Cortical thinning in persons at increased familial risk for major depression

Abstract

The brain disturbances that place a person at risk for developing depression are unknown. We imaged the brains of 131 individuals, ages 6 to 54 years, who were biological descendants (children or grandchildren) of individuals identified as having either moderate to severe, recurrent, and functionally debilitating depression or as having no lifetime history of depression. We compared cortical thickness across high- and low-risk groups, detecting large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere in persons at high risk. Thinning correlated with measures of current symptom severity, inattention, and visual memory for social and emotional stimuli. Mediator analyses indicated that cortical thickness mediated the associations of familial risk with inattention, visual memory, and clinical symptoms. These findings suggest that cortical thinning in the right hemisphere produces disturbances in arousal, attention, and memory for social stimuli, which in turn may increase the risk of developing depressive illness.

Fig. 1.

Maps of group differences in cortical thickness. At each point on the cerebral surface, the statistical significance (probability values) of differences in cortical thickness across groups (high vs. low risk) in participants from generations G2 and G3 are color coded. Warm colors (yellow, orange, and red) represent significantly thicker cortices in the high-risk group; cooler colors (blue and purple) represent thinner cortices in that group. The color bar indicates the color-coding of p-values for testing of statistical significance at each point on the surface of the brain. Cortical thickness was rescaled for overall brain size, and the statistical models controlled for the degree of familial relatedness, the age, and the sex of all participants. (Upper) P-values thresholded at P < 0.05 without correction for multiple statistical comparisons. (Lower) P-values thresholded at P < 0.05 after correction for multiple comparisons using the theory of Gaussian random fields (GRF) on a 2D manifold. Cu, cuneus; IF, inferior frontal gyrus; IOG, inferior occipital gyrus; IP, inferior parietal lobule; LG, lingual gyrus; MGF, middle frontal gyrus; MOG, middle occipital gyrus; MTG, middle temporal gyrus; OF, orbitofrontal cortex; PC, posterior cingulate; PoG, postcentral gyrus; PreCu, precuneus; PrG, precentral gyrus; SG, subgenual cortex; STG, superior temporal gyrus.

Fig. 2.

Correlations of cortical thickness with current symptom severity. (Top) Correlations of cortical thickness with the sum of the z-depression and z-anxiety measures in children and adults of both risk groups combined while covarying for age, sex, and risk status of each participant. (Bottom) Analogous correlations in the high-risk group only. Similar findings were obtained for each severity measure separately and in each risk group separately (see SI). Significant inverse correlations are evident in the right and left inferior parietal and occipital cortices, the left middle and superior temporal gyri, the right posterior cingulate and precuneus cortices, the inferior temporal cortices bilaterally, and the left orbitofrontal cortex. Because these analyses were post hoc, the maps are not GRF-corrected for multiple comparisons. Cu, cuneus; Fus, fusiform gyrus; IOG, inferior occipital gyrus; IP, inferior parietal lobule; LG, lingual gyrus; MOG, middle occipital gyrus; MTG, middle temporal gyrus; OF, orbitofrontal cortex; PC, posterior cingulate; PreCu, precuneus; SMG, supramarginal gyrus; STG, superior temporal gyrus.

Fig. 3.

Correlations of cortical thickness with behavioral measures. Warm colors (yellow, orange, and red) represent significant positive correlations. Cooler colors (blue and purple) represent inverse correlations between cortical thickness and the behavioral measure. Statistical models for the correlations accounted for the degree of familial relatedness, age, and sex of the participants. Correlations are shown for high- and low-risk groups combined, although similar maps were found in both the high- and low-risk groups separately (data not shown). Findings did not change appreciably when covarying also for risk status, indicating that these correlations are not driven by differences in cortical thickness or memory scores across the 2 risk groups. Correlations are especially strong in the lateral surface of the right compared with the left hemisphere, and the general patterns of correlation are similar to those detected when comparing cortical thickness in the high- and low-risk groups (see Fig. 1). Maps that correct for multiple comparisons using the theory of Gaussian random fields (GRF) are shown in the lower half of each panel. (Left) Greater inattention accompanied proportionately thinner cortices (n = 117). (Right) Worse visual memory performance accompanied proportionately thinner cortices (n = 119).

Fig. 4.

Mediator analyses. (Left) P-values are plotted for regression models that test whether cortical thickness mediates the association of familial risk with measures of inattention. Significant mediator effects were detected throughout the right hemisphere, particularly its posterior portions (n =117). (Middle) P-values are plotted for regression models that test whether cortical thickness mediates the association of familial risk with measures of visual memory. Significant mediator effects were detected throughout the right hemisphere (n = 119). (Right) P-values are plotted for regression models that test whether inattention mediates the association of cortical thickness with the severity of anxiety symptoms. Significant mediator effects were detected in the mid-temporal and inferior parietal cortices of the left hemisphere as well as in the posterior right hemisphere (n = 133). Similar results were obtained for mediator analyses with depressive symptoms as the dependent variable (SI). Because these analyses were intended to confirm the hypothesized mediating effects in post hoc analyses, the p-values are not corrected for multiple statistical comparisons (n =113).

Fig. 5.

Model of pathogenesis. Line arrows and adjacent p-values indicate significant bivariate associations. The correlation analyses that generated the p-values are described in the text, except for those involving cortical thickness, which are depicted in the statistical maps of Fig. 1. Block arrows indicate the directions of hypothesized causal influence within mediating pathways. The solid red box encloses the statistically significant mediator analysis in which cortical thinning mediates the associations of familial risk with measures of inattention. The dashed green box encloses the statistically significant mediator analysis in which cortical thinning mediates the associations of familial risk with measures of visual memory. The dotted blue box encloses the statistically significant mediator analysis in which inattention mediates the association of cortical thinning with the symptoms of MMD or anxiety. A familial risk for MDD produces cortical thinning of the right hemisphere. Cortical thinning in turn disrupts attention and arousal processes, as well as visual memory for social stimuli. These disruptions in turn increase the risk for developing MDD. ANX, anxiety disorder; MDD, major depressive disorder; NS, not significant.