Breathlessness in COPD: linking symptom clusters with brain activity

Rationale: Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. Methods: A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain-behaviour-breathlessness links. Results: We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared to the high symptom load group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). Conclusions: This is the largest functional neuroimaging study of COPD to date and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multi-modal models of breathlessness in identifying behavioural phenotypes, and for advancing understanding of differences in breathlessness burden

Characterisation of the material and mechanical properties of atomic force microscope cantilevers with a plan-view trapezoidal geometry

Cantilever devices have found applications in numerous scientific fields and instruments, including the atomic force microscope (AFM), and as sensors to detect a wide range of chemical and biological species. The mechanical properties, in particular, the spring constant of these devices is crucial when quantifying adhesive forces, material properties of surfaces, and in determining deposited mass for sensing applications. A key component in the spring constant of a cantilever is the plan-view shape. In recent years, the trapezoidal plan-view shape has become available since it offers certain advantages to fast-scanning AFM and can improve sensor performance in fluid environments. Euler beam equations relating cantilever stiffness to the cantilever dimensions and Young’s modulus have been proven useful and are used extensively to model cantilever mechanical behaviour and calibrate the spring constant. In this work, we derive a simple correction factor to the Euler beam equation for a beam-shaped cantilever that is applicable to any cantilever with a trapezoidal plan-view shape. This correction factor is based upon previous analytical work and simplifies the application of the previous researchers formula. A correction factor to the spring constant of an AFM cantilever is also required to calculate the torque produced by the tip when it contacts the sample surface, which is also dependent on the plan-view shape. In this work, we also derive a simple expression for the torque for triangular plan-view shaped cantilevers and show that for the current generation of trapezoidal plan-view shaped AFM cantilevers, this will be a good approximation. We shall apply both these correction factors to determine Young’s modulus for a range of trapezoidal-shaped AFM cantilevers, which are specially designed for fast-scanning. These types of AFM probes are much smaller in size when compared to standard AFM probes. In the process of analysing the mechanical properties of these cantilevers, important insights are also gained into their spring constant calibration and dimensional factors that contribute to the variability in their spring constant.Ashley D. Slattery, Adam J. Blanch, Cameron J. Shearer, Andrew J. Stapleton, Renee V. Goreham, Sarah L. Harmer, Jamie S. Quinton, and Christopher T. Gibso

The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens

Repeated exposure to cocaine increases the density of dendritic spines on medium spiny neurons in the nucleus accumbens (Acb) and pyramidal cells in the medial prefrontal cortex (mPFC). To determine if this is associated with the development of psychomotor sensitization, rats were given daily i.p. injections of 15 mg/kg of cocaine (or saline) for 8 days, either in their home cage (which failed to induce significant psychomotor sensitization) or in a distinct and relatively novel test cage (which induced robust psychomotor sensitization). Their brains were obtained 2 weeks after the last injection and processed for Golgi–Cox staining. In the Acb core (AcbC) cocaine treatment increased spine density only in the group that developed psychomotor sensitization (i.e. in the Novel but not Home group), and there was a significant positive correlation between the degree of psychomotor sensitization and spine density. In the Acb shell (AcbS) cocaine increased spine density to the same extent in both groups; i.e. independent of psychomotor sensitization. In the mPFC cocaine increased spine density in both groups, but to a significantly greater extent in the Novel group. Furthermore, when rats were treated at Home with a higher dose of cocaine (30 mg/kg), cocaine now induced psychomotor sensitization in this context, and also increased spine density in the AcbC. Thus, the context in which cocaine is experienced influences its ability to reorganize patterns of synaptic connectivity in the Acb and mPFC, and the induction of psychomotor sensitization is associated with structural plasticity in the AcbC and mPFC, but not the AcbS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73532/1/j.1460-9568.2004.03612.x.pd

Isolation rearing-induced facilitation of Pavlovian learning: Abolition by postsession intra-amygdala nafadotride

It has been shown previously in this laboratory that rats reared in social isolation acquire a Pavlovian-conditioned approach task much more rapidly than their respective controls. This study assessed the involvement specifically of the mesoamygdaloid dopamine pathway in this facilitated learning of isolates. Thus, animals were required to associate arbitrary stimuli with a pulsed light stimulus (unconditioned stimulus, US). The US, while without biological significance, was nevertheless capable of eliciting an intrinsic and sustained alerting response. Procedures ensured that the arbitrary stimuli (tone or clicker) did not elicit a response in the first instance, and were presented either paired (CS+) or unpaired (CS-) with the US. Isolates and socially reared controls received intra-amygdala infusions of the D3 dopamine receptor antagonist, L-nafadotride, or vehicle immediately following the end of each training session. The conditioned response increased over sessions in both groups of vehicle-infused rats during presentations of the CS+ stimulus, but not CS-, and isolates acquired this association more rapidly than controls. However, acquisition of this association was abolished by postsession intra-amygdala L-nafadotride. Responding to the US was largely unaffected by drug or rearing conditions. Hence, these data provide strong evidence for the specific involvement of the mesoamygdaloid dopamine projection in the facilitation of associative learning by isolation rearing. © 2002 Elsevier Science Inc. All rights reserved

Blockade of sensitisation-induced facilitation of appetitive conditioning by post-session intra-amygdala nafadotride

Prior -amphetamine experience has been reported to enhance appetitive Pavlovian conditioning. The present study assessed the involvement of the mesoamygdaloid dopamine projection in this effect. Bilateral post-session intra-amygdala infusions of the D3 dopamine receptor antagonist, -nafadotride, or vehicle were given during acquisition of a Pavlovian association in sensitised and unsensitised rats. During these sessions, subjects received presentations of a stimulus (CS+) paired with 10% sucrose availability. A second stimulus (CS−) was also presented but never paired with sucrose. Sensitised animals infused post-session with vehicle acquired a Pavlovian conditioned approach response during CS+ presentations more rapidly than controls, as we have shown previously. However, post-session intra-amygdala -nafadotride selectively retarded conditioned responding to the CS+ in both groups of animals, abolishing the difference between sensitised and unsensitised rats. These results, therefore, extend the evidence for the involvement of the mesoamygdaloid dopamine projection in Pavlovian conditioning, and the facilitation of associative learning following sensitisation

A single administration of microbial D-alanine to healthy volunteers augments reaction to negative emotions: a comparison with D-serine

Health and self-regulatio