Bill J. Yates

Physiological basis and pharmacology of motion sickness: an update

Motion sickness can occur when sensory inputs regarding body position in space are contradictory or are different from those predicted from experience. Signals from the vestibular system are essential for triggering motion sickness. The evolutionary significance of this malady is unclear, although it may simply represent the aberrant activation of vestibuloautonomic pathways that typically subserve homeostasis. The neural pathways that produce nausea and vomiting during motion sickness are presumed to be similar to those that generate illness after ingestion of toxins. The neural substrate of nausea is unknown but may include neurons in the hypothalamus and inferior frontal gyrus of the cerebral cortex. The principal motor act of vomiting is accomplished through the simultaneous contractions of inspiratory and expiratory respiratory muscles and is mediated by neurons in the lateral medullary reticular formation and perhaps by cells near the medullary midline. Cocontraction of the diaphragm and abdominal muscles increases pressure on the stomach, which causes gastric contents to be ejected through the mouth. Effective drugs for combating motion sickness include antihistamines, antimuscarinics, 5-HT1A (serotonergic) receptor agonists and neurokinin type 1 receptor antagonists. However, considerable information concerning the physiological basis and pharmacology of motion sickness is unknown; future research using animal models will be required to understand this condition.

Cervical prephrenic interneurons in the normal and lesioned spinal cord of the adult rat

Although monosynaptic bulbospinal projections to phrenic motoneurons have been extensively described, little is known about the organization of phrenic premotor neurons in the adult rat spinal cord. Because interneurons may play an important role in normal breathing and recovery following spinal cord injury, the present study has used anterograde and transneuronal retrograde tracing to study their distribution and synaptic relations. Exclusive unilateral, first‐order labeling of the phrenic motoneuron pool with pseudorabies virus demonstrated a substantial number of second‐order, bilaterally distributed cervical interneurons predominantly in the dorsal horn and around the central canal. Combined transneuronal and anterograde tracing revealed ventral respiratory column projections to prephrenic interneurons, suggesting that some propriospinal relays exist between medullary neurons and the phrenic nucleus. Dual‐labeling studies with pseudorabies virus recombinants also showed prephrenic interneurons integrated with either contralateral phrenic or intercostal motoneuron pools. The stability of interneuronal pseudorabies virus labeling patterns following lateral cervical hemisection was then addressed. Except for fewer infected contralateral interneurons at the level of the central canal, the number and distribution of phrenic‐associated interneurons was not significantly altered 2 weeks posthemisection (i.e., the point at which the earliest postinjury recovery of phrenic activity has been reported). These results demonstrate a heterogeneous population of phrenic‐related interneurons. Their connectivity and relative stability after cervical hemisection raise speculation for potentially diverse roles in modulating phrenic function normally and postinjury. J. Comp. Neurol. 511:692–709, 2008.

Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study.

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity–key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.

Cardiovascular responses elicited by linear acceleration in humans

Abstract Although activation of otolith receptors is known to elicit cardiovascular responses in animals, it is unclear whether vestibular stimulation can evoke changes in blood pressure and heart rate (which are independent of motion sickness) in humans. In the present study, ten normal subjects and three patients with profound bilateral reduction in vestibular function, who were seated upright with the torso aligned with the gravitation vector, were subjected to fore, aft, or lateral linear acceleration (≈0.2 g, attaining ≈2 m/s in 900 ms, and decelerating for 3 s at 0.07 g). The head was fixed in the upright position, pitched maximally downward (chin on chest) or maximally backward (≈40–50°) during the accelerations. In normal subjects, all directions of linear acceleration produced an average increase in systolic blood pressure of approximately 7–9 mmHg and a rapid decrease in the interval between R-waves of the electrocardiogram of 14–27 ms; these responses persisted for only a few seconds. In contrast, the cardiovascular responses in patients with vestibular dysfunction were much smaller (e.g., the maximal pressor response to forward linear acceleration was <4 mmHg). Head position during accelerations had little effect on the cardiovascular responses that were elicited in the population of normal subjects. However, although the population response was similar across directions of acceleration and head positions, many individuals exhibited larger cardiovascular changes during some stimulus conditions than during others. These data suggest that vestibular stimulation during linear accelerations can produce cardiovascular responses in humans and support the hypothesis that the vestibular system contributes to maintaining stable blood pressure during movement and changes in posture.

