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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.

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