This study provides the first evidence of a neuroanatomical correlate of an oxytocin receptor polymorphism. Using a manual tracing technique, we documented a reduction in total amygdala volume, despite greater overall gray matter volume, in healthy female OXTR rs2254298 G-allele homozygotes relative to G/A heterozygotes. Notably, decreased amygdala volume has also been found to be associated with both unipolar (e.g., Hamilton et al., 2008
) and bipolar (e.g., Kalmar et al., 2009
) depression, as well as with autism, though results in this disorder have been mixed (Howard et al., 2000
; Nacewicz et al., 2006
). Further, the present finding is consistent with documented increases total gray matter volume in adolescent males with autism spectrum disorder (Hazlett et al., 2006
Although the relation between the structure and function of the amygdala is not fully understood, mounting evidence suggests that increased size of neuroanatomical structures does not invariably predict increased neural activity; in fact, smaller amygdala volume has been found to be associated with increased neural activation to emotionally valenced stimuli in depressed individuals (Kalmar et al., 2009
). Further research is needed to relate the current finding of smaller amygdala volumes in G-allele homozygotes to alterations in metabolism and reactivity. In particular, if the volumetric reductions that characterize G-allele homozygotes are also associated with increased amygdala reactivity, this reactivity may constitute one pathway by which OXTR polymorphisms confer risk for psychopathology. Thus, examining amygdala reactivity in these individuals would allow us to gain a better understanding of the dynamics relating genes, anatomical structure, and neural functioning.
The effect of the OXTR polymorphism on amygdala volume may be mediated, in part, by exposure to corticosteroids. Brown et al. (2007)
reported that patients who received at least six months of corticosteroid treatment had smaller amygdalae and, further, that right amygdala volume was inversely correlated with length of treatment. Given that oxytocin is posited to buffer the effects of stress by dampening both HPA-axis and amygdala reactivity, as described above, it is possible that decreased transcription, or sensitivity, of oxytocin receptors leads to greater exposure to cortisol, which in turn affects amygdala volume. Future research could profitably examine whether the effect of OXTR genotype on amygdala volume is mediated by exposure to cumulative stress or cortisol.
Given the documented associations among oxytocin, the amygdala, and the brainstem, it is noteworthy that our VBM analysis revealed decreased volume in a region of caudal midbrain in G-allele homozygotes relative to carriers of the A allele. Interestingly, several lines of research have implicated altered brainstem morphometry in the pathophysiology of autism. Specifically, smaller brainstem volumes have been reported in young autistic children (e.g., Hashimoto et al., 1993
). Jou et al (2008)
not only found brainstem volumes to be decreased in a young autistic sample, but also demonstrated that regardless of diagnosis, total brainstem gray matter volume correlated positively with severity of sensory sensitivity, suggesting direct functional consequences of such volumetric reductions.
In our sample we found genotype-mediated differences in a region of brainstem proximal to the periaqueductal gray (PAG). We should note that while the use of a less stringent statistical threshold revealed gray matter differences in more medial regions of the midbrain, the PAG may be of central concern when considering oxytocin-mediated effects on anxiety. This region, implicated in fear behavior and arousal (LeDoux et al., 1998), is the target of heavy reciprocal projections from the central nucleus of the amygdala (Rizvi et al., 1991
). Research has demonstrated that activation of the brainstem (Baumgartner et al., 2008
) is significantly attenuated following oxytocin administration, likely through the mediation of activity via these amygdalar projections (Huber et al., 2005
). Complementing this indirect influence of oxytocin on brainstem activity, functional oxytocin receptors have been identified within the human central gray, among other brainstem regions (Loup et al., 1989
), suggesting that the neuropeptide directly affects brainstem structure and function. Indeed, direct administration of oxytocin into the periaqueductal gray has been shown to attenuate anxiety-related behaviors in postpartum rats (Figueira et al., 2008
Although we did not have a priori
hypotheses regarding the effect of rs2254298 genotype on ACC, the finding of increased ACC volume in G-allele homozygotes is interesting for a number of reasons. Investigators have suggested that dorsal ACC is involved in the “felt unpleasantness” of both physical and social pain, perhaps as a consequence of, or precursor to, its role in allocating attentional resources (Eisenberger & Lieberman, 2004
). Appropriately, given this formulation, abnormal function or structure in this region has been noted in pediatric anxiety disorder (McClure et al., 2007
), obsessive-compulsive disorder (Rosenberg & Keshavan, 1998
; Ursu et al., 2003
), and disorders along the autism spectrum (Di Martino et al., 2009
), each of which has also been associated with the oxytocin system. Importantly, while oxytocin receptor binding has been localized within the rat cingulate cortex, expression in this structure seems to be limited to early development (Tribollet et al., 1989
). Although comparable data are not available in humans, it is possible that transient oxytocin actions in the developing brain have lasting and consequential effects, especially when considering genetic variants, present from the earliest stages of development.
We should note four limitations of the current study. First, because our sample was composed exclusively of adolescent females, we could not examine the generalizability of the obtained results to other age groups and to males. Second, the interpretation of our results is limited by the current paucity of information concerning the OXTR rs2254298 polymorphism. It is likely that this SNP is in linkage disequilibrium with one or more unknown functional loci; additional research is required to identify the critical genes that may mediate the observed associations. Third, the group difference in amygdala volume obtained using manual tracing was not corroborated by our VBM analysis. It is likely that our ability to detect differences in amygdala volume using this exploratory procedure was limited by our sample size; studies using VBM that have reported significant group differences in amygdala volume have used larger group sample sizes (e.g., Pezawas et al., 2005
). In addition, VBM has been found to be less sensitive than is manual tracing in detecting certain volumetric effects within the amygdala (Good et al., 2002
). Finally, given the scanning resolution used in this study, we were not able to localize the observed volumetric differences to particular sub-regions of the amygdala. Nevertheless, we were able to document an overall reduction in amygdala volume in individuals who are homozygous for the OXTR rs2254298 G allele. Scanning protocols targeting the amygdala may be able to localize genotype-mediated volumetric and functional differences to regions of the amygdala known to be particularly dense in OXTR. Examining the effects of this and related polymorphisms on neuroanatomy, neural function, and HPA-axis activity will increase our understanding of how the oxytocin system affects the stress response and risk for psychopathology.