The human connectome project for disordered emotional states: Protocol and rationale for a research domain criteria study of brain connectivity in young adult anxiety and depression.

Through the Human Connectome Project (HCP) our understanding of the functional connectome of the healthy brain has been dramatically accelerated. Given the pressing public health need, we must increase our understanding of how connectome dysfunctions give rise to disordered mental states. Mental disorders arising from high levels of negative emotion or from the loss of positive emotional experience affect over 400 million people globally. Such states of disordered emotion cut across multiple diagnostic categories of mood and anxiety disorders and are compounded by accompanying disruptions in cognitive function. Not surprisingly, these forms of psychopathology are the leading cause of disability worldwide. The Research Domain Criteria (RDoC) initiative spearheaded by NIMH offers a framework for characterizing the relations among connectome dysfunctions, anchored in neural circuits and phenotypic profiles of behavior and self-reported symptoms. Here, we report on our Connectomes Related to Human Disease protocol for integrating an RDoC framework with HCP protocols to characterize connectome dysfunctions in disordered emotional states, and present quality control data from a representative sample of participants. We focus on three RDoC domains and constructs most relevant to depression and anxiety: 1) loss and acute threat within the Negative Valence System (NVS) domain; 2) reward valuation and responsiveness within the Positive Valence System (PVS) domain; and 3) working memory and cognitive control within the Cognitive System (CS) domain. For 29 healthy controls, we present preliminary imaging data: functional magnetic resonance imaging collected in the resting state and in tasks matching our constructs of interest ("Emotion", "Gambling" and "Continuous Performance" tasks), as well as diffusion-weighted imaging. All functional scans demonstrated good signal-to-noise ratio. Established neural networks were robustly identified in the resting state condition by independent component analysis. Processing of negative emotional faces significantly activated the bilateral dorsolateral prefrontal and occipital cortices, fusiform gyrus and amygdalae. Reward elicited a response in the bilateral dorsolateral prefrontal, parietal and occipital cortices, and in the striatum. Working memory was associated with activation in the dorsolateral prefrontal, parietal, motor, temporal and insular cortices, in the striatum and cerebellum. Diffusion tractography showed consistent profiles of fractional anisotropy along known white matter tracts. We also show that results are comparable to those in a matched sample from the HCP Healthy Young Adult data release. These preliminary data provide the foundation for acquisition of 250 subjects who are experiencing disordered emotional states. When complete, these data will be used to develop a neurobiological model that maps connectome dysfunctions to specific behaviors and symptoms.

Neural Circuit Markers of Familial Risk for Depression Among Healthy Youths in the Adolescent Brain Cognitive Development Study.

BACKGROUND: Family history of depression is a robust predictor of early-onset depression, which may confer risk through alterations in neural circuits that have been implicated in reward and emotional processing. These alterations may be evident in youths who are at familial risk for depression but who do not currently have depression. However, the identification of robust and replicable findings has been hindered by few studies and small sample sizes. In the current study, we sought to identify functional connectivity (FC) patterns associated with familial risk for depression. METHODS: Participants included healthy (i.e., no lifetime psychiatric diagnoses) youths at high familial risk for depression (HR) (n = 754; at least one parent with a history of depression) and healthy youths at low familial risk for psychiatric problems (LR) (n = 1745; no parental history of psychopathology) who were 9 to 10 years of age and from the Adolescent Brain Cognitive Development (ABCD) Study sample. We conducted whole-brain seed-to-voxel analyses to examine group differences in resting-state FC with the amygdala, caudate, nucleus accumbens, and putamen. We hypothesized that HR youths would exhibit global amygdala hyperconnectivity and striatal hypoconnectivity patterns primarily driven by maternal risk. RESULTS: HR youths exhibited weaker caudate-angular gyrus FC than LR youths (α = 0.04, Cohen's d = 0.17). HR youths with a history of maternal depression specifically exhibited weaker caudate-angular gyrus FC (α = 0.03, Cohen's d = 0.19) as well as weaker caudate-dorsolateral prefrontal cortex FC (α = 0.04, Cohen's d = 0.21) than LR youths. CONCLUSIONS: Weaker striatal connectivity may be related to heightened familial risk for depression, primarily driven by maternal history. Identifying brain-based markers of depression risk in youths can inform approaches to improving early detection, diagnosis, and treatment.

Familial risk for depression moderates neural circuitry in healthy preadolescents to predict adolescent depression symptoms in the Adolescent Brain Cognitive Development (ABCD) Study.

BACKGROUND: There is an imminent need to identify neural markers during preadolescence that are linked to developing depression during adolescence, especially among youth at elevated familial risk. However, longitudinal studies remain scarce and exhibit mixed findings. Here we aimed to elucidate functional connectivity (FC) patterns among preadolescents that interact with familial depression risk to predict depression two years later. METHODS: 9-10 year-olds in the Adolescent Brain Cognitive Development (ABCD) Study were classified as healthy (i.e., no lifetime psychiatric diagnoses) at high familial risk for depression (HR; n=559) or at low familial risk for psychopathology (LR; n=1203). Whole-brain seed-to-voxel resting-state FC patterns with the amygdala, putamen, nucleus accumbens, and caudate were calculated. Multi-level, mixed-effects regression analyses were conducted to test whether FC at ages 9-10 interacted with familial risk to predict depression symptoms at ages 11-12. RESULTS: HR youth demonstrated stronger associations between preadolescent FC and adolescent depression symptoms (ps<0.001) as compared to LR youth (ps>0.001), primarily among amygdala/striatal FC with visual and sensory/somatomotor networks. CONCLUSIONS: Preadolescent amygdala and striatal FC may be useful biomarkers of adolescent-onset depression, particularly for youth with family histories of depression. This research may point to neurobiologically-informed approaches to prevention and intervention for depression in adolescents.

Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety.

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

Intrinsic Connectivity and Family Dynamics: Striatolimbic Markers of Risk and Resilience in Youth at Familial Risk for Mood Disorders.

BACKGROUND: Few studies to date have characterized functional connectivity (FC) within emotion and reward networks in relation to family dynamics in youth at high familial risk for bipolar disorder (HR-BD) and major depressive disorder (HR-MDD) relative to low-risk youth (LR). Such characterization may advance our understanding of the neural underpinnings of mood disorders and lead to more effective interventions. METHODS: A total of 139 youth (43 HR-BD, 46 HR-MDD, and 50 LR) aged 12.9 ± 2.7 years were longitudinally followed for 4.5 ± 2.4 years. We characterized differences in striatolimbic FC that distinguished between HR-BD, HR-MDD, and LR and between resilience and conversion to psychopathology. We then examined whether risk status moderated FC-family dynamic associations. Finally, we examined whether baseline between-group FC differences predicted resilence versus conversion to psychopathology. RESULTS: HR-BD had greater amygdala-middle frontal gyrus and dorsal striatum-middle frontal gyrus FC relative to HR-MDD and LR, and HR-MDD had lower amygdala-fusiform gyrus and dorsal striatum-precentral gyrus FC relative to HR-BD and LR (voxel-level p < .001, cluster-level false discovery rate-corrected p < .05). Resilient youth had greater amygdala-orbitofrontal cortex and ventral striatum-dorsal anterior cingulate cortex FC relative to youth with conversion to psychopathology (voxel-level p < .001, cluster-level false discovery rate-corrected p < .05). Greater family rigidity was inversely associated with amygdala-fusiform gyrus FC across all groups (false discovery rate-corrected p = .017), with a moderating effect of bipolar risk status (HR-BD vs. HR-MDD p < .001; HR-BD vs. LR p = .005). Baseline FC differences did not predict resilence versus conversion to psychopathology. CONCLUSIONS: Findings represent neural signatures of risk and resilience in emotion and reward processing networks in youth at familial risk for mood disorders that may be targets for novel interventions tailored to the family context.

Lack of robust associations between prepandemic coping strategies and frontolimbic circuitry with depression and anxiety symptoms during the COVID-19 pandemic: A preregistered longitudinal study.

The COVID-19 pandemic is an ongoing stressor that has resulted in the exacerbation of mental health problems worldwide. However, longitudinal studies that identify preexisting behavioral and neurobiological factors associated with mental health outcomes during the pandemic are lacking. Here, we examined associations between prepandemic coping strategy engagement and frontolimbic circuitry with internalizing symptoms during the pandemic. In 85 adults (71.8% female; age 18-30 years), we assessed prototypically adaptive coping strategies (Connor-Davidson Resilience Scale), resting-state functional magnetic resonance imaging functional connectivity (FC) of frontolimbic circuitry, and depression and anxiety symptoms (Beck Depression Inventory, Screen for Child Anxiety-Related Emotional Disorders-Adult, respectively). We conducted general linear models to test preregistered hypotheses that (1) lower coping engagement prepandemic and (2) weaker frontolimbic FC prepandemic would predict elevated symptoms during the pandemic; and (3) coping would interact with FC to predict symptoms during the pandemic. Depression and anxiety symptoms worsened during the pandemic (ps < .001). Prepandemic adaptive coping engagement and frontolimbic FC were not associated with depression or anxiety symptoms during the pandemic (uncorrected ps > .05). Coping interacted with insula-rostral anterior cingulate cortex (ACC) FC (p = .003, pFDR = .014) and with insula-ventral ACC FC (p < .001, pFDR < .001) to predict depression symptoms, but these findings did not survive FDR correction after removal of outliers. Findings from our preregistered study suggest that specific prepandemic factors, particularly adaptive coping and frontolimbic circuitry, are not robustly associated with emotional responses to the pandemic. Additional studies that identify preexisting neurobehavioral factors implicated in mental health outcomes during global health crises are needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mapping Neural Circuit Biotypes to Symptoms and Behavioral Dimensions of Depression and Anxiety.

