NeuroImage 223 (2020) 117303 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/neuroimage The developing Human Connectome Project (dHCP) automated resting-state functional processing framework for newborn infants Sean P. Fitzgibbon a,∗, Samuel J. Harrison a,k, Mark Jenkinson a, Luke Baxter e, Emma C. Robinson c, Matteo Bastiani a,f,l, Jelena Bozek d, Vyacheslav Karolis a, Lucilio Cordero Grande c, Anthony N. Price c, Emer Hughes c, Antonios Makropoulos b, Jonathan Passerat-Palmbach b, Andreas Schuh b, Jianliang Gao b, Seyedeh-Rezvan Farahibozorg a, Jonathan O’Muircheartaigh c,g,h, Judit Ciarrusta c, Camilla O’Keeffe c, Jakki Brandon c, Tomoki Arichi c,i,j, Daniel Rueckert b, Joseph V. Hajnal c, A. David Edwards c, Stephen M. Smith a, Eugene Duff a,1, Jesper Andersson a,1 a Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, UK b Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, UK c Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, UK d Faculty of Electrical Engineering and Computing, University of Zagreb, Zagreb, Croatia e Paediatric Neuroimaging Group, Department of Paediatrics, University of Oxford, UK f Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, UK g Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK h MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK i Department of Bioengineering, Imperial College London, UK j Children’s Neurosciences, Evelina London Children’s Hospital, King’s Health Partners, London, UK k Translational Neuromodeling Unit, University of Zurich & ETH Zurich, Switzerland l NIHR Biomedical Research Centre, University of Nottingham, UK a r t i c l e i n f o a b s t r a c t Keywords: The developing Human Connectome Project (dHCP) aims to create a detailed 4-dimensional connectome of early Developing Human Connectome Project life spanning 20–45 weeks post-menstrual age. This is being achieved through the acquisition of multi-modal Functional MRI MRI data from over 1000 in- and ex-utero subjects combined with the development of optimised pre-processing Pipeline pipelines. In this paper we present an automated and robust pipeline to minimally pre-process highly confounded Quality control neonatal resting-state fMRI data, robustly, with low failure rates and high quality-assurance. The pipeline has Connectome Neonate been designed to specifically address the challenges that neonatal data presents including low and variable con- trast and high levels of head motion. We provide a detailed description and evaluation of the pipeline which includes integrated slice-to-volume motion correction and dynamic susceptibility distortion correction, a robust multimodal registration approach, bespoke ICA-based denoising, and an automated QC framework. We assess these components on a large cohort of dHCP subjects and demonstrate that processing refinements integrated into the pipeline provide substantial reduction in movement related distortions, resulting in significant improve- ments in SNR, and detection of high quality RSNs from neonates. 1. Introduction tome Project (dHCP, http://www.developingconnectome.org ) is to fa- cilitate mapping the structural and functional development of brain sys- An increasing focus of neuroimaging science is building accurate tems across the perinatal period (the period before and after birth).This models of the human brain’s structural and functional architecture at the is being achieved through the acquisition of multi-modal MRI data from macro-scale ( Kaiser, 2017 ) through large scale neuroimaging enterprises over 1000 in- and ex-utero subjects of 20–45 weeks post-menstrual age ( Van Essen et al., 2013 ). The mission of the developing Human Connec- (PMA), combined with the development of optimised pre-processing ∗ Corresponding author. E-mail address: sean.fi[email protected] (S.P. Fitzgibbon). 1 These authors contributed equally. https://doi.org/10.1016/j.neuroimage.2020.117303 Received 11 September 2019; Received in revised form 12 August 2020; Accepted 17 August 2020 Available online 29 August 2020 1053-8119/© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ ) S.P. Fitzgibbon, S.J. Harrison and M. Jenkinson et al. NeuroImage 223 (2020) 117303 pipelines. The ambitious scale of the project will enable developing these pipelines are currently available for download. We apply PRO- detailed normative models of the perinatal connectome. The raw and FUMO ( Harrison et al., 2015 ), a Bayesian group component decomposi- processed data from the project, along with genetic, clinical and de- tion algorithm (with a customised neonatal HRF prior), to demonstrate velopmental information ( Hughes et al., 2017 ), will be made publicly high quality RSNs from these data. A companion paper ( Baxter et al., available via a series of data releases. 