Widespread Cortical Thickness Is Associated With Neuroactive Steroid Levels

Abstract

Background: Neuroactive steroids are endogenous molecules with regenerative and neuroprotective actions. Both cortical thickness and many neuroactive steroid levels decline with age and are decreased in several neuropsychiatric disorders. However, a systematic examination of the relationship between serum neuroactive steroid levels and in vivo measures of cortical thickness in humans is lacking.

Methods: Peripheral serum levels of seven neuroactive steroids were assayed in United States military veterans. All (n = 143) subsequently underwent high-resolution structural MRI, followed by parcellelation of the cortical surface into 148 anatomically defined regions. Regression modeling was applied to test the association between neuroactive steroid levels and hemispheric total gray matter volume as well as region-specific cortical thickness. False discovery rate (FDR) correction was used to control for Type 1 error from multiple testing.

Results: Neuroactive steroid levels of allopregnanolone and pregnenolone were positively correlated with gray matter thickness in multiple regions of cingulate, parietal, and occipital association cortices (r = 0.20-0.47; p < 0.05; FDR-corrected).

Conclusion: Positive associations between serum neuroactive steroid levels and gray matter cortical thickness are found in multiple brain regions. If these results are confirmed, neuroactive steroid levels and cortical thickness may help in monitoring the clinical response in future intervention studies of neuroregenerative therapies.

Keywords: MRI; cortical thickness; gray matter; neuroactive steroids; neuroprotection; neuroregeneration.

FIGURE 1

Radar plot showing the number of significant results (log base-2) obtained from bivariate correlations of seven neurosteroids with 148 cortical regions (1036 total tests) for various approaches to handling multiple comparisons including uncorrected, FDR correction of Benjamini and Hochberg, pFDR correction of Storey, and Bonferroni correction.

FIGURE 2

Heat map of correlation between neurosteroid level and cortical thickness. Correlation strength between neurosteroid level (y-axis) and cortical thickness (x-axis) for the left hemisphere (upper heat map) and right hemisphere (lower heat map). The pattern shows concordant relationships among DHEAS, allopregnanolone, pregnenolone, and to a lesser extent with androsterone as well as concordant results between the left and right hemisphere. The strongest correlations are present in inferior frontal cortex, temporoparietal, occipitoparietal, and occiptiotemporal association cortices. Nomenclature of cortical structure is per definitions provided by Destrieux et al. (2010).

FIGURE 3

Interaction of neurosteroid level × age is associated with cortical thickness. (A) Participants under 40 years showed a positive correlation (r = 0.365) of DHEAS with cortical thickness in the left orbital gyrus but the correlation was not present (r = –0.140) in participants over 40 years (Z = 3.08; p = 0.002). (B) Participants under 40 years showed a positive correlation (r = 0.414) of DHEAS with cortical thickness in the anterior horizontal portion of the right lateral fissure but the correlation was not present (r = –0.094) in participants over 40 years (Z = 3.14; p = 0.002).

FIGURE 4

Scatter plot of log10 transformed allopregnanolone levels (x-axis) against cortical thickness (y-axis) separately for the early (blue dots/line) and late subgroups (red dots/line). Fisher’s r-to-z showed no significant difference between early (<200) and late (>200) correlations (Z = 0.901, p = 0.367).

FIGURE 5

Scatter plot of log10 transformed pregnenolone levels (x-axis) against cortical thickness (y-axis) separately for the early (blue dots/line) and late subgroups (red dots/line). Fisher’s r-to-z showed no significant difference between early (<200) and late (>200) correlations (Z = 0.673, p = 0.501).

FIGURE 6

Vertex-wide cortical thickness analysis showed an association with (A) pregnenolone in the left lateral occipto-temporal cortex, and (B) with allopregnanolone in the right medial occipital cortex and (C) right inferior medial temporo-occipital cortex (Cluster Forming Threshold (CFT) p < 0.01; corrected).