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  • Investigation into the neural correlates of emotional augmentation of clinical pain.

    24 October 2018

    Although depressive mood is an important psychological determinate of chronic pain, the neural circuitry that mediates its influence on the pain experience is largely unknown. We used functional magnetic resonance imaging (FMRI) to investigate the neurophysiological interactions between depressive symptoms and disease-relevant pain in rheumatoid arthritis (RA) patients. RA is associated with chronic joint pain and swelling, but peripheral joint pathology often does not fully explain the amount of pain a patient experiences. We investigated the neural circuitry that relates joint pain and depressive symptoms and contrasted this with experimental heat pain. We hypothesized that (1) depressive symptoms influence the cerebral processing of provoked joint pain in RA, and (2) the interaction of depressive symptoms with pain processing contributes to the pain RA patients experience on a daily basis. Twenty patients underwent whole brain FMRI during which disease-relevant joint pain was provoked. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The tender-to-swollen joint ratio (T/S) was assessed as one component of the patients' clinical pain. BDI scores correlated significantly with T/S and medial prefrontal cortex (MPFC) activation during provoked joint pain. The association between BDI scores and T/S was partly mediated by the MPFC activation. Furthermore, the MPFC activation co-varied significantly with the FMRI signal in limbic areas and in areas that process self-relevant information. These results suggest that the MPFC may play an important role in mediating the relationship between depressive symptoms and clinical pain severity in RA, possibly by engaging brain areas important for affective and self-relevant processing.

  • Imaging attentional modulation of pain in the periaqueductal gray in humans.

    24 October 2018

    Pain is an unpleasant sensory and emotional experience usually triggered by stimulation of peripheral nerves and often associated with actual or potential tissue damage. It is well known that pain perception for patients and normal subjects can be modulated by psychological factors, such as attention, stress, and arousal. Our understanding of how this modulation occurs at a neuroanatomical level is poor. Here we neuroanatomically defined a key area in the network of brain regions active in response to pain that is modulated by attention to the painful stimulus. High-resolution functional magnetic resonance imaging was used to define brain activation to painful heat stimulation applied to the hand of nine normal subjects within the periaqueductal gray region. Subjects were asked to either focus on or distract themselves from the painful stimuli, which were cued using colored lights. During the distraction condition, subjects rated the pain intensity as significantly lower compared with when they attended to the stimulus. Activation in the periaqueductal gray was significantly increased during the distraction condition, and the total increase in activation was predictive of changes in perceived intensity. This provides direct evidence supporting the notion that the periaqueductal gray is a site for higher cortical control of pain modulation in humans.

  • Cortical processing of human somatic and visceral sensation.

    24 October 2018

    Somatic sensation can be localized precisely, whereas localization of visceral sensation is vague, possibly reflecting differences in the pattern of somatic and visceral input to the cerebral cortex. We used functional magnetic resonance imaging to study the cortical processing of sensation arising from the proximal (somatic) and distal (visceral) esophagus in six healthy male subjects. Esophageal stimulation was performed by phasic distension of a 2 cm balloon at 0.5 Hz. For each esophageal region, five separate 30 sec periods of nonpainful distension were alternated with five periods of similar duration without distension. Gradient echoplanar images depicting bold contrast were acquired using a 1.5 T GE scanner. Distension of the proximal esophagus was localized precisely to the upper chest and was represented in the trunk region of the left primary somatosensory cortex. In contrast, distension of the distal esophagus was perceived diffusely over the lower chest and was represented bilaterally at the junction of the primary and secondary somatosensory cortices. Different activation patterns were also observed in the anterior cingulate gyrus with the proximal esophagus being represented in the right midanterior cingulate cortex (BA 24) and the distal esophagus in the perigenual area (BA32). Differences in the activation of the dorsolateral prefrontal cortex and cerebellum were also observed for the two esophageal regions. These findings suggest that cortical specialization in the sensory-discriminative, affective, and cognitive areas of the cortex accounts for the perceptual differences observed between the two sensory modalities.

  • Regions of interest analysis in pharmacological fMRI: how do the definition criteria influence the inferred result?

    24 October 2018

    Prior hypotheses in functional brain imaging are often formulated by constraining the data analysis to regions of interest (ROIs). In this context, this approach yields higher sensitivity than whole brain analyses, which could be particularly important in drug development studies and clinical decision making. Here we systematically examine the effects of different ROI definition criteria on the results inferred from a hypothesis-driven pharmacological fMRI experiment, with the aim of maximising sensitivity and providing a recommended procedure for similar studies. In order to achieve this, we compared different criteria for selecting both anatomical and functional ROIs. Anatomical ROIs were defined (i) specifically for each subject, (ii) at group level, and (iii) using a Talairach-like atlas, in order to assess the effects of inter-subject anatomical variability. Functional ROIs (fROIs) were defined, both for each subject and at group level, by (i) selecting the voxels with the highest Z-score from each study session, and (ii) selecting an inclusive union of significantly active voxels across all sessions. A single value was used to summarise the response within each ROI. For anatomical ROIs we used the mean of the parameter estimates (beta values) of either all voxels or the top 20% active voxels. For fROIs we used the mean beta value of all voxels constituting the ROI. The results were assessed in terms of the achieved sensitivity in detecting the experimental effect. The use of single-subject anatomical ROIs combined with a summary value calculated from the top 20% fraction of active voxels was the most reliable and sensitive approach for detecting the experimental effect. The use of fROIs from individual sessions introduced unacceptable biases in the results, while the use of union fROIs yielded a lower sensitivity than anatomical ROIs. For these reasons, fROIs should be employed with caution when it is not possible to make clear anatomical prior hypotheses.

