Brain structure and function in the fourth decade of life after extremely low birth weight: An MRI and EEG study.

OBJECTIVE: To examine potential long-term effects of extremely low birth weight (ELBW; ≤ 1000 g) on adult brain structure, brain function, and cognitive-behavioral performance. METHODS: A subset of survivors from the prospectively-followed McMaster ELBW Cohort (n = 23, MBW = 816 g) and their peers born at normal birth weight (NBW; ≥ 2500 g; n = 14, MBW = 3361 g) provided T1-weighted magnetic resonance imaging (MRI) brain scans, resting electroencephalographic (EEG) recordings, and behavioral responses to a face-processing task in their early thirties. RESULTS: Visual discrimination accuracy for human faces, resting EEG alpha power, and long-distance alpha coherence were lower in ELBW survivors than NBW adults, and volumes of white matter hypointensities (WMH) were higher. Across groups, face-processing performance was correlated positively with posterior EEG spectral power and long-distance alpha and theta coherence, and negatively with WMH. The associations between face-processing scores and parietal alpha power and theta coherence were reduced after adjustment for WMH. CONCLUSIONS: Electrocortical activity, brain functional connectivity, and higher-order processing ability may be negatively affected by WMH burden, which is greater in adults born extremely preterm. SIGNIFICANCE: Decrements in electrocortical activity and behavioral performance in adult ELBW survivors may be partly explained by increased WMH volumes in this vulnerable population.

Dynamic changes in postnatal growth predict adolescent mental health problems in survivors of extremely low birth weight (ELBW).

Although individuals born at extremely low birth weight (ELBW; ≤1000 g) are known to be at greater risk for mental health problems than individuals born at normal birth weight (NBW; ≥2500 g), contributions of postnatal growth to these relations have not been fully explored. We compared individual differences in the Ponderal Index [(PI; weight(kg)/height(m3)] and head circumference (HC) in predicting internalizing and externalizing behaviors in childhood and adolescence in a cohort of ELBW survivors (N = 137) prospectively followed since birth. Baseline models indicated that infants who were born thinner or with smaller HC showed greater PI or HC growth in the first 3 years. Latent difference score (LDS) models showed that compensatory HC growth in the first year (ΔHC = 20.72 cm), controlled for birth HC, predicted ADHD behaviors in adolescence in those born with smaller HC. LDS models also indicated that the PI increased within the first year (ΔPI = 1.568) but decreased overall between birth and age 3 years (net ΔPI = -4.597). Modeling further showed that larger increases in the PI in the first year and smaller net decreases over 3 years predicted more internalizing behaviors in adolescence. These findings suggest early growth patterns prioritizing weight over height may have negative effects on later mental health in ELBW survivors, consistent with developmental programming theories.

Long-term stability of frontal electroencephalogram alpha power and asymmetry at rest in adults born at extremely low or normal birth weight: A 10-year longitudinal study.

The idea that individual differences in resting frontal EEG alpha activity have "trait-like" features that are associated with stress vulnerabilities presumes that these physiological patterns should be stable across time. We know, however, relatively little regarding the very long-term (i.e., ≥10 years) stability of resting frontal EEG alpha power and asymmetry in typically or atypically developing populations. Here, we examined the long-term stability of regional electroencephalogram (EEG) alpha (8-13 Hz) power and asymmetry at rest across a decade in the oldest known prospectively followed cohort of extremely low birth weight (ELBW; <1000 g) adult survivors and normal birth weight (NBW; >2500 g) controls. Regional EEG was collected at rest from the left and right frontal (F3, F4) and parietal (P3, P4) scalp sites using a stretchable cap during baseline eyes-open and eyes-closed conditions in young adulthood (ages 21-25 years) and again in adulthood (ages 30-35 years). We found moderate stability in regional EEG absolute alpha spectral power measures across all scalp sites for each birth weight group between the young adulthood and adulthood assessments. As well, we found the frontal alpha asymmetry measure was stable, albeit weakly, between the two assessment periods only in the NBW group. However, parietal alpha asymmetry was weak-to-moderately stable for each birth weight group across the 10-year period. Findings are discussed in terms of their implications for understanding associations between individual differences in frontal and parietal brain activity at rest and long-term stress vulnerability in typical and atypical development.

DNA methylation profiles in adults born at extremely low birth weight.

Effects of stresses associated with extremely preterm birth may be biologically "recorded" in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.

