Atypical Brain Aging and Its Association With Working Memory Performance in Major Depressive Disorder.

BACKGROUND: Patients with major depressive disorder (MDD) can present with altered brain structure and deficits in cognitive function similar to those seen in aging. However, the interaction between age-related brain changes and brain development in MDD remains understudied. In a cohort of adolescents and adults with and without MDD, we assessed brain aging differences and associations through a newly developed tool that quantifies normative neurodevelopmental trajectories. METHODS: A total of 304 participants with MDD and 236 control participants without depression were recruited and scanned from 3 studies under the Canadian Biomarker Integration Network for Depression. Volumetric data were used to generate brain centile scores, which were examined for 1) differences between participants with MDD and control participants; 2) differences between individuals with versus without severe childhood maltreatment; and 3) correlations with depressive symptom severity, neurocognitive assessment domains, and escitalopram treatment response. RESULTS: Brain centiles were significantly lower in the MDD group than in the control group. Brain centile was also significantly correlated with working memory in the control group but not the MDD group. No significant associations were observed between depression severity or antidepressant treatment response and brain centiles. Likewise, childhood maltreatment history did not significantly affect brain centiles. CONCLUSIONS: Consistent with previous work on machine learning models that predict brain age, brain centile scores differed in people diagnosed with MDD, and MDD was associated with differential relationships between centile scores and working memory. The results support the notion of atypical development and aging in MDD, with implications for neurocognitive deficits associated with aging-related cognitive function.

An empirical analysis of structural neuroimaging profiles in a staging model of depression.

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions. Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined using three different types of analyses. Hippocampal volume decrease and cortico-limbic thinning were the most informative features for the RD vs HC comparisons. FD vs HC revealed that FD participants were characterized by a focal decrease in cortical thickness and global enlargement in amygdala volumes. Greater total amygdala volumes were significantly associated with earlier onset of illness in the FD but not the RD group. We did not confirm the construct validity of a tested clinical staging model, as a differential pattern of brain alterations was identified across the three diagnostic groups that did not parallel a stepwise clinical staging approach. The pathological processes during early stages of the illness may fundamentally differ from those that occur at later stages with clinical progression.

Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: A CAN-BIND-1 report.

Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study.

Anxious arousal predicts within-person changes in hippocampal volume in adults with a history of childhood maltreatment: A CAN-BIND4 report.

Childhood maltreatment (CM) is a strong transdiagnostic risk factor for future psychopathology. This risk is theorized to emerge partly because of glucocorticoid-mediated atrophy in the hippocampus, which leaves this area sensitive to further volume loss even through adulthood in the face of future stress and the emergence of psychopathology. This proof-of-principle study examines which specific dimensions of internalizing psychopathology in the context of a CM history are associated with decreases in hippocampal volume over a 6-month period. This study included 80 community-recruited adults (ages 18-66 years, 61.3% women) oversampled for a lifetime history of internalizing psychopathology. At baseline and a naturalistic 6-month follow-up, the symptom dimensions of the tripartite model (anxious arousal, anhedonic depression, and general distress) were assessed by self-report. Hippocampal volume was derived through T1-weighted magnetic resonance imaging scanning segmented via the volBrain HIPS pipeline. CM severity was determined via a semistructured, contextual interview with independent ratings. We found that higher levels of anxious arousal predicted decreases in hippocampal volume over time in those with greater severity of CM but were associated at a trend with increases in hippocampal volume over time in those with lower severity of maltreatment. Findings were specific to anxious arousal and the CA1 subregion of the hippocampus. These novel results suggest that for individuals with a history of CM, transdiagnostic interventions that target and reduce psychological and physiological arousal may result in the preservation of hippocampal structure and, thus, improvements in cognitive and emotional regulation in the face of stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A domain adaptation benchmark for T1-weighted brain magnetic resonance image segmentation.

Accurate brain segmentation is critical for magnetic resonance imaging (MRI) analysis pipelines. Machine-learning-based brain MR image segmentation methods are among the state-of-the-art techniques for this task. Nevertheless, the segmentations produced by machine learning models often degrade in the presence of expected domain shifts between the test and train sets data distributions. These domain shifts are expected due to several factors, such as scanner hardware and software differences, technology updates, and differences in MRI acquisition parameters. Domain adaptation (DA) methods can make machine learning models more resilient to these domain shifts. This paper proposes a benchmark for investigating DA techniques for brain MR image segmentation using data collected across sites with scanners from different vendors (Philips, Siemens, and General Electric). Our work provides labeled data, publicly available source code for a set of baseline and DA models, and a benchmark for assessing different brain MR image segmentation techniques. We applied the proposed benchmark to evaluate two segmentation tasks: skull-stripping; and white-matter, gray-matter, and cerebrospinal fluid segmentation, but the benchmark can be extended to other brain structures. Our main findings during the development of this benchmark are that there is not a single DA technique that consistently outperforms others, and hyperparameter tuning and computational times for these methods still pose a challenge before broader adoption of these methods in the clinical practice.

