Hypothesis: The Vestibular and Cerebellar Basis of the Mal de Debarquement Syndrome

The Mal de Debarquement syndrome (MdDS) generally follows sea voyages, but it can occur after turbulent flights or spontaneously. The primary features are objective or perceived continuous rocking, swaying, and/or bobbing at 0.2 Hz after sea voyages or 0.3 Hz after flights. The oscillations can continue for months or years and are immensely disturbing. Associated symptoms appear to be secondary to the incessant sensation of movement. We previously suggested that the illness can be attributed to maladaptation of the velocity storage integrator in the vestibular system, but the actual neural mechanisms driving the MdDS are unknown. Here, based on experiments in subhuman primates, we propose a series of postulates through which the MdDS is generated: (1) The MdDS is produced in the velocity storage integrator by activation of vestibular-only (VO) neurons on either side of the brainstem that are oscillating back and forth at 0.2 or 0.3 Hz. (2) The groups of VO neurons are driven by signals that originate in Purkinje cells in the cerebellar nodulus. (3) Prolonged exposure to roll, either on the sea or in the air, conditions the roll-related neurons in the nodulus. (4) The prolonged exposure causes a shift of the pitch orientation vector from its original position aligned with gravity to a position tilted in roll. (5) Successful treatment involves exposure to a full-field optokinetic stimulus rotating around the spatial vertical countering the direction of the vestibular imbalance. This is done while rolling the head at the frequency of the perceived rocking, swaying, or bobbing. We also note experiments that could be used to verify these postulates, as well as considering potential flaws in the logic. Important unanswered questions: (1) Why does the MdDS predominantly affect women? (2) What aspect of roll causes the prolongation of the tilted orientation vector, and why is it so prolonged in some individuals? (3) What produces the increase in symptoms of some patients when returning home after treatment, and how can this be avoided? We also posit that the same mechanisms underlie the less troublesome and shorter duration Mal de Debarquement.

Related papers:

title: Readaptation of the Vestibulo-Ocular Reflex Relieves the Mal De Debarquement Syndrome
abstract: The mal de debarquement syndrome (MdDS), a continuous feeling of swaying, rocking, and/or bobbing, generally follows travel on the sea. The associated symptoms cause considerable distress. The underlying neural mechanisms are unknown, and to date there have been no effective treatments for this condition. Results in monkeys and humans suggested that MdDS was caused by maladaptation of the vestibulo-ocular reflex (VOR) to roll of the head during rotation. We studied 24 subjects with persistent MdDS (3 males, 21 females; 19.1 ± 33 months). Physical findings included body oscillation at 0.2 Hz, oscillating vertical nystagmus when the head was rolled from side-to-side in darkness, and unilateral rotation during the Fukuda stepping test. We posited that the maladapted rocking and the physical symptoms could be diminished or extinguished by readapting the VOR. Subjects were treated by rolling the head from side-to-side while watching a rotating full-field visual stimulus. Seventeen of the 24 subjects had a complete or substantial recovery on average for approximately 1 year. Six were initially better, but the symptoms recurred. One subject did not respond to treatment. Thus, readaptation of the VOR has led to a cure or substantial improvement in 70% of the subjects with MdDS. We conclude that the adaptive processes associated with roll-while-rotating are responsible for producing MdDS, and that the symptoms can be reduced or resolved by readapting the VOR.

title: Mal de debarquement.
abstract: Clinical features of mal de debarquement syndrome.



Nearly all respondents were middle-aged women (26 of 27; mean age, 49.3 years). The duration of symptoms ranged from 6 months to 10 years (mean, 3.5 years; SD, 2.5 years). The symptoms were constant in 23 (85%) patients. Neither meclizine hydrochloride nor transdermal scopolamine was helpful. Benzodiazepines were of the most benefit. Balance rehabilitation physical therapy was undertaken by 15 patients, who on average reported a small benefit.



More than double the number of previously reported cases of mal de debarquement syndrome were identified by this study. The syndrome usually occurs in middle-aged women following an ocean cruise. Symptoms are often refractory to vestibular suppressants as well as physical therapy.

title: Mal de débarquement syndrome.
abstract: Mal de débarquement syndrome (MdDS) is typified by a prolonged rocking sensation - for a month or longer - that begins immediately following a lengthy exposure to motion. The provoking motion is usually a sea voyage. About 80% of MdDS sufferers are women, and most of them are middle-aged. MdDS patients are troubled by more migraine headaches than controls. Unlike dizziness caused by vestibular disorders or motion sickness, the symptoms of MdDS usually improve with re-exposure to motion. The long duration of symptoms - a month or more - distinguishes MdDS from land-sickness. Treatment of MdDS with common vestibular suppressants is nearly always ineffective. Benzodiazepines can be helpful, but their usefulness is limited by the potential for addiction. Studies are ongoing regarding treatment with visual habituation and transcranial magnetic stimulation.

title: Frequency-specific mal de debarquement
abstract: After a prolonged period of passive motion, a nonvertiginous sense of dizziness may be experienced when the subject returns to a stationary environment. Patients with this syndrome, referred to as mal de debarquement (MDD), describe a sensation of rocking, tilting, or swaying that may last from hours to years and that is generally most marked when they are stationary.1,2⇓ Possible explanations for MDD have included abnormal adaptation to motion, otolith dysfunction, migraine, or psychogenic mechanisms.1,3⇓ I describe a patient whose symptoms closely mimicked the subjective head motion dynamics associated with travel in two different cars. This case supports the contention that MDD results from an aberrant adaptive response to passive motion.

A 55-year-old woman sought treatment for a 4-year history of dizziness. She described her symptoms as a sense of rocking and pitching. These symptoms invariably followed prolonged driving trips, typically occurred in episodes lasting for hours, …

title: Mal de debarquement syndrome: new insights
abstract: Mal de Debarquement Syndrome (MdDS) is an enigmatic neurotological disorder with high morbidity, psychosocial burden, and few treatment options. Fortunately, there has been recent growth in scientific interest in understanding the biological basis of and in treating MdDS. Recent studies using functional neuroimaging have shown increased glucose metabolism in the left entorhinal cortex (EC) and amygdala in the setting of decreased prefrontal and temporal cortex metabolism in subjects with persistent MdDS. The EC is a key player in processing and gating spatial information to be stored in the hippocampus and is a major driver of brain oscillations. A limbic focus may also be key to spontaneous MdDS‐like symptoms occurring in individuals with a history of anxiety or chronic stress. Treatment with repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex can decrease the rocking dizziness of MdDS, with successful responses associated with decreases in the coherence between brain networks with nodes in the parietal and occipital lobes. A new theory of MdDS is proposed as pathology secondary to entrainment of intrinsic brain networks driven by oscillatory motion exposure coupled with an inability to subsequently desynchronize the activity of these nodes. Future treatment strategies may be directed toward unyoking these networks.

title: The relationship between symptom severity, stigma, illness intrusiveness and depression in Mal de Debarquement Syndrome
abstract: Mal de Debarquement Syndrome is a neurological disorder of motion perception, triggered by external motion. This study aimed to determine the importance of psychosocial factors in relation to depression and quality of life in Mal de Debarquement Syndrome. A total of 66 participants with self-reported Mal de Debarquement Syndrome completed quality-of-life, symptom severity, stigma, depression, and illness intrusiveness measurements in this naturalistic correlational study. Mal de Debarquement Syndrome was associated with high levels of depression and illness intrusiveness. Illness intrusiveness mediated between stigma and quality of life; also the level of stigma moderated the effect of illness intrusiveness on quality of life. Targeted interventions aimed at alleviating psychological distress may improve quality of life in Mal de Debarquement Syndrome.

title: Social, societal, and economic burden of mal de debarquement syndrome
abstract: Mal de debarquement syndrome (MdDS) is a disorder of phantom perception of self-motion of unknown cause. The purpose of this work was to describe the quality of life (QOL) of patients with MdDS and to estimate the economic costs associated with this disorder.  The estimated economic costs were based on self-reported direct and indirect costs of individuals living in the United States using Medicare reimbursement payment rates for 2011 in 79 patients. Patients with MdDS reported a poor overall QOL as indicated by a mean composite QOL score of 59.26 ± 1.89 (out of 100). The subcategories having the lowest QOL rating were role limitations due to physical problems (18.32 ± 3.20), energy (34.24 ± 1.47), and emotional problems (36.30 ± 4.00). The overall physical health composite score including balance was 49.40 ± 1.69, and the overall mental health composite score was 52.40 ± 1.83. The cost to obtain a diagnosis was $2,997 ± 337, which included requiring an average of 19 physician visits per patient. The direct cost of MdDS medical care was $826 ± 140 per patient per year, which mainly included diagnostic imaging and physician visits. The indirect costs (i.e., lost wages) were $9,781 ± 2,347 per patient per year. Among 65 patients who were gainfully employed when they acquired MdDS, the indirect costs were $11,888 ± 2,786 per patient per year. Thus, the total annual cost of the disorder ranged from $11,493 ± 2,341 to $13,561 ± 2,778 per patient per year depending on employment status prior to developing MdDS. MdDS negatively and dramatically impacts QOL, and also imposes a substantial economic burden on MdDS patients. These findings underscore the need for further basic and clinical research on MdDS.

title: Mal de debarquement syndrome: a systematic review
abstract: Mal de debarquement (MdD) is a subjective perception of self-motion after exposure to passive motion, in most cases sea travel, hence the name. Mal de debarquement occurs quite frequently in otherwise healthy individuals for a short period of time (several hours). However, in some people symptoms remain for a longer period of time or even persist and this is then called mal de debarquement syndrome (MdDS). The underlying pathogenesis is poorly understood and therefore, treatment options are limited. In general, limited studies have focused on the topic, but the past few years more and more interest has been attributed to MdDS and its facets, which is reflected by an increasing number of papers. Till date, some interesting reviews on the topic have been published, but a systematic review of the literature is lacking and could help to address the shortcomings and flaws of the current literature. We here present a systematic review of MdD(S) based on a systematic search of medical databases employing predefined criteria, using the terms “mal de debarquement” and “sea legs”. Based on this, we suggest a list of criteria that could aid healthcare professionals in the diagnosis of MdDS. Further research needs to address the blank gaps by addressing how prevalent MdD(S) really is, by digging deeper into the underlying pathophysiology and setting up prospective, randomized placebo-controlled studies to evaluate the effectiveness of possible treatment strategies.

title: Management of mal de debarquement syndrome as vestibular migraines
abstract: Mal de debarquement syndrome (MdDS) is a balance disorder that typically starts after an extended exposure to passive motion, such as a boat or plane ride. Management is typically supportive (e.g. physical therapy), and symptoms that persist beyond 6 months have been described as unlikely to remit. This study was conducted to evaluate the response of patients with MdDS to management with migraine prophylaxis, including lifestyle changes and medical therapy.

title: Effects of persistent Mal de debarquement syndrome on balance, psychological traits, and motor cortex exctiability
abstract: Mal de debarquement syndrome (MdDS) is a poorly characterized and understood disorder of perceived motion. We sought to characterize postural control and the psychological impact of MdDS. Additionally, we explored whether patients with MdDS exhibit altered corticospinal and intracortical excitability. In a case-control study we compared patients with MdDS to age- and sex-matched controls (n=8/group). Postural stability (σr) was quantified from plane phase plots based on center or pressure, and psychological indices of depression, fatigue and kinesiophobia were obtained. Transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability by quantifying the motor evoked potential (MEP) amplitude of the flexor carpi radialis, and intracortical excitability was assessed by quantifying indices of intracortical facilitation (ICF), and short-interval and long-interval intracortical inhibition using a paired-pulse TMS paradigm. The patients with MdDS exhibited greater mean (±standard error of the mean) σr during semi-tandem stance (10.9 ± 1.5 compared to 7.1 ± 0.7, p=0.04), higher levels of kinesiophobia (41.6 ± 2.8 compared to 27.3 ± 2.2), and higher levels of fatigue (27.0 ± 4.1 compared to 48.4 ± 1.0). Patients with MdDS exhibited a higher mean motor threshold (MT) (58.1 ± 2.5 compared to 47.4 ± 2.7% of stimulator output), and larger MEP (13.1 ± 3.1 compared to 5.1 ± 1.2% of maximal compound muscle action potential) but there was no difference in measures of intracortical excitability. These findings suggest that patients with MdDS exhibit impaired postural stability, and high levels of kinesiophobia and fatigue. Additionally, we observed that patients with MdDS exhibit higher MT and large MEP amplitudes, but do not exhibit differences in measures of intracortical excitability, compared to controls. These findings help characterize MdDS, and provide insight into the physiology of MdDS.