Cumulative risks predict epigenetic age in adult survivors of extremely low birth weight.

Long-term sequelae of extremely low birth weight (ELBW; ≤1000 g) may contribute to accelerated biological aging. This hypothesis was examined by analyzing a range of risk factors with a molecular age marker in adults born at ELBW or normal birth weight (NBW; ≥2500 g). DNAm age-the weighted average of DNA methylation at 353 cytosine-phosphate-guanine (CpG) sites from across the genome-was derived from a sample of 45 ELBW (Mage  = 32.35 years) and 47 NBW control (Mage  = 32.44 years) adults, using the Illumina 850k BeadChip Array. At two assessments undertaken 9 years apart (at 23 and 32 years), cumulative risks were summed from six domains with potential to affect physiological and psychological health: resting respiratory sinus arrhythmia, blood pressure, basal cortisol, grip strength, body mass index, and self-esteem. At age 32 years, cumulative risks were differentially associated with epigenetic age in ELBW survivors (interaction, p < 0.01). For each additional risk factor they possessed, ELBW survivors (B = 1.43) were biologically 2.16 years older than NBW adults (B = -0.73), by the fourth decade of life. Developmental change, epigenetic maintenance, and intervention targets are discussed.

Extremely Low Birth Weight and Accelerated Biological Aging.

BACKGROUND AND OBJECTIVES: Extremely low birth weight (ELBW) (<1000 g) survivors are exposed to elevated levels of physiologic stress during their lives and may be susceptible to accelerated aging. Using the oldest known longitudinally followed cohort of ELBW survivors, we compared biological aging in this group using an epigenetic clock to a sample of matched normal birth weight (NBW) (>2500 g) control participants. METHODS: Buccal cells were collected from 45 ELBW survivors and 49 NBW control participants at 30 to 35 years of age. Epigenetic age was calculated from the weighted average of DNA methylation at 353 cytosine-phosphate-guanine sequence within DNA sites, by using the Illumina Infinium Human Methylation EPIC 850k BeadChip array. RESULTS: Before and after statistically adjusting for neurosensory impairment and the presence of chronic health conditions, a significant sex by birth weight group interaction was observed in the 353-site epigenetic-clock assay (P = .03), whereby ELBW men had a significantly older epigenetic age than NBW men (4.6 years; P = .01). Women born at ELBW were not found to be epigenetically older than their NBW peers. CONCLUSIONS: The results of this study suggest that prenatal exposures may play an important role in aging, and that men born preterm may experience accelerated aging relative to their peers. We further highlight the need to monitor and promote the health of preterm survivors, with a particular focus on healthy aging across the life span.

Visual configural processing in adults born at extremely low birth weight.

Being born at extremely low birth weight (ELBW; ≤1,000 g) is associated with enduring visual impairments. We tested for long-term, higher order visual processing problems in the oldest known prospectively followed cohort of ELBW survivors. Configural processing (spacing among features of an object) was examined in 62 adults born at ELBW (Mage  = 31.9 years) and 82 adults born at normal birth weight (NBW; ≥2,500 g: Mage  = 32.5 years). Pairs of human faces, monkey faces, or houses were presented in a delayed match-to-sample task, where non-matching stimuli differed only in the spacing of their features. Discrimination accuracy for each stimulus type was compared between birth weight groups, adjusting for neurosensory impairment, visual acuity, binocular fusion ability, IQ, and sex. Both groups were better able to discriminate human faces than monkey faces (p < .001). However, the ELBW group discriminated between human faces (p < .001), between monkey faces (p < .001), and to some degree, between houses (p < .06), more poorly than NBW control participants, suggesting a general deficit in perceptual processing. Human face discrimination was related to performance IQ (PIQ) across groups, but especially among ELBW survivors. Coding (a PIQ subtest) also predicted human face discrimination in ELBW survivors, consistent with previously reported links between visuo-perceptive difficulties and regional slowing of cortical activity in individuals born preterm. Correlations with Coding suggested ELBW survivors may have used a feature-matching approach to processing human faces. Future studies could examine brain-based anatomical and functional evidence for altered face processing, as well as the social and memory consequences of face-processing deficits in ELBW survivors.

Exposure to antenatal corticosteroids and reduced respiratory sinus arrhythmia in adult survivors of extremely low birth weight.

