Effects of early-life adversity on white matter diffusivity changes in patients at risk for major depression

Frodl, Thomas; Carballedo, Angela; Fagan, Andrew; Lisiecka, Danuta; Ferguson, Yolande; Meaney, James

doi:10.1503/jpn.110028

Cited by 87 publications

(68 citation statements)

References 61 publications

(68 reference statements)

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“…In HCs, the T allele of rs1360780 has been found to be associated with white-matter abnormalities (Fani et al, 2014) and changes such as these have been reported in patients with MDD as well (Frodl et al, 2012;Murphy and Frodl, 2011;Ugwu et al, 2014). Specifically, two studies (Abe et al, 2010;Shimony et al, 2009) reported higher MD and lower FA scores in the prefrontal cortex.…”

Section: Discussionmentioning

confidence: 94%

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

Tozzi

Carballedo

Wetterling

et al. 2015

Neuropsychopharmacol

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The gene expressing the FK506 binding protein 51 (FKBP5) is involved in the regulation of glucocorticoid receptor sensitivity. The rs1360780 SNP in this gene (T allele vs C homozygous) has been found to be associated with major depressive disorder (MDD). The aim of our study was to investigate whether this polymorphism might be associated with altered brain structure and function in a cohort of 40 patients with MDD and 43 healthy controls. A functional magnetic resonance imaging (fMRI) emotional attention task was employed. Diffusion tensor imaging (DTI) was also conducted, extracting mean diffusivity (MD) and fractional anisotropy (FA) from brain areas that showed functional differences between patients expressing the two alleles of the rs1360780 SNP. Finally, the effect of the interaction of childhood adversity as measured by the Childhood trauma Questionnaire (CTQ) and rs1360780 allele status was analyzed in relation to DTI measures using a general linear model. All results presented are family-wise error (FWE) corrected. Functional interactions were found between genotype and diagnosis (po0.01). Patients carrying the high-risk allele, compared with patients not carrying it, showed reduced activity in the rolandic operculum, Heschl gyrus, insula, parahippocampal gyrus, posterior cingulate cortex, inferior frontal gyrus (po0.05 for all measures); and increased MD and reduced FA measures in many of these regions (po0.05). An interaction between CTQ scores and allele status was associated with DTI changes in the insula, rolandic operculum, and inferior frontal gyrus. Here, the presence of both the high-risk allele and higher CTQ scores was associated with higher MD and lower FA values (po0.05). In conclusion, MDD patients expressing the T allele of rs1360780, compared with C homozygous patients, exhibit functional and structural differences in areas involved in emotional perception and inhibition. The interaction between the T allele and childhood maltreatment explained our structural findings in these regions, suggesting that their altered maturation and function might be influenced by early chronic stress in the presence of this genetic trait.

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Section: Discussionmentioning

confidence: 94%

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

Tozzi

Carballedo

Wetterling

et al. 2015

Neuropsychopharmacol

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“…First, examining the FA skeleton revealed that a region of the right body of the corpus colosum (CC) had higher FA values in MDD relative to HC. While some reports have demonstrated that depression is associated with decreased FA values in the body of the CC (Cole et al, 2012), a study by (Frodl et al, 2012) found that unaffected first-degree healthy relatives (UHRs) of patients with MDD revealed increased FA values in the CC, which they speculated might represent vulnerable characteristics for the formation of depression. Finally, a meta-analysis of WM abnormalities in MDD that examined 17 studies that included 641 MDD patients and 581 HC (Chen et al, 2016) found that the CC consistently reveals differences between MDD and HC, particularly in the genu and body regions, even if the directionality of those differences remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the diagnostic utility of applying a machine learning algorithm to diffusion tensor MRI measures in individuals with major depressive disorder

Schnyer

Clasen

Gonzalez

et al. 2017

Psychiatry Research: Neuroimaging

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Using MRI to diagnose mental disorders has been a long-term goal. Despite this, the vast majority of prior neuroimaging work has been descriptive rather than predictive. The current study applies support vector machine (SVM) learning to MRI measures of brain white matter to classify adults with Major Depressive Disorder (MDD) and healthy controls. In a precisely matched group of individuals with MDD (n = 25) and healthy controls (n = 25), SVM learning accurately (74%) classified patients and controls across a brain map of white matter fractional anisotropy values (FA). The study revealed three main findings: 1) SVM applied to DTI derived FA maps can accurately classify MDD vs. healthy controls; 2) prediction is strongest when only right hemisphere white matter is examined; and 3) removing FA values from a region identified by univariate contrast as significantly different between MDD and healthy controls does not change the SVM accuracy. These results indicate that SVM learning applied to neuroimaging data can classify the presence versus absence of MDD and that predictive information is distributed across brain networks rather than being highly localized. Finally, MDD group differences revealed through typical univariate contrasts do not necessarily reveal patterns that provide accurate predictive information.

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“…Decreased FA of major white matter tracts is a replicable imaging finding in schizophrenia (11–15). Reduced FA has been linked to elevated cortisol in individuals exposed to early adverse events (16–19). Chronic stress may cumulatively affect white matter over time and as a consequence contribute to abnormal white matter structural connectivity (20).…”

Section: Introductionmentioning

confidence: 99%

Fornix Structural Connectivity and Allostatic Load: Empirical Evidence From Schizophrenia Patients and Healthy Controls

Savransky

Chiappelli²,

Rowland³

et al. 2017

Psychosom Med

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Objective The fornix is a white matter tract carrying the fibers connecting the hippocampus and the hypothalamus, two essential stress-regulatory structures of the brain. We tested the hypothesis that allostatic load (AL), derived from a battery of peripheral biomarkers indexing the cumulative effects of stress, is associated with abnormalities in brain white matter microstructure, especially the fornix; and that higher AL may help explain the white matter abnormalities in schizophrenia. Methods We tested AL in 44 schizophrenia patients and 33 healthy controls using thirteen pre-defined biomarkers. Diffusion tensor imaging (DTI) was used to obtain fractional anisotropy (FA) values of the fornix and other white matter tracts. Results AL scores were significantly elevated in patients compared to controls (F(3, 77)=7.87, p=0.006). AL was significantly and inversely correlated with FA of fornix in both controls (r=−0.58, p=0.001) and patients (r=−0.36, p=0.023). Several nominally significant (p<0.05 but did not survive Bonferroni correction for multiple comparison) correlations were also observed between AL and FA of other white matter tracts in schizophrenia patients. However, the fornix was the only tract exhibiting a correlation with AL in both groups. Conclusions These results provide initial evidence that allostatic processes are linked to fornix microstructure in clinical subjects.

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Effects of early-life adversity on white matter diffusivity changes in patients at risk for major depression

Cited by 87 publications

References 61 publications

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

Evaluating the diagnostic utility of applying a machine learning algorithm to diffusion tensor MRI measures in individuals with major depressive disorder

Fornix Structural Connectivity and Allostatic Load: Empirical Evidence From Schizophrenia Patients and Healthy Controls

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