Phantom Limbs and Rewired Brains

Phantom arms, legs, fingers and toes: seemingly the stuff of horror movies. Yet for nearly 70 percent of the 4 million amputees in the United States, vivid sensations in missing body parts-such as pressure, tingling, warmth, cold, and pain that can be both constant and excruciating-are all too real.

Phantom limbs have puzzled scientists for years. But recent studies have shed light on possible mechanisms underlying the phenomenon, including evidence that neurons in the brain that receive input from a limb may rewire themselves to seek input from other sources after the limb is amputated. These findings challenge the long-standing belief that the brain is immutable beyond a certain age and are leading researchers to develop new therapies for victims of phantom-limb pain and some spinal-cord injuries.

For years, psychologists attributed phantom-limb sensations to “wish fulfillment,” a purely psychological condition. Then, in 1984, a team led by Michael Merzenich, a neuroscientist at the University of California at San Francisco, conducted experiments that began to explain phantom limbs as a true physiological response. Merzenich and his colleagues first amputated the middle fingers from a group of adult owl monkeys and later stimulated the digits on the hand of each monkey that were adjacent to the amputation stump.

Placing microelectrodes, which detect electrochemical changes in actively firing neurons, into various areas of the monkeys’ brains, Merzenich found that the region of the cortex that originally fired in response to stimulation of the amputated finger was now triggered every time he touched the two adjacent fingers. The neurons had not responded to stimulation of these fingers before the amputation.

In 1991, Timothy Pons, a neuroscientist at the Laboratory of Neuropsychology at the National Institute of Mental Health, expanded on Merzenich’s findings. Working with adult macaque monkeys, Pons and his colleagues “deafferentated,” or cut, nerves that communicated sensory information between the cortex and the arm, forearm, hand, and rear of the head. The team then stimulated various body parts and found that the part of the cortex that had previously responded to the arm and back of the head now responded to stimulation of the face. Like ivy spreading over bare brick, Pons believes, surrounding neurons invaded the fallow cortical area corresponding to the deafferentated limbs, allowing it to respond to stimulation from other parts of the body.

Human Trials

The following year, Vilayanur Ramachandran, a neuroscientist at the University of California at San Diego, conducted experiments on people who had an arm or a finger amputated. Blindfolding his patients, he applied pressure to different parts of their bodies. Corroborating Pons’s results, Ramachandran discovered several subjects who reported that pressure applied to the face felt like it was coming from both the face and the phantom hand.

Ramachandran says that this finding made sense because the cortical territory once corresponding to the arm resided next to that corresponding to the face. And just as people standing next to barstools in a crowded bar are most likely to get those seats when people leave, neurons close to an area that no longer receives input have the best opportunity to move in.

Ramachandran reasoned that the pain associated with phantom limbs might result when the neurons move into new areas but do a faulty job of rewiring themselves. Errors in cortical remapping, he says, such as “cross wiring” of touch and pain input could account for pain in, say, a phantom arm that occurs from a benign touch on the face.

The human studies also showed that cortical reorganization occurred more quickly than previously suspected. While Pons had studied primates who had been deafferentated for 11 years, Ramachandran found similar evidence in people whose limbs had been amputated only four weeks before the experiments.
The notion of neural regrowth and cortical reorganization represents a radical shift in the way scientists view the brain. “Historically, it was thought that there is a critical window of opportunity during development when the brain is wired,” says Pons. Now, he says, it appears that the brain exhibits a surprising amount of plasticity throughout life.

Potential Therapies

Such plasticity could be the key to potential therapies not only for phantom-limb pain but also other afflictions of the central nervous system as well, including spinal-cord injuries in which inflammation or pressure is blocking neural pathways. In fact, over the past several months, Pons and his colleague David Good, director of the Bowman Gray School of Medicine Rehabilitation Center at Wake Forest University in North Carolina, have been observing patients with spinal cord injuries, comparing the degree of recovery to the amount of cortical reorganization as measured by MRI scans.

As expected, the researchers discovered that those who experienced the least amount of reorganization also had the most complete recovery. If the neurons do not reorganize, Pons explains, “then once things return to normal in the spinal cord, the cortex will remain unchanged and be able to function with the spinal cord the way it used to.”

Pons and Good think that artificially preventing cortical reorganization could thus help patients recover from such spinal-cord injuries, though they caution the approach would be of no use in cases where the spinal cord is actually severed. One approach to blocking cortical reorganization that the researchers are investigating entails the use of DAP-V, a drug that inhibits the electrochemical activity of glutamate, a neurotransmitter in the brain.

Normally, glutamate enables communication between neurons as they pass electrochemical messages to one another from an external stimulus, such as a blow to the hand, all the way to the brain. Similarly, after a spinal-cord injury or amputation-when neurons suddenly stop receiving input signals from their neighbors-glutamate enables the abandoned neurons to connect with other neurons that will provide them with stimulation, thereby enhancing cortical reorganization.

Pons and Good say that binding up glutamate receptors with DAP-V will prevent neuron-to-neuron communication, so that the abandoned neurons, which are no longer communicating with their lifelong partners, won’t be able to communicate with any potential new partners, either. Therefore, the researchers believe, neurons will stay tethered to their mates. And when the blockage to the spinal-cord dissipates, the original cortical connections and functions will remain intact.

Finally, because the cortical reorganization that takes place following amputation is so similar to the rewiring that occurs after spinal-cord injuries, Pons is hopeful that a pharmacological agent like DAP-V that prevents neural reorganization in the cortex might also help prevent phantom-limb pain in amputees. The researchers caution, however, that this research is in its infancy and has yet to address basic issues such as how the drug might be administered and whether it could be given for a brief period following amputation or whether it must be administered indefinitely.