A novel cortical biomarker signature accurately and reliably predicts individual pain sensitivity: The PREDICT longitudinal analytical validation study

ImportanceBiomarkers would greatly assist decision making in the diagnosis, prevention and treatment of chronic pain. ObjectiveThe present study aimed to undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of two measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME). DesignIn this cohort study (recruitment period: November 2020-October 2022), participants experienced a model of prolonged temporomandibular pain with outcomes collected over 30 days. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Days 0, 2 and 5. Pain was assessed twice daily from Days 1-30. SettingData collection occurred at a single centre: Neuroscience Research Australia. ParticipantsWe enrolled 159 healthy participants (through notices placed online and at universities across Australia), aged 18-44 with no history of chronic pain, neurological or psychiatric condition. 150 participants completed the protocol. ExposureParticipants received an injection of nerve growth factor (NGF) to the right masseter muscle on Days 0 and 2 to induce prolonged temporomandibular pain lasting up to 4 weeks. Main Outcomes and MeasuresWe determined the predictive accuracy of the PAF/CME biomarker signature using a nested control-test scheme: machine learning models were run on a training set (n = 100), where PAF and CME were predictors and pain sensitivity was the outcome. The winning classifier was assessed on a test set (n = 50) comparing the predicted pain labels against the true labels. ResultsThe final sample consisted of 66 females and 84 males with a mean age of 25.1 {+/-} 6.2. The winning classifier was logistic regression, with an outstanding area under the curve (AUC=1.00). The locked model assessed on the test set had excellent performance (AUC=0.88[0.78-0.99]). Results were reproduced across a range of methodological parameters. Moreover, inclusion of sex and pain catastrophizing as covariates did not improve model performance, suggesting the model including biomarkers only was more robust. PAF and CME biomarkers showed good-excellent test-retest reliability. Conclusions and RelevanceThis study provides evidence for a sensorimotor cortical biomarker signature for pain sensitivity. The combination of accuracy, reproducibility, and reliability, suggests the PAF/CME biomarker signature has substantial potential for clinical translation, including predicting the transition from acute to chronic pain. Key PointsO_ST_ABSQuestionC_ST_ABSCan individuals be accurately classified as high or low pain sensitive based on two features of cortical activity: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME)? FindingsIn a cohort study of 150 healthy participants, the performance of a logistic regression model was outstanding in a training set (n=100) and excellent in a test set (n=50), with the combination of slower PAF and CME depression predicting higher pain. Results were reproduced across a range of methodological parameters. MeaningA novel cortical biomarker can accurately distinguish high and low pain sensitive individuals, and may predict the transition from acute to chronic pain