Insights from serial magnetic resonance imaging in neonatal encephalopathy in term infants.

BACKGROUND: Limited serial neuroimaging studies use magnetic resonance imaging (MRI) to define the evolution of hypoxic-ischemic insults to the brain of term infants and encompass both the primary injury and its secondary impact on cerebral development. The optimal timing of MRI to fully evaluate the impact of hypoxic-ischemic encephalopathy on brain development and associated neurodevelopmental sequelae remains unknown. METHODS: Goals: (a) review literature related to serial neuroimaging in term infants with HIE; (b) describe pilot data in two infants with HIE treated with therapeutic hypothermia who had a brain injury at day 3-5 and underwent four additional MRIs over the next 12 weeks of life and developmental evaluation at 24 months of age. RESULTS: Early MRI defines primary injury on diffusion-weighted imaging, yet the full impact may not be fully apparent until after 1 month of life. CONCLUSION: The full impact of an ischemic injury on the neonatal brain may not be fully visible until several weeks after the initial insult. This suggests the benefit of obtaining later time points for MRI to fully define the extent of injury and its neurodevelopmental impact. IMPACT: Few studies inform the nature of the evolution of brain injury with hypothermia in HIE, limiting understanding of potential neuroprotection. MRI is the standard of care for prognosis in infants with HIE, however timing for optimal prognostic prediction remains unclear. Insights from MRI after the first week of life may assist in defining the full extent of brain injury and prognostic significance. A pilot study using five MRI timepoints up to 3 months of age, is presented. More data is required with a systematic evaluation of the impact of early brain injury on brain development in term infants with HIE following TH.

Music Therapy in the Neonatal Intensive Care Unit: A Center's Experience with Program Development, Implementation, and Preliminary Outcomes.

BACKGROUND: The role of music in the NICU continues to evolve, with recent studies documenting the positive impact of music therapy for hospitalized infants and families. With many potential benefits and no substantial adverse effects reported to date in medically stable infants, we aimed to create a clinical guideline to integrate this therapy into the NICU operations. METHODS: we launched and implemented a pilot music therapy clinical program within a subunit of a level-III NICU, building upon available evidence. RESULTS: In this report, we describe our experience with initial program development and early outcomes in terms of population served, frequency of music therapy, and therapeutic modalities employed to implement service delivery. CONCLUSION: we highlight the importance of establishing practices that are aligned with currently available data and recommendations, in order to facilitate delivery of a safe, evidence-based, meaningful therapeutic experience with monitoring of preliminary effects of the therapy on all those involved in the experience.

Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment.

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

White Matter Injury on Early-versus-Term-Equivalent Age Brain MRI in Infants Born Preterm.

BACKGROUND AND PURPOSE: White matter injury in infants born preterm is associated with adverse neurodevelopmental outcomes, depending on the extent and location. White matter injury can be visualized with MR imaging in the initial weeks following preterm birth but is more commonly defined at term-equivalent-age MR imaging. Our aim was to see how white matter injury detection in MR imaging compares between the 2 time points. MATERIALS AND METHODS: This study compared white matter injury on early brain MR imaging (30-34 weeks' postmenstrual age) with white matter injury assessment at term-equivalent (37-42 weeks) MR imaging, using 2 previously published and standardized scoring systems, in a cohort of 30 preterm infants born at <33 weeks' gestational age. RESULTS: There was a strong association between the systematic assessments of white matter injury at the 2 time points (P = .007) and the global injury severity (P < .001). CONCLUSIONS: Although the optimal timing to undertake neuroimaging in the preterm infant remains to be determined, both early (30-34 weeks) and term-equivalent MR imaging provide valuable information on white matter injury and the risk of associated sequelae.

Cortical growth from infancy to adolescence in preterm and term-born children.

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0-7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences.

A unit's experience with hybrid NICU design: description of care model and implications for patients, families, and professionals.

As the first extra-uterine setting for hospitalized infants, the neonatal intensive care unit (NICU) environment can make a lasting impact on their long-term neurodevelopment. This impact is likely mediated through both specific characteristics of the physical design of the care environment, as well as the experiences that occur within this environment. Recent studies document many established benefits of single-family rooms (SFRs). However, there is concern that infants who spend a prolonged time in SFRs without their parents being intimately involved in their care have reduced opportunities for meaningful experiences, with possible adverse consequences. The purpose of this report is to share an example of an application of the family-centered developmental care model through a hybrid NICU design, inclusive of both SFRs and semi-private bays. In this paper, we empirically describe the physical and operational considerations of a hybrid model, outline the strengths and challenges of this approach, and discuss implications for patients, families, and professionals.