Multi-Coil MRI Reconstruction Challenge-Assessing Brain MRI Reconstruction Models and Their Generalizability to Varying Coil Configurations.

Deep-learning-based brain magnetic resonance imaging (MRI) reconstruction methods have the potential to accelerate the MRI acquisition process. Nevertheless, the scientific community lacks appropriate benchmarks to assess the MRI reconstruction quality of high-resolution brain images, and evaluate how these proposed algorithms will behave in the presence of small, but expected data distribution shifts. The multi-coil MRI (MC-MRI) reconstruction challenge provides a benchmark that aims at addressing these issues, using a large dataset of high-resolution, three-dimensional, T1-weighted MRI scans. The challenge has two primary goals: (1) to compare different MRI reconstruction models on this dataset and (2) to assess the generalizability of these models to data acquired with a different number of receiver coils. In this paper, we describe the challenge experimental design and summarize the results of a set of baseline and state-of-the-art brain MRI reconstruction models. We provide relevant comparative information on the current MRI reconstruction state-of-the-art and highlight the challenges of obtaining generalizable models that are required prior to broader clinical adoption. The MC-MRI benchmark data, evaluation code, and current challenge leaderboard are publicly available. They provide an objective performance assessment for future developments in the field of brain MRI reconstruction.

Cerebello-limbic functional connectivity patterns in youth at clinical high risk for psychosis.

Youth at clinical high risk (CHR) for psychosis can present not only with characteristic attenuated psychotic symptoms but also may have other comorbid conditions, including anxiety and depression. These undifferentiated mood symptoms can overlap with the clinical presentation of youth with Distress syndromes. Increased resting-state functional connectivity within cerebello-thalamo-cortical (CTC) pathways has been proposed as a trait-specific biomarker for CHR. However, it is unclear whether this functional neural signature remains specific when compared to a different risk group: youth with Distress syndromes. The purpose of the present work was to describe CTC alterations that distinguish between CHR and Distressed individuals. Using machine learning algorithms, we analyzed CTC connectivity features of CHR (n = 51), Distressed (n = 41), and healthy control (n = 36) participants. We found four cerebellar (lobes VII and left Crus II anterior/posterior) and two basal ganglia (right putamen and right thalamus) nodes containing a set of specific connectivity features that distinguished between CHR, Distressed and healthy control groups. Hyperconnectivity between medial lobule VIIb, somatomotor network and middle temporal gyrus was associated with CHR status and more severe symptoms. Detailed atlas parcellation suggested that CHR individuals may have dysfunction mainly within the associative (cognitive) pathways, particularly, between those brain areas responsible for the multi-sensory signal integration.

Childhood trauma and amygdala nuclei volumes in youth at risk for mental illness.

BACKGROUND: Adults with significant childhood trauma and/or serious mental illness may exhibit persistent structural brain changes within limbic structures, including the amygdala. Little is known about the structure of the amygdala prior to the onset of SMI, despite the relatively high prevalence of trauma in at-risk youth. METHODS: Data were gathered from the Canadian Psychiatric Risk and Outcome study. A total of 182 youth with a mean age of 18.3 years completed T1-weighted MRI scans along with clinical assessments that included questionnaires on symptoms of depression and anxiety. Participants also completed the Childhood Trauma and Abuse Scale. We used a novel subfield-specific amygdala segmentation workflow as a part of FreeSurfer 6.0 to examine amygdala structure. RESULTS: Participants with higher trauma scores were more likely to have smaller amygdala volumes, particularly within the basal regions. Among various types of childhood trauma, sexual and physical abuse had the largest effects on amygdala subregions. Abuse-related differences in the right basal region mediated the severity of depression and anxiety symptoms, even though no participants met criteria for clinical diagnosis at the time of assessment. CONCLUSION: The experience of physical or sexual abuse may leave detectable structural alterations in key regions of the amygdala, potentially mediating the risk of psychopathology in trauma-exposed youth.

Accelerated brain aging in major depressive disorder and antidepressant treatment response: A CAN-BIND report.

OBJECTIVES: Previous studies suggest that major depressive disorder (MDD) may be associated with volumetric indications of accelerated brain aging. This study investigated neuroanatomical signs of accelerated aging in MDD and evaluated whether a brain age gap is associated with antidepressant response. METHODS: Individuals in a major depressive episode received escitalopram treatment (10-20 mg/d) for 8 weeks. Depression severity was assessed at baseline and at weeks 8 and 16 using the Montgomery-Asberg Depression Rating Scale (MADRS). Response to treatment was characterized by a significant reduction in the MADRS (≥50%). Nonresponders received adjunctive aripiprazole treatment (2-10 mg/d) for a further 8 weeks. The brain-predicted age difference (brain-PAD) at baseline was determined using machine learning methods trained on 3377 healthy individuals from seven publicly available datasets. The model used features from all brain regions extracted from structural magnetic resonance imaging data. RESULTS: Brain-PAD was significantly higher in older MDD participants compared to younger MDD participants [t(147.35) = -2.35, p < 0.03]. BMI was significantly associated with brain-PAD in the MDD group [r(155) = 0.19, p < 0.03]. Response to treatment was not significantly associated with brain-PAD. CONCLUSION: We found an elevated brain age gap in older individuals with MDD. Brain-PAD was not associated with overall treatment response to escitalopram monotherapy or escitalopram plus adjunctive aripiprazole.

