Dissociating Sensory and Integrative Pain Processes in the Human Insula

PROJECT SUMMARY A major challenge to treating chronic pain is patient-to-patient variability in the underlying pathophysiology, which can predominantly feature sensory dysfunction, or include higher-order dysfunction involving cognitive expectations, emotional processes, and/or sympathetic arousal. Thus, there is a need to develop therapies that can specifically modulate sensory and higher-order integrative aspects of pain processing such that they can be personalized to each patient’s pathophysiology. The goal of the proposed research is to set the stage for brain stimulation technology targeting insula that can target both bottom-up sensory processes, and top-down integrative processes that contribute to pain. Based prior findings, including preliminary evidence from our team, we hypothesize that electrical stimulation within the insula can alter pain thresholds by at least two distinct mechanisms: 1) by modulating sensory pain signals in posterior insula, and 2) by modulating higher-order, integrative pain signals in the anterior insula. We will test this hypothesis by leveraging rare opportunities to directly study human insula function in neurosurgical patients who have indwelling insular electrodes for evaluation of medically refractory epilepsy. We will combine direct intracranial electrical stimulation (iES) and quantitative sensory testing (QST), an established methods to test causal relations between local neural activity and pain processing. We will perform experiments to support the following Specific Aims: 1) To determine whether insula stimulation alters both pain and sensory thresholds in the posterior insula, but only pain thresholds in the anterior insula; 2) To determine whether thermal sensory-evoked neural activity can predict stimulation- related changes in pain and sensory thresholds. If we find that electrical stimulation of distinct insula subregions can influence distinct aspects of pain processing, it will show proof-of-concept that multi-site insula stimulation can simultaneously modulate sensory pain and higher-order, integrative aspects of pain processing. Otherwise, it will suggest that neuromodulation of sensory and higher-order pain processes will require combined targeting of insula and other brain regions (e.g., thalamus or cingulate). Thus, regardless of the outcome of these experiments, our results will inform future efforts to develop intracranial neuromodulation treatments for chronic pain that can be personalized to patient’s specific pathophysiology.