Chronic pain is associated with neuronal plasticity. Here we use resting-state functional magnetic resonance imaging to investigate functional changes in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA). We isolated five meaningful resting-state networks across the groups, of which only the default mode network (DMN) exhibited deviations from healthy controls. All patient groups showed decreased connectivity of medial prefrontal cortex (MPFC) to the posterior constituents of the DMN, and increased connectivity to the insular cortex in proportion to the intensity of pain. Multiple DMN regions, especially the MPFC, exhibited increased high frequency oscillations, conjoined with decreased phase locking with parietal regions involved in processing attention. Both phase and frequency changes correlated to pain duration in OA and CBP patients. Thus chronic pain seems to reorganize the dynamics of the DMN and as such reflect the maladaptive physiology of different types of 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.

Neural mechanisms mediating the transition from acute to chronic pain remain largely unknown. In a longitudinal brain imaging study, we followed patients with a single subacute back pain (SBP) episode for over one year as their pain subsided (SBPr), or persisted (SBPp) representing a transition to chronic pain. We discovered brain white-matter structural abnormalities (in n=24 SBP; SBPp=12 and SBPr=12), as measured by diffusion tensor imaging (DTI), at entry into the study in SBPp in comparison to SBPr. These white matter fractional anisotropy (FA) differences accurately predicted pain persistence over the next year, which was validated in a second cohort (in n=22 SBP; SBPp=11 and SBPr=11), and showed no further alterations over a one-year period. Tractography analysis indicated that abnormal regional FA was linked to differential structural connectivity to medial vs. lateral prefrontal cortex. Local FA was correlated to functional connectivity between medial prefrontal cortex and nucleus accumbens in SBPr. As we have earlier shown that the latter functional connectivity accurately predicts transition to chronic pain, we can conclude that brain structural differences, most likely existing prior to the back pain inciting event and independent of the back pain, predisposes subjects to pain chronification.

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia.Trial Registration ClinicalTrials.gov NCT02903238ClinicalTrials.gov NCT01558700

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Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic pain conditions. We used resting-state functional MRI data to analyze the brain connectome at varying scales and densities. In three chronic pain conditions, we observe disrupted kD, in proportion to individuals’ pain intensity, and associated with community membership disruption. Additionally, we observe regional degree changes, some of which were unique to each type of chronic pain. Subjects with recent onset of back pain exhibited emergence of kD only when the pain became chronic. Similarly, in neuropathic rats kD emerged weeks after injury, in proportion to pain-like behavior. Thus, we found comprehensive cross-species evidence for chronic pain being a state of global randomization of functional connectivity.

In addition to their well-established role in signaling rewarding outcomes and reward-predictive cues and in mediating positive reinforcement, there is growing evidence that nucleus accumbens (NAc) neurons also signal aversive events and cues that predict them. Here we use diffusion tractography to subdivide the right NAc into lateral-rostral (putative core, pcore) and medial-caudal (putative shell, pshell) subdivisions in humans. The two subregions exhibited differential structural connectivity, based on probabilistic tractography, to prefrontal cortical and subcortical limbic regions. We also demonstrate unique roles for each of the two subdivisions for monetary reward and thermal pain perception tasks: pshell signaling impending pain and value predictions for monetary gambles and pcore activating with anticipation of cessation of thermal pain (signaling reward value of analgesia). We examined functional connectivity for resting state, monetary reward, and thermal pain tasks, and for all three conditions observed that pcore and pshell of right NAc exhibit distinct patterns of synchrony (functional connectivity) to prefrontal cortical and subcortical limbic targets within the right hemisphere. To validate the NAc segregation, we mirrored the coordinates of right NAc pcore and pshell onto the left hemisphere and examined structural and resting state connectivity in the left hemisphere. This latter analysis closely replicated target-specific connections we obtained for the right hemisphere. Overall, we demonstrate that the human NAc can be parceled based on structural and functional connectivity, and that activity in these subdivisions differentially encodes values for expected pain relief and for expected monetary reward.

Activity of cortical local neuronal populations fluctuates continuously, and a large proportion of these fluctuations are shared across populations of neurons. Here we seek organizational rules that link these two phenomena. Using neuronal activity, as identified by functional MRI (fMRI) and for a given voxel or brain region, we derive a single measure of full bandwidth brain-oxygenation-level-dependent (BOLD) fluctuations by calculating the slope, α, for the log-linear power spectrum. For the same voxel or region, we also measure the temporal coherence of its fluctuations to other voxels or regions, based on exceeding a given threshold, Θ, for zero lag correlation, establishing functional connectivity between pairs of neuronal populations. From resting state fMRI, we calculated whole-brain group-averaged maps for α and for functional connectivity. Both maps showed similar spatial organization, with a correlation coefficient of 0.75 between the two parameters across all brain voxels, as well as variability with hodology. A computational model replicated the main results, suggesting that synaptic low-pass filtering can account for these interrelationships. We also investigated the relationship between α and structural connectivity, as determined by diffusion tensor imaging-based tractography. We observe that the correlation between α and connectivity depends on attentional state; specifically, α correlated more highly to structural connectivity during rest than while attending to a task. Overall, these results provide global rules for the dynamics between frequency characteristics of local brain activity and the architecture of underlying brain networks.