Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain

Abstract

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.

Keywords: EEG; biomarker; nerve growth factor; pain sensitivity.

Conflict of interest statement

D. A. Seminowicz and A. J. Furman have a patent pending for “A Simple and Portable Biomarker for Pain Sensitivity.” No conflicts of interest, financial or otherwise, are declared by the remaining authors.

Figures

Fig. 1.

Timeline of experimental events for both studies. EEG was always collected before nerve growth factor (NGF) injection. Arrows and associated dates indicate time points where pain ratings were collected. For Study 1, pain ratings were collected for 21 days on every other day following the first NGF injection (i.e., days 1, 3, …, 21). For Study 2, pain ratings were collected on days 2 and 4.

Fig. 2.

Peak alpha frequency (PAF) affects the magnitude, but not the pattern, of pain development. A: daily diary pain ratings for Study 1. *P < 0.05, time points where pain was found to be significantly greater than 0. B: cohort 1 median split based on the speed of pain-free, sensorimotor PAF (Fspeed) reveals that “slow” PAF individuals experience greater pain at almost all time points.

Fig. 3.

Pain-free, sensorimotor peak alpha frequency (PAF) is correlated with average NGF pain. A: spectra collected from all participants on day 0. Colored lines reflect individual participants, and black dashed line reflects the average spectra across all participants. Red zone reflects the area used to calculate PAF according to the center of gravity method. The alpha peak for the group average, and for most participants, falls within this zone. B: day 0 pain-free, sensorimotor PAF was negatively correlated with the average pain intensity reported from days 1–17. Red dotted line reflects the linear regression line of best fit.

Fig. 4.

Sensorimotor peak alpha frequency (PAF) remains stable after nerve growth factor (NGF) injection. A: mean (SD) of sensorimotor PAF estimates at each testing day (FDay). B: Study 1 sensorimotor PAF collected at day 0 is significantly correlated with sensorimotor PAF collected at all other time points. *P < 0.005. C: shifts in sensorimotor PAF (ΔPAF; average post-NGF PAF – day 0 PAF) are not related to average NGF pain. Red dotted line reflects the linear regression line of best fit.

Fig. A1.

A: daily diary reports for Study 2. *P < 0.05, pain scores significantly different from 0. B. cohort 1 median split based on pain-free, sensorimotor peak alpha frequency (PAF) reveals that “slow” PAF individuals experienced greater pain on day 2 but not day 4.

Fig. A2.

Day 0 pain-free, sensorimotor peak alpha frequency (PAF) is not correlated with the maximum pain reported from days 1–21. Red dotted line reflects the linear regression line of best fit.

Fig. A3.

A and B: relationship of peak alpha frequency (PAF) to average pain is consistent across channels. C and D: relationship of post-nerve growth factor PAF shifts (ΔPAF) to average pain is also consistent across channels. Topoplot (topogaphical map) colors reflect Spearman coefficients.

Fig. A4.

Pain-free, sensorimotor peak alpha frequency (PAF) is correlated with multiple pain diary days. A: the relationship appears to first become stable at day 5, the first available diary report following the final nerve growth factor injection. B: box and whisker plots of Spearman coefficients (ρ) for pain-free PAF calculated from each EEG channel and pain reported on each day. The pattern of results is nearly identical to what was found for the sensorimotor region of interest. Red lines reflect medians, box edges reflect the 25th and 75th percentiles, and circles reflect outliers. C: topoplots (topographical maps) of ρ coefficients for pain-free, PAF calculated at each EEG channel and daily pain reports. Coefficients obtained for each day’s pain diary for consistent across channels.

Fig. A5.

Relationship of post-nerve growth factor (NGF) peak alpha frequency (PAF) shifts (ΔPAF) to pain sensitivity depend on pain-free, sensorimotor PAF. A: for individuals with pain-free PAF close to 10 Hz, ΔPAF is negatively correlated with average pain. B: for individuals with pain-free PAF not close to 10 Hz, ΔPAF is not related to average pain. C: changes in PAF after NGF, normalized (Norm.) to pain-free PAF, are moderately related to average NGF pain. D: relationship between normalized ΔPAF and pain is not dependent on the scaling factor. Red dotted lines reflect linear regression lines of best fit.