Efavirenz modulation of sleep spindles and sleep spectral profile.

Non-nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non-nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug-drug and drug-disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment. Forty healthy male subjects were randomized to receive placebo or efavirenz 600 mg nightly for 7 days after completion of a 3-day placebo run-in period. Treatment with efavirenz was associated with reduced time to sleep onset in the Maintenance of Wakefulness Test, an increase in non-rapid eye movement sleep, a large exposure-related decrease in sigma band spectral density and sleep spindle density during non-rapid eye movement sleep, and reduced performance on an attention switching task. Because efavirenz has been shown to have serotonin 2A receptor partial-agonist properties, we reasoned that antagonism of serotonin 2A receptor signalling in the thalamic reticular nucleus, which generates sleep spindles and promotes attention, may be responsible. Consistent with predictions, treatment of healthy volunteers with a single dose of a serotonin 2A receptor antagonist was found to significantly suppress sigma band spectral density in an exposure-related manner and modulated the overall spectral profile in a manner highly similar to that observed with efavirenz, consistent with the notion that efavirenz exhibits serotonin 2A receptor partial-agonist pharmacology in humans.

Preoperative brain injury in transposition of the great arteries is associated with oxygenation and time to surgery, not balloon atrial septostomy.

BACKGROUND: Preoperative brain injury is an increasingly recognized phenomenon in neonates with complex congenital heart disease. Recently, reports have been published that associate preoperative brain injury in neonates with transposition of the great arteries with the performance of balloon atrial septostomy (BAS), a procedure that improves systemic oxygenation preoperatively. It is unclear whether BAS is the cause of brain injury or is a confounder, because neonates who require BAS are typically more hypoxemic. We sought to determine the relationship between preoperative brain injury in neonates with transposition of the great arteries and the performance of BAS. We hypothesized that brain injury results from hypoxic injury, not from the BAS itself. METHODS AND RESULTS: Infants with transposition of the great arteries (n=26) were retrospectively included from a larger cohort of infants with congenital heart disease who underwent preoperative brain MRI as part of 2 separate prospective studies. Data collected included all preoperative pulse oximetry recordings, all values from preoperative arterial blood gas measurements, and BAS procedure data. MRI scans were performed on the day of surgery, before the surgical repair. Of the 26 neonates, 14 underwent BAS. No stroke was seen in the entire cohort, whereas 10 (38%) of 26 patients were found to have hypoxic brain injury in the form of periventricular leukomalacia. Periventricular leukomalacia was not associated with BAS; however, neonates with periventricular leukomalacia had lower preoperative oxygenation (P=0.026) and a longer time to surgery (P=0.028) than those without periventricular leukomalacia. CONCLUSIONS: Preoperative brain injury in neonates with transposition of the great arteries is associated with hypoxemia and longer time to surgery. We found no association between BAS and brain injury.

Functional magnetic resonance imaging and working memory in adolescents with gestational cocaine exposure.

OBJECTIVE: To assess the effect of gestational cocaine exposure on the prefrontal cortex (PFC) with functional magnetic resonance imaging (fMRI). STUDY DESIGN: Using an n-back task, we obtained fMRI with a 3T Siemens scanner on 49 adolescents, 25 who were exposed to cocaine and 24 who were not exposed. The primary outcome was PFC activation during task performance. Five functionally derived regions of interest (ROI) were defined; in addition, 2 a priori anatomical ROIs were generated for Brodmann regions 10 and 46. RESULTS: Of the 49 adolescents who underwent imaging, data from 17 who were exposed to cocaine and 17 who were not exposed were in the final analysis. Groups had similar performance on the n-back task (P >/= .4), with both showing a fewer number of correct responses on the 2-back than the 1-back (P < .001), indicating increased demands on working memory with greater task difficulty. In functionally derived ROIs, imaging results showed increased activation for both groups in the 2-back versus the 1-back condition. In anatomical ROIs, both groups showed greater activation in the 2-back versus the 1-back condition, with activation in the non-exposed group proportionally greater for the left prefrontal region (P = .05). CONCLUSION: In this sample of adolescents, participants who were exposed to cocaine and participants who were not exposed were similar in performance on an executive function task and in fMRI activation patterns during task performance.

Environmental stimulation, parental nurturance and cognitive development in humans.

