Brain health in preterm infants: importance of early-life pain and analgesia exposure.

"Everyday" exposures in the neonatal period, such as pain, may impact brain health in preterm infants. Specifically, greater exposure to painful procedures in the initial weeks after birth have been related to abnormalities in brain maturation and growth and poorer neurodevelopmental outcomes in preterm infants. Despite an increasing focus on the importance of treating pain in preterm infants, there is a lack of consensus of optimal approaches to managing pain in this population. This may be due to recent findings suggesting that commonly used analgesic and sedative medications in preterm infants may also have adverse effects of brain maturation and neurodevelopmental outcomes. This review provides an overview of potential impacts of pain and analgesia exposure on preterm brain health while highlighting research areas in need of additional investigations for the development of optimal pain management strategies in this population.

Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries.

AIM: To examine whether antenatal diagnosis modifies relationships between neonatal brain volumes and 18-month neurodevelopmental outcomes in children with transposition of the great arteries (TGA). METHOD: In a retrospective cohort of 139 children with TGA (77 antenatally diagnosed), we obtained total brain volumes (TBVs) on pre- (n = 102) and postoperative (n = 112) magnetic resonance imaging. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Generalized estimating equations with interaction terms were used to determine whether antenatal diagnosis modified associations between TBVs and neurodevelopmental outcomes accounting for postmenstrual age at scan, brain injury, and ventricular septal defect. RESULTS: Infants with postnatal diagnosis had more preoperative hypotension (35% vs 14%, p = 0.004). The interactions between antenatal diagnosis and TBVs were significantly related to cognitive (p = 0.003) outcomes. Specifically, smaller TBVs were associated with lower cognitive scores in infants diagnosed postnatally; this association was attenuated in those diagnosed antenatally. INTERPRETATION: Antenatal diagnosis modifies associations between neonatal brain volume and 18-month cognitive outcome in infants with TGA. These findings suggest that antenatal diagnosis may be neuroprotective, possibly through improved preoperative clinical status. These data highlight the need to improve antenatal diagnosis rates. WHAT THIS PAPER ADDS: Antenatal diagnosis of transposition of the great arteries modified relationships between neonatal brain volume and neurodevelopment. Smaller brain volumes related to poorer cognitive scores with postnatal diagnosis only. There was more preoperative hypotension in the postnatal diagnosis group.

Major Surgery, Brain Injury, and Neurodevelopmental Outcomes in Very Preterm Infants.

OBJECTIVES: We determined whether (1) major surgery is associated with an increased risk for brain injury and adverse neurodevelopment and (2) brain injury modifies associations between major surgery and neurodevelopment in very preterm infants. METHODS: Prospectively enrolled infants across 3 tertiary neonatal intensive care units underwent early-life and/or term-equivalent age MRI to detect moderate-severe brain injury. Eighteen-month neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development, third edition. Multivariable logistic and linear regressions were used to determine associations of major surgery with brain injury and neurodevelopment, adjusting for clinical confounders. RESULTS: There were 294 infants in this study. Major surgery was associated with brain injury (odds ratio 2.54, 95% CI 1.12-5.75, p = 0.03) and poorer motor outcomes (ß = -7.92, 95% CI -12.21 to -3.64, p < 0.001), adjusting for clinical confounders. Brain injury x major surgery interaction significantly predicted motor scores (p = 0.04): Lowest motor scores were in infants who required major surgery and had brain injury. DISCUSSION: There is an increased risk for brain injury and adverse motor outcomes in very preterm infants who require major surgery, which may be a marker of clinical illness severity. Routine brain MRI to detect brain injury and close neurodevelopmental surveillance should be considered in this subgroup of infants.

Child Neurology: Cortical Malformations in Preterm Infants: Case From a Prospective Cohort.

Malformations of cortical development (MCD) are a rare group of disorders with heterogeneous clinical, neuroimaging, and genetic features. MCD consist of disruptions in the development of the cerebral cortex secondary to genetic, metabolic, infectious, or vascular etiologies. MCD are typically classified by stage of disrupted cortical development as secondary to abnormal: (1) neuronal proliferation or apoptosis, (2) neuronal migration, or (3) postmigrational cortical development. MCD are typically detected with brain MRI when an infant or child becomes symptomatic, presenting with seizures, developmental delay, or cerebral palsy. With recent advances in neuroimaging, cortical malformations can be detected using ultrasound or MRI during the fetal period or in the neonatal period. Of interest, preterm infants are born at a time when many cortical developmental processes are still occurring. However, there is a paucity of literature describing the neonatal imaging findings, clinical presentation, and evolution over time of cortical malformations in preterm infants. In this study, we present the neuroimaging findings from early life to term-equivalent age and childhood neurodevelopmental outcomes of an infant born very preterm (<32 weeks' postmenstrual age) with MCD detected incidentally on neonatal research brain MRI. These brain MRIs were performed as part of a prospective longitudinal cohort study of 160 very preterm infants; MCD were detected incidentally in 2 infants.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Declining Incidence of Postoperative Neonatal Brain Injury in Congenital Heart Disease.

BACKGROUND: Brain injury is common in neonates with complex neonatal congenital heart disease (CHD) and affects neurodevelopmental outcomes. OBJECTIVES: Given advancements in perioperative care, we sought to determine if the rate of preoperative and postoperative brain injury detected by using brain magnetic resonance imaging (MRI) and associated clinical risk factors have changed over time in complex CHD. METHODS: A total of 270 term newborns with complex CHD were prospectively enrolled for preoperative and postoperative brain MRIs between 2001 and 2021 with a total of 466 MRI scans. Brain injuries in the form of white matter injury (WMI) or focal stroke and clinical factors were compared across 4 epochs of 5-year intervals with logistic regression. RESULTS: Rates of preoperative WMI and stroke did not change over time. After adjusting for timing of the postoperative MRI, site, and cardiac group, the odds of newly acquired postoperative WMI were significantly lower in Epoch 4 compared with Epoch 1 (OR: 0.29; 95% CI: 0.09-1.00; P = 0.05). The adjusted probability of postoperative WMI declined significantly by 18.7% from Epoch 1 (24%) to Epoch 4 (6%). Among clinical risk factors, lowest systolic, mean, and diastolic blood pressures in the first 24 hours after surgery were significantly higher in the most recent epoch. CONCLUSIONS: The prevalence of postoperative WMI has declined, whereas preoperative WMI rates remain constant. More robust postoperative blood pressures may explain these findings by minimizing periods of ischemia and supporting cerebral perfusion. These results suggest potential modifiable clinical targets in the postoperative time period to minimize the burden of WMI.

Pearls & Oy-sters: Genetic Epilepsy: An Important Cause of Neonatal Seizures in Infants With Complex Congenital Heart Disease.

Genetic epilepsies, such as KCNQ2 gene variants, though uncommon, are potential causes of neonatal seizures in infants with complex congenital heart disease (CHD). KCNQ2-related seizures commonly present as tonic posturing with autonomic changes and a distinctive amplitude-integrated EEG (aEEG) pattern with increase in amplitude immediately followed by background suppression. Seizures are typically refractory to commonly used antiepileptics in this age group and respond best to sodium channel blockers such as carbamazepine and fosphenytoin. We report the cases of two neonates with complex CHD who presented with seizures secondary to KCNQ2 gene variation and how early recognition of clinical and EEG features led to early treatment and improved seizure burden. When investigating the etiology of neonatal seizures in the perioperative complex cardiac infant, genetic etiologies, such as KCNQ2 variants should be considered, particularly in the absence of clinical exam and neuroimaging features consistent with brain injury. These two cases highlight the importance of a precision medicine approach utilizing clinical examination and seizure semiology, bedside aEEG monitoring, genetic testing, and targeted treatments to improve patient care and outcomes.

Neurodevelopment and Cognition Across the Lifespan in Patients With Single-Ventricle Physiology: Abnormal Brain Maturation and Accumulation of Brain Injuries.

The proportion of adults with single-ventricle physiology (SVP) has significantly increased over time. Improved longevity, however, may be associated with increased risks to brain health in adulthood. Children with SVP are at risk for neurodevelopmental impairment early in life and neurocognitive impairment as they age, and existing epidemiologic evidence suggests that adults with complex congenital heart disease, including SVP, are at increased risk of stroke and dementia, as compared with age-matched controls. Mechanisms that could contribute to increased potential for cognitive impairment in adults with SVP include the following: (i) baseline brain dysmaturation beginning in utero; (ii) subsequent acquired injury occurring in early childhood from staged surgeries; and (iii) pathophysiologic factors related to SVP itself, both in childhood and potentially throughout the lifespan as new arrhythmias, heart failure, and other issues may develop. Associated pathophysiologic mechanisms may include thromboembolism, hypercoagulability, hypoxia, hypoperfusion, and inflammation. Despite increasingly robust pediatric literature with neuroradiologic-neuropsychology correlates in SVP, there is a dearth of similar research in adults, with respect to both complex congenital heart disease overall and SVP specifically. Unanswered questions in adults with SVP include the following: (i) what is the prevalence of baseline brain injury and neurocognitive impairment in adulthood; (ii) what is the incident risk of these issues over time; and (iii) how much may be mediated by incident brain injury across the lifespan in adulthood, as opposed to from underlying susceptibility from dysmaturation and early childhood insults. In this review, we describe what is known regarding the brain health in individuals with SVP across the lifespan, and identify priority areas for future research.

Head circumference, total cerebral volume and neurodevelopment in preterm neonates.

OBJECTIVES: To assess the association of head circumference (HC) <10th percentile at birth and discharge from the neonatal intensive care unit (NICU) with neurodevelopment in very preterm (24-32 weeks' gestational age) neonates, and to compare the association of HC and total cerebral volume (TCV) with neurodevelopmental outcomes. DESIGN: In a prospective cohort, semiautomatically segmented TCV and manually segmented white matter injury (WMI) volumes were obtained. Multivariable regressions were used to study the association of HC and TCV with neurodevelopmental outcomes, accounting for birth gestational age, WMI and postnatal illness. SETTING: Participants born in 2006-2013 at British Columbia Women's Hospital were recruited. PATIENTS: 168 neonates had HC measurements at birth and discharge and MRI at term-equivalent age (TEA). 143 children were assessed at 4.5 years. MAIN OUTCOME MEASURES: Motor, cognitive and language outcomes at 4.5 years were assessed using the Movement Assessment Battery for Children Second Edition (M-ABC) and Wechsler Preschool and Primary Scale of Intelligence Third Edition Full Scale IQ (FSIQ) and Verbal IQ (VIQ). RESULTS: Small birth HC was associated with lower M-ABC and FSIQ scores. In children with small birth HC, small discharge HC was associated with lower M-ABC, FSIQ and VIQ scores, while normal HC at discharge was no longer associated with adverse outcomes. HC strongly correlated with TCV at TEA. TCV did not correlate with outcomes. CONCLUSIONS: Small birth HC is associated with poorer neurodevelopment, independent of postnatal illness and WMI. Normalisation of HC during NICU care appears to moderate this risk.

Imaging Microglial Activation in Untreated First-Episode Psychosis: A PET Study With [18F]FEPPA.

OBJECTIVE: Neuroinflammation and abnormal immune responses are increasingly implicated in the pathophysiology of schizophrenia. Previous positron emission tomography (PET) studies targeting the translocator protein 18 kDa (TSPO) have been limited by high nonspecific binding of the first-generation radioligand, low-resolution scanners, small sample sizes, and psychotic patients being on antipsychotics or not being in the first episode of their illness. The present study uses the novel second-generation TSPO PET radioligand [18F]FEPPA to evaluate whether microglial activation is elevated in the dorsolateral prefrontal cortex and hippocampus of untreated patients with first-episode psychosis. METHOD: Nineteen untreated patients with first-episode psychosis (14 of them antipsychotic naive) and 20 healthy volunteers underwent a high-resolution [18F]FEPPA PET scan and MRI. Dynamic PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were corrected for TSPO rs6971 polymorphism (which is implicated in differential binding affinity). RESULTS: No significant differences were observed between patients and healthy volunteers in microglial activation, as indexed by [18F]FEPPA VT, in either the dorsolateral prefrontal cortex or the hippocampus. There were no significant correlations between [18F]FEPPA VT and duration of illness, clinical presentation, or neuropsychological measures after adjusting for multiple testing. CONCLUSIONS: The lack of significant differences in [18F]FEPPA VT between groups suggests that microglial activation is not present in first-episode psychosis.

Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([(18)F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [(18)F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [(18)F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [(18)F]-FEPPA total volume of distribution (VT) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [(18)F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [(18)F]-FEPPA VT were observed between groups in either gray (F(1,39) = 0.179, P = .674) or white matter regions (F(1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.