Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes.

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N = 3) or ventral (N = 3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the left or right nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that it was possible to selectively activate subpopulations of vagal neurons using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e., Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

Integration of vestibular and hindlimb inputs by vestibular nucleus neurons: multisensory influences on postural control.

We recently demonstrated in decerebrate and conscious cat preparations that hindlimb somatosensory inputs converge with vestibular afferent input onto neurons in multiple central nervous system (CNS) locations that participate in balance control. Although it is known that head position and limb state modulate postural reflexes, presumably through vestibulospinal and reticulospinal pathways, the combined influence of the two inputs on the activity of neurons in these brainstem regions is unknown. In the present study, we evaluated the responses of vestibular nucleus (VN) neurons to vestibular and hindlimb stimuli delivered separately and together in conscious cats. We hypothesized that VN neuronal firing during activation of vestibular and limb proprioceptive inputs would be well fit by an additive model. Extracellular single-unit recordings were obtained from VN neurons. Sinusoidal whole body rotation in the roll plane was used as the search stimulus. Units responding to the search stimulus were tested for their responses to 10° ramp-and-hold roll body rotation, 60° extension hindlimb movement, and both movements delivered simultaneously. Composite response histograms were fit by a model of low- and high-pass filtered limb and body position signals using least squares nonlinear regression. We found that VN neuronal activity during combined vestibular and hindlimb proprioceptive stimulation in the conscious cat is well fit by a simple additive model for signals with similar temporal dynamics. The mean R2 value for goodness of fit across all units was 0.74 ± 0.17. It is likely that VN neurons that exhibit these integrative properties participate in adjusting vestibulospinal outflow in response to limb state.NEW & NOTEWORTHY Vestibular nucleus neurons receive convergent information from hindlimb somatosensory inputs and vestibular inputs. In this study, extracellular single-unit recordings of vestibular nucleus neurons during conditions of passively applied limb movement, passive whole body rotations, and combined stimulation were well fit by an additive model. The integration of hindlimb somatosensory inputs with vestibular inputs at the first stage of vestibular processing suggests that vestibular nucleus neurons account for limb position in determining vestibulospinal responses to postural perturbations.

Responses of neurons in the rostral ventrolateral medulla of conscious cats to anticipated and passive movements.

The vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that neurons in the rostral ventrolateral medulla (RVLM) respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, although such movements do not affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that RVLM neurons in conscious animals respond to signals from the vestibular otolith organs elicited by large-amplitude static tilts. The activity of approximately one-third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, was modulated by vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM neurons failed to respond to a light cue signaling the movement, suggesting that feedforward cardiovascular responses do not occur before passive movements that require cardiovascular adjustments.

Responses of Neurons in the Medullary Lateral Tegmental Field and Nucleus Tractus Solitarius to Vestibular Stimuli in Conscious Felines.

Considerable evidence shows that the vestibular system contributes to adjusting sympathetic nervous system activity to maintain adequate blood pressure during movement and changes in posture. However, only a few prior experiments entailed recordings in conscious animals from brainstem neurons presumed to convey baroreceptor and vestibular inputs to neurons in the rostral ventrolateral medulla (RVLM) that provide inputs to sympathetic preganglionic neurons in the spinal cord. In this study, recordings were made in conscious felines from neurons in the medullary lateral tegmental field (LTF) and nucleus tractus solitarius (NTS) identified as regulating sympathetic nervous system activity by exhibiting changes in firing rate related to the cardiac cycle, or cardiac-related activity (CRA). Approximately 38% of LTF and NTS neurons responded to static 40° head up tilts with a change in firing rate (increase for 60% of the neurons, decrease for 40%) of ~50%. However, few of these neurons responded to 10° sinusoidal rotations in the pitch plane, in contrast to prior findings in decerebrate animals that the firing rates of both NTS and LTF neurons are modulated by small-amplitude body rotations. Thus, as previously demonstrated for RVLM neurons, in conscious animals NTS and LTF neurons only respond to large rotations that lead to changes in sympathetic nervous system activity. The similar responses to head-up rotations of LTF and NTS neurons with those documented for RVLM neurons suggest that LTF and NTS neurons are components of the vestibulo-sympathetic reflex pathway. However, a difference between NTS/LTF and RVLM neurons was variability in CRA over time. This variability was significantly greater for RVLM neurons, raising the hypothesis that the responsiveness of these neurons to baroreceptor input is adjusted based on the animal's vigilance and alertness.

Machine learning prediction of emesis and gastrointestinal state in ferrets.

