Deviations From Normative Functioning Underlying Emotional Episodic Memory Revealed Cross-Scale Neurodiverse Alterations Linked to Affective Symptoms in Distinct Psychiatric Disorders

Abstract

Background

Affective symptoms are a prevalent psychopathological feature in various psychiatric disorders. However, the underlying neurobiological mechanisms are complex and not yet fully understood.

Methods

We used normative modeling to establish a reference for functional activation of functional magnetic resonance imaging based on an emotional episodic memory task, which is frequently used to study affective symptoms in psychiatric disorders. This normative reference was derived from a large dataset of healthy individuals (n = 409) and used to evaluate individualized functional alterations by calculating deviations from this reference in a clinical dataset, which included 164 healthy control participants and patients with major depressive disorder (MDD) (n = 56), bipolar disorder (BD) (n = 31), and schizophrenia (SZ) (n = 73). The functional deviations were mapped to emotional networks (ENs) with specific emotional functions and used to predict affective symptoms in different mental disorders. The microscale cellular signatures underlying macroscale variations were identified using imaging transcriptomic analysis and associated with affective symptoms.

Results

We observed distinct patterns of cross-scale neural alterations linked to affective symptoms in 3 psychiatric disorders. Macroscale neural dysfunctions in distinct disorders were embedded into non-overlapping ENs and significantly associated with affective symptoms. Oligodendrocytes may mediate the network-specific impairments and microglia for MDD, astrocytes for BD, and excitatory neurons for SZ as replicable cell-type correlates of affective symptoms.

Conclusions

These findings revealed cross-scale neural alterations underlying affective symptoms in psychiatric disorders, providing a basis for understanding their neuropathological patterns and guiding individualized treatment.