2019 ) assesses the pipeline, applying it to a stimulus response dataset. In As the human infant enters the world, core functional neural systems order to present the clearest description of the pipeline stages through- are rapidly developing to provide essential functional capabilities. Char- out the paper, we do not separate out Methods and Results sections, acterisation of the perinatal brain using fMRI can provide insights into but intermix descriptions of methods, their assessment procedures and the relative developmental trajectories of brain systems during this cru- results. cial period of development ( Cusack et al., 2017 ). FMRI has been used to characterise the neural activity associated with the sensorimotor sys- 2. Subjects and fMRI acquisition tems ( Arichi et al., 2010 ), olfaction ( Arichi et al., 2013 ), and visual ( Deen et al., 2017 ), auditory ( Anderson et al., 2001 ), vocal ( Dehaene- 2.1. Subjects Lambertz et al., 2002 ), and emotional perception ( Blasi et al., 2011 ; Graham et al., 2013 ). However, whilst task-based studies are informa- MR images were acquired as a part of the dHCP which was approved tive, they are difficult to perform in young, pre-verbal infants. Studies by the National Research Ethics Committee and informed written con- of spontaneous brain activity are ideally suited to the perinatal period sent given by the parents of all participants. and can provide an overall view of the spatial and temporal organisa- Data from two cohorts of dHCP subjects are used in this paper, re- tion of functional systems and their maturation. Using this approach, ferred to as dHCP-538 and dHCP-40. The dHCP-538 is a large cohort a number of studies have explored the emergence of the resting-state that comprises 538 scans and is used to evaluate overall performance of functional networks (RSNs) in infants ( Fransson et al., 2007 ; Lin et al., the dHCP neonatal fMRI pipeline, as well as to assess most processing 2008 ; Liu et al., 2008 ). These RSNs are found to be emerging in the stages. The dHCP-40 is a smaller subset that comprised 40 scans and is preterm period and are largely present at the age of normal birth (40 used to specifically contrast and evaluate the more computationally de- weeks PMA), ( Doria et al., 2010 ; Fransson et al., 2007 ; Gao et al., 2015 ; manding motion and distortion correction algorithms (see Section 3.4 ). He and Parikh, 2016 ; Smyser et al., 2010 ), increasing in strength over The dHCP-538 cohort comprises 538 scans that passed upstream QC the first year of life ( Damaraju et al., 2014 ). prior to the dHCP neonatal fMRI pipeline described in this paper (see Acquisition, pre-processing, and analysing MRI data from the fe- supplementary section 9.2), and had been processed with the pipeline tal and neonatal population presents unique challenges as the tis- as of the time of writing. These 538 scans were obtained from 422 sub- sue composition, anatomy, and function undergo rapid changes dur- jects scanned once and 58 subjects scanned twice (480 subjects in total). ing the perinatal period and markedly differ from those in the adult The first scan was pre-term, < 37 weeks PMA, and second scan was term brain ( Ajayi-Obe et al., 2000 ; Dubois et al., 2014 ; Gilmore et al., equivalent age. The dHCP-538 contains 215 females and 265 males, and 2012 ; Inder et al., 1999 ; Kapellou et al., 2006 ). These differences has a mean PMA at scan of 39.81 weeks ( = 3.36). This cohort is a su- demand re-evaluation of established pipelines ( Cusack et al., 2017 ; perset of the 1st (2017) and 2nd (2019) dHCP public data releases. The Mongerson et al., 2017 ; Smyser et al., 2016 ). Changes in tissue composi- dHCP-40 scans are from 40 subjects (all scanned once) that were re- tion, due to processes such as myelination, and neural and vascular prun- leased in the 1st dHCP data release, in 2017. The dHCP-40 contains ing ( Dubois et al., 2014 ; Kozberg and Hillman, 2016 ) affect imaging con- 15 females and 25 males and has a mean PMA at scan of 39.81 weeks trast ( Goksan et al., 2017 ; Rivkin et al., 2004 ). These changes require be- ( = 2.17). The joint distribution of age-at-birth and age-at-scan for both spoke developmental structural templates ( Kuklisova-Murgasova et al., cohorts is presented in Fig. 1 2011 ; Schuh et al., 2018 ; Shi et al., 2018 ) and optimised registration techniques ( Deen et al., 2017 ; Goksan et al., 2015 ). Care is required 2.2. Acquisition protocol summary to ensure that the effects of changing relative voxel resolution and SNR on analyses are ameliorated and monitored ( Cusack et al., 2017 ; All data were acquired on a 3T Philips Achieva with a dedicated Gao et al., 2015 ). Infant brain haemodynamics differ from adults, and neonatal imaging system including a neonatal 32-channel phased-array can show substantial changes over the perinatal period ( Arichi et al., head coil ( Hughes et al., 2017 ), sited within the neonatal intensive 2012 ; Cornelissen et al., 2013 ; Kozberg and Hillman, 2016 ).