Hypoxia evokes a sequence of raphe-pontomedullary network operations for inspiratory drive amplification and gasping.

Hypoxia can trigger a sequence of breathing-related behaviors, from tachypnea to apneusis to apnea and gasping, an autoresuscitative behavior that, via large tidal volumes and altered intrathoracic pressure, can enhance coronary perfusion, carotid blood flow, and sympathetic activity, and thereby coordinate cardiac and respiratory functions. We tested the hypothesis that hypoxia-evoked gasps are amplified through a disinhibitory microcircuit within the inspiratory neuron chain and a distributed efference copy mechanism that generates coordinated gasp-like discharges concurrently in other circuits of the raphe-pontomedullary respiratory network. Data were obtained from 6 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated adult cats. Arterial blood pressure, phrenic nerve activity, end-tidal CO2, and other parameters were monitored. Hypoxia was produced by ventilation with a gas mixture of 5% O2 in nitrogen (N2). Neuron spike trains were recorded at multiple pontomedullary sites simultaneously and evaluated for firing rate modulations and short-time scale correlations indicative of functional connectivity. Experimental perturbations evoked reconfiguration of raphe-pontomedullary circuits during tachypnea, apneusis and augmented bursts, apnea, and gasping. The functional connectivity, altered firing rates, efference copy of gasp drive, and coordinated step increments in blood pressure reported here support a distributed brain stem network model for amplification and broadcasting of inspiratory drive during autoresuscitative gasping that begins with a reduction in inhibition by expiratory neurons and an initial loss of inspiratory drive during hypoxic apnea.

Blood pressure drives multispectral tuning of inspiration via a linked-loop neural network.

The respiratory motor pattern is coordinated with cardiovascular system regulation. Inspiratory drive and respiratory phase durations are tuned by blood pressure and baroreceptor reflexes. We hypothesized that perturbations of systemic arterial blood pressure modulate inspiratory drive through a raphe-pontomedullary network. In 15 adult decerebrate vagotomized neuromuscular-blocked cats, we used multielectrode arrays to record the activities of 704 neurons within the medullary ventral respiratory column, pons, and raphe areas during baroreceptor-evoked perturbations of breathing, as measured by altered peak activity in integrated efferent phrenic nerve activity and changes in respiratory phase durations. Blood pressure was transiently (30 s) elevated or reduced by inflations of an embolectomy catheter in the descending aorta or inferior vena cava. S-transform time-frequency representations were calculated for multiunit phrenic nerve activity and some spike trains to identify changes in rhythmic activity during perturbations. Altered firing rates in response to either or both conditions were detected for 474 of 704 tested cells. Spike trains of 17,805 neuron pairs were evaluated for short-time scale correlational signatures indicative of functional connectivity with standard cross-correlation analysis, supplemented with gravitational clustering; ∼70% of tested (498 of 704) and responding neurons (333 of 474) were involved in a functional correlation with at least one other cell. Changes in high-frequency oscillations in the spiking of inspiratory neurons and the evocation or resetting of slow quasi-periodic fluctuations in the respiratory motor pattern associated with oscillations of arterial pressure were observed. The results support a linked-loop pontomedullary network architecture for multispectral tuning of inspiration.NEW & NOTEWORTHY The brain network that supports cardiorespiratory coupling remains poorly understood. Using multielectrode arrays, we tested the hypothesis that blood pressure and baroreceptor reflexes "tune" the breathing motor pattern via a raphe-pontomedullary network. Neuron responses to changes in arterial pressure and identified functional connectivity, together with altered high frequency and slow Lundberg B-wave oscillations, support a model with linked recurrent inhibitory loops that stabilize the respiratory network and provide a path for transmission of baroreceptor signals.

Access to Allied Health Care Services in Canadian Interdisciplinary Complex Nerve Injury Programs.

