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. 2022 Oct;272(7):1253-1272.
doi: 10.1007/s00406-022-01411-x. Epub 2022 Apr 30.

Association between aerobic fitness and the functional connectome in patients with schizophrenia

Lukas Roell  1   2 , Isabel Maurus  3 , Daniel Keeser  3   4   5 , Temmuz Karali  3   4   5 , Boris Papazov  4 , Alkomiet Hasan  6 , Andrea Schmitt  3   7 , Irina Papazova  6 , Moritz Lembeck  3 , Dusan Hirjak  8 , Eliska Sykorova  8 , Cristina E Thieme  8 , Susanne Muenz  3 , Valentina Seitz  3 , David Greska  3 , Mattia Campana  3 , Elias Wagner  3 , Lisa Loehrs  3 , Sophia Stoecklein  4 , Birgit Ertl-Wagner  4   9 , Johannes Poemsl  10 , Astrid Roeh  6 , Berend Malchow  11 , Katriona Keller-Varady  12 , Andreas Meyer-Lindenberg  8 , Peter Falkai  3
Affiliations

Association between aerobic fitness and the functional connectome in patients with schizophrenia

Lukas Roell et al. Eur Arch Psychiatry Clin Neurosci. 2022 Oct.

Abstract

Background: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown.

Objective: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links.

Methods: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses.

Results: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition.

Conclusion: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences.

Trial registration: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Keywords: Exercise; Fitness; Functional connectivity; Neuroimaging; Schizophrenia; fMRI.

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Conflict of interest statement

AS was an honorary speaker for TAD Pharma and Roche and a member of Roche advisory boards. AH is co-editor of the German (DGPPN) schizophrenia treatment guidelines and first author of the WFSBP schizophrenia treatment guidelines; he has been on the advisory boards and has received speaker fees from Janssen-Cilag, Lundbeck, and Otsuka. PF is a co-editor of the German (DGPPN) schizophrenia treatment guidelines and a co-author of the WFSBP schizophrenia treatment guidelines; he is on the advisory boards and receives speaker fees from Janssen, Lundbeck, Otsuka, Servier, and Richter. AML has received consultant fees from Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, Sumitomo Dainippon Pharma Co., Academic Medical Center of the University of Amsterdam, Synapsis Foundation-Alzheimer Research Switzerland, IBS Center for Synaptic Brain Dysfunction, Blueprint Partnership, University of Cambridge, Dt. Zentrum für Neurodegenerative Erkrankungen, Zürich University, Brain Mind Institute, L.E.K. Consulting, ICARE Schizophrenia, Science Advances, Fondation FondaMental, v Behring Röntgen Stiftung, The Wolfson Foundation, and Sage Therapeutics; Additionally, he has received speaker fees from Lundbeck International Foundation, Paul-Martini-Stiftung, Lilly Deutschland, Atheneum, Fama Public Relations, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Janssen-Cilag, Hertie Stiftung, Bodelschwingh-Klinik, Pfizer, Atheneum, University of Freiburg, Schizophrenia Academy, Hong Kong Society of Biological Psychiatry, Fama Public Relations, Spanish Society of Psychiatry, Italian Society of Biological Psychiatry, Reunions I Ciencia S.L., and Brain Center Rudolf Magnus UMC Utrecht as well as the Prix Roger de Spoelberch grant and the CINP Lilly Neuroscience Clinical Research Award 2016. BEW’s spouse is an employee of Siemens Healthineers. IM, LR, DK, TK, BP, DH, ES, SM, VS, MC, EW, LL, AR, ML, KV, IP, BM, JP and SS report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Workflow of the three resting-state fMRI analysis approaches. The analysis steps of the three fMRI approaches that aim to examine the functional connectome from different perspectives are visualized. Details on the workflows are described in the manuscript text
Fig. 2
Fig. 2
Visualization of the ICNs. The 18 ICNs based on Laird et al. [12] are illustrated. ICNs are z-standardized, thresholded at z > 4 and mapped onto the MNI152NLin2009cAsym standard space with a resolution of 2 mm in neurological convention. Color mapping is not standardized across ICNs
Fig. 3
Fig. 3
BFs and partial correlations between aerobic fitness and between-ICN connectivity. Correlation tests resulting in a BF10 around three or higher are labelled with the corresponding between-ICN connection. Categorical scheme of the BF10 according to Lee and Wagenmarkers [65]: BF10 > 1: anecdotal evidence for H1, BF10 > 3: moderate evidence for H1, BF10 > 10: strong evidence for H1, BF10 > 30: very strong evidence for H1, BF10 > 100: extreme evidence for H1, N = 58
Fig. 4
Fig. 4
BFs and partial correlations between-ICN FC and clinical and cognitive scores. Correlation tests resulting in a BF10 around three or higher are labelled with the corresponding name of the test battery. Categorical scheme of the BF10 according to Lee and Wagenmarkers [65]: BF10 > 1: anecdotal evidence for H1, BF10 > 3: moderate evidence for H1, BF10 > 10: strong evidence for H1, BF10 > 30: very strong evidence for H1, BF10 > 100: extreme evidence for H1, N = 72–79
Fig. 5
Fig. 5
BFs and partial correlations between aerobic fitness and within-ICN connectivity. On the left-hand side, BFs of the multilevel partial correlation tests between aerobic fitness and within-ICN FC are displayed and colored according to evidence strength. On the right, the corresponding correlation coefficients and the HDIs are visualized. Categorical scheme of the BF10 according to Lee and Wagenmarkers [65]: BF10 > 1: anecdotal evidence for H1, BF10 > 3: moderate evidence for H1, BF10 > 10: strong evidence for H1, BF10 > 30: very strong evidence for H1, BF10 > 100: extreme evidence for H1, N = 58
Fig. 6
Fig. 6
BFs and partial correlations between within-ICN FC and clinical and cognitive scores. Visualization of the BFs and correlation coefficients of the Bayesian multilevel partial correlation tests including within-ICN connectivity and clinical and cognitive scores. Correlation tests resulting in a BF10 of two or higher are labelled with the corresponding name of the test battery. Categorical scheme of the BF10 according to Lee and Wagenmarkers [65]: BF10 > 1: anecdotal evidence for H1, BF10 > 3: moderate evidence for H1, BF10 > 10: strong evidence for H1, BF10 > 30: very strong evidence for H1, BF10 > 100: extreme evidence for H1, N = 72–79
Fig. 7
Fig. 7
BFs and partial correlations between aerobic fitness and seed-based connectivity of anatomical clusters. Tests resulting in a BF10 < 1 are labelled as inconclusive. Tests resulting in a BF10 > 1 are either assigned to the eight most consistent clusters CENTRAL–CENTRAL, CENTRAL–LIM, CEREB–CEREB, CEREB–NUC, LIM–TEMP, NUC–NUC, OCC–TEMP, TEMP–TEMP or labelled as SINGLE. N = 58, CENTRAL: central cortical structures, LIM: limbic lobe, CEREB: cerebellum, NUC: subcortical nuclei, TEMP: temporal lobe, OCC: occipital lobe, SINGLE = single connections that were linked to aerobic fitness, but were not part of a robust cluster
See this image and copyright information in PMC

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