Brain Size and Signal Decline with Advance of Schizophrenia

Schizophrenia was once considered to be a life sentence: once you were diagnosed, the damage was already done. But a new HMS study hints at a future when we may be able to interrupt this debilitating illness.

Courtesy Dean Salisbury

A measure of mental illness. A normal human brain (top left) and a schizophrenic’s brain at first hospitalization show no abnormalities in the Heschl gyrus. In schizophrenics, however, these areas decreased in size after 20 months. Similarly, subjects’ MMN brain wave amplitude (bottom left) dampened considerably from first hospitalization (Time 1) to 20 months later (Time 2). Researchers found that Heschl gyrus size and MMN amplitude were tightly correlated (right), providing a quantifiable index for brain damage in schizophrenia.

Dean Salisbury, HMS associate professor of psychiatry at McLean Hospital, and Robert McCarley, HMS professor of psychiatry at the VA Boston Healthcare System, have found both structural and functional evidence that schizophrenia is a progressive disorder, according to their report in the May Archives of General Psychiatry. “This changes our view of the disorder … and could possibly lead to a therapy that could arrest the course of schizophrenia,” said McCarley.

Researchers have debated whether or not schizophrenia, which attacks both the frontal and temporal lobes of the brain, is set at birth or develops over time. Previous magnetic resonance imaging (MRI) studies of schizophrenics showed no progressive changes in the brain, but a few studies near first hospitalization did show a change in brain size. Still, the results were controversial—stronger evidence was needed.

What researchers sought to uncover was a decrease in brain size that corresponded to a loss of brain function. Salisbury and McCarley found just that—a tight correlation between a brain wave called mismatch negativity (MMN) and the volume of the Heschl gyrus, a section of the temporal lobes.

MMN brain waves, caused by auditory cues, are tested by playing a series of identical beeps, with an occasional “oddball” beep thrown in. The brain automatically responds to this difference by producing an MMN, which originates from the Heschl gyrus.

In a series of three experiments spanning 18 months, McCarley and Salisbury found that schizophrenics’ MMN waves were initially normal, but quickly diminished over time. In one test group, 14 out of 16 schizophrenia patients displayed an MMN decline over time, and in an additional test, 11 out of 11 test subjects showed a combined decrease in Heschl gyrus volume and MMN response.

While the sample sizes were relatively small, the researchers noted that long-term studies with the psychiatrically ill can be difficult—half of their subjects never returned for further tests. However, McCarley and Salisbury are following up with another study of new patients as a replication sample.

Not only does the study give hope of ending the onslaught of schizophrenia, it provides a tool to monitor the process. “Drugs that try to halt the shrinkage [of the brain] can be developed, and we can use the MMN to track that,” said Salisbury.

Gregory Light, an assistant professor of psychiatry at the University of California, San Diego, who is not an author on the study, believes the work is groundbreaking: “It’s really a substantial contribution to the science of understanding schizophrenia,” he said.

—Lauren Cahoon

Tail Injection Cures Brain Inflammation in Mice

Overcoming two major hurdles, scientists have delivered small interfering RNA (siRNA) into the brains of mice with a tail vein injection and protected them from deadly viral encephalitis. The researchers designed a molecular package that crossed the blood–brain barrier and then spread through the brain to treat the disease.

The results, published online June 17 in Nature, suggest that it may be possible to direct promising gene-silencing therapies to the brain. In one experiment to test the specificity of the brain-targeting system, for example, the researchers knocked down SOD1, the most commonly mutated gene in the inherited form of amyotrophic lateral sclerosis (ALS), a common, fatal motor neuron disorder with no effective treatment.

“It’s a potentially big breakthrough,” said John Rossi, chair of molecular biology at the Beckman Research Institute in City of Hope, Calif., author of an accompanying commentary for the print edition. “It’s the first real clear-cut case of delivering siRNA into the brain without injecting directly into the brain.”

The project was conducted by postdoctoral fellow Priti Kumar in the lab of Premlata Shankar and Manjunath Swamy, HMS assistant professors of pediatrics at the Immune Disease Institute (formerly the CBR Institute for Biomedical Research).