Although electrogastrography (EGG) could be a critical tool in the diagnosis of patients with gastrointestinal (GI) disease, it remains under-utilized. The lack of spatial and temporal resolution using current EGG methods presents a significant roadblock to more widespread usage. Human and preclinical studies have shown that GI myoelectric electrodes can record signals containing significantly more information than can be derived from abdominal surface electrodes. The current study sought to assess the efficacy of multi-electrode arrays, surgically implanted on the serosal surface of the GI tract, from gastric fundus-to-duodenum, in recording myoelectric signals. It also examines the potential for machine learning algorithms to predict functional states, such as retching and emesis, from GI signal features. Studies were performed using ferrets, a gold standard model for emesis testing. Our results include simultaneous recordings from up to six GI recording sites in both anesthetized and chronically implanted free-moving ferrets. Testing conditions to produce different gastric states included gastric distension, intragastric infusion of emetine (a prototypical emetic agent), and feeding. Despite the observed variability in GI signals, machine learning algorithms, including k-nearest neighbors and support vector machines, were able to detect the state of the stomach with high overall accuracy (>75%). The present study is the first demonstration of machine learning algorithms to detect the physiological state of the stomach and onset of retching, which could provide a methodology to diagnose GI diseases and symptoms such as nausea and vomiting.

Cardiovascular adjustments during anticipated postural changes.

It is well-documented that feedforward cardiovascular responses occur at the onset of exercise, but it is unclear if such responses are associated with other types of movements. In this study, we tested the hypothesis that feedforward cardiovascular responses occur when a passive (imposed) 60° head-up tilt is anticipated, such that changes in heart rate and carotid artery blood flow (CBF) commence prior to the onset of the rotation. A light cue preceded head-up tilts by 10 sec, and heart rate and CBF were determined for 5-sec time periods prior to and during tilts. Even after these stimuli were provided for thousands of trials spanning several months, no systematic changes in CBF and heart rate occurred prior to tilts, and variability in cardiovascular adjustments during tilt remained substantial over time. We also hypothesized that substitution of 20° for 60° tilts in a subset of trials would result in exaggerated cardiovascular responses (as animals expected 60° tilts), which were not observed. These data suggest that cardiovascular adjustments during passive changes in posture are mainly elicited by feedback mechanisms, and that anticipation of passive head-up tilts does not diminish the likelihood that a decrease in carotid blood flow will occur during the movements.

Sound-Evoked Biceps Myogenic Potentials Reflect Asymmetric Vestibular Drive to Spastic Muscles in Chronic Hemiparetic Stroke Survivors.

Aberrant vestibular nuclear function is proposed to be a principle driver of limb muscle spasticity after stroke. We sought to determine whether altered cortical modulation of descending vestibulospinal pathways post-stroke could impact the excitability of biceps brachii motoneurons. Twelve chronic hemispheric stroke survivors aged 46-68 years were enrolled. Sound evoked biceps myogenic potentials (SEBMPs) were recorded from the spastic and contralateral biceps muscles using surface EMG electrodes. We assessed the impact of descending vestibulospinal pathways on biceps muscle activity and evaluated the relationship between vestibular function and the severity of spasticity. Spastic SEBMP responses were recorded in 11/12 subjects. Almost 60% of stroke subjects showed evoked responses solely on the spastic side. These data strongly support the idea that vestibular drive is asymmetrically distributed to biceps motoneuron pools in hemiparetic spastic stroke survivors. This abnormal vestibular drive is very likely to be a factor mediating the striking differences in motoneuron excitability between the clinically affected and clinically spared sides. This study extends our previous observations on vestibular nuclear changes following hemispheric stroke and potentially sheds light on the underlying mechanisms of post-stroke spasticity.

Descending Influences on Vestibulospinal and Vestibulosympathetic Reflexes.

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.

Neurons in the pontomedullary reticular formation receive converging inputs from the hindlimb and labyrinth.

The integration of inputs from vestibular and proprioceptive sensors within the central nervous system is critical to postural regulation. We recently demonstrated in both decerebrate and conscious cats that labyrinthine and hindlimb inputs converge onto vestibular nucleus neurons. The pontomedullary reticular formation (pmRF) also plays a key role in postural control, and additionally participates in regulating locomotion. Thus, we hypothesized that like vestibular nucleus neurons, pmRF neurons integrate inputs from the limb and labyrinth. To test this hypothesis, we recorded the responses of pmRF neurons to passive ramp-and-hold movements of the hindlimb and to whole-body tilts, in both decerebrate and conscious felines. We found that pmRF neuronal activity was modulated by hindlimb movement in the rostral-caudal plane. Most neurons in both decerebrate (83% of units) and conscious (61% of units) animals encoded both flexion and extension movements of the hindlimb. In addition, hindlimb somatosensory inputs converged with vestibular inputs onto pmRF neurons in both preparations. Pontomedullary reticular formation neurons receiving convergent vestibular and limb inputs likely participate in balance control by governing reticulospinal outflow.

