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. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Int J Dev Neurosci. 2019 Sep 26;79:11–20. doi: 10.1016/j.ijdevneu.2019.09.005

QUANTITATIVE MRI STUDY OF INFANT REGIONAL BRAIN SIZE FOLLOWING SURGERY FOR LONG-GAP ESOPHAGEAL ATRESIA REQUIRING PROLONGED CRITICAL CARE

Chandler Rebecca Lee Mongerson 1, Russell William Jennings 2,3, David Zurakowski 1,2,3, Dusica Bajic 1,2,3,*
PMCID: PMC6897486  NIHMSID: NIHMS1544342  PMID: 31563705

Abstract

Introduction.

Little is known regarding the impact of concurrent critical illness and thoracic noncardiac perioperative critical care on postnatal brain development. Previously, we reported smaller total brain volumes in both critically ill full-term and premature patients following complex perioperative critical care for long-gap esophageal atresia (LGEA). In the current report, we assessed trends in regional brain sizes during infancy, and probed for any group differences.

Methods.

Full-term (n=13) and preterm (n=13) patients without any previously known neurological concerns, and control infants (n=16), underwent non-sedated 3T MRI at < 1 old. T2-weighted images underwent semi-automated brain segmentation using Morphologically Adaptive Neonatal Tissue Segmentation (MANTiS). Regional tissue volumes of the forebrain, deep gray matter (DGM), cerebellum, and brainstem are presented as absolute (cm3) and normalized (% total brain volume (%TBV)) values. Group differences were assessed using a general linear model univariate analysis with corrected age at scan as a covariate.

Results.

Absolute volumes of regions analyzed increased with advancing age, paralleling total brain size, but were significantly smaller in both full-term and premature patients compared to controls. Normalized volumes (%TBV) of forebrain, DGM, and cerebellum were not different between subject groups analyzed. Normalized brainstem volumes showed significant group differences that warrant future studies to confirm the same finding.

Discussion.

Both full-term and premature critically ill infants undergoing life-saving surgery for LGEA are at risk of smaller total and regional brain sizes. Normalized volumes support globally delayed or diminished brain growth in patients. Future research should look into neurodevelopmental outcomes of infants born with LGEA.

Keywords: long-gap esophageal atresia, full-term, postoperative pain, sedation, term, tolerance

SUMMARY

Recent evidence suggests that critical illness and/or prolonged exposure to sedation may have negative effects on infant brain development. Our study provides novel evidence that both full-term and premature critically ill infants with long-gap esophageal atresia are at risk of globally smaller brain size and its major components (viz. forebrain, deep gray matter, cerebellum) following life-saving thoracic noncardiac surgery and complex critical care with prolonged sedation. Behavioral impact of such findings requires future neurodevelopmental follow up in this unique infant population.

1. INTRODUCTION1

Rapid and dynamic brain growth and maturation throughout the first year of life is sensitive to environmental/external stimuli (Tierney and Nelson, 2009). Studies of early brain plasticity suggest early exposure to stressors (e.g. procedural pain or prolonged exposure to analgesic medications) in the neonatal intensive care unit (NICU) may disrupt the normal interplay of brain maturation processes (Anand and Scalzo, 2000; Doesburg et al., 2013; Duerden et al., 2018; Hauser and Knapp, 2017; Smith et al., 2011). Disruption of time-sensitive neurodevelopmental events can result in delayed brain maturation and have been implicated in poor long-term developmental outcomes (Atkinson and Braddick, 2007; Bjuland et al., 2013; Howard et al., 2011; Martinussen et al., 2005; Pineda et al., 2013; Skranes et al., 2012; Zubiaurre-Elorza et al., 2012) and psychiatric disorders (Ecker et al., 2013; Greenstein et al., 2006). Notably, prematurity – defined as birth <37 weeks gestational age (GA) – is associated with increased risk of adverse neurologic sequelae, manifesting as cognitive (Atkinson and Braddick, 2007; Howard et al., 2011; Ortibus et al., 2012) and behavioral (Bruggink et al., 2008; Grunau et al., 1994; Pineda et al., 2013) disorders later in life. Moreover, it is frequently assumed that full-term gestation is neuroprotective. However, emerging evidence implicates critical illness (e.g. chronic lung disease, patent ductus arteriosus, postnatal infection, and need for mechanical ventilation) as an important risk factor for altered regional brain development irrespective of prematurity (Bonifacio et al., 2010; Shim et al., 2012).

