Summary

Three Mayo investigators have joined forces to discover better ways to treat carpal tunnel syndrome. In the short term this team wants to further define, develop, and validate an animal model that can be used to explain how carpal tunnel syndrome develops. Findings may lead to early detection, preventative strategies and new therapies that will reduce the need for surgical treatment of carpal tunnel syndrome.

If you've felt the numbness in the hand or the pain radiating from the fingers to the shoulder, you know how debilitating carpal tunnel syndrome can be. It affects 12 to 15 million people in the United States alone, but the factors that cause it remain a mystery. To solve medical mysteries, the team approach is a traditional strategy at Mayo Clinic that goes back to the Mayo brothers in the early part of the last century. In this case, a 21st Century team draws specialists together from the areas of orthopedics, biomechanics and neurology. Peter Amadio, M.D., Chair of Orthopedic Research at Mayo Clinic, has joined forces with Kai-Nan An, Ph.D., Co-Director of the Mayo Biomechanics and Motion Analysis Laboratory, and Phillip Low, M.D., Head of the Peripheral Nerve Laboratory, to investigate potential causes of carpal tunnel syndrome.

Benefits of a Team Approach

Medical knowledge and technological advances are evolving at an unprecedented rate, making it impossible for an individual investigator to keep up with everything in their chosen field. "Multidisciplinary collaboration is the future of biomedical scientific research," Says Dr. An. "Many of the clinical problems are so complex that they can only be addressed through the contribution of investigators with different backgrounds and perspectives."

Drs. Amadio, An, and Low, each have over 20 years of research experience at Mayo Clinic, and each has developed world-renowned expertise in a different area. They each bring a unique perspective and complementary set of skills to the study of carpal tunnel syndrome.

Dr. Amadio, the lead investigator on this project, is an orthopedic surgeon/scientist. "I enjoy working with him because he is forever looking at ways and means for improving the understanding of pathogenesis and pathophysiology, and translating that into the clinical practice," explains Dr. Low.

Left to right: Kai-Nan An, Ph.D., Phillip Low, M.D., and Peter Amadio, M.D.

Dr. An is a biomechanical engineer whose research interests have expanded to include soft tissue mechanics. To all that know and respect Dr. An, this statement by Dr. Low will come as no surprise, "Dr. An approaches his research the same way he approaches life, with gentleness and persistence."

"Dr. Low is a world-renowned neurologist with a special interest in peripheral nerve disorders." says Dr. An. He brings an expertise in nerve electrophysiology and morphology, as well as knowledge of nerve structure, function and response to injury.

The collaboration of Drs. Amadio, An and Low extends to embrace several members of their respective laboratories and includes the contributions of a molecular biologist, a histologist, a veterinarian, and additional engineers and clinicians.

"Together we approach the problem in a much more complete fashion, in a way that permits a more insightful understanding of the disorder," says Dr. Low.

Carpal Tunnel Syndrome

Carpal Tunnel Syndrome is the result of pressure placed on the median nerve, which causes pain, numbness, and tingling in the thumb and first two fingers. The carpal tunnel is an oval-shaped canal in the wrist that is surrounded by the carpal bones on one side and a tough sheath of connective tissue called the either the transverse carpal ligament or flexor retinaculum on the other. The median nerve and eight tendons are located within the carpal tunnel. Approximately half of the people who see a physician for carpal tunnel disease will undergo surgery to enlarge the carpal tunnel area, which releases the pressure on the median nerve.

Subsynovial Connective Tissue

Between the flexor retinaculum and the tendon lies the subsynovial connective tissue, connecting the tendons responsible for flexing the fingers with the synovial membrane that surrounds each tendon. Researchers know that the subsynovial connective tissue becomes thicker in people with carpal tunnel syndrome. The team's current activities build on the years of work conducted by Drs. Amadio and An investigating the subsynovial connective tissue in normal people and in people with carpal tunnel syndrome. Chunfeng Zhao, M.D., of the Biomechanics Laboratory, was responsible for the day-to-day management of the motion analysis and mechanical testing for these studies. Biomechanics Laboratory engineers Mark Zobitz and Lawrence Berglund contribute greatly to designing the mechanical modeling instrumentation and testing protocols.

"Carpal tunnel syndrome is believed to be related to the cumulative trauma of the connective tissue in the tunnel, which is caused by motion and force in the tissue," says Dr. An, "We translated the anatomy and physiology into a biomechanical model and addressed it analytically and experimentally."