Transneuronal tracing of neural pathways controlling activity of diaphragm motoneurons in the ferret.

Previous studies have shown that neurons in addition to those in the medullary respiratory groups are involved in activating phrenic motoneurons during a number of behaviors, including vomiting and reaction to vestibular stimulation. However, the location of premotor inspiratory neurons outside of the main medullary respiratory groups is largely unknown, particularly in emetic species. In the present study, the transneuronal tracer pseudorabies virus was injected into the diaphragm of the ferret, and the locations of retrogradely-labeled motoneurons and transneuronally-labeled pre-motoneurons in the brainstem and cervical and thoracic spinal cord were mapped. Injections of a monosynaptic tracer, cholera toxin, were also made in order to verify the location of motoneurons innervating the diaphragm. Phrenic motoneurons identified with pseudorabies virus and cholera toxin were confined largely to the C5-C7 levels of spinal cord, and often gave rise to prominent polarized dendritic arbors that extended across the midline. At post-inoculation survival times > or = three days, transneuronally-labeled interneurons were located in the cervical and thoracic spinal cord and portions of the brainstem, including the midline pontomedullary reticular formation and the lateral medullary reticular formation. Double-labeling studies revealed that although the infected midline neurons were located in the proximity of serotonergic neurons, only a small number of the virus-containing cells were positive for serotonin. These findings suggest that neurons in the midline of the medulla and pons influence the activity of phrenic motoneurons, perhaps during inspiratory behaviors unique to emetic animals (such as vomiting).

Pressor response elicited by nose-up vestibular stimulation in cats.

The purpose of the present study was to determine whether selective activation of vestibular receptors produces changes in blood pressure. Blood pressure was recorded during trapezoidal head rotations in cats with extensive denervations to eliminate nonlabyrinthine inputs that could be produced by the movements. Large (50°) nose-up trapezoidal head tilts produced an increase in blood pressure of approximately 18 mmHg; ear-down tilt produced little change in blood pressure. The changes in blood pressure began approximately 1.4 s after the plateau of the stimulus. The responses to nose-up tilt were abolished following intracranial transections of the WIIIth cranial nerves. These data suggest that vestibular inputs elicited by nose-up movements of the head act to rapidly increase blood pressure. This mechanism may contribute to counteracting the orthostatic hypotension induced by nose-up body rotation in quadrupeds.

Convergence of limb, visceral, and vertical semicircular canal or otolith inputs onto vestibular nucleus neurons.

The major goal of this study was to determine the patterns of convergence of non-labyrinthine inputs from the limbs and viscera onto vestibular nucleus neurons receiving signals from vertical semicircular canals or otolith organs. A secondary aim was to ascertain whether the effects of non-labyrinthine inputs on the activity of vestibular nucleus neurons is affected by bilateral peripheral vestibular lesions. The majority (72%) of vestibular nucleus neurons in labyrinth-intact animals whose firing was modulated by vertical rotations responded to electrical stimulation of limb and/or visceral nerves. The activity of even more vestibular nucleus neurons (93%) was affected by limb or visceral nerve stimulation in chronically labyrinthectomized preparations. Some neurons received non-labyrinthine inputs from a variety of peripheral sources, including antagonist muscles acting at the same joint, whereas others received inputs from more limited sources. There was no apparent relationship between the spatial and dynamic properties of a neuron’s responses to tilts in vertical planes and the non-labyrinthine inputs that it received. These data suggest that non-labyrinthine inputs elicited during movement will modulate the processing of information by the central vestibular system, and may contribute to the recovery of spontaneous activity of vestibular nucleus neurons following peripheral vestibular lesions. Furthermore, some vestibular nucleus neurons with non-labyrinthine inputs may be activated only during particular behaviors that elicit a specific combination of limb and visceral inputs.

