Assessing Pain Research: A Narrative Review of Emerging Pain Methods, Their Technosocial Implications, and Opportunities for Multidisciplinary Approaches.

Pain research traverses many disciplines and methodologies. Yet, despite our understanding and field-wide acceptance of the multifactorial essence of pain as a sensory perception, emotional experience, and biopsychosocial condition, pain scientists and practitioners often remain siloed within their domain expertise and associated techniques. The context in which the field finds itself today-with increasing reliance on digital technologies, an on-going pandemic, and continued disparities in pain care-requires new collaborations and different approaches to measuring pain. Here, we review the state-of-the-art in human pain research, summarizing emerging practices and cutting-edge techniques across multiple methods and technologies. For each, we outline foreseeable technosocial considerations, reflecting on implications for standards of care, pain management, research, and societal impact. Through overviewing alternative data sources and varied ways of measuring pain and by reflecting on the concerns, limitations, and challenges facing the field, we hope to create critical dialogues, inspire more collaborations, and foster new ideas for future pain research methods.

Content-specific activity in frontoparietal and default-mode networks during prior-guided visual perception.

How prior knowledge shapes perceptual processing across the human brain, particularly in the frontoparietal (FPN) and default-mode (DMN) networks, remains unknown. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), we elucidated the effects that the acquisition of prior knowledge has on perceptual processing across the brain. We observed that prior knowledge significantly impacted neural representations in the FPN and DMN, rendering responses to individual visual images more distinct from each other, and more similar to the image-specific prior. In addition, neural representations were structured in a hierarchy that remained stable across perceptual conditions, with early visual areas and DMN anchored at the two extremes. Two large-scale cortical gradients occur along this hierarchy: first, dimensionality of the neural representational space increased along the hierarchy; second, prior's impact on neural representations was greater in higher-order areas. These results reveal extensive and graded influences of prior knowledge on perceptual processing across the brain.

Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations.

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.

BOLD temporal variability differentiates wakefulness from anesthesia-induced unconsciousness.

Even though a number of findings, based on information content or information integration, are shown to define neural underpinnings characteristic of a conscious experience, the neurophysiological mechanism of consciousness is still poorly understood. Here, we investigated the brain activity and functional connectivity changes that occur in the isoflurane-anesthetized unconscious state in contrast to the awake state in rats (awake and/or anesthetized, n = 68 rats). We examined nine information measures previously shown to distinguish between conscious states: blood oxygen level-dependent (BOLD) variability, functional connectivity strength, modularity, weighted modularity, efficiency, clustering coefficient, small-worldness, and spatial and temporal Lempel-Ziv complexity measure. We also identified modular membership, seed-based network connectivity, and absolute and normalized power spectrums to assess the integrity of the BOLD functional networks between awake and anesthesia. fMRI BOLD variability and related absolute power were the only information measures significantly higher during the awake state compared with isoflurane anesthesia across animals, and with varying levels of anesthesia, after correcting for motion and respiration confounds. Thus, we conclude that, at least under the specific conditions examined here, global measures of information integration/sharing do not properly distinguish the anesthetized state from wakefulness, and heightened overall, global and local, BOLD variability is the most reliable determinant of conscious brain activity relative to isoflurane anesthesia. NEW & NOTEWORTHY Multiple metrics previously suggested to be able to distinguish between states of consciousness were compared, within and across rats in awake and isoflurane anesthesia-induced unconsciousness. All measures tested showed sensitivity to confounds, correcting for motion and for respiration changes due to anesthesia. Resting state local BOLD variability and the related absolute power were the only information measures that robustly differentiated wakefulness states. These results caution against the general applicability of global information measures in identifying levels of consciousness, thus challenging the popular concept that these measures reflect states of consciousness, and also pointing to local signal variability as a more reliable indicator of states of wakefulness.

Initial-state-dependent, robust, transient neural dynamics encode conscious visual perception.

Recent research has identified late-latency, long-lasting neural activity as a robust correlate of conscious perception. Yet, the dynamical nature of this activity is poorly understood, and the mechanisms governing its presence or absence and the associated conscious perception remain elusive. We applied dynamic-pattern analysis to whole-brain slow (< 5 Hz) cortical dynamics recorded by magnetoencephalography (MEG) in human subjects performing a threshold-level visual perception task. Up to 1 second before stimulus onset, brain activity pattern across widespread cortices significantly predicted whether a threshold-level visual stimulus was later consciously perceived. This initial state of brain activity interacts nonlinearly with stimulus input to shape the evolving cortical activity trajectory, with seen and unseen trials following well separated trajectories. We observed that cortical activity trajectories during conscious perception are fast evolving and robust to small variations in the initial state. In addition, spontaneous brain activity pattern prior to stimulus onset also influences unconscious perceptual making in unseen trials. Together, these results suggest that brain dynamics underlying conscious visual perception belongs to the class of initial-state-dependent, robust, transient neural dynamics.

Unconsciously elicited perceptual prior.

Increasing evidence over the past decade suggests that vision is not simply a passive, feed-forward process in which cortical areas relay progressively more abstract information to those higher up in the visual hierarchy, but rather an inferential process with top-down processes actively guiding and shaping perception. However, one major question that persists is whether such processes can be influenced by unconsciously perceived stimuli. Recent psychophysics and neuroimaging studies have revealed that while consciously perceived stimuli elicit stronger responses in higher visual and frontoparietal areas than those that fail to reach conscious awareness, the latter can still drive high-level brain and behavioral responses. We investigated whether unconscious processing of a masked natural image could facilitate subsequent conscious recognition of its degraded counterpart (a black-and-white "Mooney" image) presented many seconds later. We found that this is indeed the case, suggesting that conscious vision may be influenced by priors established by unconscious processing of a fleeting image.

Corticolimbic anatomical characteristics predetermine risk for chronic pain.

SEE TRACEY DOI101093/BRAIN/AWW147 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Mechanisms of chronic pain remain poorly understood. We tracked brain properties in subacute back pain patients longitudinally for 3 years as they either recovered from or transitioned to chronic pain. Whole-brain comparisons indicated corticolimbic, but not pain-related circuitry, white matter connections predisposed patients to chronic pain. Intra-corticolimbic white matter connectivity analysis identified three segregated communities: dorsal medial prefrontal cortex-amygdala-accumbens, ventral medial prefrontal cortex-amygdala, and orbitofrontal cortex-amygdala-hippocampus. Higher incidence of white matter and functional connections within the dorsal medial prefrontal cortex-amygdala-accumbens circuit, as well as smaller amygdala volume, represented independent risk factors, together accounting for 60% of the variance for pain persistence. Opioid gene polymorphisms and negative mood contributed indirectly through corticolimbic anatomical factors, to risk for chronic pain. Our results imply that persistence of chronic pain is predetermined by corticolimbic neuroanatomical factors.

Identifying brain nociceptive information transmission in patients with chronic somatic pain.

INTRODUCTION: Recent advances regarding mechanisms of chronic pain emphasize the role of corticolimbic circuitry in predicting risk for chronic pain, independently from site of injury-related parameters. These results compel revisiting the role of peripheral nociceptive signaling in chronic pain. We address this issue by examining what brain circuitry transmit information regarding the intensity of chronic pain and how this information may be related to a common co-morbidity, depression. METHODS: Resting state functional MRI was used in a large group of chronic pain patients (n=40 chronic back pain, CBP, and n=44 osteoarthritis, OA patients), and in comparison to healthy subjects (n=88). We used a graph theoretical measure, degree count, to investigate voxel-wise information sharing/transmission in the brain. Degree count, a functional connectivity based measure, identifies the number of voxels functionally connected to every given voxel. Subdividing the chronic pain cohort into discovery, replication, and also for overall group we show that only degree counts of diencephalic voxels centered in the ventral lateral thalamus reflected intensity of chronic pain, independently of depression. RESULTS: Pain intensity was reliably associated with degree count of the thalamus, which was correlated negatively with components of the default mode network and positively with the periaqueductal grey (in contrast to healthy controls). Depression scores were not reliably associated with regional degree count. CONCLUSION: Collectively the results suggest that, across two types of chronic pain, nociceptive specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pro-nociceptive descending modulation, and interrupting cortical cognitive processes.

