Dose-dependent Respiratory Depression by Remifentanil in the Rabbit Parabrachial Nucleus/Kölliker-Fuse Complex and Pre-Bötzinger Complex.

Background: Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker-Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations.

Methods: Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits.

Multi-Level Regulation of Opioid-Induced Respiratory Depression.

Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from depression of the Parabrachial/Kölliker-Fuse Complex, which provides excitatory drive to preBötzinger Complex neurons mediating respiratory phase-switch. Opioids also depress awake drive from the forebrain and chemodrive.

Structure and function of the perivascular fluid compartment and vertebral venous plexus: Illumining a novel theory on mechanisms underlying the pathogenesis of Alzheimer's, cerebral small vessel, and neurodegenerative diseases.

Blood dynamically and richly supplies the cerebral tissue via microvessels invested in pia matter perforating the cerebral substance. Arteries penetrating the cerebral substance derive an investment from one or two successive layers of pia mater, luminally apposed to the pial-glial basal lamina of the microvasculature and abluminally apposed to a series of aquaporin IV-studded astrocytic end feet constituting the soi-disant glia limitans. The full investment of successive layers forms the variably continuous walls of the periarteriolar, pericapillary, and perivenular divisions of the perivascular fluid compartment.

Galenic Pial Arteriovenous Fistulas in Adults.

Background: Vein of Galen aneurysmal malformations (VOGMs) are pial arteriovenous fistulas possessing Galenic venous drainage most commonly presenting during the neonatal period and infancy, with initial discovery during adulthood quite rare.

Objectives And Methods: We conducted a literature survey of the PubMed database in order to identify Galenic pial arteriovenous fistulas (GPAVFs) with major manifestation or initial presentation during adulthood. Inclusionary criteria included pial AVFs with Galenic drainage with major manifestation or initial presentation at, or older than, 18 years.

Modulation of Respiratory System by Limb Muscle Afferents in Intact and Injured Spinal Cord.

Breathing constantly adapts to environmental, metabolic or behavioral changes by responding to different sensory information, including afferent feedback from muscles. Importantly, not just respiratory muscle feedback influences respiratory activity. Afferent sensory information from rhythmically moving limbs has also been shown to play an essential role in the breathing.

The Neuroplastic and Therapeutic Potential of Spinal Interneurons in the Injured Spinal Cord.

The central nervous system is not a static, hard-wired organ. Examples of neuroplasticity, whether at the level of the synapse, the cell, or within and between circuits, can be found during development, throughout the progression of disease, or after injury. One essential component of the molecular, anatomical, and functional changes associated with neuroplasticity is the spinal interneuron (SpIN).

Paced breathing and phrenic nerve responses evoked by epidural stimulation following complete high cervical spinal cord injury in rats.

Spinal cord injury (SCI) at the level of cervical segments often results in life-threatening respiratory complications and requires long-term mechanical ventilator assistance. Thus restoring diaphragm activity and regaining voluntary control of breathing are the primary clinical goals for patients with respiratory dysfunction following cervical SCI. Epidural stimulation (EDS) is a promising strategy that has been explored extensively for nonrespiratory functions and to a limited extent within the respiratory system.

Spontaneous respiratory plasticity following unilateral high cervical spinal cord injury in behaving rats.

Unilateral cervical C2 hemisection (C2Hx) is a classic model of spinal cord injury (SCI) for studying respiratory dysfunction and plasticity. However, most previous studies were performed under anesthesia, which significantly alters respiratory network. Therefore, the goal of this work was to assess spontaneous diaphragm recovery post-C2Hx in awake, freely behaving animals.

Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord.

Cervical spinal cord injuries (SCI) result in devastating functional consequences, including respiratory dysfunction. This is largely attributed to the disruption of phrenic pathways, which control the diaphragm. Recent work has identified spinal interneurons as possible contributors to respiratory neuroplasticity.

Supraspinal respiratory plasticity following acute cervical spinal cord injury.

Impaired breathing is a devastating result of high cervical spinal cord injuries (SCI) due to partial or full denervation of phrenic motoneurons, which innervate the diaphragm - a primary muscle of respiration. Consequently, people with cervical level injuries often become dependent on assisted ventilation and are susceptible to secondary complications. However, there is mounting evidence for limited spontaneous recovery of respiratory function following injury, demonstrating the neuroplastic potential of respiratory networks.

Enhancing neural activity to drive respiratory plasticity following cervical spinal cord injury.

Cervical spinal cord injury (SCI) results in permanent life-altering sensorimotor deficits, among which impaired breathing is one of the most devastating and life-threatening. While clinical and experimental research has revealed that some spontaneous respiratory improvement (functional plasticity) can occur post-SCI, the extent of the recovery is limited and significant deficits persist. Thus, increasing effort is being made to develop therapies that harness and enhance this neuroplastic potential to optimize long-term recovery of breathing in injured individuals.

Effects of vagotomy on hypoglossal and phrenic responses to hypercapnia in the decerebrate rat.

Hypercapnia characterizes a variety of physiological and pathological states and must be compensated effectively by the respiratory, cardiovascular, renal, and intra- and extracellular pH buffering systems to maintain homeostasis. Several studies have examined the respiratory response to hypercapnia, but contemporaneous changes in respiratory frequency and tidal volume prevent investigating the pure influence on respiratory amplitude. Therefore, we sought to test the effect of hypercapnia on hypoglossal (XII) and phrenic nerve (PN) inspiratory (Insp) and XII pre-inspiratory (pre-I) activities in vagus-intact and vagus-denervated animals.

Perturbations of Respiratory Rhythm and Pattern by Disrupting Synaptic Inhibition within Pre-Bötzinger and Bötzinger Complexes.

The pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes are the brainstem compartments containing interneurons considered to be critically involved in generating respiratory rhythm and motor pattern in mammals. Current models postulate that both generation of the rhythm and coordination of the inspiratory-expiratory pattern involve inhibitory synaptic interactions within and between these regions. Both regions contain glycinergic and GABAergic neurons, and rhythmically active neurons in these regions receive appropriately coordinated phasic inhibition necessary for generation of the normal three-phase respiratory pattern.

Patterns of Phrenic Nerve Discharge after Complete High Cervical Spinal Cord Injury in the Decerebrate Rat.

Studies conducted since the second half of the 19th century have revealed spontaneous as well as pharmacologically induced phasic/rhythmic discharge in spinal respiratory motor outputs of cats, dogs, rabbits, and neonatal rats following high cervical transection (Tx). The extent to which these various studies validate the existence of a true spinal respiratory rhythm generator remains debated. In this set of studies, we seek to characterize patterns of spontaneous phasic/rhythmic, asphyxia-induced, and pharmacologically induced activity occurring in phrenic nerve (PhN) discharge after complete high cervical (C1-C2) spinal cord transection.

Dynamic changes in phrenic motor output following high cervical hemisection in the decerebrate rat.

Hemisection of the spinal cord at C2 eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e.

The role of spinal GABAergic circuits in the control of phrenic nerve motor output.

While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus.

Fast oscillations during gasping and other non-eupneic respiratory behaviors: Clues to central pattern generation.

The mammalian nervous system exhibits fast synchronous oscillations, which are especially prominent in respiratory-related nerve discharges. In the phrenic nerve, they include high- (HFO), medium- (MFO), and low-frequency (LFO) oscillations. Because motoneurons firing at HFO-related frequencies had never been recorded, an epiphenomenological mechanism for their existence had been posited.

Inhibition of A5 Neurons Facilitates the Occurrence of REM Sleep-Like Episodes in Urethane-Anesthetized Rats: A New Role for Noradrenergic A5 Neurons?

When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons.

Motoneuron firing patterns underlying fast oscillations in phrenic nerve discharge in the rat.

Fast oscillations are ubiquitous throughout the mammalian central nervous system and are especially prominent in respiratory motor outputs, including the phrenic nerves (PhNs). Some investigators have argued for an epiphenomenological basis for PhN high-frequency oscillations because phrenic motoneurons (PhMNs) firing at these same frequencies have never been recorded, although their existence has never been tested systematically. Experiments were performed on 18 paralyzed, unanesthetized, decerebrate adult rats in which whole PhN and individual PhMN activity were recorded.

GABAAergic and glycinergic inhibition in the phrenic nucleus organizes and couples fast oscillations in motor output.

One of the characteristics of respiratory motor output is the presence of fast synchronous oscillations, at rates far exceeding the basic breathing rhythm, within a given functional population. However, the mechanisms responsible for organizing phrenic output into two dominant bands in vivo, medium (MFO)- and high (HFO)-frequency oscillations, have yet to be elucidated. We hypothesize that GABA(A)ergic and glycinergic inhibition within the phrenic motor nucleus underlies the specific organization of these oscillations.

Sparse firing frequency-based neuron spike train classification.

Peri-stimulus time histograms (PSTHs) reveal the temporal distribution of action potentials, averaged over many stimulus presentations. PSTHs have been used as model responses to solve the classification problem, in which a single response (i.e.

Temperature and state dependence of dynamic phrenic oscillations in the decerebrate juvenile rat.

The aim of the present study was to determine characteristics of fast oscillations in the juvenile rat phrenic nerve (Ph) and to establish their temperature and state dependence. Two different age-matched decerebrate, baro- and chemodenervated rat preparations, in vivo and in situ arterially perfused models, were used to examine three systemic properties: 1) generation and dynamics of fast oscillations in Ph activity (both preparations), 2) responses to anoxia (both preparations), and 3) the effects of temperature on fast oscillations (in situ only). Both juvenile preparations generated power and coherence in two major bands analogous to adult medium- and high-frequency oscillations (HFO) at frequencies that increased with temperature but were lower than in adults.

Retention of lung distension information in pump cell spike trains.

Respiratory control requires feedback signals from the viscera, including mechanoreceptors and chemoreceptors. We previously showed that typical pulmonary stretch receptor (PSR) spike trains provide the central nervous system with approximately 31% of the theoretical maximum information regarding the amplitude of lung distension. However, it is unknown whether the spatiotemporal convergence of many PSR inputs onto second-order neurons (e.

Selective loss of high-frequency oscillations in phrenic and hypoglossal activity in the decerebrate rat during gasping.

Respiratory motor outputs contain medium-(MFO) and high-frequency oscillations (HFO) that are much faster than the fundamental breathing rhythm. However, the associated changes in power spectral characteristics of the major respiratory outputs in unanesthetized animals during the transition from normal eupneic breathing to hypoxic gasping have not been well characterized. Experiments were performed on nine unanesthetized, chemo- and barodenervated, decerebrate adult rats, in which asphyxia elicited hyperpnea, followed by apnea and gasping.

Time-frequency coherence analysis of phrenic and hypoglossal activity in the decerebrate rat during eupnea, hyperpnea, and gasping.

Fast respiratory rhythms include medium- (MFO) and high-frequency oscillations (HFO), which are much faster than the fundamental breathing rhythm. According to previous studies, HFO is characterized by high coherence (Coh) in phrenic (Ph) nerve activity, thereby providing a means of distinguishing between these two types of oscillations. Changes in Coh between the Ph and hypoglossal (XII) nerves during the transition from normal eupnic breathing to gasping have not been characterized.