Effects of lesions of the caudal cerebellar vermis on cardiovascular regulation in awake cats

The vestibular system is known to participate in cardiovascular regulation during movement and postural alterations. The present study considered whether lesions of two regions of the posterior cerebellar vermis (the nodulus and uvula) that provide inputs to vestibular nucleus regions that affect control of blood pressure would alter cardiovascular responses during changes in posture. Blood pressure and heart rate were monitored in awake cats during nose-up tilts up to 60 degrees in amplitude before and following aspiration lesions of the nodulus or uvula; in most animals, cardiovascular responses were also recorded following the subsequent removal of vestibular inputs. Lesions of the nodulus or uvula did not affect baseline blood pressure or heart rate, although cardiovascular responses during nose-up tilts were altered. Increases in heart rate that typically occurred during 60 degrees nose-up tilt were attenuated in all three animals with lesions affecting both dorsal and ventral portions of the uvula; in contrast, the heart rate responses were augmented in the two animals with lesions mainly confined to the nodulus. Furthermore, following subsequent removal of vestibular inputs, uvulectomized animals, but not those with nodulus lesions, experienced more severe orthostatic hypotension than has previously been reported in cerebellum-intact animals with bilateral labyrinthectomies. These data suggest that the cerebellar nodulus and uvula modulate vestibulo-cardiovascular responses, although the two regions play different roles in cardiovascular regulation.

Vestibular inputs to the lateral tegmental field of the cat: potential role in autonomic control

The lateral tegmental field (LTF), which is comprised of the lateral reticular formation near the obex, is an important integrative area involved in cardiovascular control and the production of emesis. Using neuroanatomical and electrophysiological techniques, we tested the hypothesis that LTF neurons receive vestibular inputs; the neurons studied included those projecting into the subretrofacial rostral ventrolateral medulla (sRVLM), which contains cells that make direct connections with sympathetic preganglionic neurons. Injections of the anterograde tracer PHA-L into the medial and inferior vestibular nuclei produced labeled terminals in the LTF. Electrical stimulation of the vestibular nerve affected the firing rate of LTF neurons, including approximately one-third of those antidromically activated from the sRVLM. The response latencies ranged from 1.5 to 20 ms, suggesting that the neurons received both direct and polysynaptic vestibular inputs from the vestibular nuclei. The LTF may be involved in the production of vestibulosympathetic reflexes and vestibular-elicited vomiting.

Patterning of sympathetic nerve activity in response to vestibular stimulation

Growing evidence suggests a role for the vestibular system in regulation of autonomic outflow during postural adjustments. In the present paper we review evidence for the patterning of sympathetic nerve activity elicited by vestibular stimulation. In response to electrical activation of vestibular afferents, firing of sympathetic nerves located throughout the body is altered. However, activity of the renal nerve is most sensitive to vestibular inputs. In contrast, high-intensity simultaneous activation of cutaneous and muscle inputs elicits equivalent changes in firing of the renal, superior mesenteric and lumbar colonic nerves. Responses of muscle vasoconstrictor (MVC) efferents to vestibular stimulation are either inhibitory (Type I) or are comprised of a combination of excitation and inhibition (Type II). Interestingly, single MVC units located in the hindlimb exhibited predominantly Type I responses while those located in the forelimb and face exhibited Type II responses. Furthermore, brachial and femoral arterial blood flows were dissociated in response to vestibular stimulation, such that brachial vascular resistance increased while femoral resistance decreased. These studies demonstrate that vestibulosympathetic reflexes are patterned according to both the anatomical location and innervation target of a particular sympathetic nerve, and can lead to distinct changes in local blood flow.