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Schizophrenia by the Back Route

News from the Johns Hopkins Department of Psychiatry and Behavioral Sciences

Dr. Sarah Reading
Dr. Sarah Reading

I’ve held a heart as it beats. I’ve sat with people as they lay dying. But nothing in my training ever moved me as have patients with schizophrenia. Never to reflect quietly? To hear terrifying, bodiless voices? In medical school I decided it’s the most fascinating and devastating of diseases. And we’ve known so little about it, for so long.”

 For someone so eager to understand schizophrenia, psychiatrist Sarah Reading has chosen, apparently, the longer back way—by first researching Huntington’s disease (HD). With its uncontrollable body movements, HD is a different beast from schizophrenia, though both diseases cause cognitive problems and psychosis. But Reading’s route makes sense. We know the genetics behind Huntington’s. The mutant huntingtin protein it produces is a staple of HD research. “It’s our prototype for neuropsychiatric illness,” she says, “and a great model for learning how a flawed brain leads to psychosis or other psychiatric problems.” 

Reading is one of the first to image the working brains of HD patients; her studies should both strengthen and add to what’s emerging from Hopkins labs to open up both diseases. The work’s at the faint-glimmer stage, but when light starts streaming in, it should also clarify Parkinson’s, Alzheimer’s and bipolar disease.

Three years ago, when Reading first came to Hopkins’ Wednesday HD clinic, she experienced “a disconnect of sorts” talking with patients genetically marked for Huntington’s but still lacking hallmark motor symptoms. The cognitive disturbances she saw, however, surprised her. “We sensed they have problems, but standard tests don’t pick them up.” So Reading sought to confirm the early flaws, using her background in psychiatric neuroimaging, with the idea that their appearance might point out a prime time for therapy.

In two separate studies, patients had functional MRI (fMRI) scans, lying in the scanner while their hands pushed buttons for a variety of cognitive tests. The results revealed slowed-down brain regions tied to planning and anticipation—executive functions—far earlier than HD’s major movement, mood or thinking problems appear, her team found. The flaws parallel early shrinking of the caudate nucleus—the brain’s focus of the disease.

But more than mapping HD’s course, Reading aims to learn what’s wrong on a whole- brain level. How, for instance, do abnormal signals her team’s picked up in one part of the brain connect to a dying caudate nucleus? “In short,” she says, “I’m really interested in the white matter, the wiring.” Until recently, that would have been futile. No way existed to follow the nerve tracts that course between brain centers like so much transmitting spaghetti.

Enter DTI—a powerful technique Hopkins researchers are nurturing. A type of MRI,  diffusion tensor imaging lets them check signs of brain “connectivity” such as how thick or plentiful nerve tracts are. By combining fMRI and DTI, Reading is increasingly able to “check the connections” in sickness and in health.

“Cognitive problems arise from abnormalities over wide areas in the brain,” she says. “So we hope to examine the connections between them to see if flaws arise in a disease-specific pattern.” In HD, the idea that wiring goes awry early on is tremendously interesting, she says. “And in schizophrenia, abnormal development of wiring may be its basis.” 

For more information, call 410-955-2398.

Find other Hopkins Newsletter articles from past issues.