For infants born with congenital diaphragmatic hernia, many studies report extracorporeal membrane oxygenation (ECMO) as a potential risk factor for higher rates of adverse neurodevelopmental outcomes (Ahmad et al., 1999; McGahren et al., 1997). However, there are limited data regarding short- and long-term sequelae in infants born with noncardiac congenital anomalies undergoing thoracic surgery without ECMO. Recent investigations reported higher incidence of brain injury (Stolwijk et al., 2017) and long-term neurodevelopmental delay (Laing et al., 2011; Stolwijk et al., 2016) following neonatal surgery and complex critical care. At Boston Children’s Hospital, the Esophageal and Airway Treatment Center afforded the opportunity to study a unique population of full-term and premature infants born with gastrointestinal congenital anomalies (viz. long-gap esophageal atresia (LGEA) (Bairdain et al., 2015; Kunisaki and Foker, 2012)) that require surgical treatment without the confounding variable of ECMO as part of perioperative critical care management. Using noninvasive magnetic resonance imaging (MRI), our previous report (Mongerson et al., 2019) showed (1) qualitative brain findings with constellation of signs implicating brain atrophy and (2) disproportionately smaller total brain volume and larger extra-axial spaces in both full-term and premature patients following complex perioperative treatment for LGEA that included Foker process (Foker et al., 2009; Kunisaki and Foker, 2012) and prolonged sedation (≥5 days) with opioids and benzodiazepines to facilitate postoperative mechanical ventilation. Sedation in infancy ≥5 days is associated with pharmacological dependence to sedative agents (Solodiuk et al., 2019). Our aim in the present study was to further investigate regional brain volumes (viz. total forebrain, forebrain deep gray matter, cerebellum and brainstem) in aforementioned patient population using the novel Morphologically Adaptive Neonatal Tissue Segmentation (MANTiS) tool (Beare et al., 2016). In this cross-sectional study, we assessed trends in regional brain sizes during infancy, and probed for any group differences.

2. METHODS

2.1. Study Design and Participants

We conducted a pilot infant MRI study with ethical approval from Boston Children’s Hospital Institutional Review Board (IRB-P000007855) as a ‘no more than minimal risk’ study. Informed written parental consent was obtained prior to participation, in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Family of each subject received a $90 gift card for subject’s participation in the non-sedated research brain MRI scan. Eligibility criteria included <1-year-old full-term (37 to 42 weeks GA at birth) and moderate-to-late preterm (28 to 36 weeks GA at birth) patients who underwent thoracic noncardiac surgery for gastrointestinal congenital anomalies (viz. Foker process for LGEA repair (Bairdain et al., 2015; Kunisaki and Foker, 2012)). Complex postoperative critical care included: (1) prolonged sedation (≥5 days) to facilitate postoperative mechanical ventilation, which resulted in pharmacological dependence to sedative agents (Anand et al., 1999; Dewey, 1984; Solodiuk et al., 2019) and (2) subsequent weaning from sedation medications (viz. opioids and benzodiazepines). Although we did not analyze potential symptoms of withdrawal or withdrawal prevention management (for Review on weaning treatment see (Vet et al., 2016)), we confirmed administration of opioids and benzodiazepines was indicated specifically for weaning management as per primary team and/or pain service consult notes. Representative timeline illustrating sequence of perioperative critical care was presented elsewhere (Hodkinson et al., 2019; Mongerson et al., 2019). Healthy full-term infants with no prior exposure to surgery, anesthesia or sedation were also recruited as a reference baseline for typical infant brain development. Controls were recruited from a pool of Boston Children’s Hospital outpatients and two newborn centers (Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital) via fliers and advertisement. Exclusion criteria included: (1) extreme prematurity (<28 weeks GA at birth); (2) cardiac surgeries and/or ECMO exposure; (3) cranial ultrasound findings (e.g. ventricular enlargement with or without gray matter and/or ventricular hemorrhage); (4) neurological disease (e.g. seizures); (5) chromosomal abnormalities (e.g. Down syndrome); (6) prenatal drug exposure; and/or (7) MRI incompatible implants. Final data analysis included 3 groups: full-term and moderate-to-late preterm patients, and full-term controls. This study is extension of our previous work (Mongerson et al., 2019) with the following changes: (1) addition of two new control subjects (8 and 9 months-old), and (2) replacement follow up scans for 2 previously analyzed infants to improve quality of T2-weighted images used for detailed brain segmentation (3 months-old control subject and 5 months full-term patient). Summary of recruitment details (e.g. number of subjects screened, eligible, and enrolled) and group characteristics (demographics and clinical information) are shown in Table 1.

