Assistant Professor Children's Hospital Los Angeles Children's Hospital of Los Angeles Los Angeles, California, United States
Background: HIE brain injury evolves. Serial imaging has shown that injuries that appear as focal on early MRIs often expand over the first week to involve larger areas of the deep grey nuclei (DGN) and/or cortex. Therapeutic hypothermia (TH) appears to attenuate the severity and progression of HIE brain injury1 and we have shown that neurotransmitter concentrations are reduced during TH2. Still, the therapeutic effects of TH are incompletely understood, and it is not known whether brain activity changes during TH and whether this contributes to neuroprotection.
Objective: To determine the effects of TH on functional connectivity in neonates with HIE.
Design/Methods: Resting state-fMRI data were acquired from 20 neonates with HIE during whole-body TH and after re-warming (WARM) using an EPI-BOLD sequence (TR = 2s; 150 dynamics). Data were pre-processed using a modified BAIC pipeline. The data were then normalized to a standard neonatal brain template (AAL)3, and the BOLD time series data were extracted for each brain region, low pass filtered (≤ 0.1 Hz) and linearly de-trended. Functional connectivity between brain regions was computed as pairwise correlation coefficients of the time series data. We used a paired t-test to determine if functional connectivity was significantly different between TH and WARM. To determine if this effect was global or regional, we computed mean difference maps (rWARM - rTH) across all subjects.
Results: Data from 8 neonates were excluded (excessive motion: 5; artifacts: 2; large MCA infarct: 1). Results from the remaining 12 (6F, 6M; Mean GA 38.2 ± 1.6; 10 moderate HIE, 2 severe) are shown below. On average, overall functional connectivity was reduced during TH as compared to WARM (p < 0.001, Fig. 1). The mean difference map showed that the reduction in functional connectivity was not uniform; rather, the largest reductions (blue regions in Fig 2) were among corticocortical connections. By contrast, there were fewer differences in connectivity strength among DGN or the DGN and cortical regions during TH as compared to WARM. Conclusion(s): Functional connectivity was reduced during TH as compared to after rewarming, particularly among cortico-cortical connections. This suggests that TH may help to mitigate energy failure by reducing neural activity -- and thereby energy demand--, across selective brain networks. References: 1Gano D et al. Pediatr Res 2013;74:82–7. 2Wisnowski JL et al. J Cereb Blood Flow Metab 2015;36:1075–86. 3Shi F, Y et al. Plos One 2011; I 6(4): e18746.
Fig. 1. Functional connectivity was reduced during TH as compared to WARM. Shown above is the distribution of pair-wise correlation coefficients, averaged across all 12 subjects during TH and WARM.
Fig. 2. The heat map above shows the mean differences between TH and WARM among 90 x 90 pairwise connections between frontal, insula (Ins), cingulate (Cing), inferior (inf) temporal-occipital, parietal, DGN and lateral (lat) temporal regions of interest. As shown, most of the differences are negative (blue), meaning connectivity strength is reduced during TH. Brain regions are labeled in accordance with the neonatal AAL template3.
Authors/Institutions: Jessica L. Wisnowski, Children's Hospital of Los Angeles, Los Angeles, California, United States; Varun Vasudev, Children's Hospital of Los Angeles, Los Angeles, California, United States; Eugenia Ho, Children's Hospital of Los Angeles, Los Angeles, California, United States; Benita Tamrazi, Children's Hospital of Los Angeles, Los Angeles, California, United States; Stefan Blüml, Children's Hospital of Los Angeles, Los Angeles, California, United States; Tai-Wei Wu, Children's Hospital of Los Angeles, Los Angeles, California, United States; Vidya Rajagopalan, Children's Hospital of Los Angeles, Los Angeles, California, United States
