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.

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). Resting state BOLD signal was transformed into frequency space (Welch’s method), averaged across subjects, and its spatial distribution studied as a function of four frequency bands, spanning the full bandwidth of BOLD. 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), vs. 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 frequency properties of BOLD 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 voxel-wise 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.

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain-that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.

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.

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, cmdbc (Acancmd-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 production of cmdbc/cmdbc; 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 (cmdbc/cmdbc) 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.

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.

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.

BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.