  • Sleep

    24 October 2018

  • The nocturnal bottleneck and the evolution of activity patterns in mammals.

    24 October 2018

    In 1942, Walls described the concept of a 'nocturnal bottleneck' in placental mammals, where these species could survive only by avoiding daytime activity during times in which dinosaurs were the dominant taxon. Walls based this concept of a longer episode of nocturnality in early eutherian mammals by comparing the visual systems of reptiles, birds and all three extant taxa of the mammalian lineage, namely the monotremes, marsupials (now included in the metatherians) and placentals (included in the eutherians). This review describes the status of what has become known as the nocturnal bottleneck hypothesis, giving an overview of the chronobiological patterns of activity. We review the ecological plausibility that the activity patterns of (early) eutherian mammals were restricted to the night, based on arguments relating to endothermia, energy balance, foraging and predation, taking into account recent palaeontological information. We also assess genes, relating to light detection (visual and non-visual systems) and the photolyase DNA protection system that were lost in the eutherian mammalian lineage. Our conclusion presently is that arguments in favour of the nocturnal bottleneck hypothesis in eutherians prevail.

  • Evolution and functional characterisation of melanopsins in a deep-sea chimaera (elephant shark, Callorhinchus milii).

    24 October 2018

    Non-visual photoreception in mammals is primarily mediated by two splice variants that derive from a single melanopsin (OPN4M) gene, whose expression is restricted to a subset of retinal ganglion cells. Physiologically, this sensory system regulates the photoentrainment of many biological rhythms, such as sleep via the melatonin endocrine system and pupil constriction. By contrast, melanopsin exists as two distinct lineages in non-mammals, opn4m and opn4x, and is broadly expressed in a wide range of tissue types, including the eye, brain, pineal gland and skin. Despite these findings, the evolution and function of melanopsin in early vertebrates are largely unknown. We, therefore, investigated the complement of opn4 classes present in the genome of a model deep-sea cartilaginous species, the elephant shark (Callorhinchus milii), as a representative vertebrate that resides at the base of the gnathostome (jawed vertebrate) lineage. We reveal that three melanopsin genes, opn4m1, opn4m2 and opn4x, are expressed in multiple tissues of the elephant shark. The two opn4m genes are likely to have arisen as a result of a lineage-specific duplication, whereas "long" and "short" splice variants are generated from a single opn4x gene. By using a heterologous expression system, we suggest that these genes encode functional photopigments that exhibit both "invertebrate-like" bistable and classical "vertebrate-like" monostable biochemical characteristics. We discuss the evolution and function of these melanopsin pigments within the context of the diverse photic and ecological environments inhabited by this chimaerid holocephalan, as well as the origin of non-visual sensory systems in early vertebrates.

  • Melanopsin phototransduction: slowly emerging from the dark.

    24 October 2018

    Melanopsin expressing retinal ganglion cells represent a third class of ocular photoreceptors and are involved in irradiance detection and non-image-forming responses to light including pupil constriction, circadian entrainment, and regulation of sleep. Over recent years, there has been a rapid increase in our understanding of the anatomical variety of pRGC subtypes, the regions of the brain which they innervate, and the behavioral responses of melanopsin-based light detection. However, by contrast, our understanding of the intracellular signaling cascade initiated following activation of melanopsin has, until recently, remained poorly characterized. This chapter focus on the melanopsin signaling pathway, detailing the cellular mechanisms of phototransduction that occur within pRGCs, highlighting recent advances, but also the gaps in our understanding of this important light detecting system.

  • Differential expression of melanopsin isoforms Opn4L and Opn4S during postnatal development of the mouse retina.

    24 October 2018

    Photosensitive retinal ganglion cells (pRGCs) respond to light from birth and represent the earliest known light detection system to develop in the mouse retina. A number of morphologically and functionally distinct subtypes of pRGCs have been described in the adult retina, and have been linked to different physiological roles. We have previously identified two distinct isoforms of mouse melanopsin, Opn4L and Opn4S, which are generated by alternate splicing of the Opn4 locus. These isoforms are differentially expressed in pRGC subtypes of the adult mouse retina, with both Opn4L and Opn4S detected in M1 type pRGCs, and only Opn4L detected in M2 type pRGCs. Here we investigate the developmental expression of Opn4L and Opn4S and show a differential profile of expression during postnatal development. Opn4S mRNA is detected at relatively constant levels throughout postnatal development, with levels of Opn4S protein showing a marked increase between P0 and P3, and then increasing progressively over time until adult levels are reached by P10. By contrast, levels of Opn4L mRNA and protein are low at birth and show a marked increase at P14 and P30 compared to earlier time points. We suggest that these differing profiles of expression are associated with the functional maturation of M1 and M2 subtypes of pRGCs. Based upon our data, Opn4S expressing M1 type pRGCs mature first and are the dominant pRGC subtype in the neonate retina, whereas increased expression of Opn4L and the maturation of M2 type pRGCs occurs later, between P10 and P14, at a similar time to the maturation of rod and cone photoreceptors. We suggest that the distinct functions associated with these cell types will develop at different times during postnatal development.