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July 18, 2006

Risk and Resilience Markers in Bipolar Disorder: Brain Responses to Emotional Challenge in Bipolar Patients and Their Healthy Siblings

By: Stephanie Kruger, M.D., Martin Alda, M.D., F.R.C.P.C., L. Trevor Young, M.D., Ph.D., F.R.C.P.C., Kim Goldapple, B.S., Saghar Parikh, M.D., F.R.C.P.C., and Helen S. Mayberg, M.D.
Published: American Journal of Psychiatry, 163:257-564, February 2006.

Purpose of the Study

Studies indicate that there is a high level of genetic influence in the development of bipolar disorder, but that it is not the only factor; many people who are genetically predisposed never become bipolar. Yet some scientists believe that although the full blown disorder is never developed, these individuals "manifest traits associated with the illness, namely pathological reactivity to emotional stress." This means that they have similar vulnerability to stress that can be seen in bipolar disorder.

This study aims to look for these bipolar traits at the brain level. They have hypothesized that exposure to mood related stress (in this case sadness) would reveal similar brain activity in those predisposed but who did not have the disorder (the hypothesized regions are; medial frontal cortex, dorsal anterior cingulated, dorsolateral prefrontal cortex, and anterior insula). They also hypothesized that there would be regions of resilience in these participants. These regions of resilience would be the protecting factors for not developing the disorder.


This study utilized nine bipolar disorder type I subjects, and their "healthy" siblings (these siblings acted as the group that was predisposed, but didn't have bipolar disorder. This was extensively evaluated prior to the study with DSM-IV criteria). The bipolar subjects were considered euthymic (not depressed or manic), stable for at least 3 years and were responding well to their lithium treatment

The study also included comparative analyses between a previous group of participants (from an earlier study of the same thing) who were taking valproate, had been euthymic for at least 6 months, and the current lithium bipolar participants.

They measured regional cerebral blood flow (rCBF) changes with positron emission tomography (PET) after asking participants to write a short autobiographical script of a sad life event. This was their "induction of transient intense sadness" which has been used and validated in other research. They performed the PET scan 1 min after the participants had reviewed what they wrote and reached peak emotion. Peak emotion of sadness was assessed using a likert scale, (0 not sad to 7 very sad). They performed 2 “rest” scans and two sadness scans.


8 lithium participants and 2 siblings showed tears during the inducted sadness portion of the experiment. The siblings had a slightly higher anxiety rating from the induced sadness, but were similar to their bipolar siblings in terms of emotion provoking time, and stability after the study (though the siblings felt less "overwhelmed" by sadness than the bipolar participants).

The bipolar participants and their siblings showed increased rCBF in the premotor cortex, dorsal and rostral anterior cingulated, anterior insula, and cerebellumn. They showed decreases of rCBF in the orbitofrontal cortex, and the inferior temporal cortex. The difference between these groups was the changes in medial frontal cortex rCBF. The "healthy" siblings showed an increase in rCBF, in the medial frontal cortex, while the bipolar participants treated with lithium showed a decrease.

When comparing the lithium bipolar participants to the valproate bipolar participants, differences in the rostral anterior cingulate and the dorsolateral prefrontal cortex were found. The lithium treated participants showed an increase in rCBF of the rostral anterior cingulated, while the valproate treated participants showed a decrease. The valproate group also showed a decrease in dorsolateral prefrontal cortex rCBF, while no changes were present in this region in the lithium group.


Although the siblings didn't meet the criteria to be diagnosed with a psychiatric disorder, the brain imaging in this study suggested that provoking emotions in these "healthy" siblings showed similar brain activity as their bipolar siblings. The increase in rCBF of the ventral medial frontal cortex in the non bipolar siblings is hypothesized to be a resilience factor preventing bipolar symptoms. Research shows that this region is associated with processing of emotional tasks; which includes reassessment of feelings, and increased self awareness. This is further supported with the reports of the non bipolar siblings not feeling overwhelmed emotionally.

To further analyze the differences in predisposed individuals, non predisposed, and diagnosed patients, brain scans using the same method of this study were examined in healthy, non predisposed participants. Similarities of the siblings were found again; the healthy subjects had no change in medial frontal cortex, and had increased rCBF in the subgenual cingulate (which neither sibling groups showed). This supports the hypothesis that similar brain regions are affected in those predisposed and those diagnosed, that are not present in individuals with no predisposition, and no psychiatric illness.

When examining the results of the litium group versus the valproate group, no consistant conclusions could be drawn. The valproate patients had less of a favorable outcome in their treatment, but this study cannot prove whether the lithium "stabilizes pathways responsible for emotional and behavioral reactions to stressful events or that the course of illness in these highly selected bipolar patients may leave cortical circuits at least partially intact."


Although this study aimed to find a link between those genetically predisposed and those with the disorder, one could argue that many of the siblings lacked the actual genetic exposure (siblings only share about 50% of their genes). Without genetic mapping, theres no way to be sure these siblings had the genetic predisposition.

Another theory may be that these similarities were not a result of genetics, but rather a result of developing cognitive skills in the same environment. Growing up with the same parents, possibly attending similar schools may cause these siblings to form similar neurocognitive connections.

Also, more research is needed to determine the cognitive mechanisms of the apparent cortical resilience found in the “predisposed” siblings, as well as analyzing early brain scans of those who develop bipolar disorder, and whether these resilience factors are present or absent.

Read Full Article:

Risk and Resilience Markers in Bipolar Disorder: Brain Responses to Emotional Challenge in Bipolar Patients and Their healthy Siblings American Jounral of Psychiatry ( Feb 2006.


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