Dissociating neural representations of pain and salience using intracranial human brain recordings

Chronic pain is a major healthcare problem, affecting 20% of the population and costing society approximately $600 billion dollars per year. Intracranial neuromodulation therapies such as deep brain stimulation have great therapeutic potential, but their development is hindered by a poor understanding of brain circuits underlying pain. Identifying pain-specific brain circuits is challenging because of the confound of salience. Salient stimuli, such as a surprising loud sound, are defined as those that are highly distinct from the environment. They typically evoke several reflexive processes including increased attention, preparatory motor activity, and sympathetic arousal, such as pupil dilation. Painful stimuli are generally highly salient and evoke widespread activation in neural circuits that process salient stimuli (including non- painful stimuli, e.g., a surprising, loud sound). Thus, there is a need to identify neural circuits that are specific for pain, as distinguished from neural circuits for salience, to inform future targeted brain stimulation protocols for the treatment of chronic pain. Our central hypothesis is that nociceptive stimuli evoke pain- specific neural activity across widespread brain regions that is distinct from salience-related neural activity. Our approach will be to obtain intracranial electroencephalography (iEEG) measurements in 20 neurosurgical patients as they perform thermal pain and auditory salience tasks. iEEG measurements are possible in patients who are admitted to the hospital for evaluation of medically refractory epilepsy (who typically do not have chronic pain). Patients are implanted with intraparenchymal depth electrodes in widespread brain regions (based on clinical criteria alone) and given the option to participate in research studies within the safeguards of an established Institutional Review Board (IRB) protocol. These recordings provide the rare opportunity to measure neural activity in the human brain with high spatiotemporal resolution and broad anatomical sampling and can complement prior non-invasive neuroimaging studies. Our preliminary studies in two patients show that a) iEEG can identify neural populations that encode thermosensory intensity, pain ratings, and salience, and b) that we can measure pupil dilation following salient stimuli as an independent measure of sympathetic arousal in the clinical setting. We will build on these preliminary results to test our hypothesis via the following complementary Specific Aims: 1) To disentangle pain and salience neural circuits using thermosensory and auditory stimuli, and 2) To disentangle pain and salience neural circuits using concurrent pupil measurements. Regardless of the outcome, the proposed research will improve our understanding of human brain circuits that process pain and how they relate to those for salience. In the long-term, our studies can inform intracranial brain stimulation therapies to target pain-specific neural circuits in treatment-refractory chronic pain. Project Number: 1R21NS145164-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Ashwin Ramayya | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $423,500 | Activity Code: R21 | Study Section: Neurobiology of Pain and Itch Study Section [NPI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11373369