Human Brain Mapping Functio nal integrity in children with anoxic brain injury from drowning Journal:For Human Peer Brain Mapping Review Manuscript ID HBM-16-0612.R3 Wiley - Manuscript type: Research Article Date Submitted by the Author: 10-Jul-2017 Complete List of Authors: Ishaque, Mariam; UT Health Science Center San Antonio, Research Imaging Institute Manning, Janessa; Wayne State University Woolsey, Mary; UT Health Science Center San Antonio, Research Imaging Institute Franklin, Crystal; UT Health Science Center San Antonio, Research Imaging Institute Tullis, Elizabeth; UT Health Science Center San Antonio, Research Imaging Institute Beckmann, Christian; Donders Centre for Cognitive Neuroimaging, Fox, Peter; University of Texas Health Science Center, Research Imaging Institute; South Texas Veterans Health Care System; Shenzhen University anoxic brain injury, hypoxic-ischemic encephalopathy, neural networks, Keywords: functional magnetic resonance imaging, independent components analysis, resting-state, fMRI, locked-in syndrome, minimally conscious state, ICA John Wiley & Sons, Inc. Page 1 of 51 Human Brain Mapping 1 1 2 Functional integrity in children with anoxic brain injury from drowning 3 4 Mariam Ishaque 1, 2 *, Janessa H. Manning 3, Mary D. Woolsey 1, Crystal G. Franklin 1, Elizabeth W. 5 4 5,6,7 1,2,8,9 6 Tullis , Christian F. Beckmann , Peter T. Fox * 7 8 9 1. Research Imaging Institute, University of Texas Health Science Center at 10 San Antonio, San Antonio, Texas, USA 11 12 2. Department of Radiology, University of Texas Health Science Center at 13 San Antonio, San Antonio, Texas, USA 14 3. Merrill Palmer Skillman Institute, Wayne State University, Detroit, Michigan, USA 15 4. Conrad Smiles Fund 16 5. Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for 17 Brain, Cognition and Behaviour, Nijmegen, The Netherlands 18 6. Donders InstituteFor for Brain, CognitionPeer and Behaviou Reviewr, Donders Center for Cognitive Neuroimaging, 19 Radboud University, Nijmegen, The Netherlands 20 7. Centre for Functional MRI of the Brain, University of Oxford, Oxford, United Kingdom 21 8. South Texas Veterans Healthcare System, San Antonio, Texas, USA 22 9. Shenzhen University School of Medicine, Shenzhen, People's Republic of China 23 24 25 26 *Corresponding Authors : Mariam Ishaque, Peter T. Fox 27 Address : 7703 Floyd Curl Drive, San Antonio, TX 78229 28 29 Email : [email protected]; [email protected] 30 31 Phone : (469) 441-7065; (210) 567-8150 32 33 Fax : (210) 567-8103 34 35 36 Running Title : Functional integrity with pediatric drowning 37 38 Keywords : anoxic brain injury, locked-in syndrome, minimally conscious state, functional magnetic 39 40 resonance imaging, hypoxic-ischemic encephalopathy, independent components analysis, neural 41 42 networks, resting state, fMRI, rs-fMRI, rs-fcMRI 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Human Brain Mapping Page 2 of 51 2 1 2 ABSTRACT 3 4 5 Drowning is a leading cause of accidental injury and death in young children. Anoxic brain injury (ABI) 6 7 is a common consequence of drowning and can cause severe neurological morbidity in survivors. 8 9 Assessment of functional status and prognostication in drowning victims can be extremely challenging, 10 11 12 both acutely and chronically. Structural neuroimaging modalities (CT and MRI) have been of limited 13 14 clinical value. Here, we tested the utility of resting-state functional MRI (rs-fMRI) for assessing brain 15 16 functional integrity in this population. Eleven children with chronic, spastic quadriplegia due to 17 18 For Peer Review 19 drowning-induced ABI were investigated. All were comatose immediately after the injury and gradually 20 21 regained consciousness, but with varying ability to communicate their cognitive state. Eleven 22 23 24 neurotypical children matched for age and gender formed the control group. Resting-state fMRI and co- 25 26 registered T1-weighted anatomical MRI were acquired at night during drug-aided sleep. Network 27 28 integrity was quantified by independent components analysis (ICA), at both group- and per-subject 29 30 31 levels. Functional-status assessments based on in-home observations were provided by families and 32 33 caregivers. Motor ICNs were grossly compromised in ABI patients both group-wise and individually, 34 35 concordant with their prominent motor deficits. Striking preservations of perceptual and cognitive ICNs 36 37 38 were observed, and the degree of network preservation correlated (ρ = 0.74) with the per-subject 39 40 functional status assessments. Collectively, our findings indicate that rs-fMRI has promise for assessing 41 42 brain functional integrity in ABI and, potentially, in other disorders. Further, our observations suggest 43 44 45 that the severe motor deficits observed in this population can mask relatively intact perceptual and 46 47 cognitive capabilities. 