TABLE 1. Recruitment and Group Characteristics.

summarizes study recruitment process for the 3 groups (controls, and full-term and preterm patients), as well as demographic and clinical characteristics of all subjects included in the T2-weighted analysis. Out of all eligible subjects, 28% (16/58) of controls, 21% (13/63) of full-term patients, and 27% (13/49) of premature patients were successfully scanned and data was analyzed. Primary diagnoses are shown stratified based on noncardiac congenital anomaly diagnoses: (1) isolated LGEA, (2) LGEA with TEF, and (3) Other that included LGEA as part of VACTERL association (without cardiac involvement). Typically, infants diagnosed with VACTERL exhibit ≥3 of the characteristic features (viz. vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities). None of the infants included in analysis had exposure to extracorporeal membrane oxygenation. For other exclusion criteria, see Methods. Abbreviations: GA, gestational age; CA, corrected age; LGEA, long-gap esophageal atresia; TEF, tracheo-esophageal fistula.

n Controls Full-Term Patients Premature Patients
Recruitment Process
Considered/(Chart) Reviewed 61 173 108
Eligible (%Reviewed) 58 (95%) 63 (36%) 49 (45%)
Approached (%Eligible) 55 (95%) 40 (63%) 23 (47%)
Consented (%Approached) 21 (38%) 19 (48%) 18 (78%)
Scanned (%Consented) 21 (100%) 13 (68%) 13 (72%)
Included/Analyzed (%Scanned) 16 (76%) 13 (100%) 13 (100%)
Demographic Characteristics
Sex (male), n (%) 15 (94%) 7 (54%) 8 (62%)
Average GA at birth (weeks) ± SD 39.2 ± 1.2 38.5 ± 1.1 32.2 ± 2.9
Median CA at scan [range] (months) 3.2 [0.5-11.7] 5.4 [0.7-13.0] 3.8 [1.4-7.5]
Multiple births, n (%) 1 (6%) 1 (8%) 2 (15%)
Primary diagnoses
 Isolated LGEA, n (%) 0 3 (23%) 3 (23%)
 LGEA with TEF, n (%) 0 5 (38%) 9 (69%)
 Other, n (%) 0 5 (38%) 1 (8%)
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2.2. MRI Acquisition

All infants were scanned in late evenings or at night without any sedation using a 3T TrioTim MRI system equipped with 32-channel receive-only head coil and body-transmission (Siemens Healthcare Inc., USA). Patients’ scans were acquired following completion of all treatment, just prior to discharge. Both foam earplugs (Newmatic Medical, Birmingham, AL) and earmuffs (MRI-Safe Neonatal Noise Guards, Universal Medical, Norwood, MA) were placed for noise protection. Infants were also bundled and cradled in MRI-safe Deluxe+ carrycot (DockATot, Wilmington, NC), which allowed for easier positioning of sleeping baby into the scanner. Infants were continuously monitored for stable heart rate and oxygenation throughout “feed and wrap” scanning approach. Structural T2-weighted images were collected using an axial fast spin echo sequence (repetition time= 12.62 s; echo time= 110 ms; flip angle= 120°; field of view= 180x180 mm2; 63 slices of 2mm thickness; voxel size= 0.35x0.35 mm2). T2 images were collected for all scanned full-term and premature patients (n=13/group), and 16/21 (76%) full-term controls. Of those 16 controls, only one infant had incomplete data collection (partial brain coverage) that precluded analysis of total brain and forebrain volumes (n=15 healthy controls) but allowed for absolute volume quantification of remaining brain regions – deep gray matter, cerebellum, and brainstem (n=16 controls). Total number of scans included in the analysis per group is summarized in Table 1.

2.3. Volumetric MRI Data Analysis

T2-weighted image segmentation was done using Morphologically Adaptive Neonatal Tissue Segmentation (MANTiS) toolbox (Beare et al., 2016) as previously described (Mongerson et al., 2019). Since MANTiS (Beare et al., 2016) employs a neonatal brain MRI template/atlas (Kuklisova-Murgasova et al., 2011), we used tools in FMRIB Software Library (FSL; v.5.0) for additional T2 image preprocessing and postsegmentation editing (see below) in older infants.

2.3.1. Preprocessing

(i) Intracranial space segmentation: T2 images were skull-stripped using “Simple Watershed Scalping” module in the MANTiS toolbox followed by manual editing in FSLview as needed; (ii) Bias field-correction using FMRIB’s Automated Segmentation Tool (FAST) (Zhang et al., 2001) was done to improve subsequent registration and tissue segmentation; and (iii) Setting image origin using “Origin to Center of Mass” module in the MANTiS toolbox.

2.3.2. MANTiS Segmentation.

Preprocessed intracranial images underwent the MANTiS segmentation pipeline (Beare et al., 2016), which produced probabilistic tissue segmentations. Four out of 8 final automated MANTiS tissue classifications (viz. cortical gray and white matter delineations, hippocampus and amygdala) were not evaluated in this study due to unreliable output segmentations in older infants. In turn, we analyzed the remaining 4 tissue segmentations: cerebrospinal fluid (CSF; data previously reported, see Fig.4 in (Mongerson et al., 2019)), deep gray matter (DGM), cerebellum, and brainstem (Figure 1). Analysis of CSF was needed for calculation of total brain mask (Figure 1A) as difference between intracranial space and CSF volumes (see below).

