A hermetic on-cryostat helium source for low temperature experiments.

We describe a helium source cell for use in cryogenic experiments that is hermetically sealed in situ on the cold plate of a cryostat. The source cell is filled with helium gas at room temperature and, subsequently, sealed using a cold weld crimping tool before the cryostat is closed and cooled down. At low temperatures, the helium condenses and collects in a connected experimental volume, as monitored via the frequency response of a planar superconducting resonator device sensitive to small amounts of liquid helium. This on-cryostat helium source negates the use of a filling tube between the cryogenic volumes and room temperature, thereby preventing unwanted effects such as temperature instabilities that arise from the thermomechanical motion of helium within the system. This helium source can be used in experiments investigating the properties of quantum fluids or to better thermalize quantum devices.

Medial Prefrontal Cortex Activity to Reward Outcome Moderates the Association Between Victimization Due to Sexual Orientation and Depression in Youth.

BACKGROUND: Sexual minority youth (SMY) are 3 times more likely to experience depression than heterosexual peers. Minority stress theory posits that this association is explained by sexual orientation victimization, which acts as a stressor to impact depression. For those vulnerable to the effects of stress, victimization may worsen depression by altering activity in neural reward systems. This study examines whether neural reward systems moderate the influence of sexual orientation victimization, a common and distressing experience in SMY, on depression. METHODS: A total of 81 participants ages 15 to 22 years (41% SMY, 52% marginalized race) reported sexual orientation victimization, depression severity, and anhedonia severity, and underwent a monetary reward functional magnetic resonance imaging task. Significant activation to reward > neutral outcome (pfamilywise error < .05) was determined within a meta-analytically derived Neurosynth reward mask. A univariate linear model examined the impact of reward activation and identity on victimization-depression relationships. RESULTS: SMY reported higher depression (p < .001), anhedonia (p = .03), and orientation victimization (p < .001) than heterosexual youth. The bilateral ventral striatum, medial prefrontal cortex (mPFC), anterior cingulate cortex, and right orbitofrontal cortex were significantly active to reward. mPFC activation moderated associations between sexual orientation victimization and depression (p = .03), with higher depression severity observed in those with a combination of higher mPFC activation and greater orientation victimization. CONCLUSIONS: Sexual orientation victimization was related to depression but only in the context of higher mPFC activation, a pattern observed in depressed youth. These novel results provide evidence for neural reward sensitivity as a vulnerability factor for depression in SMY, suggesting mechanisms for disparities, and are a first step toward a clinical neuroscience understanding of minority stress in SMY.

Validation of an emotional stop-signal task to probe individual differences in emotional response inhibition: Relationships with positive and negative urgency.

Performance on an emotional stop-signal task designed to assess emotional response inhibition has been associated with Negative Urgency and psychopathology, particularly self-injurious behaviors. Indeed, difficulty inhibiting prepotent negative responses to aversive stimuli on the emotional stop-signal task (i.e. poor negative emotional response inhibition) partially explains the association between Negative Urgency and non-suicidal self-injury. Here, we combine existing data sets from clinical (hospitalised psychiatric inpatients) and non-clinical (community/student participants) samples aged 18-65 years (N = 450) to examine the psychometric properties of this behavioural task and evaluate hypotheses that emotional stop-signal task metrics relate to distinct impulsive traits among participants who also completed the UPPS-P (n = 223). We specifically predicted associations between worse negative emotional response inhibition (i.e. commission errors during stop-signal trials representing negative reactions to unpleasant images) and Negative Urgency, whereas commission errors to positive stimuli - reflecting worse positive emotional response inhibition - would relate to Positive Urgency. Results support the emotional stop-signal task's convergent and discriminant validity: as hypothesised, poor negative emotional response inhibition was specifically associated with Negative Urgency and no other impulsive traits on the UPPS-P. However, we did not find the hypothesised association between positive emotional response inhibition and Positive Urgency. Correlations between emotional stop-signal task performance and self-report measures were the modest, similar to other behavioural tasks. Participants who completed the emotional stop-signal task twice (n = 61) additionally provide preliminary evidence for test-retest reliability. Together, findings suggest adequate reliability and validity of the emotional stop-signal task to derive candidate behavioural markers of neurocognitive functioning associated with Negative Urgency and psychopathology.

