Opioids depress cortical centers responsible for the volitional control of respiration

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem

Sub-cortical and brainstem sites associated with chemo-stimulated increases in ventilation in humans

We investigated the neural basis for spontaneous chemo-stimulated increases in ventilation in awake, healthy humans. Blood oxygen level dependent (BOLD) functional MRI was performed in nine healthy subjects using T2weighted echo planar imaging. Brain volumes (52 transverse slices, cortex to high spinal cord) were acquired every 3.9 s. The 30 min paradigm consisted of six, 5-min cycles, each cycle comprising 45 s of hypoxic-isocapnia, 45 s of isooxic-hypercapnia and 45 s of hypoxic-hypercapnia, with 55 s of non-stimulatory hyperoxic-isocapnia (control) separating each stimulus period. Ventilation was significantly (p < 0.001) increased during hypoxic-isocapnia, isooxic-hypercapnia and hypoxic-hypercapnia (17.0, 13.8, 24.9 L/min respectively) vs. control (8.4 L/min) and was associated with significant (p < 0.05, corrected for multiple comparisons) signal increases within a bilateral network that included the basal ganglia, thalamus, red nucleus, cerebellum, parietal cortex, cingulate and superior mid pons. The neuroanatomical structures identified provide evidence for the spontaneous control of breathing to be mediated by higher brain centres, as well as respiratory nuclei in the brainstem

Diversity in olfactory bulb size in birds reflects allometry, ecology, and phylogeny

The relative size of olfactory bulbs (OBs) is correlated with olfactory capabilities across vertebrates and is widely used to assess the relative importance of olfaction to a species’ ecology. In birds, variations in the relative size of OBs are correlated with some behaviors; however, the factors that have led to the high level of diversity seen in OB sizes across birds are still not well understood. In this study, we use the relative size of OBs as a neuroanatomical proxy for olfactory capabilities in 135 species of birds, representing 21 orders. We examine the scaling of OBs with brain size across avian orders, determine likely ancestral states and test for correlations between OB sizes and habitat, ecology, and behavior. The size of avian OBs varied with the size of the brain and this allometric relationship was for the most part isometric, although species did deviate from this trend. Large OBs were characteristic of more basal species and in more recently derived species the OBs were small. Living and foraging in a semiaquatic environment was the strongest variable driving the evolution of large OBs in birds; olfaction may provide cues for navigation and foraging in this otherwise featureless environment. Some of the diversity in OB sizes was also undoubtedly due to differences in migratory behavior, foraging strategies and social structure. In summary, relative OB size in birds reflect allometry, phylogeny and behavior in ways that parallel that of other vertebrate classes. This provides comparative evidence that supports recent experimental studies into avian olfaction and suggests that olfaction is an important sensory modality for all avian species

Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis

Michael McGuckin and colleagues identify two mutations that cause aberrant mucin oligomerization in mice. The resulting phenotype, including endoplasmic reticulum stress, resembles clinical and pathologic features of human ulcerative colitis

Mapping of the cerebral vascular response to hypoxia and hypercapnia using quantitative perfusion MRI at 3 T

Changes in breathing change the concentration of oxygen and carbon dioxide in arterial blood resulting in changes in cerebral blood flow (CBF). This mechanism can be described by the cerebral vascular response (CVR), which has been shown to be altered in different physiological and pathophysiological states. CBF maps of grey matter (GM) were determined with a pulsed arterial spin labelling technique at 3 T in a group of 19 subjects under baseline conditions, hypoxia, and hypercapnia. Experimental conditions allowed a change in either arterial oxygen (hypoxia) or carbon dioxide (hypercapnia) concentration compared with the baseline, leaving the other variable constant, in order to separate the effects of these two variables. From these results, maps were calculated showing the regional distribution of the CVR to hypoxia and hypercapnia in GM. Maps of CVR to hypoxia showed very high intra-subject variations, with some GM regions exhibiting a positive response and others a negative response. Per 10% decrease in arterial oxygen saturation, there was a statistically significant 7.0 +/- 2.9% (mean +/- SEM) increase in GM-CBF for the group. However, 70% of subjects showed an overall positive CVR (positive responders), and the remaining 30% an overall negative CVR (negative responders). Maps of CVR to hypercapnia showed less intra-subject variation. Per 1 mm Hg increase in partial pressure of end-tidal carbon dioxide, there was a statistically significant 5.8 +/- 0.9% increase in GM-CBF, all subjects showing an overall positive CVR. As the brain is particularly vulnerable to hypoxia, a condition associated with cardiorespiratory diseases, CVR maps may help in the clinic to identify the areas most prone to damage because of a reduced CVR

