Anja Hayen

Dyspnoea and the brain

Chronic dyspnoea is a devastating symptom that debilitates millions of people worldwide. It causes a large burden on both patient and carer, and significant costs to society and health services. Treatment options are limited. Much effort has been directed at optimising lung function and improving exercise capacity, however, the brain mechanisms underlying dyspnoea perception have received less attention. In this review, we focus on cognitive and affective aspects of dyspnoea and discuss how novel neuroimaging methods can provide quantitative measures of these subjective sensations. We draw parallels with the more advanced field of chronic pain, and explain some of the challenges faced when imaging dyspnoea. To date, brain mechanisms of dyspnoea have been investigated in a handful of studies by a limited number of authors. These have found consistent activation in the insular cortex, the anterior cingulate cortex and the amygdala. Novel neuroimaging methods and an improved understanding of perceptual mechanisms underlying dyspnoea now position us to transform dyspnoea research. Future research should investigate how brain regions associated with dyspnoea interact, as well as accurately correlate this neuronal activation with reliable behavioural measures. A better understanding of the brain processes underlying dyspnoea perception will lead to new therapies that will improve quality of life for a very large group of patients.

Opposing roles of nucleus accumbens core and shell dopamine in the modulation of limbic information processing

The dopaminergic innervation of the nucleus accumbens (NAc) is implicated in the selection and integration of motivationally relevant corticolimbic information that governs behavioral output. However, it is unknown whether the dopaminergic innervations of two anatomically distinct subregions of the NAc, core and shell, have differential roles in this gating process, and whether dopaminergic mechanisms are important in regulating the balance of limbic control over appetitive behavior at the point of learning. Having previously shown that repeated systemic pretreatment with amphetamine disrupts the regulation of competing limbic control over appetitive behavior in mice, we hereby examined the effects of repeated pretraining intra-NAc shell or core microinfusions of d-amphetamine, general dopamine (DA) receptor antagonist cis-flupenthixol, or vehicle solution (saline) upon a simultaneously acquired conditioned cue and place preference task in rats. Repeated infusions of amphetamine into the NAc shell and core had opposite effects on the acquisition of conditioned place preference by significantly enhancing and attenuating, respectively, hippocampal-dependent place conditioning. In contrast, direct infusions of flupenthixol into the NAc shell attenuated place conditioning, while NAc core flupenthixol infusions not only attenuated cue conditioning, but also enhanced conditioned place preference. These findings implicate the NAc shell DA as being necessary for enabling hippocampal-dependent spatial information to gain control over appetitive learning, and the NAc core DA as being important for allowing basolateral amygdala-dependent information to gain control over appetitive learning. It is further proposed that NAc core DA may be critical in regulating limbic information flow through the NAc shell.

Understanding dyspnea as a complex individual experience

Dyspnea is the highly threatening experience of breathlessness experienced by patients with diverse pathologies, including respiratory, cardiovascular, and neuromuscular diseases, cancer and panic disorder. This debilitating symptom is especially prominent in the elderly and the obese, two growing populations in the Western world. It has further been found that women suffer more strongly from dyspnea than men. Despite optimization of disease-specific treatments, dyspnea is often inadequately treated. The immense burden faced by patients, families and the healthcare system makes improving management of chronic dyspnea a priority. Dyspnea is a multidimensional sensation that encompasses an array of unpleasant respiratory sensations that vary according to underlying cause and patient characteristics. Biopsychological factors beyond disease pathology exacerbate the perception of dyspnea, increase symptom severity and reduce quality of life. Psychological state (especially comorbid anxiety and depression), hormone status, gender, body weight (obesity) and general fitness level are particularly important. Neuroimaging has started to uncover the neural mechanisms involved in the processing of sensory and affective components of dyspnea. Awareness of biopsychological factors beyond pathology is essential for diagnosis and treatment of dyspnea. Increasing understanding the interactions between biopsychological factors and dyspnea perception will enhance the development of symptomatic treatments that specifically address each patients most pressing needs at a specific stage in life. Future neuroimaging research can provide objective markers to fully understand the role of biopsychological factors in the perception of dyspnea in the hope of uncovering target areas for pharmacologic and non-pharmacologic therapy.

Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia.

Although recent diagnostic criteria for Alzheimers disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta‐analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies.

Dyspnea-Related Cues Engage the Prefrontal Cortex: Evidence From Functional Brain Imaging in COPD

BACKGROUND: Dyspnea is the major source of disability in COPD. In COPD, environmental cues (eg, the prospect of having to climb stairs) become associated with dyspnea and may trigger dyspnea even before physical activity commences. We hypothesized that brain activation relating to such cues would be different between patients with COPD and healthy control subjects, reflecting greater engagement of emotional mechanisms in patients. METHODS: Using functional MRI (FMRI), we investigated brain responses to dyspnea-related word cues in 41 patients with COPD and 40 healthy age-matched control subjects. We combined these findings with scores on self-report questionnaires, thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enabled identification of brain networks responsible for pain processing despite absence of a physical challenge. RESULTS: Patients with COPD demonstrated activation in the medial prefrontal cortex and anterior cingulate cortex, which correlated with the visual analog scale (VAS) response to word cues. This activity independently correlated with patient responses on questionnaires of depression, fatigue, and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex, and precuneus correlated with the VAS dyspnea scale but not with the questionnaires. CONCLUSIONS: The findings suggest that engagement of the emotional circuitry of the brain is important for interpretation of dyspnea-related cues in COPD and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and the findings suggest that such mechanisms may be relevant in COPD.

The effects of altered intrathoracic pressure on resting cerebral blood flow and its response to visual stimulation

Investigating how intrathoracic pressure changes affect cerebral blood flow (CBF) is important for a clear interpretation of neuroimaging data in patients with abnormal respiratory physiology, intensive care patients receiving mechanical ventilation and in research paradigms that manipulate intrathoracic pressure. Here, we investigated the effect of experimentally increased and decreased intrathoracic pressures upon CBF and the stimulus-evoked CBF response to visual stimulation. Twenty healthy volunteers received intermittent inspiratory and expiratory loads (plus or minus 9 cmH2O for 270 s) and viewed an intermittent 2 Hz flashing checkerboard, while maintaining stable end-tidal CO2. CBF was recorded with transcranial Doppler sonography (TCD) and whole-brain pseudo-continuous arterial spin labeling magnetic resonance imaging (PCASL MRI). Application of inspiratory loading (negative intrathoracic pressure) showed an increase in TCD-measured CBF of 4% and a PCASL-measured increase in grey matter CBF of 5%, but did not alter mean arterial pressure (MAP). Expiratory loading (positive intrathoracic pressure) did not alter CBF, while MAP increased by 3%. Neither loading condition altered the perfusion response to visual stimulation in the primary visual cortex. In both loading conditions localized CBF increases were observed in the somatosensory and motor cortices, and in the cerebellum. Altered intrathoracic pressures, whether induced experimentally, therapeutically or through a disease process, have possible significant effects on CBF and should be considered as a potential systematic confound in the interpretation of perfusion-based neuroimaging data.

Opioid suppression of conditioned anticipatory brain responses to breathlessness

Abstract Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low‐dose remifentanil (0.7 ng/ml target‐controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil‐induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness. HighlightsThe mechanisms of how low‐dose opioids relieve breathlessness are unknown.We tested whether low‐dose opioids affect conditioned anticipation and perception of breathlessness.Low‐dose opioids reduced unpleasantness, but not intensity of breathlessness.Reduced breathlessness unpleasantness was associated with activation of the endogenous opioid system.Breathlessness relief was predicted by decreased anticipatory activity in amygdala/hippocampus.

Development of a dyspnoea word cue set for studies of emotional processing in COPD.

Highlights • The first cue-based task to explore recall of dyspnoea and dyspnoea-related anxiety in COPD.• Patients’ dyspnoea and dyspnoea-anxiety ratings agreed with established measures of dyspnoea.• Patients’ dyspnea-anxiety ratings changed in accordance with clinical improvement.• The task was reliable and well tolerated.• The task is suitable for FMRI use and may aid dyspnoea neuroimaging research.

Opposing roles of prelimbic and infralimbic dopamine in conditioned cue and place preference.

RationaleIncreasing evidence points to the prelimbic (PL) and infralimbic (IL) cortices of the medial prefrontal cortex (mPFC) and their dopaminergic innervations subserving opposing roles in the regulation of instrumental behavior. However, it is at present unclear if they hold similar roles in the regulation of Pavlovian learning.ObjectiveThe present study investigated the role of the dopaminergic innervations of the PL and IL in the modulation of Pavlovian appetitive cue and place conditioning, previously shown to be dependent on the basolateral amygdala and hippocampus, respectively.MethodsRats received preconditioning microinfusions of d-amphetamine, cis-flupenthixol, or vehicle solution directly into the PL or IL and were trained to simultaneously acquire conditioned cue and place preference in a radial maze.ResultsPreconditioning blockade of dopamine neurotransmission in the PL and amphetamine microinfusions in the IL had the same effect of attenuating place conditioning. In contrast, place conditioning remained intact following preconditioning amphetamine microinfusions in the PL and dopamine receptor blockade in the IL. Instead, conditioned cue preference was attenuated following IL dopamine receptor blockade.ConclusionThese data indicate that PL dopaminergic mechanisms are critical for the acquisition of appetitive place learning, while IL dopamine may oppose the influence of PL dopamine upon hippocampal-dependent learning. Furthermore, they implicate a functional reciprocity between mPFC and associated subregions of the nucleus accumbens in the regulation of limbic information processing.

Subjective evaluation of experimental dyspnoea--effects of isocapnia and repeated exposure.

Highlights • Functional neuroimaging is poised to understand brain processing of dyspnoea.• Experimental dyspnoea alters PaCO2, which confounds FMRI contrast.• Experimentally stabilizing CO2 had minimal effects on perception of respiratory loads.• No perceptual habituation to resistive loads occurred over four experimental sessions.