To our knowledge, this is the first study to report differences in GM volume in young healthy offspring at genetic risk for BD (HBO). The main findings from this study were that compared to age-matched healthy low-risk controls (CONT), HBO had increased, not decreased, GM volume in the left parahippocampus/hippocampus. The increased GM volume in HBO significantly positively correlated with pubertal maturation scores but not age. There were additional increases in GM volume in HBO in other a priori regions, including the amygdala and OMPFC, but these did not survive after controlling for multiple comparisons. Similarly, although HBO showed decreased GM volume relative to CONT in middle frontal and temporal gyrus and caudate nucleus, these too did not survive after controlling for multiple comparisons.
Our findings of increased parahippocampal/hippocampal GM volume in HBO are in sharp contrast to findings from MRI studies in adult and pediatric BD. Although some studies have found hippocampal differences between adult BD patients relative to healthy controls,34
most studies typically have not found any significant differences in parahippocampal or hippocampal GM volume.35
Decreases in hippocampal GM volume have been reported in adolescent BD,12,13
suggesting the involvement of the hippocampus in the pathophysiology of adolescent BD that may represent a particular characteristic of early-onset BD. Our findings are congruent, however, with previous data from studies in adults at risk for BD; a study that compared adult monozygotic twins discordant for BD found a smaller right hippocampus in the twin with BD relative to the twin without BD.36
The finding of increased GM volume in the parahippocampus/hippocampus in HBO is particularly interesting because of the potential role of these regions in the regulation of stress and emotional responses. The hippocampus has been implicated in inhibition of the stress response via inhibitory connections with many of the subcortical structures involved in this response.37
As part of the limbic system, the parahippocampal gyrus has multiple direct connections with the hippocampus and amygdala,38
and it has been suggested that a dynamic relationship between the amygdala and parahippocampal gyrus may confer a protective effect against potentially harmful experiences.39
Previous findings indeed indicate that individuals with parahippocampal gyral, but not amygdalar, resections show abnormal appraisal of dissonant musical cues in that, unlike healthy controls, they label these cues as pleasant rather than highly unpleasant.40
A recent study reported significant decreases in parahippocampal gyral activity to emotional words in adults with BD relative to age-matched healthy controls.41
These findings therefore support a protective role for the parahippocampal gyrus in the normal appraisal of emotional information, which may become dysfunctional in adult BD.
Although it is possible that the pattern of increased GM volume in the left parahippocampus/hippocampus in HBO represents a potential neuroanatomical risk marker for BD, this interpretation is problematic given that decreased rather than increased GM volume in the hippocampus has been reported in youths with BD.12,13
Moreover, it is unlikely that sudden morphological changes occur specifically with BD onset. Elucidating the role of this region in the subsequent development of BD in genetically at-risk pediatric populations can be addressed only by longitudinal studies examining subcortical development before and after the onset of the disorder.
Another interpretation of the observed GM increase in HBO is that it may have a potential role in protecting against or delaying subsequent development of BD, given that HBO in our study were completely free of any Axis I disorder. Pediatric or adult BD onset is often preceded and/or accompanied by other psychiatric disorders such as disruptive behavior disorders or anxiety disorders.1,42
It is therefore possible that the HBO in our sample represent a potentially emotionally resilient group despite being at risk for BD. The pattern of increased rather than decreased GM volume observed in our HBO group may be interpreted as being associated with successful affect regulation that acts as a compensatory mechanism against the development of mood or anxiety disorders or because of being exposed repeatedly to situations (e.g., family conflict) that require these bipolar offspring to regulate their affect. The latter interpretation would be consistent with recent evidence demonstrating that cognitive activity itself can alter brain morphometry in certain relevant brain structures.43
Thus, examining behavior or neural systems associated with affect regulation in these bipolar offspring would allow us to begin addressing this question.