BACKGROUND: Despite tremendous advances in characterizing human neural circuits that govern emotional and cognitive functions impaired in depression and anxiety, we lack a circuit-based taxonomy for depression and anxiety that captures transdiagnostic heterogeneity and informs clinical decision making. METHODS: We developed and tested a novel system for quantifying 6 brain circuits reproducibly and at the individual patient level. We implemented standardized circuit definitions relative to a healthy reference sample and algorithms to generate circuit clinical scores for the overall circuit and its constituent regions. RESULTS: In new data from primary and generalizability samples of depression and anxiety (N = 250), we demonstrated that overall disconnections within task-free salience and default mode circuits map onto symptoms of anxious avoidance, loss of pleasure, threat dysregulation, and negative emotional biases-core characteristics that transcend diagnoses-and poorer daily function. Regional dysfunctions within task-evoked cognitive control and affective circuits may implicate symptoms of cognitive and valence-congruent emotional functions. Circuit dysfunction scores also distinguished response to antidepressant and behavioral intervention treatments in an independent sample (n = 205). CONCLUSIONS: Our findings articulate circuit dimensions that relate to transdiagnostic symptoms across mood and anxiety disorders. Our novel system offers a foundation for deploying standardized circuit assessments across research groups, trials, and clinics to advance more precise classifications and treatment targets for psychiatry.

Associations between early-life stress exposure and internalizing symptomatology during the COVID-19 pandemic: Assessing the role of neurobehavioral mediators.

Background: The ongoing COVID-19 pandemic is a major stressor that has been associated with increased risk for psychiatric illness in the general population. Recent work has highlighted that experiences of early-life stress (ELS) may impact individuals' psychological functioning and vulnerability for developing internalizing psychopathology in response to pandemic-related stress. However, little is known about the neurobehavioral factors that may mediate the association between ELS exposure and COVID-related internalizing symptomatology. The current study sought to examine the mediating roles of pre-pandemic resting-state frontoamygdala connectivity and concurrent emotion regulation (ER) in the association between ELS and pandemic-related internalizing symptomatology. Methods: Retrospective life-stress histories, concurrent self-reported ER strategies (i.e., reappraisal and suppression), concurrent self-reported internalizing symptomatology (i.e., depression- and anxiety-related symptomatology), and resting-state functional connectivity data from a sample of adults (N = 64, M age = 22.12, female = 68.75%) were utilized. Results: There were no significant direct associations between ELS and COVID-related internalizing symptomatology. Neither frontoamygdala functional connectivity nor ER strategy use mediated an association between ELS and COVID-related internalizing symptomatology (ps > 0.05). Exploratory analyses identified a significant moderating effect of reappraisal use on the association between ELS and internalizing symptomatology (ß = -0.818, p = 0.047), such that increased reappraisal use buffered the impact of ELS on psychopathology. Conclusions: While frontoamygdala connectivity and ER do not appear to mediate the association between ELS and COVID-related internalizing symptomatology, our findings suggest that the use of reappraisal may buffer against the effect of ELS on mental health during the pandemic.

Reduced functional connectivity of default mode network subsystems in depression: Meta-analytic evidence and relationship with trait rumination.

Resting-state functional connectivity changes in the default mode network (DMN) of patients with major depressive disorder (MDD) have been linked to rumination. The DMN is divided into three subsystems: a midline Core, a dorsal medial prefrontal cortex (DMPFC) subsystem, and a medial temporal lobe (MTL) subsystem. We examined resting-state functional connectivity within and between DMN subsystems in MDD and its association with rumination. First, we conducted a meta-analysis on a large multi-site dataset of 618 MDD and 683 controls to quantify the differences in DMN subsystem functional connectivity between MDD and controls. Second, we tested the association of DMN subsystem functional connectivity and rumination in a sample of 115 unmedicated participants with symptoms of anxiety/depression and 48 controls. In our meta-analysis, only functional connectivity in the DMN Core was significantly reduced in MDD compared to controls (g = -0.246, CI = [-0.417; -0.074], pFDR = 0.048). Functional connectivity in the DMPFC subsystem and between the Core and DMPFC subsystems was slightly reduced but not significantly (g = -0.162, CI = [-0.310; -0.013], pFDR = 0.096; g = -0.249, CI = [-0.464; -0.034], pFDR = 0.084). Results were heterogeneous across sites for connectivity in the Core and between Core and DMPFC (I2 = 0.348 and I2 = 0.576 respectively). Prediction intervals consistently encompassed 0. In the independent sample we collected, functional connectivity within the DMN Core, DMPFC and between Core and DMPFC was not reduced in MDD compared to controls (all pFDR > 0.05). Trait rumination did not predict connectivity within and between DMN subsystems (all pFDR > 0.05). We conclude that MDD as a diagnostic category shows slightly reduced functional connectivity within the DMN Core, independent of illness duration, treatment, symptoms and trait rumination. However, this effect is small, highly variable and heterogeneous across samples, so that we could only detect it at the meta-analytic level, with a sample size of several hundreds. Our results indicate that reduced Core DMN connectivity has significant limitations as a potential clinical or prognostic marker for the diagnosis of MDD and might be more relevant to consider as a characteristic distinguishing a subgroup of individuals within this diagnostic category.

Coping Strategies, Neural Structure, and Depression and Anxiety During the COVID-19 Pandemic: A Longitudinal Study in a Naturalistic Sample Spanning Clinical Diagnoses and Subclinical Symptoms.

BACKGROUND: Although the COVID-19 pandemic has been shown to worsen anxiety and depression symptoms, we do not understand which behavioral and neural factors may mitigate this impact. To address this gap, we assessed whether adaptive and maladaptive coping strategies affect symptom trajectory during the pandemic. We also examined whether pre-pandemic integrity of brain regions implicated in depression and anxiety affect pandemic symptoms. METHODS: In a naturalistic sample of 169 adults (66.9% female; age 19-74 years) spanning psychiatric diagnoses and subclinical symptoms, we assessed anhedonia, tension, and anxious arousal symptoms using validated components (21-item Depression, Anxiety, and Stress Scale), coping strategies (Brief-Coping Orientation to Problems Experienced), and gray matter volume (amygdala) and cortical thickness (hippocampus, insula, anterior cingulate cortex) from magnetic resonance imaging T1-weighted scans. We conducted general linear mixed-effects models to test preregistered hypotheses that 1) maladaptive coping pre-pandemic and 2) lower structural integrity pre-pandemic would predict more severe pandemic symptoms; and 3) coping would interact with neural structure to predict pandemic symptoms. RESULTS: Greater use of maladaptive coping strategies was associated with more severe anxious arousal symptoms during the pandemic (p = .011, false discovery rate-corrected p [p FDR] = .035), specifically less self-distraction (p = .014, p FDR = .042) and greater self-blame (p = .002, p FDR = .012). Reduced insula thickness pre-pandemic predicted more severe anxious arousal symptoms (p = .001, p FDR = .027). Self-distraction interacted with amygdala volume to predict anhedonia symptoms (p = .005, p FDR = .020). CONCLUSIONS: Maladaptive coping strategies and structural variation in brain regions may influence clinical symptoms during a prolonged stressful event (e.g., COVID-19 pandemic). Future studies that identify behavioral and neural factors implicated in responses to global health crises are warranted for fostering resilience.

Greater baseline connectivity of the salience and negative affect circuits are associated with natural improvements in anxiety over time in untreated participants.

BACKGROUND: There is limited research examining the natural trajectories of depression and anxiety, how these trajectories relate to baseline neural circuit function, and how symptom trajectory-circuit relationships are impacted by engagement in lifestyle activities including exercise, hobbies, and social interactions. To address these gaps, we assessed these relations over three months in untreated participants. METHODS: 262 adults (59.5% female, mean age 35) with symptoms of anxiety and depression, untreated with pharmacotherapy or behavioral therapy, completed the DASS-42, WHOQOL, and custom surveys at baseline and follow-up to assess symptoms, psychosocial function, and lifestyle activity engagement. At baseline, participants underwent fMRI under task-free and task-evoked conditions. We quantified six circuits implicated in these symptoms: default mode, salience, negative and positive affect, attention, and cognitive control. RESULTS: From baseline to 3 months, some participants demonstrated a natural improvement in anxiety (24%) and depression (26%) symptoms. Greater baseline salience circuit connectivity (pFDR=0.045), specifically between the left and right insula (pFDR=0.045), and greater negative affect circuit connectivity elicited by sad faces (pFDR=0.030) were associated with anxiety symptom improvement. While engagement in lifestyle activities were not associated with anxiety improvements, engagement in hobbies moderated the association between negative affect circuit connectivity and anxiety symptom improvement (p = 0.048). LIMITATIONS: The observational design limits causal inference. CONCLUSIONS: Our findings highlight the role of the salience and negative affect circuits as potential circuit markers of natural anxiety symptom improvements over time. Future studies that identify biomarkers associated with symptom improvements are critical for the development of personalized treatment targets.

Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial.

There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p < 0.001) which was associated with improvement in physical QoL (p < 0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p < 0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p < 0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p < 0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p < 0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.

Integrating sleep, neuroimaging, and computational approaches for precision psychiatry.

In advancing precision psychiatry, we focus on what imaging technology and computational approaches offer for the future of diagnostic subtyping and personalized tailoring of interventions for sleep impairment in mood and anxiety disorders. Current diagnostic criteria for mood and anxiety tend to lump different forms of sleep disturbance together. Parsing the biological features of sleep impairment and brain circuit dysfunction is one approach to identifying subtypes within these disorders that are mechanistically coherent and offer targets for intervention. We focus on two large-scale neural circuits implicated in sleep impairment and in mood and anxiety disorders: the default mode network and negative affective network. Through a synthesis of existing knowledge about these networks, we pose a testable framework for understanding how hyper- versus hypo-engagement of these networks may underlie distinct features of mood and sleep impairment. Within this framework we consider whether poor sleep quality may have an explanatory role in previously observed associations between network dysfunction and mood symptoms. We expand this framework to future directions including the potential for connecting circuit-defined subtypes to more distal features derived from digital phenotyping and wearable technologies, and how new discovery may be advanced through machine learning approaches.

Correction: Paying attention to attention in depression.

In the original Article, Naoise Mac Giollabhui was incorrectly cited as "Giollabhui, N. M" instead of "Mac Giollabhui, N" in reference 163. This has been updated in the HTML and PDF versions of this Article.

Worth working for: The influence of effort costs on teens' choices during a novel decision making game.

Decision making requires consideration of both the benefits of a given choice and the costs, which can include risk, delay, and effort. Previous research has examined the developmental trajectory of adolescent decision making regarding risk and delay; however, the effects of effort on adolescent decision making remain largely unexplored. In the present study, we pilot tested a novel, developmentally-appropriate task designed to examine developmental differences in the willingness to expend effort during goal pursuit in adolescents (ages 13-16, n = 23) versus young adults (ages 18-23, n = 25). Self-reported reward responsivity correlated with task-related parameter estimates for effort and reward, providing evidence of task validity. Adolescents exhibited reduced sensitivity to physical effort costs compared to adults, effects which did not appear to be driven by differences in subjective task motivation or awareness of the effort requirements. These findings provide preliminary evidence that adolescence may be a time of increased willingness to expend effort during goal pursuit. Effort-based decision making is an understudied but exciting avenue for developmental research, as the willingness to engage in effortful pursuit of new experiences during adolescence may help to facilitate the path to independence.

Paying attention to attention in depression.

Attention is the gate through which sensory information enters our conscious experiences. Oftentimes, patients with major depressive disorder (MDD) complain of concentration difficulties that negatively impact their day-to-day function, and these attention problems are not alleviated by current first-line treatments. In spite of attention's influence on many aspects of cognitive and emotional functioning, and the inclusion of concentration difficulties in the diagnostic criteria for MDD, the focus of depression as a disease is typically on mood features, with attentional features considered less of an imperative for investigation. Here, we summarize the breadth and depth of findings from the cognitive neurosciences regarding the neural mechanisms supporting goal-directed attention in order to better understand how these might go awry in depression. First, we characterize behavioral impairments in selective, sustained, and divided attention in depressed individuals. We then discuss interactions between goal-directed attention and other aspects of cognition (cognitive control, perception, and decision-making) and emotional functioning (negative biases, internally-focused attention, and interactions of mood and attention). We then review evidence for neurobiological mechanisms supporting attention, including the organization of large-scale neural networks and electrophysiological synchrony. Finally, we discuss the failure of current first-line treatments to alleviate attention impairments in MDD and review evidence for more targeted pharmacological, brain stimulation, and behavioral interventions. By synthesizing findings across disciplines and delineating avenues for future research, we aim to provide a clearer outline of how attention impairments may arise in the context of MDD and how, mechanistically, they may negatively impact daily functioning across various domains.