Vestibular nucleus neurons respond to hindlimb movement in the conscious cat.

The limbs constitute the sole interface with the ground during most waking activities in mammalian species; it is therefore expected that somatosensory inputs from the limbs provide important information to the central nervous system for balance control. In the decerebrate cat model, the activity of a subset of neurons in the vestibular nuclei (VN) has been previously shown to be modulated by hindlimb movement. However, decerebration can profoundly alter the effects of sensory inputs on the activity of brain stem neurons, resulting in epiphenomenal responses. Thus, before this study, it was unclear whether and how somatosensory inputs from the limb affected the activity of VN neurons in conscious animals. We recorded brain stem neuronal activity in the conscious cat and characterized the responses of VN neurons to flexion and extension hindlimb movements and to whole body vertical tilts (vestibular stimulation). Among 96 VN neurons whose activity was modulated by vestibular stimulation, the firing rate of 65 neurons (67.7%) was also affected by passive hindlimb movement. VN neurons in conscious cats most commonly encoded hindlimb movement irrespective of the direction of movement (n = 33, 50.8%), in that they responded to all flexion and extension movements of the limb. Other VN neurons overtly encoded information about the direction of hindlimb movement (n = 27, 41.5%), and the remainder had more complex responses. These data confirm that hindlimb somatosensory and vestibular inputs converge onto VN neurons of the conscious cat, suggesting that VN neurons integrate somatosensory inputs from the limbs in computations that affect motor outflow to maintain balance.

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

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

Asymmetries in vestibular evoked myogenic potentials in chronic stroke survivors with spastic hypertonia: evidence for a vestibulospinal role.

OBJECTIVE: Indirect evidence suggests that lateralized changes in motoneuron behavior post-stroke are potentially due to a depolarizing supraspinal drive to the motoneuron pool, but the pathways responsible are unknown. In this study, we assessed vestibular evoked myogenic potentials (VEMPs) in the neck muscles of hemispheric stroke survivors with contralesional spasticity to quantify the relative levels of vestibular drive to the spastic-paretic and contralateral motoneuron pools. METHODS: VEMPs were recorded from each sternocleidomastoid muscle in chronic stroke survivors. Side-to-side differences in cVEMP amplitude were calculated and expressed as an asymmetry ratio, a proxy for the relative amount of vestibular drive to each side. RESULTS: Spastic-paretic VEMPs were larger than contralateral VEMPs in 13/16 subjects. There was a strong positive relationship between the degree of asymmetry and the severity of spasticity in this subset of subjects. Remaining subjects had larger contralateral responses. CONCLUSION: Vestibular drive to cervical motoneurons is asymmetric in spastic stroke survivors, supporting our hypothesis that there is an imbalance in descending vestibular drive to motoneuron pools post-stroke. We speculate this imbalance is a consequence of the unilateral disruption of inhibitory corticobulbar projections to the vestibular nuclei. SIGNIFICANCE: This study sheds new light on the underlying mechanisms of post-stroke spasticity.

Integration of nonlabyrinthine inputs by the vestibular system: role in compensation following bilateral damage to the inner ear.

Inputs from the skin and muscles of the limbs and trunk as well as the viscera are relayed to the medial, inferior, and lateral vestibular nuclei. Vestibular nucleus neurons very quickly regain spontaneous activity following a bilateral vestibular neurectomy, presumably due to the presence of such nonlabyrinthine inputs. The firing of a small fraction of vestibular nucleus neurons in animals lacking labyrinthine inputs can be modulated by whole-body tilts; these responses are eliminated by a spinal transection, showing that they are predominantly elicited by inputs from the trunk and limbs. The ability to adjust blood distribution in the body and maintain stable blood pressure during movement is diminished following a bilateral vestibular neurectomy, but compensation occurs within a week. However, bilateral lesions of the caudal portions of the vestibular nuclei produce severe and long-lasting cardiovascular disturbances during postural alterations, suggesting that the presence of nonlabyrinthine signals to the vestibular nuclei is essential for compensation of posturally-related autonomic responses to occur. Despite these observations, the functional significance of nonlabyrinthine inputs to the central vestibular system remains unclear, either in modulating the processing of vestibular inputs or compensating for their loss.