The significant positive correlation between left parahippocampal/hippocampal GM volume and pubertal maturation in HBO, but not CONT, may be further support of the protective role of this GM volume increase in HBO. Although there is no evidence directly linking BD with puberty onset, large-scale studies examining BD age at onset (e.g., STEP-BD) report a high frequency of first episodes occurring between 13 and 18 years (i.e., during puberty).44
If structural neural abnormalities reported in youths with BD are potential mediators for the development of BD, then it is plausible that the increased parahippocampal/hippocampal GM volume associated with pubertal maturation in HBO could play a neuroprotective role by providing additional neural resources in affect regulation. Further-more, this increase in parahippocampal/hippocampal GM volume could not be attributed to an effect of age because there was no significant correlation between parahippocampal/hippocampal GM volume and age in either HBO or CONT.
The interpretation that this parahippocampal/hippocampal GM volume increase in HBO plays a neuroprotective role remains speculative until longitudinal follow-up studies are conducted to determine who will go on to develop BD. Moreover, future studies examining regional neural activity during emotional information processing or affect regulation tasks in HBO without Axis I disorder will allow us to examine the extent to which abnormal patterns of parahippocampal/hippocampal activity during these tasks may accompany the increase in GM volume in these regions in HBO.
Our findings of increased GM volume in the parahippocampus/hippocampus are in contrast with some MRI studies conducted in individuals who are at high risk for BD.18
However, it is important to note that most of these studies included healthy control participants who, although not meeting criteria for BD, either had a history of mood disorder or met criteria for other psychiatric disorders.21,22
Our findings in HBO allow us to address questions not only regarding the nature of neuroanatomical abnormalities that may confer risk for BD but also how such abnormalities may protect against the development of BD. They also provide a neuroanatomical focus for future study of the neurodevelopmental trajectory of BD in youths at genetic risk for BD.
The left-sided localization of the parahippocampal/hippocampal GM volume increase in HBO is additionally interesting. The left more than the right hemisphere has been linked with positive emotion processing.45
Previous findings from functional neuroimaging studies in adults with BD have also indicated abnormally increased left amygdalar activity to positive emotional stimuli.46
However, our findings are inconsistent with the reported decreased GM volume in bilateral hippocampus in adolescent BD.13
Nevertheless, these findings suggest that it is possible that increased leftsided parahippocampal/hippocampal GM volume in HBO may, in particular, protect against abnormal positive emotion processing that may be associated with the development of BD.
One important point that merits discussion is with regard to the potential limitation of the VBM technique. First, given that the computation of VBM statistical parametric map requires several thousands of independent statistical comparisons, the likelihood of type I error is increased. As such, it is important to include appropriate corrections to protect against type I error to ensure that results reflect statistically significant differences. The recommended approach to control for type I error in VBM is to include voxel-wise corrections such as the FWE correction, which we used in this study.23
However, these corrections are rather conservative, thereby potentially increasing type II error. The latter point is particularly relevant given our sample size. One way to circumvent this potential limitation could have been to conduct analyses on hand-traced data. However, such an approach encompasses its own set of limitations.47
For instance, hand tracing is subjective to tracer position of anatomical landmarks and is restricted to predefined regions of interest, at the expense of detecting differences observed in whole-brain analyses. In this regard, hand tracing encompasses its own source of error, particularly given the level of accuracy, reliability, and training of the research staff. A methodological strength of VBM in this regard is that VBM enables researchers to conduct whole-brain analyses and is sensitive to systematic differences in GM volume.47
Furthermore, by using automated anatomical templates, it is possible to replicate findings in a different sample or to investigate the same regions in different populations or research centers.
In addition, the findings from the present study are limited by certain factors, including the relatively small sample size, although such sample sizes do provide adequate power to detect medium to large effect sizes.48
The stringent criteria we used in recruiting our sample, namely, the absence of any Axis I disorder, necessarily limited the number of participants in the present study and the ability to match on sex or exclude the few offspring with a parent with BD-II. Another limitation is related to the cross-sectional design, which prevented examination of neurodevelopmental trajectories underlying BD. The next stage, therefore, is to follow HBO participants in the present study to allow examination of the extent to which increased GM volume in the parahippocampus/hippocampus may be associated with the subsequent development of BD or another mood disorder.
In summary, findings from this study using VBM analyses are the first to show increased GM volume in the parahippocampus/hippocampus in healthy offspring at genetic risk for BD. Prospective studies examining the relationship between alterations in these regions and subsequent development of BD in these healthy offspring will allow us to increase our understanding of the role of this and other regions in either conferring risk for or protecting against the development of BD.