Nerve transfer surgery for patients with nerve and spinal cord injuries can result in dramatic functional improvements. As a result, interdisciplinary complex nerve injury programs (CNIPs) have been established in many Canadian centers, providing electrodiagnostic and surgical consultations in a single encounter. We sought to determine which allied health care services are included in Canadian CNIPs, at the 3rd Annual Canadian Peripheral Nerve Symposium. Twenty CNIPs responded to a brief survey and reported access as follows: occupational therapy = 60%, physiotherapy = 40%, social work = 20%, and mental health = 10%. Access to allied health services is variable in CNIPs across Canada, possibly resulting in heterogeneity in patient care.

Central Respiration and Mechanical Ventilation in the Gating of Swallow With Breathing.

Swallow-breathing coordination safeguards the lower airways from tracheal aspiration of bolus material as it moves through the pharynx into the esophagus. Impaired movements of the shared muscles or structures of the aerodigestive tract, or disruptions in the interaction of brainstem swallow and respiratory central pattern generators (CPGs) result in dysphagia. To maximize lower airway protection these CPGs integrate respiratory rhythm generation signals and vagal afferent feedback to synchronize swallow with breathing. Despite extensive study, the roles of central respiratory activity and vagal feedback from the lungs as key elements for effective swallow-breathing coordination remain unclear. The effect of altered timing of bronchopulmonary vagal afferent input on swallows triggered during electrical stimulation of the superior laryngeal nerves or by injection of water into the pharyngeal cavity was studied in decerebrate, paralyzed, and artificially ventilated cats. We observed two types of single swallows that produced distinct effects on central respiratory-rhythm across all conditions: post-inspiratory type swallows disrupted central-inspiratory activity without affecting expiration, whereas expiratory type swallows prolonged expiration without affecting central-inspiratory activity. Repetitive swallows observed during apnea reset the E2 phase of central respiration and produced facilitation of swallow motor output nerve burst durations. Moreover, swallow initiation was negatively modulated by vagal feedback and was reset by lung inflation. Collectively, these findings support a novel model of reciprocal inhibition between the swallow CPG and inspiratory or expiratory cells of the respiratory CPG where lung distension and phases of central respiratory activity represent a dual peripheral and central gating mechanism of swallow-breathing coordination.

Upper Extremity Functional Status of Female Youth Softball Pitchers Using the Kerlan-Jobe Orthopaedic Clinic Questionnaire.

BACKGROUND: Softball is a popular sport with a high incidence of upper extremity injuries. The Kerlan-Jobe Orthopaedic Clinic (KJOC) questionnaire is a validated performance and functional assessment tool used in overhead athletes. Upper extremity pain patterns and baseline KJOC scores have not been reported for active female youth softball pitchers. PURPOSE/HYPOTHESIS: The purpose of this study was to establish the prevalence of upper extremity pain and its effect in female youth softball pitchers over a competitive season. We hypothesized that participants who missed time due to injury in the past year would have lower KJOC scores. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Fifty-three female softball pitchers aged 12 to 18 years were recruited from softball clinics in Vancouver, British Columbia, Canada. All participants self-identified as a pitcher on a competitive travel team. Participants were administered the KJOC questionnaire before and during the playing season. Missed time due to injury in the past year, current pain patterns, and KJOC scores were primary outcomes. RESULTS: The mean (±SD) preseason KJOC score was 87.2 ± 10.6. In the preseason, 22.6% of pitchers reported playing with arm trouble, and 32.1% missed time due to injury in the past year. The mean KJOC score for pitchers reporting a previous injury (n = 17) was significantly lower compared with those without an injury (n = 36) (79.5 ± 13.8 vs 90.9 ± 6.2, respectively; P = .02). The posterior shoulder was the most commonly reported pain location. For the cohort completing the questionnaire both before and during the playing season (n = 35), mean KJOC scores did not change significantly over the playing season (P = .64). Lower preseason KJOC scores were significantly related to the in-season injury risk (P = .016). Pitchers with a preseason score of less than 90 had a 3.5 (95% CI, 1.1-11.2) times greater risk of reporting an in-season injury. CONCLUSION: Female youth softball pitchers have a high baseline functional status. However, 1 in 3 pitchers reported missed time due to injury in the previous year, and shoulder pain was more prevalent than elbow pain. The KJOC questionnaire can be used by coaches, researchers, and clinicians to identify youth softball pitchers at risk for injuries who may benefit from interventions.

Impact of Critical Illness Polyneuromyopathy in Rehabilitation: A Prospective Observational Study.

BACKGROUND: Critical illness polyneuromyopathy (CIPNM) increasingly is recognized as a source of disability in patients requiring intensive care unit (ICU) admission. The prevalence and impact of CIPNM on patients in the rehabilitation setting has not been established. OBJECTIVES: To determine the proportion of at-risk rehabilitation inpatients with evidence of CIPNM and the functional sequelae of this disorder. DESIGN: Prospective observational study. SETTING: Tertiary academic rehabilitation hospital. PATIENTS: Rehabilitation inpatients with a history of ICU admission for at least 72 hours. METHODS: Electrodiagnostic studies were performed to evaluate for axonal neuropathy and/or myopathy in at least one upper and one lower limb. MAIN OUTCOME MEASUREMENTS: The primary outcome was prevalence of CIPNM. Secondary outcomes included Functional Independence Measure (FIM) scores, rehabilitation length of stay (RLOS), and discharge disposition. RESULTS: A total of 33 participants were enrolled; 70% had evidence of CIPNM. Admission FIM score, discharge FIM, FIM gain, and FIM efficiency were 64.1, 89.9, 25.5, and 0.31 in those with CIPNM versus 78.4, 94.6, 16.1, and 0.33 in those without CIPNM, respectively. Average RLOS was 123 days versus 76 days and discharge to home was 57% versus 90% in the CIPNM and non-CIPNM groups, respectively. CONCLUSIONS: CIPNM is very common in rehabilitation inpatients with a history of ICU admission. It was associated with a lower functional status at rehabilitation admission, but functional improvement was at a similar rate to those without CIPNM. Longer RLOS stay may be required to achieve the same functional level. LEVEL OF EVIDENCE: III.

Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations.

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius (p-NTS)-medial medulla, the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphe nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for postinspiratory neuron inhibition of rostral VRC I-Driver (pre-Bötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive pericolumnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL-pF neurons with functional links to widespread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns. NEW & NOTEWORTHY We tested the long-standing hypothesis that carotid chemoreceptors tune the frequency and depth of breathing through parallel circuit operations targeting the ventral respiratory column. Responses to stimulation of the chemoreceptors and identified functional connectivity support differential tuning of inspiratory neuron burst duration and firing rate and a model of brain stem network architecture incorporating tonic expiratory "hub" neurons regulated by convergent neuronal chains and loops through rostral lateral tegmental field neurons with quasi-periodic discharge patterns.

Systematic review of adjunct therapies to improve outcomes following botulinum toxin injection for treatment of limb spasticity.

OBJECTIVE: To determine the quality of evidence from randomized controlled trials on the efficacy of adjunct therapies following botulinum toxin injections for limb spasticity. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials electronic databases were searched for English language human studies from 1980 to 21 May 2015. STUDY SELECTION: Randomized controlled trials assessing adjunct therapies postbotulinum toxin injection for treatment of spasticity were included. Of the 268 studies screened, 17 met selection criteria. DATA EXTRACTION: Two reviewers independently assessed risk of bias using the Physiotherapy Evidence Database (PEDro) scale and graded according to Sackett's levels of evidence. DATA SYNTHESIS: Ten adjunct therapies were identified. Evidence suggests that adjunct use of electrical stimulation, modified constraint-induced movement therapy, physiotherapy (all Level 1), casting and dynamic splinting (both Level 2) result in improved Modified Ashworth Scale scores by at least 1 grade. There is Level 1 and 2 evidence that adjunct taping, segmental muscle vibration, cyclic functional electrical stimulation, and motorized arm ergometer may not improve outcomes compared with botulinum toxin injections alone. There is Level 1 evidence that casting is better than taping, taping is better than electrical stimulation and stretching, and extracorporeal shock wave therapy is better than electrical stimulation for outcomes including the Modified Ashworth Scale, range of motion and gait. All results are based on single studies. CONCLUSION: There is high level evidence to suggest that adjunct therapies may improve outcomes following botulinum toxin injection. No results have been confirmed by independent replication. All interventions would benefit from further study.

Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea.

Hyperventilation is a common feature of disordered breathing. Apnea ensues if CO2 drive is sufficiently reduced. We tested the hypothesis that medullary raphé, ventral respiratory column (VRC), and pontine neurons have functional connectivity and persistent or evoked activities appropriate for roles in the suppression of drive and rhythm during hyperventilation and apnea. Phrenic nerve activity, arterial blood pressure, end-tidal CO2, and other parameters were monitored in 10 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated cats. Multielectrode arrays recorded spiking activity of 649 neurons. Loss and return of rhythmic activity during passive hyperventilation to apnea were identified with the S-transform. Diverse fluctuating activity patterns were recorded in the raphé-pontomedullary respiratory network during the transition to hypocapnic apnea. The firing rates of 160 neurons increased during apnea; the rates of 241 others decreased or stopped. VRC inspiratory neurons were usually the last to cease firing or lose rhythmic activity during the transition to apnea. Mayer wave-related oscillations (0.04-0.1 Hz) in firing rate were also disrupted during apnea. Four-hundred neurons (62%) were elements of pairs with at least one hyperventilation-responsive neuron and a correlational signature of interaction identified by cross-correlation or gravitational clustering. Our results support a model with distinct groups of chemoresponsive raphé neurons contributing to hypocapnic apnea through parallel processes that incorporate disfacilitation and active inhibition of inspiratory motor drive by expiratory neurons. During apnea, carotid chemoreceptors can evoke rhythm reemergence and an inspiratory shift in the balance of reciprocal inhibition via suppression of ongoing tonic expiratory neuron activity.

A joint computational respiratory neural network-biomechanical model for breathing and airway defensive behaviors.

Data-driven computational neural network models have been used to study mechanisms for generating the motor patterns for breathing and breathing related behaviors such as coughing. These models have commonly been evaluated in open loop conditions or with feedback of lung volume simply represented as a filtered version of phrenic motor output. Limitations of these approaches preclude assessment of the influence of mechanical properties of the musculoskeletal system and motivated development of a biomechanical model of the respiratory muscles, airway, and lungs using published measures from human subjects. Here we describe the model and some aspects of its behavior when linked to a computational brainstem respiratory network model for breathing and airway defensive behavior composed of discrete "integrate and fire" populations. The network incorporated multiple circuit paths and operations for tuning inspiratory drive suggested by prior work. Results from neuromechanical system simulations included generation of a eupneic-like breathing pattern and the observation that increased respiratory drive and operating volume result in higher peak flow rates during cough, even when the expiratory drive is unchanged, or when the expiratory abdominal pressure is unchanged. Sequential elimination of the model's sources of inspiratory drive during cough also suggested a role for disinhibitory regulation via tonic expiratory neurons, a result that was subsequently supported by an analysis of in vivo data. Comparisons with antecedent models, discrepancies with experimental results, and some model limitations are noted.

Central chemoreceptor modulation of breathing via multipath tuning in medullary ventrolateral respiratory column circuits.

