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.

Longitudinal Data in Two Groups Longitudinal Data in Two Groups with interaction of covariate by group 42 Adapting the CAT12 workflow for unusual populations Customized Tissue Probability Maps 46 Customized DARTEL-template Other variants of computational morphometry Deformation-based morphometry (DBM) Surface-based morphometry (SBM) Region of interest (ROI) analysis Additional information on native, normalized and modulated volumes Naming convention of output files Calling CAT from the UNIX command line Technical information CAT12 Citation References 1 Note to filter sizes for Gaussian smoothing Due to the high accuracy of the spatial registration approaches used in CAT12, you can also try to use smaller filter sizes. However, for very small filter sizes or even no filtering, you have to apply a non-parametric permutation test such as the TFCE-statistics. Please also note that for the analysis of cortical folding measures such as gyrification or cortical complexity the filter sizes have to be larger (i.e. in the range of 15-25mm). This is due to the underlying nature of this measure that reflects contributions from both sulci as well as gyri. Therefore, the filter size should exceed the distance between a gyral crown and a sulcal fundus.

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.

Heightened pain sensitivity, the amount of pain experienced in response to a noxious event, is a known risk factor for development of chronic pain. We have previously reported that pain-free, sensorimotor peak alpha frequency (PAF) is a reliable biomarker of pain sensitivity for thermal, prolonged pains lasting tens of minutes. To test whether PAF can provide information about pain sensitivity occurring over clinically relevant timescales (i.e., weeks), EEG was recorded before and while participants experienced a long-lasting pain model, repeated intramuscular injection of nerve growth factor (NGF), that produces progressively developing muscle pain for up to 21 days. We demonstrate that pain-free, sensorimotor PAF is negatively correlated with NGF pain sensitivity; increasingly slower PAF is associated with increasingly greater pain sensitivity. Furthermore, PAF remained stable following NGF injection, indicating that the presence of NGF pain for multiple weeks is not sufficient to induce the PAF slowing reported in chronic pain. In total, our results demonstrate that slower pain-free, sensorimotor PAF is associated with heightened sensitivity to a long-lasting musculoskeletal pain and also suggest that the apparent slowing of PAF in chronic pain may reflect predisease pain sensitivity. NEW & NOTEWORTHY Pain sensitivity, the intensity of pain experienced after injury, has been identified as an important risk factor in the development of chronic pain. Biomarkers of pain sensitivity have the potential to ease chronic pain burdens by preventing disease emergence. In the current study, we demonstrate that the speed of pain-free, sensorimotor peak alpha frequency recorded during resting-state EEG predicts pain sensitivity to a clinically-relevant, human model of prolonged pain that persists for weeks.

Observing successful pain treatment in others can induce anticipatory neural processes that, in turn, relieve pain. Previous studies have suggested that social learning and observation influence placebo hypoalgesia. Here, we used electroencephalography (EEG) to determine the neurophysiological changes associated with pain relief acquired through the observation. Thirty-one participants observed a demonstrator undergo painful heat stimulations paired with a “control” cream and non-painful ones paired with a “treatment” cream, which actually were both Vanicreams. After their observation, the participants then received the same creams and stimulations. We found that the treatment cream led to lower self-reported pain intensity ratings than the control cream. Anticipatory treatment cues elicited smaller P2 in electrodes F1, Fz, FC1, and FCz than the control condition. The P2 component localization indicated a higher current density in the right middle frontal gyrus, a region associated with attentional engagement. In placebo responders, the sensorimotor cortex activity captured in electrodes C3, Cz, and C4 indicated that hypoalgesia was positively correlated with resting state peak alpha frequency (PAF). These results suggest that observationally-induced placebo hypoalgesia may be driven by anticipatory mechanisms that modulate frontal attentional processes. Furthermore, resting state PAF could serve as a predictor of observationally-induced hypoalgesia.

A wealth of evidence in rodents and humans supports the central roles of two learning systems--hippocampal place learning and striatal response learning--in the formation of spatial representations to support navigation. Individual differences in the ways that these mechanisms are engaged during initial encoding and subsequent navigation may provide a powerful framework for explaining the wide range of variability found in the strategies and solutions that make up human navigational styles. Previous work has revealed that activation in the hippocampal and striatal networks during learning could predict navigational style. Here, we used functional magnetic resonance imaging to investigate the relative activations in these systems during both initial encoding and the act of dynamic navigation in a learned environment. Participants learned a virtual environment and were tested on subsequent navigation to targets within the environment. We observed that a given individual had a consistent balance of memory system engagement across both initial encoding and subsequent navigation, a balance that successfully predicted the participants' tendencies to use novel shortcuts versus familiar paths during dynamic navigation. This was further supported by the observation that the activation during subsequent retrieval was not dependent on the type of solution used on a given trial. Taken together, our results suggest a model in which the place- and response-learning systems are present in parallel to support a variety of navigational behaviors, but stable biases in the engagement of these systems influence what solutions might be available for any given individual.

We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 β-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. Stress was induced via a forced-swim paradigm. In a separate group of ovariectomized rats, E2 treatment induced visceral hypersensitivity at the 2 days post-stress time point, and this hypersensitivity returned to baseline at the 18 days post-stress time point. Vehicle-treated rats show no hypersensitivity following stress. During the MRI scans, rats were exposed to noxious colorectal distention. Across groups and time points, noxious visceral stimulation led to activations in the insula, anterior cingulate, and left amygdala, parabrachial nuclei, and cerebellum. A group-by-time interaction was seen in the right amygdala, ventral striatum-pallidum, cerebellum, hippocampus, mediodorsal thalamus, and pontine nuclei. Closer inspection of the data revealed that vehicle-treated rats showed consistent activations and deactivations across time, whereas estrogen-treated animals showed minimal deactivation with noxious visceral stimulation. This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control groups and larger sample sizes are needed to fully understand the interactions between sex hormones, stress, and noxious stimulation on brain activity.

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