Disrupted self-referential processing and empathy-based interventions in mental disorders: neural mechanisms, cognitive biases, and therapeutic integration

Disruptions in self-referential processing (SRP), the mental activity of linking experiences to the self, are a transdiagnostic feature across psychiatric disorders such as schizophrenia, major depressive disorder, and anxiety disorders. These disruptions involve distorted self-perception, negative cognitive-affective biases, and altered connectivity in the default mode network and medial prefrontal cortex. SRP and empathy have a bidirectional relationship: impaired self-processing can hinder understanding others' states, while poor empathic attunement may worsen maladaptive self-focus. This interplay contributes to social withdrawal and emotional dysregulation. Interventions like metacognitive therapy, mindfulness, and psychedelic-assisted psychotherapy show preliminary promise for modulating shared neurocognitive mechanisms and improving social functioning.

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Abstract

Self-referential processing (SRP), the mental activity of linking experiences and stimuli to the self, is fundamental to shaping identity, regulating affect, and navigating complex social environments. Disruptions in SRP are increasingly recognized as a transdiagnostic hallmark across psychiatric disorders, including schizophrenia spectrum disorders, major depressive disorder, and anxiety disorders. Such disruptions often manifest as distorted self-perception, negative cognitive-affective biases, and dysfunctional connectivity within key neural networks, particularly the default mode network (DMN) and the medial prefrontal cortex (mPFC). Emerging evidence reveals a dynamic bidirectional relationship between SRP and empathy. Impairments in self-processing may hinder the capacity to accurately infer others’ emotional and cognitive states, while deficits in empathic attunement may reinforce maladaptive self-focus. This interplay contributes to social withdrawal, interpersonal dysfunction, and emotional dysregulation across diagnostic boundaries. Recent therapeutic advances suggest that interventions targeting the interface between SRP and empathy may effectively modulate shared neurocognitive mechanisms. Such interventions include metacognitive therapy, mindfulness-based interventions, and psychedelic-assisted psychotherapy. These therapeutic approaches show preliminary but promising evidence for reducing maladaptive self-focused attention, enhancing emotion regulation, and improving social functioning. This review synthesizes empirical evidence regarding the neural underpinnings of SRP, delineates disorder-specific alterations in self-referential processing, and examines the bidirectional interplay between SRP and empathic functioning. We further outline a conceptual framework for empathy-based interventions targeting SRP dysfunction and propose future directions for precision psychiatry research. Emphasis is placed on developing personalized, mechanism-driven therapeutic strategies informed by computational modeling, transdiagnostic biomarker identification, and digital therapeutic platforms.