Magnetic-Stimulation Trial Reveals Difficulty of Studying Brain-damage Treatments

by Aalok Mehta

January 26, 2009

It sounds like a miracle—a new study showing dramatic improvement in a brain-damaged patient after six weeks of experimental transcranial magnetic stimulation (TMS) treatment.

Josh Villa, who entered a vegetative state after he was severely injured in a car crash, can now respond to simple questions and mumble words, greatly easing the burden of his caretakers, says Theresa Pape, lead author of the study, which was published online Oct. 24 in Brain Stimulation.

But experts warn that such a short trial, though tantalizing, offers little hard evidence as to whether TMS actually helped the patient or if the recovery was spontaneous, which is not uncommon in the 18 months following a brain injury.

The uncertainty underscores the difficulties doctors face in developing effective therapies for patients in comas or vegetative states. With their limited knowledge of how the brain responds to trauma, scientists must rely on long, complex trials to fully vet potential new treatments.

“The difficulty of such studies cannot be overemphasized,” says Nicholas Schiff, a neurologist at Weill Cornell Medical College. “Recovery from multifocal brain injury is a complex and poorly understood process, which places severe demands on study design, data collection and analysis methods.”

‘Significant’ changes …

TMS—in which an electromagnetic coil is used to incite electrical activity in the brain—has been explored for the treatment of stroke, Parkinson’s disease and other conditions. The U.S. Food and Drug Administration also recently cleared a TMS device for use in severe cases of depression.

Pape, a clinical neuroscientist at the U.S. Department of Veterans Affairs in Chicago, decided to test the technique on Villa about a year after his accident. The scientists targeted Villa’s right dorsolateral prefrontal cortex, a region of the brain tied to attention and memory.

Though the study was designed to look primarily at safety, after 30 sessions of treatment Villa’s behavior showed significant changes, Pape says. He began to notice when people were talking to him and started obeying one-step commands; then he began mumbling slurred but recognizable words such as “help.”

“He was in a vegetative state—essentially unresponsive,” Pape says. “He progressed to a minimally conscious state.

“We actually saw more neurobehavioral gains than I could have hoped for. We expected to see small gains. We didn’t expect this.”

After the initial treatments ended, however, Villa’s condition regressed slightly, and 10 additional sessions offered no further improvements, Pape says.

… But insignificant results?

But even making small efficacy claims based on this study is problematic, says Schiff, who just last year reported promising results from a deep brain stimulation (DBS) trial on a brain-damaged patient. Unlike this safety study, a proper efficacy study would have looked at patients further removed from their time of injury and would have used off-and-on rounds of treatment to quantify the effects.

“The study presented does not actually indicate any linkage of the rTMS [repetitive transcranial magnetic stimulation] to the behavioral changes in the patient, who, as the authors note, had between a 20 and 44 percent chance of spontaneous recovery to the level observed by one year,” he says.

“As far as I can tell, this report shows that the patient was not adversely affected by rTMS and that there was a loose temporal correlation with the application of rTMS that was not statistically linked to the rTMS.”

But he offered a note of hope for future studies, such as one planned by Pape on a second patient, since TMS affects many of the same brain areas he has pinpointed in his DBS studies. “The rationale is there,” he says. “If DBS worked, one might expect TMS to work as well.”