the system is functioning normally, we are usually unaware of a distinct sensation arising from vestibular activity since it is integrated with visual, proprioceptive and other sensory information such that combined experience leads to a sense of motion. In addition, the important contributions that the vestibular system normally makes to gaze stabilization and postural control are difficult to fully comprehend. For this reason, clinical studies have provided many important insights into function of the vestibular system. Perhaps the best known clinical case is a report by a physician JC in 1952, who suffered from complete vestibular loss following treatment with streptomycin (an ototoxic antibiotic) for leg infection. He described his symptoms following treatment, and commented that “By bracing my head between two of the metal bars at the head of the bed I found I could minimize the effect of the pulse beat that made the letters of the page jump and blur” and that [When walking] “in these corridors I had the peculiar sensation that I was inside a flexible tube, fixed at the end nearest me but swaying free at the far end.”
In JC as well as other patients with abnormal vestibular function, normal activities that we take for granted become difficult since even small head movements are accompanied by gaze instability and postural imbalance. Similarly, less complete loss of function can produce an imbalance which manifests as a dramatic, sudden onset of vertigo. In all cases, symptoms typically resolve over time, such that patients can resume most usual activities by using information from other sensory systems that provide information about movement and posture. However, while these sensory substitution strategies are effective they are frequently incomplete. As a result, more challenging head movements are accompanied by gaze instability as well as other motion-induced vestibular symptoms and signs.
Many recent studies of vestibular-deficient patients have more specifically investigated the role of the vestibular system in controlling gaze, balance, and posture (e.g., Cullen 2004, Horak 2006, Maurer et al. 2000), and sensory substitution (e.g., Peterka et al. 2006). During movements, sensory information from somatosensory, vestibular and visual systems is integrated based on the goal of the action. The vestibulo-ocular reflex (VOR), which functions to stabilize gaze and ensure clear vision during everyday activities, has been well characterized and shows impressive adaptation in response to behavioral requirements. The relative simplicity of the pathways that mediate the VOR, have made it an excellent model system for bridging the gap between the cells, neuronal circuits, and behavior. The vestibular system also plays a critical role in ensuring postural equilibrium by producing appropriate adjustments during both self generated movements and externally applied disturbances. The findings of clinical, behavioral and neurophysiological studies have led to a better understanding of the role of the vestibular system during every day activities. This article reviews the findings of recent behavioral, single-unit recording, and lesion studies. These results are considered in relation to the insights that they provide into understanding the vestibular function, and into general concepts that can be applied to other systems.
THE VESTIBULAR SENSORY ORGANS AND THEIR RECEPTORS
The otolith organs
The utricle and the saccule are sensitive to linear acceleration. The sensory epithelium of these organs consists of hair cells that release transmitter tonically, resulting in spontaneous activity in vestibular nerve fibers. The cilia which emerge from the hair cells are embedded in a gelatinous matrix containing solid CaCO3 crystals (the otoconia) which overlies the cells (Figure 2). In response to linear acceleration, the crystals are left behind due to their inertia. The resultant bending of the cilia causes either excitation or inhibition of haircells. Being sensitive to acceleration, the otolith organs detect the direction and magnitude of gravity, as well as transient linear accelerations due to movement (Fernandez and Goldberg 1976a, 1976b, 1976c).
The semicircular canals
The three semicircular canals, arranged in three orthogonal planes, are sensitive to angular (rotational) acceleration (e.g., see (Reisine et al. 1988)). Each canal is comprised of a circular path of fluid continuity, interrupted at the ampulla (that contains the sensory epithelium) by a water tight, elastic membrane called the cupula (Figure 2). Similar to the otoliths, the sensory cells exhibit constant release of neurotransmitters that is modified by the direction of cupula deflection. Although the stimulus on the semicircular canals is angular acceleration, the neural output from the sensory cells represents the velocity of rotation. This mathematical integration of the input signal is due to the mechanics of the canals, mainly the increase in viscous properties of the fluid due to the small size of the canal (diameter of ~0.3 mm) (Curthoys et al. 1977; Igarashi et al. 1981; Wilson and Melvill Jones 1979). By combining the input of the three canals, the brain can create a 3-dimensional representation of the vector of the instantaneous speed of head rotation relative to space.
Two canal-related vestibular disorders are worth mentioning here: benign paroxysmal positional vertigo (BPPV) and Menier’s disease (e.g., Goebel 2001). BPPV is the most common peripheral vestibular disorder and is believed to be due to deposition of otoconia from the otolith organs on the cupula of semicircular canals. As a result, patients experience brief spells of vertigo with specific head movements, due to the abnormal stimulation of the canals. The second pathological condition, Menier’s disease, is the result of progressive degeneration of sensory epithelium of the inner ear due to endolymphatic hydrops and increased inner ear pressure. This leads to episodic vertigo, fluctuant hearing loss, tinnitus, and aural fullness.
Two types of hair cells in vestibular sensory organs
There are two types of haircells in the vestibular receptors: Type II haircells are cylindrical cells that are phylogenetically older and present in both amniotes (i.e., mammals, reptiles, and birds) and non-amniotes, whereas flask-shaped type I hair cells are present only in amniotes (Eatock and Hurley 2003). These two cell types have specific cellular properties including differences in potassium channel densities: larger amounts of calcium activated potassium channels in type I hair cells can contribute to their higher sensitivity to high frequency stimulation (Eatock and Hurley 2003; Eatock et al. 2002; Hurley et al. 2006; Limon et al. 2005; Wooltorton et al. 2007). As discussed in the next section, type I haircells provide inputs to irregular vestibular-nerve afferent fibers, whereas type II haircells are connected to regular afferents.
PRIMARY VESTIBULAR AFFERENTS: ANATOMY AND FUNCTION
Two types of vestibular afferents
Vestibular-nerve afferents innervate vestibular receptors and carry signals to the vestibular nuclei (VN). Afferents can be functionally grouped on the basis of the regularity of their resting discharge (Figure 3A, left, inset), measured by a normalized coefficient of variation (CV*) (Goldberg et al. 1984). Regular units show low variability in interspike intervals (ISI) of resting discharge (CV*<0.1), while irregular units have higher variability in resting discharge ISI (CV*>0.1). Importantly, regular and irregular units have distinct morphological properties (Fig 3A, top). In both the otoliths and semicircular canals, regular afferents have smaller axon diameter and provide bouton endings to type II haircells located at the periphery of the vestibular neuroepithelium. Irregular units are further divided into two groups: some provide calyx endings to type I haircells located at the center of neuroepithelium (C-irregulars) and the rest provide a mixed innervation of calyx endings to type I haircells and bouton endings to type II haircells (dimorphic or D-irregulars) (Baird et al. 1988).
Signals encoded by afferents during passive movements
Afferents innervating the otolith organs carry information about linear acceleration imposed on the otolith organs. These afferents respond similarly to both gravitational forces and translational accelerations over a wide range of frequencies. The dynamic response of otolith afferents is more in phase with acceleration of rotation, with small leads or lags, and their sensitivity increases with increasing frequencies of movement (Angelaki and Dickman 2000; Fernandez and Goldberg 1976a, 1976b, 1976c). In contrast, due to the mechanical properties of the semicircular canals (see above), response of afferents innervating the canals is more in phase with the velocity of rotation (Fernandez and Goldberg 1971; Hullar et al. 2005; Hullar and Minor 1999; Sadeghi et al. 2007b).