Figure 1. Brain Segmentation.

Figure 1

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Representative edited MANTiS segmentations of (A) total brain that excludes ventricles (red), (B) forebrain (orange), (C) deep gray matter (yellow), (D) cerebellum (cyan), and (E) brainstem (blue) in a full-term patient scanned at 8.9 months of age. Segmentations are shown overlaid on T2-weighted image (gray-scale) in sagittal, coronal, and axial views with corresponding structural 3-D renderings (left to right). Anatomical abbreviations were adopted from previous literature (Paxinos and Watson, 1998). Abbreviations: *, middle cerebellar peduncle; A, anterior; aic, anterior internal capsule; BS, brainstem; Cb, cerebellum; GP, globus pallidus; HCd, head of caudate; Hip, hippocampus; L, left; Md, medulla; Mid, midbrain; P, posterior; pic, posterior internal capsule; Pn, pons; Pu, putamen; R, right; Th, thalamus.

2.3.3. Post-Segmentation Editing.

Selected regions of interest were visually inspected and noted tissue misclassifications found for older infants were edited as follows:

(1). CSF segmentation:

Output was (i) masked to zero voxels outside the intracranial space, (ii) thresholded at 40% to eliminate voxels with <40% probability of representing CSF, and (iii) converted to a binary mask. CSF masks underwent additional (iv) complex editing. Namely, a CSF partial volume estimate generated by FAST (see 2.3.1. Preprocessing above) was (a) thresholded at 50% to eliminate voxels with <50% of their volume comprising CSF, (b) converted to a binary mask, and then (c) combined with MANTiS’s thresholded/binarized CSF mask to create a ‘comprehensive’ CSF image (i.e. all CSF accounted for in previously excluded cisterns, 4th ventricle, and sulcal spaces). Finally, the latter underwent additional minor (d) manual editing to erase remaining misclassified hyperintense brain tissue. Details of CSF results are reported elsewhere (Mongerson et al., 2019).

(2). Brain regions’ segmentations:

Automated probabilistic maps of the DGM, cerebellum and brainstem, were (i) masked to zero voxels outside the intracranial space to exclude rare inclusion of background voxels in tissue segmentations, (ii) thresholded at 50% (eliminating voxels with <50% probability of representing respective tissues), and (iii) converted to binary masks for subsequent (iv) manual editing. Specifically, segmentation masks were visualized overlaid on anatomical T2 images using ITK-SNAP (Yushkevich et al., 2006) (www.itksnap.org) and manual editing was applied as per following anatomical definitions:

  • DGM: This MANTiS segmentation includes basal ganglia, thalamus, and intervening internal capsule (Beare et al., 2016). Only minor corrections were applied to DGM segmentations to (i) erase the corpus callosum - if included, (ii) add-in missing edge of the mask (in one case of 9 month-old infant), and (iii) fill internal holes in the mask either manually or using fslmaths with -fillh operation. Representative mask of DGM is shown in Figure 1C.

  • Cerebellum: The cerebellum segmentation (Figure 1D) excluded cerebellar peduncles (Isgum et al., 2015; Zwicker et al., 2016), with cerebellar-brainstem boundary defined as the point at which cerebellar peduncles were thinnest (Luft et al., 1998). Corrections were mostly related to missing cerebellar tissue at the edges in infants older than 3 months of age.

  • Brainstem: The brainstem segmentation included cerebellar peduncles, with anatomical boundaries enforced as follows: interiorly, beginning inclusion of tissue at the level of the Foramen Magnum; superiorly, terminating tracing at the level of mammillary bodies and posterior commissure; anteriorly, by CSF cisterns and 3red ventricle; and posteriorly, by CSF cisterns and 4th ventricle. Brainstem manual editing was required to erase misclassified surrounding tissues. Representative mask of brainstem is shown in Figure 1D.

2.3.4. Volumetric Analysis.

Segmentation volumes of the intracranial space, CSF, DGM, cerebellum, and brainstem were obtained in terminal using fslstats with -V operation. Total brain volume (TBV) was calculated as the difference between intracranial space and CSF and served for purpose of normalization. Forebrain volume was calculated as follows: TBV − (cerebellum + brainstem). Volumetric measures for respective brain tissue segmentations are presented in terms of absolute (cm3) and normalized volumes (%TBV) (Choe et al., 2013). Normalization using TBV is appropriate for understanding how a brain region of interest changes proportionally with respect to the brain as a whole (O’Brien et al., 2011).

2.4. Statistical Analysis

As this was a pilot study and no prior information were available regarding the brain volumes in the selected groups of patients with LGEA, a convenience sample size of 13 patients/group was chosen, based on the anticipated number of eligible infants at our institution and an estimated 50% enrollment rate. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS; v.23.0, IBM Corporation, Armonk, NY). Normal distribution of continuous variables was confirmed by Shapiro-Wilk test. Both absolute (cm3) and normalized (%TBV) volumes were related to group status using a general linear model (GLM) univariate analysis with corrected age at scan as a covariate. GLM is a flexible generalization of ordinary linear regression that allows for response variables that have error distribution models other than a normal distribution (McCullagh and Nelder, 1989). Specifically, we evaluated the main effect of group and of age at scan, as well as group by age interactions for all variables. Statistical significance was assessed at the α<0.05.

3. RESULTS

Brain segmentation of T2-weighted images (Figure 1) allowed for volumetric comparisons between full-term and premature patients, and full-term controls (Table 1). Absolute intracranial (F(1,37)=139.40, p<0.001) and total brain volumes (F(1,37)=180.47, p<0.001) increased with advancing age for all groups (Figure 2A and B, respectively). Only total brain volume, but not intracranial volume – a proxy of head circumference, was significantly smaller in both patient groups when compared to controls (statistical details in Figure 2). Such findings are consistent with our previous report (Mongerson et al., 2019) after addition of 2 new controls and replacement follow up scans for 2 previously analyzed infants to improve quality of T2-weighted images. Obtained total brain volumes (Figure 2B) were used for subsequent normalization of regional brain structural volumes.

Figure 2. Intracranial and Total Brain Volumes.

Figure 2

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Graphs display individual absolute intracranial (as a proxy of head circumference) and total brain volumes (cm3; excludes ventricles) obtained from T2-weighted MRI scans for the three groups: (1) controls (n=15; open circles), (2) full-term patients (n=13; gray circles), and (3) premature patients (n=13; black circles). Total brain volumes were not available for 1/16 controls (infant scanned at 11.7 months-old) due to partial forebrain coverage. Presented data is updated from our previous work (Mongerson et al., 2019) with addition of two new control subjects (8 and 9 months old), and replacement follow up scans for 2 previously analyzed infants to improve quality of T2-weighted images (3 months-old control subject and 5 months full-term patient). GLM univariate analysis for main effect of group confirmed our previous findings of lack of difference in intracranial volumes between groups (F(2,37)=2.07, p=0.14; Panel A), and significantly lower total brain volumes (F(2,37)=10.96, p<0.001) in both full-term and premature patients in comparison to controls (p<0.001), with no differences between patient groups (Panel B).

3.1. Absolute Regional Brain Volumes

Representative brain segmentations used for regional brain volume analysis of forebrain, DGM, cerebellum, and brainstem are illustrated in Figure 1B–E. Similar to total brain size, absolute volumes (cm3) of all regional structures significantly increased with advancing age irrespective of group status (Figure 3, left panels): forebrain (F(1,37)=160.00, p<0.001), DGM (F(1,38)=83.23, p<0.001), cerebellum (F(1,38)=319.26, p<0.001), and brainstem (F(1,38)=117.87, p<0.001), confirming regional brain growth with age in both patients’ groups and controls. Significant interaction between age at scan and group status was observed for absolute volumes of forebrain (F(2,35)=5.42, p=0.009), DGM (F(2,36)=5.91, p=0.006), and cerebellum (F(2,36)=7.10, p=0.003), but not the brainstem (F(2,36)=1.06, p=0.36). These findings suggest altered group trends in regional brain sizes over time for all brain regions analyzed except the brainstem. Lastly, absolute volumes of all brain regions were significantly lower in both full-term and premature patients in comparison to controls (p≤0.002) with no differences between patient groups (statistical details in Figure 3, left panels).

Figure 3. Regional Brain Volumes.

Figure 3

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Graphs display individual absolute (cm3, left panels) and normalized volumes as a % total brain volume (%TBV, right panels) for the three groups: (1) controls (n=16; open circles), (2) full-term patients (n=13; gray circles), and (3) premature patients (n=13; black circles). Total brain (for normalization) and forebrain volumes were not available for 1/16 controls (infant scanned at 11.7 months-old) due to incomplete brain coverage. GLM univariate analysis of absolute volumes for main effect of group (left panels) showed significant differences: (A) forebrain (F(2,37)=10.82, p<0.001), (B) deep gray matter (DGM; F(2,38)=12.75, p<0.001), (C) cerebellum (F(2,38)=9.11, p=0.001), and (D) brainstem (F(2,38)=15.19, p<0.001). Specifically, absolute volumes of all structures were significantly lower in patients in comparison to controls (p≤0.002) with no significant differences detected between full-term and premature patients. Normalized volumes (right panels) of forebrain, DGM and brainstem significantly decreased with advancing age, while those of the cerebellum increased. No main effect of group was detected for normative volumes of forebrain, DGM, and cerebellum. Analysis showed significant group differences in normalized brainstem volumes (F(2,37)=4.24, p=0.02) between full-term patients and controls (p=0.008) and full-term and preterm patients (p=0.04), but not preterm patients and controls (p=0.59). Since clinical value differences in normalized brainstem volumes are very small, they should be interpreted with caution.

