The present study used 3-D anatomical surface modeling techniques, as well as traditional volumetry, to investigate caudate nucleus structural integrity in LLD. There were three principal findings. First, reduction in the caudate nucleus can be examined in detail using 3-D anatomical surface modeling techniques, revealing the profile of systematic differences in depressed subjects. Second, elderly depressed subjects had significant caudate volume reductions (around 13%) bilaterally compared with elderly comparison subjects with no psychiatric history. These differences were localized primarily to the head of the caudate nucleus, left greater than right. Third, caudate volume was correlated with depression severity.
An important story is emerging from studies in depressed individuals, examining the relationships between caudate nucleus volume and depression severity, cognitive functioning and serotonin transporter genotype. The present study shows that lower caudate volume is associated with more severe depression in elderly subjects, similar to those in midlife.45
In LLD, lower caudate volume may also be associated with psychomotor slowing,23
which appears to be the core cognitive deficit, accounting for a large proportion of impairment in most other cognitive domains.31
These findings taken together, suggest that the caudate nucleus plays an important role in both the mood and cognitive characteristics of some depressed elders, although we know little about the temporal or pathophysiologic nature of caudate nucleus reduction in LLD; it is unknown whether severe depression leads to cell loss or vice versa. Moreover, it is also unknown whether lower caudate nucleus volume is causally related to severe depression or whether it is related to developmental differences (implying a predispositional risk factor) or neurodegenerative changes (implying an ongoing pathological process). Caudate nucleus involvement has not been well-studied in neurodegenerative disorders, but three recent imaging studies46–48
have reported localized atrophy of the caudate head in Alzheimer disease. Also there is evidence that the caudate nucleus may be damaged by vascular disease in at least some elders with depression,16,49
and there may be a genetic link in some individuals with LLD due to an association between the serotonin transporter gene s-allele and lower caudate volume.24
This study further suggests that the critical volume loss may not be in the caudate nucleus in general but may be localized within the anterior portion, and more specifically, the head, particularly on the left. Notably, the head of the caudate is particularly rich in serotonergic fibers.50,51
This fits well with recent models emphasizing the relation between this sub-region of the caudate, which is innervated by the amygdala (see e.g.,52
), and mood regulation (see Refs. 27
The prominent reduction in the most anterior part of the caudate also fits well with the vascular depression hypothesis of LLD (see Ref. 54
for a recent review). The vascular depression hypothesis posits that a subgroup of individuals with LLD (especially those with late-onset depression) experience disruption of prefrontal systems that mediate both mood and executive functions, by either single vascular lesions or an accumulation of lesions.21,22
We cannot identify the etiology of the reduced volume in the anterior caudate in our LLD subjects. Nevertheless, in the context of the particularly strong connections between the anterior caudate and frontal cortical areas, our finding lends support to the notion that striatal lesions may disconnect subcortical regions particularly involved in mood from frontal cortical regions that mediate executive functions.
Our analysis may have been aided by the fact that the depressed subjects were all recruited from a university-based depression research center. That is, in all cases, the depressed subjects, the primary caregiver, or a family member determined that the individual's change in mood was sufficiently severe to seek medical attention. If we had selected cases for analysis from a population study, for example, we would have been able to evaluate central nervous system structural changes before their clinical expression, and then the locus and extent of caudate reduction might differ from that observed here.
The primary limitations of this study include the relatively small group sizes and the sole focus on caudate nucleus measures. Nevertheless, the depressed subjects in this study were all carefully evaluated within the ACISR/LLMD which has a long record of using well-established research diagnostic criteria. An unexpected finding was that the maps localizing reduction () were not significant after stringent correction for multiple comparisons (permutation testing), although maps of the percent deficit reached 10% anteriorly () and overall volume reductions were significant. In past studies maps have proven to be as powerful, or more powerful, than traditional volumetry for detecting volume reductions, but, as was the case here, maps can miss an effect detected volumetrically if the effect is weak at each specific location on the structure (leading to nonsignificant point-wise p values), but nevertheless is strong enough to produce a significant overall volume reduction. In other studies, these 3-D mesh techniques have generally been more powerful for identifying cross-sectional differences in anatomy between clinical groups (e.g., the caudate nucleus in Fragile × Syndrome and the hippocampus in epilepsy, schizophrenia, autism, and methamphetamine users),37,43,44,55,56
and have provided important longitudinal information about change in status in Alzheimer disease, mild cognitive impairment, and normal brain development.36,38,57
Their use here helped to identify potential loci of systematic differences between LLD and nondepressed comparison subjects, which may be useful for future analysis of effects of treatment with various therapeutic or prevention strategies.