Defining the forebrain neurophysiological representation of pain

ABSTRACT
A significant portion of patients in the United States will suffer from chronic pain at some point in their lives,
and for a portion of these patients, our current medical and surgical options are inadequate. Novel treatments
aimed at stimulating cerebral circuits involved in nociception for clinical pain relief are promising, but require
further development of both targeting and stimulation strategies. Yet, the neural mechanisms of how human
nociception manifests as the perception of pain in cerebral circuits remains poorly understood. This proposal
leverages neurophysiological access to cortical and subcortical targets in patients undergoing the placement of
intracranial EEG electrodes to characterize pain networks in the human brain with specific access to the less
often studied nodes in the “pain network” thought to be associated with the emotional and cognitive spheres of
pain processing, including the prefrontal cortex, amygdala, insula, and anterior cingulate regions. This unique
access will allow detailed exploration of the pain experience in a naturalistic setting based on patients’ self-
reported measures of post surgical pain, which will then be contrasted with opiate induced pain reduction. The
subset of patients with pre-existing chronic pain conditions will be analyzed for variation in the biomarker
signal. Our preliminary findings have yielded two overarching hypotheses: 1) periods of self-reported post-
surgical pain will be associated with reduced beta power in prefrontal cortex, an association that will be
reversed by the administration of opioids associated with pain relief and 2) the subset of patients with pre-
existing chronic pain conditions will have predictable variance, with increases in baseline high beta/low gamma
signal compared to patients without chronic pain. Through the use of novel clinical-research hybrid electrodes
that allow for targeted, high-resolution electrophysiological recordings, candidate target regions will then be
stimulated in an effort to re-create the associated pain reduced state electrophysiologically and clinically. This
unique access into human pain circuits will guide further understanding of the physiology of these neural
signatures and advance the long-term goal of developing novel paradigms to therapeutically modulate cerebral
circuits for the treatment of chronic, intractable pain.
This mentored award will provide critical and tailored training in 1) advanced aspects of neurophysiology
2) human experimental and clinical trial design, 3) rigorous epidemiological methods, 4) advanced
biostatistics, and 5) validated psychophysical methods for the assessment of pain under the direction
of Dr. Eric Halgren, a leading human neurophysiologist. A complementary team of co-mentors, advisors,
and consultants has been assembled, including Mary Heinricher, a leader in the field of human and
animal pain modulation, Terry Sejnowski, a pioneer in the field of theoretical neurobiology, Mark Wallace,
an expert in the field of adult pain management, and Fadel Zeidan, an expert in the functional imaging of pain
pathways in humans. The proposed research alongside a detailed career-development plan will facilitate an
improved understanding of the anatomical and electrophysiological substrates of human pain, and lay the
foundation for a successful transition towards an independent research career focused on the data-driven
advancement of neurosurgical therapeutic modalities for chronic pain.

Grant Number: 5K08NS123543-04
NIH Institute/Center: NIH
Principal Investigator: Sharona Ben-Haim