Serial neuroimaging of brain growth and development in very preterm infants receiving tailored neuropromotive support in the NICU. Protocol for a prospective cohort study.

Introduction: Children born very preterm (VP) remain at risk for long-term neurodevelopmental impairment. Patterns of brain growth and injury, and how early neuropromotive therapies might mitigate developmental risk in VP infants remain insufficiently understood. Methods: This is a prospective cohort study of VP infants born at/before 32 weeks gestation. The study will enroll n = 75 consecutively-born VP infants in a level-III NICU. Exposed infants will be categorized into two groups (group 1: low-risk, n = 25 or group 2: high-risk, n = 25) based on the degree of neurological injury on early brain magnetic resonance imaging (MRI) at enrollment. Infants in the low-risk group (i.e., without significant injury defined as intraventricular hemorrhage with dilation, moderate or severe white matter injury, or cerebellar hemorrhage) will receive neurodevelopmental support utilizing the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, while infants in the high-risk group (with neurological injury) will receive more intensive neurorehabilitative support (SENSE-plus). Age-specific, tailored sensory experiences will be facilitated contingently, preferentially by the infant's family with coaching from NICU staff. VP infants in exposure groups will undergo a brain MRI approximately every 2 weeks from enrollment until term-equivalent to monitor brain growth and evolution of injury. Exposed infants will be compared with a reference group (group 3: n = 25), i.e. VP infants whose families decline initial enrollment in SENSE, and subsequently undergo a term-equivalent brain MRI for other purposes. The primary aim of this study is characterization of term-equivalent brain growth and development among VP infants receiving NICU-based neuropromotive interventions compared to VP infants receiving the standard of care. Secondary aims include defining the timing and factors associated with total and regional brain growth on serial brain MRI among VP infants, (Aim 2), and using early imaging to tailor developmental intervention in the NICU while exploring associations with outcomes in VP infants at discharge and at two years corrected age (Aim 3). Discussion: This study will address gaps in understanding patterns of brain growth and injury drawing on serial MRI of hospitalized VP infants. These data will also explore the impact of intensive, tailored neuropromotive support delivered prior to term-equivalent on child and family outcomes.

Acute Diffusion-Weighted Imaging Signaling Severe Periventricular Leukomalacia in Preterm Infants: Case Report and Review of Literature.

Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.

Amplitude-Integrated Electroencephalography Evolution and Magnetic Resonance Imaging Injury in Mild and Moderate to Severe Neonatal Encephalopathy.

OBJECTIVE: This study aimed to describe the evolution of amplitude-integrated electroencephalography (aEEG) in neonatal encephalopathy (NE) during therapeutic hypothermia (TH) and evaluate the association between aEEG parameters and magnetic resonance imaging (MRI) injury. STUDY DESIGN: aEEG data of infants who underwent TH were reviewed for background, sleep wake cycling (SWC), and seizures. Conventional electroencephalography (cEEG) background was assessed from the reports. Discordance of background on aEEG and cEEG was defined if there was a difference in the severity of the background. MRI injury (total score ≥ 5) was assessed by using the Weeke scoring system. RESULTS: A total of 46 infants were included; 23 (50%) with mild NE and 23 (50%) with moderate to severe NE. Comparing mild NE with moderate to severe NE, the initial aEEG background differed with more mild being continuous (70 vs. 52%), with fewer being discontinuous (0 vs. 22%) and flat tracing (0 vs. 4%), whereas burst suppression (4 vs. 4%) and low voltage (26 vs. 18%) did not differ. There was a notably common discordance between the background assessment on cEEG with aEEG in 82% with continuous and 40% low voltage aEEG background. MRI abnormalities were identified in four infants with mild NE and seven infants with moderate to severe NE. MRI injury was associated with aEEG seizures in infants with moderate to severe NE. CONCLUSION: aEEG seizures are useful to predict MRI injury in moderate to severe NE infants. There is a large discrepancy between aEEG, cEEG, and MRI in neonates treated by TH. KEY POINTS: · MRI injury was identified in 29% of moderate NE infants and in 50% of severe NE infants.. · aEEG seizures were associated with MRI injury in the moderate to severe NE infants.. · MRI injury was identified in 16% infants with mild NE.. · Mild NE infants with normal aEEG were unlikely to have MRI injury.. · There was a large discrepancy between aEEG, cEEG, and MRI in infants treated by TH..

