Multi-timescale dynamics organize descending pain modulation

Abstract

Descending pain-modulatory circuits must coordinate rapid nociceptive responses with slower changes in physiological state, yet how their activity is organized across time remains poorly understood. We investigated this question in physiologically identified pain-modulating neurons of the rostral ventromedial medulla (RVM). The RVM contains ON- and OFF-cells that exert descending control over spinal nociceptive transmission, regulating pain sensitivity and behaviors. By integrating neuronal recordings with probabilistic modeling, we show that unstimulated and stimulus-driven conditions give rise to distinct timescales of ON- and OFF-cell dynamics. During noxious stimulation, we find that population responses undergo rapid activation (<1 s) followed by superimposed slow (~ 100 s) and fast (<10 s) recovery dynamics. In the absence of stimulation, the same neurons exhibit slow quasi-periodic fluctuations in firing activity with a characteristic timescale of approximately five minutes. Gaussian-process models show that these slow dynamics are statistically predictable from past activity, indicating structured temporal organization beyond stimulus-evoked responses. Taken together, these results indicate that descending pain-control circuits exhibit structured dynamics encompassing rapid pain-related signaling and slower fluctuations consistent with ongoing physiological state.