Tractography values.

*<p>significant p–value.</p><p>Abbreviations: FA, Fractional Anisotropy; AD, Axial Diffusivity; RD, Radial Diffusivity; MD, Mean Diffusivity MDD, Major Depressive Disorder.</p

Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging

<div><p>Background</p><p>The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem’s role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.</p><p>Methods</p><p>MDD patients (n = 95) and age- and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants.</p><p>Results</p><p>MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a “bottom up” afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity.</p><p>Conclusions</p><p>The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala-mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD.</p></div

The three brainstem tracts identified using probabilistic tractography.

<p>A: Nigrostriatal tract (Left and Right in red). B: Solitary tract (Left and Right in green). C: Corticospinal tract (Left and Right in blue) superimposed over a representative DTI image.</p

Demographic characteristics.

*<p>Difference between MDD & Control at p<0.001.</p><p>Abbreviations: HRSD₁₇, 17-item Hamilton Rating Scale for Depression; MDD, Major Depressive Disorder.</p

Early Exposure to Traumatic Stressors Impairs Emotional Brain Circuitry

<div><p>Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.</p> </div

Grey matter and white matter regions of interest used in the study.

<div><p>(top row) Different brain lobes (A) and the rostral and caudal anterior cingulate sub-regions (B) parcelled using freesurfer for a representative dataset (bottom row (C)). Fractional anisotropy skeleton (in green) representing the major white matter tracts for all subjects is overlaid on the MNI standard brain. Sections of the tract sekeleton representing the cingulate and limbic white matter tracts are shown: cingulum cingulate bundle (orange); cingulum hippocampus bundle (pink); fornix (yellow); stria (blue) and uncinate fasciculus (red).</p> <p>Abbreviations: ACC, anterior cingulate cortex.</p></div

Linear regression analyses to assess effect of <i>MAPT</i> diplotype and <i>GSK3B</i> genotypes on total grey matter and intracranial volume^a.

a<p>Genotypes were tested separately in models including age and sex as <i>a priori</i> predictors. Values for all predictors in each model are given in Tables S1 and S2 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071750#pone.0071750.s001" target="_blank">Information S1</a>.</p>b<p>Coded as follows: <i>MAPT</i>, H1H1 = 0, H1H2 = 1, H2H2 = 2; rs3755557, AA = 0, AT = 1, TT = 2; rs334558, GG = 0, AG = 1, AA = 2.</p>c<p>Meta-analyses with a significant effect after correction for multiple comparisons are in <b>bold.</b></p

Effect of <i>GSK3B</i> rs3755557 on transcription.

<p>a) Comparison of expression levels from <i>GSK3B</i> promoter constructs by luciferase reporter gene assay. Constructs contained either the A or T allele of rs3755557 on a background of either the T or C allele of rs334558. Error bars indicate standard error of the mean from 3 independent experiments. *, <i>p</i><0.05. b) Electrophoretic mobility shift assay to show differential binding of either Oct-1 or Pbx-1 transcription factors to labeled oligomers corresponding to either the A or T allele of rs3755557. c) Quantification of gel shift assay. Error bars indicate standard error of the mean density of bands corresponding to (Oct-1), (Pbx-1) and (Oct-1+ Pbx-1) binding for each allele.</p

Demographics of cohorts examined in this study.

a<p>Mean ± standard deviation.</p>b<p>Genotype counts (percentages in parentheses).</p>c<p>Genotype counts for MAS and OATS cohorts derived from imputed allele dosage scores, rounded to the nearest whole number. Raw dosage scores were used for linear regression analyses.</p>d<p>Genotype counts for OATS cohort derived from imputed allele dosage scores, rounded to the nearest whole number. Raw dosage scores were used for linear regression analyses.</p