Expectation violation and attention to pain jointly modulate neural gain in somatosensory cortex

The neural processing and experience of pain are influenced by both expectations and attention. For example, the amplitude of event-related pain responses is enhanced by both novel and unexpected pain, and by moving the focus of attention towards a painful stimulus. Under predictive coding, this congruence can be explained by appeal to a precision-weighting mechanism, which mediates bottom-up and top-down attentional processes by modulating the influence of feedforward and feedback signals throughout the cortical hierarchy. The influence of expectation and attention on pain processing can be mapped onto changes in effective connectivity between or within specific neuronal populations, using a canonical microcircuit (CMC) model of hierarchical processing. We thus implemented a CMC within dynamic causal modelling for magnetoencephalography in human subjects, to investigate how expectation violation and attention to pain modulate intrinsic (within-source) and extrinsic (between-source) connectivity in the somatosensory hierarchy. This enabled us to establish whether both expectancy and attentional processes are mediated by a similar precision-encoding mechanism within a network of somatosensory, frontal and parietal sources. We found that both unexpected and attended pain modulated the gain of superficial pyramidal cells in primary and secondary somatosensory cortex. This modulation occurred in the context of increased lateralized recurrent connectivity between somatosensory and fronto-parietal sources, driven by unexpected painful occurrences. Finally, the strength of effective connectivity parameters in S1, S2 and IFG predicted individual differences in subjective pain modulation ratings. Our findings suggest that neuromodulatory gain control in the somatosensory hierarchy underlies the influence of both expectation violation and attention on cortical processing and pain perception

Delta and gamma oscillations in operculo-insular cortex underlie innocuous cold thermosensation

Cold-sensitive and nociceptive neural pathways interact to shape the quality and intensity of thermal and pain perception. Yet the central processing of cold thermosensation in the human brain has not been extensively studied. Here, we used magnetoencephalography and EEG in healthy volunteers to investigate the time course (evoked fields and potentials) and oscillatory activity associated with the perception of cold temperature changes. Nonnoxious cold stimuli consisting of Δ3°C and Δ5°C decrements from an adapting temperature of 35°C were delivered on the dorsum of the left hand via a contact thermode. Cold-evoked fields peaked at around 240 and 500 ms, at peak latencies similar to the N1 and P2 cold-evoked potentials. Importantly, cold-related changes in oscillatory power indicated that innocuous thermosensation is mediated by oscillatory activity in the range of delta (1–4 Hz) and gamma (55–90 Hz) rhythms, originating in operculo-insular cortical regions. We suggest that delta rhythms coordinate functional integration between operculo-insular and frontoparietal regions, while gamma rhythms reflect local sensory processing in operculo-insular areas

Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent GWAS. We found that pQTLs for genes encoding ITIM/ITAM family members were more frequently associated with AD than those for non-ITIM/ITAM genes. Further testing of one family member, SIGLEC14 which encodes an ITAM, uncovered substantial copy number variations, identified an SNP as a proxy for gene deletion, and found that gene expression correlates significantly with gene deletion. We also found that SIGLEC14 deletion increases the expression of SIGLEC5, an ITIM. We conclude that many genes in this ITIM/ITAM family likely impact AD risk, and that complex genetics including copy number variation, opposing function of encoded proteins, and coupled gene expression may mask these AD risk associations at the genome-wide level

Anterior insula coordinates hierarchical processing of tactile mismatch responses

The body underlies our sense of self, emotion, and agency. Signals arising from the skin convey warmth, social touch, and the physical characteristics of external stimuli. Surprising or unexpected tactile sensations can herald events of motivational salience, including imminent threats (e.g., an insect bite) and hedonic rewards (e.g., a caressing touch). Awareness of such events is thought to depend upon the hierarchical integration of body-related mismatch responses by the anterior insula. To investigate this possibility, we measured brain activity using functional magnetic resonance imaging, while healthy participants performed a roving tactile oddball task. Mass-univariate analysis demonstrated robust activations in limbic, somatosensory, and prefrontal cortical areas previously implicated in tactile deviancy, body awareness, and cognitive control. Dynamic Causal Modelling revealed that unexpected stimuli increased the strength of forward connections along a caudal to rostral hierarchy-projecting from thalamic and somatosensory regions towards insula, cingulate and prefrontal cortices. Within this ascending flow of sensory information, the AIC was the only region to show increased backwards connectivity to the somatosensory cortex, augmenting a reciprocal exchange of neuronal signals. Further, participants who rated stimulus changes as easier to detect showed stronger modulation of descending PFC to AIC connections by deviance. These results suggest that the AIC coordinates hierarchical processing of tactile prediction error. They are interpreted in support of an embodied predictive coding model where AIC mediated body awareness is involved in anchoring a global neuronal workspace

Improving Community Health through Hospital-Public Health Collaboration: Insights and Lessons Learned from Successful Partnerships

From the introduction: Health care expenditures in the United States currently consume over 17 percent of the nation’s gross domestic product, a much larger share than other developed nations. Yet, despite this large investment, studies by Commonwealth Fund, the Institute of Medicine, and other organizations show the USA lags behind other developed nations on multiple metrics of population health such as infant mortality and life expectancy. Moreover, there is extensive evidence of disparities in access, cost, and quality of health care services. Thus, we are confronted by a striking paradox: the USA spends a large and growing proportion of our resources on health care, but the outcomes in terms of access to services, the quality of those services, and the health of our population do not match other countries whose spending per capita is lower. It is evident that many factors contribute to this paradox — demographic, environmental, genetic, lifestyle, and socioeconomic — and all warrant societal attention. Improving access to outpatient and inpatient medical services and the quality of those services, while important, cannot resolve the paradox. Across the country, there is growing awareness that restraining the increase in health expenditures and improving the health status of families, communities, and society at large will require a broader approach that addresses the full array of factors affecting health status. Greater attention and resources must be devoted to promoting a safer environment, healthy lifestyles, prevention of illnesses and injuries, and early detection and treatment of health problems, as well as dealing with the underlying determinants of health. This approach necessitates integrating basic principles of public health into organizing and delivering health and medical services.https://uknowledge.uky.edu/hsm_book/1001/thumbnail.jp

Double layer SiO2–TiO2 sol–gel thin films on glass for antireflection, antifogging, and UV recoverable self-cleaning

Double layer thin films, mechanically stable and adhering to glass, were produced through the sol–gel process, using tetraethyl orthosilicate and titanium butoxide as precursors. The refractive index of the titania and silica– titania composite layers were typically 2.1 and 1.7, and their physical thicknesses were approximately 65 nm and 81 nm, respectively, as determined by ellipsometry. These optical constants allowed attainment of quarterwave optical thicknesses at the center of the visible spectrum (550 nm) as designed, with an increase of 3.4% in transmittance. The nanometric surface roughness, measured by optical profilometry, was effective to decrease light scattering and water contact angles to below 10◦ . As novelty in dip-coated sol–gel films, superhydrophilicity for self-cleaning, antifogging, and antireflection in the mid-visible spectrum were simultaneously attained with durability of 9 weeks in the dark. Further application of UV light allowed regeneration of contact angles for self-cleaning

Genetic variants and functional pathways associated with resilience to Alzheimer\u27s disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer\u27s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer\u27s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values \u3c 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values \u3c 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer\u27s disease (P-values \u3e 0.42) nor associated with APOE (P-values \u3e 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer\u27s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Crowdsourced estimation of cognitive decline and resilience in Alzheimer's disease

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET)

Background Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. Methods This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. Discussion Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered 25/06/2019 in EudraCT (2019-000942-36)