title: Voxel Based Morphometry Alterations in Mal de Debarquement Syndrome
abstract: Mal de debarquement syndrome (MdDS) is a disorder of chronic self-motion perception that occurs though entrainment to rhythmic background motion, such as from sea voyage, and involves the perception of low-frequency rocking that can last for months or years. The neural basis of this persistent sensory perception abnormality is not well understood.  We investigated grey matter volume differences underlying persistent MdDS by performing voxel-based morphometry on whole brain and pre-specified ROIs in 28 individuals with MdDS and comparing them to 18 age, sex, and handedness matched controls.  MdDS participants exhibited greater grey matter volume in the left inferior parietal lobule, right inferior occipital gyrus (area V3v), right temporal pole, bilateral cerebellar hemispheric lobules VIII/IX and left lobule VIIa/VIIb. Grey matter volumes were lower in bilateral inferior frontal, orbitofrontal, pregenual anterior cingulate cortex (pgACC) and left superior medial gyri (t = 3.0, p<0.005uncorr). In ROI analyses, there were no volume differences in the middle occipital gyrus (region of V5/MT) or parietal operculum 2 (region of the parietoinsular vestibular cortex). Illness duration was positively related to grey matter volume in bilateral inferior frontal gyrus/anterior insula (IFG/AI), right posterior insula, superior parietal lobule, left middle occipital gyrus (V5/MT), bilateral postcentral gyrus, anterior cerebellum, and left cerebellar hemisphere and vermian lobule IX. In contrast, illness duration was negatively related to volume in pgACC, posterior middle cingulate gyrus (MCC), left middle frontal gyrus (dorsolateral prefrontal cortex-DLPFC), and right cerebellar hemispheric lobule VIIIb (t = 3.0, p<0.005uncorr). The most significant differences were decreased volume in the pgACC and increased volume in the left IFG/AI with longer illness duration (qFDRcorr <0.05). Concurrent medication use did not correlate with these findings or have a relationship with duration of illness. MdDS participants showed positive correlations between grey matter volume in pgACC and bilateral cerebellar lobules VIII/IX, which was not seen in controls.  Individuals with MdDS show brain volume differences from healthy controls as well as duration of illness dependent volume changes in (a) visual-vestibular processing areas (IPL, SPL, V3, V5/MT), (b) default mode network structures (cerebellar IX, IPL, ACC), (c) salience network structures (ACC and IFG/AI) (d) somatosensory network structures (postcentral gyrus, MCC, anterior cerebellum, cerebellar lobule VIII), and (e) a structure within the central executive network (DLPFC). The identification of these associations may enhance future investigations into how exposure to oscillating environments can modulate brain function and affect motion perception as well cognitive and affective control.

title: Mal de debarquement: Pseudo-hallucinations from vestibular memory?
abstract: Mal de debarquement (MdD) literally means ‘‘sickness of disembarkation’’ and refers to the illusion of movement felt as an after–effect of travelling on a boat, train or airplane. This sensation is physiological and usually stops after several hours. In some individuals, however, illusory movement persists for weeks, months or even years after the voyage which is referred to as ‘‘persistent mal de debarquement’’. This disorder can be frightening or even disabling for affected individuals as testified on several internet sites dedicated to chronic MdD. The pathophysiology of both acute and persistent MdD is mysterious. We present two patients with the chronic variant of MdD who may further our understanding of the condition.

title: Neuroimaging studies in patients with Charles Bonnet Syndrome
abstract: Charles Bonnet Syndrome (CBS) is characterized by complex formed and recurrent visual hallucinations in psychologically normal people, and is often associated with eye pathology. Many psychiatrists have taken an interest in CBS because this syndrome could provide clues to the mechanisms underlying visual hallucinations. In the present paper, we review previous neuroimaging studies in patients with CBS and summarize the results of these studies. There could be a fundamental dysfunction in the primary and secondary visual cortices in some patients with CBS, and transient cortical activation occurs in the inferior lateral temporal cortex during the appearance of visual hallucinations in CBS patients. External visual stimuli are perceived in the retina and are transmitted to the primary visual cortex (Brodmann area (BA) 17). The stimuli are transmitted from BA 17 to the secondary visual cortex (BA 18) and then to the visual association cortices (BA 19 and BA 37). In general, our perception of external visual stimuli normally has an inhibitory effect on the endogenous activation of the visual cortex. Visual loss due to certain conditions, of which eye pathology is the most commonly postulated in CBS patients, produces a state of sensory deprivation that releases the visual cortex from regulation by external stimuli, resulting in visual hallucinations (cortical release phenomenon). The results of previous neuroimaging studies suggest that the cortical release phenomenon hypothesis for the occurrence of visual hallucinations in patients with CBS is plausible. In addition, the results indicate that not only eye pathology, but also dysfunction in the primary and secondary visual cortices could result in deprivation of external visual stimuli.

title: Adaptation of the angular vestibulo-ocular reflex to head movements in rotating frames of reference
abstract: Head movements in a rotating frame of reference are commonly encountered, but their long term effects on the angular vestibulo-ocular reflex (aVOR) are not well understood. To study this, monkeys were oscillated about a naso-occipital (roll) axis for several hours while rotating about a spatial vertical axis (roll-while-rotating, RWR). This induced oscillations in roll and pitch eye velocity and continuous horizontal (yaw) nystagmus. For several hours thereafter, simple roll in darkness induced horizontal nystagmus and pitch and roll oscillations. The rising and falling time constants of the horizontal velocity indicated that the nystagmus arose in velocity storage. The continuous nystagmus was correlated with a phase shift of vertical eye velocity from 90° to 0° re head position. As the phases reverted toward pre-adaptive values, the horizontal velocity declined. Similar yaw nystagmus and pitch and roll velocities were produced by oscillation in roll after adaptation with roll and horizontal optokinetic nystagmus (OKN), but not after adaptation with pitch-while-rotating (PWR). Findings were explained by a model that shifted the roll orientation vector of velocity storage toward the pitch axis during adaptation with RWR and Roll & OKN. This shift produced modulation in vertical eye velocity in the post adaptive state, which was approximately in phase with roll head position, generating horizontal nystagmus. Similar orientation changes to prolonged exposure to complex motion environments may be responsible for producing post-stimulus motion sickness and/or mal de debarquement.

title: Velocity storage in the vestibulo-ocular reflex arc (VOR)
abstract: SummaryVestibular and optokinetic nystagmus (OKN) of monkeys were induced by platform and visual surround rotation. Vision prolonged per-rotatory nystagmus and cancelled or reduced post-rotatory nystagmus recorded in darkness. Presumably, activity stored during OKN summed with activity arising in the semicircular canals. The limit of summation was about 120 °/s, the level of saturation of optokinetic after-nystagmus (OKAN). OKN and vestibular nystagmus, induced in the same or in opposite directions diminished or enhanced post-rotatory nystagmus up to 120 °/s. We postulate that a common storage mechanism is used for producing vestibular nystagmus, OKN, and OKAN. Evidence for this is the similar time course of vestibular nystagmus and OKAN and their summation. In addition, stored activity is lost in a similar way by viewing a stationary surround during either OKAN or vestibular nystagmus (fixation suppression).These responses were modelled using direct pathways and a non-ideal integrator coupled to the visual and peripheral vestibular systems. The direct pathways are responsible for rapid changes in eye velocity while the integrator stores activity and mediates slower changes. The integrator stabilizes eye velocity during whole field rotation and extends the time over which the vestibulo-ocular reflex can compensate for head movement.

title: The vestibulo-ocular reflex in three dimensions
abstract: The purpose of this paper is to review the kinematics and dynamics of the vestibulo-ocular reflex (VOR) in three dimensions. We give a brief, didactic tutorial on vectors and matrices and their importance as representational schemes for describing the kinematics and dynamics of the angular and linear accelerations that activate the vestibular system. We show how the vectors associated with angular and linear head accelerations are transformed by the peripheral and central vestibular systems to drive the oculomotor system to produce eye movements in three-dimensional space. We also review critical questions and controversies related to the compensatory and orientation behavior of the VOR. One such question is how the central vestibular system distinguishes tilts of the head, which generate interaural linear acceleration from translations along the interaural axis. Another question is how the velocity-position integrator is implemented centrally. The review has been placed in the context of a model that explains the behavior of the VOR in three dimensions. Model processes have been related to peripheral and central neural behavior in order to gain insight into the nature of the three-dimensional organization and the controversial questions that are addressed.

title: The Physiology of the Vestibuloocular Reflex (VOR)
abstract: In this chapter, we have introduced the physiology of the vestibuloocular reflex and its compensatory and orienting functions. Advances in technology have frequently resulted in advances in basic understanding of the system. Means are now available to record the movements of the eyes, body, and limbs in freely moving subjects and to study vestibular function more precisely at a cellular level. From this, new understanding of the physiology of the vestibular system will emerge, particularly at the cellular level, which will probably dwarf all previous efforts. The clinical significance of this system is great because the reflexes that provide postural control during standing and help stabilize gaze and the body while walking and running are vital to normal function and can easily be disordered, both by disease and by aging. Thus, the physiology warrants deeper investigation solely for its clinical importance. Beyond that, however, the vestibular system sits at the heart of the motion-sensing apparatus of the brain, and it can serve as a model system for studying how the brain integrates information from many sensory systems to generate a motor output whose function is both well-known and vital to normal behavior and survival.

title: Baclofen, motion sickness susceptibility and the neural basis for velocity storage.
abstract: Reduction of the dominant time constant (T(VOR)) of the angular vestibulo-ocular reflex (aVOR) by habituation is associated with a decrease in motion sickness susceptibility. Baclofen, a GABA(b) agonist, reduces the time constant of the velocity storage integrator in the aVOR in a dose-dependent manner. The high frequency aVOR gain is unaltered by baclofen. Here we demonstrate that the reduction in T(VOR) produced by oral administration of 20 mg of baclofen causes a significant reduction in motion sickness susceptibility, tested with roll while rotating (RWR). These data show that motion sickness susceptibility can be pharmacologically manipulated with a GABA(b) agonist and support our conclusion that motion sickness is generated through velocity storage. We also show how baclofen acts on velocity storage at the neural level. A vestibular-plus-saccade (VPS) neuron was recorded in the rostral medial vestibular nucleus (rMVN) of a cynomolgus monkey, an area where we postulate that velocity storage is generated. The cell had a time constant during steps of velocity that was close to that of the T(VOR). After parenteral administration of baclofen, there was a similar decrease in the time constants of the VPS neuron and the T(VOR). This is the first demonstration of the concurrence of unit and aVOR time constants before and after baclofen. The data support the hypothesis that the velocity storage integrator is generated through activity of vestibular-only (VO) and VPS neurons in rMVN and suggest that GABA(b) synapses on VO and VPS neurons are likely to be involved in the baclofen-induced reduction in motion sickness susceptibility.

title: Compensatory nystagmus conditioned during adaptation to living in a rotating room.
abstract: Seven men were rotated at 5.4 revs/min in a room for 64 hr. Controlled tests before and during this interval demonstrated that disorientation and nystagmus attributable to Coriolis acceleration effects diminished markedly. A compensatory nystagmus, induced by head or whole-body movements, was recorded more than 1 hr after the rotation had ceased. Factors of possible significance in conditioning the compensatory nystagmus are: 1) otolith and proprioceptor sensory influx prior to and during discordant canal input: 2) a consistent sensory influx for each stimulus-producing movement: 3) intention in stimulus-producing movements: 4) visual inhibition. Contributions of compensatory and arousal factors to vestibular suppression are considered in relation to practical problems of transfer of habituation from one acceleration environment to another. Submitted on December 1, 1961

title: Persistent mal de debarquement syndrome: a motion-induced subjective disorder of balance.
abstract: Six patients with a distinct syndrome of persistent sensations of imbalance are presented. Common features included onset following a period of motion exposure, symptoms lasting months to years, mild unsteadiness and anxiety, minimal relief from antivertiginous medication, and normal neurologic and quantitative vestibulo-ocular examinations. One patient experienced recurrent episodes. Mal de debarquement refers to sensations of motion experienced on return to stable land after adaptation to motion lasting from hours to days in normal individuals. The presented patients exemplify a syndrome of persistent mal de debarquement. The entity is found in a relatively small number of dizzy patients. Persistent mal de debarquement is discussed in the context of what is known about long-term vestibulo-ocular adaptation to alterations of visual or vestibular environments.

