This is the first study, to our knowledge, using VBM to examine brain morphology in pediatric OCD patients as well as in unaffected siblings of OCD patients. Based upon prior neuroimaging studies implicating aberrant frontostriatal circuits in both adult and pediatric OCD patients [34
], we predicted abnormalities in the anterior cingulate, striatum and thalamus. Consistent with one of these predictions, alterations in the left ACC were observed as well as an, unexpected alteration in the bilateral SFG in OCD patients compared to healthy controls. Furthermore, we found increased gray matter density in the right putamen of OCD patients compared to their unaffected siblings.
Our finding of reduced left ACC gray matter density in OCD patients compared to healthy controls is intriguing. Alterations in the ACC may reflect previously described abnormalities of the direct-indirect basal ganglia pathway in the orbitofrontal-subcortical and limbic circuits [32
]. It has been suggested that abnormal ACC activity may reflect a dysfunctional action-monitoring system in patients with OCD [43
]. Developmental studies of the ACC in children have demonstrated correlations between its size and ability to regulate inhibitory processes [8
]. Indeed, the presence of alterations in ACC in pediatric OCD patients may support and reflect prior findings of inhibitory control abnormalities present early in the course of illness [35
]. In a previous study, we have reported larger total ACC gray matter volumes in pediatric OCD [33
]. However, our current study, using VBM, is using a whole brain approach, which may only reveal partial and not total gray matter differences between subjects. Our findings here may differ from our prior study in that we are reporting gray matter density, the probability of finding gray matter in a given voxel, rather than gray matter volume. It is also possible that these conflicting results may relate to differences between subject samples between these studies as well as the heterogeneity of OCD [26
]. Concurrent with our findings, a recent VBM study of adults with OCD reported reduced ACC gray matter density [44
The SFG has also been identified as a potential area of interest in the pathophysiology of obsessive-compulsive disorder. Abnormal functionality of the SFG has been previously implicated in several studies in adults using positron emission tomography (PET) [25
] and single photon emission computed tomography (SPECT) [23
], though the results of these studies are conflicting. Lacerda et al [23
] found significant increases in regional cerebral blood flow (rCBF) in the right SFG in OCD patients versus healthy control subjects, while Lucey et al [25
], found significant bilateral decreases in resting rCBF in a population of OCD patients versus healthy controls. Castillo et al [9
], found no significant differences in average ratios of rCBF in a population of pediatric OCD patients before and after treatment with clomipramine. Adler et al [2
] found significant increases in neural activation of several frontal cortical regions, including the SFG, during symptom provocation using functional magnetic resonance imaging (fMRI). Another study, using electroencephalography (EEG), found reduced activity in the SFG in a sample of OCD patients versus controls during the NoGo portion (i.e. inhibition response) of a Go-NoGo task [18
]. Despite evidence indicating functional SFG abnormalities in OCD, there has been only one volumetric analysis of the SFG [42
], which reported no significant differences in combined gray and white matter in adult OCD subjects compared to healthy controls.
Our finding of greater gray matter density in the right putamen of OCD patients as compared to their unaffected siblings is especially interesting. The putamen has been implicated in the pathophysiology of OCD; indeed, a recent VBM analysis of adult OCD patients reported increased gray matter volumes bilaterally in the ventral putamen [31
]. Previously, we found smaller putamen volumes in OCD patients as compared to healthy controls [34
]. In our current study, no difference was noted between siblings and healthy controls nor OCD patients and healthy controls with regard to putamen gray matter density.
These neuroimaging findings may reflect potential brain maturational deviations in both affected and unaffected populations, although due to the cross-sectional approach of these analyses, we are unable to draw any conclusions regarding age-related changes in our subjects. Prior neuroimaging studies have reported significant age-related changes in gray matter during childhood and adolescence [11
]. It has been postulated that smaller gray matter density may reflect increased synaptic pruning during adolescence and early adulthood [13
]. Prior studies of pediatric OCD patients suggest that a developmentally mediated network dysplasia, secondary to abnormal peri-adolescent pruning mechanisms may contribute to the development of OCD in childhood [33
]. Different gray matter patterns in affected patients and unaffected at-risk subjects may reflect a failure of normal pruning or defective neural proliferation. Finally, low GM density in subjects with OCD may reflect white matter hypertrophy expanding into the cortex and lowering the probability of finding GM in a particular cortical or nuclear voxel.
The absence of predicted alterations [12
] in the thalamus may be a result of the small sample size. Furthermore, as OCD is a clinically heterogenous disorder, and studies have reported specific neural correlates of OCD symptom dimensions, structural and functional abnormalities may be missed in studies that do not examine groups of patients differentiated by specific symptom dimensions [26
There are several limitations to the preliminary findings, especially regarding the exploratory analysis of this novel high-risk sibling population. The sample size is small and, despite small volume corrections for multiple comparisons, future assessment of a larger cohort of patients and siblings will be important to reduce the potential for both Type I and Type II errors. Comorbid disorders in OCD patients are another limitation. Furthermore, although the sibling subjects are at greater risk for the development of OCD than healthy controls, we are unable to verify that they will indeed develop the disorder. Therefore, it is premature to conclude that differences between unaffected high-risk subjects and affected siblings represent markers for risk of developing OCD. Nonetheless, we believe that the uniqueness of our sample, e.g., psychotropic naïve pediatric OCD patients and unaffected siblings, may contribute to a broader understanding of neurodevelopmental factors involved in the etiopathogenesis of OCD. Clearly, future reports of longitudinal analyses of these populations will be informative.