Experiments focusing on semicircular canal afferents indicate that regular and irregular canal afferents use different coding strategies (Sadeghi et al. 2007a). This is mainly the result of the amount of resting discharge variability. This variability is higher for irregular afferents compared to regular afferents, which results in higher power in the resting discharge power spectrum over the range of physiologically relevant frequencies (Fig 3A). This will result in low signal to noise ratio and little information in their spike times, particularly at lower frequencies of rotation (Fig 3B, right) (Sadeghi et al. 2007a). However, the response of the irregular units can be quantified by a rate code with increases in gain and phase lead of the response as a function of frequency of rotation (Fig 3B, left) (Hullar et al. 2005; Hullar and Minor 1999; Sadeghi et al. 2007b). In contrast, the lower variability in the resting discharge of regular afferents (Fig 3A, left) results in higher signal to noise ratio and higher information in the spike times (Fig 3B, right). In this way, regular afferents carry most of the information in their spike times and use temporal codes for transferring information across the range of physiologically relevant frequencies of up to 20 Hz (Sadeghi et al. 2007a). Thus, while regular afferents give detailed information about the head movements using temporal codes, irregular afferents use mostly rate codes and act as event detectors at high frequencies of movement. Recent studies have begun to study the implications of the different coding strategies at the next level of processing in the vestibular nuclei (Massot et al. 2011).
Response of afferents to active movements
To maintain postural and perceptual stability and accurately guide behavior, the nervous system must differentiate between vestibular signals imposed by the external world and those that result from our own actions. Recent studies have shown, however, that semicircular canal afferents similarly encode self-generated (i.e., active) and externally applied (i.e., passive) movements (Cullen and Minor 2002; Sadeghi et al. 2007b). As discussed below, the differentiation between active and passive movements first occurs at the next level of signal processing, that is the vestibular nuclei.
SECOND ORDER VESTIBULAR NEURONS
The four main nuclei of the vestibular complex
The vestibular complex comprises four main nuclei (Figure 4A): the medial vestibular nucleus (MVN), the superior vestibular nucleus (SVN), the lateral vestibular nucleus (LVN), and the inferior (or descending) vestibular nucleus (IVN), as well as some other minor subgroups. While there is no real segregation of inputs from afferents, the MVN and SVN receive inputs mostly from horizontal and vertical semicircular canals, respectively. The utricular afferents terminate mainly in the IVN, and also send projections to the LVN,MVN, and SVN. Saccule fibers mainly innervate the LVN and IVN. In addition to these direct projections from vestibular afferents, neurons in the vestibular nuclei also receive inputs from cortical, cerebellar, and other brainstem structures. The impressive convergence of information at the level of the vestibular nuclei is shown in Figure 4B. In alert animals these inputs relay somatosensory and visual inputs as well as signals related to eye movements and premotor head movement commands to the vestibular nuclei. As a result, in every day life, these extra-vestibular inputs modify the processing of vestibular information at an early stage of sensory processing.
Responses during passive rotations
The rotational sensitivities of neurons in the vestibular nuclei have been well quantified in head-restrained alert monkeys, and responses are consistent with the projections of the vestibular afferents (see section 3.1) . Neurons that are sensitive to horizontal (or yaw axis) rotations are found primarily in the rostral MVN and the ventro-LVN (Chubb et al. 1984; Cullen and McCrea 1993; Fuchs and Kimm 1975; Keller and Daniels 1975; Scudder and Fuchs 1992). Neurons that are sensitive to vertical (pitch or roll axes) rotations have been recorded primarily in the SVN, MVN, and y-group (Dickman and Angelaki 2004; Partsalis et al. 1995; Tomlinson and Robinson 1984) (Tomlinson and Robinson, 1984; Partsalis et al., 1995; Dickman and Angelaki 2004). Rotationally-sensitive neurons in both the horizontal and vertical systems can be divided into 3 main classes based on their responses to voluntary eye movements and passive whole-body rotations. These include: 1) Position-Vestibular-Pause (PVP) neurons, 2) Vestibular-Only (VO) neurons, and 3) Eye-Head (EH) neurons.
Controlling the axis of gaze
The vestibulo-ocular reflex (VOR) effectively stabilizes gaze during everyday activities such as walking and running by moving the eye in the opposite direction to the on-going head motion. The three-neuron arc (Figure 5A) that is responsible for mediating the VOR evoked by head rotation was first described by Lorente de No' in 1933. This pathway consists of projections from vestibular afferents to neurons in the vestibular nuclei, which in turn project to extraocular motoneurons. The simplicity of this three-neuron arc is reflected in the fast response time of the VOR (Figure 5A, inset); compensatory eye movements lag head movements by only 5-6 ms in the primate (Huterer and Cullen 2002; Minor et al. 1999).