3.2. Normalized Regional Brain Volumes

Analysis of normalized regional brain volumes as %TBV accounts for individual differences in global brain size, allowing for detection of disproportionate volumetric changes of certain structures over time (Figure 3, right panels). Normalized volumes of regional structures significantly decreased with advancing age in infancy for forebrain (F(1,37)=93.99, p<0.001), DGM (F(1,37)=18.97, p<0.001), and brainstem (F(1,37)=7.77, p=0.008) while those of the cerebellum increased (F(1,37)=117.51, p<0.001). No significant interactions between age at scan and group status were observed for any of the structures: forebrain (F(2,35)=0.73, p=0.49), DGM (F(2,35)=2.71, p=0.08), cerebellum (F(2,35)=0.67, p=0.52) or brainstem (F(2,35)=1.40 p=0.26), which suggests similar trend lines in regional brain sizes between groups over time. Similarly, no group differences were observed in normalized volumes for forebrain, DGM and cerebellum (statistical details in Figure 3A–C, right panels). In contrast, normalized brainstem volumetric analysis (Figure 3D, right panel) showed differences between full-term patients and controls (p=0.008) and full-term and preterm patients (p=0.04), but not between preterm patients and controls (p=0.59). Even though brainstem analysis indicated potential significant group differences, clinically, value differences in normalized brainstem volumes are very small and should be interpreted with caution.

4. DISCUSSION

Current report extends our previous qualitative and quantitative findings of lower TBV and greater CSF in full-term and premature patients following perioperative care for LGEA in the absence of difference in intracranial volume, a proxy of head circumference (Mongerson et al., 2019). Specifically, we show smaller absolute regional brain volumes in patients compared to control infants with no heightened vulnerability of forebrain, deep gray matter or cerebellum suggesting generalized reduction in global brain size.

4.1. Infant Total and Regional Brain Volumes

Although previous volumetric studies at early ages (Choe et al., 2013; Gilmore et al., 2007; Knickmeyer et al., 2008; Matsuzawa et al., 2001) have provided invaluable information about early brain development, to our knowledge, current report is the first quantitative study that provides information on regional brain size in the setting of thoracic noncardiac perioperative critical care. We report smaller regional brain volumes that paralleled smaller TBV implicating global brain atrophy in both full-term and premature infants following LGEA treatment. Such findings suggest that brain development – not only in premature, but in full-term infants might be affected by the critical illness and complex perioperative treatment for LGEA that involves Foker Process (Foker et al., 2009; Kunisaki and Foker, 2012), repeated anesthesia and prolonged sedation.

4.1.1. Absolute Brain Volumes.

We show that absolute volumes of all explored brain regions (forebrain, DGM, cerebellum, and brainstem) increased with advancing age, but were significantly smaller in both full-term and premature patients following thoracic noncardiac perioperative critical care for LGEA when compared to controls, with no differences between patient groups (Figure 3, left panels). The overall high rate of postnatal brain growth in the first year of life has been extensively reported for TBV (Gilmore et al., 2012; Knickmeyer et al., 2008; Shi et al., 2011) and its ‘sub-regions’ (Choe et al., 2013; Gilmore et al., 2018; Peterson et al., 2003). Indeed, study by Choe et al. (Choe et al., 2013), which involved detailed manual segmentation of global and discrete anatomical structures, reported that absolute volume increases from 3 to 13 months of age for all brain regions (except for midbrain). Effect of prematurity on regional brain growth has been well documented. A retrospective study in moderately premature infants (born at 30 - 35 weeks GA) (Niwa et al., 2017) reported smaller cerebral hemispheres and DGM, but not cerebellar and brainstem volumes, in comparison to full-term infants scanned at term-equivalent age. Furthermore, prematurity has been repeatedly implicated in smaller DGM volumes at term-equivalent age (Boardman et al., 2006; Inder et al., 2005; Loh et al., 2017; Srinivasan et al., 2007) associated with poorer neurodevelopmental outcomes at 7 years of age (Loh et al., 2017). Another study in premature infants found a strong correlation between cumulative opioid dose and incidence of cerebellum injury and size, even after adjusting for major confounds including prematurity at birth and elements of clinical care (McPherson et al., 2015). Similar study in very preterm infants by Zwicker et al. (Zwicker et al., 2016) reported a strong correlation between cumulative opioid treatment and cerebellar volume, impaired cerebellar growth in the neonatal period, and poorer motor and cognitive neurodevelopmental outcomes in early childhood. Interestingly, authors did not find such correlation for total brain volume or several sub-tissues therein (cortical gray and white matter, and DGM). However, none of these studies looked into regional brain volumes of infants undergoing complex perioperative critical care with prolonged sedation as presented in this report.