Emotional Response Inhibition: A Shared Neurocognitive Deficit in Eating Disorder Symptoms and Nonsuicidal Self-Injury.

Eating disorder (ED) symptoms often co-occur with non-suicidal self-injury (NSSI). This comorbidity is consistent with evidence that trait negative urgency increases risk for both of these phenomena. We previously found that impaired late-stage negative emotional response inhibition (i.e., negative emotional action termination or NEAT) might represent a neurocognitive mechanism for heightened negative urgency among people with NSSI history. The current study evaluated whether relations between negative urgency and ED symptoms similarly reflect deficits in this neurocognitive process. A total of 105 community adults completed an assessment of ED symptoms, negative urgency, and an emotional response inhibition task. Results indicated that, contrary to predictions, negative urgency and NEAT contributed independent variance to the prediction of ED symptoms, while controlling for demographic covariates and NSSI history. Worse NEAT was also uniquely associated with restrictive eating, after accounting for negative urgency. Our findings suggest that difficulty inhibiting ongoing motor responses triggered by negative emotional reactions (i.e., NEAT) may be a shared neurocognitive characteristic of ED symptoms and NSSI. However, negative urgency and NEAT dysfunction capture separate variance in the prediction of ED-related cognitions and behaviors, distinct from the pattern of results we previously observed in NSSI.

Symmetry, bifurcations, and chaos in a distributed respiratory control system.

A multivariate model is outlined for a distributed respiratory central pattern generator (RCPG) and its afferent control. Oscillatory behavior of the system depends on structure and symmetry of a matrix of phase-switching functions (F omega, phi) that control distribution of central excitation (CE) and inhibition (CI) within the circuit. The matrix diagonal (F omega) controls activation of CI variables as excitatory inputs are altered (e.g., central and afferent contributions to inspiratory off switch); off-diagonal terms (F phi) distribute excitations within the CI system and produce complex eigenvalues at the switching points between inspiration and expiration. For null F phi, phase switchings of saddle equilibria located at end expiration and end inspiration are overdamped all-or-nothing events; graded control of CI is seen for phi > 0. When coupling is significant (phi >> 0), CI dynamics become underdamped, admitting a domain of inputs where chaotic behavior is predictably observed. For the homogeneous RCPG (symmetric F omega, phi), CE oscillations are one-dimensional limit cycles (D = 1) or weakly chaotic (D approximately equal to 1). When perturbations from symmetry are significant, the distributed RCPG becomes partitioned where strongly chaotic oscillations (D > or = 2) and central apnea (D = 0) are seen more frequently. The equations provide means for mapping Silnikov bifurcations that alter the geometry and dimension of the breathing pattern and formalisms for discussing RCPG processing of afferent information.

Geometry of respiratory phase switching.

A second-order ordinary differential equation is outlined for the temporal dynamics of the respiratory central pattern generator (RCPG). Recurrent interactions between central excitation and inhibition confine the breathing cycle to the interior of a heteroclinic orbit between switching points (saddle equilibria) located at end expiration (E-I) and end inspiration (I-E). Dynamics depend on four eigenvalues that control inspiratory drive (lambda), excitability of inspiratory off switch (omega 1; stage 1 expiration), rate of central excitation disinhibition (omega 2; stage 2 expiration), and damping of the oscillator (epsilon). Ratios omega 2/lambda and omega 1/lambda determine local E-I and I-E phase switching, whereas inspiratory-to-expiratory balance varies as omega 2/(lambda omega 1). Stable apnea is seen when (lambda omega 2)/epsilon is near zero; inspiratory apneusis is seen when (lambda omega 1)/epsilon is low. The equations provide formalisms for discussing phase switching, apneas, apneuses, phase resetting and singularities, rapid shallow breathing, postinhibitory rebound excitation, redundancy, gating within the RCPG, and behavioral control of breathing. The model is offered as an explicit alternative to the harmonic oscillator models that have been used in the past to describe RCPG function.