Type I PVP neurons, which constitute most of the intermediate leg of the VOR pathway, derive their name from the signals they carry during head-restrained rotation and eye movement paradigms (Figure 5B). Their firing rates increase with contralaterally directed eye position. They are sensitive to ipsilaterally directed head velocity during vestibular stimulation (i.e. a type I response), and their discharges cease (pause) for ipsilaterally directed saccades and vestibular quick phases. PVP neurons process vestibular information in a manner that depends on the subject’s current gaze strategy.
First, the transmission of vestibularly driven information is suppressed when the visual axis of gaze is redirected using combined eye-head orienting movements (Figure 5C) (McCrea and Gdowski 2003; Roy and Cullen 1998, 2002). The suppression of PVP transmission is useful in this circumstance, since the eye movement command generated by the VOR pathway would function to drive the eye in the opposite direction to the intended change in gaze. In contrast, PVP neurons robustly encode head velocity signals whenever the behavioral goal is to stabilize the visual axis of gaze relative to space regardless of whether head movement is actively or passively generated (Roy and Cullen 1998, 2002).
Second, the magnitude of PVP modulation to head rotation depends on whether the visual axis is oriented on a near or far target. This is because the eyes translate as well as rotate relative to space since they cannot both be perfectly aligned with the axis of rotation. Consequently for the same amplitude of head rotation, a larger VOR gain is necessary to stabilize a near than a far earth-fixed target. Differences in the responses of the PVP neurons that mediate the direct VOR pathways are consistent with these distance-related changes in VOR gain (Chen-Huang and McCrea 1999).
Controlling the vestibulo-spinal and vestibulo-collic reflexesIn addition to its crucial role in stabilizing the eye relative to space via the VOR, the vestibular system also coordinates postural reflexes. Vestibular reflexes such as the vestibulo-collic reflex (VCR) are critical for maintaining head and body posture during our daily activities. The VCR functions to stabilize the head relative to inertial space by generating a command to move the head in the opposite direction to that of the current head-in-space velocity (Baker et al. 1985; Ezure and Sasaki 1978; Goldberg and Peterson 1986; Peterson et al. 1981; Wilson et al. 1990). Vestibular-only (VO) neurons in the VN project to the cervical spinal cord and are thought to mediate the VCR pathway (Figure 6A) (Boyle 1993; Boyle et al. 1996; Gdowski and McCrea 1999; Wilson et al. 1990). VO neurons are modulated during passive whole-body rotation (Figure 6B) and are insensitive to eye movements (Figure 6A, inset). These neurons also most likely control vestibulo-spinal reflexes since neurons that project to the cervical spinal cord can have multiple axon collaterals which also project widely to other segments in the spinal cord (i.e. thoracic and lumbar; (Abzug et al. 1974; Shinoda et al. 1988). Recent studies have shown attenuation in the head-velocity signals carried by VO neurons during gaze shifts (Figure 6C) (Roy and Cullen 2001).
Processing of self-produced head movement
The ability to distinguish self-generated sensory events from those that arise externally is essential for perceptual stability and accurate motor control. Over 50 years ago, Von Holst and Mittelstaedt (von Holst and Mittelstaedt 1950) proposed the Principle of Reafference, in which a copy of the expected sensory results of a motor command (termed reafference) is subtracted from the actual sensory signal to create a perception of the outside world (termed exafference) (Figure 7). There is, however, evidence for the cancellation of reafference at the level of the second order neurons in the vestibular nuclei. The head velocity-related modulation of vestibular-only neurons is dramatically attenuated during self-produced head movement (McCrea et al. 1999; Roy and Cullen 2001). Moreover, neurons continue to selectively respond to passive head motion when a monkey generates voluntary head-on-body movements while undergoing passive whole-body rotation. The findings of recent studies suggest that an internal model of the sensory consequences of active head motion is used to selectively suppress reafference at the level of the vestibular nuclei (Roy and Cullen 2004). The differentiation of sensory stimulation that arises from passive versus active movement is not only crucial for perceptual stability, but it is also required to produce accurate neural representations of the environment in order to accurately guide behaviour. In particular, the reduced sensitivities of these neurons during active head movements is consistent with their functional role in head stabilization, since their modulation would actually be counterproductive during self-generated movements.
