Research paperWhite matter microstructure in boys with persistent depressive disorder
Introduction
Major depressive disorder (MDD) is one of the leading mental health problems in adults with an estimated worldwide lifetime prevalence of 11.2% (Kessler et al., 2015). Many cases of adult MDD begin in adolescence and risk factors for depression may occur even earlier (Kennard et al., 2006, Kovacs and Lopez-Duran, 2010). Adolescence is marked by continued changes in brain maturation and a rise in depressive symptoms during adolescence has often been associated with these changes (e.g., Davey et al., 2008; Foland-Ross et al., 2015; Schmaal et al., 2015).
Grey and white matter exhibit differential developmental patterns with the former showing an overall decrease and the latter an overall increase in volume from late childhood to early adulthood (Mills and Tamnes, 2014). While these measures focus on the macrostructure of the tissue, it is also possible to examine changes in the white matter microstructure using diffusion weighted imaging. White matter restricts the movement of water molecules, which is greater along the long axis of a fibre than across it. Common metrics used to describe these properties are fractional anisotropy (FA) and mean diffusivity (MD). In addition, axonal (AD) and radial diffusivity (RD) corresponding to movement along and across fibre bundles respectively can also be determined. FA is frequently reported in studies of white matter microstructure and lower FA is often interpreted as a reduction in myelination but it may equally correspond to differences in axon diameter, fibre bundle density, crossing fiber, myelin thickness or the cytoskeleton (Chanraud et al., 2010, Jones et al., 2013, Winston, 2012).
Global white matter FA shows a gradual increase throughout childhood and adolescence with associated decreases in MD and RD (Mills and Tamnes, 2014). However, regional differences have been observed with fiber connecting frontal and temporal cortices (Colby et al., 2011, Lebel and Beaulieu, 2011, Tamnes et al., 2010) including the cingulum and uncinate fasciculi, which develop at a slower rate than some of the other fiber (Lebel et al., 2012, Olson et al., 2015, Westlye et al., 2010). Environmental stressor or genetic predisposition may differentially affect the development of white matter pathways and concomitant changes may relate to the development of depressive symptoms (Ladouceur et al., 2012).
To date there have been only few investigations into white matter microstructure in pediatric depressive disorders and there is little consistency across results. Tracts that have been reported by more than two studies include the cingulum, the uncinate fasciuli and the inferior fronto-occipital fasciculi (Aghajani et al., 2013, Bessette et al., 2014, Cullen et al., 2010, Henderson et al., 2013, LeWinn et al., 2014). Changes in the microstructure of the corpus callosum have also been reported by several studies but vary in the exact location with differences reported in the genu (Bessette et al., 2014, LeWinn et al., 2014) as well as the body (Aghajani et al., 2013, Bessette et al., 2014, LeWinn et al., 2014). Generally, lower FA is observed in these fibre bundles in the clinical group but increased FA has also been reported (Aghajani et al., 2013, Henderson et al., 2013). In addition to the above findings, a whole range of other fibre bundles have been reported by individual studies that have not yet been replicated (e.g., Bessette et al., 2014).
In a review of structural and functional neuroimaging studies of pediatric MDD, Hulvershorn et al. (2011) propose that at least some of the alterations in brain structure and function may predate psychopathology. Support comes from a study that examined a group of adolescents with a parental history of depression that reported lower FA in the left cingulum, the splenium of the corpus callosum, the uncinate, superior longitudinal and inferior fronto-occipital fasciculi (Huang, Fan et al., 2011). However, the study only included a small sample size (18 high-risk youth and 13 controls) and has not yet been replicated. While Huang et al. (2011) did not find correlations with symptoms, other studies have found associations between FA in the uncinate and trait anxiety in healthy individuals (Kim and Whalen, 2009, Montag et al., 2012); thus it is not clear whether lower FA precedes symptom onset or simply reflects symptom severity. Although the function of the uncinate is still largely unknown several previous studies have implicated its role in reversal learning, reward processing and long-term memory retrieval (Olson et al., 2015). The latter two are often impaired in MDD suggesting that white matter microstructure in the uncinate may be altered.
