Citation: Melis, M.; Schroyen, G.; Blommaert, J.; Leenaerts, N.; Smeets, A.; Van Der Gucht, K.; Sunaert, S.; Deprez, S. The Impact of Mindfulness on Functional Brain Connectivity and Peripheral Inflammation in Breast Cancer Survivors with Cognitive Complaints. Cancers 2023, 15, 3632. https://doi.org/10.3390/ cancers15143632 Academic Editors: Diane Von Ah, Alexandre Chan and Brenna C. McDonald Received: 5 May 2023 Revised: 6 July 2023 Accepted: 12 July 2023 Published: 15 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article The Impact of Mindfulness on Functional Brain Connectivity and Peripheral Inflammation in Breast Cancer Survivors with Cognitive Complaints Michelle Melis 1,2,3,4, *, Gwen Schroyen 1,3,4 , Jeroen Blommaert 3,4,5 , Nicolas Leenaerts 3,6 , Ann Smeets 4,7,8 , Katleen Van Der Gucht 9,10,11 , Stefan Sunaert 1,3,12,† and Sabine Deprez 1,3,4,† 1 Department of Imaging and Pathology, Translational MRI, Catholic University Leuven, 1000 Brussels, Belgium; gwen.schroyen@hotmail.be (G.S.); stefan.sunaert@kuleuven.be (S.S.); sabine.deprez@kuleuven.be (S.D.) 2 Research Foundation Flanders (FWO), 1000 Brussels, Belgium 3 Leuven Brain Institute, Catholic University Leuven, 3000 Leuven, Belgium; jeroen.blommaert@kuleuven.be (J.B.); nicolas.leenaerts@kuleuven.be (N.L.) 4 Leuven Cancer Institute, Catholic University Leuven, 3000 Leuven, Belgium; ann.smeets@uzleuven.be 5 Department of Oncology, Gynecological Oncology, Catholic University Leuven, 3000 Leuven, Belgium 6 Department of Neurosciences, Mind-Body Research, Catholic University Leuven, 3000 Leuven, Belgium 7 Department of Oncology, Surgical Oncology, Catholic University Leuven, 3000 Leuven, Belgium 8 Department of Surgical Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium 9 Tilburg School of Social and Behavioral Sciences, Tilburg University, 5037 AB Tilburg, The Netherlands; katleen.vandergucht@kuleuven.be 10 Leuven Mindfulness Centre, Faculty of Psychology and Educational Sciences, Catholic University Leuven, 3000 Leuven, Belgium 11 Neuromodulation Laboratory, Biomedical Sciences Group, Department of Rehabilitation Sciences, Catholic University Leuven, 3000 Leuven, Belgium 12 Department of Radiology, University Hospitals Leuven, 3000 Leuven, Belgium * Correspondence: michelle.melis@kuleuven.be † These authors contributed equally to this work. Simple Summary: Cognitive impairment is a common side effect of cancer treatment and impacts the quality of life of cancer survivors. As there is currently no golden standard for the treatment of cancer-related cognitive impairment (CRCI), we investigated the potential of a mindfulness-based intervention to impact the underlying mechanisms of CRCI. Breast cancer survivors with cognitive complaints (n = 117) were randomly assigned to a mindfulness, physical training, or waitlist control group. Resting state functional MRI data and serum blood samples were collected and compared before and after the intervention. We could not identify differences between the groups in resting state functional connectivity. However, the functional organization of attention-, salience- and executive functioning-related neural networks differed between both intervention groups and the waitlist control group. Additionally, physical training could alter therapy-induced immune deregulation. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI. Abstract: Background: Cancer-related cognitive impairment (CRCI) has been linked to functional brain changes and inflammatory processes. Hence, interventions targeting these underlying mech- anisms are needed. In this study, we investigated the effects of a mindfulness-based intervention on brain function and inflammatory profiles in breast cancer survivors with CRCI. Methods: Fe- male breast cancer survivors reporting cognitive complaints (n = 117) were randomly assigned to a mindfulness-based intervention (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Region-of-interest (ROI) and graph theory analyses of resting state functional MRI data were performed to study longitudinal group differences in functional connectivity and organization in the default mode, dorsal attention, salience, and frontoparietal network. Additionally, bead-based immunoassays were used to investigate the differences in inflammatory profiles on serum samples. Cancers 2023, 15, 3632. https://doi.org/10.3390/cancers15143632 https://www.mdpi.com/journal/cancers