Association between the expression of lncRNA BASP-AS1 and volume of right hippocampal tail moderated by episode duration in major depressive disorder: a CAN-BIND 1 report.

The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (ß = -0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (ß = -0.48, 95% C.I. [-0.80, -0.16]. t = -2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.

Dual-domain cascade of U-nets for multi-channel magnetic resonance image reconstruction.

The U-net is a deep-learning network model that has been used to solve a number of inverse problems. In this work, the concatenation of two-element U-nets, termed the W-net, operating in k-space (K) and image (I) domains, were evaluated for multi-channel magnetic resonance (MR) image reconstruction. The two-element network combinations were evaluated for the four possible image-k-space domain configurations: a) W-net II, b) W-net KK, c) W-net IK, and d) W-net KI. Selected four element (WW-nets) and six element (WWW-nets) networks were also examined. Two configurations of each network were compared: 1) each coil channel was processed independently, and 2) all channels were processed simultaneously. One hundred and eleven volumetric, T1-weighted, 12-channel coil k-space datasets were used in the experiments. Normalized root mean squared error, peak signal-to-noise ratio and visual information fidelity were used to assess the reconstructed images against the fully sampled reference images. Our results indicated that networks that operate solely in the image domain were better when independently processing individual channels of multi-channel data. Dual-domain methods were better when simultaneously reconstructing all channels of multi-channel data. In addition, the best cascade of U-nets performed better (p < 0.01) than the previously published, state-of-the-art Deep Cascade and Hybrid Cascade models in three out of four experiments.

Aberrant limbic brain structures in young individuals at risk for mental illness.

AIM: Alterations in limbic structures may be present before the onset of serious mental illness, but whether subfield-specific limbic brain changes parallel stages in clinical risk is unknown. To address this gap, we compared the hippocampus, amygdala, and thalamus subfield-specific volumes in adolescents at various stages of risk for mental illness. METHODS: MRI scans were obtained from 182 participants (aged 12-25 years) from the Canadian Psychiatric Risk and Outcome study. The sample comprised of four groups: asymptomatic youth at risk due to family history of mental illness (Stage 0, n = 32); youth with early symptoms of distress (Stage 1a, n = 41); youth with subthreshold psychotic symptoms (Stage 1b, n = 72); and healthy comparison participants with no family history of serious mental illness (n = 37). Analyses included between-group comparisons of brain measurements and correlational analyses that aimed to identify significant associations between neuroimaging and clinical measurements. A machine-learning technique examined the discriminative properties of the clinical staging model. RESULTS: Subfield-specific limbic volume deficits were detected at every stage of risk for mental illness. A machine-learning classifier identified volume deficits within the body of the hippocampus, left amygdala nuclei, and medial-lateral nuclei of the thalamus that were most informative in differentiating between risk stages. CONCLUSION: Aberrant subfield-specific changes within the limbic system may serve as biological evidence to support transdiagnostic clinical staging in mental illness. Differential patterns of volume deficits characterize those at risk for mental illness and may be indicative of a risk-stage progression.

Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report.

Finding a clinically useful neuroimaging biomarker that can predict treatment response in patients with major depressive disorder (MDD) is challenging, in part because of poor reproducibility and generalizability of findings across studies. Previous work has suggested that posterior hippocampal volumes in depressed patients may be associated with antidepressant treatment outcomes. The primary purpose of this investigation was to examine further whether posterior hippocampal volumes predict remission following antidepressant treatment. Magnetic resonance imaging (MRI) scans from 196 patients with MDD and 110 healthy participants were obtained as part of the first study in the Canadian Biomarker Integration Network in Depression program (CAN-BIND 1) in which patients were treated for 16 weeks with open-label medication. Hippocampal volumes were measured using both a manual segmentation protocol and FreeSurfer 6.0. Baseline hippocampal tail (Ht) volumes were significantly smaller in patients with depression compared to healthy participants. Larger baseline Ht volumes were positively associated with remission status at weeks 8 and 16. Participants who achieved early sustained remission had significantly greater Ht volumes compared to those who did not achieve remission by week 16. Ht volume is a prognostic biomarker for antidepressant treatment outcomes in patients with MDD.

Testing a deep convolutional neural network for automated hippocampus segmentation in a longitudinal sample of healthy participants.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies.