We used magnetic resonance imaging (MRI) in a multigenerational cohort of individuals who were either affected or unaffected with MDD to search for a brain-based endophenotype (14
). The first generation in this multigenerational cohort was identified as being either a clinically identified sample of adults who had MDD that was recurrent, moderate to severe, and functionally debilitating, or else a matched comparison group of individuals and their spouses from the same community who had no discernible lifetime history of MDD or other psychiatric illness (15
). Each of these groups in Generation 1 (G1) had children who were followed until adulthood as Generation 2 (G2), and those individuals in turn had children who were followed until adulthood as Generation 3 (G3). These three generations were followed longitudinally over five waves of assessment for the new onset and presence of psychiatric diagnoses. Those longitudinal assessments in this cohort (15
) and similar two-generation studies (17
) have shown that chronic severe depression is familial, with offspring of depressed individuals having a three- to five-fold increased risk of developing MDD themselves, and they helped to define the natural history of familial MDD, which tends to present initially with elevated rates of anxiety disorders before puberty, transforming to MDD beginning in mid to late adolescence. These multigenerational family studies have also shown that familial MDD tends to have an earlier onset and to be more severe, more recurrent, and less responsive to treatment than is nonfamilial MDD.
We obtained anatomical MRIs in 131 members of the second and third generations of this multigenerational cohort. We defined as being at “high familial risk” for developing MDD those members of G2 and G3 who were biological descendants of the MDD group in G1. Those defined as being at “low familial risk” were the G2 and G3 biological descendants of the unaffected control group in G1. The high- and low-risk groups contained 66 and 65 individuals, respectively. As expected, the frequencies of lifetime MDD and anxiety disorders were significantly greater in the high-risk group than in the low-risk group (56% versus 23% for MDD; 52% versus 21% for anxiety disorders). Severity ratings of depression and anxiety symptoms at the time of the MRI scan were similar across groups, however, reflecting the fact that most of the participants in both of the risk groups were not in an MDD episode at the time of scan.
The anatomical images and the methods used to process them permitted detailed comparisons of two measures of brain structure across the high- and low-risk groups (19
). One was a measure of the thickness of the cortical mantle, the ~6-mm-thick layer of gray matter at the surface of the brain that contains most of the nerve cell bodies and neuropil (axonal and dendritic arbors and synapses) and that is the locus of most of the computational functions in the brain. Cortical thickness was compared across groups at each millimeter-sized point on the cerebral surface. The other was a measure of local volumes that permitted comparison of those volumes at each millimeter-sized cube throughout the three-dimensional substance of the brain. We plotted in color the results of the statistical comparisons at each of these points.
These analyses revealed thinning of the cortical mantle over the lateral convexity of the right hemisphere and the medial surface of the left hemisphere in the high-risk group. The thinning in both of these regions was massive in its spatial extent, extending from the back of the brain to the front, sparing only an anterior portion of the surface of the right temporal cortex (). It was also massive in its magnitude within each of those broad cortical regions, with reductions in thickness averaging nearly 30%. In contrast, areas of local thickening were also detected in the high-risk group in the cingulate cortex along the medial wall of the right cerebral hemisphere, especially the ventral anterior and posterior cingulate cortices. Thickening was also detected in the medial orbitofrontal cortex in the same hemisphere.
Figure 1 Maps of cortical thickness. The statistical significance (probability values) of analyses of cortical thickness are color-coded at each point of the cerebral surface. The color bar indicates the color-coding of p-values for tests of statistical significance (more ...)
The analyses also revealed prominent volume reductions in the white matter of the frontal and parietal lobes bilaterally () (M.J. Dubin, M.M. Weissman, D. Xu, et al., manuscript submitted). We determined that the white matter fiber tracts most likely to pass through the regions of frontal and parietal hypoplasia were the superior longitudinal fasciculus (21
), the anterior half of the corpus callosum, and the cortical projections with the thalamus, brainstem, and spinal tracts. Of these various tracts, the superior longitudinal fasciculus is the one that passes through the regions of frontal and parietal hypoplasia and that connects the dorsal frontal cortex to the posterior temporal and parietal cortices, regions where cortical thinning was most prominent in the high-risk group. This fiber tract therefore could produce circuit-based disturbances that would associate the frontal and parietal white matter hypoplasia with the pattern of cortical thinning that we observed. We were interested in knowing whether the findings of cortical thinning and white matter hypoplasia were present in the same people and to the same extent, or whether these represented two distinct anatomical abnormalities within the high-risk population.
Figure 2 Maps of local white matter volume. The statistical significance (probability values) of analyses for measures of local volumes of brain tissue, covarying for age and sex, are color-coded at each point within brain parenchyma. (a) Volumes are compared (more ...)
We therefore assessed whether these two regional disturbances in the cortex and white matter were correlated, and therefore were both portions of the same underlying putative endophenotype. We performed two complementary correlation analyses, one that correlated a single average measure of cortical thickness for each gyrus of the right hemisphere with local volumes at each point of the white matter, and another that correlated a single average measure of local volume in frontal white matter with measures of thickness at each point of the right-hemisphere cortex. Both analyses provided overwhelming evidence that the cortical thinning and white matter hypoplasia are highly correlated and part of the same underlying endophenotype (). Moreover, these analyses showed that cortical thickness and white matter volumes are highly intercorrelated even within the low-risk group alone, suggesting that these measures probably covary strongly even in the general population, and that they are likely components of a single circuit or set of brain circuits. Nearly identical correlations in the high-risk group alone then suggested that this set of circuits was hypoplastic within the high-risk group. In other words, our findings of reduced cortical thickness and reduced white matter volumes likely derived from the hypoplasia of an entire circuit or set of circuits in the high-risk group. Despite the strong intercorrelations of cortical thinning with white matter hypoplasia, we emphasize this set of findings could not formally assess and identify a direction of causality to determine whether the processes responsible for cortical thinning caused the white matter tract abnormalities, whether the white matter abnormalities caused the cortical thinning, or whether some pathological process produced a hypoplasia throughout the entire circuit, including both the cortex and white matter tracts that interconnect them.
Figure 3 Correlation of average local white matter volumes with cortical thickness. At each point on the surface of the brain, the average value of the local white matter volumes in the region of frontal and parietal hypoplasia for each person was correlated with (more ...)