The same neurons in vestibular nuclei that respond to passive head rotations also respond to full field visual motion or optic flow (Boyle et al. 1985; Waespe and Henn 1977a, 1979, 1977b). The observation that neurons within the vestibular nuclei simultaneously process visual and vestibular inputs has been used to explain why full-field motion on the retina not only provides an observer with an indication of how fast, and in what direction, the visual world is moving, but leads to the sensation of self-rotation. When vestibular and visual stimulation are paired to move in unison so that a conflict situation arises, both the neuronal modulation and the resultant nystagmus are minimal. Likewise, the percept of self-motion is reduced.
Convergence of otolith and canal signals
Most neurons in the vestibular nuclei receive convergent inputs from the otolith end organs and semicircular canals. Thus neurons not only encode rotations, but also respond to linear (inertial) accelerations of motion including the constant influence of gravity. As expected from Einstein’s equivalence principle, the otolith organs and, in turn, the otolith afferents, cannot distinguish accelerations due to head tilt (relative to gravity) from translational self-motion (Angelaki and Dickman 2000). Convergence of signals from the canals (which are activated during tilt but not during pure translation) and otoliths in the vestibular nuclei, fastigial nucleus of the cerebellum, and Purkinje cells in the cortex of nodulus and uvula of the cerebellum provides a means to solve this problem: an internal estimate of gravity is produced in these areas, which is subtracted from the otolith-afferents signal, leading to an estimation of the inertial motion. While the nodulus-uvula Purkinje cells encode inertial motion, the firing rate of neurons of the vestibular nuclei and fastigial nucleus provides a mixture of responses (Angelaki et al. 2004; Shaikh et al. 2005; Yakusheva et al. 2007).
Vestibular Adaptation and Compensation
The vestibular system is capable of impressive adaptation in response to environmental requirements. An extreme case of vestibulo-spinal reflex adaptation is seen in astronauts during microgravity in space flights (Minor 1998). For example, the amplitude of the otolith-spinal reflexes decrease immediately after entering weightlessness and remains less than normal (Watt et al. 1986). A dramatic illustration of the adaptive capabilities in the VOR can be observed in subjects that chronically view the world through reversing prisms (Gonshor and Jones 1976). The VOR response reversed over a period of 3-4 weeks to produce stabilization of the world on the retina during head movements. In more commonly encountered situations the requirements for vestibular adaptation are less challenging. Nevertheless, in humans the VOR must be continuously adjusted in the first years of life to compensate for significant changes in head circumference (~30% in the first year). Moreover later in life, adaptive changes in VOR performance are required to compensate for the magnification of corrective lenses that are worn for common visual conditions. Recent experiments have provided evidence that short-term adaptation occurs in the flocculus of the cerebellum. Long-term memory of this adaptation is then stored in a group of cells in VN, called floccular target cells or FTNs (Broussard and Lisberger 1992), which receive inputs from the cerebellum (Boyden et al. 2004; Kassardjian et al. 2005).
Compensation in vestibular pathways is critical in response to loss of haircells as a result of aging or diseases that affect any part of its pathway (e.g., vestibular nerve neuromas, vestibular neuritis, or trauma). In the extreme case of complete loss of vestibular inputs from one side (e.g., after vestibular neuritis), the symptoms are severe. Acutely, the eye shows an involuntary movement called spontaneous nystagmus (i.e., movements with slow components toward the lesioned side and fast components toward the intact side), the head is tilted toward the lesioned side, and the subject falls toward the lesioned side. During movements, the subject moves toward the lesioned side and shows a deficient VOR response. The lack of vestibular inputs is extremely debilitating, because simple activities like walking or driving are accompanied by symptoms and signs such as imbalance and oscillopsia (i.e., the illusion that the environment is moving when we move our heads). Interestingly, in the first few weeks following the lesion, static symptoms such as spontaneous nystagmus and head tilt toward the side of the lesion are overcome and almost completely disappear. Furthermore, during this period the VOR response recovers, particularly for ipsilesional low-frequency rotations (Curthoys and Halmagyi 1995; Sadeghi et al. 2006).
