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Reduced gray matter (GM) volume may represent a hallmark of major depressive disorder (MDD) neuropathology, typified by wide-ranging distribution of structural alteration. In the study, we aimed to replicate and extend our previous finding of profound and widespread GM loss in MDD, and evaluate the diagnostic accuracy of a structural biomarker derived from GM volume in an interconnected pattern across the brain. In a sub-study of the International Study to Predict Optimized Treatment in Depression (iSPOT-D), two cohorts of clinically defined MDD participants "Test" (n = 98) and "Replication" (n = 131) were assessed alongside healthy controls (n = 66). Using 3T MRI T1-weighted volumes, GM volume differences were evaluated using voxel-based morphometry. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate an MDD diagnostic biomarker based on a precise spatial pattern of GM loss constructed using principal component analysis. We demonstrated a highly conserved symmetric widespread pattern of reduced GM volume in MDD, replicating our previous findings. Three bilateral dominant clusters were observed: Cluster 1: midline/cingulate (GM reduction: Test: 6.4%, Replication: 5.3%), Cluster 2: medial temporal lobe (GM reduction: Test: 8.2%, Replication: 11.9%), Cluster 3: prefrontal cortex (GM reduction: Test: 12.1%, Replication: 23.2%). We developed a biomarker reflecting the global pattern of GM reduction, achieving good diagnostic classification performance (AUC: Test = 0.75, Replication = 0.84). This study establishes that a highly specific pattern of reduced GM volume is a feature of MDD, suggestive of a structural basis for this disease. We introduce and validate a novel diagnostic biomarker based on this pattern.

Occipital bending (OB) describes asymmetry of the occipital lobes where one lobe wraps across the midline, and has been associated with the presence of mood disorders. We evaluated the relationship between OB and major depressive disorder (MDD) in a large population of subjects from the International Study to Predict Optimized Treatment in Depression. MDD patients (n = 231) and healthy controls (n = 68) underwent MRI and neuropsychiatric evaluation, including response or remission to antidepressant medication at baseline and at 8 weeks. Cortical thickness, ventricular volumes and regional grey matter volumes were measured. OB was visually assessed and OB angle measured using a semi-automated method. Correlations with MDD diagnosis, MRI measures and clinical features were tested. Results demonstrated a greater proportion of rightwards OB in MDD compared to control subjects (p = 0.02). There was no difference in the total prevalence of OB (combined left and rightward bending) between MDD and controls. MDD subjects with right OB had greater cortical thickness in three medial occipital regions (cuneus, lingual gyrus and calcarine sulcus) on the left. Lateral ventricular size was 20% lower bilaterally in right OB MDD subjects compared to non-OB MDD subjects. OB was not associated with severity (HDRS-17). Our data suggest the presence of a strong link between greater rightward occipital bending and MDD. Rightward-OB is associated with greater left medial occipital cortical thickness, and with reduced lateral ventricular size. The cause for greater rightward bending in MDD patients is unclear, however our data suggest a developmental aetiology., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable., Methods: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67)., Results: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis., Conclusions: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD 17 ) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD 17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

Background: Structural neuroimaging studies revealed a consistent pattern of volumetric reductions in both hippocampus (HC) and anterior cingulate cortex (ACC) of individuals with major depressive episode(s) (MDE). This study investigated HC and ACC volume differences in currently depressed individuals (n = 150), individuals with a past lifetime MDE history (n = 79) and healthy controls (n = 287)., Methods: Non-demented individuals were recruited from a cohort of community-dwelling older adults (ESPRIT study). T1-weighted magnetic resonance images and FreeSurfer Software (automated method) were used. Concerning HC, a manual method of measurement dividing HC into head, body, and tail was also used. General Linear Model was applied adjusting for covariates., Results: Current depression was associated with lower left posterior HC volume, using manual measurement, in comparison to healthy status. However, when we slightly changed sub-group inclusion criteria, results did not survive to correction for multiple comparisons., Conclusions: The finding of lower left posterior HC volume in currently depressed individuals but not in those with a past MDE compared to healthy controls could be related to brain neuroplasticity. Additionally, our results may suggest manual measures to be more sensitive than automated methods., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation., Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed., Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow., Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression.

Previous studies suggest that altered corneal temperature may be a feature of schizophrenia, but the association between major depressive disorder (MDD) and corneal temperature has yet to be assessed. The aim of this study is to investigate whether eye temperature is different among MDD patients than among healthy individuals. We used a thermographic camera to measure and compare the temperature profile across the corneas of 16 patients with MDD and 16 age- and sex-matched healthy subjects. We found that the average corneal temperature between the two groups did not differ statistically, although clinical severity correlated positively with right corneal temperature. Corneal temperature may be an indicator of clinical severity in psychiatric disorders, including depression.

A number of genome-wide association studies (GWAS) have investigated risk factors for major depressive disorder (MDD), however there has been little attempt to replicate these findings in population-based studies of depressive symptoms. Variants within three genes, BICC1, PCLO and GRM7 were selected for replication in our study based on the following criteria: they were identified in a prior MDD GWAS study; a subsequent study found evidence that they influenced depression risk; and there is a solid biological basis for a role in depression. We firstly investigated whether these variants were associated with depressive symptoms in our population-based cohort of 929 elderly (238 with clinical depressive symptoms and 691 controls), and secondly to investigate associations with structural brain alterations. A number of nominally significant associations were identified, but none reached Bonferroni-corrected significance levels. Common SNPs in BICC1 and PCLO were associated with a 50% and 30% decreased risk of depression, respectively. PCLO rs2522833 was also associated with the volume of grey matter (p=1.6×10(-3)), and to a lesser extent with hippocampal volume and white matter lesions. Among depressed individuals rs9870680 (GRM7) was associated with the volume of grey and white matter (p=10(-4) and 8.3×10(-3), respectively). Our results provide some support for the involvement of BICC1 and PCLO in late-life depressive disorders and preliminary evidence that these genetic variants may also influence brain structural volumes. However effect sizes remain modest and associations did not reach corrected significance levels. Further large imaging studies are needed to confirm our findings., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: No electrophysiological neuroimaging or genetic markers have been established that strongly relate to a diagnosis of major depression or its severity. The objective of this paper is to describe the preliminary evaluation of a potential new biomarker for depression utilizing the recording of electrical activity from the outer ear canal referred to as electrovestibulography (EVestG)., Methods: Sensory oto-acoustic features were extracted from EVestG data to compare 31 healthy age- and gender-matched individuals as controls to 43 major depressive disorder (MDD) subjects (22 symptomatic (MDD-S), 21 reduced symptomatic (MDD-R)). The stimulus was a single supine-vertical translation. The six features examined were based on the measured firing pattern interval histogram and the shape of the average field potential response., Results: An unbiased classification accuracy of 85, 87 and 77% was achieved for separating Control from MDD-S, Control from MDD, and MDD-S from MDD-R groups respectively. Features used showed low but significant correlations (P < 0.05) with MADRS and CORE assessments., Conclusions: The results support the use of separate features for measuring MDD symptomatology versus diagnosing MDD, representing plausible different mechanisms of brain function in MDD-S and MDD-R. The first evidence of the successful application of sensory oto-acoustic features toward diagnosing and measuring the symptomatology of MDD is presented.

