Brain Mechanisms of Pain Fear Acquisition and Extinction in Humans

Systems Neuroscience

Using intracranial recordings from patients with epilepsy, we aim to explore the brain mechanisms supporting pain-related fear acquisition and extinction

Sustained fear ofpain is an important component of chronic pain related disability, but itsunderlying neurophysiological mechanisms are less explored in humans. Thesemechanisms can be studied by classical learning and memory paradigm such asfear conditioning. During a fear conditioning paradigm, a conditioned stimulusis repeatedly paired with a noxious stimulus until the subjects shows aconditioned response to the conditioned stimulus. Using this simpleconditioning paradigm, decades of advanced neuroimaging studies have indicatedthat structures within the frontal and medical temporal lobes play a key rolesub-serving fear conditioning. For example, a large body neuroimaging studiespoint to that anterior cingulate cortex (ACC) is an essential component forattention and fear conditioning. The amygdala (AMY) is the key brain structuresub-serving fear learning. The hippocampus (HIP) is transiently involved inencoding the spatial memory, and the prefrontal cortex (PFC)–AMY interactionshave been shown to play a crucial role in the fear memory extinction. Moreimportantly, since many of the behavioral responses observed in fearconditioning paradigms are closely resemble the characteristic and physiologicalsymptoms of anxiety-related chronic disorders, it is generally accepted thatunderstanding the brain mechanisms of pain-related fear learning and extinctionwill have vital clinical relevance for the treatment of pain.

A hallmark of theneural activity in the brain that regulates and encodes learning and memoryis rhythmic discharges. Remarkably, little is known about the basicneurophysiological mechanisms in the neural circuitry supporting and mediatingfear conditioning in humans. There is a desperate need for uncovering such animportant brain mechanism. To uncover the neurophysiological mechanisms of fearconditioning in humans, the proposed research plans to study the intracranialrecordings obtained from patients with epilepsy and movement disorders duringfear conditioning. Patient participants will undergo intracranial recordings,basic structural MRI acquisitions as a part of the standard routine clinicalcare for their uncontrolled disease symptoms. In our pilot studies of pain, wehave identified several pain-related neural oscillations in the brain regionsthat have a role in processing and maintaining learning and memory in theproposed populations. With this 3Cavaliers award, the proposed research seeksto further test the hypothesis that the identified neural oscillations in thebrain are associated with behavior states, pain experience, and pain phenotype.More specifically, using brain recordings acquired from different human brainrecording platforms,  the proposed research aims to 1) furtherdelineate the brain oscillatory activities and brain network connectivity thatgive rise to fear of pain acquisition, 2) to study thebrain mechanisms mediating the pain fear extinction.

The proposed research represents a technical advancement based upon the resolutions ofneural oscillatory recordings directly acquired from different patientpopulations, which provide unprecedented temporal and spatial resolutions forstudying the fear conditioning related brain oscillatory activities in humans.Understanding the essential brain mechanisms underlying fear conditioning will greatlyincrease our ability to manage pain and will inform new development of moretargeted neuromodulation therapy for millions of patients suffer with uncontrolledpain.

I am willing to self-fund my token, Chang-Chia Liu, Ph.D.

Desired outcomes

Using brain recordings acquired from different human brainrecording platforms,  the proposed research aims to 1) delineate the brain oscillatory activities and brain network connectivity thatgive rise to fear of pain, 2) to explore thebrain mechanism mediating the pain fear extinction in humans.