Understanding the neuronal mechanisms that mediate compensation has been an active area of investigation over the past 40 years. In vivo studies have shown that acutely, following a unilateral peripheral lesion, the resting discharge of VN cells on the ipsilesional side decreases while resting discharge on the contralesional side increases (Ris et al. 1995; Ris and Godaux 1998). This asymmetry underlies the static symptoms that are observed clinically. After a week, the resting discharge increases on the ipsilesional side and decreases on the contralesional side and the new balance results in recovery from the static symptoms. In addition, an acute decrease in the sensitivity of VN neurons results in the decrease in VOR responses, which is particularly striking for ipsilaterally directed head turns. The compensatory changes which are observed at the level of vestibular nuclei are thought to be achieved through three main mechanisms:
- Evidence from in vitro studies suggest that this compensation can be the result of changes in intrinsic properties of cells on contra and ipsilesional sides (Beraneck et al. 2003; Beraneck et al. 2004).
- Other in vivo and in vitro studies have suggested that extravestibular signals, such as somatosensory, visual, or neck proprioceptive signals, can either substitute vestibular signals or facilitate the response of VN neurons to the remaining vestibular inputs (Della Santina et al. 2001; Dichgans et al. 1973; Newlands et al. 2001; Newlands and Perachio 1991; Ris and Godaux 1998; Vibert et al. 1999).
- There is evidence that changes in commissural connections between the VN on the two sides play a role in the compensation process (Dieringer and Precht 1979a, 1979b).
Theoretical studies further support these findings and suggest a reorganization in the commissural system, resulting in strengthening of control of the intact side over the defective side (Galiana et al. 1984).
Finally, it is important to note that, following a unilateral lesion, compensation processes are not able to restore the VOR completely over the long term. The VOR remains deficient in response to high-frequency, high-acceleration, or high-velocity rotations, particularly in the ipsilesional direction (Gilchrist et al. 1998; Halmagyi et al. 1990; Sadeghi et al. 2006).
Multimodal processing in the vestibular nuclei
Unlike other sensory systems, the information encoded by vestibular system becomes strongly multisensory and multimodal at the first stage of central processing. As detailed above, this occurs because the vestibular nuclei receive inputs from a wide range of cortical, cerebellar, and other brainstem structures in addition to direct inputs from the vestibular afferents. Recent studies have emphasized the importance of extra-vestibular signals in shaping the ‘simple’ sensory-motor transformations that mediate vestibulo-ocular and vestibulo-spinal reflexes. The multisensory and multimodal interactions that occur in vestibular processing also play an essential role in higher-order vestibular functions, like self-motion perception and spatial orientation. For example, proprioceptive-vestibular interactions, coupled with corollary discharge of a motor plan, allow the brain to distinguish actively-generated from passive head movements (see Processing of self-produced head movement). In addition, interactions between otolith and canal signals allow the vestibular system to compute inertial motion (i.e., motion of the head in space) making a critical contribution to both navigation and spatial orientation (see Convergence of otolith and canal signals).
It should also be noted that an important result of the multisensory nature of vestibular processing, is that vestibular representations at higher levels of processing are encoded in multiple reference frames. For example, the maintenance of posture and balance and perception of self-motion require knowledge of body position, orientation and movement. By combining vestibular signals, which encode motion in a head-centered frame, with neck proprioceptive information that signals the position of the head relative to the body, a reference frame transformation takes place in the regions of the vestibulo-cerebellum, whereby the brain constructs an internal estimate of body motion in space. The processing of vestibular information at higher levels is further discussed in Higher order vestibular processing.