Purpose/aim: Antenatal corticosteroid (ACS) therapy has dramatically increased survival rates among extremely low birth weight (ELBW) infants. However, the long-term effects of ACS on autonomic nervous system function have not been explored. Using the world's oldest longitudinally followed cohort of ELBW infants we compared respiratory sinus arrhythmia (RSA) among ELBW survivors whose mothers received ACS (ELBW-S), those who did not (ELBW-NS) and normal birth weight (NBW) controls in their 20 and 30 s. Methods: Resting electrocardiogram (ECG) was recorded from ELBW-S (n = 28), ELBW-NS (n = 36), and matched NBW controls (n = 79) at 22-26 and 29-36 years. Resting RSA was compared across groups via analyses of covariance (ANCOVA), adjusting for sex, medication use, postnatal steroid exposure and the presence of chronic health conditions. RSA was also compared across assessments for each group. Results: At 29-36 years, resting RSA in ELBW-S was significantly lower than in NBW controls. RSA in the ELBW-NS group was intermediate between ELBW-S and NBW groups. Although the ELBW-S group also showed nominally reduced RSA compared to NBW controls at the 22-26-year visit, this difference was not statistically significant. Conclusions: ELBW survivors exposed to ACS had lower RSA than NBW controls during their 30 s, suggestive of a decline in parasympathetic input to heart. ELBW survivors who received ACS may be particularly vulnerable to cardiovascular problems in later life.

Associations Between Colonic Motor Patterns and Autonomic Nervous System Activity Assessed by High-Resolution Manometry and Concurrent Heart Rate Variability.

Abnormal colonic motility may be associated with dysfunction of the autonomic nervous system (ANS). Our aim was to evaluate if associations between colonic motor patterns and autonomic neural activity could be demonstrated by assessing changes in heart rate variability (HRV) in healthy volunteers. A total of 145 colonic motor patterns were assessed in 11 healthy volunteers by High-Resolution Colonic Manometry (HRCM) using an 84-channel water-perfused catheter. Motor patterns were evoked by balloon distention, a meal and luminal bisacodyl. The electrocardiogram (ECG) and cardiac impedance were assessed during colonic manometry. Respiratory sinus arrhythmia (RSA) and root mean square of successive differences of beat-to-beat intervals (RMSSD) served as measures of parasympathetic reactivity while the Baevsky's Stress Index (SI) and the pre-ejection period (PEP) were used as measures of sympathetic reactivity. Taking all motor patterns into account, our data show that colonic motor patterns are accompanied by increased parasympathetic activity and decreased sympathetic activity that may occur without eliciting a significant change in heart rate. Motor Complexes (more than one motor pattern occurring in close proximity), High-Amplitude Propagating Pressure Waves followed by Simultaneous Pressure Waves (HAPW-SPWs) and HAPWs without SPWs are all associated with an increase in RSA and a decrease in SI. Hence RSA and SI may best reflect autonomic activity in the colon during these motor patterns as compared to RMSSD and PEP. SI and PEP do not measure identical sympathetic reactivity. The SPW, which is a very low amplitude pressure wave, did not significantly change the autonomic measures employed here. In conclusion, colonic motor patterns are associated with activity in the ANS which is reflected in autonomic measures of heart rate variability. These autonomic measures may serve as proxies for autonomic neural dysfunction in patients with colonic dysmotility.

Trajectories of psychopathology in extremely low birth weight survivors from early adolescence to adulthood: a 20-year longitudinal study.

BACKGROUND: Individuals born extremely preterm are exposed to significant perinatal stresses that are associated with an increased risk of psychopathology. However, a paucity of longitudinal studies has prevented the empirical examination of long-term, dynamic effects of perinatal adversity on mental health. Here, internalizing and externalizing problems from adolescence through adulthood were compared in individuals born at extremely low birth weight (ELBW; <1,000 g) and normal birth weight (NBW; >2,500 g). METHODS: Internalizing and externalizing data were collected over 20 years in three waves, during adolescence, young adulthood, and adulthood. Growth models were used to compare longitudinal trajectories in a geographically based sample of 151 ELBW survivors and 137 NBW control participants born between 1977 and 1982 matched for age, sex, and socioeconomic status at age 8. RESULTS: After adjusting for sex, socioeconomic and immigrant status, and family functioning, ELBW survivors failed to show the normative, age-related decline in internalizing problems over time relative to their NBW peers (ß = .21; p < .01). Both groups exhibited small declines in externalizing problems over the same period. Self-esteem (but not physical health, IQ, or maternal mood) partially mediated the association between ELBW status and internalizing problems. CONCLUSIONS: Extremely low birth weight survivors experienced a blunting of the expected improvement in depression and anxiety from adolescence to adulthood. These findings suggest that altered physiological regulatory systems supporting emotional and cognitive processing may contribute to the maintenance of internalizing problems in this population.

