Modulating nociception networks: the impact of low-intensity focused ultrasound on thalamocortical connectivity

Pain engages multiple brain networks, with the thalamus serving as a critical subcortical hub. This study aims to explore the effects of low-intensity transcranial focused ultrasound-induced suppression on the organization of thalamocortical nociceptive networks. We employed MR-guided focused ultrasound, a potential non-invasive therapy, with real-time ultrasound beam localization feedback and fMRI monitoring. We first functionally identified the focused ultrasound target at the thalamic ventroposterior lateral nucleus by mapping the whole-brain blood oxygenation level-dependent responses to nociceptive heat stimulation of the hand using fMRI in each individual macaque monkey under light anaesthesia. The blood oxygenation level-dependent fMRI signals from the heat-responsive thalamic ventroposterior lateral nucleus were analysed to derive thalamocortical effective functional connectivity network using the psychophysical interaction method. Nineteen cortical regions across sensorimotor, cognitive, associative and limbic networks exhibited strong effective functional connectivity to the thalamic ventroposterior lateral during heat nociceptive processing. Focused ultrasound-induced suppression of heat activity in the thalamic ventroposterior lateral nucleus altered nociceptive responses in most of the 19 regions. Data-driven hierarchical clustering analyses of blood oxygenation level-dependent time courses across all thalamocortical region-of-interest pairs identified two effective functional connectivity subnetworks. The concurrent suppression of thalamic heat response with focused ultrasound reorganized these subnetworks and modified thalamocortical connection strength. Our findings suggest that the thalamic ventroposterior lateral nucleus has extensive and causal connections to a wide array of cortical areas during nociceptive processing. The combination of MR-guided focused ultrasound with fMRI enables precise dissection and modulation of nociceptive networks in the brain, a capability that no other device-based neuromodulation methods have achieved. This presents a promising non-invasive tool for modulating pain networks with profound clinical relevance. The robust modulation of nociceptive effective functional connectivity networks by focused ultrasound strongly supports the thalamic ventroposterior lateral as a viable target for pain management strategies.