Bipolar brain

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ANN ARBOR, MI - People with bipolar disorder have an average of thirty percent more of an important class of signal-sending brain cells, according to new evidence being published by University of Michigan researchers.

The finding, published in the October 2000 issue of the American Journal of Psychiatry, solidifies the idea that the disorder has unavoidable biological and genetic roots, and may explain why it runs in families.

The discovery is the first neurochemical difference to be found between asymptomatic bipolar and non-bipolar people. It could help the understanding and treatment of a disease that affects as much as 1.5 percent of the population. Bipolar disorder has in the past been known as manic depression.

"To put it simply, these patients' brains are wired differently, in a way that we might expect to predispose them to bouts of mania and depression," says Jon-Kar Zubieta, M.D., Ph.D., assistant professor of psychiatry and radiology at the University of Michigan Health System. "Now, we must expand and apply this knowledge to give them a treatment strategy based on solid science, not on the current method of trial and error. We should also work to find an exact genetic origin, and to relate those genetic origins to what is happening in the brain."

Bipolar disorder is marked by wild, cyclical mood swings, which typically begin in a person's late teens or twenties and strike men and women with equal frequency. Its milder, type II form causes depression alternating with hyperactivity, while the more severe type I disorder produces frenzied, even psychotic episodes that may send the patient to the hospital, followed by deep, crippling depressions. Current treatment uses a mix of mood-stabilizing, anti-psychotic and antidepressant drugs, but patients and physicians often struggle to strike the right combination.

Zubieta and his colleagues made the discovery in 16 patients with type I bipolar disorder using a brain imaging technique called positron emission tomography, or PET. The scans let them see the density of cells that release the brain chemicals dopamine, serotonin and norepinephrine.

These monoamines, as the chemicals are called, send signals between brain cells, or neurons. They're involved in mood regulation, stress responses, pleasure, reward, and cognitive functions like concentration, attention, and executive functions. Scientists have hypothesized their role in bipolar disorder for decades, but have never proven it.

The new University of Michigan result points to a clear difference in the density of monoamine-releasing cells in the brains of bipolar people even when they are not having symptoms. Zeroing the PET scanner in on areas of the brain where monoamine-releasing cells are concentrated, the team looked for the faint signal of a weakly radioactive tracer, DTBZ, which they had injected into the bloodstream of the 16 participants and 16 people without bipolar disorder.

DTBZ binds only to a protein called VMAT2 inside monoamine-releasing cells, making it a good tracking device for the density of those cells. It is also often used in PET scanning to study Parkinson's disease, which is characterized by a severe shortage of cells that produce dopamine. On PET scans, DTBZ density - and therefore monoamine cell density - can be quantified by the amount of radioactive signal present in different areas.

By looking at the intensity of the DTBZ signal in all the subjects' brains, the University of Michigan team found that bipolar patients averaged 31 percent more binding sites in the region known as the thalamus, and 28 percent more in the ventral brain stem. In the thalamus, bipolar women actually had levels nearing those of healthy comparison subjects, but bipolar men had a 42 percent higher binding rate, suggesting that there may be specific biological causes for the clinical differences in the course of the illness in men and women.

Adding in the results of functional tests, they found that the more monoamine cells patients had, the lower their scores on tests of executive function and verbal learning. This finding confirms earlier results from research at the University of Michigan, and suggests that the altered brain chemistry due to the excess monoamine cells may directly impact the patients' cognitive and social function.

The study was carefully designed to produce consistent results. It compared brain scans and neuropsychological test results from bipolar disorder I patients who were using medications to control their symptoms, and healthy subjects matched to the bipolar subjects for age, sex, ethnicity, handedness and other factors. Careful physical and psychiatric exams ruled out differences caused by other variables.

Now, Zubieta and his colleagues hope their initial finding will lead to further research on brain chemistry and bipolar disorder. Specifically, more study is needed to examine which kinds of monoamine cells are involved - Zubieta especially suspects those that produce serotonin and norepinephrine. Those findings could help define specific subtypes of bipolar disorder, and aid development of medications and drug combinations that target a specific patient's personal brain chemistry to alleviate symptoms.

Genetic research, too, will be needed to find out why bipolar brains grow more than the usual allotment of such cells. Bipolar disorder I has a strong but still unknown tie to DNA; studies of identical twins show that if one twin has it, the other has an 80 percent chance of having it, too. Zubieta is hopeful that genetic markers will one day be found that can help people know their risk of developing bipolar disorder.

A combination of both genetic research and neuroimaging studies would help define both the genetic components of this illness, and their relationship with the expression of specific brain chemical markers in specific patients.

The University of Michigan is launching a new trial that will enroll patients who have just been diagnosed with bipolar disorder, and those with a family history of the disease that puts them at higher risk.

"The reality is that we still have only sketches of what is going on in these brains, what the basic changes are, and how they are related to the course of illness," Zubieta says. "We need to look farther."

The study was funded by the University of Michigan's General Clinical Research Center, by the National Alliance for Research on Schizophrenia and Depression, and by the Mental Illness Research Association's Arthur Forrest Tull II Research Fund.