The Chemical Fingerprints of Mental Illness

This article was a feature story in Technology Review’s December 2005/January 2006 print issue. It has been divided into three parts for presentation online. This is part 2; part 1 appeared on Monday, January 23, and part 3 will appear on Wednesday, January 25.

Part 1 discussed the work of John Port, a neuroradiologist at the Mayo Clinic who is using MRI to explore the parts of the brain that may be involved in bipolar disorder, also known as manic-depression.”I’m dedicating the rest of my career to coming up with an imaging test that will help psychiatrists diagnose” bipolar disorder and other illnesses, Port told Technology Review.

Port is one of many researchers now experimenting with MRI spectroscopy, in which software produces an image of the brain based on a spectroscopic scan. The image is made up of individual data points called voxels, cubes analogous to the pixels in a 2-D computer image. Each corresponds to a volume about the size of a kidney bean. For each voxel, Port gets a reading on the presence or absence of certain chemicals that are indicators of brain function.

To understand how MRI spectroscopy works, it’s necessary to understand a bit about how magnetic resonance imaging works more generally. MRI scanners pick up extremely faint electromagnetic signals coming from protons in the atoms of molecules that make up the body’s tissues – in this case, brain tissue.

“Think of it like listening for a pin drop in a thunderstorm,” Port says. Each proton has a magnetic field that points in a certain direction, as the earth’s does. When the MRI is turned on, its magnet aligns the protons’ magnetic fields in the same direction. Bursts of radio frequency energy temporarily knock some of the protons out of alignment. When the protons snap back into place, they release energy, generating a minuscule signal that the MRI’s detectors can pick up. By flipping the protons different ways and measuring various properties of those flips, including the time they take, researchers can identify various tissues and chemicals in the brain.

Using MRI spectroscopy, Port can measure levels of chemicals such as n-acetyl aspartate, which is found only in neurons, or glutamate, which stimulates nerve-cell activity. When Port used the technique across many areas of the brain in bipolar patients and compared the results to those from healthy controls, he came up with a chemical fingerprint that seemed to be an indicator of bipolar disorder.

“When we compared all the bipolar patients in any mood state with their matched normal control subjects, we found that two areas of the brain were significantly different,” Port says. Port and his team also identified changes in many regions of the brains of people with bipolar disorder that indicated whether they were in a manic state or depressed. “We found a chemical measure of the mood state,” he says.

So has Port found the long-sought diagnostic test for bipolar disorder? Does his chemical fingerprint reliably identify people who have bipolar disorder and exclude those who don’t?

Maybe, but he can’t be sure yet. “We think we’re on to something good,” he says, but “we have to check it and make sure it will be clinically useful.” It’s a question of trying the technique with enough patients to be sure that it is statistically valid – that it won’t produce too many false positives or false negatives. It doesn’t have to be perfect, but it has to be good enough to add useful information to what psychiatrists can discern through their traditional methods of diagnosis, interviews, and analyses of patient histories.

If Port is correct, however, and the technique proves itself, it would be a landmark in psychiatric research: a diagnostic test for bipolar disorder. And if the technique works with bipolar disorder, it could be adaptable to other psychiatric illnesses.

Port and others are also experimenting with diffusion tensor imaging. DTI measures water diffusion in the brain. Water flows through the brain as it does anywhere else – along the path of least resistance. In the brain, that’s along the axons, the neurons’ long tails, which convey electrical signals to other neurons. (It’s from the fatty, white insulation that surrounds most axons that “white matter” takes its name; the rest of the neuron, and uninsulated axons, together constitute “gray matter.”)

Port is just beginning to research the technique. But eventually researchers will be able to use “DTI clinically to look for diseases that interfere with white matter – amyotrophic lateral sclerosis [Lou Gehrig’s disease] and schizophrenia,” Port says.

Diagnosing Development

The techniques Port is studying, if they prove successful, will be used in diagnosing people already showing signs of mental illness. But what about others who are predisposed to problems but have not yet begun to exhibit symptoms? Can the MRI technology help to find these people so that they can be helped before symptoms appear?

Home page image courtesy of Bradley Peterson.

Tomorrow: How Bradley Peterson at Columbia University is using MRI to study the brains of infants to understand the complications of premature birth.

Paul Raeburn’s most recent book is Acquainted with the Night, a memoir of raising children with depression and bipolar disorder.