A hallmark feature of chronic pain is its ability to impact other sensory and affective experiences. It is notably associated with hypersensitivity at the site of tissue injury. It is less clear, however, if chronic pain can also induce a generalized site-nonspecific enhancement in the aversive response to nociceptive inputs. Here, we showed that chronic pain in one limb in rats increased the aversive response to acute pain stimuli in the opposite limb, as assessed by conditioned place aversion. Interestingly, neural activities in the anterior cingulate cortex (ACC) correlated with noxious intensities, and optogenetic modulation of ACC neurons showed bidirectional control of the aversive response to acute pain. Chronic pain, however, altered acute pain intensity representation in the ACC to increase the aversive response to noxious stimuli at anatomically unrelated sites. Thus, chronic pain can disrupt cortical circuitry to enhance the aversive experience in a generalized anatomically nonspecific manner.DOI: http://dx.doi.org/10.7554/eLife.25302.001

Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms, and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain–machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing), and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top–down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviors caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.

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Objective. The primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) are two of the most important cortical brain regions encoding the sensory-discriminative and affective-emotional aspects of pain, respectively. However, the functional connectivity of these two areas during pain processing remains unclear. Developing methods to dissect the functional connectivity and directed information flow between cortical pain circuits can reveal insight into neural mechanisms of pain perception. Approach. We recorded multichannel local field potentials (LFPs) from the S1 and ACC in freely behaving rats under various conditions of pain stimulus (thermal versus mechanical) and pain state (naive versus chronic pain). We applied Granger causality (GC) analysis to the LFP recordings and inferred frequency-dependent GC statistics between the S1 and ACC. Main results. We found an increased information flow during noxious pain stimulus presentation in both S1ACC and ACCS1 directions, especially at theta and gamma frequency bands. Similar results were found for thermal and mechanical pain stimuli. The chronic pain state shares common observations, except for further elevated GC measures especially in the gamma band. Furthermore, time-varying GC analysis revealed a negative correlation between the direction-specific and frequency-dependent GC and animal’s paw withdrawal latency. In addition, we used computer simulations to investigate the impact of model mismatch, noise, missing variables, and common input on the conditional GC estimate. We also compared the GC results with the transfer entropy (TE) estimates. Significance. Our results reveal functional connectivity and directed information flow between the S1 and ACC during various pain conditions. The dynamic GC analysis support the hypothesis of cortico-cortical information loop in pain perception, consistent with the computational predictive coding paradigm.

Pain is a complex, multidimensional experience that involves dynamic interactions between sensory-discriminative and affective-emotional processes. Pain experiences have a high degree of variability depending on their context and prior anticipation. Viewing pain perception as a perceptual inference problem, we use a predictive coding paradigm to characterize both evoked and spontaneous pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) of freely behaving rats-two regions known to encode the sensory-discriminative and affective-emotional aspects of pain, respectively. We further propose a framework of predictive coding to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Specifically, we develop a high-level, empirical and phenomenological model to describe the macroscopic dynamics of bottom-up and top-down activity. Supported by recent experimental data, we also develop a mechanistic mean-field model to describe the mesoscopic population neuronal dynamics in the S1 and ACC populations, in both naive and chronic pain-treated animals. Our proposed predictive coding models not only replicate important experimental findings, but also provide new mechanistic insight into the uncertainty of expectation, placebo or nocebo effect, and chronic pain. Author SummaryPain perception in the mammalian brain is encoded through multiple brain circuits.The experience of pain is often associated with brain rhythms or neuronal oscillations at different frequencies. Understanding the temporal coordination of neural oscillatory activity from different brain regions is important for dissecting pain circuit mechanisms and revealing differences between distinct pain conditions. Predictive coding is a general computational framework to understand perceptual inference by integrating bottom-up sensory information and top-down expectation. Supported by experimental data, we propose a predictive coding framework for pain perception, and develop empirical and biologically-constrained computational models to characterize oscillatory dynamics of neuronal populations from two cortical circuits-one for the sensory-discriminative PLOS 2/49 experience and the other for affective-emotional experience, and further characterize their temporal coordination under various pain conditions. Our computational study of biologically-constrained neuronal population model reveals important mechanistic insight on pain perception, placebo analgesia, and chronic pain. Introduction 1Pain is a basic experience that is subjective and multidimensional. Pain processing 2 involves sensory, affective, and cognitive processing across distributed neural 3 circuits [1-5]. However, a complete understanding of pain perception and cortical pain 4 processing has remained elusive. Given the same nociceptive stimuli, the context 5 matters for pain percept. Human neuroimaging studies have shown that among many 6 brain regions, the primary somatosensory cortex (S1) a...

Chronic pain alters cortical and subcortical plasticity, causing enhanced sensory and affective responses to peripheral nociceptive inputs. Previous studies have shown that ketamine had the potential to inhibit abnormally amplified affective responses of single neurons by suppressing hyperactivity in the anterior cingulate cortex (ACC). However, the mechanism of this enduring effect has yet to be understood at the network level. In this study, we recorded local field potentials from the ACC of freely moving rats. Animals were injected with complete Freund’s adjuvant (CFA) to induce persistent inflammatory pain. Mechanical stimulations were administered to the hind paw before and after CFA administration. We found a significant increase in the high-gamma band (60–100 Hz) power in response to evoked pain after CFA treatment. Ketamine, however, reduced the high-gamma band power in response to evoked pain in CFA-treated rats. In addition, ketamine had a sustained effect on the high-gamma band power lasting up to five days after a single dose administration. These results demonstrate that ketamine has the potential to alter maladaptive neural responses in the ACC induced by chronic pain.