Beyond the uncinate Henderson et al. (2013) showed that irritability was associated with lower FA in the sagittal striatum, anterior corona radiata, and tracts leading to prefrontal and temporal cortices while anhedonic symptoms were associated with structural alterations in the anterior limb of the internal capsule and projection fiber to the orbitofrontal cortex. White matter associations with other symptoms that often coexist with depressive disorders such as low self-esteem, hopelessness and attention difficulties have not been examined in children and adolescents with depressive disorders.
Most investigations thus far have employed the tract based spatial statistics (TBSS) procedure (Smith et al., 2006) that projects volumetric data onto a white matter skeleton. While this has advantages to other methods such as voxel-based morphometry, TBSS has limited anatomical specificity and fails to take into account orientation information in the diffusion data (Bach et al., 2014). In addition, previous methods most commonly report values averaged across tracts and do not provide location specific information within tracts. Yet, a recent study has shown that there is considerable variation within tracts as they mature (Chen et al., 2016). To improve upon previous shortcomings the current study used full tensor information for improved registration and employed tract specific analysis to localize any white matter differences within tracts. Our aim was to investigate white matter microstructural differences between a sample of boys with persistent depressive disorder and matched typically developing children. Studying a group of children characterized by chronic but mild symptoms may contribute to a better understanding of whether persistency of symptoms may impact on brain structure to a greater degree than severity of symptoms. In addition, these children are at increased risk of developing a major depressive episode (Klein et al., 2000) and information about underlying neurobiology may help in identifying risk factors that may potentially be the target of early interventions. In line with previous findings in pediatric depression we expected lower FA in white matter fibre tracts in the clinical group, particularly the uncinate fasciculi and the inferior-fronto-occipital fasiculi. We also predicted to find an association between depressive symptoms and FA in the left uncinate fasciculus.
Section snippets
Participants
A total of 50 male young people aged nine to sixteen years participated in this study. 25 met DSM-V diagnostic criteria for persistent depressive disorder (DSM-IV dysthymic disorder) and were recruited from a pediatric psychiatric outpatient clinic at The Royal Children's Hospital, Melbourne, Australia. Our previous study using functional magnetic resonance imaging (fMRI) (Vilgis et al., 2014) included 10 of the 25 patients with DD and 10 of the 25 typically developing children. Diagnoses were
Results
Groups did not differ in age but significant differences in IQ and depressive symptoms were found. No significant differences between the underlying distributions in maternal education were found between the two groups. There were also no significant differences in absolute and relative head motion between the clinical and control group (Table 1).
Discussion
This study aimed to address the question whether white matter microstructural properties differ in young people with persistent depressive disorder compared to typically developing children. Because several previous studies in pediatric depression have shown alterations in FA in the UNC and IFO we hypothesized that these tracts would show lower FA in the present sample. We found clusters in both the UNC and IFO that exhibited lower FA in the clinical compared to the TD group. Differences were
Conflict of interest
All authors declare that they have no conflicts of interest.
Funding
NHMRC project grants 384419 and 569533 provided funds for the data collection. The study was also supported by the Murdoch Childrens Research Institute, the Royal Children's Hospital, The Royal Children's Hospital Foundation, Department of Paediatrics The University of Melbourne and the Victorian Government's Operational Infrastructure Support Program. TS was supported by a NHMRC Career Development Award.
Ethical approval
All procedures performed in
Acknowledgements
This research was conducted within the Academic Child Psychiatry Unit, University of Melbourne, Royal Children's Hospital (clinical research assessments and scans) and the Developmental Imaging research group, Murdoch Childrens Research Institute and the Children's MRI Centre, Royal Children's Hospital, Melbourne, Victoria (imaging analyses). NHMRC project grants 384419 and 569533 provided funds for the data collection. It was also supported by the Murdoch Childrens Research Institute, the
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