Functional MRI: Unlocking the Mystery of Chronic Pain

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Voyages into "Inner space" can be as exciting as ones into outer space. One of the most mysterious parts of the human inner universe is the brain. As Winston Churchill said of Russia, "It is a riddle wrapped in a mystery inside an enigma." However, modern science is beginning to unlock its secrets. An important one for many O&P patients is the mystery of chronic pain.

"More than 50 million people in the United States are living with chronic pain" Professor Richard Chapman, PhD, told The O&P EDGE. Chapman is director of the Pain Research Center in the Anesthesiology Department at the University of Utah School of Medicine, Salt Lake City. "Many of them have no identifiable source of pain, and for those who do, the suffering is way out of proportion to the source. About 85 percent of back pain has no identifiable cause."

One type of chronic pain has been a mystery in both etiology and treatment, lingering long after the injury or condition that caused it has healed, or tormenting its sufferers without a discernible physical cause. This type of pain-complex regional pain syndrome (CRPS)-is a chronic disorder characterized by continuous, intense pain that is out of proportion to the original injury or has no identifiable initiating cause. CRPS-I, also known as reflex sympathetic dystrophy, occurs without an identified cause; CRPS-II, also known as causalgia, results from an identified nerve injury; however, the injury often is minor and well-healed. CRPS most often affects arms, legs, hands, and feet, with dramatic changes in color and temperature of the skin over the affected body part, accompanied by intense burning pain, allodynia (painful skin sensations triggered by stimuli that normally are not painful, such as a light touch or a breeze), sweating, and swelling.

As an example of how intense the suffering can be, two Israeli patients, who were later part of a research study, had their limbs amputated by a medical team in Haifa, Israel, in a desperate effort to end their pain. One had suffered a rotator cuff injury, the other, a broken toe.

The out-of-proportion severity of the pain had led many health professionals and others to consider the symptoms as psychological in nature rather than the result of physical damage. However, research studies have solved at least part of the mystery

Damage Is Real

At the time of these studies, researchers noted that although nerve damage is identifiable in CRPS-II, no research had yet shown actual nerve involvement in CRPS-I. In 2005, a research team from the Albany Medical College, New York, performed a microscopic, intricate analysis of skin specimens from the two Israelis. The examination showed that all sites in the skin where nerve endings were present, including hair follicles, blood vessels, sweat glands, and epidermis, were markedly abnormal. Results of the study, headed by Frank L. Rice, PhD, and Phillip J. Albrecht, PhD, of the Center for Neuropharmacology and Neuroscience at Albany Medical College, were presented in the article, "Pathologic Alterations of Cutaneous Innervation and Vasculature in Affected Limbs from Patients with Complex Regional Pain Syndrome," in the February 2006 issue of Pain, published by the International Association for the Study of Pain (IASP).

A team headed by Anne Louise Oaklander, MD, PhD, from Massachusetts General Hospital, Boston, a teaching and research hospital, was pursuing similar research. Since small-fiber nerve endings transmit pain messages and control skin color and temperature, and because damage to those fibers is associated with other painful conditions, the team hypothesized that these fibers also could be involved in CRPS-I.

Learned control of brain activity leads to improved pain control.  This figure shows increases in brain activity in the anterior cingulate cortex, a brain region involved with the perception of pain.  Increased control of this region led to corresponding changes in pain.
Learned control of brain activity leads to improved pain control. This figure shows increases in brain activity in the anterior cingulate cortex, a brain region involved with the perception of pain. Increased control of this region led to corresponding changes in pain.

The team studied 18 CRPS-I patients and seven control patients with similar chronic pain known to be caused by arthritis. Skin biopsies from affected and unaffected areas of the CRPS-I patients' bodies showed that the density of small-fiber nerve endings was reduced by 25 to 30 percent in affected areas compared with unaffected areas. The arthritis patients did not have comparable nerve loss, indicating that the damage was specific to CRPS-I, not chronic pain in general. "These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI [minimal distal nerve injury] affecting nociceptive small-fibers," Oaklander stated in the study, "Evidence of Focal Small-Fiber Axonal Degeneration in Complex Regional Pain Syndrome-I (Reflex Sympathetic Dystrophy)," also published in Pain, February 2006. "This type of nerve injury will remain undetected in most clinical settings," she added.

