Brain structural network alterations related to serum cortisol levels in drug-naïve, first-episode major depressive disorder patients: a source-based morphometric study.

Higher cortisol levels due to a hyperactive hypothalamic-pituitary-adrenal axis have been reported in patients with major depressive disorder (MDD). Increased cortisol levels change both the brain morphology and function in MDD patients. The multivariate source-based morphometry (SBM) technique has been applied to investigate neuroanatomical changes in some neuropsychiatric diseases, but not MDD. We aimed to examine the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve MDD patients using SBM. Forty-two patients with MDD and 39 controls were recruited via interviews. Morning serum cortisol levels were measured, and high-resolution T1-weighted imaging followed by SBM analysis was performed in all participants. The patients had significantly higher serum cortisol levels than the controls. We found two GM sources, which were significantly different between patients with MDD and controls (prefrontal network, p < .01; insula-temporal network, p < .01). Serum cortisol levels showed a statistically significant negative correlation with the loading coefficients of the prefrontal network (r = - 0.354, p = 0.02). In conclusion, increased serum cortisol levels were associated with reductions in the prefrontal network in the early stage of MDD, and SBM may be a useful approach for analyzing structural MRI data.

An independent component analysis reveals brain structural networks related to TNF-α in drug-naïve, first-episode major depressive disorder: a source-based morphometric study.

In a previous mouse study, social defeat stress-induced microglial activation released tumor necrosis factor-α (TNF-α), leading to neuronal changes in the prefrontal cortex (PFC) and behavioral changes (anxiety). We aimed to investigate the relationship between gray-matter (GM) structural networks and serum TNF-α in patients with major depression disorder (MDD) using multivariate source-based morphometry (SBM). Forty-five first-episode and drug-naïve MDD patients and 38 healthy subjects (HSs) were recruited. High-resolution T1-weighted imaging was performed and serum TNF-α levels were measured in all MDD patients and HSs. After acquiring GM structural networks using SBM, we compared the Z-transformed loading coefficients (Z-scores) between MDD patients and HSs, and investigated the relationship between the Z-scores and the serum TNF-α levels in MDD patients. The serum TNF-α levels in MDD patients were significantly higher than those in HSs. We extracted two independent GM structural networks (the prefrontal network and the insula-temporal network) with significant differences between MDD patients and HSs (-0.305 ± 0.85 and 0.253 ± 0.82; P = 0.03 in the prefrontal network, and -0.268 ± 0.86 and 0.467 ± 0.71; P < 0.01 in the insula-temporal network). The serum TNF-α levels were significantly correlated with the Z-scores in the prefrontal network after Bonferroni correction (r = -0.419, p < 0.01); however, the correlation in the insula-temporal network was not significant (r = -0.290, p = 0.11). Elevated serum TNF-α levels in the early stage of MDD were associated with alteration of the prefrontal network.

Early volume reduction of the hippocampus after whole-brain radiation therapy: an automated brain structure segmentation study.

PURPOSE: To assess atrophy differences among brain regions and time-dependent changes after whole-brain radiation therapy (WBRT). MATERIALS AND METHODS: Twenty patients with lung cancer who underwent both WBRT and chemotherapy (WBRT group) and 18 patients with lung cancer who underwent only chemotherapy (control group) were recruited. Three-dimensional T1WI were analyzed to calculate volume reduction ratio after WBRT in various brain structures. The volume reduction ratio of the hippocampus was compared among following 3 periods: 0-3, 4-7, and 8-11 months after WBRT. RESULTS: The volume reduction ratio of the hippocampus was significantly higher in the WBRT group than in the control group (p < 0.05). In WBRT group, the volume reduction ratio of the hippocampus was significantly higher than that of the cortex and white matter (p < 0.05). There were significant differences in the volume reduction ratio between of 0-3 months and that of 4-7 months (p = 0.02) and between 4-7 months and that of 8-11 months (p = 0.01). CONCLUSION: The hippocampus is more vulnerable to the radiation compared with other brain regions and may become atrophic even in the early stage after WBRT.

Genetic effects on white matter integrity in drug-naive patients with major depressive disorder: a diffusion tensor imaging study of 17 genetic loci associated with depressive symptoms.

BACKGROUND: A genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method. METHODS: Thirty-five drug-naive MDD patients with a first depressive episode and 47 age-and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype-diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs. RESULTS: For the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P<0.05, family-wise error corrected) in only one SNP, rs301806, in the arginine-glutamic acid dipeptide (RE) repeats (RERE) gene. CONCLUSION: The RERE polymorphism was associated with WM alterations in first-episode and drug-naive MDD patients, which may be at least partially related to the manifestation of MDD. Future studies are needed to explore the gene-environment interactions with regard to individual WM integrity.

Brain structural connectivity and neuroticism in healthy adults.

Understanding the neural correlates of the neurotic brain is important because neuroticism is a risk factor for the development of psychopathology. We examined the correlation between brain structural networks and neuroticism based on NEO Five-Factor Inventory (NEO-FFI) scores. Fifty-one healthy participants (female, n = 18; male, n = 33; mean age, 38.5 ± 11.7 years) underwent the NEO-FFI test and magnetic resonance imaging (MRI), including diffusion tensor imaging and 3D T1WI. Using MRI data, for each participant, we constructed whole-brain interregional connectivity matrices by deterministic tractography and calculated the graph theoretical network measures, including the characteristic path length, global clustering coefficient, small-worldness, and betweenness centrality (BET) in 83 brain regions from the Desikan-Killiany atlas with subcortical segmentation using FreeSurfer. In relation to the BET, neuroticism score had a negative correlation in the left isthmus cingulate cortex, left superior parietal, left superior temporal, right caudal middle frontal, and right entorhinal cortices, and a positive correlation in the bilateral frontal pole, left caudal anterior cingulate cortex, and left fusiform gyrus. No other measurements showed significant correlations. Our results imply that the brain regions related to neuroticism exist in various regions, and that the neuroticism trait is likely formed as a result of interactions among these regions. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan.

Relationship between white matter integrity and serum inflammatory cytokine levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.

Recently, accumulated evidence has indicated a role of inflammation in the pathogenesis of major depressive disorder (MDD). Therefore, we evaluated the relationship between white matter integrity and serum cytokine levels during the first depressive episode in drug-naive MDD patients, using a tract-based spatial statistics (TBSS) method. A total of 35 drug-naive MDD patients with a first depressive episode and 35 healthy subjects (HS) underwent diffusion tensor imaging, and an analysis was conducted using TBSS. We measured serum cytokine levels (interleukin [IL]-1ß, IL-6, interferon-γ, and tumor necrosis factor-α). Fractional anisotropy (FA) values of the bilateral inferior fronto-occipital fasciculus (IFOF) and genu of the corpus callosum in MDD patients were decreased significantly to the HS (p < 0.05 with family-wise error [FWE] correction) and were significantly inversely correlated with the IL-1ß levels (p < 0.05, with FWE correction). No regions showed a correlation between FA values and other serum cytokine levels. Our results suggested that the microstructural changes in IFOF and genu of the corpus callosum are associated with the high IL-1ß levels in the early stage of MDD.

Relationship between interleukin (IL)-6 and brain morphology in drug-naïve, first-episode major depressive disorder using surface-based morphometry.

There is a growing body of evidence to support the involvement of proinflammatory cytokines in the pathophysiology of depression; however, no previous studies have examined the relationship between cytokines and the brain morphology of patients with major depressive disorder (MDD). We therefore evaluated the relationship between serum cytokine levels and cortical thinning during the first depressive episode in drug-naïve patients with MDD. We measured the serum cytokine levels (IL-1ß, IL-6, IFN-γ, and TNFα), and whole-brain cortical thickness and hippocampal subfield volumes on brain magnetic resonance imaging (MRI) using surface-based morphometry in 40 patients with MDD and 47 healthy volunteers (controls). Only the serum IL-6 level was significantly higher in patients with MDD than in controls. The prefrontal cortex (PFC) thickness was significantly reduced in patients with MDD, and showed a significant inverse correlation with the serum IL-6 level. Although high serum IL-6 levels were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes, the presence or absence of MDD had no effect on the volume of any hippocampal subfields. Our results suggest that IL-6 may play a key role in the morphological changes in the PFC during the early stage of MDD.