Ventrolateral respiratory column (VRC) circuits that modulate breathing in response to changes in central chemoreceptor drive are incompletely understood. We employed multielectrode arrays and spike train correlation methods to test predictions of the hypothesis that pre-Bötzinger complex (pre-BötC) and retrotrapezoid nucleus/parafacial (RTN-pF) circuits cooperate in chemoreceptor-evoked tuning of ventral respiratory group (VRG) inspiratory neurons. Central chemoreceptors were selectively stimulated by injections of CO(2)-saturated saline into the vertebral artery in seven decerebrate, vagotomized, neuromuscularly blocked, and artificially ventilated cats. Among sampled neurons in the Bötzinger complex (BötC)-to-VRG region, 70% (161 of 231) had a significant change in firing rate after chemoreceptor stimulation, as did 70% (101 of 144) of the RTN-pF neurons. Other responsive neurons (24 BötC-VRG; 11 RTN-pF) had a change in the depth of respiratory modulation without a significant change in average firing rate. Seventy BötC-VRG chemoresponsive neurons triggered 189 offset-feature correlograms (96 peaks; 93 troughs) with at least one responsive BötC-VRG cell. Functional input from at least one RTN-pF cell could be inferred for 45 BötC-VRG neurons (19%). Eleven RTN-pF cells were correlated with more than one BötC-VRG target neuron, providing evidence for divergent connectivity. Thirty-seven RTN-pF neurons, 24 of which were chemoresponsive, were correlated with at least one chemoresponsive BötC-VRG neuron. Correlation linkage maps and spike-triggered averages of phrenic nerve signals suggest transmission of chemoreceptor drive via a multipath network architecture: RTN-pF modulation of pre-BötC-VRG rostral-to-caudal excitatory inspiratory neuron chains is tuned by feedforward and recurrent inhibition from other inspiratory neurons and from "tonic" expiratory neurons.

Botulinum toxin injection for management of thoracic outlet syndrome: a double-blind, randomized, controlled trial.

We studied the effect of botulinum toxin type A (BTX-A) injections to the scalene muscles on pain in subjects with thoracic outlet syndrome (TOS) in this double-blind, randomized, parallel group trial with follow-up at 6 weeks, 3 months, and 6 months. Thirty-eight patients referred to physiatrists for management of TOS with BTX-A injection were included. One subject was lost to follow-up and all other subjects completed the trial. A 75-unit dose of BTX-A reconstituted with 0.75 cc of normal saline was injected to the anterior scalene (37.5 units) and middle scalene (37.5 units) muscles using electromyographic guidance. The primary outcome measure was pain as measured on a horizontal visual analog scale (VAS) 6 weeks-post-injection. Secondary outcomes were paresthesias measured on a VAS and function measured with the Disabilities of the Arm, Shoulder and Hand (DASH) and Short-form 36 (SF-36) questionnaires. For the primary outcome measure of VAS scores for pain at 6 weeks, the difference in the means adjusted for baseline VAS scores between placebo and BTX-A was 5.03 mm in favor of BTX-A (95% confidence interval -15.7 to 5.7, P=.36). Changes in secondary outcome measures were also not statistically significant. We conclude that BTX-A injections to the scalene muscles did not result in clinically or statistically significant improvements in pain, paresthesias, or function in this population of subjects with TOS.

Central and peripheral chemoreceptors evoke distinct responses in simultaneously recorded neurons of the raphé-pontomedullary respiratory network.

The brainstem network for generating and modulating the respiratory motor pattern includes neurons of the medullary ventrolateral respiratory column (VRC), dorsolateral pons (PRG) and raphé nuclei. Midline raphé neurons are proposed to be elements of a distributed brainstem system of central chemoreceptors, as well as modulators of central chemoreceptors at other sites, including the retrotrapezoid nucleus. Stimulation of the raphé system or peripheral chemoreceptors can induce a long-term facilitation of phrenic nerve activity; central chemoreceptor stimulation does not. The network mechanisms through which each class of chemoreceptor differentially influences breathing are poorly understood. Microelectrode arrays were used to monitor sets of spike trains from 114 PRG, 198 VRC and 166 midline neurons in six decerebrate vagotomized cats; 356 were recorded during sequential stimulation of both receptor classes via brief CO(2)-saturated saline injections in vertebral (central) and carotid arteries (peripheral). Seventy neurons responded to both stimuli. More neurons were responsive only to peripheral challenges than those responsive only to central chemoreceptor stimulation (PRG, 20 : 4; VRC, 41 : 10; midline, 25 : 13). Of 16 474 pairs of neurons evaluated for short-time scale correlations, similar percentages of reference neurons in each brain region had correlation features indicative of a specific interaction with at least one target neuron: PRG (59.6%), VRC (51.0%) and raphé nuclei (45.8%). The results suggest a brainstem network architecture with connectivity that shapes the respiratory motor pattern via overlapping circuits that modulate central and peripheral chemoreceptor-mediated influences on breathing.