THE EFFERENT VESTIBULAR SYSTEM: ANATOMY AND FUNCTIONVestibular efferent neurons are located near the abducens nucleus in the brainstem (Figure 8A), 8B) to vestibular receptors (type II) and afferents (type I and II) (Gacek and Lyon 1974; Goldberg and Fernandez 1980; Rasmussen and Gacek 1958). Vestibular efferent projections are excitatory and increase the resting discharge of the afferents, while decreasing their sensitivity (squirrel monkeys: (Goldberg and Fernandez 1980), toadfish: (Highstein and Baker 1985)). Thus, theoretically, efferents can increase the dynamic range of afferent responses. Furthermore, in frog (Bricout-Berthout et al. 1984; Caston and Bricout-Berthout 1984) and toadfish (Boyle and Highstein 1990; Highstein and Baker 1985) vestibular afferents respond to somatosensory, auditory, or visual stimuli, presumably as a result of inputs mediated by the vestibular efferent system. However, the situation is different in alert primates under normal conditions, since afferent fibers do not carry any extravestibular signals (visual: (Keller 1976), neck proprioception: (Sadeghi et al. 2007b), efference copy of neck motor command: (Cullen and Minor 2002). Nevertheless, efferent-mediated responses are observed in primate afferents in response to high velocity rotations (Sadeghi et al. 2009).
Furthermore, vestibular afferents do not play a role in vestibular adaptation (Miles and Braitman 1980) or long-term compensation (Sadeghi et al. 2007b). Thus, the functional role of the efferent system in alert primates has remained elusive.
HIGHER ORDER VESTIBULAR PROCESSING
There are five main regions of the cerebellum that receive either primary (i.e. from afferents) or secondary (i.e. from vestibular nuclei) vestibular input including:
- the nodulus and ventral uvula,
- the flocculus and ventral paraflocculus,
- the oculomotor vermis of posterior lobe,
- lobules I-V of the anterior lobe, and
- the deep cerebellar nuclei.
As described below, each of these regions makes an important contribution to the processing of vestibular sensory information:
- The vestibular nuclei are reciprocally interconnected with the nodulus/uvula of the cerebellum (Wearne et al. 1998). These areas of the cerebellum make significant contributions to the computation of inertial motion (Angelaki and Hess 1995; Wearne et al. 1998).
- The flocculus and adjoining paraflocculus is involved in the generation and the plasticity of compensatory eye movements, including visual ocular following reflexes (i.e. smooth pursuit and the optokinetic reflex) and the VOR (Buttner and Waespe 1984; Lisberger and Fuchs 1978; Lisberger et al. 1994a; Lisberger et al. 1994b; Miles et al. 1980a; Miles et al. 1980b; Noda and Suzuki 1979).
- Neurons in lobules VI and VII of the vermis, which is called the oculomotor vermis, contribute to visual-vestibular processing (Sato and Noda 1992; Suzuki and Keller 1988, 1982). In addition to its vestibular inputs, this cerebellar region receives eye movement signals from the nucleus preopositus (Belknap and McCrea 1988) as well as pursuit-related inputs from the dorsolateral pontine nuclei (Brodal 1979; Yamada and Noda 1987)—a region into which cortical pursuit areas MT and MST both project (Glickstein et al. 1980).
- The anterior region of the cerebellar vermis (lobules I-V) encodes both vestibular and neck proprioceptive-related signals (Manzoni et al. 2004; Manzoni et al. 1998a, 1998b; Manzoni et al. 1999) and is thought to control of vestibulo-spinal reflexes. The integration of vestibular and proprioceptive information ensures that the motor responses produced by these reflexes are appropriate to maintain body stability.
- The signal processing done in the fastigial nucleus of the deep cerebellar nuclei is tightly linked to the vestibular system. It receives both primary and secondary vestibular inputs as well as input from the cerebellar vermis. The fastigial nucleus plays an important role in the generation of postural reflexes and orienting behaviors, and accordingly projects to brainstem structures that control these behaviors including the vestibular nuclei and medial reticular formation. Many neurons in this area integrate vestibular and proprioceptive inputs, and in turn encode vestibular signals in a body-centered reference frame (Kleine et al. 2004; Shaikh et al. 2004).