A bilateral cortico-bulbar network associated with breath holding in humans, determined by functional magnetic resonance imaging

Few tasks are simpler to perform than a breath hold; however, the neural basis underlying this voluntary inhibitory behaviour, which must suppress spontaneous respiratory motor output, is unknown. Here, using blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI), we investigated the neural network responsible for volitional breath holding in 8 healthy humans. BOLD images of the whole brain (156 brain volumes, voxel resolution 3 × 3 × 3 mm) were acquired every 5.2 s. All breath holds were performed for 15 s at resting expiratory lung volume when respiratory musculature was presumed to be relaxed, which ensured that the protocol highlighted the inhibitory components underlying the breath hold. An experimental paradigm was designed to dissociate the time course of the whole-brain BOLD signal from the time course of the local, neural-related BOLD signal associated with the inhibitory task. We identified a bilateral network of cortical and subcortical structures including the insula, basal ganglia, frontal cortex, parietal cortex and thalamus, which are in common with response inhibition tasks, and in addition, activity within the pons. From these results we speculate that the pons has a role in integrating information from supra-brainstem structures, and in turn it exerts an inhibitory effect on medullary respiratory neurones to inhibit breathing during breath holding

Microwave Tomography for Brain Imaging: Feasibility Assessment for Stroke Detection

There is a need for a medical imaging technology, that supplements current clinical brain imaging techniques, for the near-patient and mobile assessment of cerebral vascular disease. Microwave tomography (MWT) is a novel imaging modality that has this potential. The aim of the study was to assess the feasibility, and potential performance characteristics, of MWT for brain imaging with particular focus on stroke detection. The study was conducted using MWT computer simulations and 2D head model with stroke. A nonlinear Newton reconstruction approach was used. The MWT imaging of deep brain tissues presents a significant challenge, as the brain is an object of interest that is located inside a high dielectric contrast shield, comprising the skull and CSF. However, high performance, nonlinear MWT inversion methods produced biologically meaningful images of the brain including images of stroke. It is suggested that multifrequency MWT has the potential to significantly improve imaging results

Regional cerebrovascular responses to hypercapnia and hypoxia

A limited number of studies using differing imaging approaches suggest that there are regional variation in the cerebrovascular response to hypercapnia and hypoxia. However there are limitations to these studies. In particular, it is not clear if existing studies of hypoxia have fully accounted for the confounding effects of the changes in arterial PCO2 on cerebral perfusion that, if uncontrolled, will accompany the hypoxic stimulus. We determined quantitative maps of grey matter cerebral blood flow using a multi-slice pulsed arterial spin labelling MRI method at 3 T at rest, during conditions of isocapnic euoxia, hypercapnia, and mild isocapnic hypoxia. From these data, we determined grey matter cerebrovascular reactivity maps which show the spatial distribution of the responses to these interventions. Whilst, overall, cerebral perfusion increased with hypercapnia and hypoxia, hypoxia cerebrovascular reactivity maps showed very high variation both within and between individuals: most grey matter regions exhibiting a positive cerebrovascular reactivity, but some exhibiting a negative reactivity. The physiological explanation for this variation remains unclear and it is not known if these local differences will vary with state or with regional brain activity. The potential interaction between hypoxic or hypercapnic cerebrovascular changes and neurally related changes in brain perfusion is of particular interest for functional imaging studies of brain activation in which arterial blood gases are altered. We have determined the interaction between global hypoxia and hypercapnia-induced blood oxygen level-dependent (BOLD) MRI signal and local neurally related BOLD signal. Although statistically significant interactions were present, physiologically the effects were weak and, in practice, they did not change the statistical outcome related to the analysis of the neurally related signals. These data suggest that such respiratory-related confounds can be successfully accounted for in functional imaging studies