Neural signaling and network connectivity in the brainstem and spinal cord: an fMRI investigation of fixed-temperature (38 °C, 46 °C, 51 °C) thermal stimulation and sex differences in humans.

Abstract

Pain is a multidimensional experience mediated by both peripheral input and central processing. While much of the existing research has focused on cortical mechanisms, the spinal cord and brainstem play a critical role in descending modulation of pain. Investigating how these subcortical systems respond to varying thermal stimulation offers insight into the physiological organization of pain networks, particularly with respect to stimulus intensity and sex-related variability. This thesis used functional magnetic resonance imaging (fMRI) to examine neural signaling and directional connectivity within brainstem and spinal cord regions during constant-temperature thermal stimulation at 38 °C, 46 °C, and 51 °C. The first study examined how temperature intensity influenced subjective pain ratings, pupil diameter, and functional connectivity using Structural and Physiological Modeling (SAPM). Higher temperatures were associated with significantly increased pain intensity and unpleasantness, larger pupil responses, and distinct patterns of blood oxygenation level dependent (BOLD) connectivity. The greatest number ofx significant connections emerged at 46 °C, while 51 °C produced less consistent engagement, indicating a non-linear response pattern. Building on these findings, the second study assessed sex differences in response to the same thermal conditions. Although males and females reported comparable pain intensity, females exhibited lower pain unpleasantness ratings at 51 °C and showed distinct connectivity patterns. Specifically, females demonstrated stronger engagement of top-down modulatory pathways, while males showed stronger sensory-related input to the spinal cord. Together, these findings advance understanding of how stimulus intensity and assigned sex modulate central pain networks. The results support the involvement of non-linear mechanisms in descending modulation and contribute to characterizing individual variability in pain perception.