title: Measuring vessel motions using a rapid-deployment device on ships of opportunity
abstract: Vessel motion data have many uses including seakeeping, vessel response model validation, under-keel clearance and cargo studies. However accurate measurements using survey-grade DGPS equipment on ships of opportunity can be hazardous for both the instruments and the personnel attending them in extreme weather conditions. These are frequently the very conditions for which the measurements are most desirable. For waterway-specific investigations where particular conditions are targeted, a portable, robust and easy to set-up/dismount solution is required to opportunistically measure vessel motions when conditions of interest occur. This paper describes OMC International's development and implementation of such a device for full scale vessel motion data collection, the “iHeave” vessel motion recorder. The OMC iHeave is a carry-on, set-and forget device for the accurate recording of short-duration vessel motions. Originally designed for use by marine pilots for an under-keel clearance study at the "Graveyard of the Pacific" Columbia River Bar, the iHeave is simple to use and self-contained. It can be rapidly mounted inside the bridge of almost any vessel while underway and requires no additional cabling or connections. At the time of writing some 32 winter transits over the Columbia River Bar have been measured by the Bar Pilots using an OMC iHeave device. Based on IMU technology (solid state accelerometers and gyroscopes), the iHeave measures and records all 6 degrees of motion (roll, pitch, yaw, surge, sway and heave) experienced by a vessel with accuracy comparable to the more traditional DGPS based approach.

title: Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity
abstract: The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.

title: The cerebellar nodulus and ventral uvula control the torsional vestibulo-ocular reflex.
abstract: 1. The vestibulo-ocular reflex (VOR) was investigated in rhesus monkeys before and after surgical ablation of the cerebellar nodulus and ventral uvula. The lesion resulted in an alteration of the torsional VOR: compensatory eye movements were poor in the low frequency range and the time constant was reduced to values comparable to those of primary semicircular canal afferents. In addition, animals permanently lost their ability to generate torsional optokinetic nystagmus (OKN). 2. The effects of the lesion on the torsional VOR differed from those observed in the horizontal and vertical vestibulo-ocular systems. While the vertical VOR and OKN were unaltered, the horizontal VOR and OKN were characterized by increased time constants and smaller phase leads during low frequency head oscillations. 3. These results suggest that the cerebellar nodulus and/or ventral uvula exert a distinct and specific dynamic control on the torsional vestibulo-ocular and optokinetic reflexes. Such specific effects on the torsional system could reflect a functional segregation of the vestibulo-cerebellum in terms of the controls of torsional versus horizontal and vertical slow phase eye movements.

title: Lesion of the nodulus and ventral uvula abolish steady-state off-vertical axis otolith response.
abstract: 1. During rotations that dynamically activate utricular and saccular primary afferents, the otolith system centrally detects the velocity and direction of rotation of the head in space. This property is experimentally manifested as a steady-state compensatory nystagmus during constant velocity off-vertical axis rotations. The computational, physiological, and anatomic details of this response remain presently unknown. Here we report that surgical inactivation of the cerebellar nodulus and ventral uvula abolished the ability of the otolith system to generate steady-state nystagmus during constant velocity rotation and to improve the dynamics of the vestibuloocular reflex (VOR) during low-frequency sinusoidal oscillations about off-vertical axes in rhesus monkeys. These results suggest that the cerebellar nodulus and/or ventral uvula comprise part of the neural substrate that is involved in these computations.

title: Control of the three-dimensional dynamic characteristics of the angular vestibulo-ocular reflex by the nodulus and uvula.
abstract: Publisher Summary This chapter explains that spatial orientation of the angular vestibulo-ocular reflex (aVOR) is controlled by the nodulus and uvula. The data suggest that nodulo-uvular modules separately control the time constants of velocity storage about individual semicircular canal-related axes, as well as crosscoupling among these axes. The aVOR is a sensorimotor system with unique properties for studying behavioral manifestations of the zonal structure of the cerebellar cortex. It is naturally subdivided according to the coordinate frame of the semicircular canals into three functional components, which are separately represented in the vestibular nuclei and the cerebellar cortex. The chapter shows that computations performed by the nodulus and uvula differentially control the three-dimensional dynamic characteristics of velocity storage that determine the spatial orientation of the aVOR. Time constants about a vertical axis are represented in lateral modules, whereas time constants about horizontal axes are represented in more medial zones.

title: Control of spatial orientation of the angular vestibuloocular reflex by the nodulus and uvula.
abstract: Spatial orientation of the angular vestibuloocular reflex (aVOR) was studied in rhesus monkeys after complete and partial ablation of the nodulus and ventral uvula. Horizontal, vertical, and torsional components of slow phases of nystagmus were analyzed to determine the axes of eye rotation, the time constants (Tcs) of velocity storage, and its orientation vectors. The gravito-inertial acceleration vector (GIA) was tilted relative to the head during optokinetic afternystagmus (OKAN), centrifugation, and reorientation of the head during postrotatory nystagmus. When the GIA was tilted relative to the head in normal animals, horizontal Tcs decreased, vertical and/or roll time constants (Tc(vert/roll)) lengthened according to the orientation of the GIA, and vertical and/or roll eye velocity components appeared (cross-coupling). This shifted the axis of eye rotation toward alignment with the tilted GIA. Horizontal and vertical/roll Tcs varied inversely, with T(chor) being longest and T(cvert/roll) shortest when monkeys were upright, and the reverse when stimuli were around the vertical or roll axes. Vertical or roll Tcs were longest when the axes of eye rotation were aligned with the spatial vertical, respectively. After complete nodulo-uvulectomy, T(chor) became longer, and periodic alternating nystagmus (PAN) developed in darkness. T(chor) could not be shortened in any of paradigms tested. In addition, yaw-to-vertical/roll cross-coupling was lost, and the axes of eye rotation remained fixed during nystagmus, regardless of the tilt of the GIA with respect to the head. After central portions of the nodulus and uvula were ablated, leaving lateral portions of the nodulus intact, yaw-to-vertical/roll cross-coupling and control of Tc(vert/roll) was lost or greatly reduced. However, control of Tchor was maintained, and T(chor) continued to vary as a function of the tilted GIA. Despite this, the eye velocity vector remained aligned with the head during yaw axis stimulation after partial nodulo-uvulectomy, regardless of GIA orientation to the head. The data were related to a three-dimensional model of the aVOR, which simulated the experimental results. The model provides a basis for understanding how the nodulus and uvula control processing within the vestibular nuclei responsible for spatial orientation of the aVOR. We conclude that the three-dimensional dynamics of the velocity storage system are determined in the nodulus and ventral uvula. We propose that the horizontal and vertical/roll Tcs are separately controlled in the nodulus and uvula with the dynamic characteristics of vertical/roll components modulated in central portions and the horizontal components laterally, presumably in a semicircular canal-based coordinate frame.

title: Vertical optokinetic nystagmus and vestibular nystagmus in the monkey: Up-down asymmetry and effects of gravity
abstract: Summary1.Vertical optokinetic nystagmus (OKN) i.e., OKN in the sagittal plane, was asymmetrical in the monkey when it was induced with animals lying on their sides in a 90° roll position. In typical monkeys the slow phase velocity of downward OKN (slow phases up) increased proportionally with stimulus velocity at close to unity gain to about 60°/s and saturated at about 100°/s. Upward OKN (slow phases down) increased with close to unity gain only to about 40°/s and saturated at about 60°/s. The slow phase velocity of upward OKN was usually irregular and its frequency was lower than that of downward or horizontal OKN.2.Upward and downward optokinetic afternystagmus (OKAN) were also asymmetrical. Upward OKAN was weak or absent and when present it usually saturated at 10°/s. Downward OKAN was stronger, increasing with a gain of about 0.7 with regard to stimulus velocity to a saturation velocity of about 50–60°/s. This was usually about 10–30°/s less than the saturation velocity of horizontal OKAN. The weak or absent upward OKAN indicates that stored activity related to slow phase eye velocity contributes little to the production of upward OKN. In agreement with this, there was little or no slow rise in slow phase velocity to a steady state level during upward OKN. Instead eye velocity rose to its peak velocity at the onset of stimulation. The lack of stored velocity information is probably largely responsible for the differences in regularity, gain and frequency between upward and downward OKN.3.Vertical vestibular nystagmus was induced by rotating monkeys in darkness with steps of velocity about a vertical axis, while they were lying on their sides in a 90° roll position. The velocities of the initial upward and downward slow phases were approximately equal. Gains of the vertical VOR ranged from about 0.5 to 0.98 for stimuli up to 1507s.4.Despite equivalent initial gains for upward and downward nystagmus, the vertical VOR was asymmetrical in that downward nystagmus had a higher frequency and generally lasted longer than upward nystagmus. Time constants of downward nystagmus (slow phases up) were about 15 s on average and were similar to those of horizontal nystagmus. Mean time constants of upward nystagmus (slow phases down) were about 8 s. This is only slightly longer than the average time constant of afferent activity in the semicircular canal nerves induced by steps of velocity. It indicates that stored activity related to slow phase velocity makes a smaller contribution to upward than downward or horizontal vestibular nystagmus.5.The asymmetry in vertical velocity storage was confirmed in experiments on visual-vestibular interactions. After rotation in light that evoked downward nystagmus, stored activity related to downward nystagmus cancelled or reduced upward post-rotatory nystagmus. Downward post-rotatory nystagmus was not diminished after rotation in light that had induced upward nystagmus. The difference between post-rotatory nystagmus after rotation in light and in darkness was approximately equal to the optokinetic after-nystagmus (OKAN) elicited by that velocity of rotation.6.Downward optokinetic or vestibular nystagmus was not suppressed as well as upward nystagmus when monkeys were exposed to a subject-stationary, visual surround. The eyes did not move into the slow phase direction during suppression of downward nystagmus, and slow phase eye velocity fell more slowly. In addition, stored activity was discharged more slowly during downward than horizontal nystagmus.7.Head position with respect to gravity had a striking effect on downward OKAN. When monkeys were upright, time constants of downward OKAN were much shorter and OKAN saturated at a lower velocity than when animals were in the lateral position. Consistent with reduced velocity storage in the upright position, downward OKN was irregular and had a lower saturation velocity than when animals were on their sides. When upward OKAN was present, it too was much weaker in the upright position. This indicates that information coming from the otolith organs plays an important role in conditioning the velocity storage mechanism responsible for vertical OKAN.8.The data show that there is an asymmetry in velocity storage for optokinetic and vestibular nystagmus in the sagittal plane when animals are out of the upright position. The presence of stored velocity information would enhance the low frequency characteristics of upward compensatory eye movements induced by the VOR during downward head movements. The functional significance of the asymmetry in the velocity storage mechanism for eye movements in the sagittal plane when animals are in the lateral or 90° roll position is not clear. However, these results parallel findings from experiments on movement perception in the sagittal plane of humans with subjects upright or on their sides (Young et al. 1975).

title: Spatial orientation of the vestibular system: dependence of optokinetic after-nystagmus on gravity.
abstract: 1. Monkeys received optokinetic stimulation at 60 degrees/s about their yaw (animal vertical) and pitch (animal horizontal) axes, as well as about other head-centered axes in the coronal plane. The animals were upright or tilted in right-side-down positions with regard to gravity. The stimuli induced horizontal, vertical, and oblique optokinetic nystagmus (OKN). OKN was followed by optokinetic after-nystagmus (OKAN), which was recorded in darkness. 2. When monkeys were tilted, stimulation that generated horizontal or yaw axis eye velocity during OKN induced a vertical or pitch component of slow phase velocity during OKAN. This has been designated as "cross-coupling" of OKAN. Eigenvalues and eigenvectors associated with the system generating OKAN were found as a function of tilt. They were determined by use of the Levenberg-Marquardt algorithm to minimize the mean square error between the output of a model of OKAN and the data. 3. The eigenvector associated with yaw OKAN (yaw axis eigenvector) was maintained close to the spatial vertical regardless of the angle of tilt. The eigenvector associated with pitch OKAN (pitch axis eigenvector) was always aligned with the body axis. The data indicate that velocity storage can be modeled by a piecewise linear system, the structure of which is dependent on gravity and the yaw axis eigenvector, which tends to align with gravity. 4. Yaw axis eigenvectors were also determined by giving optokinetic stimulation about head-centered axes in the coronal plane with the animal in various angles of tilt. A technique using a spectral analysis of residuals was developed to estimate whether yaw and pitch OKAN slow phase velocities decayed concurrently at the same relative rate and over the same time course. The eigenvectors determined by this method were in agreement with those obtained by analyzing OKAN elicited by yaw OKN. 5. During yaw OKN with the animal in tilted positions, the mean vector of the ensuing nystagmus was closer to the body axis than to the spatial vertical. This suggests that there is suppression of the cross-coupled pitch component during OKN. The direction of the stimulus may be utilized to suppress components of velocity storage not coincident with the direction of stimulus motion. 6. There were similarities between the monkey eigenvectors and human perception of the spatial vertical, and the mean of eigenvectors for upward and downward eye velocities overlay human 1-g perceptual data.(ABSTRACT TRUNCATED AT 400

title: Modeling the spatiotemporal organization of velocity storage in the vestibuloocular reflex by optokinetic studies.
abstract: 1. A generalized three-dimensional state space model of visual vestibular interaction was developed. Matrix and dynamical system operators associated with inputs from the semicircular canals, otolith velocity estimator, and the visual system have been incorporated into the model, which focus on their relationship to the velocity storage integrator. 2. A relationship was postulated between the eigenvalues and the direction of the eigenvectors of the system matrix and the orientation of the spatial vertical. It was assumed that the system matrix for a tilted position was a composition of two linear transformations of the system matrix for the upright position. One transformation modifies the eigenvalues of the system matrix, whereas another rotates the eigenvectors of the system matrix. The pitch and roll eigenvectors rotate with the head, whereas the yaw axis eigenvector remains approximately spatially invariant. 3. Based on the three-dimensional model, a computational procedure was formulated to identify the eigenvalues and eigenvectors of the system matrix with the use of a modification of the marquardt algorithm. With the use of data obtained from a monkey, it was shown that the three-dimensional behavior of velocity storage cannot be predicted solely in terms of its time constants, i.e., the inverse of its eigenvalues. With the use of the same eigenvalues the data could either be fit or not fit, depending on the eigenvector directions. Therefore, it is necessary to specify eigenvector directions when characterizing velocity storage in three dimensions. 4. Parameters found with the use of the Marquardt algorithm were incorporated into the model. Diagonal matrices in a head coordinate frame were introduced for coupling the visual system to the integrator and to the direct optokinetic pathway. Simulations of optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN) were run. The model predicted the behavior of yaw and pitch OKN and OKAN when the animal is upright. It also predicted the cross-coupling in the side down position. The trajectories in velocity space were also accurately simulated. 5. One of the predictions of the model is that when the stimulus direction is along an eigenvector, the trajectory in velocity space is a straight line. Using the "spectral width" of the residuals from a straight line sequence during OKAN, we developed a methodology to estimate how close the OKAN decay was to an eigenvector trajectory. 6. Thus we have developed a model-based approach for studying and interpreting the response characteristics of velocity storage in three dimensions.(ABSTRACT TRUNCATED AT 400

title: Modeling 3-D slow phase velocity estimation during off-vertical-axis rotation (OVAR).
abstract: Off-vertical-axis rotation (OVAR) in darkness generates continuous compensatory eye velocity. No model has yet been presented that defines the signal processing necessary to estimate head velocity in three dimensions for arbitrary rotations during OVAR. The present study develops a model capable of estimating all 3 components of head velocity in space accurately. It shows that processing of two patterns of otolith activation, one delayed with respect to the other, for each plane of eye movement is not sufficient. (A pattern in this context is an array of signals emanating from the otoliths. Each component of the array is a signal corresponding to a class of otolith hair cells with a given polarization vector as described by Tou and Gonzalez in 1974.) The key result is that estimation of head velocity in space can be achieved by processing three temporally displaced patterns, each representing a sampling of gravity as the head rotates. A vector cross product of differences between pairs of the sampled gravity vectors implements the estimation. An interesting property of this model is that the component of velocity about the axis of rotation reduces to that derived previously using the pattern estimator model described by Raphan and Schnabolk in 1988 and Fanelli et al in 1990. This study suggests that the central nervous system (CNS) maintains a current as well as 2 delayed representations of gravity at every head orientation during rotation. It also suggests that computing vector cross products and implementing delays may be fundamental operations in the CNS for generating orientation information associated with motion.

title: A HYPOTHETICAL EXPLANATION FOR PERIODIC ALTERNATING NYSTAGMUS: INSTABILITY IN THE OPTOKINETIC‐VESTIBULAR SYSTEM *
abstract: Spontaneous nystagmus that periodically reverses direction has been reported in a variety of circumstances: as a variant of congenital nystagmus; in association with acquired neurological lesions, especially in the region of the craniocervical junction; and as a transient manifestation of anticonvulsant intoxication.'-6 Periods of oscillation ranging from a few seconds to minutes have been r e p ~ r t e d . ~ . ~ Sometimes this nystagmus is present only in darkness.' It has been reported in blind patients with no other evidence of neurological disease? Within the subjects of these reports exists a group of patients who show an indefatigable nystagmus, in light or darkness, which regularly reverses direction with a period often of 3-4 minutes, and in whom acquired disease of the nervous system seems most likely to be the cause.' It is this form of periodic alternating nystagmus (PAN) that we address here, using clinical studies and control-systems analysis to develop a hypothetical explanation, or model, of the phenomenon. We propose that PAN arises from (1) an instability in the brain-stem neural networks that generate slow phases of vestibular and optokinetic nystagmus, (2) the action of an adaptive network that normally acts to null prolonged, inappropriate nystagmus, and (3) an inability to use retinal-error-velocity information.

title: Instabilities in Eye Movement Control: A Model of Periodic Alternating Nystagmus
abstract: Nystagmus is a pattern of eye movement characterized by smooth rotations of the eye in one direction and rapid rotations in the opposite direction that reset eye position. Periodic alternating nystagmus (PAN) is a form of uncontrollable nystagmus that has been described as an unstable but amplitude-limited oscillation. PAN has been observed previously only in subjects with vestibulo-cerebellar damage. We describe results in which PAN can be produced in normal subjects by prolonged rotation in darkness. We propose a new model in which the neural circuits that control eye movement are inherently unstable, but this instability is kept in check under normal circumstances by the cerebellum. Circumstances which alter this cerebellar restraint, such as vestibulocerebellar damage or plasticity due to rotation in darkness, can lead to PAN.

title: Dynamic modification of the vestibulo-ocular reflex by the nodulus and uvula.
abstract: The time constant of the decay of slow-phase eye velocity of postrotatory nystagmus or optokinetic after-nystagmus is reduced during exposure to a stationary visual surround (visual suppression). It is also reduced after tilting the head (tilt suppression). A "dump" mechanism in the vestibulo-ocular reflex has been proposed to rapidly discharge activity from the central vestibular system during both types of suppression. Monkeys lost this mechanism after lesions of the nodulus and uvula. They also lost the ability to habituate the time constant of nystagmus on repeated exposure to optokinetic and vestibular stimuli. Periodic alternating nystagmus, which is believed to represent an instability in the vestibulo-ocular reflex, was observed in two of three monkeys. These data indicate that the nodulus and uvula play an important role in suppressing, habituating, and stabilizing the vestibulo-ocular reflex.

title: Coding of Velocity Storage in the Vestibular Nuclei
abstract: Semicircular canal afferents sense angular acceleration and output angular velocity with a short time constant of ≈4.5 s. This output is prolonged by a central integrative network, velocity storage that lengthens the time constants of eye velocity. This mechanism utilizes canal, otolith, and visual (optokinetic) information to align the axis of eye velocity toward the spatial vertical when head orientation is off-vertical axis. Previous studies indicated that vestibular-only (VO) and vestibular-pause-saccade (VPS) neurons located in the medial and superior vestibular nucleus could code all aspects of velocity storage. A recently developed technique enabled prolonged recording while animals were rotated and received optokinetic stimulation about a spatial vertical axis while upright, side-down, prone, and supine. Firing rates of 33 VO and 8 VPS neurons were studied in alert cynomolgus monkeys. Majority VO neurons were closely correlated with the horizontal component of velocity storage in head coordinates, regardless of head orientation in space. Approximately, half of all tested neurons (46%) code horizontal component of velocity in head coordinates, while the other half (54%) changed their firing rates as the head was oriented relative to the spatial vertical, coding the horizontal component of eye velocity in spatial coordinates. Some VO neurons only coded the cross-coupled pitch or roll components that move the axis of eye rotation toward the spatial vertical. Sixty-five percent of these VO and VPS neurons were more sensitive to rotation in one direction (predominantly contralateral), providing directional orientation for the subset of VO neurons on either side of the brainstem. This indicates that the three-dimensional velocity storage integrator is composed of directional subsets of neurons that are likely to be the bases for the spatial characteristics of velocity storage. Most VPS neurons ceased firing during drowsiness, but the firing rates of VO neurons were unaffected by states of alertness and declined with the time constant of velocity storage. Thus, the VO neurons are the prime components of the mechanism of coding for velocity storage, whereas the VPS neurons are likely to provide the path from the vestibular to the oculomotor system for the VO neurons.

title: Unit Activity in the Vestibular Nuclei of Monkeys during Off‐Vertical Axis Rotation
abstract: Yaw rotation about an axis tilted from the spatial vertical induces horizontal eye velocity that is comprised of two components: a steady-state or bias component and an oscillating component dependent on head position with regard to gravity.’-“ There is considerable evidence that both components arise from activity generated by the ~toliths.~-’ Models have been developed that can estimate head velocity from the otolith signals and produce eye velocity through activation of the velocity storage integrator.”1° However, the neural basis for many of the theoretical predictions has not been explored. The purpose of this study was to record single units in the

title: Firing behavior of vestibular neurons during active and passive head movements: vestibulo-spinal and other non-eye-movement related neurons.
abstract: The firing behavior of 51 non-eye movement related central vestibular neurons that were sensitive to passive head rotation in the plane of the horizontal semicircular canal was studied in three squirrel monkeys whose heads were free to move in the horizontal plane. Unit sensitivity to active head movements during spontaneous gaze saccades was compared with sensitivity to passive head rotation. Most units (29/35 tested) were activated at monosynaptic latencies following electrical stimulation of the ipsilateral vestibular nerve. Nine were vestibulo-spinal units that were antidromically activated following electrical stimulation of the ventromedial funiculi of the spinal cord at C1. All of the units were less sensitive to active head movements than to passive whole body rotation. In the majority of cells (37/51, 73%), including all nine identified vestibulo-spinal units, the vestibular signals related to active head movements were canceled. The remaining units (n = 14, 27%) were sensitive to active head movements, but their responses were attenuated by 20-75%. Most units were nearly as sensitive to passive head-on-trunk rotation as they were to whole body rotation; this suggests that vestibular signals related to active head movements were cancelled primarily by subtraction of a head movement efference copy signal. The sensitivity of most units to passive whole body rotation was unchanged during gaze saccades. A fundamental feature of sensory processing is the ability to distinguish between self-generated and externally induced sensory events. Our observations suggest that the distinction is made at an early stage of processing in the vestibular system.