Brain Area Shrinks in Chronic Pain Sufferers

A scary part of chronic pain, including CRPS, is that it can involve loss of neocortical gray matter in the prefrontal cortex of the brain-the part of the brain involved in interpreting data and decision-making. A study headed by A. Vania Apkarian, PhD, of the Northwestern University Feinberg School of Medicine Physiology Department, Chicago, Illinois, showed that patients with chronic back pain (CBP) displayed 5 to 11 percent less neocortical gray-matter volume than control subjects. The magnitude of this decrease is equivalent to the gray-matter volume lost in 10 to 20 years of normal aging. "The decreased volume was related to pain duration, indicating a 1.3 cm 3 loss of gray matter for every year of chronic pain," according to the study ("Chronic Back Pain Is Associated with Decreased Prefrontal and Thalamic Gray Matter Density," The Journal of Neuroscience, November 17, 2004).

Another study headed by Apkarian ("Chronic Pain Patients Are Impaired on an Emotional Decision-Making Task"), published in Pain, March 2004, revealed that "chronic pain is associated with a specific cognitive deficit, which may impact everyday behavior, especially in risky, emotionally laden situations." However, other cognitive abilities, such as attention, short-term memory, and general intelligence tested normal.

If people recover from, or better control, chronic pain, can this gray-matter atrophy be reversed? "That's an important question," Apkarian told The O&P EDGE. "We don't have the answer yet."

Chronic pain can lead to depression, discouragement, fatigue, and family and career issues, Chapman notes.

The sooner patients with chronic pain seek treatment, the better.

Functional MRI: Unlocking Mysteries

A large part of chronic pain's mystery is why and how the brain amplifies pain messages, and why it seems to replay them over and over, like a CD on autoplay, even after the original stimulus, if there was one, has healed. To top off the problem, drugs and therapies that help alleviate acute pain often do little or nothing to help chronic pain sufferers.

A new technology, functional magnetic resonance imaging (fMRI), which allows researchers to view brain activity in near-real time, is opening a window into the brain. Previously, MRI mages required hours or even days for processing.

Functional MRI has revealed that chronic pain is largely wocessed in a different brain region than acute pain, which explains why treatments for acute pain have little effect on chronic pain. The technology has opened the door to biofeedback pain control as well as improved testing of new drugs and other therapies.

To help explain the mechanism of chronic pain, "you have to distinguish between 'pain'-a conscious construct of the mind, which involves emotional, subjective reaction-and 'nociception,' the electrical signals that travel to the brain during an injury or insult somewhere in the body," says Sean Mackey, MD, PhD, Neuroscience Institute, Stanford University, California. Pain can thus be generated and maintained within the brain itself, he explains. One example is when a stroke affects certain brain areas, such as the thalamus. This can cause the patient to suffer terrible, burning pain in undamaged parts of the body, from which no nociceptive messages are being sent.

Using fMRI, Mackey and his associates researched whether or lot people could potentially learn to control their pain through feedback. The researchers asked two basic questions: (1) Can people, when seeing their own brain activity in real time, learn to control it, making their brain stronger in that area; and (2) does that increase in activity lead to a change in people's perception or behavior associated with that region [perceiving less pain]?" The answers turned out to be "yes."

These results open the door to other possible areas, Mackey quotes. Could people use a similar technique to control drug and alcohol addiction, anxiety, and depression? Could they systematically increase brain performance in areas related to reasoning and memory, much like exercising one's muscles in a gym? These goals may be possible, Mackey says, but they bring up ethical issues. For instance, given the fierce competition to get into top-notch universities, would some parents send their children for this type of treatment to "pump p" their kids' brains in certain areas, giving those children in unfair advantage? Mackey also emphasizes that the technology is not a currently available treatment for chronic pain although it offers possibilities for the future.

"We'd like to get to the heart of how people change their pain activity in real time, how they engage that brain region," Mackey says. "We really don't know." Functional MRI also can show the effects of drugs and other therapies on the brain region that processes chronic pain.

A study headed by Apkarian shows promising results for d-cycloserine, which has been used as an antibiotic and for various psychiatric conditions.

While some cases of chronic pain may be literally "all in the head," the physical, functional, and emotional harm is real and quantifiable. The frontiers the brain's mysteries are being explored, and the future of chronic pain treatment looks promising.

Miki Fairley is a contributing editor for The O&P EDGE and a freelance writer based in southwest Colorado. She can be contacted via e-mail: