Insight into sleep's role in schizophrenia offers potential treatment path

"One of the most exciting advances in sleep research over the last decade has been the growing understanding of sleep's causal relationship to psychiatric disorders," said senior author Robert Stickgold, MD, PhD, director of the Center for Sleep and Cognition at BIDMC. "Here, we reviewed the evidence that reduced sleep spindle activity predates the onset of schizophrenia and contributes to its cognitive deficits and other symptoms."

Visible on an electroencephalogram (EEG) -- which measures the brain's electrical activity -- sleep spindles are bursts of brain activity lasting less than a second. They occur only during the non-REM phase of sleep and play a role in the memory consolidation process that takes place during sleep. Scientists suspect sleep spindles solidify memories by strengthening synaptic connections among neurons. Among both healthy subjects and individuals with schizophrenia higher sleep spindle activity correlates with enhanced sleep-dependent memory processing and higher IQ.

For nearly a century, researchers have been aware of the link between sleep disturbances and schizophrenia, but these disturbances have long been considered a secondary consequence of the illness. Now, a growing body of literature suggests sleep abnormalities actually contribute to the onset, relapse and manifestations of schizophrenia -- not the other way around. A chronic and severe mental disorder, schizophrenia is marked by psychotic symptoms including hallucinations, delusions and thought disorders. But, the scientists wrote, for many people with schizophrenia, it's the chronic cognitive deficits -- impaired memory, inability to focus and poor executive functioning -- that can be most debilitating, keeping up to 80 percent of people with the disorder out of the workforce even when their psychotic symptoms are well-controlled.

Stickgold and colleagues, including first author Dara Manoach, PhD, a neuropsychologist at Massachusetts General Hospital and an associate professor of psychology at Harvard Medical School (HMS), reviewed a spate of studies, which -- while small -- link reduced spindle activity with the cognitive symptoms common to schizophrenia, including poor motor procedural memory and learning, worse executive function and lower IQ. Tests of healthy people similarly correlate increased spindle activity with enhanced performance in these areas. "It makes sense that if you have a deficit in these spindles, you'll also have a deficit in these cognitive functions," said Stickgold, who is also an associate professor of psychiatry at HMS. "But it wasn't known if reduced sleep spindle activity was a basic feature of schizophrenia or a side effect of living with it and taking medications for a decade or longer."

Some of Stickgold's own research helped untangle that question. In one study reviewed, Stickgold, Manoach and colleagues, including Matcheri Keshavan, MD, vice chair of public psychiatry at BIDMC and the Stanley Cobb professor of psychiatry at HMS, analyzed sleep data from non-psychotic, young first-degree relatives of patients with schizophrenia.

"While they don't have schizophrenia themselves, they share half their genes with somebody who does," Stickgold explained. "The question was, would that be enough to show spindle deficits? It was, suggesting that just having some of the genes associated with illness can be enough to cause this spindle deficit." Recent advances in genetics have also illuminated the relationship between sleep spindles and schizophrenia. More than 150 genes have been shown to be associated with the disorder, and some genetic variants may contribute more to schizophrenia than others.

A study published two years ago identified one gene variant strongly linked to schizophrenia. The gene encodes a calcium channel -- a chemical revolving door that regulates a cell's internal voltage -- found in high concentrations in neurons in the very area of the brain that generates sleep spindles. "We can really draw a straight line all the way from the gene to the disease, like a prosecutor in court," Stickgold said. "That has never been done before for a psychiatric disorder. It's exciting in that it offers a whole new dimension of treatment options."

In healthy people, the generic sleep medication zolpidem increased sleep spindle activity, and that increase has been linked to improved memory. Few studies have attempted to manipulate sleep spindle activity in patients with schizophrenia, the researchers noted. Increasing spindle activity to improve cognitive deficits represents a novel therapeutic target.

"It's becoming increasingly clear that sleep not only controls memory and emotional processing in all of us, but that deficits in sleep probably contribute to a wide range of psychiatric disorders, including schizophrenia, ADHD, bipolar disorder, PTSD and depression," Stickgold said. "Now we can begin tracing it all the way from the genes to the disorders themselves. Study coauthors include Dara S. Manoach, PhD, of Massachusetts General Hospital and HMS; Jen Q. Pan, PhD, of the Broad Institute of Harvard and MIT; and Shaun M. Purcell, PhD, of Massachusetts General Hospital and the Broad Institute of Harvard and MIT.