Elsevier

Biological Psychiatry

Volume 73, Issue 2, 15 January 2013, Pages 144-152
Biological Psychiatry

Archival Report
Brain Structural Signature of Familial Predisposition for Bipolar Disorder: Replicable Evidence For Involvement of the Right Inferior Frontal Gyrus

https://doi.org/10.1016/j.biopsych.2012.06.015Get rights and content

Background

To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD.

Methods

This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment.

Results

Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden.

Conclusions

Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.

Section snippets

Methods and Materials

We report on two related studies. Study 1 was a two-center genetic HR design study aimed at identifying biological risk factors for BD. We recruited offspring from families of well-characterized adult probands with BD and divided them on the basis of the presence or absence of personal history of mood disorders. Including both affected and unaffected offspring is necessary to establish the presence of neurobiological changes in families and their association with the illness. We performed VBM

Description of the Participants

For Study 1, we recruited 50 Unaffected HR (30 in Halifax, 20 in Prague), 36 Affected Familial (21 in Halifax, 15 in Prague), 19 Young BD (all in Prague), and 49 Control (31 in Halifax, 18 in Prague) participants. At each center, the groups were comparable in age, sex, handedness, and global brain volumes, with the exception of the Young BD participants, who were older than the respective Controls (Table 1, Table 2).

For Study 2, we recruited 17 Li, 12 Non-Li, and 11 Control individuals. The

Discussion

We present replicated evidence for dynamic structural changes of rIFG in the course of BD. The larger rIFG met criteria for biological risk factor of BD, because it was present among both the Unaffected HR and Affected Familial subjects from both centers and was associated with the early stages of illness in an unrelated clinical sample of Young BD participants. Interestingly, the same region was negatively correlated with the duration of illness. As a result, patients with BD who had a

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