Deviations From Normative Functioning Underlying Emotional Episodic Memory Revealed Cross-Scale Neurodiverse...

Area of Science:

• Neuroscience
• Psychiatry
• Computational Biology

Background:

• Affective symptoms are common in psychiatric disorders, but their neurobiological basis remains unclear.
• Understanding the neural mechanisms of affective symptoms is crucial for developing effective treatments.

Purpose of the Study:

• To establish a normative reference for brain functional activation using fMRI during an emotional memory task.
• To identify and characterize cross-scale neural alterations associated with affective symptoms in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ).
• To explore the cellular signatures underlying these neural alterations and their relationship to affective symptoms.

Main Methods:

• Normative modeling of functional magnetic resonance imaging (fMRI) data from 409 healthy individuals to create a reference for emotional episodic memory task activation.
• Evaluation of individualized functional alterations in clinical datasets (164 healthy controls, 56 MDD, 31 BD, 73 SZ) by calculating deviations from the normative reference.
• Mapping functional deviations to emotional networks (ENs) and correlating them with affective symptoms.
• Imaging transcriptomic analysis to identify microscale cellular signatures linked to macroscale neural variations.

Main Results:

• Distinct patterns of cross-scale neural alterations were observed across MDD, BD, and SZ, specifically linked to affective symptoms.
• Macroscale neural dysfunctions were localized within non-overlapping ENs and significantly correlated with symptom severity.
• Specific cell types were identified as potential mediators: oligodendrocytes for network impairments, and microglia (MDD), astrocytes (BD), and excitatory neurons (SZ) as replicable cell-type correlates.

Conclusions:

• The study identified cross-scale neural alterations underlying affective symptoms in major depressive disorder, bipolar disorder, and schizophrenia.
• These findings provide a foundation for understanding the neuropathological patterns of affective symptoms.
• The results may guide the development of individualized treatment strategies for psychiatric disorders.