Quieting the voices of schizophrenia

In early trials, magnetic stimulation is shown effective in halting or reducing auditory hallucinations.

Nearly 20 years ago when Stan W. was out on the high seas, menacing voices began to torment him. They told him that his commanding officer was the devil and that he should dive off the boat. Soon thereafter, he was discharged from the Coast Guard and diagnosed with schizophrenia, a form of psychosis that affects about 1 percent of the world’s population. Plagued by voices and at times unable to distinguish reality from illusion, Stan W. could not hold a job and was intermittently hospitalized. Doctors tried to control his symptoms with antipsychotic drugs, but to no avail. When the 48-year-old man arrived at Yale’s Schizophrenia Research Clinic about a year ago, he was experiencing some 400 auditory hallucinations a day, voices that told him, “Go slit your throat with a razor,” “Go get drunk” and “You are stupid.”

A year later, following an experimental treatment that uses electromagnetic waves to reduce brain activity in the area thought to produce auditory hallucinations, Stan W.’s voices have been quieted and he plans to be married. “He’s not cured, but he feels much better,” said Ralph E. Hoffman, M.D., assistant medical director of the Yale-New Haven Psychiatric Hospital and an associate professor of psychiatry. (The names and some of the details of the patients’ stories have been changed to protect their privacy.)

Schizophrenia, one of the most complex and puzzling mental illnesses, as yet has no cure. The delusions, hallucinations and disordered thinking that often accompany the disease prompt one in 10 people with schizophrenia to commit suicide; hundreds of thousands are permanently debilitated by the disorder. While many patients have been able to suppress their symptoms with drugs, a quarter of all schizophrenics who hear voices don’t respond well, or at all, to medication.

At Yale, Hoffman has designed treatments using repetitive transcranial magnetic stimulation (rTMS), a therapy used since the mid-1990s to help patients with severe depression. The procedure uses a high-powered electromagnet to target the speech-processing areas of the brain from which auditory hallucinations are thought to arise. Previous research had shown that rTMS, when delivered to the scalp, produces an electrical current in the brain itself and, if given once per second for 15 minutes, can selectively reduce brain reactivity. The region of the cerebral cortex that is altered is relatively small, from 2 to 4 centimeters in diameter. Studies in animal models have suggested that these results can be sustained weeks after rTMS is applied. Building on this information, as well as on experiments suggesting that auditory hallucinations may be generated, at least in part, by the activation of neurocircuitry underlying speech perception, Hoffman set out to see if rTMS could calm the voices inside schizophrenic patients’ heads.

While his research is in the early stages, findings have indicated that rTMS may be able to silence, or at least quiet, the hallucinations in some patients by reducing neural activity in the left temporoparietal cortex or other targeted speech-processing areas. “There’s some evidence suggesting perhaps that what we are doing is selectively eliminating abnormal brain activation, while leaving normal brain processes unimpaired,” he said.

Hoffman’s experiments using rTMS to treat schizophrenics made headlines in March 2000, following publication of his initial findings in The Lancet. His study showed that eight of 12 patients treated with 40 minutes of magnetic stimulation above the left ear had the severity and frequency of their voices drop by half. Most patients experienced relief that lasted from one day to two weeks. These results were found to be statistically significant compared to those for a placebo control group. In a follow-up trial, Hoffman increased the length of the magnetic stimulation threefold and found that the degree and duration of improvement in patients rose dramatically. About three-quarters of the 24 patients showed significant benefit from the treatment and half had their voices quieted or silenced for at least four months. For some patients these improvements have lasted more than one year.

During the procedure, a small electromagnetic coil is placed on the scalp and pulses roughly the strength of an MRI scan pass through the skull. While most of his studies have focused on the left temporoparietal cortex, Hoffman is also using neuroimaging studies of hallucinating patients to find other parts of the brain, such as the prefrontal cortex, Wernicke’s area and Broca’s area, that may be targeted in particular individuals to stop their hallucinations more effectively. Robert J. Buchanan, M.D., and Kun Wu, M.D., Ph.D., in the Department of Neurosurgery, are helping to develop a computer imaging system for visualizing the scalp locations corresponding to these brain areas that in certain cases are also pathologically active during hallucinations.

While Hoffman emphasizes that more research needs to be done to determine whether rTMS can be used safely and effectively as an alternative treatment, many of his patients have reported significant relief. Victor B., a 50-year-old business owner and father, has suffered from schizophrenia since his mid-30s. “I became so paranoid and dysfunctional that I was afraid to leave home.” Medication had failed to help him and he said that many times suicide seemed the only escape from the terrifying voices.

The first rTMS study at Yale provided significant relief for Victor B., reducing the severity of his hallucinations from about 500 per day to about 70 a day for several months. Since his second trial a few months ago using a higher dosage of rTMS that was positioned using neuroimaging data, he says his voices have disappeared entirely.

Hearing sounds, not words

In a recent experiment conducted by Yale scientists, bird songs, a dog’s bark and snowflakes stuck in the memories of people with schizophrenia, while simple words did not. In other words, verbal memories posed a greater difficulty to people with schizophrenia than did nonverbal memories. This could have a profound effect on cognitive function, said Bruce Wexler, M.D., associate professor of psychiatry and principal investigator on the study published earlier this year in Schizophrenia Research. “The use of internal language mechanisms to enhance cognition,” said Wexler, “is an essential aspect of a wide range of normal human brain functions.”

Et Cetera

A definite link to diabetes

For the past decade, pediatricians have noticed an upswing in the number of young patients presenting with type 2, or adult-onset, diabetes—a diagnosis almost unheard of in children until recently. Now the anecdotal evidence has been quantified and linked to the rise in childhood obesity. In an article published in March in The New England Journal of Medicine, Yale pediatric endocrinologist Sonia Caprio, M.D., and colleagues reported that of 167 severely obese children and adolescents a quarter of the children and 21 percent of the adolescents exhibited glucose intolerance, an indicator of diabetes. That intolerance was as prevalent among Caucasians as it was among Hispanics and African-Americans. Long-term complications of diabetes include premature atherosclerosis, early coronary artery disease, kidney disorders, eye disorders and nerve problems.

Schwann cells transplanted again

A second patient at Yale has received a transplant of cells in an ongoing clinical trial that is attempting to treat multiple sclerosis by repairing myelin in the brain and spinal cord. “The patient is doing fine,” said Timothy L. Vollmer, M.D., HS ’83, associate professor of neurology. “He has a high level of disability because of the location of the lesions in his brain, but he is otherwise healthy.”

Vollmer and his team performed the surgery in two stages in early March, and the 29-year-old patient was discharged a few days later. The team harvested Schwann cells found in peripheral nerves of the patient’s ankle and transplanted them into his brain. Their goal is to determine whether the Schwann cells survive in the brain and are able to restore myelin, a protective sheathing that is destroyed by multiple sclerosis.

Five patients are scheduled to participate in this clinical trial. The first was a woman who received a transplant last July. The trial is supported by the Myelin Project.


			Originally published in Yale Medicine, Summer 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.