Rates of major depressive disorder (MDD) following traumatic brain injury (TBI) are estimated to be between 20% and 45%, a higher prevalence than that seen in the general population. These increased rates may be due to specific changes in brain function following TBI. Event related potentials (ERPs) are well suited for measuring the electrophysiological differences between groups in areas of cognitive processing impaired in both MDD and TBI, such as response inhibition. The current study presented an emotional Go/Nogo task (with schematic emotional faces as stimuli) to participants with TBI, participants with MDD, and participants with both TBI and MDD (TBI-MDD). Topographical distribution of activity and global field power comparisons were made across stimulus-locked epochs between these groups and healthy controls. The results indicated that ERPs were not altered by TBI alone. Both MDD and TBI-MDD groups showed similar alterations in topographical distribution and global field power in the N2 window, as well as late epoch alterations. The MDD and TBI-MDD groups showed significantly less fronto-central negativity during the N2 window in Nogo trials compared with the control group. The MDD and TBI-MDD groups also showed significantly less global field power in Nogo trials than Go trials during the N2 window while the control group showed the opposite pattern. The MDD and TBI-MDD groups showed no mood-congruent bias in behavioural or ERP measures. The results suggest that TBI-MDD displays similar electrophysiological changes to those found in the MDD group without TBI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Previous research suggests that many people who sustain a traumatic brain injury (TBI), even of the mild form, will develop major depression (MD). We previously reported white matter integrity differences between those who did and did not develop MD after mild TBI. In this current paper, we aimed to investigate whether there were also volumetric differences between these groups, as suggested by previous volumetric studies in mild TBI populations. A sample of TBI-with-MD subjects (N=14), TBI-without-MD subjects (N=12), MD-without-TBI (N=26) and control subjects (no TBI or MD, N=23), received structural MRI brain scans. T1-weighted data were analysed using the Freesurfer software package which produces automated volumetric results. The findings of this study indicate that (1) TBI patients who develop MD have reduced volume in temporal, parietal and lingual regions compared to TBI patients who do not develop MD, and (2) MD patients with a history of TBI have decreased volume in the temporal region compared to those who had MD but without a history of TBI. We also found that more severe MD in those with TBI-with-MD significantly correlated with reduced volume in anterior cingulate, temporal lobe and insula. These findings suggest that volumetric reduction to specific regions, including parietal, temporal and occipital lobes, after a mild TBI may underlie the susceptibility of these patients developing major depression, in addition to altered white matter integrity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Unlabelled: It is common for depression to develop after traumatic brain injury (TBI), yet despite poorer recovery, there is a lack in our understanding of whether post-TBI brain changes involved in depression are akin to those in people with depression without TBI. Modern neuroimaging has helped recognize degrees of diffuse axonal injury (DAI) as being related to extent of TBI, but its ability to predict long-term functioning is limited and has not been considered in the context of post-TBI depression. A more recent brain imaging technique (diffusion tensor imaging; DTI) can measure the integrity of white matter by measuring the directionality or anisotropy of water molecule diffusion along the axons of nerve fibers., Aim: To review DTI results in the TBI and depression literatures to determine whether this can elucidate the etiology of the development of depression after TBI., Method: We reviewed the TBI/DTI (40 articles) and depression/DTI literatures (17 articles). No articles were found that used DTI to investigate depression post-TBI, although there were some common brain regions identified between the TBI/DTI and depression/DTI studies, including frontotemporal, corpus callosum, and structures contained within the basal ganglia. Specifically, the internal capsule was commonly reported to have significantly reduced fractional anisotropy, which agrees with deep brain stimulation studies., Conclusion: It is suggested that measuring the degree of DAI by utilizing DTI in those with or without depression post-TBI, will greatly enhance prediction of functional outcome.

Objective: To identify possible differences in the mean midsagittal corpus callosum (CC) total and subdivision areas in treatment-resistant schizophrenia and depression (TRS and TRD) patients., Method: Areas of the total CC and its five equidistant subregions (from CC1 to CC5) obtained by parallel grid partitioning schemes were manually segmented from brain MRI of 42 TRS, 45 TRD patients and 30 healthy controls. The intracranial volume (ICV) normalized areas were calculated and compared between groups., Results: When compared with controls, patients with TRS had reduced ICV and a larger CC5, and TRD patients had a smaller CC4 while no significant difference in CC total area in patients with TRS or TRD was found. Multiple individual segments and total CC areas were significantly larger in TRS than TRD patients after normalization., Conclusion: Patients with TRS and TRD have different CC morphological characteristics, and therefore there may be aberrant interhemispheric connectivity in schizophrenia and major depressive disorder patients.

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery-Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

Despite a growing interest in this area, we continue to lack an understanding of the pathophysiology of depression and of treatment-resistant depression (TRD) in particular. The role of the medial temporal lobe, particularly the hippocampus, has been widely implicated in the aetiology of depression. However, related structures such as the entorhinal cortex have not been systematically examined. This research study aimed to examine possible abnormalities in the volume of the entorhinal cortex (ERC) in TRD patients. A group of 45 TRD patients and 30 healthy age- and sex-matched controls underwent magnetic resonance imaging (MRI). ERC volumes were manually traced from MRI data using ANALYZE software. An analysis of variance was conducted between subject groups and in the sexes separately while controlling for the effects of brain size via intracranial volume (ICV). Results revealed significant reductions in the volume of the left ERC of female patients. Although preliminary, our findings suggest that anatomical abnormalities in the ERC may confer vulnerability to treatment resistance. Confirmatory longitudinal studies are required to determine whether these abnormalities predate the onset of depression or are the result of a more chronic, treatment-resistant course of illness.

Studies of patients with major depression disorder (MDD) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD and control subjects, using a strict measurement protocol, in order to elucidate morphological-specific volumetric differences. Forty-five subjects with treatment-resistant MDD and 26 controls underwent psychiatric assessments and brain magnetic resonance imaging (MRI). The findings of this study indicate that (1) MDD results in reduced hippocampal volume, particularly in the tail section, (2) region of interest (ROI) estimation protocols and sample characteristics may help explain volumetric differences between previous MDD studies, and (3) specific ROI atrophy in treatment-resistant depression is influenced by sex.