The RNA fragment works against the fatal viral encephalitis by silencing a shared genetic sequence in the Japanese encephalitis virus and West Nile virus, two related mosquito-borne flaviruses, the researchers showed last year (see Focus, March 10, 2006). The big drawbacks were that the siRNA only worked in the localized infected cells near the injection site and could not travel through the brain like the viruses.

For the latest study, Kumar and her colleagues tried a lot of ways to deliver the siRNA to the brain through blood vessels.

tiny part of the rabies virus glycoprotein (RVG), first mapped by Yale researchers nearly 30 years ago, showed the most impressive diffusion throughout the mouse brains. The peptide binds to nicotinic acetylcholine receptors plentiful on the endothelial lining of brain capillary cells and on the neurons themselves. The authors believe RVG passes through capillary cells and travels into neurons.

Unfortunately, the peptide does not bind to nucleic acids. With the help of collaborators in Seoul, Korea, the team fused RVG to another cell-penetrating peptide composed of nine arginine (9R) residues that can carry siRNA into cells. Seven out of nine mice challenged with Japanese encephalitis virus survived after an intravenous injection of the RVG-9R carrying the siRNA, compared with none of the untreated infected mice.

“It is proof of principle, but there is a long list of things to do before it will be ready for clinical trials in people,” Swamy said.

The list includes further toxicology and bioavailability studies on the RVG-targeting peptide (named CORVUS by the institute’s technology development officer) as well as devising a better packaging system to ensure more siRNA arrives in the brain, Kumar said.

—Carol Cruzan Morton

Regulatory T Cells May Lull Immune Activators to Sleep

Caffeine, the world’s most relished drug, works in the brain by blocking the receptor for the sleep-inducing compound adenosine. It now appears that a recently discovered and hotly debated class of immune cells, the regulatory T cells, may take an opposite tack: producing adenosine for purposes of their own, namely, to quell other lymphocytes.

“Simplistically, one could say that these T regulatory cells, in generating adenosine, are putting T effector cells to sleep,” said Simon Robson. He and Terry Strom, both HMS professors of medicine in the Transplantation Center at Beth Israel Deaconess Medical Center, along with colleagues, report that adenosine production—and hence the T cells’ sleep-inducing effects—are the handiwork of two proteins found on the surface of the regulatory Ts. This is the first time the proteins, CD39 and CD73, have been identified on the surface of regulatory T cells. The findings, which appear in the May 14 Journal of Experimental Medicine, could lead to new approaches to identifying and understanding these elusive cells.

One of the big problems with regulatory T cell research is the lack of distinguishing features: the cells’ two main surface markers, CD4 and CD25, are found on other kinds of lymphocytes. Scientists have been searching for additional surface features. Robson and his colleagues had been studying how the ectoenzymes CD39 and CD73 help to quell clotting and inflammation in blood vessels. They knew the pair work hand in hand in endothelial cells to help produce extracellular adenosine. There were hints that CD39 might also play a role in the immune system, but it was not clear exactly how.

Using antibodies, Silvia Deaglio and Karen Dwyer, both HMS visiting assistant professors of medicine at BID, found the CD39 and CD73 markers were highly expressed on CD4+CD25+ T cells. Working with HMS instructor in medicine Wenda Gao, they confirmed that the ectoenzyme-bearing cells express other markers found on regulatory T cells and exhibit high levels of extracellular adenosine. The clincher came when the researchers cocultured separately the CD39-bearing cells and the CD39-knockout cells with T effector cells. Those bearing the CD39 protein suppressed T effector proliferation much more effectively.

Intriguingly, even the knockouts were able to suppress 50 percent of proliferation, suggesting that the CD39 adenosine-producing pathway is not the only suppressive mechanism in the regulatory T cell’s armamentarium, Robson said.

He and his colleagues also confirmed earlier work suggesting that adenosine is working on the effector cells through the A2A receptor. The findings could help open the door to new immune modulating therapies. “An A2A agonist could be used as an immune suppressant,” said Robson. “It may work to alleviate transplantation rejection, rheumatoid arthritis, inflammatory bowel disease, and other autoimmune conditions.”

—Misia Landau

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