McLean Hospital and Children's Hospital Boston Research May Lead to New Therapeutic Approaches to Chronic Pain

The first-ever functional brain imaging study of chronic pain conducted in children, done by researchers at Harvard-affiliated McLean Hospital and Children's Hospital Boston, has shed new light on a mysterious condition known as complex regional pain syndrome (CRPS) and offers hope for a better understanding of the disorder in both children and adults. The study, supported by the Mayday Fund of New York, is the result of a joint effort between researchers at Children's who treated the patients in the study and the P.A.I.N. (Pain & Analgesia Imaging and Neuroscience) group at McLean, who conducted the imaging tests.

"Studying pain in children offers us insights into how the brain may cure itself because the young brain is so adaptable relative to the adult brain," says David Borsook, MD, PhD, director of the P.A.I.N. group at McLean, and senior author of the study published in the current issue of Brain (abstract). "This may offer very important insights into the development of new therapeutic approaches to chronic pain-a condition that more than 50 million Americans suffer from with relatively little in terms of highly effective therapies."

CPRS is a disorder of the peripheral nervous system characterized by severe pain, hypersensitivity to stimuli, poor circulation, abnormal sweating, muscle atrophy, joint problems, movement disorders and cognitive changes, among other symptoms.

"This is a significant pain problem that often leaves individuals incapacitated, wheel chair-bound and limited in their physical abilities," notes Borsook, who added that in the pediatric population, girls are affected more frequently than boys. "It can be difficult to diagnose and without proper treatment children and adults living with CPRS live in absolute agony."

Typically, the condition stems from an initial injury, usually the hands or feet, and spreads sometimes to the opposite limb or side of the body, even to the entire body. It is more common in women and is now being seen in some girls after they have suffered sports injuries.

"CRPS is a frightening illness because it can develop as a result of a seemingly trivial injury," says Borsook. "For example, a 14-year-old girl can sprain an ankle during a basketball game, but what seems like a common and easily treatable injury can develop in to CRPS, causing extreme pain throughout her body."

In their novel study, the McLean and Children's researchers developed the first model of the illness that allows them to examine the efficacy of interventional treatments."

"The central nervous system imaging of pain in pediatric patients is a nascent development within the increasingly productive field of functional MRI (fMRI)," explains Alyssa Lebel, MD, senior associate in Pain Medicine and Neurology at Children's and first author on the paper. "This non-invasive technique provides a unique window into regions of the brain actively engaged in pain transmission and modulation. Contrast to adult, pediatric patients are still developing these regions, along with their connections, and may show fMRI patterns of activation in response to pain that differ from adults. Additionally, children often recover symptomatically from painful disorders, such as CRPS."

Lebel notes that the research team's data provides early information about provocative changes in central nervous system (CNS) circuitry in symptomatic and recovered patients with CRPS, as well as demonstrates that the technique is tolerable and acceptable to children with neuropathic pain.

"We will continue to study pediatric patients with CRPS and with other painful disorders, such as headache, to begin to define the pediatric CNS circuitry of acute and chronic pain," says Lebel. "Such information may eventually allow current and novel therapeutic interventions to target the CNS processes ultimately responsible for the complex sensory and emotional experience of pediatric pain."

   In children, the symptoms often appear to resolve in time, while in adults resolution is less common. Treatment is generally limited to pain medications and physical therapy. Because the symptoms in children frequently reverse, the researchers decided to image the brains of children with the condition both while symptoms were present and then after the symptoms had gone away-a comparison that cannot be done in adults.

"Our team took advantage of the opportunity to look at children in the pain state and the non-pain state," said Borsook, who is co-director of the P.A.I.N. Group of the Department of Radiology at Children's with Lino Becerra, PhD. "We were trying to define what happens to a changing brain as it adapts over time in those afflicted with this syndrome." A key advantage of imaging children is that they do not usually have other illnesses and are not typically on other medications that might influence the findings, he adds.

"This paper is not just a first for kids, but also has implications for understanding the adult condition," he said.

The imaging studies revealed some unexpected findings. Most importantly, the images taken in the non-pain state showed that brain recovery was not complete.

"The brain changes seen during the pain state don't disappear during the early non-pain state. As a result, subsequent injuries could rekindle the condition or other problems could occur later," Borsook warns.

Further studies will seek to evaluate how long it takes brains to recover fully and determine the efficacy of treatments.

"Our results suggest significant changes in CNS circuitry in pediatric patients with CRPS may outlast the signs and symptoms," report the authors. They conclude that even with a more rapid resolution of pain in children, the effect of the nerve damage and other changes that occur in CRPS at a time of development of brain connections may have prolonged effects upon brain circuitry. This could impact upon pain processing in these individuals later in life.

This initial research has been pivotal in establishing a newly formed program P.A.I.N. Group at Children's using fMRI to evaluate pediatric pain disorders; the program has been supported by the hospital and the Departments of Radiology and Anesthesiology.

"It brings new research to understanding acute and chronic pain disorders in childhood," says Borsook. "Furthermore, it integrates programs that are already at the forefront of pediatric pain treatment (such as the newly established Mayo Pediatric Pain Rehabilitation Program at Children's) with modern neuroimaging facilities recently established at Children's Waltham."

 

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