Differential Impact of Anxious Misery Psychopathology on Multiple Representations of the Functional Connectome

Darsol Seok; Joanne Beer; Marc Jaskir; Nathan Smyk; Adna Jaganjac; Walid Makhoul; Philip Cook; Mark Elliott; Russell Shinohara; Yvette I Sheline

doi:10.1016/j.bpsgos.2021.11.004

Differential Impact of Anxious Misery Psychopathology on Multiple Representations of the Functional Connectome

Biol Psychiatry Glob Open Sci. 2021 Nov 18;2(4):489-499. doi: 10.1016/j.bpsgos.2021.11.004. eCollection 2022 Oct.

Authors

Darsol Seok¹, Joanne Beer², Marc Jaskir¹, Nathan Smyk¹, Adna Jaganjac¹, Walid Makhoul¹, Philip Cook³, Mark Elliott³, Russell Shinohara^{1

2

4}, Yvette I Sheline^{1

3

5}

Affiliations

¹ Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
² Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
³ Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
⁴ Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
⁵ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Abstract

Background: One aim of characterizing dimensional psychopathology is associating different domains of affective dysfunction with brain circuitry. The functional connectome, as measured by functional magnetic resonance imaging, can be modeled and associated with psychopathology through multiple methods; some methods assess univariate relationships while others summarize broad patterns of activity. It remains unclear whether different dimensions of psychopathology require different representations of the connectome to generate reproducible associations.

Methods: Patients experiencing anxious misery symptomology (depression, anxiety, and trauma; n = 192) received resting-state functional magnetic resonance imaging scans. Three modeling approaches (seed-based correlation analysis, edgewise regression, and brain basis set modeling), each relying on increasingly broader representations of the functional connectome, were used to associate connectivity patterns with six data-driven dimensions of psychopathology: anxiety sensitivity, anxious arousal, rumination, anhedonia, insomnia, and negative affect. To protect against overfitting, 50 participants were held out in a testing dataset, leaving 142 participants as training data.

Results: Different modeling approaches varied in the extent to which they could model different symptom dimensions: seed-based correlation analysis failed to reproducibly model any symptoms, subsets of the connectome (edgewise regression) were sufficient to model insomnia and anxious arousal, and broad representations of the entire connectome (brain basis set modeling) were necessary to model negative affect and ruminative thought.

Conclusions: These results indicate that different methods of representing the functional connectome differ in the degree that they can model different symptom dimensions, highlighting the potential sufficiency of subsets of connections for some dimensions and the necessity of connectome-wide approaches in others.

Keywords: Anxious misery; Dimensional psychopathology; RDoC; Transdiagnostic; fMRI functional connectivity.