Nonlinear systems identification: autocorrelation vs. autoskewness.

Autocorrelation function (C1) or autoregressive model parameters are often estimated for temporal analysis of physiological measurements. However, statistical approximations truncated at linear terms are unlikely to be of sufficient accuracy for patients whose homeostatic control systems cannot be presumed to be stable local to a single equilibrium. Thus a quadratic variant of C1 [autoskewness function (C2)] is introduced to detect nonlinearities in an output signal as a function of time delays. By use of simulations of nonlinear autoregressive models, C2 is shown to identify only those nonlinearities that "break" the symmetry of a system, altering the mean and skewness of its outputs. Case studies of patients with cardiopulmonary dysfunction demonstrate a range of ventilatory patterns seen in the clinical environment; whereas testing of C1 reveals their breath-by-breath minute ventilation to be significantly autocorrelated, the C2 test concludes that the correlation is nonlinear and asymmetrically distributed. Higher-order functionals [e.g., autokurtosis (C3)] are necessary for global analysis of metastable systems that continuously "switch" between multiple equilibrium states and unstable systems exhibiting nonequilibrium dynamics.

Entrainment of respiration to rocking in premature infants: coherence analysis.

Vestibular influences on breathing pattern were investigated in 18 premature infants in the neonatal intensive care nursery. Respiratory abdominal movements were recorded while the babies were manually rocked at varying rates between 30 and 60 cycles/min (cpm). Coherence spectra were estimated between the respiratory and rocker signals, and their magnitudes were evaluated at the rocking frequency, with coherence spectra > 0.85 indicative of strong entrainment to rocking. At least one incident of entrainment was seen in 15 of 18 infants, with 2:1 ratios (2 breaths/rocker cycle) occurring at rocking frequencies of 30-40 cpm (8 of 18 subjects) and 1:1 entrainment at rates of 42-50 cpm (5 of 18 subjects). More complex synchronization was observed in three infants, with patterns consisting of alternans between 2:1 and 3:2 ratios (5:3 entrainment). Infants > 35 wk postconceptional age exhibited greater coherence to rocking than infants < 35 wk (P < 0.01), indicating a maturational change in the reflex may occur. Results show that the natural stimulation of rocking a newborn provides a phasic input to its respiratory pattern generator that is capable of resetting the system's oscillation and entraining its rhythm.

Vagal afferent activity increases dynamical dimension of respiration in rats.

Geometric and numerical techniques from nonlinear dynamics are employed to characterize the respiratory patterns of adult rats. In phase space constructions from volume measurements, the respiratory behavior of the vagotomized rat is seen to be unimodal and periodic, whereas that of the vagi-intact animal is bimodal and sensitive to initial conditions and displays stretching and folding of trajectories. By use of the correlation integral, the dimension and entropy were estimated for the respiratory patterns of five urethan-anesthetized rats (before and after vagotomy) and two awake animals (resting, vagi intact only). The results indicate that the central respiratory pattern of the anesthetized vagotomized rat behaves primarily as a single degree-of-freedom oscillator, which can be moved into a regime of low-order chaos in the presence of feedback from pulmonary stretch receptors, contributing significantly to the variability observed in the respiratory pattern of the vagi-intact animal. A model designed to emulate the Hering-Breuer inflation reflex demonstrates that the inspiration-inhibiting action of the reflex interacting with the oscillator at a critical phase transition is sufficient to drive the central pattern generator output into low-order chaos.

Bifurcations of the respiratory pattern associated with reduced lung volume in the rat.

