Sensorimotor Peak Alpha Frequency Is a Reliable Biomarker of Prolonged Pain Sensitivity.

Previous research has observed that the speed of alpha band oscillations (8-12 Hz range) recorded during resting electroencephalography is slowed in chronic pain patients. While this slowing may reflect pathological changes that occur during the chronification of pain, an alternative explanation is that healthy individuals with slower alpha oscillations are more sensitive to prolonged pain, and by extension, more susceptible to developing chronic pain. To test this hypothesis, we examined the relationship between the pain-free, resting alpha oscillation speed of healthy individuals and their sensitivity to two models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two visits separated by 8 weeks on average (n = 61 Visit 1, n = 46 Visit 2). We observed that the speed of an individual's pain-free alpha oscillations was negatively correlated with sensitivity to both models and that this relationship was reliable across short (minutes) and long (weeks) timescales. Furthermore, the speed of pain-free alpha oscillations can successfully identify the most pain sensitive individuals, which we validated on data from a separate, independent study. These results suggest that alpha oscillation speed is a reliable biomarker of prolonged pain sensitivity with potential for prospectively identifying pain sensitivity in the clinic.

Cerebral peak alpha frequency predicts individual differences in pain sensitivity.

The identification of neurobiological markers that predict individual predisposition to pain are not only important for development of effective pain treatments, but would also yield a more complete understanding of how pain is implemented in the brain. In the current study using electroencephalography (EEG), we investigated the relationship between the peak frequency of alpha activity over sensorimotor cortex and pain intensity during capsaicin-heat pain (C-HP), a prolonged pain model known to induce spinal central sensitization in primates. We found that peak alpha frequency (PAF) recorded during a pain-free period preceding the induction of prolonged pain correlated with subsequent pain intensity reports: slower peak frequency at pain-free state was associated with higher pain during the prolonged pain condition. Moreover, the degree to which PAF decreased between pain-free and prolonged pain states was correlated with pain intensity. These two metrics were statistically uncorrelated and in combination were able to account for 50% of the variability in pain intensity. Altogether, our findings suggest that pain-free state PAF over relevant sensory systems could serve as a marker of individual predisposition to prolonged pain. Moreover, slowing of PAF in response to prolonged pain could represent an objective marker for subjective pain intensity. Our findings potentially lead the way for investigations in clinical populations in which alpha oscillations and the brain areas contributing to their generation are used in identifying and formulating treatment strategies for patients more likely to develop chronic pain.

Astrocyte store-operated calcium entry is required for centrally mediated neuropathic pain.

Central sensitization is a critical step in chronic neuropathic pain formation following acute nerve injury. Central sensitization is defined by nociceptive and somatosensory circuitry changes in the spinal cord leading to dysfunction of antinociceptive gamma-aminobutyric acid (GABA)ergic cells (Li et al., 2019), amplification of ascending nociceptive signals, and hypersensitivity (Woolf, 2011). Astrocytes are key mediators of the neurocircuitry changes that underlie central sensitization and neuropathic pain, and astrocytes respond to and regulate neuronal function through complex Ca2+ signaling mechanisms. Clear definition of the astrocyte Ca2+ signaling mechanisms involved in central sensitization may lead to new therapeutic targets for treatment of chronic neuropathic pain, as well as enhance our understanding of the complex central nervous system (CNS) adaptions that occur following nerve injury. Ca2+ release from astrocyte endoplasmic reticulum (ER) Ca2+ stores via the inositol 1,4,5-trisphosphate receptor (IP3R) is required for centrally mediated neuropathic pain (Kim et al, 2016); however recent evidence suggests the involvement of additional astrocyte Ca2+ signaling mechanisms. We therefore investigated the role of astrocyte store-operated Ca2+ entry (SOCE), which mediates Ca2+ influx in response to ER Ca2+ store depletion. Using an adult Drosophila melanogaster model of central sensitization based on thermal allodynia in response to leg amputation nerve injury (Khuong et al., 2019), we show that astrocytes exhibit SOCE-dependent Ca2+ signaling events three to four days following nerve injury. Astrocyte-specific suppression of Stim and Orai, the key mediators of SOCE Ca2+ influx, completely inhibited the development of thermal allodynia seven days following injury, and also inhibited the loss of ventral nerve cord (VNC) GABAergic neurons that is required for central sensitization in flies. We lastly show that constitutive SOCE in astrocytes results in thermal allodynia even in the absence of nerve injury. Our results collectively demonstrate that astrocyte SOCE is necessary and sufficient for central sensitization and development of hypersensitivity in Drosophila, adding key new understanding to the astrocyte Ca2+ signaling mechanisms involved in chronic pain.