Researchers develop new model to study schizophrenia and other neurological conditions

August 30, 2013, Salk Institute
From Left to Right are: Gene Stoner, Raynard Fung, Ricardo Gil Da Costa and Tom Albright. Credit: Salk Institute for Biological Studies

Schizophrenia is one of the most devastating neurological conditions, with only 30 percent of sufferers ever experiencing full recovery. While current medications can control most psychotic symptoms, their side effects can leave individuals so severely impaired that the disease ranks among the top ten causes of disability in developed countries.

Now, in this week's issue of the Proceedings of the National Academy of Sciences, Thomas Albright and Ricardo Gil-da-Costa of the Salk Institute for Biological Studies describe a that completes the bridge between cellular and human studies of schizophrenia, an advance that should help speed the development of therapeutics for schizophrenia and other neurological disorders.

"Part of the terror of schizophrenia is that the brain can't properly integrate sensory information, so the world is a disorientating series of unrelated bits of input," says Albright, the Conrad T. Prebys Chair in Vision Research. "We've created a model that tests the ability to do sensory integration, which should be extremely useful for ."

Currently, over 1.1 percent of the world's population has schizophrenia, with an estimated three million individuals in the United States alone. The economic cost is high: In 2002, Americans spent nearly $63 billion on treatment and managing disability. The emotional cost is higher still: Ten percent of those with schizophrenia are driven to commit suicide by the burden of coping with the disease.

Initially, it was thought that excessive amounts of the dopamine caused , and indeed, current work by blocking dopamine from entering brain cells. But nearly all of these drugs have severe cognitive side effects, which led researchers to speculate that some other mechanism must also be involved.

A major clue to understanding schizophrenia came with the development of phencyclidine (PCP) in 1956. It was intended to keep patients safely asleep during surgeries, but many woke up with symptoms similar to those experienced by people with schizophrenia, including hallucinations and the disorientation of feeling "dissociated" from their limbs, resulting in PCP being abandoned for clinical purposes. A decade later, it was replaced by a derivative called ketamine. At doses high enough to put patients to sleep, ketamine is an effective anesthetic. At lower doses, it temporarily produces the same schizophrenia-like effects as PCP.

The two drugs are part of a class called N-methyl-D-aspartate receptor antagonists. Essentially, they work by gumming up the mechanism by which glutamate, the main excitatory neurotransmitter, would enter . Thus, it is clear that dopamine dysfunction accounts for some of the symptoms of psychosis, although that is probably not the full story.

"While dopamine has limited reach in the brain, any dysfunction in glutamate would be expected to have the sort of widespread effects we see in the perceptual disorders associated with schizophrenia," says Albright. "Nevertheless, which neurotransmitter was primary to these disorders——glutamate or dopamine—— has been argued about for years."

Standing in the way of a definitive answer was a researcher's Catch-22: Many experiments designed to understand cognitive disorders such as schizophrenia or Alzheimer's require a participant's conscious attention-yet these disorders interfere with attention.

To get around this, scientists turned to electroencephalograms (EEGs), which can be used to detect changes in cases where a subject is not consciously paying attention to a stimulus, by recording the brain's electrical signals through electrodes placed in a scalp cap. In one test, a series of tones is played, but an "oddball" tone breaks the pattern in the sequence. A healthy brain can still easily spot the differences, even if a participant is concentrating on another task, such as reading a magazine.

"The test works because the brain is a prediction machine-it's built to anticipate what should come next," says Albright. "If you have healthy working memory, you should be able to perceive a pattern and notice when something violates it, but patients suffering from some mental health disorders lack that basic ability."

In their latest research, Albright's team detected the difference through two signals, event-related brain potentials called mismatch negativity (MMN) and P3. The MMN reflects differential brain activity to the detected oddball tone, below the level of conscious awareness. P3 picks up the next phase: a subject's attention orientation to the oddball tone.

Still, a gap in understanding remained. While scientists could do cellular work in animal models on the role of dopamine versus glutamate, and they could do EEGs in human beings, a bridge between the two remained elusive. Such a bridge can help scientists understanding of how healthy and disordered brains work from the cellular level all the way to the multiple interactions between brain areas. Moreover, it can enable pre-clinical and clinical trials linking cellular and systems levels for successful therapeutic avenues.

Gil-da-Costa has at last crossed the bridge by crafting the first non-invasive scalp EEG setup that records accurately from the brains of non-human primates, with the same proportional density of electrodes as a human cap and no distortions in signal caused by an incorrect fit. This setup allows him to get accurate measurements of MMN and P3, with the same protocols that are followed in humans. As a result, the lab has come closer than ever before to untangling the roles of dopamine and glutamate.

"While rodents are essential for understanding mechanisms at a cellular or molecular level, at a higher cognitive level, the best you could do was a sort of rough analogy. Now, finally, we can have a one-to-one correspondence," says Gil-da-Costa. "For sensory integration, our findings with this model support the glutamate hypothesis."

Pharmaceutical companies are interested in the model, because of the potential for more precise testing and the universality of the MMN/P3 assays. "These brain makers are the same across dozens of neurological diseases, as well as brain trauma, so you can test potential therapies not just for schizophrenia, but for conditions such as Parkinson's, Alzheimer's, bi-polar disorder, and traumatic brain injuries," says Gil-da-Costa. "We hope this will help begin a new era in neurological therapeutics."

Explore further: High levels of glutamate in brain may kick-start schizophrenia

Related Stories

High levels of glutamate in brain may kick-start schizophrenia

April 18, 2013
An excess of the brain neurotransmitter glutamate may cause a transition to psychosis in people who are at risk for schizophrenia, reports a study from investigators at Columbia University Medical Center (CUMC) published ...

The mysterious GRIN3A and the cause of schizophrenia

March 14, 2013
Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for ...

Scientists unpack testosterone's role in schizophrenia

April 26, 2013
Testosterone may trigger a brain chemical process linked to schizophrenia but the same sex hormone can also improve cognitive thinking skills in men with the disorder, two new studies show.

Improving the search for new schizophrenia treatments

April 5, 2013
(Medical Xpress)—Controlling the symptoms of schizophrenia is the job of antipsychotic drugs which block a set of specific neural signals. But the way these drugs work can lead to a host of severe and debilitating long-term ...

New treatment for schizophrenia discovered

July 1, 2013
A research group led by professor Jesper Ekelund showed that by giving a very large dose of famotidine (200 mg daily), sufficient amounts of the drug are able to penetrate the so-called blood-brain barrier to affect the histamine ...

Recommended for you

Study listens in on speech development in early childhood

January 15, 2018
If you've ever listened in on two toddlers at play, you might have wondered how much of their babbling might get lost in translation. A new study from the University of Toronto provides surprising insights into how much children ...

Study suggests people dislike you more for humblebragging than for regular boasting

January 12, 2018
A team of researchers from Harvard University and UNC-Chapel Hill has conducted a study regarding humblebragging—in which a person boasts about an achievement but tries to make it sound less boastful by minimizing it—and ...

Can writing your 'to-do's' help you to doze? Study suggests jotting down tasks can speed the trip to dreamland

January 11, 2018
Writing a "to-do" list at bedtime may aid in falling asleep, according to a Baylor University study. Research compared sleep patterns of participants who took five minutes to write down upcoming duties versus participants ...

Study identifies brain circuit controlling social behavior

January 11, 2018
A new study by researchers at Roche in Basel, Switzerland has identified a key brain region of the neural circuit that controls social behavior. Increasing the activity of this region, called the habenula, led to social problems ...

Tamper-resistant oxycodone tablets have no impact on overall opioid use

January 11, 2018
The introduction of tamper-resistant opioid tablets does not have an effect on rates of opioid use or harms at a population level, according to a new study led by the National Drug and Alcohol Research Centre (NDARC) at UNSW ...

Suicides by drugs in U.S. are undercounted, new study suggests

January 11, 2018
The rate of suicides by drug intoxication in the United States may be vastly underreported and misclassified, according to a new study co-written by Mark Kaplan, professor of social welfare at the UCLA Luskin School of Public ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.