4.1.2. Normalized Brain Volumes.

Relative to total brain tissue, normative volumes of forebrain, DGM, and cerebellum did not differ between the groups. Although brainstem analysis indicated potential significant group differences (full-term patients were different from both controls and premature patients), normalized brainstem values show numerically very small differences and should be interpreted with caution. Future studies with more power and narrower clinical criteria for inclusion in premature patients should be considered. Importantly, trajectories of all normalized volumes followed those previously reported in the literature for normally developing full-term infants across the first year of life (Choe et al., 2013). Although brain regions analyzed were more refined in study by Choe et al. (Choe et al., 2013), authors reported normalized values decreased without gender differences for cerebrum, thalamus, and brainstem, and proportionally increased without a gender effect for cerebellum. Our results are consistent with these findings.

4.2. Brain Findings in Thoracic Noncardiac Congenital Anomalies

To date, infants with noncardiac congenital anomalies have not been extensively investigated. Recent report by Stolwijk et al. (Stolwijk et al., 2017) revealed mild to moderate brain abnormalities in 58% of full-term and 75% of premature infants. Only 37% of infants with gastrointestinal abnormalities were without any brain lesions. In addition to prematurity, authors concluded that that the type of congenital anomaly seemed to be the best predictor of parenchymal lesions, with up to 53% of infants with esophageal atresia displaying qualitative lesions on MRI (parenchymal lesions in 36% and nonparenchymal abnormalities in 24%). Our previous work in the cohort of patients in current study reported qualitative MRI findings with 46%-possible and 54%-very likely brain atrophy in full-term patients with LGEA (see Fig.6 in (Mongerson et al., 2019)). Many studies have shown that prematurity is associated with smaller total brain volumes (Gui et al., 2018), which in turn is associated with poorer long-term outcomes (Cheong et al., 2013; Cheong et al., 2016; Keunen et al., 2016). Furthermore, early MRI brain tissue volumes are reportedly strongly predictive of long-term neurodevelopmental outcomes (Cheong et al., 2016; Narberhaus et al., 2007; Rose et al., 2015). Indeed, literature is supportive of using early neuroimaging in predicting neurodevelopmental outcomes (El-Dib et al., 2010; Kwon et al., 2014; Peterson et al., 2003; Woodward et al., 2006). Future longitudinal data should assess neurodevelopmental outcomes of both full-term and premature patients with LGEA undergoing life-saving thoracic noncardiac perioperative critical care with prolonged sedation. Further studies in this vulnerable clinical population of full-term and premature infants are needed and should be performed with diffusion tensor imaging and tractography to shed light on the neural mechanisms underlying implied decreased brain growth, as well as longitudinal follow up to help understand the neurocognitive correlates of these findings.

4.3. Study Limitations

Several limitations should be addressed when interpreting presented results.

4.3.1. Study Groups.

This study lacked a true control group due to the absence of infants with similar non-cardiac LGEA that undergo alternate treatment. We were not able to recruit infants that received only prolonged sedation (without surgery), nor premature infants that did not require medical care. Although infants with known brain abnormalities and neurologic disease were excluded from this study, there are no pretreatment MRIs available to rule out inherently smaller brains in subjects analyzed. Notably, studies in infants with congenital diaphragmatic hernia requiring cardiac surgery with ECMO exposure have shown brain abnormalities prior to cardiac surgery (Ortinau et al., 2013). Second, patients with LGEA without cardiac involvement are somewhat heterogeneous group because of individual level of underlying disease and treatment complexity. Because cases of LGEA cohort are rare, we pooled them together since they all share requirement for Foker process necessitating prolonged sedation associated with development of dependence to sedation drugs (viz. opioids and benzodiazepines). While sex distributions in patient groups were balanced, the control group was predominantly comprised of males. Given reported sex-dependent relationships of whole brain sizes (Benavides et al., 2018; Holland et al., 2014; Thompson et al., 2018), future studies with increased power should look into gender differences. Of note, one study found that normalization of regional brain volumes (%TBV) reportedly corrected for sex-specific differences, with the exception of caudate and cerebellar vermis for which a Male < Female relationship persisted (Choe et al., 2013). Finally, this is a single center study from Esophageal and Airway Treatment Center at Boston Children’s Hospital, and future multicenter studies are needed to confirm presented results. Predefined perinatal and several potentially relevant perioperative risk factors in the pathogenesis of or susceptibility to global decreased brain size should be investigated in future studies (e.g. hypoglycemia, cerebral perfusion, hypocarbia, length of mechanical ventilation and sedation, cumulative anesthesia exposure, vasopressor treatment, culture-proven sepsis).

