Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

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.

Chronic pain is maladaptive and influences brain function and behavior by altering the flow and integration of information across brain regions. Here we use a power spectral analysis to investigate impact of presence of chronic pain on brain oscillatory activity in humans. We examine changes in BOLD fluctuations, across different frequencies, in chronic back pain (CBP) patients (n=15) as compared to healthy controls (n=15) during resting state fMRI. While healthy subjects exhibited a specific, frequency band dependent, large-scale neural organization, patients showed increased high frequency BOLD oscillations (0.12–0.20 Hz) circumscribed mainly to medial prefrontal cortex (mPFC) and parts of the default-mode network (DMN). In the patients a correlation analysis related the mPFC aberrant BOLD high frequency dynamics to altered functional connectivity to pain signaling/modulating brain regions, thus linking BOLD frequency changes to function. We also found that increased frequency fluctuations within the mPFC were temporally synchronous with spontaneous pain changes in patients during a pain-rating task. These observations provide novel insights about the nature of CBP, identifying how it disturbs the resting brain, and link high frequency BOLD oscillations to perception.

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury, SNI). We observed inter-related changes: 1) In resting-state fMRI, functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; 2) contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28 days after SNI; 3) In SNI (but not sham) covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and 4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.

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.