Rats with intact vagal reflexes exhibit patterns of breathing that contain greater degrees of freedom than those seen after vagotomy. To determine how alterations in end-expiratory volume modify the respiratory pattern, continuous positive (CPAP) and negative (CNAP) airway pressure was applied to tracheal openings of nine urethan-anesthetized vagi-intact rats (+3 to -9 cmH2O). Phase portraits (e.g., volume vs. flow curves), power spectra, correlation integral curves, and inspiratory-to-expiratory duration (TI/TE) ratios are used to interpret the vagal-dependent responses to changes in mean tracheal pressure (Ptr). With CPAP, respiratory oscillation was highly periodic and one dimensional, with TI/TE near 1.0. As Ptr was reduced in a stepwise manner, transient bursts of inspiratory airflow developed local to the expiratory-inspiratory transition, with amplitude increasing proportionally with the level of CNAP. These oscillatory "expiratory interrupts" (doubling TI/TE in five of nine cases) produced highly variable and asymmetric respiratory patterns. Progressive increases in correlation dimension (maximum = 1.8-3.0) and tendencies toward broadband power spectra were seen as Ptr was lowered. The irregular phase-switching dynamics seen with CNAP (which disappeared after vagotomy) are consistent with onset of low-dimensional chaos, probably correlated with activation of feedback mechanisms responsive to lung deflation.

Bifurcations of the respiratory pattern produced with phasic vagal stimulation in the rat.

Geometric methods from nonlinear dynamics are employed to evaluate dynamic processing of vagal afferent information by the respiratory central pattern generator (RCPG). While measuring airflow and diaphragm EMG, we applied brief electrical stimuli (40- to 130-ms duration) to one afferent vagus of bilaterally vagotomized urethan-anesthetized rats during every breath at various phases of the respiratory cycle. Stimuli applied during early or late inspiration of every breath evoke highly predictable one-dimensional responses: reversible (graded inhibition) or irreversible (off-switching) inhibition of inspiratory activity, respectively. Stimulation during midinspiration produces higher-dimensional oscillations that wander unpredictably over a continuum of graded inhibition and off-switching; "spiral" attractors and "horseshoe" return maps at this phase are characteristic of Silnikov's bifurcation. Stimuli applied during early expiration always prolonged expiratory duration, but those delivered during midexpiration evoked unpredictable wandering between prolongations and shortening of expiratory duration. A narrow time window surrounds the expiratory-inspiratory (E-I) transition, where stimuli elicit either breaths of short duration and low amplitude (irreversible E-I transition, decreased total respiratory cycle duration) or transient bursts of inspiratory activity at the E-I transition followed by a prolonged breath (reversible E-I transition, increased total respiratory cycle duration). We conclude that RCPG "gating" of and adaptation to vagal feedback combine to produce complex breath-to-breath dynamics in the rat that are consistent with low-dimensional chaos.

Role of deflation-sensitive feedback in control of end-expiratory volume in rats.

Rats breathing from reduced end-expiratory volumes (EEV) exhibit transient bursting of inspiratory airflow local to the expiratory-inspiratory transition (E-I) accompanied by increases in inspiration-to-expiration duration ratio. Continuous positive (CPAP) and negative (CNAP) airway pressures (+3 to -9 cmH2O) were applied to tracheal openings of 17 unilaterally vagotomized rats (urethan anesthetized) to evaluate the feedback mechanisms associated with these oscillatory "expiratory interrupts." Whole nerve recordings of afferent vagus (Vag) were primarily inspiratory with CPAP. As tracheal pressure was reduced in a stepwise manner, progressive decreases in inspiratory peaks and increases in activity during late expiration were seen on Vag. Single-fiber recordings correlate Vag expiratory activity with slowly adapting receptors sensitive to lung deflation. With CNAP, 1) progressively earlier onsets of activity in inspiratory muscles (e.g., diaphragm, genioglossus, posterior cricoarytenoid) were observed (increased inspiratory duration, decreased expiratory duration); oscillations at E-I developed only when expiratory peaks on Vag were significant. 2) Thyroarytenoid muscle exhibited onset of electromyographic activity that immediately succeeded onset of Vag during late expiration. When the trachea is intact, these two actions might combine to produce a respiratory pattern similar to the "grunting" often seen in newborns breathing from reduced EEVs. In contrast to larger mammals, rats rely strongly on deflation reflexes for control of E-I phase switching, presumably to aid in maintenance of an elevated EEV.