Differences between early and late MRI in infants with neonatal encephalopathy following therapeutic hypothermia.

BACKGROUND: MRI is the gold standard test to define brain injury in infants with neonatal encephalopathy(NE). As imaging findings evolve considerably over the first week, early imaging may not fully reflect the final nature of the injury. This study aimed to compare day 4 versus second week MRI in infants with NE. METHODS: Retrospective cohort study including infants who received therapeutic hypothermia(TH) for NE and had two MRIs: early (≤7days) and late (>7days). MRIs were clinically reported and also reviewed by study investigators. RESULTS: 94infants with NE were included (40mild,49moderate,5severe). Twenty-four infants(26%) had a normal early scan of which 3/24(13%) had injury noted on repeat MRI. Seventy infants(74%) had abnormal findings noted on early MRI, of which 4/70(6%) had further evolution of injury while 11/70(16%) had complete resolution of findings. Applying a grading system resulted in a change of grade in 7 infants. CONCLUSION: In infants who received TH for NE, 19% had changes noted between their early and late MRIs. While the impact on predicting neurodevelopmental outcome was not studied, relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI allows for better characterization of injury. IMPACT: MRI is the gold standard tool to define brain injury in infants with NE, however, imaging findings evolve considerably over the first week of life. Most centers perform a single MRI on day 4 after rewarming. In our cohort, 19% of infants had a notable change in their MRI findings between early (within the first week) and late (beyond the first week) scans. Relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI following hypothermia allows for better characterization of brain injury.

Novel metrics to characterize temporal lobe of very preterm infants on term-equivalent brain MRI.

BACKGROUND: Preterm birth adversely impacts brain development and contributes to neurodevelopmental impairment; the temporal lobe may be particularly vulnerable to the impact of very preterm (VP) birth. Yet, no prior magnetic resonance imaging (MRI) scoring system incorporated a method to quantify temporal lobe size in VP infants. METHODS: We developed and applied three metrics (temporal lobe length, extra-axial space, and temporal horn width) to quantify temporal lobe structure on term-equivalent brain MRIs obtained from 74 VP and 16 term infants. We compared metrics between VP and term infants and explored associations of each metric with perinatal risk factors. RESULTS: All metrics had excellent reliability (intra-class correlation coefficient 0.62-0.98). VP infants had lower mean temporal lobe length (76.8 mm versus 79.2 mm, p = 0.02); however, the difference attenuated after correction for postmenstrual age. VP infants had larger temporal horn widths compared with term infants (2.6 mm versus 1.8 mm, p < 0.001). Temporal lobe length was positively associated with gestational age, birth weight, and male sex, and negatively associated with the duration of parenteral nutrition. CONCLUSIONS: The proposed metrics are reliable and sensitive in distinguishing differences in temporal lobe development between VP and full-term infants. IMPACT: We developed a novel method for quantifying temporal lobe size among very preterm infants at term equivalent using simple metrics performed on brain MRI. Temporal lobe metrics were reliable, correlated with brain volume from volumetric analysis, and were sensitive in identifying differences in temporal lobe development among preterm compared with term infants, specifically larger temporal horn size in preterm infants. This temporal lobe metric system will enable future work to delineate the perinatal and postnatal factors that impact temporal lobe growth, and better understand the relationship between temporal lobe disturbance and neurodevelopment in very preterm infants.

Long-lasting effects of very preterm birth on brain structure in adulthood: A systematic review and meta-analysis.