title: Sensory processing in the vestibular nuclei during active head movements.
abstract: Many secondary vestibular neurons are sensitive to head on trunk rotation during reflex-induced and voluntary head movements. During passive whole body rotation the interaction of head on trunk signals related to the vestibulo-collic reflex with vestibular signals increases the rotational gain of many secondary vestibular neurons, including many that project to the spinal cord. In some units, the sensitivity to head on trunk and vestibular input is matched and the resulting interaction produces an output that is related to the trunk velocity in space. In other units the head on trunk inputs are stronger and the resulting interaction produces an output that is larger during the reflex. During voluntary head movements, inputs related to head on trunk movement combine destructively with vestibular signals, and often cancel the sensory reafferent consequences of self-generated movements. Cancellation of sensory vestibular signals was observed in all of the antidromically identified secondary vestibulospinal units, even though many of these units were not significantly affected by reflexive head on trunk movements. The results imply that the inputs to vestibular neurons related to head on trunk rotation during reflexive and voluntary movements arise from different sources. We suggest that the relative strength of reflexive head on trunk input to different vestibular neurons might reflect the different functional roles they have in controlling the posture of the neck and body.

title: Descending Influences on Vestibulospinal and Vestibulosympathetic Reflexes
abstract: This review considers the integration of vestibular and other signals by the central nervous system pathways that participate in balance control and blood pressure regulation, with an emphasis on how this integration may modify posture-related responses in accordance with behavioral context. Two pathways convey vestibular signals to limb motoneurons: the lateral vestibulospinal tract and reticulospinal projections. Both pathways receive direct inputs from the cerebral cortex and cerebellum, and also integrate vestibular, spinal, and other inputs. Decerebration in animals or strokes that interrupt corticobulbar projections in humans alter the gain of vestibulospinal reflexes and the responses of vestibular nucleus neurons to particular stimuli. This evidence shows that supratentorial regions modify the activity of the vestibular system, but the functional importance of descending influences on vestibulospinal reflexes acting on the limbs is currently unknown. It is often overlooked that the vestibulospinal and reticulospinal systems mainly terminate on spinal interneurons, and not directly on motoneurons, yet little is known about the transformation of vestibular signals that occurs in the spinal cord. Unexpected changes in body position that elicit vestibulospinal reflexes can also produce vestibulosympathetic responses that serve to maintain stable blood pressure. Vestibulosympathetic reflexes are mediated, at least in part, through a specialized group of reticulospinal neurons in the rostral ventrolateral medulla that project to sympathetic preganglionic neurons in the spinal cord. However, other pathways may also contribute to these responses, including those that dually participate in motor control and regulation of sympathetic nervous system activity. Vestibulosympathetic reflexes differ in conscious and decerebrate animals, indicating that supratentorial regions alter these responses. However, as with vestibular reflexes acting on the limbs, little is known about the physiological significance of descending control of vestibulosympathetic pathways.

title: A non-visual mechanism for voluntary cancellation of the vestibulo-ocular reflex
abstract: SummarySquirrel monkeys were trained to cancel their vestibulo-ocular reflex (VOR) by fixating a visual target that was head stationary during passive vestibular stimulation. The monkeys were seated on a vestibular turntable, and their heads were restrained. A small visual target (0.2°) was projected from the vestibular turntable onto a tangent screen. The monkeys' ability to suppress their VOR by fixating a head stationary target while the turntable was moving was compared to their ability to pursue the target when it was moved in the same manner.Squirrel monkeys were better able to suppress their VOR when the turntable was moved at high velocities than they were able to pursue targets that were moving at high velocities. The gaze velocity gain during VOR cancellation began to decrease when the head velocity was above 80°/s, and was greater than 0.6 when the head velocity was above 150°/s. However, gaze velocity gain during smooth pursuit decreased significantly when the target velocity was greater than 60°/s, and was less than 0.4 when the target velocity was 150°/s or more.The latency of VOR suppression was significantly shorter than the latency of smooth pursuit while the monkey was cancelling its VOR. When an unpredictable step change in head acceleration was generated while the monkey was cancelling its VOR, the VOR evoked by the head acceleration step began to be suppressed shortly after the initiation of the step (≈ 30 ms). On the other hand, the latency of the smooth pursuit eye movement elicited when the visual target was accelerated in the same manner during VOR cancellation was ≈ 100 ms. The comparison between these two results suggests that the monkeys did not use visual information related to target motion to suppress their VOR at an early latency.The monkeys' ability to suppress the VOR evoked by an unexpected change in head acceleration depended on the size of the head acceleration step. The VOR evoked by unexpected step changes in head acceleration was progressively less suppressed at an early latency as the size of the acceleration step increased, and was not suppressed at an early latency when the step change in head acceleration was greater than 500°/s2.During smooth pursuit eye movements, unexpected step changes in head acceleration evoked a VOR that was suppressed at an early latency (≈ 50 ms) if the head movement was in the same direction as the ongoing smooth pursuit eye movement. The amount of early VOR suppression increased as the pursuit eye velocity increased.We conclude that squirrel monkeys utilize a fast, non-visual mechanism for cancelling their VOR while they are fixating a visual target and their head is moving. This non-visual mechanism appears to be turned on when the head is moving and the monkey is fixating a head stationary target. The mechanism probably utilizes a voluntarily gated vestibular signal to cancel the signals in VOR pathways at the level of the extraocular motorneurons. Although the VOR cancellation mechanism is not capable of completely suppressing the VOR evoked by large unexpected changes in head acceleration, we suggest that it is capable of suppressing the VOR generated by most voluntary head movements during combined eye and head gaze pursuit and that the function of this gated VOR cancellation system is to extend the range and accuracy of eye-head tracking movements.

title: Responses of Vestibular and Prepositus Neurons to Head Movements during Voluntary Suppression of the Vestibuloocular Reflex
abstract: Neurons in the vestibular nuclei and the prepositus nucleus exhibited several different types of changes in their firing behavior during voluntary cancellation of the horizontal VOR. The head velocity sensitivity of type I position-vestibular-pause neurons was reduced during cancellation, while type II vestibular neurons exhibit an increase in their sensitivity. The firing behavior of burst tonic neurons in the medial vestibular nucleus, the prepositus nucleus, like the cells in the abducens nucleus, was closely related to the eye movements generated when the VOR is cancelled. Other cells in the PH and MVN respond primarily to smooth pursuit eye movements. We suggest that the behavior of abducens neurons during the VOR and during VOR cancellation can be explained if they receive inputs from PVP neurons, burst tonic neurons, and smooth pursuit neurons.

title: Firing behavior of brain stem neurons during voluntary cancellation of the horizontal vestibuloocular reflex. II. Eye movement related neurons.
abstract: 1. The single-unit activity of neurons in the vestibular nucleus, the prepositus nucleus, and the abducens nucleus, whose activity was primarily related to horizontal eye movements, was recorded in alert squirrel monkeys that were trained to track a small visual target by generating smooth pursuit eye movements and to cancel their horizontal vestibuloocular reflex (VOR) by fixating a head stationary target. 2. The spiking behavior of each cell was recorded during 1) spontaneous eye movements, 2) horizontal smooth pursuit of a target that was moved sinusoidally +/- 20 degrees/s at 0.5 Hz, 3) horizontal VOR evoked by 0.5-Hz sinusoidal turntable rotations +/- 40 degrees/s (VORs), and 4) voluntary cancellation of the VOR by fixation of a head-stationary target during 0.5-Hz sinusoidal turntable rotation at +/- 40 degrees/s (VORCs). The responses of most (28/42) of the units were recorded during unpredictable 100-ms steps in head acceleration (400 degrees/s2) that were generated while the monkey was fixating a target light. The acceleration steps were generated either when the monkey was stationary or when the turntable was already rotating (VORt trials), and the monkey was canceling its VOR (VORCt trials). 3. The firing behavior of all 12 of the abducens neurons recorded was closely related to horizontal eye position and eye velocity during all of the behavioral paradigms used, although there was a small but significant increase in the eye position sensitivity of many of these units when the eye was moving (smooth pursuit) versus when the eye was stationary (fixation). 4. Many neurons in the prepositus nucleus and the medial vestibular nucleus (n = 15) were similar to abducens neurons, in that their firing rate was related primarily to horizontal eye position and eye velocity, regardless of the behavioral paradigm used. These cells were, on average, more sensitive to eye position and smooth pursuit eye velocity than were abducens neurons. 5. The firing rate of 15 other neurons in the prepositus and medial vestibular nucleus was related primarily to horizontal smooth pursuit eye movements. The tonic firing rate of all of these smooth pursuit (SP) cells was related to horizontal eye position, and the majority generated bursts of spikes during saccades in all directions but their off direction. Six of the SP neurons fired in phase with ipsilateral eye movements, whereas the remaining nine were sensitive to eye movements in the opposite direction.(ABSTRACT TRUNCATED AT 400

title: 
 l-Baclofen-sensitive GABAB binding sites in the medial vestibular nucleus localized by immunocytochemistry
abstract: L-Baclofen-sensitive GABAB binding sites in the medial vestibular nucleus (MVN) were identified immunocytochemically and visualized ultrastructurally in L-baclofen-preinjected rats and monkeys, using a mouse monoclonal antibody with specificity for the p-chlorophenyl moiety of baclofen. Saline-preinjected animals showed no immunostain. In drug-injected animals, there was evidence for both pre- and postsynaptic GABAergic inhibition in MVN mediated by GABAB receptors. These neural elements could be utilized in control of velocity storage in the vestibulo-ocular reflex.

title: Ultrastructure of vestibular commissural neurons related to velocity storage in the monkey
abstract: The angular vestibulo-ocular reflex maintains gaze during head movements. It is thought to be mediated by two components: direct and velocity storage pathways. The direct angular vestibulo-ocular reflex is conveyed by a three neuron chain from the labyrinth to the ocular motoneurons. The indirect pathway involves a more complex neural network that utilizes a portion of the vestibular commissure. The purpose of the present study was to identify the ultrastructural characteristics of commissural neurons in the medial vestibular nucleus that are related to the velocity storage component of the angular vestibulo-ocular reflex. Ultrastructural studies of degenerating medial vestibular nucleus neurons were conducted in monkeys following midline section of rostral medullary commissural fibers with subsequent behavioral testing. After this lesion, oculomotor and vestibular functions attributable to velocity storage were abolished, whereas the direct angular vestibulo-ocular reflex pathway remained intact. Since this damage was functionally discrete, degenerating neurons were interpreted as potential participants in the velocity storage network. Ultrastructural observations indicate that commissural neurons related to velocity storage are small and medium sized cells having large nuclei with deep indentations and relatively little cytoplasm, which are located in the lateral crescents of rostral medial vestibular nucleus. The morphology of degenerating dendritic profiles varied. Some contained numerous round or tubular mitochondria in a pale cytoplasmic matrix with few other organelles, while others had few mitochondria but many cisterns and vacuoles in dense granular cytoplasm. The commissural nature of these cells was further suggested by the presence of two different types of degenerating axon terminals in the rostral medial vestibular nucleus: those with a moderate density of large spherical synaptic vesicles, and those with pleomorphic, primarily ellipsoid synaptic vesicles. The recognition of two types of degenerating terminals further supports our interpretation that at least two morphological types of commissural neurons participate in the velocity storage network. The degenerating boutons formed contacts with a variety of postsynaptic partners. In particular, synapses were observed between degenerating boutons and non-degenerating dendrites, and between intact terminals and degenerating dendrites. However, degenerating pre- and postsynaptic elements were rarely observed in direct contact, suggesting that additional neurons are interposed in the indirect pathway commissural system. On the basis of these ultrastructural observations, it is concluded that vestibular commissural neurons involved in the mediation of velocity storage have distinguishing ultrastructural features and synaptology, that are different from those of direct pathway neurons.

title: Baclofen and velocity storage: a model of the effects of the drug on the vestibulo‐ocular reflex in the rhesus monkey.
abstract: 1. Baclofen had a characteristic effect on vestibular and optokinetic nystagmus in rhesus monkeys. Each aspect of nystagmus that is dependent on the velocity‐storage mechanism in the vestibulo‐ocular reflex (v.o.r.) was altered by the drug: (a) Baclofen reduced the dominant time constant of the v.o.r. in a dose‐dependent manner up to 5 mg/kg, the highest dosage used. The alteration in v.o.r. time constant began within 15 min of injection, was maximal between 1 and 4 h, and lasted for 14‐18 h. This effect mirrors changes in plasma levels of baclofen after oral doses in humans (Faigle, Keberle & Agen, 1980). (b) Slow‐phase velocities of steady‐state nystagmus induced by rotation about axes tilted from the vertical (off‐vertical axis rotation, o.v.a.r.) were reduced after baclofen and could not be maintained at previous levels.  were reduced. Since baclofen is a GABA agonist, systems utilizing GABA and acting on GABAB receptors appear to produce inhibitory control of velocity storage. 2. The step gain of the v.o.r., measured at the beginning and end of constant‐velocity rotation in darkness, was unaffected by baclofen, as were saccades, quick phases of nystagmus, and the ability to hold positions of fixation or to generate linear slow phases of nystagmus. This indicates that it is possible to use baclofen to manipulate the dominant time constant of the v.o.r. and of o.k.a.n. in relative isolation from effects on other oculomotor components. 3. Baclofen caused a dose‐dependent reduction in the initial jump in eye velocity at the onset of o.k.n., suggesting that the initial jump is also under inhibitory control of GABAB receptors. However, there were still occasional slow phases with velocities up to 30‐40 deg/s after baclofen, and animals were capable of visually suppressing the v.o.r. This indicates that pathways responsible for causing rapid changes in slowphase velocity were capable of functioning, at least intermittently, in the presence of the drug.(ABSTRACT TRUNCATED AT 400

title: Effects of midline medullary lesions on velocity storage and the vestibulo-ocular reflex
abstract: Summary1. Crossing fibers were sectioned at the midline of the medulla caudal to the abducens nucleus in four cynomolgus monkeys. In two animals the lesions caused the time constant of horizontal and vertical per- and post-rotatory nystagmus to fall to 5–8 s. The slow rise in optokinetic nystagmus (OKN), as well as optokinetic after-nystagmus (OKAN) and cross-coupling of horizontal to vertical OKN and OKAN were abolished. Steady state velocities could not be maintained during off-vertical axis rotation (OVAR). Pitch and yaw nystagmus were affected similarly. We conclude that the ability to store activity related to slow phase eye velocity, i.e., “velocity storage”, was lost in these monkeys for nystagmus about any axis. Velocity storage was partially affected by a small midline lesion in the same region in a third animal. There was no effect of a more superficial midline section in a fourth monkey, and it served as a control. 2. The gain (eye velocity/head velocity) of the vestibuloocular reflex (VOR) was unaffected by the midline lesions. Saccades were normal, as was the ability to hold the eyes in eccentric gaze positions. The gain of the fast component of OKN increased in one monkey to compensate for the loss of the slow component. 3. One animal was tested for its ability to adapt the gain of the VOR due to visual-vestibular mismatch after lesion. Average changes in gain in response to wearing magnifying (2.2 x) and reducing (0.5 x) lenses, were + 35% and — 30%, respectively. This is within the range of normal monkeys. Thus, a midline lesion that abolished velocity storage did not alter that animal's ability to adapt the gain of the VOR. 4. Lesions that reduced or abolished velocity storage interrupted crossing fibers in the rostral medulla, caudal to the abducens nuclei. Cells that contributed axons to this portion of the crossing fibers are most likely located in central portions of the medial vestibular nucleus (MVN) and/or in rostral portion of the descending vestibular nucleus (DVN). The implication is that velocity storage arises from neurons in MVN and DVN whose axons cross the midline.

title: Adaptation of orientation vectors of otolith-related central vestibular neurons to gravity.
abstract: Behavioral experiments indicate that central pathways that process otolith-ocular and perceptual information have adaptive capabilities. Because polarization vectors of otolith afferents are directly related to the electro-mechanical properties of the hair cell bundle, it is unlikely that they change their direction of excitation. This indicates that the adaptation must take place in central pathways. Here we demonstrate for the first time that otolith polarization vectors of canal-otolith convergent neurons in the vestibular nuclei have adaptive capability. A total of 10 vestibular-only and vestibular-plus-saccade neurons were recorded extracellularly in two monkeys before and after they were in side-down positions for 2 h. The spatial characteristics of the otolith input were determined from the response vector orientation (RVO), which is the projection of the otolith polarization vector, onto the head horizontal plane. The RVOs had no specific orientation before animals were in side-down positions but moved toward the gravitational axis after the animals were tilted for extended periods. Vector reorientations varied from 0 to 109 degrees and were linearly related to the original deviation of the RVOs from gravity in the position of adaptation. Such reorientation of central polarization vectors could provide the basis for changes in perception and eye movements related to prolonged head tilts relative to gravity or in microgravity.

title: Adaptation of Orientation of Central Otolith‐only Neurons
abstract: Otolith‐only neurons were recorded extracellularly in the vestibular nuclei before and after cynomolgus monkeys were held on‐side for up to 3 hr. The aim was to determine whether the polarization vectors of these neurons reorient toward the spatial vertical as do canal‐otolith convergent neurons. Otolith input was characterized by tilting the animal 30° from the upright position while positioning the head in different directions in yaw. This determined the response vector orientation (RVO), that is, the projection of the otolith polarization vector onto the head horizontal plane. Changes in the RVO of otolith‐only neurons ranged from 2°–16°, which was on average considerably less than the changes previously noted in canal‐otolith convergent vestibulo‐only (VO) and vestibular plus saccade (VPS) neurons, which ranged up to 109°. Some of the otolith‐only neurons had marked sensitivity changes. These findings suggest that otolith‐only neurons tend to maintain a head‐fixed orientation during prolonged head tilts relative to gravity. In contrast, canal‐convergent VO and VPS neurons optimize their response vector orientation to gravity when the head is oriented for prolonged periods.

title: Orientation adaptation of eye movement–related vestibular neurons due to prolonged head tilt
abstract: Sixteen neurons, including vestibular‐only (VO), eye–head velocity (EHV), and position‐vestibular‐pause (PVP) neurons sensitive to head tilt were recorded in the rostromedial and in superior vestibular nuclei. Projection of the otolith polarization vector to the horizontal plane (response vector orientation [RVO]) was determined before and after prolonged head orientation in side‐down position. The RVO of VO neurons shifted toward alignment with the axis of gravity when the head was in the position of adaptation. PVP neurons had similar changes in RVO. There were also changes in RVO in some EHV neurons, but generally in directions not related to gravity. Modeling studies have suggested that the tendency to align RVOs with gravity leads to tuning of gravity‐dependent angular vestibular ocular reflex (aVOR) gain changes to the position of adaptation. Thus, coding of orientation in PVP neurons would contribute significantly to the gravity‐dependent adaptation of the aVOR.

title: Diversity of vestibular nuclei neurons targeted by cerebellar nodulus inhibition
abstract: Electrical stimulation of the cerebellar nodulus and ventral uvula decreases the time constant of the horizontal vestibulo‐ocular reflex during yaw rotation. Unlike the flocculus and ventral paraflocculus which target a particular cell group, nodulus/ventral uvula inhibition targets a large diversity of cell types in the vestibular nuclei. Twenty per cent of nodulus/ventral uvula‐target neurons were sensitive to both vestibular stimuli and eye movements, whereas the majority was only sensitive to vestibular stimuli. Most nodulus/ventral uvula‐target cells responded to both rotation and translation and only approximately half discriminated translational and gravitational accelerations. Projections of the nodulus/ventral uvula to both eye movement‐and non‐eye movement‐sensitive vestibular nuclei neurons suggest a role in both eye movement generation and vestibulo‐spinal or thalamo‐cortical systems.

title: Stimulation of the nodulus and uvula discharges velocity storage in the vestibulo-ocular reflex
abstract: The nodulus and sublobule d of the uvula of rhesus and cynomolgus monkeys were electrically stimulated with short trains of pulses to study changes in horizontal slow-phase eye velocity. Nodulus and uvula stimulation produced a rapid decline in horizontal slow phase velocity, one aspect of the spatial reorientation of the axis of eye rotation that occurs when the head is tilted with regard to gravity during per- and post-rotatory nystagmus and optokinetic after-nystagmus (OKAN). Nodulus and uvula stimulation also reproduced the reduction of the horizontal time constant of post-rotatory nystagmus and OKAN that occurs during visual suppression. The brief electric stimuli (4–5 s) induced little slow-phase velocity and had no effect on the initial jump in eye velocity at the onset or the end of angular rotation. Effects of stimulation were unilateral, suggesting specificity of the output pathways. Activation of more caudal sites in the uvula produced nystagmus with a rapid rise in eye velocity, but the effects did not outlast the stimulus and did not affect VOR or OKAN time constants. Thus, stimulation of caudal parts of the uvula did not affect eye velocity produced by velocity storage. We postulate that the nodulus and sublobule d of the uvula control the time constant of the yaw axis (horizontal) component of slow-phase eye velocity produced by velocity storage.

title: Quantitative analysis of the velocity characteristics of optokinetic nystagmus and optokinetic after‐nystagmus
abstract: 1. Velocity characteristics of optokinetic nystagmus (OKN) and optokinetic after‐nystagmus (OKAN) induced by constant velocity full field rotation were studied in rhesus monkeys. A technique is described for estimating the dominant time constant of slow phase velocity curves and of monotonically changing data. Time constants obtained by this technique were used in formulating a model of the mechanism responsible for producing OKN and OKAN.

title: The relation of motion sickness to the spatial–temporal properties of velocity storage
abstract: Tilting the head in roll to or from the upright while rotating at a constant velocity (roll while rotating, RWR) alters the position of the semicircular canals relative to the axis of rotation. This produces vertical and horizontal nystagmus, disorientation, vertigo, and nausea. With recurrent exposure, subjects habituate and can make more head movements before experiencing overpowering motion sickness. We questioned whether promethazine lessened the vertigo or delayed the habituation, whether habituation of the vertigo was related to the central vestibular time constant, i.e., to the time constant of velocity storage, and whether the severity of the motion sickness was related to deviation of the axis of eye velocity from gravity. Sixteen subjects received promethazine and placebo in a double-blind, crossover study in two consecutive 4-day test series 1 month apart, termed series I and II. Horizontal and vertical eye movements were recorded with video-oculography while subjects performed roll head movements of approx. 45° over 2 s to and from the upright position while being rotated at 138°/s around a vertical axis. Motion sickness was scaled from 1 (no sickness) to an endpoint of 20, at which time the subject was too sick to continue or was about to vomit. Habituation was determined by the number of head movements that subjects made before reaching the maximum motion sickness score of 20. Head movements increased steadily in each session with repeated testing, and there was no difference between the number of head movements made by the promethazine and placebo groups. Horizontal and vertical angular vestibulo-ocular reflex (aVOR) time constants declined in each test, with the declines being closely correlated to the increase in the number of head movements. The strength of vertiginous sensation was associated with the amount of deviation of the axis of eye velocity from gravity; the larger the deviation of the eye velocity axis from gravity, the more severe the motion sickness. Thus, promethazine neither reduced the nausea associated with RWR, nor retarded or hastened habituation. The inverse relationship between the aVOR time constants and number of head movements to motion sickness, and the association of the severity of motion sickness with the extent, strength, and time of deviation of eye velocity from gravity supports the postulate that the spatiotemporal properties of velocity storage, which are processed between the nodulus and uvula of the vestibulocerebellum and the vestibular nuclei, are likely to represent the source of the conflict responsible for producing motion sickness.

title: Habituation and adaptation of the vestibuloocular reflex: a model of differential control by the vestibulocerebellum
abstract: SummaryWe habituated the dominant time constant of the horizontal vestibuloocular reflex (VOR) of rhesus and cynomolgus monkeys by repeated testing with steps of velocity about a vertical axis and adapted the gain of the VOR by altering visual input with magnifying and reducing lenses. After baseline values were established, the nodulus and ventral uvula of the vestibulocerebellum were ablated in two monkeys, and the effects of nodulouvulectomy and flocculectomy on VOR gain adaptation and habituation were compared. The VOR time constant decreased with repeated testing, rapidly at first and more slowly thereafter. The gain of the VOR was unaffected. Massed trials were more effective than distributed trials in producing habituation. Regardless of the schedule of testing, the VOR time constant never fell below the time constant of the semicircular canals (≈5 s). This finding indicates that only the slow component of the vestibular response, the component produced by velocity storage, was habituated. In agreement with this, the time constant of optokinetic after-nystagmus (OKAN) was habituated concurrently with the VOR. Average values for VOR habituation were obtained on a per session basis for six animals. The VOR gain was adapted by natural head movements in partially habituated monkeys while they wore ×2.2 magnifying or ×0.5 reducing lenses. Adaptation occurred rapidly and reached about ±30%, similar to values obtained using forced rotation. VOR gain adaptation did not cause additional habituation of the time constant. When the VOR gain was reduced in animals with a long VOR time constant, there were overshoots in eye velocity that peaked at about 6–8 s after the onset or end of constant-velocity rotation. These overshoots occurred at times when the velocity storage integrator would have been maximally activated by semicircular canal input. Since the activity generated in the canals is not altered by visual adaptation, this finding indicates that the gain element that controls rapid changes in eye velocity in the VOR is separate from that which couples afferent input to velocity storage. Nodulouvulectomy caused a prompt and permanent loss of habituation, returning VOR time constants to initial values. VOR gain adaptation, which is lost after flocculectomy, was unaffected by nodulouvulectomy. Flocculectomy did not alter habituation of the VOR or of OKAN. Using a simplified model of the VOR, the decrease in the duration of vestibular nystagmus due to habituation was related to a decrement in the dominant time constant of the velocity storage integrator (1/h0). Nodulouvulectomy, which reversed habituation, would be effected by decreasing h0, thereby increasing the VOR time constant. Small values of h0 would cause velocity storage to approach an ideal integrative process, leading the system to become unstable. By controlling the VOR time constant through habituation, the nodulus and uvula can stabilize the slow component of the VOR. VOR gain adaptation was related to a modification of the direct vestibular path gain g1, without altering the coupling to velocity storage g0 or its time constant (1/h0). The mismatched direct- and indirect-pathway gains simulated the overshoots in the dynamic response to a step in velocity, that were observed experimentally. We conclude that independent distributed elements in the VOR modify its dynamic response, under control of separate parts of the vestibulocerebellum.

title: Activity of neurons in the beta nucleus of the inferior olive of the rabbit evoked by natural vestibular stimulation
abstract: The inferior olive (IO) appears to be organized functionally in discrete subnuclei that receive transmitter-specific inputs. In particular, the IO receives a GABAergic input that is most densely concentrated in the β -nucleus. In this experiment, we examined the functional specificity of neurons in the β -nucleus of the IO of rabbits by recording their activity during natural vestibular and optokinetic stimulation. Rabbits were anesthetized and positioned in a triaxial servo- controlled rate table with the head fixed at the center of rotation. Contour-rich visual stimuli were rear-projected onto a 70 deg tangent screen and moved at constant velocities. Recording sites in the β -nucleus were verified by subsequent histological analysis of marking microlesions. Neurons in the β -nucleus responded to roll vestibular stimulation about the longitudinal axis. These neurons were excited when the rabbit was rolled onto the side which was contralateral to the recording site, and inhibited when the rabbit was rolled ipsilaterally. Thirty-eight of the 75 β -nucleus neurons that were responsive to roll vestibular stimulation also responded to static tilt, indicating an otolithic as well as a vertical semicircular canal origin of the vestibular input. The modulated activity of none of the neurons could be attributed to stimulation of the horizontal semicircular canals. All the recorded neurons were found in a region of the β -nucleus that was retrogradely labeled following HRP injections into the cerebellar nodulus. Using a “null point” technique, we found that there was a differential projection of information from the anterior and posterior semicircular canals onto to the β -nucleus. Stimulation of the ipsilateral anterior-contralateral posterior semicircular canals modulates activity of the neurons in the caudal 500 μm of the β -nucleus. Stimulation of the ipsilateral posterior-contralateral anterior semicircular canals modulates activity of neurons located more rostrally. β -nucleus neurons and the olivocerebellar circuits in which they participate may constitute an important pathway for the control and adaptive modification of postural reflexes.

title: Vestibularly induced slow oscillations in climbing fiber responses of Purkinje cells in the cerebellar nodulus of the rabbit
abstract: In this report we describe an interesting form of plasticity in climbing fiber responses evoked in Purkinje cells of the rabbit cerebellum by periodic vestibular stimulation. The cerebellar nodulus receives a vestibular as well as a visual climbing fiber afferent input from the contralateral inferior olive. The vestibular input to the inferior olive originates from the ipsilateral medial and descending vestibular nuclei and terminates within the beta-nucleus. This projection to the beta-nucleus from secondary vestibular neurons is GABAergic. This means that vestibularly evoked activity of neurons in the beta-nucleus is controlled by modulation of an inhibitory input, rather than by modification of an excitatory input. We have recorded the climbing fiber responses of single Purkinje cells in the uvula-nodulus (lobules 9c, 9d and 10) of rabbits and we have characterized the climbing fiber response of each Purkinje cell from which we recorded by testing its sensitivity to otolithic stimulation, semicircular canal stimulation and optokinetic stimulation. Vestibularly evoked climbing fiber responses recorded from the left nodulus were stationary. They were repeatedly evoked, for tens of minutes, by sinusoidally rotating the rabbit about the longitudinal axis onto its left side . When the vestibular stimulus was stopped the discharge of these climbing fiber responses returned to non-periodic spontaneous levels. However, the vestibularly evoked climbing fiber discharge of approximately 5% of Purkinje cells was not stationary.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Influence of vestibular and visual climbing fiber signals on Purkinje cell discharge in the cerebellar nodulus of the rabbit.
abstract: Extracellular recordings of the climbing fiber responses (CFRs) of single Purkinje cells were made in the cerebellar nodulus and ventral uvula of anesthetized pigmented rabbits. Natural vestibular and optokinetic stimuli were used to evoke responses from these Purkinje cells. Using a null response technique we sorted vestibularly-evoked CFRs into two canal-related categories. CFRs were related to either the ipsilateral anterior and contralateral posterior semicircular canal (iAC+cPC) or to the ipsilateral posterior and contralateral anterior semicircular canal (iPC+cAC). Both canal-related CFRs also responded to downward optokinetic stimulation.

title: Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers
abstract: Previously we have shown that four regions of the cerebellum, the uvula‐nodulus, flocculus, ventral paraflocculus, and anterior lobe 1, receive extensive, but not exclusive, cholinergic mossy fiber projections. In the present experiment we have studied the origin of three of these projections in the rat and rabbit (uvula‐nodulus, flocculus, ventral paraflocculus), using choline acetyltransferase (ChAT) immunohistochemistry in combination with a double label, retrogradely transported horseradish peroxidase (HRP).

title: Vestibular primary afferent projection to the cerebellum of the rabbit
abstract: The vestibular primary afferent projection to the cerebellum of the rabbit was studied with retrograde and orthograde tracers. We injected individual lobules of the cerebellum with horseradish peroxidase (HRP) or wheat germ agglutinin‐HRP (WGA‐HRP). Following these injections the numbers of labeled and unlabeled cells in Scarpa's ganglion were counted. Approximately 64–89% of the cells in Scarpa's ganglion were labeled retrogradely following uvula‐nodular injections. About 2% of the cells in the ipsilateral Scarpa's ganglion were labeled after injections of the flocculus. Virtually no cells were labeled following injections of the ventral paraflocculus.

title: Vestibular and visual climbing fiber signals evoked in the uvula-nodulus of the rabbit cerebellum by natural stimulation.
abstract: 1. The cerebellar uvula-nodulus receives vestibular projections from primary and secondary vestibular afferents as well as vestibularly related climbing fibers. It also receives visually related information from climbing fiber pathways. In this experiment we investigated how this information is mapped onto the uvula-nodulus. We studied the specificity, dynamics, and topographic distribution of climbing fiber responses (CFRs), simple spike responses, and mossy fiber terminal responses evoked by vestibular and optokinetic stimulation in rabbits anesthetized with alpha-chloralose. 2. Vestibularly evoked CFRs were found in the ventral uvula and nodulus. These responses were evoked during static roll tilt of the rabbit about a longitudinal axis and by sinusoidal oscillation about the longitudinal axis. Purely static responses were attributed to stimulation of the utricular otolith by the linear acceleration of gravity. CFRs that lacked a static component were attributed to activation of the semicircular canals. 3. Using a "null technique" we showed that the canal-sensitive CFRs were caused by stimulation of the anterior or posterior semicircular canals. Of the CFRs classified as canal related, 96% could be attributed to stimulation of the vertical semicircular canals. 4. Increases in CFRs were correlated with decreases in simple spike responses in half the Purkinje cells from which we recorded. These climbing-fiber-induced pauses in simple spikes occurred during spontaneous climbing fiber discharge as well as during climbing fiber discharge evoked by vestibular stimulation. The duration of this pause was inversely proportional to the spontaneous level of simple spikes before the occurrence of a CFR. In the other half of the recorded population of Purkinje cells, vestibularly driven CFRs did not alter the simple spike responses. 5. Vestibularly and visually mediated CFRs were topographically represented on the surface of the uvula-nodulus. CFRs driven by ipsilateral otolithic inputs were distributed over the entire mediolateral surface of the uvula-nodulus. CFRs driven by the ipsilateral posterior semicircular canal were distributed in a sagittal strip approximately 1.5 mm wide, extending laterally from the midline of the nodulus. CFRs driven exclusively by horizontal, posterior-->anterior optokinetic stimulation of the ipsilateral eye were distributed in a sagittal strip approximately 0.5 mm wide located 0.5-1.0 mm from the midline and restricted to the ventral nodulus. CFRs driven by the ipsilateral anterior semicircular canal were found in a sagittal strip approximately 1.0 mm wide extending 1.0-2.0 mm from the midline. 6. The sagittal, topographically arrayed climbing fiber strips effectively map a mediolateral gradient of possible postural responses based on vestibular and optokinetic information.

title: Vestibular blueprint in early vertebrates
abstract: Central vestibular neurons form identifiable subgroups within the boundaries of classically outlined octavolateral nuclei in primitive vertebrates that are distinct from those processing lateral line, electrosensory, and auditory signals. Each vestibular subgroup exhibits a particular morpho-physiological property that receives origin-specific sensory inputs from semicircular canal and otolith organs. Behaviorally characterized phenotypes send discrete axonal projections to extraocular, spinal, and cerebellar targets including other ipsi- and contralateral vestibular nuclei. The anatomical locations of vestibuloocular and vestibulospinal neurons correlate with genetically defined hindbrain compartments that are well conserved throughout vertebrate evolution though some variability exists in fossil and extant vertebrate species. The different vestibular subgroups exhibit a robust sensorimotor signal processing complemented with a high degree of vestibular and visual adaptive plasticity.

title: Neuroepithelial 'compartments' and the specification of vestibular projections.
abstract: The implication that there exist coherent vestibulo-ocular neuron pools with specific functions may provide new insight into how conjugate eye movements are synthesized within the vestibulo-ocular reflex. The systematic relationship between pool position and synergistic principle terminations, the 'hodological mosaic' suggests, moreover, a determinate groundplan established by developmental mechanisms operative at early stages in the hindbrain neuroepithelium. From such a groundplan, evolutionary and use-dependent modifications could mold connectivity patterns functionally appropriate for each species and individual. How the expression of developmentally regulatory genes contributes to establishing the mosaic organization of the vestibular system is the current focus of our research.

