A pilot study of combined endurance and resistance exercise rehabilitation for verbal memory and functional connectivity improvement in epilepsy Jane B. Allendorfer a,g, ⁎, Gabrielle A. Brokamp a , Rodolphe Nenert a , Jerzy P. Szaflarski a,d,f , Charity J. Morgan b , S. Craig Tuggle e,g , Lawrence Ver Hoef a,f,h , Roy C. Martin a , Basia A. Szaflarski a , Manmeet Kaur a , Adrienne C. Lahti c , Marcas M. Bamman e,g,h a Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA b Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA c Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA d Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA e Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA f UAB Epilepsy Center, University of Alabama at Birmingham, Birmingham, AL, USA g UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, USA h Birmingham VA Medical Center, Birmingham, AL, USA abstract article info Article history: Received 26 February 2019 Revised 12 April 2019 Accepted 13 April 2019 Available online xxxx Memory impairment is common in persons with epilepsy (PWE), and exercise may be a strategy for its improve- ment. In this pilot study, we hypothesized that exercise rehabilitation would improve physical fitness and verbal memory and induce changes in brain networks involved in memory processes. We examined the effects of com- bined endurance and resistance exercise rehabilitation on memory and resting state functional connectivity (rsFC). Participants were randomized to exercise (PWE-E) or control (PWE-noE). The exercise intervention consisted of 18 supervised sessions on nonconsecutive days over 6 weeks. Before and after the intervention period, both groups completed self-report assessments (Short Form-36 (SF-36), Baecke Questionnaire (BQ) of habitual physical activity, and Profile of Mood States (POMS)), cognitive testing (California Verbal Learning Test-II (CVLT- II)), and magnetic resonance imaging (MRI); PWE-E also completed exercise performance tests. After completing the study, PWE-noE were offered cross-over to the exercise arm. There were no differences in baseline demographic, clinical, or assessment variables between 8 PWE-noE and 9 PWE-E. Persons with epilepsy that participated in exer- cise intervention increased maximum voluntary strength (all strength tests p b 0.05) and exhibited nonsignificant improvement in cardiorespiratory fitness (p = 0.15). Groups did not show significant changes in quality of life (QOL) or habitual physical activity between visits. However, there was an effect of visit on POMS total mood distur- bance (TMD) measure showing improvement from baseline to visit 2 (p = 0.023). There were significant group by visit interactions on CVLT-II learning score (p = 0.044) and total recognition discriminability (d′) (p = 0.007). Per- sons with epilepsy that participated in exercise intervention had significant reductions in paracingulate rsFC with the anterior cingulate and increases in rsFC for the cerebellum, thalamus, posterior cingulate cortex (PCC), and left and right inferior parietal lobule (IPL) (corrected p b 0.05). Change in CVLT-II learning score was associated with rsFC changes for the paracingulate cortex (r S = -0.67; p = 0.0033), left IPL (r S = 0.70; p = 0.0019), and right IPL (r S = 0.71; p = 0.0015) while change in d′ was associated with change in cerebellum rsFC to angular/ Keywords: Epilepsy Physical exercise Verbal memory Complementary therapy Resting state functional connectivity fMRI Epilepsy & Behavior 96 (2019) 44–56 Abbreviations: 1RM, one-repetition maximum; ANOVA, analysis of variance; ASDs, antiseizure drugs; BQ, Baecke Questionnaire; CVLT-II, California Verbal Learning Test-II; d′, total recognition discriminability; fMRI, functional magnetic resonance imaging; GXT, maximal graded exercise test; HRR, heart rate reserve; IEDs, interictal epileptiform discharges; IGE, idi- opathic generalized epilepsy; IPL, inferior parietal lobule; LLA, leisure and locomotion activities (from BQ); MCS, mental component score (from SF-36); MNI, Montreal Neurological Institute; MoCA, Montreal Cognitive Assessment; OPA, occupational physical activity during work (from BQ); PAR-Q, Physical Activity Readiness Questionnaire; PEL, physical exercise dur- ing leisure time (from BQ); PCA, principal component analysis; PCC, posterior cingulate cortex; PCS, physical component score (from SF-36); POMS, Profile of Mood States; PWE, persons with epilepsy; PWE-E, persons with epilepsy that participated in exercise intervention; PWE-noE, persons with epilepsy that participated as no-exercise controls; QOL, quality of life; ROIs, regions of interest; rsFC, resting state functional connectivity; rs-fMRI, resting state functional magnetic resonance imaging; SF-36, Short Form-36; SIPN, seizure initiation and propagation network; STG/SMG, superior temporal/supramarginal gyrus; TMD, total mood disturbance (from POMS); TRE, treatment-resistant epilepsy; UAB, University of Alabama at Birmingham; UABEC, University of Alabama at Birmingham Epilepsy Center; UCEM, University of Alabama at Birmingham Center for Exercise Medicine; VO 2 , oxygen uptake; VO 2 max, maximum attained oxygen uptake. ⁎ Corresponding author at: Department of Neurology, University of Alabama at Birmingham (UAB) Epilepsy Center, 312 Civitan International Research Center, 1719 6th Avenue South, Birmingham, AL 35294, USA. E-mail address: jallendorfer@uabmc.edu (J.B. Allendorfer). https://doi.org/10.1016/j.yebeh.2019.04.020 1525-5050/© 2019 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh