Neurocognitive evidence for mental imagery-driven hypoalgesic and hyperalgesic pain regulation

Mental imagery has the potential to influence perception by directly altering sensory, cognitive, and affective brain activity associated with imagined content. While it is well established that mental imagery can both exacerbate and alleviate acute and chronic pain, it is currently unknown how imagery mechanisms regulate pain perception. For example, studies to date have been unable to determine whether imagery effects depend upon a general redirection of attention away from pain or focused attentional mechanisms. To address these issues, we recorded subjective, behavioral and ERP responses using 64-channel EEG while healthy human participants applied a mental imagery strategy to decrease or increase pain sensations. When imagining a glove covering the forearm, participants reported decreased perceived intensity and unpleasantness, classified fewer high-intensity stimuli as painful, and showed a more conservative response bias. In contrast, when imagining a lesion on the forearm, participants reported increased pain intensity and unpleasantness, classified more lowintensity stimuli as painful, and displayed a more liberal response bias. Using a mass-univariate approach,we further showed differential modulation of the N2 potentials across conditions, with inhibition and facilitation respectively increasing and decreasing N2 amplitudes between 122 and 180 ms. Within this time window, source localization associated inhibiting vs. facilitating pain with neural activity in cortical regions involved in cognitive inhibitory control and in the retrieval of semantic information (i.e., right inferior frontal and temporal regions). In contrast, the main sources of neural activity associatedwith facilitating vs. inhibiting pain were identified in cortical regions typically implicated in salience processing and emotion regulation (i.e., left insular, inferior-middle frontal, supplementary motor and precentral regions). Overall, these findings suggest that the content of a mental image directly alters pain-related decision and evaluative processing to flexibly produce hypoalgesic and hyperalgesic outcomes

Influence of body position, emotions, placebo and cognitive modulation on pain experience and pain-related somatosensory ERPs

The present work contributed to our understanding of the neurocognitive mechanisms underlying pain modulation through sensory, attentional, emotional and cognitive processes. We used subjective, behavioral, and electrophysiological indexes to reveal the effects of body position, emotions, placebo expectations and cognitive reappraisal on subjective pain experience and pain-related somatosensory potentials. Four studies were conducted to investigate different forms of pain modulation. Study 1 tested the hypothesis that the horizontal body position reduces pain perception and cortical pain processing. We demonstrated that the supine vs. sitting body position was associated with dampened perception of non-painful stimuli and inhibited cortical late processing (300-600 ms) of non-painful and painful stimuli, related to neural activity within frontal right regions (anterior cingulate cortex and superior frontal gyrus). Study 2 investigated gender differences in the emotional modulation of pain. Although males and females did not differ at the behavioral level and reported reduced pain ratings only during the visual perception of erotic pictures, striking gender differences emerged in the N2 and P2 potentials, elicited by painful stimuli. Males showed inhibited cortical processing of pain stimuli when viewing erotic pictures only, whereas females showed a differentiated cortical pain modulation for each emotional content took into consideration (erotic vs. sport/adventure vs. neutral vs. fear/threat vs. mutilation pictures), in particular for N2 potentials. In Study 3, we examine the role of individual beliefs on the effectiveness of a traditional and a homeopathic analgesic treatment. We utilized a deceptive paradigm, i.e., neither the participants nor the experimenters were aware that the administered treatment was an inert substance. We found that only the participants who took a treatment that was coherent with their beliefs showed a reduced cortical pain processing, indicated by dampened P2 amplitudes. Finally, Study 4 demonstrated that healthy participants are able to modify their pain experience using an imaginary-based reappraisal strategy. Perceived pain intensity and unpleasantness were either reduced or enhanced with respect to a neutral condition, and an effective pain inhibition was associated with increased N2 and decreased P2 amplitude

A mechanism for spatial perception on human skin

Our perception of where touch occurs on our skin shapes our interactions with the world. Most accounts of cutaneous localisation emphasise spatial transformations from a skin-based reference frame into body-centred and external egocentric coordinates. We investigated another possible method of tactile localisation based on an intrinsic perception of ‘skin space’. The arrangement of cutaneous receptive fields (RFs) could allow one to track a stimulus as it moves across the skin, similarly to the way animals navigate using path integration. We applied curved tactile motions to the hands of human volunteers. Participants identified the location midway between the start and end points of each motion path. Their bisection judgements were systematically biased towards the integrated motion path, consistent with the characteristic inward error that occurs in navigation by path integration. We thus showed that integration of continuous sensory inputs across several tactile RFs provides an intrinsic mechanism for spatial perception

Beyond labeled lines: A population coding account of the thermal grill illusion

Heat and pain illusions (synthetic heat and the thermal grill illusion) can be generated by simultaneous cold and warm stimulation on the skin at temperatures that would normally be perceived as innocuous in isolation. Historically, two key questions have dominated the literature: which specific pathway conveys the illusory perceptions of heat and pain, and where, specifically, does the illusory pain originate in the central nervous system? Two major theories - the addition and disinhibition theories - have suggested distinct pathways, as well as specific spinal or supraspinal mechanisms. However, both theories fail to fully explain experimental findings on illusory heat and pain phenomena. We suggest that the disagreement between previous theories and experimental evidence can be solved by abandoning the assumption of one-to-one relations between pathways and perceived qualities. We argue that a population coding framework, based on distributed activity across non-nociceptive and nociceptive pathways, offers a more powerful explanation of illusory heat and pain. This framework offers new hypotheses regarding the neural mechanisms underlying temperature and pain perception