Aggrecan is required for growth plate cytoarchitecture and differentiation.

The proteoglycan aggrecan is a prominent component of the extracellular matrix in growth plate cartilage. A naturally occurring, recessive, perinatally lethal mutation in the aggrecan core protein gene, cmd(bc) (Acan(cmd-Bc)), that deletes the entire protein-coding sequence provided a model in which to characterize the phenotypic and morphologic effects of aggrecan deletion on skeletal development. We also generated a novel transgenic mouse, Tg(COL2A1-ACAN), that has the chick ACAN coding sequence driven by the mouse COL2A1 promoter to enable the production of cmd(bc)/cmd(bc); Tg(COL2A1-ACAN) rescue embryos. These were used to assess the impact of aggrecan on growth plate organization, chondrocyte survival and proliferation, and the expression of mRNAs encoding chondrocyte differentiation markers and growth factors. Homozygous mutant (cmd(bc)/cmd(bc)) embryos exhibited severe defects in all skeletal elements with deformed and shortened (50%) limb elements. Expression of aggrecan in rescue embryos reversed the skeletal defects to varying degrees with a 20% increase in limb element length and near-full reversal (80%) of size and diameter of the ribcage and vertebrae. Aggrecan-null growth plates were devoid of matrix and lacked chondrocyte organization and differentiation, while those of the rescue embryos exhibited matrix production concomitant with partial zonation of chondrocytes having proliferative and hypertrophic morphologies. Deformation of the trachea, likely the cause of the mutation's lethality, was reduced in the rescue embryos. Aggrecan-null embryos also had abnormal patterns of COL10A1, SOX9, IHH, PTCH1, and FGFR3 mRNA expression in the growth plate. Expression of chick aggrecan in the rescue embryos notably increased COLX expression, accompanied by the reappearance of a hypertrophic zone and IHH expression. Significantly, in transgenic rescue embryos, the cell death and decreased proliferation phenotypes exhibited by the mutants were reversed; both were restored to wild-type levels. These findings suggest that aggrecan has a major role in regulating the expression of key growth factors and signaling molecules during development of cartilaginous tissue and is essential for proper chondrocyte organization, morphology, and survival during embryonic limb development.

Risky monetary behavior in chronic back pain is associated with altered modular connectivity of the nucleus accumbens.

BACKGROUND: The nucleus accumbens (NAc) has a well established role in reward processing. Yet, there is growing evidence showing that NAc function, and its connections to other parts of the brain, is also critically involved in the emergence of chronic back pain (CBP). Pain patients are known to perform abnormally in reward-related tasks, which suggests an intriguing link between pain, NAc connectivity, and reward behavior. In the present study, we compared performance on a gambling task (indicating willingness to risk losing money) between healthy pain-free controls (CON) and individuals with CBP. We then measured modular connectivity of each participants' NAc with resting state functional MRI to investigate how connectivity accounts for reward behavior in the presence and absence of pain. RESULTS: We found gain sensitivity was significantly higher in CBP patients. These scores were significantly correlated to connectivity within the NAc module defined by CON subjects ( which had strong connections to the frontal cortex), but not within that defined by CBP patients ( which was more strongly connected to subcortical areas). An important part of our study was based on the precedence that a range of behaviors, from simple to complex, can be predicted from brain activity during rest. Thus, to corroborate our results we compared them closely to an independent study correlating the same connectivity metric to impulsive behaviors in healthy participants. We found that our CBP patients were highly similarin connectivity to this study's highly-impulsive healthy subjects, strengthening the notion that there is an important link between the brain systems that support chronic pain and reward processing. CONCLUSIONS: Our results support previous findings that chronic back pain is accompanied by altered connectivity of the NAc. This lends itself to riskier behavior in these patients, a finding which establishes a potential cognitive consequence or co-morbidity of long-term pain and provides a behavioral link to growing research showing that chronic pain is related to abnormal changes in the dopaminergic system.

Anatomical and functional assemblies of brain BOLD oscillations.

