Brain-Region Size May Be Long-Sought Biomarker

After seven years of work, a group of Canadian and Czech scientists have made a provocative discovery—that a certain area of the brain appears to differentiate youth or young adults with bipolar disorder or individuals at genetic risk of bipolar disorder from healthy control subjects. This brain change thus might someday serve as a biomarker for bipolar disorder.

The lead scientist was Tomas Hajek, M.D., Ph.D., an associate professor of psychiatry at Dalhousie University in Halifax, Canada. The results appeared July 23 in Biological Psychiatry.

The study included 154 subjects—19 adolescents or young adults with bipolar disorder, 50 nonaffected relatives of individuals with bipolar disorder, 36 affected relatives of individuals with bipolar disorder, and 49 healthy control subjects.

Using structural magnetic resonance imaging, the scientists found that the subjects with bipolar disorder as well as their affected and unaffected relatives had a significantly larger inferior frontal gyrus in the brain than control subjects did. Moreover, essentially the same results were found whether subjects had been recruited in Canada or in the Czech Republic.

Although other researchers have found an enlarged inferior frontal gyrus in bipolar disorder subjects in early stages of the illness, this appears to be the first time that an enlarged inferior frontal gyrus has also been found in family members of bipolar subjects with or without the illness. Thus it looks as if an abnormally large inferior frontal gyrus might be a biomarker for bipolar disorder.

“The finding that the inferior frontal gyrus may be a biomarker for bipolar disorder is exciting and important,” Kiki Chang, M.D., a professor of psychiatry and director of the pediatric bipolar disorders program at Stanford University, told Psychiatric News. Chang was not involved with the study.

“The finding also makes sense,” Chang said, “as the inferior frontal gyrus…is very important in emotional regulation and socio-emotional learning. We and others have found increased activation in this area in youth with bipolar disorder in response to emotional tasks, and I suspect that there is abnormal functional connectivity of this region with the amygdala in youth at risk for, and with, early bipolar disorder.”

But perhaps the most crucial aspect of the finding, Chang said, is that an enlarged inferior frontal gyrus might be used for early identification of people with bipolar disorder before symptoms arise or perhaps even for efforts to prevent the disorder in those at high genetic risk for it. Yet before that could happen, scientists must determine whether an enlarged inferior frontal gyrus is specific to bipolar disorder or also occurs in other mental illnesses, Chang cautioned.

Many other questions need to be answered as well, Hajek indicated to Psychiatric News.

For instance, it is not known which functions of the inferior frontal gyrus are most relevant to bipolar disorder or whether the structural changes in this region are caused by abnormal functional demands or by impaired white-matter connections.

Since abnormally small—not abnormally large—brain structures are usually linked with mental illness, why did Hajek and his colleagues find that an enlarged inferior frontal gyrus, not an abnormally small one, was linked with bipolar disorder? Hajek admitted that he was surprised by this finding, but was reassured by the consistent, replicated nature of their results.

And while people early in the course of bipolar disorder seem to possess an abnormally large inferior frontal gyrus, those further along in the illness seem to possess an abnormally small inferior frontal gyrus, Hajek and his group found in a related study.

Wouldn’t one expect the abnormally large inferior frontal gyrus to become even larger as illness progresses? Very possibly, said Hajek. So what may be going on here, he conjectured, is that “neurotoxic effects of the illness, which decrease gray-matter volume, may interact with compensatory mechanisms, which increase gray-matter volume. The overall size of the inferior frontal gyrus may depend on the sum of these two opposing processes.”

In other words, he explained, “early in the course of illness the ‘healing’ mechanisms of the brain may overcompensate for the toxic effects of the illness and may make the inferior frontal gyrus abnormally large. With progression of the illness, as the toxic effects of the disease accumulate, the compensatory mechanisms may become insufficient, and the inferior frontal gyrus shrinks in size. This may be an example of structural plasticity of the brain in response to the neurotoxic effects of bipolar disorders.”

The study was funded by the Canadian Institutes of Health Research, the Nova Scotia Health Research Foundation, the Dalhousie Clinical Research Scholarship, and the Czech Republic’s Ministry of Health and Ministry of Education.