The respiratory resistance sensitivity task: An automated method for quantifying respiratory interoception and metacognition

The ability to sense, monitor, and control respiration – e.g., respiratory interoception (henceforth, respiroception) is a core homeostatic ability. Beyond the regulation of gas exchange, enhanced awareness of respiratory sensations is directly related to psychiatric symptoms such as panic and anxiety. Indeed, chronic breathlessness (dyspnea) is associated with a fourfold increase in the risk of developing depression and anxiety, and the regulation of the breath is a key aspect of many mindfulness-based approaches to the treatment of mental illness. Physiologically speaking, the ability to accurately monitor respiratory sensations is important for optimizing cardiorespiratory function during athletic exertion, and can be a key indicator of illness. Given the important role of respiroception in mental and physical health, it is unsurprising that there is increased interest in the quantification of respiratory psychophysiology across different perceptual and metacognitive levels of the psychological hierarchy. Compared to other more popular modalities of interoception, such as in the cardiac domain, there are relatively few methods available for measuring aspects of respiroception. Existing inspiratory loading tasks are difficult to administer and frequently require expensive medical equipment, or offer poor granularity in their quantification of respiratory-related perceptual ability. To facilitate the study of respiroception, we here present a new, fully automated and computer-controlled apparatus and psychophysiological method, which can flexibly and easily measure respiratory-related interoceptive sensitivity, bias and metacognition, in as little as 30 min of testing, using easy to make 3D printable parts.ISSN:0301-0511ISSN:1873-624

Cohort Profile:DOLORisk Dundee: a longitudinal study of chronic neuropathic pain

Purpose Neuropathic pain is a common disorder of the somatosensory system that affects 7%–10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.Participants DOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised ‘core’ study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later).Findings to date At baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain.Future plans The cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank

Development and external validation of multivariable risk models to predict incident and resolved neuropathic pain:a DOLORisk Dundee study

Neuropathic pain is difficult to treat, and an understanding of the risk factors for its onset and resolution is warranted. This study aimed to develop and externally validate two clinical risk models to predict onset and resolution of chronic neuropathic pain. Participants of Generation Scotland: Scottish Family Health Study (GS; general Scottish population; n = 20,221) and Genetic of Diabetes Audit and Research in Tayside Scotland (GoDARTS; n = 5236) were sent a questionnaire on neuropathic pain and followed- -up 18 months later. Chronic neuropathic pain was defined using DN4 scores (≥ 3/7) and pain for 3 months or more. The models were developed in GS using logistic regression with backward elimination based on the Akaike information criterion. External validation was conducted in GoDARTS and assessed model discrimination (ROC and Precision-Recall curves), calibration and clinical utility (decision curve analysis [DCA]). Analysis revealed incidences of neuropathic pain onset (6.0% in GS [236/3903] and 10.7% in GoDARTS [61/571]) and resolution (42.6% in GS [230/540] and 23.7% in GoDARTS [56/236]). Psychosocial and lifestyle factors were included in both onset and resolved prediction models. In GoDARTS, these models showed adequate discrimination (ROC = 0.636 and 0.699), but there was evidence of miscalibration (Intercept = − 0.511 and − 0.424; slope = 0.623 and 0.999). The DCA indicated that the models would provide clinical benefit over a range of possible risk thresholds. To our knowledge, these are the first externally validated risk models for neuropathic pain. The findings are of interest to patients and clinicians in the community, who may take preventative or remedial measures. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11478-0

Metacognitive ability correlates with hippocampal and prefrontal microstructure

The ability to introspectively evaluate our experiences to form accurate metacognitive beliefs, or insight, is an essential component of decision-making. Previous research suggests individuals vary substantially in their level of insight, and that this variation is related to brain volume and function, particularly in the anterior prefrontal cortex (aPFC). However, the neurobiological mechanisms underlying these effects are unclear, as qualitative, macroscopic measures such as brain volume can be related to a variety of microstructural features. Here we leverage a high-resolution (800 µm isotropic) multi-parameter mapping technique in 48 healthy individuals to delineate quantitative markers of in vivo histological features underlying metacognitive ability. Specifically, we examined how neuroimaging markers of local grey matter myelination and iron content relate to insight as measured by a signal-theoretic model of subjective confidence. Our results revealed a pattern of microstructural correlates of perceptual metacognition in the aPFC, precuneus, hippocampus, and visual cortices. In particular, we extend previous volumetric findings to show that right aPFC myeloarchitecture positively relates to metacognitive insight. In contrast, decreased myelination in the left hippocampus correlated with better metacognitive insight. These results highlight the ability of quantitative neuroimaging to reveal novel brainbehaviour correlates and may motivate future research on their environmental and developmental underpinnings

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele