Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

A Multilevel Examination of Cognitive Control in Adolescents With Nonsuicidal Self-injury.

Background: Nonsuicidal self-injury (NSSI), a transdiagnostic behavior, often emerges during adolescence. This study used the Research Domain Criteria approach to examine cognitive control (CC) with a focus on response inhibition and urgency relative to NSSI severity in adolescents. Methods: One hundred thirty-eight adolescents, assigned female sex at birth, with a continuum of NSSI severity completed negative and positive urgency measurements (self-report), an emotional Go/NoGo task within negative and positive contexts (behavioral), and structural and functional imaging during resting state and task (brain metrics). Cortical thickness, subcortical volume, resting-state functional connectivity, and task activation focused on an a priori-defined CC network. Eighty-four participants had all these main measures. Correlations and stepwise model selection followed by multiple regression were used to examine the association between NSSI severity and multiunit CC measurements. Results: Higher NSSI severity correlated with higher negative urgency and lower accuracy during positive no-inhibition (Go). Brain NSSI severity correlates varied across modalities and valence. For right medial prefrontal cortex and right caudate, higher NSSI severity correlated with greater negative but lower positive inhibition (NoGo) activation. The opposite pattern was observed for the right dorsolateral prefrontal cortex. Higher NSSI severity correlated with lower left dorsal anterior cingulate cortex (ACC) negative inhibition activation and thicker left dorsal ACC, yet it was correlated with higher right rostral ACC positive inhibition activation and thinner right rostral ACC, as well as lower CC network resting-state functional connectivity. Conclusions: Findings revealed multifaceted signatures of NSSI severity across CC units of analysis, confirming the relevance of this domain in adolescent NSSI and illustrating how multimodal approaches can shed light on psychopathology.

Concurrent validity and reliability of suicide risk assessment instruments: A meta-analysis of 20 instruments across 27 international cohorts.

OBJECTIVE: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. METHOD: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. RESULTS: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. CONCLUSIONS: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adolescent non-suicidal self-injury during the COVID-19 pandemic: A prospective longitudinal study of biological predictors of maladaptive emotion regulation.

BACKGROUND: Non-suicidal self-injury (NSSI) in adolescence is thought to stem from interactions between vulnerability in developing biological systems and experience of stressors. The current study assesses whether multiple levels of the stress system's response to threat could prospectively predict NSSI engagement during the COVID-19 pandemic, a shared, time-locked stressor. METHODS: Participants were 64 female adolescents (ages 12-16) from community and clinical settings who were oversampled for NSSI histories. Prior to the onset of the COVID-19 pandemic, adolescents completed a protocol that measured hypothalamic-pituitary-adrenal axis response to a social stressor (via salivary cortisol), amygdala volume, amygdala emotion-evoked activation, and frontolimbic resting-state functional connectivity. During early months of the pandemic (Summer 2020), measures of NSSI behavior (Inventory of Statements About Self-Injury), emotion regulation difficulties (Difficulties in Emotion Regulation Scale), perceived stress (Perceived Stress Scale), and pandemic-related stressors (Epidemic Pandemic Impacts Inventory) were collected. Multinomial logistic regression was used to assess if pre-pandemic biomarkers predicted mid-pandemic NSSI engagement: persistence of NSSI (Persist; N = 21), cessation of NSSI (Desist; N = 26), and no history of NSSI (Never; N = 17). Linear regressions explored if pre-pandemic biomarkers predicted mid-pandemic difficulties in emotion regulation and perceived stress. RESULTS: Higher pre-pandemic overall cortisol response to stress and amygdala emotion-evoked activation characterized adolescents who persisted in NSSI, compared to those who desisted. These findings remained significant when controlling for pandemic related stressors. Lower prepandemic cortisol reactivity predicted more difficulties in emotion regulation during the pandemic. This finding did not remain significant after controlling for pandemic related stressors. CONCLUSIONS: Findings suggest that patterns in key biological threat response systems may confer vulnerability for risk outcomes including NSSI engagement in adolescent females in the context of a shared, novel, naturally-occurring stressor. The results point to the importance of multi-level, longitudinal approaches for understanding the interface between developing neurobiological systems and experiential stress in at-risk adolescents. Identified patterns give insight into potential risk assessment strategies based on an understanding of the multi-level threat response.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Structural and Functional Neural Correlates of Treatment Response for Interpersonal Psychotherapy for Depressed Adolescents.

Precision medicine approaches hold tremendous promise to advance current clinical practice by providing information about which individuals will benefit from which treatments. This pilot study evaluated if baseline structure and function of the salience and emotion brain regions implicated in adolescent depression, specifically the amygdala and anterior cingulate cortex (ACC), predict response to Interpersonal Psychotherapy for Depressed Adolescents (IPT-A). Adolescents (n = 15; mean age = 14.5 (1.6); 80.0% female) diagnosed with a depressive disorder completed brain scans before the start of a 16 week trial of IPT-A. Clinical measures assessing depressive symptoms were completed before, during, and after a trial of therapy. Results show that at baseline, greater ACC activation in the context of an emotion-matching task and greater amygdala-ACC resting-state functional connectivity was related to greater improvement in depression symptoms. There was minimal evidence that brain structure predicted changes in depressive symptoms. The present study is the first to evaluate neural predictors of IPT-A response. While the results are preliminary, these findings suggest some avenues for future research to pursue in the hopes that more will benefit from treatment.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Depression, Non-Suicidal Self-Injury, and Suicidality in Adolescents: Common and Distinct Precursors, Correlates, and Outcomes.

Depression, non-suicidal self-injury (NSSI), and suicidal thoughts and behaviors (STB) often emerge during adolescence. Despite considerable overlap in clinical presentation, risk factors, and implicated neurobiology, there is also evidence for divergence in terms of precursors, correlates, and outcomes. The complex interrelationships amongst these three clinical domains require considering both shared and divergent patterns of risk for depression, NSSI, and STB; a clearer understanding of these developmental trajectories will be needed to guide optimization and tailoring of early interventions.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

A perceptual eyebox for near-eye displays.

In near-eye display systems that support three-dimensional (3D) augmented and virtual reality, a central factor in determining the user experience is the size of the eyebox. The eyebox refers to a volume where the eye receives an acceptable view of the image with respect to a set of criteria and thresholds. The size and location of this volume are primarily driven by optical architecture choices in which designers trade-off a number of constraints, such as field of view, image quality, and product design. It is thus important to clearly quantify how design decisions affect the properties of the eyebox. Recent work has started evaluating the eyebox in 3D based purely on optical criteria. However, such analyses do not incorporate perceptual criteria that determine visual quality, which are particularly important for binocular 3D systems. To address this limitation, we introduce the framework of a perceptual eyebox. The perceptual eyebox is the volume where the eye(s) must be located for the user to experience a visual percept falling within a perceptually-defined criterion. We combine optical and perceptual data to characterize an example perceptual eyebox for display visibility in augmented reality. The key contributions in this paper include: comparing the perceptual eyebox for monocular and binocular display designs, modeling the effects of user eye separation, and examining the effects of eye rotation on the eyebox volume.

Neural and Behavioral Correlates of Clinical Improvement to Ketamine in Adolescents With Treatment Resistant Depression.

Treatment-resistant depression (TRD) is a serious problem in adolescents. Development and optimization of novel interventions for these youth will require a deeper knowledge of the neurobiology of depression. A well-established phenomenon of depression is an attention bias toward negativity and away from positivity that is evidenced behaviorally and neurally, but it is unclear how symptom reduction is related to changes to this bias. Neurobiological research using a treatment probe has promise to help discover the neural changes that accompany symptom improvement. Ketamine has utility for such research because of its known rapid and strong antidepressant effects in the context of TRD. Our previous study of six open-label ketamine infusions in 11 adolescents with TRD showed variable response, ranging from full remission, partial response, non-response, or clinical worsening. In this study, we examined the performance of these participants on Word Face Stroop (WFS) fMRI task where they indicated the valence of affective words superimposed onto either congruent or incongruent emotional faces before and after the ketamine infusions. Participants also completed a clinical assessment (including measurement of depression symptomology and anhedonia/pleasure) before and after the ketamine infusions. Following ketamine treatment, better WFS performance correlated with self-reported decreased depressive symptoms and increased pleasure. Analyses of corticolimbic, corticostriatal and default mode (DMN) networks showed that across networks, decreased activation during all conditions (congruent negative, congruent positive, incongruent negative, and incongruent positive) correlated with decreases in depressive symptoms and with increases in pleasure. These findings suggest that in adolescents with TRD, clinical improvement may require an attenuation of the negativity bias and re-tuning of these three critical neural networks to attenuate DMN and limbic regions activation and allow more efficient recruitment of the reward network. Lower activation across conditions may facilitate shifting across different salient emotional stimuli rather than getting trapped in downward negative spirals.

Natural statistics of depth edges modulate perceptual stability.

Binocular fusion relies on matching points in the two eyes that correspond to the same physical feature in the world; however, not all world features are binocularly visible. Near depth edges, some regions of a scene are often visible to only one eye (so-called half occlusions). Accurate detection of these monocularly visible regions is likely to be important for stable visual perception. If monocular regions are not detected as such, the visual system may attempt to binocularly fuse non-corresponding points, which can result in unstable percepts. We investigated the hypothesis that the visual system capitalizes on statistical regularities associated with depth edges in natural scenes to aid binocular fusion and facilitate perceptual stability. By sampling from a large set of stereoscopic natural images with co-registered distance information, we found evidence that monocularly visible regions near depth edges primarily result from background occlusions. Accordingly, monocular regions tended to be more visually similar to the adjacent binocularly visible background region than to the adjacent binocularly visible foreground. Consistent with our hypothesis, perceptual experiments showed that perception tended to be more stable when the image properties of the depth edge were statistically more likely given the probability of occurrence in natural scenes (i.e., when monocular regions were more visually similar to the binocular background). The generality of these results was supported by a parametric study with simulated environments. Exploiting regularities in natural environments may allow the visual system to facilitate fusion and perceptual stability when both binocular and monocular regions are visible.

Navigational aid use by individuals with visual impairments.

Navigation is a multifaceted task, which requires using a combination of strategies and cues from the environment. Navigation can be particularly challenging for individuals with impaired vision, because many informative cues are visual. As mobile computing technology rapidly advances, the range of potential approaches to assist visually impaired people with navigation is also broadening. For computer-based navigational aids, the way in which information is gathered, processed, and presented is key to success and represents a vast space of potential approaches. In an effort to improve understanding and provide guidance on this issue, we present the results of a phone survey about navigational aids from a sample of individuals with impaired vision. The survey assessed the usefulness of existing navigational aids (both low-tech and high-tech) for different aspects of navigation. With an emphasis on indoor wayfinding (orienting oneself and following a route in a building), we also collected responses about specific targets the survey participants search for while navigating, and strategies they commonly use. Our results indicate that indoor wayfinding is a relatively under-supported task during navigation despite rapid advances in technology. These results also provide insights for creating navigational aids that are designed more specifically for the current challenges individuals with impaired vision may experience during this task.

Plasticity and Adaptation in Adult Binocular Vision.

Understanding the relationship between changes in sensory perception and functional/structural changes in the brain is a major endeavor in the field of systems neuroscience. Progress in this area holds the potential to reveal how the brain adapts to the demands of a complex and changing environment, as well as to assist with the development of therapeutic interventions to reverse the negative effects of abnormal experience. The cells and circuits that make up the mammalian visual system provide a unique scientific test-bed for studying brain plasticity, thanks to the rich literature on their basic organization and similarity across a range of species. In this minireview, we highlight recent advances in the study of plasticity in adult binocular vision, emphasizing the importance of considering changes that occur over different timescales. We discuss key new insights, significant open questions, and how this research is leading to a broader understanding of the ways that the adult brain maintains a robust ability for adaptation and change.

Valence-based Word-Face Stroop task reveals differential emotional interference in patients with major depression.

Word-Face Stroop task creates emotional conflict between affective words and affective faces. In this task, healthy participants consistently slow down while responding to incongruent cases. Such interference related slowdown is associated with recruitment of inhibitory processes to eliminate task-irrelevant information. We created a valence-based Word-Face Stroop task, in which participants were asked to indicate whether the words in the foreground are positive, negative or neutral. Healthy participants were faster and more accurate than un-medicated patients with major depression disorder (MDD). In addition, a significant congruence by group interaction is observed: healthy participants slowed down for incongruent cases, but MDD patients did not. Furthermore, for the negative words, healthy individuals made more errors while responding to incongruent cases but MDD patients made the lowest number of errors for this category. The emotional percepts of the patients were intact, because correct response rates in word valence judgments for positive/negative words, and reaction times for happy/sad faces had similar patterns with those of controls. These findings are supported by the analytical rumination interpretation of depression: patients lose speed/accuracy in laboratory tasks due to processing load spent during continuous rumination. However, for tasks in line with their preoccupation, continual practice makes the patients more vigilant and adept.

Impaired Bottom-Up Effective Connectivity Between Amygdala and Subgenual Anterior Cingulate Cortex in Unmedicated Adolescents with Major Depression: Results from a Dynamic Causal Modeling Analysis.

Major depressive disorder (MDD) is a significant contributor to lifetime disability and frequently emerges in adolescence, yet little is known about the neural mechanisms of MDD in adolescents. Dynamic causal modeling (DCM) analysis is an innovative tool that can shed light on neural network abnormalities. A DCM analysis was conducted to test several frontolimbic effective connectivity models in 27 adolescents with MDD and 21 healthy adolescents. The best neural model for each person was identified using Bayesian model selection. The findings revealed that the two adolescent groups fit similar optimal neural models. The best across-groups model was then used to infer upon both within-group and between-group tests of intrinsic and modulation parameters of the network connections. First, for model validation, within-group tests revealed robust evidence for bottom-up connectivity, but less evidence for strong top-down connectivity in both groups. Second, we tested for differences between groups on the validated parameters of the best model. This revealed that adolescents with MDD had significantly weaker bottom-up connectivity in one pathway, from amygdala to sgACC (p=0.008), than healthy controls. This study provides the first examination of effective connectivity using DCM within neural circuitry implicated in emotion processing in adolescents with MDD. These findings aid in advancing understanding the neurobiology of early-onset MDD during adolescence and have implications for future research investigating how effective connectivity changes across contexts, with development, over the course of the disease, and after intervention.