Voxel-based morphometric brain comparison between healthy subjects and major depressive disorder patients in Japanese with the s/s genotype of 5-HTTLPR.

Individuals with s/s genotype of serotonin transporter gene-linked promotor region (5-HTTLPR), which appear with a high frequency in Japanese, exhibit more diagnosable depression in relation to stressful life events than those with the s/l or l/l genotype. We prospectively investigated the brain volume changes in first-episode and medication naïve major depression disorder patients (MDD) with the s/s genotype in Japanese. We assessed the differences between 27 MDD with the s/s genotype and 44 healthy subjects (HS) with the same genotype using a whole-brain voxel-by-voxel statistical analysis of MRI. Gray matter volume in a brain region with significant clusters obtained via voxel-based morphometry analysis were measured and, as an exploratory analysis, evaluated for relationships to the subcategory scores (core, sleep, activity, psychic, somatic anxiety, delusion) of the Hamilton Depression Rating Scale (HAM-D) and the Social Readjustment Rating Scale (SRRS). The brain volume in the left insula lobe was significantly smaller in the MDD than in the HS. The left insula lobe volume correlated negatively with the "psychic" score of HAM-D and the SRRS. In a Japanese population with the s/s genotype, we found an atrophy of the insula in the MDD, which might be associated with "psychic" symptom and stress events.

Utility of real-time prospective motion correction (PROMO) for segmentation of cerebral cortex on 3D T1-weighted imaging: Voxel-based morphometry analysis for uncooperative patients.

OBJECTIVE: To assess the utility of the motion correction method with prospective motion correction (PROMO) in a voxel-based morphometry (VBM) analysis for 'uncooperative' patient populations. METHODS: High-resolution 3D T1-weighted imaging both with and without PROMO were performed in 33 uncooperative patients with Parkinson's disease (n = 11) or dementia (n = 22). We compared the grey matter (GM) volumes and cortical thickness between the scans with and without PROMO. RESULTS: For the mean total GM volume with the VBM analysis, the scan without PROMO showed a significantly smaller volume than that with PROMO (p < 0.05), which was caused by segmentation problems due to motion during acquisition. The whole-brain VBM analysis showed significant GM volume reductions in some regions in the scans without PROMO (familywise error corrected p < 0.05). In the cortical thickness analysis, the scans without PROMO also showed decreased cortical thickness compared to the scan with PROMO (p < 0.05). CONCLUSION: Our results with the uncooperative patients indicate that the use of PROMO can reduce misclassification during segmentation of the VBM analyses, although it may not prevent GM volume reduction. KEY POINTS: • Motion artifacts pose significant problems for VBM analyses. • PROMO correction can reduce the motion artifacts in high-resolution 3D T1WI. • The use of PROMO may improve the precision of VBM analyses.

Utility of real-time prospective motion correction (PROMO) on 3D T1-weighted imaging in automated brain structure measurements.

PROspective MOtion correction (PROMO) can prevent motion artefacts. The aim of this study was to determine whether brain structure measurements of motion-corrected images with PROMO were reliable and equivalent to conventional images without motion artefacts. The following T1-weighted images were obtained in healthy subjects: (A) resting scans with and without PROMO and (B) two types of motion scans ("side-to-side" and "nodding" motions) with and without PROMO. The total gray matter volumes and cortical thicknesses were significantly decreased in motion scans without PROMO as compared to the resting scans without PROMO (p < 0.05). Conversely, Bland-Altman analysis indicated no bias between motion scans with PROMO, which have good image quality, and resting scans without PROMO. In addition, there was no bias between resting scans with and without PROMO. The use of PROMO facilitated more reliable brain structure measurements in subjects moving during data acquisition.