UNCORRECTED PROOF 1 Q1 Brain structural connectivity increases concurrent with functional 2 improvement: Q2 Evidence from diffusion tensor MRI in children 3 with cerebral palsy during therapy 4 Zoë A. Englander a,b,* , Jessica Sun c,d , Laura Case e , Mohamad A. Mikati c , Joanne Kurtzberg c,d , Allen W. Song a,b,f 5 a Brain Imaging and Analysis Center, Duke University Medical Center, United States Q3 6 b Department of Biomedical Engineering, Duke University Medical Center, United States 7 c Department of Pediatrics, Duke University Medical Center, United States 8 d The Robertson Cell and Translational Therapy Center, Duke University Medical Center, United States 9 e Division of Physical Therapy, Duke University Medical Center, United States 10 f Department of Radiology, Duke University Medical Center, United States abstract 11 article info 12 Article history: 13 Received 5 November 2014 14 Received in revised form 18 December 2014 15 Accepted 1 January 2015 16 Available online xxxx 17 Keywords: 18 Cerebral palsy 19 Diffusion tensor imaging 20 Structural connectome 21 GMFM-66 22 Cerebral palsy (CP) refers to a heterogeneous group of permanent but non-progressive movement disorders 23 caused by injury to the developing fetal or infant brain (Bax et al., 2005). Because of its serious long-term conse- 24 quences, effective interventions that can help improve motor function, independence, and quality of life are crit- 25 ically needed. Our ongoing longitudinal clinical trial to treat children with CP is specifically designed to meet this 26 challenge. To maximize the potential for functional improvement, all children in this trial received autologous 27 cord blood transfusions (with order randomized with a placebo administration over 2 years) in conjunction 28 with more standard physical and occupational therapies. As a part of this trial, magnetic resonance imaging 29 (MRI) is used to improve our understanding of how these interventions affect brain development, and to develop 30 biomarkers of treatment efficacy. In this report, diffusion tensor imaging (DTI) Q4 and subsequent brain connectome 31 analyses were performed in a subset of children enrolled in the clinical trial (n = 17), who all exhibited positive 32 but varying degrees of functional improvement over the first 2-year period of the study. Strong correlations be- 33 tween increases in white matter (WM) connectivity and functional improvement were demonstrated; however 34 no significant relationships between either of these factors with the age of the child at time of enrollment were 35 identified. Thus, our data indicate that increases in brain connectivity reflect improved functional abilities in 36 children with CP. In future work, this potential biomarker can be used to help differentiate the underlying mech- 37 anisms of functional improvement, as well as to identify treatments that can best facilitate functional improve- 38 ment upon un-blinding of the timing of autologous cord blood transfusions at the completion of this study. 39 © 2015 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license 40 (http://creativecommons.org/licenses/by-nc-nd/4.0/). 41 42 43 44 45 1. Introduction 46 Q6 Cerebral palsy (CP) is estimated to affect 3–4 out of 1000 children 47 (Yeargin-Allsopp et al., 2008) and consists of disordered movement, 48 often in conjunction with deficits in sensation, cognition, communica- 49 tion, and behavior (Bax et al., 2005; Aisen et al., 2011). A variety of dis- 50 turbances in the developing fetal or infant brain may lead to CP, with the 51 resulting neurological deficits correlated with degree and location of 52 damage to brain structure (Accardo et al., 2004). Brain damage in CP 53 often consists of diffuse damage and/or focal lesions in white matter 54 (WM), which are often most severe in periventricular regions (Haynes 55 et al., 2003). While CP is typically diagnosed via neurological as- 56 sessment, neuroimaging techniques such as T 2 weighted imaging, and 57 more recently diffusion MRI, have been used to characterize WM abnor- 58 malities associated with functional deficits in this disorder at a single 59 time point (for a systematic review see Scheck et al. (2012)). 60 There is extensive literature on neuroimaging studies concerned 61 with functional recovery in brain disorders, (Staudt et al., 2006; 62 Sawaki et al., 2008; Sharma et al., 2009; Pajonk et al., 2010; Bosnell 63 et al., 2011; Johansen-Berg, 2012; Madhavan et al., 2014). Neuroimag- 64 ing studies specifically in CP have indicated relationships between func- 65 tional and structural changes within discrete anatomical regions, mostly 66 focusing on sensorimotor regions of interest (ROIs) (Trivedi et al., 2008; 67 Jain et al., 2014). Additionally, initial evaluations of the efficacy of experi- 68 mental treatments for CP – including autologous stem cell therapy – have 69 been performed (Bae et al., 2012; Lee et al., 2012; Min et al., 2013), also NeuroImage: Clinical xxx (2015) xxx–xxx * Corresponding author at: Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, United States. Tel: +1 919 681 2742. E-mail address: zoe.englander@duke.edu (Z.A. Englander). YNICL-00418; No. of pages: 10; 4C: http://dx.doi.org/10.1016/j.nicl.2015.01.002 2213-1582/© 2015 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents lists available at ScienceDirect NeuroImage: Clinical journal homepage: www.elsevier.com/locate/ynicl Please cite this article as: Englander, Z.A., et al., Brain structural connectivity increases concurrent with functional improvement: Evidence from diffusion tensor MRI in children wit..., NeuroImage: Clinical (2015), http://dx.doi.org/10.1016/j.nicl.2015.01.002