Early life experiences, such as very preterm (VP) birth, can affect brain and cognitive development. Several prior studies investigated brain structure in adults born VP; synthesising these studies may help to provide a clearer understanding of long-term effects of VP birth on the brain. We systematically searched Medline and Embase for articles that investigated brain structure using MRI in adulthood in individuals born VP (<32 weeks' gestation) or with very low birth weight (VLBW; <1500 g), and controls born at term or with normal birth weight. In total, 77 studies met the review inclusion criteria, of which 28 studies were eligible for meta-analyses, including data from up to 797 VP/VLBW participants and 518 controls, aged 18-33 years. VP/VLBW adults exhibited volumetric, morphologic and microstructural alterations in subcortical and temporal cortical regions compared with controls, with pooled standardised mean differences up to - 1.0 (95% confidence interval: -1.2, -0.8). This study suggests there is a persisting neurological impact of VP birth, which may provide developmental neurobiological insights for adult cognition in high-risk populations.

Reading Aloud with Infants in the Neonatal Intensive Care Unit: A Unit-Based Program to Enhance Language Enrichment and Support Early Foundational Relationships.

OBJECTIVE: Early meaningful auditory experiences in the neonatal intensive care unit (NICU) enhance language outcomes and promote cognitive and social-emotional development. METHODS: This is a descriptive report sharing our level III NICU experience of building a reading-aloud enrichment program with the goals of enhancing infant neurodevelopment and strengthening early parent-infant relationships. RESULTS: We propose a roadmap for program development, outline challenges and possible ways to mitigate them, and highlight opportunities for further research in this area. KEY POINTS: · Early auditory experiences enhance language, cognitive, and social-emotional development.. · High-risk infants experience an atypical neurosensory environment while receiving care in the NICU.. · Reading aloud in the NICU enhances language enrichment and supports early foundational relationships.. · We describe our center's experience with building a reading-aloud enrichment program in the NICU..

Growth of prefrontal and limbic brain regions and anxiety disorders in children born very preterm.

BACKGROUND: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. METHODS: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. RESULTS: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (ß = -0.461, p = 0.020), TBV (ß = -0.503, p = 0.021), left (ß = -0.518, p = 0.020) and right hippocampi (ß = -0.469, p = 0.020) and left medial orbitofrontal cortex (ß = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. CONCLUSIONS: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.

Magnetic resonance venography to evaluate cerebral sinovenous thrombosis in infants receiving therapeutic hypothermia.

BACKGROUND: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT. METHODS: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI). RESULTS: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT. CONCLUSION: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population. IMPACT: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT.

Brain Injury in Infants Evaluated for, But Not Treated with, Therapeutic Hypothermia.

Defining neonatal encephalopathy clinically to qualify for therapeutic hypothermia is challenging. This study examines magnetic resonance imaging outcomes of 39 infants who were evaluated and not cooled using criteria inclusive of mild encephalopathy. Infants evaluated for therapeutic hypothermia are at risk for brain injury and may benefit from neuroimaging and follow-up.

"My Brigham Baby" Application: A Pilot Study Using Technology to Enhance Parent's Experience in the Neonatal Intensive Care Unit.

OBJECTIVE: This study aimed to describe the family psychosocial experience in a level-III neonatal intensive care unit (NICU), and to assess how it evolved after rollout of an educational smartphone application (App) called "My Brigham Baby." STUDY DESIGN: We surveyed 25 NICU parents pre-App rollout (before coronavirus disease 2019 [COVID-19] pandemic) and 25 parents post-App rollout (during pandemic). Collected data included parental self-reported discharge readiness, symptoms of stress and anxiety, and parenting skill confidence. Survey scores were assessed as total or mean scores, and by category of severity. RESULTS: Pre-and post-App parents had comparable demographics, and their infants had similar clinical characteristics during their NICU stay. Discharge readiness differed by group status (p = 0.02) and was characterized by a greater frequency in being "very ready" for discharge among the post-App rollout parent group compared with the pre-App group (56 vs. 20%, p = 0.027), and parenting confidence shifted toward more optimal scores post-App rollout. Parental stress and anxiety symptoms did not significantly differ between groups despite possible stress contagion from the COVID-19 pandemic. CONCLUSION: This pilot study suggests that technology Apps are feasible interventions within NICU settings and may enhance parental experiences related to NICU hospitalization. KEY POINTS: · Parents' experience increased psychological distress during the time their infant is cared for in the NICU, which has downstream consequences for the family unit.. · In our study, surveyed parents reported higher discharge readiness and parenting confidence shifted toward improvement after rollout of a family education and support smartphone application in a level-III NICU.. · This pilot study suggests that technology applications are feasible interventions that might enhance parental experiences during NICU hospitalization..