title: Rhombomeric organization of vestibular pathways in larval frogs
abstract: Rhombencephalic subnuclei and projection pathways related to vestibular function were mapped in larval ranid frogs. The retention of overt postembryonic rhombomeres (r) allowed direct visualization of the locations of neurons retrogradely labeled with fluorescent dextran amines from the midbrain oculomotor complex, cerebellum, vestibular nuclei, and spinal cord. Oculomotor projecting vestibular neurons were mainly located in bilateral r1/2, ipsilateral r3, and contralateral r5–8, and spinal projecting vestibular neurons mainly in ipsilateral r4 and contralateral r5. Vestibular commissural neurons were located in r1–3 and r5–7 and were largely excluded from r4. Cerebellar projecting neurons included contralateral inferior olivary neurons in r8 and vestibular neurons in bilateral r6/7 and contralateral r1/2. Mapping these results onto adult anuran vestibular organization indicates that the superior vestibular nucleus derives from larval r1/2, the lateral vestibular nucleus from r3/4, and the major portions of the medial and descending vestibular nuclei from r5–8. The lateral vestibulospinal tract projects from an origin in r4, whereas a possible ascending tract of Deiters arises in r3. Rhombomere 5 contains a nuclear group that appears homologous to the tangential nucleus of fish, reptiles, and birds and thus likely serves gravistatic and linear vestibulomotor reflexes. Comparisons between frogs and other vertebrates suggest that vestibular neurons performing similar computational roles during head movements originate from the same segmental locations in different species.  2001.

title: The frog as a unique vertebrate model for studying the rhombomeric organization of functionally identified hindbrain neurons
abstract: The segmental organization of cranial nerve efferent, vestibular, and precerebellar neurons of larval ranid frogs is essentially retained in adult frogs, indicating the absence of any substantial postembryonic longitudinal migration of hindbrain neurons in this group. Comparison of the rhombomeric organization of vestibulomotor and branchiomotor pathways across different species suggests that the frog hindbrain blueprint is common to most vertebrates. The unique segmental stability seen in frogs can be used to create a quantitative stereotactic map of the adult brain that mirrors the embryonic and larval rhombomeric framework. Such a map allows the large number of physiologically identified hindbrain neurons in adult frogs to be linked with their underlying genetic specification. Transgenic reporters and antisense knockdown of gene activities suspected of having necessary functions in patterning neurons within specific rhombomeres may allow direct testing of the proposed map.

title: XVI Eye Movements from Semicircular Canal Nerve Stimulation in the Cat
abstract: Al though the eye movements induced by semicircular canal st imulation have been k n o w n for m a n y years, there have been few reports of the activity evoked in the eye muscles by single semicircular canals. Szentagothai in agreement wi th Hogyes found t ha t s t imula­ t ion of a single canal in dogs wi th an ' appropr ia te ' endolymphat ic cu r ren t produced eye muscle act ivi ty in one ipsilateral and one cont ra ­ lateral eye muscle.''^'-** F luu r s t imulated the ampul la ry nerves of precoUicularly transected cats and described two pa t te rns of oculomo­ tor activity.^ Electric s t imulat ion of a single anter ior canal nerve usually resulted in "conjugate eye movements u p w a r d , " one posterior canal in "conjugate eye movements d o w n w a r d , " and one lateral canal nerve in conjugate horizontal deviations. In about oneth i rd of his experiments disconjugate movements were observed which were sim­ ilar to those described by Szentagothai in dogs.^^'^^ U t s u m i polarized each ampulla in rabbits and produced still another pa t t e rn of discon­ jugate movements .

title: COMPENSATORY EYE MOVEMENTS INDUCED BY VERTICAL SEMICIRCULAR CANAL STIMULATION.
abstract: Electric stimulation of single anterior or posterior semicircular canal nerves induced disconjugate eye movements in monkey, cat, dog and rabbit. These movements were different but characteristic for each canal nerve stimulated in each species. This is in contrast to eye movements evoked by lateral canal nerve stimulation which were conjugate and horizontal in these species. We investigated the relationship of these disconjugate eye movements to acceleratory head rotations in the plane of the vertical canals. Ocular deviations were calculated which would oppose head rotations in several vertical planes. The axes for these rotations lay at 45°, 90° and 0° from the midsagittal plane of the head and were parallel to the plane of the lateral canals. These rotations corresponded to head movements which would have excited single anterior or posterior canals, bilateral anterior or posterior canals, or unilateral anterior and posterior canals respectively. The eye movements evoked by vertical semicircular canal nerve stimulation appeared to be the same as the eye movements which were predicted to oppose rotation in the planes of these semicircular canals. Eye movements from single anterior canal nerve stimulation which appeared disconjugate from the front of the animal were associated when viewed from the plane of rotation of the head. These data show that the degree of ocular dissociation and the direction of the eye movements can be mathematically approximated if the plane of the excited semicircular canal and the angle of the optic axis of the animal are known. The most important factor in determining the form of the induced eye movements from species to species is the lateral or frontal positioning of the eyes in the head. The results also show that the central neural organization which produces these movements must vary from species to species to provide the precise ocular compensation in direction which exists for acceleratory head rotation.

title: A quantitative analysis of the spatial organization of the vestibulo-ocular reflexes in lateral- and frontal-eyed animals—I. Orientation of semicircular canals and extraocular muscles
abstract: The spatial relationship between extraocular muscles and semicircular canals was evaluated in cat (frontal-eyed animal) and rabbit (lateral-eyed animal). Semicircular canal orientations in the rabbit were determined by a principal components analysis of data points obtained from the exposed osseous canals using a three-axis micromanipulator. Canal orientations were presented in terms of unit sensitivity vectors. Orientation of extraocular muscles in rabbits and cats was derived from measurements of the insertion and origin of each muscle with respect to a reference point on the skull and a calculated estimate of the center of the eye. Muscle orientations were presented in terms of unit action vectors. Semicircular canal planes of the rabbit labyrinth were not orthogonal, having deviations up to 14 degrees. Pairs of antagonistically acting vertical semicircular canals, left (right) anterior-right (left) posterior deviated from coplanarity by 16 degrees, while the deviation for the horizontal canals was 9 degrees. In both animals, muscles of an antagonistic pair were coplanar to within 8 degrees, with the exception of the oblique muscles in the rabbit for which the deviation was 19 degrees. The three pairs of antagonistic muscles were almost orthogonal to each other, the maximum deviation between any of the pairs being 8 degrees in the cat and 18 degrees in the rabbit. Comparing extraocular muscle planes and semicircular canal planes reveals that they are roughly aligned. However, there were slight but consistent differences between a given semicircular canal plane and the planes of the muscles to which this canal is connected by the classical three-neuron-arc (principal vestibulo-ocular reflex circuits).(ABSTRACT TRUNCATED AT 250 WORDS)

title: HEAD, EYE, BODY AND LIMB MOVEMENTS FROM SEMICIRCULAR CANAL NERVES.
abstract: Electric stimulation of single ampullary nerves in alert cats and monkeys produced rapid stereotyped head movements. These head movements were similar in the cat and monkey and appeared to be in a plane parallel to the plane of the canal whose nerve was stimulated. Body and limb responses also were evoked. They were more pronounced in the cat than in the monkey and consisted of varying degrees of ipsilateral forelimb extension, contralateral forelimb flexion, curvature of the trunk, and contralateral circling. By stimulating canals singly or in combination head movements could be produced in any spatial plane. These findings demonstrate the specific nature of the reflex head and postural movements produced by the semicircular canals in these animals.

title: On the vestibular labyrinth of Brachiosaurus brancai.
abstract: The extensive remains of large sauropods, excavated in the Upper Jurassic layers of the Tendaguru region of Tanzania, East Africa by Janensch [15], include an intact fossil cast of a vestibular labyrinth and an endocast of the large Brachiosaurus brancai. The approximately 150 million year old labyrinth cast demonstrates clearly a form and organisation congruent in detail to those of extant vertebrate species. Besides the near-orthogonal arrangement of semicircular canals (SCCs), the superior and inferior branches of the vestibulo-acoustic nerve, the endolymphatic duct, the oval and round windows, and the cochlea can be identified. The orientation of the labyrinth in the temporal bone is also equivalent to that of many extant vertebrates. Furthermore, the existence of the twelve cranial nerves can be identified from the endocast. The present study was initiated after the photogrammetric measurement of the skeleton volume of B. brancai [13] yielded a realistic estimate of body mass (74.42 metric tons). Dimensional analysis shows that body mass and average SCC dimensions of B. brancai generally fit with the allometric relationship found in previous studies of extant species. However, the anterior SCC is significantly larger than the allometric relationship would predict. This would indicate greater sensitivity, supporting the idea that the behavioural repertoire must have included much slower pitch movements of the head. These slower movements would most likely have involved flexion of the neck, rather than head pitching about the atlas joint. Pursuing the relationship between body mass and SCC dimensions further, the SCC frequency response is estimated by scaling up from the SCC dimensions of the rhesus monkey; this yields a range between 0.008-26 Hz, approximately one octave lower than for humans.

title: Stereoselective Transport of Baclofen Across the Blood–Brain Barrier in Rats as Determined by the Unit Impulse Response Methodology
abstract: The blood–brain barrier transport characteristics of racemic baclofen and the separate R- and S-enantiomers have been determined in vivo in rats by using the unit impulse response methodology. Transport rate was determined as blood–brain barrier clearance, the volume of plasma per unit time cleared of baclofen by transport across the blood–brain barrier. Plasma elimination kinetics and CSF elimination kinetics did not differ among racemic baclofen and the R-and S-enantiomers. Transport of each compound could be described by a linear V(t] curve, suggesting the absence of saturable transport processes in the concentration range studied. However, for R-baclofen the blood–brain barrier clearance (4.7 ± 1.0 µl/min, mean ± SE; n = 6) and cumulative transported amount (0.085 ± 0.007%; n = 6) were significantly higher than these values for the S-enantiomer (1.1 ± 0.3 µl/min, 0.031 ± 0.005%; n = 6) and racemic baclofen (1.0 ± 0.1 µl/min, 0.036 ± 0.003%; n = 6). These findings indicate that there is stereoselective transport of baclofen across the blood–brain barrier.

title: Study on Brain Interstitial Fluid Distribution and Blood-Brain Barrier Transport of Baclofen in Rats by Microdialysis
abstract: AbstractPurpose. This study was performed to examine the distribution in the brain interstitial fluid (ISF) and the blood-brain barrier (BBB) transport of baclofen in rats by a microdialysis technique.
Methods. Following an i.v. bolus administration and/or the constant i.v. infusion of baclofen to the microdialysis cannula-bearing anesthetized rats, the concentrations of baclofen in the hippocampal ISF, whole brain tissue, cerebrospinal fluid (CSF), and plasma were determined by high-performance liquid chromatography (HPLC). Data were kinetically analyzed to estimate the transport parameters, i.e., the influx clearance (CLin) from plasma to brain and the efflux rate constant (keff) from brain to plasma, and the steady-state volume of distribution in the brain (Vd).
Results. The concentrations of baclofen in ISF, whole brain tissue, and CSF at the pseudo-steady state were almost 30-fold lower than the plasma unbound concentration, suggesting the restricted distribution of baclofen in the brain. The estimated values of CLin and keff were 0.00157 ± 0.00076 ml/min/g of brain and 0.0872 ± 0.0252 min−1, respectively. The efflux clearance (CLout) calculated by multiplying keff by Vd (0.816 ± 0.559 ml/g of brain) was 0.0712 ± 0.0529 ml/min/g of brain, and it was significantly 40-fold greater than the CLin value and fully greater than the convective flow in ISF. Furthermore, no significant concentration gradient was observed between ISF and CSF. These results suggest that the CLout value mainly reflects the efflux clearance through the BBB. Additionally, the hippocampal ISF/plasma concentration ratio of baclofen was markedly increased by both systemic administration of probenecid and its direct instillation into ISF.
Conclusions. The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.

title: Transporting therapeutics across the blood-brain barrier.
abstract: In 1996, we are half-way through the Decade of the Brain, yet we still have few effective treatments for major disorders of the central nervous system. These include affective disorders, epilepsy, neurodegenerative disorders, brain tumours, infections and HIV encephalopathy; sufferers far outnumber the morbidity of cancer or heart disease. Increased understanding of the pharmacology of the brain and its blood supply, and methods for rational drug design, are leading to potential new drug therapies based on highly specific actions on particular target sites, such as neurotransmitter receptors and uptake systems. These methods are capable of reducing the side effects that are common with more general treatments. However, all these treatments and potential treatments meet a formidable obstacle--the blood-brain barrier. In this article, we review the properties of this barrier that complicate drug delivery to the brain, and some of the most hopeful strategies for overcoming or bypassing the barrier in humans.