Neonatal Functional and Structural Connectivity Are Associated with Cerebral Palsy at Two Years of Age

Stephanie L. Merhar; Elveda Gozdas; Jean A. Tkach; Nehal A. Parikh; Beth M. Kline-Fath; Lili He; Weihong Yuan; Mekibib Altaye; James L. Leach; Scott K. Holland

doi:10.1055/s-0039-1683874

American Journal of Perinatology, Table of Contents

Am J Perinatol 2020; 37(02): 137-145
DOI: 10.1055/s-0039-1683874

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Neonatal Functional and Structural Connectivity Are Associated with Cerebral Palsy at Two Years of Age

Stephanie L. Merhar

¹Division of Neonatology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

²Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio

,

Elveda Gozdas

³Psychiatry and Behavioral Sciences, Stanford University, Stanford, California

,

Jean A. Tkach

⁴Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

⁵Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

Nehal A. Parikh

¹Division of Neonatology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

²Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio

,

Beth M. Kline-Fath

⁵Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

Lili He

¹Division of Neonatology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

Weihong Yuan

⁵Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

⁶Pediatric Neuroimaging Research Consortium, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

Mekibib Altaye

⁷Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

James L. Leach

⁵Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

,

Scott K. Holland

⁸Medpace Imaging Core Laboratory, Medpace Inc., Cincinnati, Ohio

› Author Affiliations

Abstract

Objective The accuracy of structural magnetic resonance imaging (MRI) to predict later cerebral palsy (CP) in newborns with perinatal brain injury is variable. Diffusion tensor imaging (DTI) and task-based functional MRI (fMRI) show promise as predictive tools. We hypothesized that infants who later developed CP would have reduced structural and functional connectivity as compared with those without CP.

Study Design We performed DTI and fMRI using a passive motor task at 40 to 48 weeks' postmenstrual age in 12 infants with perinatal brain injury. CP was diagnosed at age 2 using a standardized examination.

Results Five infants had CP at 2 years of age, and seven did not have CP. Tract-based spatial statistics showed a widespread reduction of fractional anisotropy (FA) in almost all white matter tracts in the CP group. Using the median FA value in the corticospinal tracts as a cutoff, FA was 100% sensitive and 86% specific to predict CP compared with a sensitivity of 60 to 80% and a specificity of 71% for structural MRI. During fMRI, the CP group had reduced functional connectivity from the right supplemental motor area as compared with the non-CP group.

Conclusion DTI and fMRI obtained soon after birth are potential biomarkers to predict CP in newborns with perinatal brain injury.

Keywords

functional MRI - diffusion tensor imaging - cerebral palsy - hypoxic–ischemic encephalopathy

