Emotion-cognition dysregulation in major depression: Multidimensional biases, neural circuit imbalance, and translational opportunities

Abstract

Major depressive disorder is increasingly conceptualized as a disorder of emotion-cognition dysregulation. Convergent evidence shows reliable negative biases in recognition and attention (facilitated capture by threat, impaired disengagement), overgeneral and negatively weighted autobiographical memory, blunted processing of positive/rewarding stimuli, and preferential reliance on maladaptive regulation strategies (rumination, suppression). At the systems level, task-based and resting-state functional magnetic resonance imaging support the presence of a limbic-prefrontal imbalance - amygdala/insula hyperreactivity with reduced top-down control from dorsolateral/ventromedial prefrontal cortex and anterior cingulate - accompanied by large-scale network disruption (default-mode hyperconnectivity and weakened coupling to salience and frontoparietal control networks). Electrophysiology adds temporal specificity: Enhanced early components to negative faces (e.g., N170), reduced late positive potential to appetitive cues, diminished prefrontal theta power, altered gamma activity, and perturbed theta-gamma coupling. Mechanistic contributors include monoaminergic imbalance, hypothalamic-pituitary-adrenal-axis activation, inflammatory signaling, and excitatory-inhibitory disequilibrium, moderated by cognitive style, early adversity, sex, and age. Translational opportunities span composite behavioral-neural signatures for diagnosis and stratification, risk forecasting, and treatment selection/monitoring; partial normalization of biases and circuits has been observed with cognitive behavioral therapy, selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, and noninvasive neuromodulation (repetitive transcranial magnetic stimulation/transcranial direct current stimulation), especially with imaging-guided targeting. Priorities include standardized paradigms, longitudinal multimodal designs, and mechanistic modeling to qualify biomarkers and enable mechanism-guided, precision interventions.

Keywords: Major depressive disorder; Emotion-cognition dysregulation; Amygdala-prefrontal circuitry; Attentional bias; Emotion regulation; Biomarkers

Core Tip: This review reframes major depression as an emotion–cognition dysregulation syndrome characterized by a limbic-prefrontal imbalance and large-scale network disruption. By integrating behavioral signatures (negative attention/memory bias, impaired reappraisal) with neural markers (amygdala/insula hyperreactivity, weakened prefrontal control, default mode network-frontoparietal control network/salience network dyscoupling), it outlines composite biomarkers for diagnosis, stratified risk prediction, and mechanism-guided therapies (e.g., imaging-informed neuromodulation). The field now needs standardized tasks and longitudinal multimodal designs to operationalize precision psychiatry.