Peripheral immune-redox signatures associate with cortical network alterations in anhedonic depression

Area of Science:

• Neuroscience
• Psychiatry
• Genomics

Background:

• Anhedonia is a key symptom of major depressive disorder (MDD).
• The relationship between peripheral molecular markers and brain network structure in MDD anhedonia is unclear.
• Previous research has not fully elucidated the role of blood-based molecular signatures in relation to cortical network alterations in anhedonia.

Purpose of the Study:

• To investigate the links between peripheral molecular signatures and cortical network architecture in unmedicated MDD patients with high versus low anhedonia.
• To identify specific brain network differences associated with high anhedonia.
• To explore the relationship between peripheral gene expression and brain network organization.

Main Methods:

• Structural MRI was used to construct morphometric similarity networks (MSNs) in 56 MDD patients with high anhedonia (HA), 61 with low anhedonia (LA), and 93 healthy controls (HC).
• Whole-blood RNA sequencing (n=199) was integrated with MSN features using sparse partial least squares-canonical correlation (sPLS-C).
• Gene Ontology and MAGMA analyses were performed for pathway context, with blood analyses repeated after leukocyte composition adjustment.

Main Results:

• High anhedonia (HA) patients exhibited greater MSN integration, particularly in default-mode and somatomotor networks, compared to LA patients.
• MSN patterns correlated negatively with dopamine-transporter and kappa-opioid-receptor densities.
• Peripheral transcriptomic signatures linked to MSN features were enriched for T-cell activation and lymphocyte apoptosis; however, these differences were largely composition-driven after adjusting for blood cell counts.

Conclusions:

• Cortical network alterations in anhedonia are associated with peripheral immune-redox pathways.
• Observed differences in peripheral blood signatures between high and low anhedonia groups are primarily driven by blood cell composition.
• This multimodal approach highlights immune-modulatory targets and synaptic adhesion biology for potential precision interventions in MDD.