P.3.15 White matter architecture in major depression with anxious distress symptoms

Abstract

Background: The syndromic heterogeneity of Major Depressive Disorder (MDD) makes it extremely difficult to fully understand its pathophysiology and formulate targeted, personalized treatments [1]. As the newly introduced Anxious Distress (ANX) specifier for MDD in DSM-5 [1] aims to tackle this problem by allowing meaningful, symptom-based subtyping, there is great interest to elucidate the neurobiological profile of this specifier [2]. Although indirect evidence links MDD with co-occurring ANX (MDD/ANX+) to frontolimbic network dysfunctions [2,3], no study has directly probed brain connectional profiles among this subgroup of MDD patients. Aim(s): The current study hence uniquely probed whether MDD/ANX+ relates to distinct perturbations in frontolimbic white matter (WM) connections tentatively theorized in MDD/ANX+ pathophysiology. Method(s): Tract-based spatial statistics (TBSS) with non-parametric permutation testing was used to analyze diffusion tensor imaging (DTI) data on WM microstructure in MDD/ANX+ patients (N=20), relative to MDD patients without ANX (MDD/ANX-; N=29) and healthy controls (HC; N=39). Using TBSS, we probed fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity as proxies for WM integrity, whilst utilizing both a categorical (between-groups) and dimensional (within-patients) approach to thoroughly assess how Anxious Distress in MDD impacts frontolimbic WM connectivity. Age, sex, education, scan location, antidepressant use, and comorbidity were corrected for, with all results additionally adjusted for multiple comparisons using threshold-free cluster enhancement with family-wise error correction (P<0.05, corrected). Result(s): The categorical analyses revealed diminished WM integrity of the anterior thalamic radiation (ATR) among MDD/ANX+ patients relative to MDD/ANX- and HC participants (P<0.01). Closer examination revealed that the effect site was in the vicinity of the brainstem/substantia nigra area, in which the change in FA was mainly driven by increased axial, radial and mean diffusivity levels (suggestive of abnormally increased fiber bundle coherence and demyelination). In contrast, dimensional analyses within MDD patients linked elevated ANX specifier scores to diminished integrity of the uncinate fasciculus (UNC) and cingulum (CIN) pathways (P<0.01). Examination of non-FA measures revealed that these changes in FA were both mainly driven by decreased axial, increased radial, and preserved mean diffusivity (suggestive of demyelination and axonal injury). Conclusion(s): These novel findings collectively link MDD/ANX+ to distinct WM anomalies in frontolimbic tracts, which ostensibly carry relevance for emotional homeostasis on the cognitive, behavioral, and physiological level. The data moreover suggest that while ATR microstructural changes might be more relevant for differentiating MDD/ANX+ from other MDD subtypes and healthy controls, alterations in UNC and CIN are perhaps more indicative of MDD/ANX+ severity. Taken as a whole, the findings seem to provide important new clues on the pathophysiology of MDD with Anxious Distress symptoms by highlighting WM microstructural changes as a potential pathomechanism. For a deeper understanding of WM architecture in MDD/ANX+, it would be important to examine whether WM alterations predict susceptibility, chronicity and treatment response in this specific class of MDD patients.Copyright © 2019