Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies

D Martins; O Dipasquale; K Davies; E Cooper; J Tibble; M Veronese; M Frigo; S C R Williams; F Turkheimer; M Cercignani; N A Harrison

doi:10.1016/j.bbi.2022.03.004

Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies

Brain Behav Immun. 2022 May:102:312-323. doi: 10.1016/j.bbi.2022.03.004. Epub 2022 Mar 5.

Authors

D Martins¹, O Dipasquale², K Davies³, E Cooper⁴, J Tibble⁵, M Veronese⁶, M Frigo⁷, S C R Williams², F Turkheimer², M Cercignani⁸, N A Harrison⁹

Affiliations

¹ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK. Electronic address: daniel.martins@kcl.ac.uk.
² Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK.
³ Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton BN1 9RY, UK; Department of Rheumatology, Brighton & Sussex University Hospitals, Brighton, UK.
⁴ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton BN1 9RY, UK; Department of Rheumatology, Brighton & Sussex University Hospitals, Brighton, UK; Department of Hepatology, Brighton & Sussex University Hospitals, Brighton, UK; Department of Information Engineering, University of Padua, Padua, Italy; Université Côte d'Azur, INRIA, France; Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF24 4HQ, UK; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton, BN1 9RY, UK.
⁵ Department of Hepatology, Brighton & Sussex University Hospitals, Brighton, UK.
⁶ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK; Department of Information Engineering, University of Padua, Padua, Italy.
⁷ Université Côte d'Azur, INRIA, France.
⁸ Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF24 4HQ, UK.
⁹ Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF24 4HQ, UK; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton, BN1 9RY, UK. Electronic address: HarrisonN4@cardiff.ac.uk.

PMID: 35259429
DOI: 10.1016/j.bbi.2022.03.004

Abstract

Background: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood.

Methods: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment.

Results: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms.

Conclusions: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

Keywords: Anti-TNF; Depression; Global brain connectivity; Imaging transcriptomics; Interferon-α; Transcriptomic vulnerability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents / pharmacology
Brain
Humans
Inflammation
Interferon-alpha / adverse effects
Transcriptome*
Tumor Necrosis Factor Inhibitors*

Substances

Anti-Inflammatory Agents
Interferon-alpha
Tumor Necrosis Factor Inhibitors

Grants and funding

MR/J005142/1/MRC_/Medical Research Council/United Kingdom