The effects of environmental stimulation and parental nurturance on brain development have been studied extensively in animals. Much less is known about the relations between childhood experience and cognitive development in humans. Using a longitudinally collected data set with ecologically valid in-home measures of childhood experience and later in-laboratory behavioral measures of cognitive ability, we were able to test hypotheses concerning the effects of environmental stimulation and parental nurturance. A double dissociation was found: On the one hand, there was a selective relation between parental nurturance and memory development, consistent with the animal literature on maternal buffering of stress hormone effects on hippocampal development. On the other hand, there was a selective relation between environmental stimulation and language development. The relevance of these findings to socioeconomic gradients in cognitive ability is discussed.

Development and psychometric assessment of the collaborative care for attention-deficit disorders scale.

OBJECTIVE: To describe the development and assess the validity and reliability of the Collaborative Care for Attention-Deficit Disorders Scale (CCADDS), a measure of collaborative care processes for children with attention-deficit/hyperactivity disorder who attend primary care practices. METHODS: Collaborative care was conceptualized as a multidimensional construct. The 41-item CCADDS was developed from an existing instrument, review of the literature, focus groups, and an expert panel. The CCADDS was field tested in a national mail survey of 600 stratified and randomly selected practicing general pediatricians. Psychometric analysis included assessments of factor structure, construct validity, and internal consistency. RESULTS: The overall response rate was 51%. Most respondents were male (56%), 46 years old or older (59%), and white (69%). Common factor analysis identified 3 subscales: beliefs, collaborative activities, and connectedness. Internal consistency reliability (coefficient alpha) for the overall scale was .91, and subscale scores ranged from .80 to .89. The CCADDS correlated with a validated measure of provider psychosocial orientation (r = -.36, P < .001) and with self-reported frequency of mental health referrals or consultations (r = -.24 to -.42, P < .001). CCADDS scores were similar among physicians by race/ethnicity, gender, age group, and practice location. CONCLUSIONS: Scores on the CCADDS were reliable for measuring collaborative care processes in this sample of primary care clinicians who provide treatment for children with attention-deficit/hyperactivity disorder. Evidence for validity of scores was limited. Future research is needed to confirm its psychometric properties and factor structure and provide guidance on score interpretation.

A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome.

OBJECTIVE: The objective of the study was to examine the effect of selective fetoscopic laser photocoagulation (SFLP) vs serial amnioreduction (AR) on perinatal mortality in severe twin-twin transfusion syndrome (TTTS). STUDY DESIGN: This was a 5 year multicenter, prospective, randomized controlled trial. The primary outcome variable was 30 day postnatal survival of donors and recipients. RESULTS: There was no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11 of 20) vs 55% (11 of 20) (P = 1.0, odds ratio [OR] 1, 95% confidence interval [CI] 0.242 to 4.14) or recipients at 30% (6 of 20) vs 45% (9 of 20) (P = .51, OR 1.88, 95% CI 0.44 to 8.64). There was no difference in 30 day survival of 1 or both twins on a per-pregnancy basis between AR at 75% (15 of 20) and SFLP at 65% (13 of 20) (P = .73, OR 1.62, 95% CI 0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) was not statistically significant for AR at 60% (24 of 40) vs SFLP 45% (18 of 40) (P = .18, OR 2.01, 95% CI 0.76 to 5.44). There was a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14 of 20) vs the AR arm at 35% (7 of 20) (P = .25, OR 5.31, 95% CI 1.19 to 27.6). This was offset by increased recipient neonatal mortality of 30% (6 of 20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality (P = .055, OR 3.025/point) by logistic regression analysis. CONCLUSION: The outcome of the trial did not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS.

Effects of heavy in utero cocaine exposure on adolescent caudate morphology.

We assess the effects of in utero cocaine and polysubstance exposure on the adolescent caudate nucleus through high-resolution magnetic resonance imaging. Cocaine exposure may compromise the developing brain through disruption of neural ontogeny in dopaminergic systems, effects secondary to fetal hypoxemia, or altered cerebrovascular reactivity. Cocaine exposure may also lead to neonatal lesions in the caudate. However, long-term or latent effects of intrauterine cocaine exposure are rarely found. We use T(1)-weighted magnetic resonance imaging to quantify caudate nucleus morphology in matched control and exposed groups. The literature suggests that in utero cocaine exposure consequences in adolescents may be subtle, or masked by other variables. Our comparison focuses on contrasting the control group with high-exposure subjects (mothers who reported 2 median of 117 days of cocaine use during pregnancy; 82% tested positive for cocaine use at term). We use advanced image registration and segmentation tools to quantify left and right caudate morphology. Our results indicate that the caudate is significantly larger in controls versus subjects (P < 0.0025), implying cocaine exposure-related detriments to the dopaminergic system. The right (P < 0.025) and left (P < 0.035) caudate, studied independently, show the same significant trend. Permutation testing and the false discovery rate were used to assess significance.

Correlates of behavioral care management strategies used by primary care pediatric providers.

OBJECTIVE: To identify correlates of behavioral management strategies and to test whether children with more severe behavioral problems have care transferred to mental health specialists. METHODS: Secondary analysis of the Child Behavior Study. Children aged 4 to 15 years were identified with new behavioral problems at nonurgent visits to primary care clinicians. Treatment strategies were categorized into mutually exclusive groups: primary care (psychotropic prescription and/or office-based counseling), mental health care (referral for or ongoing specialist mental health care), joint care (primary care and mental health care), or observation. Child-, family-, clinician-, and practice-level characteristics were assessed for association with management strategies by use of multivariate methods. RESULTS: A total of 1377 children from 201 practices in 44 states and Puerto Rico were newly identified with behavioral problems. Behavioral/conduct (41 per cent), attentional/hyperactivity (37 per cent), adjustment (32 per cent), and emotional (22 per cent) problems were most commonly identified. Children with comorbid behavioral problems were more likely to be managed with joint care than other treatment strategies. In addition, clinicians who were male or who had greater mental health orientation were more likely to provide joint care than mental health care only. CONCLUSIONS: Clinicians were more likely to manage new behavioral problems jointly with mental health providers than use other strategies if children had coexisting mental health problems or if providers had stronger beliefs about psychosocial aspects of care. These results do not support the hypothesis that children with more severe behavioral problems are transferred to specialists but suggest that primary care and mental health care clinicians may benefit from collaborating on treatment plans.

Neurocognitive correlates of problem behavior in environmentally at-risk adolescents.

OBJECTIVE: This study prospectively examines the correlation between neurocognitive (NC) functioning and problem behavior in early adolescence. METHODS: As part of a longitudinal study, African American urban youths of lower socioeconomic status, mean age 12.1 years (SD=1.2, n=111), were administered a battery of 16 NC tasks assessing eight NC systems (two tasks per system) including four systems primarily associated with frontal cortex and four primarily associated with nonfrontal cortex. The former systems included (1) executive cognitive functioning (ECF), (2) cognitive control, (3) working memory, and (4) reward processing. The latter systems included (5) receptive language, (6) spatial cognition, (7) visual cognition, and (8) memory. The Teacher's Report Form of the Achenbach System of Empirically Based Assessment was performed approximately at the same age that the NC assessments were performed. Bivariate correlations were calculated between the eight NC system composite scores and the externalizing scores. RESULTS: Significant negative relationships were found between ECF and receptive language ability and externalizing behavior. Further analyses, using linear regression, showed that receptive language was more predictive of externalizing behavior than ECF. CONCLUSION: Based on these results we conclude that (1) NC functioning, specifically in ECF and in receptive language systems, was associated with adolescent problem behavior and (2) receptive language was more strongly associated with problem behavior than ECF.

Childhood poverty: specific associations with neurocognitive development.

Growing up in poverty is associated with reduced cognitive achievement as measured by standardized intelligence tests, but little is known about the underlying neurocognitive systems responsible for this effect. We administered a battery of tasks designed to tax-specific neurocognitive systems to healthy low and middle SES children screened for medical history and matched for age, gender and ethnicity. Higher SES was associated with better performance on the tasks, as expected, but the SES disparity was significantly nonuniform across neurocognitive systems. Pronounced differences were found in Left perisylvian/Language and Medial temporal/Memory systems, along with significant differences in Lateral/Prefrontal/Working memory and Anterior cingulate/Cognitive control and smaller, nonsignificant differences in Occipitotemporal/Pattern vision and Parietal/Spatial cognition.

The optimal analysis of MRI data to quantify the distribution of a microbicide.

OBJECTIVE: The objective of this study was to systematically review the use of MRI for the evaluation of deployment characteristics of vaginal microbicides and to understand the relationship of gel spread with potential influencing factors. METHODS: Data from four clinical trials that used MRI to assess the deployment of a vaginal gel were combined. A linear mixed model best represented the spread of gel over time. Significant covariates that influence vaginal gel spread are baseline dimensions of the vagina, time from insertion, gel type, ambulation and volume of gel. RESULTS: These data demonstrate that MRI has outstanding intraperson validity and reproducibility. Therefore, paired design, using linear modeling adjusting for significant covariates, is the most efficient study design for comparison of products or volumes. Division of the vagina into two distinct anatomical regions best explains difference in gel spread, i.e., upper area (above the pelvic diaphragm) and lower area (below pelvic diaphragm). CONCLUSION: We conclude that the concept of spread from the cervix to the introits, in one dimension, is inadequate to explain spread of gel due to the complex shape of the vagina.

Distribution of a 3.5-mL (1.0%) C31G vaginal gel using magnetic resonance imaging.

C31G (Savvy) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion.

Lithium citrate for Canavan disease.

Current evidence suggests that the effects of lithium on metabolic and signaling pathways in the brain may vary depending on the specific clinical condition or disease model. For example, lithium increases levels of cerebral N-acetyl aspartate in patients with bipolar disorder but does not appear to affect N-acetyl aspartate levels in normal human subjects. Conversely, lithium significantly decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of Canavan disease in which cerebral N-acetyl aspartate is chronically elevated. While N-acetyl aspartate is a commonly used surrogate marker for neuronal density and correlates with neuronal viability, grossly elevated whole-brain levels of N-acetyl aspartate in Canavan disease are associated with dysmyelination and mental retardation. This report describes the first clinical application of lithium in a human subject with Canavan disease. Spectroscopic and clinical changes were observed over the time period in which lithium was administered, which reversed during a 2-week wash-out period after withdrawal of lithium. This investigation reports decreased N-acetyl aspartate levels in the brain regions tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination, suggesting that a larger, controlled trial of lithium may be warranted as supportive therapy for Canavan disease by decreasing abnormally elevated N-acetyl aspartate.

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.

Symptom stability in adult obsessive-compulsive disorder: data from a naturalistic two-year follow-up study.

OBJECTIVE: Little is known about the longitudinal course of symptoms in adult patients with obsessive-compulsive disorder (OCD), although some evidence exists regarding symptom stability in children and adolescents. This study systematically investigated the temporal stability of individual symptoms and symptom dimensions of OCD in adult patients who were followed prospectively for 2 years. METHOD: One hundred seventeen adult outpatients with OCD from three U.S. sites were administered the Yale-Brown Obsessive Compulsive Scale symptom checklist four times over a period of 2 years. Eighty-one (69%), 83 (71%), and 67 (57%) patients were available 6 months, 1 year, and 2 years after initial screening, respectively. Different analytic methods assessed the stability of OCD symptoms within and between previously identified symptom dimensions. RESULTS: For the most part, patients maintained their symptoms throughout follow-up, although some symptoms were more stable than others. For the symptoms that changed, changes occurred within rather than between symptom dimensions; qualitative shifts from one dimension to another were rare. The strongest predictor of the presence of a particular symptom was having had that symptom in the past. Although most patients had received pharmacological and behavioral treatment during the follow-up period, changes within symptom dimensions could not be explained by overall clinical improvement over time. CONCLUSIONS: Symptoms of adult patients with OCD might be more stable across time than previously thought, with some symptoms waxing and waning within symptom dimensions and rarely involving shifts between dimensions. Longer follow-up studies involving larger samples are needed to better understand the fluctuations of OCD symptoms across time.

Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects.

OBJECTIVE: Impaired neurodevelopmental outcome represents a major morbidity for survivors of infant heart surgery for congenital heart defects. Previous studies in these neonates have reported preoperative microcephaly, periventricular leukomalacia, and other findings. The hypothesis of this study is that preoperative cerebral blood flow is substantially diminished and might relate to preoperative neurologic conditions. METHODS: Preoperative brain magnetic resonance imaging was performed. Cerebral blood flow measurements in infants with congenital heart defects were obtained by using a novel noninvasive magnetic resonance imaging technique, pulsed arterial spin-label perfusion magnetic resonance imaging. Cerebral blood flow was measured before the operation under standard ventilation and repeated after increased carbon dioxide. RESULTS: A total of 25 term infants were studied. The average age at the time of the operation was 4.4 +/- 4.6 days. Congenital heart defects varied widely. Microcephaly occurred in 24% (6/25). Baseline cerebral blood flow was 19.7 +/- 9.2 mL . 100 g -1 . min -1 (8.0-42.2 mL . 100 g -1 . min -1 ). Five patients had cerebral blood flow measurements of less than 10 mL . 100 g -1 . min -1 . Mean hypercarbic cerebral blood flow increased to 40.1 +/- 20.3 mL . 100 g -1 . min -1 (11.4-94.0 mL . 100 g -1 . min -1 , P < .001). Pairwise analyses found that low hemoglobin levels were associated with higher baseline cerebral blood flow values ( P = .04). Periventricular leukomalacia occurred in 28% (7/25) and was associated with decreased baseline cerebral blood flow values ( P = .05) and a smaller change in cerebral blood flow with hypercarbia ( P = .003). CONCLUSIONS: Structural brain abnormalities are common in these neonates before surgical intervention. Preoperative cerebral blood flow for this cohort was low and drastically reduced in some patients. Low cerebral blood flow values were associated with periventricular leukomalacia. Carbon dioxide reactivity was preserved but might be compromised by some aspects of the cardiac anatomy. The full spectrum of cerebral blood flow measurements with this technique in congenital heart defects and their long-term significance require continued investigation.

Age-related, regional, hemispheric, and medial-lateral differences in myelin integrity in vivo in the normal adult brain.

BACKGROUND AND PURPOSE: Clinical validation of magnetization transfer (MT) imaging is important for investigating clinical disease and organization of normal brain function. We determined whether an in vivo quantitative measure sensitive to white matter is distributed in functionally important ways. METHODS: Axial 1.5-T MR images with and those without MT were obtained. MT ratios (MTRs) were computed for 33 regions of interest (ROIs) in 27 healthy adults (aged 18-69 years) without evidence of cognitive or radiographic abnormalities. Three tests of reliability yielded coefficients above 0.97. MTRs for the whole brain, groups of structures, and individual ROIs were calculated. Low standard errors confirmed the consistency of the technique. RESULTS: Age, education, sex, and hand dominance were not correlated with whole-brain MTR (mean = 37.35, SD = 1.25), but age was associated with the cerebellum and some lobes at a trend level. MTRs were as follows, in descending order: corpus callosum, cingulate, white matter, brain stem, subcortical nuclei, and cerebellum. MTRs were selectively higher in the prefrontal lobe versus the posterior frontal lobe and in the lateral temporal lobe versus medial temporal lobe. MTR was higher in the left hemisphere than in the right hemisphere for the whole brain, frontal and temporal lobes, and lenticular nuclei. CONCLUSION: MT imaging showed selective age, medial-lateral, and hemispheric differences, giving evidence of normal aging effects on the white matter in the absence of T2- weighted hyperintensities. These differences support neurocognitive theories of the organization of brain function. MT imaging appears to be a robust technique for use in cognitive neuroscience.

In vivo distribution of a vaginal gel: MRI evaluation of the effects of gel volume, time and simulated intercourse.

A microbicide is designed to coat the vaginal epithelium and prevent transmission of HIV. Complete coverage is desired for optimal protection. In vivo factors affecting coverage have not yet been studied. This randomized crossover trial evaluates the effect of gel volume and patient activity upon vaginal epithelial coating. Gynol II gel was mixed with a magnetic resonance imaging (MRI) contrast agent. Ten women self-inserted, on separate visits, 3 or 5 mL of gel and underwent serial MRI scanning both before and after simulated intercourse. Gel spread was dependent upon time and volume. There was modest spread during the first hour and greater spread 6 h after insertion. Five milliliters of gel resulted in statistically significantly greater coverage immediately following insertion, within the first 30 min and at 6 h after insertion. Simulated intercourse greatly enhances gel spread. After simulated intercourse, the distribution of the gel at each volume was similar. Less leakage of gel was reported with the smaller volume.

Risk factors for preoperative periventricular leukomalacia in term neonates with hypoplastic left heart syndrome are patient related.

BACKGROUND: Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury, called periventricular leukomalacia (PVL), in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). METHODS: Neonates with HLHS or HLHS variants from 3 prospective magnetic resonance imaging studies (2003-2010) were selected for this cohort. Preoperative brain magnetic resonance imaging was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs vaginal), time of diagnosis (prenatal vs postnatal), HLHS subtypes, brain total maturation score, time to surgery, individual averaged daily preoperative blood gases, and complete blood cell count values was used to determine significant associations. RESULTS: A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks; 86% (49/57) had a prenatal diagnosis, with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, 71% (41/57). Preoperative PVL was identified in 19% (11/57). Male patients with AA (P = .004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL (P = .005). CONCLUSIONS: In neonates with HLHS, nonmodifiable patient-related factors, including male sex with AA (lack of antegrade blood flow) and lower total brain maturation score, placed neonates at the greatest risk for preoperative white matter injury.