Vestibular thalamus and cortical projections
Neurons in several areas of cortex respond to vestibular stimulation (Figure 9). These include area 2v of the intraparietal sulcus (Buttner and Buettner 1978), area 3a in the sulcus centralis (Odkvist et al. 1974), ventral intraparietal area (VIP) (Bremmer et al. 2002), medial superior temporal area (MST) (Duffy 1998) and parietoinsular vestibular cortex (PIVC) (Grusser et al. 1990a). Areas 3a, T3, and PIVC receive vestibular projections through thalams (reviewed in: Fukushima 1997). Of these areas PIVC, is generally considered as the main vestibular cortex since information from other vestibular cortical areas converge in PIVC (reviewed in: (Guldin and Grusser 1998)). In addition, most of the neurons in PIVC receive vestibular input, stimulation of this area produces vestibular sensation in humans (Penfield 1957), lesions of this area impairs perception of subjective vertical (Brandt et al. 1994), vestibular aurae in epileptic patients is related to activation of this area (Smith 1960), and cerebral blood flow of PIVC area increases during vestibular stimulation (Friberg et al. 1985). Although neurons in regions of the thalamus and cortex which receive direct and indirect inputs from the vestibular nuclei are largely insensitive to eye movements (Buttner and Lang 1979; Grusser et al. 1990b; Magnin and Fuchs 1977), most neurons receive convergent vestibular, visual and somatosensory inputs (Akbarian et al. 1988; Akbarian et al. 1992) further emphasizing the inherently multimodal nature of vestibular processing.
Cortical processing of vestibular input is important for generating appropriate motor response and provides us with our subjective sense of movement and orientation in space. Neurons in area VIP of area 7 show differential activity in response to active and passive head movements including changes in the strength, timing, and direction selectivity of their responses under the two conditions (Bremmer et al. 2002; Klam and Graf 2006, 2003). This differential encoding of vestibular information is important for shaping appropriate motor responses to guide voluntary movements. Most recently, studies have focused on how the responses of neurons in the dorsal medial superior temporal cortex (MSTd) contribute to our perception of self-motion (Duffy 1998; Gu et al. 2006; Page and Duffy 2003). This cortical area has long been known to process optic flow information. Experiments demonstrating a functional link between area MSTd and heading perception based on vestibular signals further support the proposal that that MSTd plays a role in self-motion perception (Fetsch et al. 2007; Gu et al. 2007).
As a final point, corticofugal projections project back to vestibular nuclei (Akbarian et al. 1994), thereby also modulating vestibular processing at an earlier stage. How these feedback projections influence sensory processing at the level of the VN remains to be determined.
- Recent studies have advanced our understanding of the functional role of the auditory efferent system. In contrast, while the vestibular efferent system has been well characterized using anatomical and electrophysiological approaches, its function still remains a mystery.
- While we have gained considerable insights into adaptive processes that induce and encode changes to modify VOR performance, further studies—at the cellular, neuronal, and circuit levels—are required to understand fully the mechanisms that underlie VOR plasticity, as well as the compensation that occurs following vestibular damage.
- The distinction between coding of passive versus active head movements has been tested during rotations (at the level of the vestibular periphery and vestibular nuclei). However, whether neurons respond differently during passive and active translational movements remains to be explored.
- To date, most prior studies of vestibular signal processing have concentrated on the brainstem vestibular nuclei and vestibulo-cerebellum. Vestibular information, however, is also encoded by neurons in the thalamus and cortex. Further experimental studies are required to understand how vestibular information is processed in these brain areas, and how this information is used to compute internal estimates of self-motion and spatial orientation.
- There are many open questions regarding the nature of the neural code that is used to encode vestibular information at the level of the sensory periphery, vestibular nuclei as well as upstream structures that contribute to the perception of self-motion. Future studies are required to address the implications of different coding strategies used by regular and irregular afferents and how information from the two afferent streams is integrated and decoded by central neurons.
- Prior studies describing the transformation of vestibular information from a head-centered to other reference frames (i.e. body-centered and eye-centered) considered only passive head movement stimuli. However, it remains to be determined if vestibular information is encoded in the same reference frames during actively generated movements or instead transformations are behavior-dependant.
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