Clinically meaningful changes in quantitative measures of asthma severity.

OBJECTIVE: To determine minimum clinically meaningful improvements in peak expiratory flow rate (PEFR) and dyspnea visual analog score (VAS) in patients with acute asthma exacerbation. METHODS: Patients presenting to the emergency department (ED) with acute asthma exacerbation were eligible. The PEFR and VAS were assessed at presentation and after initial asthma therapy. During reassessment, subjects were asked to describe their asthma symptoms as "much better," "a little better," "no change," "a little worse," or "much worse." Correspondence between self-reported improvement and changes in PEFR and VAS was assessed. The "minimum clinically significant change" in either index was defined as the difference between pre- and posttreatment measures in subjects reporting their symptoms "a little better." RESULTS: One hundred fifty-six subjects were included. Asthma symptoms were "much better" in 99 (64%), "a little better" in 41 (26%), and "unimproved" (composed of patients describing symptoms as "no change," "a little worse," or "much worse") in 16 (10%). The mean VAS change among the "a little better" subjects was 2.2 cm (95% CI = 1.1 to 3.4), significantly greater than the -0.4 cm (95% CI = -2.1 to 1.4) change in the "unimproved" subjects. The mean change in percent predicted PEFR among the "a little better" subjects was 11.9 (95% CI = 7.3 to 16.1), not statistically different from the change of 6.1 (95% CI = 1.1 to 11.3) in the "no change" subjects. The "much better" group showed significantly greater changes in both measures than either of the other groups. A VAS change of > or =0.5 cm reliably discriminated between subjects with and without symptom improvement. CONCLUSIONS: Improvements in VAS of 2.2 cm and in predicted PEFR of about 12 percentage points are minimal clinically significant improvements during ED asthma therapy. The dyspnea VAS is valid in assessing symptomatic changes and may detect small subjective improvements better than the PEFR.

Variational approaches toward nonlinear time-series analysis.

Linear autoregressive models (AR) have broad applications toward spectral analyses and digital filtering of signals, as well as identification, prediction, and control of dynamical systems. However, the symmetric Gaussian properties of linear AR presume independence between the first and second order moments of system outputs. Using nonlinear AR to quantify interactions between the mean and autocovariance of a signal, analysts can discriminate asymmetric frequency components, estimate the relative contribution of system nonlinearities toward mean output, evaluate relative structural stability of a system, and predict critical regions where bifurcations in its dynamics might occur. Quadratic analyses are performed on simulated outputs from a nonlinear model and various experimental time series (Canadian lynx population, respiratory volume dynamics in rat, Cheyne-Stokes respiration in patients with congestive heart failure, intracranial pressures in patient with cerebral hematoma). These case studies demonstrate the utility of the techniques for evaluating the qualitative behaviors of dynamical systems in the presence of slowly varying inputs.

Measuring relative acetylcholine receptor agonist binding by selective proton nuclear magnetic resonance relaxation experiments.

A method is presented that uses selective proton Nuclear Magnetic Resonance (NMR) relaxation measurements of nicotine in the presence of the acetylcholine receptor to obtain relative binding constants for acetylcholine, carbamylcholine, and muscarine. For receptors from Torpedo californica the results show that (a) the binding constants are in the order acetylcholine greater than nicotine greater than carbamylcholine greater than muscarine; (b) selective NMR measurements provide a rapid and direct method for monitoring both the specific and nonspecific binding of agonists to these receptors and to the lipid; (c) alpha-bungarotoxin can be used to distinguish between specific and nonspecific binding to the receptor; (d) the receptor--substrate interaction causes a large change in the selective relaxation time of the agonists even at concentrations 100x greater than that of the receptor. This last observation means that these measurements provide a rapid method to monitor drug binding when only small amounts of receptor are available. Furthermore, the binding strategies presented here may be useful for the NMR determination of the conformation of the ligand in its bound state.