Direction-sensitive neural correlates of voluntary pain regulation: regional response attenuation during down-regulation and exploratory prefrontal-valuation coupling

Voluntary cognitive regulation can increase or decrease pain, but direction-sensitive neural correlates may emerge at different analytical levels. We reanalyzed 3,201 thermal-stimulation trials from 33 participants, integrating 0-200 warmth/pain ratings, regional fMRI activity, and trial-wise lagged coupling. Both instructions shifted ratings in the intended direction, with no reliable difference in mean success. Down-regulation was associated with lower bilateral S2/opercular and insular activity and higher left dlPFC/IFJ activity after FDR correction across 32 regions; run-matched comparisons were weaker and none survived the corresponding correction. Contrast-map Neurologic Pain Signature attenuation did not replicate in a rating-adjusted FWL-LSS trial-wise analysis despite strong temperature sensitivity. Up-regulation success covaried with an exploratory, post selection lagged dlPFC/IFJ-valuation composite (r = -0.546, 95% CI [-0.764, -0.270]). The association exceeded matched reverse-direction, zero-lag, and time-reversed controls, lay outside permutation and circular-shift nulls, and persisted after AR(1) prewhitening. A transition-level analysis across 297 up-regulation transitions preserved a negative success-by-source interaction (adjusted three-target mean beta = -0.163, cluster-bootstrap 95% CI [-0.290, -0.054], Freedman-Lane p = 0.010). Six session-wise DCM variants showed no consistent regulation-versus-passive effective-connectivity effect and did not independently validate an up-specific directed mechanism. These analyses identify a down-regulation-associated regional pattern and a candidate prefrontal-valuation coupling association requiring independent confirmation.