Full Text

References

References
1 Novak I, McIntyre S, Morgan C. , et al. A systematic review of interventions for children with cerebral palsy: state of the evidence. Dev Med Child Neurol 2013; 55 (10) 885-910
2 Kim DY, Park HK, Kim NS, Hwang SJ, Lee HJ. Neonatal diffusion tensor brain imaging predicts later motor outcome in preterm neonates with white matter abnormalities. Ital J Pediatr 2016; 42 (01) 104
3 van Kooij BJ, de Vries LS, Ball G. , et al. Neonatal tract-based spatial statistics findings and outcome in preterm infants. Am J Neuroradiol 2012; 33 (01) 188-194
4 Roze E, Harris PA, Ball G. , et al. Tractography of the corticospinal tracts in infants with focal perinatal injury: comparison with normal controls and to motor development. Neuroradiology 2012; 54 (05) 507-516
5 Massaro AN, Evangelou I, Fatemi A. , et al. White matter tract integrity and developmental outcome in newborn infants with hypoxic-ischemic encephalopathy treated with hypothermia. Dev Med Child Neurol 2015; 57 (05) 441-448
6 Tusor N, Wusthoff C, Smee N. , et al. Prediction of neurodevelopmental outcome after hypoxic-ischemic encephalopathy treated with hypothermia by diffusion tensor imaging analyzed using tract-based spatial statistics. Pediatr Res 2012; 72 (01) 63-69
7 Ancora G, Testa C, Grandi S. , et al. Prognostic value of brain proton MR spectroscopy and diffusion tensor imaging in newborns with hypoxic-ischemic encephalopathy treated by brain cooling. Neuroradiology 2013; 55 (08) 1017-1025
8 Smyser CD, Wheelock MD, Limbrick DD, Neil JJ. Neonatal brain injury and aberrant connectivity. Neuroimage 2019; 185: 609-623
9 He L, Parikh N. . Reduced Functional Connectivity Is Present at Birth in Preterm Infants with Language Delays at Age 2 (abstract) Organization for Human Brain Mapping: Vancouver, Canada; 2017
10 Merhar SL, Gozdas E, Tkach JA. , et al. Functional and structural connectivity of the visual system in infants with perinatal brain injury. Pediatr Res 2016; 80 (01) 43-48
11 Smyser CD, Inder TE, Shimony JS. , et al. Longitudinal analysis of neural network development in preterm infants. Cereb Cortex 2010; 20 (12) 2852-2862
12 Gao W, Alcauter S, Smith JK, Gilmore JH, Lin W. Development of human brain cortical network architecture during infancy. Brain Struct Funct 2015; 220 (02) 1173-1186
13 Linke AC, Wild C, Zubiaurre-Elorza L. , et al. Disruption to functional networks in neonates with perinatal brain injury predicts motor skills at 8 months. Neuroimage Clin 2018; 18: 399-406
14 Novak I, Morgan C, Adde L. , et al. Early, accurate diagnosis and early intervention in cerebral palsy: advances in diagnosis and treatment. JAMA Pediatr 2017; 171 (09) 897-907
15 Newman JE, Bann CM, Vohr BR, Dusick AM, Higgins RD. ; Follow-Up Study Group of Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Improving the Neonatal Research Network annual certification for neurologic examination of the 18-22 month child. J Pediatr 2012; 161 (06) 1041-1046
16 Palisano RJ, Hanna SE, Rosenbaum PL. , et al. Validation of a model of gross motor function for children with cerebral palsy. Phys Ther 2000; 80 (10) 974-985
17 Smith SM, Jenkinson M, Woolrich MW. , et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23 (Suppl (Suppl. 01) S208-S219
18 Jenkinson M, Smith S. A global optimisation method for robust affine registration of brain images. Med Image Anal 2001; 5 (02) 143-156
19 Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002; 17 (03) 143-155
20 Behrens TE, Woolrich MW, Jenkinson M. , et al. Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magn Reson Med 2003; 50 (05) 1077-1088
21 Oishi K, Mori S, Donohue PK. , et al. Multi-contrast human neonatal brain atlas: application to normal neonate development analysis. Neuroimage 2011; 56 (01) 8-20
22 Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ. Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 1999; 18 (08) 712-721
23 Smith SM, Jenkinson M, Johansen-Berg H. , et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 2006; 31 (04) 1487-1505
24 Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 2002; 15 (01) 1-25
25 Akazawa K, Chang L, Yamakawa R. , et al. Probabilistic maps of the white matter tracts with known associated functions on the neonatal brain atlas: application to evaluate longitudinal developmental trajectories in term-born and preterm-born infants. Neuroimage 2016; 128: 167-179
26 Shi F, Yap PT, Wu G. , et al. Infant brain atlases from neonates to 1- and 2-year-olds. PLoS One 2011; 6 (04) e18746
27 Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2012; 2 (03) 125-141
28 Behzadi Y, Restom K, Liau J, Liu TT. A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. Neuroimage 2007; 37 (01) 90-101
29 Shi F, Salzwedel AP, Lin W, Gilmore JH, Gao W. Functional brain parcellations of the infant brain and the associated developmental trends. Cereb Cortex 2018; 28 (04) 1358-1368
30 Volpe JJ. Neurology of the Newborn. 5th ed. Philadelphia, PA: Elsevier Health Sciences; 2008
31 Barkovich AJ, Hajnal BL, Vigneron D. , et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol 1998; 19 (01) 143-149
32 Shankaran S, McDonald SA, Laptook AR. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal magnetic resonance imaging pattern of brain injury as a biomarker of childhood outcomes following a trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Pediatr 2015; 167 (05) 987-93
33 Rutherford MA, Pennock JM, Counsell SJ. , et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998; 102 (2 Pt 1): 323-328
34 Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006; 355 (07) 685-694
35 Edwards AD, Redshaw ME, Kennea N. , et al; ePrime Investigators. Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation. Arch Dis Child Fetal Neonatal Ed 2018; 103 (01) F15-F21
36 Kidokoro H, Neil JJ, Inder TE. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. Am J Neuroradiol 2013; 34 (11) 2208-2214
37 Thayyil S, Chandrasekaran M, Taylor A. , et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics 2010; 125 (02) e382-e395
38 Rutherford M, Ramenghi LA, Edwards AD. , et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010; 9 (01) 39-45
39 Hintz SR, Barnes PD, Bulas D. , et al; SUPPORT Study Group of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics 2015; 135 (01) e32-e42
40 Van't Hooft J, van der Lee JH, Opmeer BC. , et al. Predicting developmental outcomes in premature infants by term equivalent MRI: systematic review and meta-analysis. Syst Rev 2015; 4: 71
41 Erberich SG, Friedlich P, Seri I, Nelson Jr MD, Blüml S. Functional MRI in neonates using neonatal head coil and MR compatible incubator. Neuroimage 2003; 20 (02) 683-692
42 Arichi T, Moraux A, Melendez A. , et al. Somatosensory cortical activation identified by functional MRI in preterm and term infants. Neuroimage 2010; 49 (03) 2063-2071
43 Heep A, Scheef L, Jankowski J. , et al. Functional magnetic resonance imaging of the sensorimotor system in preterm infants. Pediatrics 2009; 123 (01) 294-300