Brain oscillatory activity has long been thought to have spatial properties, the details of which are unresolved. Here we examine spatial organizational rules for the human brain oscillatory activity as measured by blood oxygen level-dependent (BOLD) signal. Resting-state BOLD signal was transformed into frequency space (Welch's method) and averaged across subjects, and its spatial distribution was studied as a function of four frequency bands, spanning the full BOLD bandwidth. The brain showed anatomically constrained distribution of power for each frequency band. This result was replicated on a repository dataset of 195 subjects. Next, we examined larger-scale organization by parceling the neocortex into regions approximating Brodmann areas (BAs). This indicated that BAs of simple function/connectivity (unimodal), versus complex properties (transmodal), are dominated by low-frequency BOLD oscillations, and within the visual ventral stream we observe a graded shift of power to higher-frequency bands for BAs further removed from the primary visual cortex (increased complexity), linking BOLD frequency properties to hodology. Additionally, BOLD oscillation properties for the default mode network demonstrated that it is composed of distinct frequency-dependent regions. When the same analysis was performed on a visual-motor task, frequency-dependent global and voxelwise shifts in BOLD oscillations could be detected at brain sites mostly outside those identified with general linear modeling. Thus, analysis of BOLD oscillations in full bandwidth uncovers novel brain organizational rules, linking anatomical structures and functional networks to characteristic BOLD oscillations. The approach also identifies changes in brain intrinsic properties in relation to responses to external inputs.

Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate.

In contrast to the functional role of heparan sulfate proteoglycans (HSPGs), the importance of chondroitin sulfate proteoglycans (CSPGs) in modulating signaling pathways involving hedgehog proteins, wingless-related proteins and fibroblast growth factors remains unclear. To elucidate the importance of sulfated CSPGs in signaling paradigms required for endochondral bone formation, the brachymorphic (bm) mouse was used as a model for undersulfated CSPGs. The bm mouse exhibits a postnatal chondrodysplasia caused by a mutation in the phosphoadenosine phosphosulfate (PAPS) synthetase (Papss2) gene, leading to reduced levels of PAPS and undersulfated proteoglycans. Biochemical analysis of the glycosaminoglycan (GAG) content in bm cartilage via sulfate labeling and fluorophore-assisted carbohydrate electrophoresis revealed preferential undersulfation of chondroitin chains (CS) and normal sulfation of heparan sulfate chains. In situ hybridization and immunohistochemical analysis of bm limb growth plates showed diminished Indian hedgehog (Ihh) signaling and abnormal Ihh protein distribution in the extracellular matrix. Consistent with the decrease in hedgehog signaling, BrdU incorporation exhibited a significant reduction in chondrocyte proliferation. Direct measurements of Ihh binding to defined GAG chains demonstrated that Ihh interacts with CS, particularly chondroitin-4-sulfate. Furthermore, co-immunoprecipitation experiments showed that Ihh binds to the major cartilage CSPG aggrecan via its CS chains. Overall, this study demonstrates an important function for CSPGs in modulating Ihh signaling in the developing growth plate, and highlights the importance of carbohydrate sulfation in regulating growth factor signaling.

Proactive stability control while carrying loads and negotiating an elevated surface.

In this study, proactive stability control while handling loads and negotiating an elevated surface was examined. Ten young healthy males completed two gait-mode conditions--level walking and negotiating a raised surface. Load-handling conditions were: no load, empty box (reduced visual information), and loaded box (reduced visual information combined with increased inertial load). The lower limb trajectory in the sagittal plane was not modified as a function of reduced visual information or increased inertial load. The step width decreased while stepping over the surface and carrying the loaded box. The trunk pitch angle was biased backwards for both the empty box and the loaded box. When carrying the empty box and negotiating the surface, the trunk pitch range of motion (ROM) increased which may have been a strategy to increase visual exteroceptive information. As increased net trunk pitch could destabilize the system, concurrent stabilizing strategies--decreased gait velocity and reduced net trunk roll velocity--were observed. To meet the equilibrium goals when carrying the loaded box, the trunk pitch ROM and net pitch velocity were reduced during both level walking and surface accommodation. Trunk roll ROM was reduced when carrying the load and negotiating the surface. This study extends our knowledge regarding whole body coordination strategies during anticipatory locomotor adaptations.