Study on relationship between pain and higher brain functions

University of Texas Medical Branch at Galveston professor Volker Neugebauer has been awarded a four-year, $1.36 million grant by the National Institute of Neurological Disorders and Stroke to conduct an innovative study of the relationship between pain and parts of the brain associated with cognitive thought and emotional response.

The goal of Neugebauer's study is to understand a process that causes hyperactivity in the amygdala, a key emotional center, leading to persistent pain and uncomfortable states like fear and anxiety. The investigation will focus on pain-induced disruption of nerve-signal traffic between the amygdala and the medial prefrontal cortex, a region of the brain involved in so-called "executive" decision-making functions.

"Normally in the brain we have a balanced interaction between the amygdala and the prefrontal cortex, with the amygdala providing valuable emotion-based information to the cortex and the medial prefrontal cortex sending back signals that keep amygdala activity under control," Neugebauer said. "But abnormal pain input can trigger changes in the amygdala that enhance its output, overpowering the medial prefrontal cortex."

When this occurs, the medial prefrontal cortex loses the ability to control the amygdala, creating a vicious cycle of sustained disturbance.

"The amygdala activity continues independently of the original input, resulting in these persistent pain and emotion states," Neugebauer said. "We think this happens in chronic pain, and also in anxiety disorders and post-traumatic stress disorder, when the normal fear response persists abnormally. We're going to study the mechanics of this process, trying to identify specific targets that could allow us to regain control of amygdala activity."

To accomplish this objective, Neugebauer will conduct behavioral experiments and studies of brain electrical activity in laboratory rats that have been given experimental compounds known to increase cortical output. Then, working with thin slices of rat brain, he'll apply electrophysiological techniques that allow him to zero in on particular synapses - tiny gaps between nerve cells, across which signals are transmitted by molecules called neurotransmitters.

"In our behavioral studies we'll be doing tests to determine how our cortical manipulations affect decision-making, emotional aspects of behavior and anxiety-like behavior in rats suffering from pain very like that of arthritis," Neugebauer said. "Then we'll make electrophysiological recordings of individual neurons of intact, living animals - neurons in the cortex, neurons in the amygdala - as we manipulate cortical activity, so we can study this interaction. Finally, we'll take slices from the cortex and the amygdala, which allows us to pinpoint the site of drug action and the site of changes in a particular synapse."

Such detailed analysis of the engagement between the prefrontal cortex and the amygdala and its involvement in persistent pain and emotional disturbance has never been done before, Neugebauer said, and it has potential for broader applications; the brain circuits involved in addiction, for example, show similarities to those he will be investigating. In addition, he notes, better insights into the connections between a cognitive brain center and an emotional one may have implications for cognitive-behavioral therapy - a psychotherapeutic approach that emphasizes the use of cognitive techniques to overcome emotional distress.

"I'm not going to go so far as to say that this will definitely lead to a new pain therapy, but I think as a concept it could lead to a new strategy to deal with the more complex aspects of pain," Neugebauer said. "It should also be useful as a model, a tool for helping us understand more of how the brain is involved in these conditions when things go wrong. And finally, I think that it really has broad appeal for other fields, areas like PTSD, addiction and anxiety."