Mayo Discoveries Thus Far

In people without a history of carpal tunnel syndrome:

• The layers of subsynovial connective tissue look like a flaky pastry, such as baklava.
• The layers of subsynovial connective tissue are loosely connected and move independently of the tendon in a sequential gliding motion. First the tendon moves, then the subsynovial connective tissue glides along it. Much like when your arm moves and your shirt sleeve slides along it.

In people with carpal tunnel syndrome:

• The layers of the subsynovial connective tissue are thickened and fused together.
• Two abnormal patterns of tendon/subsynovial connective tissue movement were observed.
  Pattern 1: The tendon and subsynovial connective tissue are attached to each other and move at the same time. This suggests that more force may be required to flex and move the wrist and respective finger, increasing the amount of force on the tendon and likely causing increased fatigue.
  Pattern 2: The subsynovial connective tissue rips free and no longer moves in a coordinated fashion with the tendon.
• With the help of ultrasound researcher Marek Belohlavek, M.D., Ph.D., the team adapted ultrasound technology to visualize the abnormal movement of the subsynovial connective tissue in relation to the tendon. This technology uses principles of ultrasound similar to those used for cardiovascular imaging of the moving heart or blood moving through vessels. In the future, this technology may be used for early diagnosis or screening people with an increased risk of developing carpal tunnel syndrome.
• Thickening of subsynovial connective tissue is worst closest to the tendon. This suggests that the thickened tissue may be the result of an injury that causes the subsynovial connective tissue to shear (stretch and/or split) and consequently form scar tissue. The team proposes that this scarring may impede the gliding of the subsynovial tissue over the tendon as well as the ability of the tendons to move independently of one another. Injury to the subsynovial connective tissue may also damage the blood supply to the tendon, synovial membrane and median nerve.

Validating the Animal Model

The team's hypothesis is that damage to the subsynovial connective tissue results in changes that lead to increased pressure within the carpal tunnel and compression of the median nerve. Studies are underway to validate that an animal model developed by the team does indeed mimic the development of carpal tunnel syndrome in humans.

Carpal tunnel-like thickening in the subsynovial connective tissue surrounding the tendon is produced by injecting a concentrated solution of dextrose—a form of sugar that is the main source of energy for cells. The hypothesis is that the concentrated solution perturbs the osmotic regulation of the cells, causing the liquid within the cells to be drawn out into the space surrounding the cells, leaving the cells dehydrated. Three to four months after this simple procedure, median nerve problems become apparent.

Normal connective tissue (top) and in carpal tunnel patient (bottom)

At specific time points the median nerves and surrounding tissue are evaluated by nerve conduction and histopathology studies. Histopathology is the microscopic study of slices of tissues that are stained to highlight certain types of cells. Hand surgeon Steven L. Moran, M.D., an expert in cytokine biology, along with Yu Long Sun, Ph.D., Biomechanics Laboratory, are responsible for microscopic analyses of tissues and cells. The nerve conduction studies are performed in Dr. Low's Peripheral Nerve Laboratory by James Schmelzer, an electrophysiologist with more than two decades of experience performing peripheral nerve testing. Electrophysiological conduction can estimate how many nerve fibers are working, measure how fast the impulses are traveling through the nerve fibers, and determine the type of nerve fiber (sensory nerves that receive stimuli or motor nerves that conduct impulses from the brain to contract muscles). Nerve conduction studies are performed by stimulating the nerve with a highly defined stimuli, and then using electrodes to record the output. Slowed impulses are associated with median nerve damage in carpal tunnel syndrome. Validation will be achieved if the data derived from the animal model closely mirror the data collected from humans.

Future Studies

Once the animal model is validated, it will be a valuable tool for future carpal tunnel studies. "The common thought is that carpal tunnel syndrome is caused by repetitive injury, but we really don't know that yet," says Dr. Amadio. "Indeed, we usually do not know the cause at all. That is why this work is so important. It will allow us to do something that is impossible in our patients." The team plans to investigate vascular changes found in the thickened connective tissue surrounding the tendon that may result in decreased nourishment to the surrounding tissues. Another focus is the decreased permeability of the thickened connective tissue that may trap fluid causing swelling and increased pressure on the nerve and other structures. They also want to study the thickening of the connective tissue itself that may impede the movement of tendons and cause additional strain. "If we can identify the sequence of events that leads to carpal tunnel syndrome, we can design more effective interventions to prevent or reverse it," says Dr. Amadio.