Maladaptive Compensatory Neural Mechanisms Associated with Activity-Related Osteoarthritis Pain: Dissociation of Psychological and Activity-Related Neural Mechanisms of WOMAC Pain and VAS Pain

<b>Background/Objectives:</b> Knee osteoarthritis (KOA) is one of the most common causes of chronic pain and disability in older adults. Its mechanisms are both peripheral and central, causing discordance between pain intensity and disease severity. To provide better, mechanism-driven treatments for KOA, it is important to understand the emotional, physical, and neurophysiological factors that influence pain intensity. Thus, we proposed a multivariate model investigation of the multimodal predictors of pain intensity in patients with chronic KOA pain. <b>Methods</b>: We conducted an extensive assessment of 105 KOA patients. We used two different types of outcomes: (i) activity-related (Western Ontario and McMaster Universities Osteoarthritis [WOMAC] pain scale), and (ii) non-specific (visual analog scale [VAS]) pain assessments. <b>Results:</b> We found the following. (1) A higher WOMAC pain score was predicted by sensory-motor markers (lower intracortical inhibition [<i>p</i> = 0.021] and higher beta-band oscillations [<i>p</i> = 0.027]) and central sensitization (dysfunctional CPM response [<i>p</i> < 0.001]), in addition to the psychological and peripheral sensitization factors (adjusted R² = 52%, F (5, 99) = 22.81, <i>p</i> < 0.0001). (2) Conversely, higher VAS pain intensity was only predicted by psychological factors (higher depression [<i>p</i> = 0.021] and pain catastrophizing [<i>p</i> = 0.003]), peripheral sensitization (lower pain thresholds), and worse motor function (balance test) (adjusted R² = 36%, F (5, 99) = 12.57, <i>p</i> < 0.0001). Interestingly, no TMS or EEG markers were associated with VAS pain. <b>Conclusions:</b> Our study supports the notion that pain during physical activity is associated with a neural signature that demonstrates a lack of compensatory mechanisms for pain (decreased cortical inhibition, higher beta-band oscillations, and defective CPM), and it is different from the pain at rest, measured by the VAS, which is related mostly to emotional circuit dysregulation. These findings are important for developing better-targeted neural therapies given the contribution of different neural mechanisms to OA pain.