4.3.2. MRI Acquisition Challenge in Non-sedated Infants.

Although motion during MRI acquisition remains a significant challenge (Gao et al., 2014; Hughes et al., 2017), our efforts to refine scan protocols allowed for improved rates of successful scan completion (100% scanned patients). We noted only very minor head motion, such as single slice disruption (e.g. easily approximate artifact-corrupted slice using 3D rendering tool in ITK-SNAP) or slight ringing artifact. In total, described minor motion artifacts were seen in a limited number of infants: 2/16 controls, 2/13 full-term patients and 3/13 preterm patients. Given incidences were roughly evenly dispersed across groups and the low probability that such minor artifacts would impact gross brain volume estimations, the decision was made to include these subjects.

4.3.3. Methodological Considerations of Infant Brain Segmentation.

In this study, we employed the previously developed neonatal brain segmentation tool MANTiS (Beare et al., 2016). Since MANTiS employs a neonatal brain MRI template/atlas (Kuklisova-Murgasova et al., 2011), extensive editing of automated segmentations was needed prior to volumetric quantification in older infants (>4 months of age). For example, evolving tissue contrasts in the first year of life due to ongoing myelination may have contributed to inclusion of corpus callosum in DGM segmentations of older infants. Furthermore, due to poor signal-to-noise ratio between developing gray matter and unmyelinated tracts on MRI – compounded with the continuum of ongoing myelination across the first year of life – we were not able to accurately analyze separate cortical gray and white matter volumes. Similarly, compounded with poor reliability of automated segmentations for smaller nuclei of hippocampus and amygdala, we chose to include those tissue classifications as part of the forebrain volume (comprised of cortical gray and white matter, hippocampus, amygdala, and DGM). Reliability of gray-white matter distinctions in structural MRI images for accurate quantification, particularly in the transitional period between 4 and 8 months of age, currently represents a major technical challenge that remains to be resolved. Since finer anatomical divisions may improve our understanding of brain changes in this unique cohort of infants and their later outcomes, future technical improvements in acquisition parameters and preprocessing tools will be important to better characterize more specific regional brain sizes.

CONCLUSIONS

This study provides evidence that both full-term and premature infants with thoracic noncardiac congenital anomalies (viz. LGEA) undergoing surgery and complex critical care involving prolonged sedation are at risk of globally decreased or delayed brain growth. In addition to careful perioperative and critical care monitoring of vital signs and neurologic function as part of the standard of care, clinical teams should consider neuroimaging of infants with LGEA before and/or following Foker process since head circumference might not represent the best measure for this unique cohort of infants. Additional research is warranted into potential mechanisms of presented smaller regional brain sizes and potential long-term neurodevelopmental outcomes.

HIGHLIGHTS.

  1. We compared regional brain size between critically ill surgical patients and control infants using MRI.

  2. Following complex thoracic perioperative critical care with sedation, both full-term and preterm patients had smaller regional brain volumes compared to controls.

  3. Both full-term and preterm patients showed no heightened vulnerability of one brain region, suggesting generalized reduction in global brain size.

ACKNOWLEDGMENTS

This work was supported by the NIDA K08 DA035972-01 and Trailblazer Award from the Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital (DB). The authors express tremendous gratitude to infants and their parents for participation in our study. Authors would also like to thank: (i) Dorothy Gallagher, RN and Jean Solodiuk, RN, PhD for their help with recruitment; (ii) Kristina Pelkola BS, RT and Dianne Biagotti, BS, RT for MRI facilitating scheduling in the evenings and weekends; (iii) All MRI technologists for their invaluable help with scanning; and last but not least (iv) Colleagues from the Fetal-Neonatal Neuroimaging & Developmental Science Center (FNNDSC) for their technical support. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supported by NIH K08 DA035972-01 and Trailblazer Award (D.Bajic).

1. ABBREVIATIONS:

CSF

cerebrospinal fluid

DGM

deep gray matter

ECMO

extracorporeal membrane oxygenation

FAST

FMRIB’s Automated Segmentation Tool

FSL

FMRIB Software Library

GA

gestational age

GLM

general linear model

LGEA

long-gap esophageal atresia

MANTiS

Morphologically Adaptive Neonatal Tissue Segmentation

MRI

magnetic resonance imaging

NICU

neonatal intensive care unit

SPSS

Statistical Package for the Social Sciences

TBV

total brain volume

Footnotes

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Declarations of interest: None

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