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 3 of 51 Human Brain Mapping 3 1 2 INTRODUCTION 3 4 5 Drowning is the second most prevalent cause of unintentional injury death in children 1 to 4 years of age. 6 7 Nonfatal drowning (i.e., cardiopulmonary resuscitation is successful) is prevalent in this age group, with 8 9 an estimated 2 out of 3 drowned children surviving [Borse and Sleet, 2009; Kriel et al., 1994; Topjian et 10 11 12 al., 2012]. Neurological morbidity from anoxic brain injury (ABI) is a frequent outcome, as the brain is 13 14 exquisitely sensitive to oxygen deprivation [Topjian et al. 2012]. 15 16 17 18 For Peer Review 19 Functional assessment and prognostication are extremely challenging in this disorder, both acutely and 20 21 chronically. In the acute state, victims are typically comatose and may remain unresponsive for weeks. 22 23 24 Acutely, T1- and T2-weighted MRI are often normal or suggest diffuse swelling; chronically, diffuse 25 26 atrophy is the most frequently reported finding [Rafaat et al., 2008; Rabinsten and Resnick, 2009]. 27 28 When focal pathology is present, basal ganglia and cerebellar damage are the most commonly reported 29 30 31 and both are associated with poor outcomes [Rabinsten and Resnick, 2009]. In the chronic state, spastic 32 33 quadriparesis resembling severe cerebral palsy is the most common presentation. This entails loss of 34 35 self-mobility, self-feeding and verbal communication, with various movement disorders being reported 36 37 38 [Lu-Emerson and Khot, 2010]. Children with anoxic brain damage are frequently deemed to be in a 39 40 minimally conscious or vegetative state, but these determinations may well be flawed, as 41 42 communication and task-cooperation limitations often preclude reliable assessment of cognitive status 43 44 45 [Ibsen and Koch, 2002; Topjian et al., 2012; Childs et al., 1993; Levy et al., 1985]. 46 47 48 49 50 The neuropathology of pediatric, non-fatal ABI is not well established. Post-drowning anoxic injury has 51 52 been described as diffusely affecting grey matter more than white matter, reflecting the respective 53 54 metabolic demands of the two tissue types [Huang and Castillo, 2008; Rabinstein and Resnick, 2009]. 55 56 57 However, the possibility of a more selective injury must be considered in view of the predominant 58 59 motor-system disability observed in survivors. Until recently, structural imaging methods had 60 John Wiley & Sons, Inc. Human Brain Mapping Page 4 of 51 4 1 2 contributed little to our understanding of the disorder. The limited utility of these methods stemmed 3 4 chiefly from the use of standard, clinical acquisition protocols which were not optimized for this 5 6 7 condition (the neuropathology of was unknown), compounded by a reliance on visual inspection for 8 9 image interpretation (i.e., on non-quantitative methods) [Gutierrez et al., 2010; Howard et al., 2011; 10 11 Huang and Castillo, 2008; Topjian et al., 2012]. In the same patient cohort reported here, our group 12 13 14 recently reported quantitative analyses of two structural imaging modalities. Voxel-based morphometry 15 16 (VBM) was applied to T1-weighted MRI to independently quantify grey and white matter tissue loss 17 18 [Ishaque et al., 2016]. GreyFor matter loss Peer was largely restrictedReview to the basal ganglia and thalamus; white 19 20 21 matter loss predominately affected the posterior limb of the internal capsule (PLIC). Tract-based spatial 22 23 statistics (TBSS) was applied to diffusion-weighted MRI to quantify fractional anisotropy and mean 24 25 26 diffusivity [Ishaque et al., 2017]. TBSS independently confirmed our VBM white-matter findings, also 27 28 showing highly focal, deep subcortical lesions. Further, per-subject motor-function scores correlated 29 30 highly with both fractional anisotropy (Spearman’s ρ = 0.8) and mean diffusivity (ρ = -0.83) in the PLIC. 31 32 33 For both modalities, the lesion was largely confined to the lenticulostriate vascular distribution, 34 35 suggesting that this end-arterial watershed zone may be uniquely susceptible in young children. A 36 37 similar distribution has been reported in perinatal asphyxia using diffusion tensor imaging (DTI) 38 39 40 [Barkovich et al., 2001] and magnetic resonance spectroscopy [Pu et al., 2000], lending further credence 41 42 to this hypothesis. Descending corticospinal and corticobulbar fibers (pyramidal tract) pass through the 43 44 PLIC, the cerebral peduncles (midbrain) and anterior pons en route to the pyramidal decussation 45 46 47 (medulla). Collectively, these observations suggest that pediatric drowning victims may be an at-risk 48 49 population for a selective de-efferentation syndrome, with disproportionate motor impairment and 50 51 52 relatively preserved perceptual and cognitive function. To test this hypothesis, we implemented rs-fMRI 53 54 and quantitative behavioral assessments in the same pediatric ABI cohort in the present study. 55 56 57 58 59 60 John Wiley & Sons, Inc.