Respiratory sinus arrhythmia in the fourth decade of life depends on birth weight and the DRD4 gene: Implications for understanding the development of emotion regulation.

INTRODUCTION: The long allele of the DRD4 gene can confer different behavioral and emotional phenotypes depending upon environmental exposure, although the physiological changes underlying these phenotypes are not fully known. We sought to extend this work by assessing the interaction of the DRD4 gene and exposure to perinatal adversity (indexed by extremely low birth weight [ELBW]) on resting respiratory sinus arrhythmia (RSA), a neurophysiological measure of emotion regulation, in adulthood. METHODS: We examined the interaction between the DRD4 gene and perinatal adversity on RSA at age 30-35 in a longitudinal cohort of ELBW survivors (n = 49) and NBW controls (n = 63). Buccal DNA samples were genotyped for short and long carriers of the exon III DRD4 VNTR gene. Resting RSA was assessed by electrocardiogram. RESULTS: We report an interaction between birth weight status and DRD4 gene (F = 9.42, p = 0.003) in predicting RSA, such that DRD4 long carriers had the highest and lowest resting RSA depending on whether they were born NBW or ELBW, respectively. DRD4 short carriers were less sensitive to birth weight. Additionally, reduced RSA was correlated with a history of major depressive disorder, suggesting it was a reliable index of emotion dysregulation. DISCUSSION: These results suggest that the perinatal environment influences autonomic nervous system functioning in individuals with genotypes that confer additional sensitivity. Whether the long-term autonomic outcomes of this environmental sensitivity are beneficial or detrimental appears to depend on the quality of the early life environment, and may influence the development of emotion regulatory and psychiatric problems in adulthood.

Developmental programming of happiness.

Being born at an extremely low birth weight (ELBW; <1,000 grams) is presumed to reflect a suboptimal intrauterine environment and thus presents an opportunity for examining developmental programming hypotheses. Interfacing prenatal programming and differential susceptibility hypotheses, we tested whether individuals with ELBW in different childhood rearing environments showed different attention biases to positive and negative facial emotions in adulthood. Using the oldest known, prospectively followed cohort of ELBW survivors, we found that relative to normal birth weight controls (NBW; >2,500 grams), ELBW survivors displayed the highest and lowest attention bias to happy faces at age 30-35, depending on whether their total family income at age 8 was relatively low (environmental match) or high (environmental mismatch), respectively. This bias to happy faces was associated with a reduced likelihood of emotional problems. Findings suggest that differential susceptibility to positive emotions may be prenatally programmed, with effects lasting into adulthood. We discuss implications for integrating prenatal programming and differential susceptibility hypotheses, and the developmental origins of postnatal plasticity and resilience.

Mental health of extremely low birth weight survivors: A systematic review and meta-analysis.

Although individuals born at extremely low birth weight (ELBW; < 1,000 g) are the most vulnerable of all preterm survivors, their risk for mental health problems across the life span has not been systematically reviewed. The primary objective of this systematic review and meta-analysis was to ascertain whether the risk for mental health problems is greater for ELBW survivors than their normal birth weight (NBW) peers in childhood, adolescence, and adulthood. Forty-one studies assessing 2,712 ELBW children, adolescents, and adults and 11,127 NBW controls were reviewed. Group differences in mental health outcomes were assessed using random effects meta-analyses. The impacts of birthplace, birth era, and neurosensory impairment on mental health outcomes were assessed in subgroup analyses. Children born at ELBW were reported by parents and teachers to be at significantly greater risk than NBW controls for inattention and hyperactivity, internalizing, and externalizing symptoms. ELBW children were also at greater risk for conduct and oppositional disorders, autistic symptoms, and social difficulties. Risks for parent-reported inattention and hyperactivity, internalizing, and social problems were greater in adolescents born at ELBW. In contrast, ELBW teens self-reported lower inattention, hyperactivity, and oppositional behavior levels than their NBW peers. Depression, anxiety, and social difficulties were elevated in ELBW survivors in adulthood. Group differences were robust to region of birth, era of birth, and the presence of neurosensory impairments. The complex needs faced by children born at ELBW continue throughout development, with long-term consequences for psychological and social well-being. (PsycINFO Database Record

Extremely low birth weight babies grown up: Gene-environment interaction predicts internalizing problems in the third and fourth decades of life.

Extremely low birth weight (ELBW; <1000 g) infants have been exposed to stressful intrauterine and early postnatal environments. Even greater early adversity has been experienced by ELBW survivors who were also born small for gestational age (SGA; <10th percentile for GA) compared to those born appropriate for GA (AGA). ELBW survivors, particularly those born SGA, face increased risk for internalizing problems compared to normal BW (NBW; ≥2500 g) controls. Internalizing problems are related to allelic variations in the promoter region of the serotonin transporter linked polymorphic region gene (5-HTTLPR). We followed the oldest longitudinal cohort of ELBW survivors to adulthood. Participants provided buccal cells and reported on internalizing problems, using the Young Adult Self-Report when they were in their mid-20s (ELBW/SGA, N = 28; ELBW/AGA, N = 60; NBW, N = 81) and mid-30s (ELBW/SGA, N = 27; ELBW/AGA, N = 58; NBW, N = 76). The findings indicate that ELBW/SGAs carrying the 5-HTTLPR short allele reported increased internalizing problems, particularly depression, during the third and fourth decades of life. This is the first known report on gene-environment interactions predicting psychopathology among ELBW survivors. Our findings elucidate putative neurobiological pathways that underlie risk for psychopathology.

Characterizing Population EEG Dynamics throughout Adulthood.

For decades, electroencephalography (EEG) has been a useful tool for investigating the neural mechanisms underlying human psychological processes. However, the amount of time needed to gather EEG data means that most laboratory studies use relatively small sample sizes. Using the Muse, a portable and wireless four-channel EEG headband, we obtained EEG recordings from 6029 subjects 18-88 years in age while they completed a category exemplar task followed by a meditation exercise. Here, we report age-related changes in EEG power at a fine chronological scale for δ, θ, α, and ß bands, as well as peak α frequency and α asymmetry measures for both frontal and temporoparietal sites. We found that EEG power changed as a function of age, and that the age-related changes depended on sex and frequency band. We found an overall age-related shift in band power from lower to higher frequencies, especially for females. We also found a gradual, year-by-year slowing of the peak α frequency with increasing age. Finally, our analysis of α asymmetry revealed greater relative right frontal activity. Our results replicate several previous age- and sex-related findings and show how some previously observed changes during childhood extend throughout the lifespan. Unlike previous age-related EEG studies that were limited by sample size and restricted age ranges, our work highlights the advantage of using large, representative samples to address questions about developmental brain changes. We discuss our findings in terms of their relevance to attentional processes and brain-based models of emotional well-being and aging.

Regional electroencephalogram (EEG) alpha power and asymmetry in older adults: a study of short-term test-retest reliability.

Although regional alpha power and asymmetry measures have been widely used as indices of individual differences in emotional processing and affective style in younger populations, there have been relatively few studies that have examined these measures in older adults. Here, we examined the short-term test-retest reliability of resting regional alpha power (7.5-12.5 Hz) and asymmetry in a sample of 38 active, community-dwelling older adults (M age = 71.2, SD = 6.5 years). Resting electroencephalogram recordings were made before and after a perceptual computer task. Pearson and intra-class correlations indicated acceptable test-retest reliability for alpha power and asymmetry measures in all regions. Interestingly, alpha asymmetry appeared to be less affected by the task than was alpha power. Findings suggest that alpha asymmetry may reflect more enduring, "trait-like" characteristics, while alpha power may reflect more "state-like" processes in older adults.

Cardiovascular Responses to Psychosocial Stress Reflect Motivation State in Adults Born at Extremely Low Birth Weight.

Background. Adults born extremely preterm appear to have more difficulty managing the stresses of early adulthood than their term-born peers. Objective. To examine the effects of being born at extremely low birth weight (ELBW; birth weight < 1000 g) versus at full term on cardiovascular responses to stress. Method. Cardiovascular responses were elicited during administration of a widely used laboratory stressor, the Trier Social Stress Test (TSST). Results. Term-born adults exhibited a larger decrease in total peripheral resistance and larger increase in cardiac output for TSST performance, reflecting greater resilience, than did ELBW adults. Furthermore, in ELBW participants but not controls, cardiovascular responses were correlated with anxiety, suggesting that their responses reflected feelings of stress. Conclusions. Skills-training and practice with relevant stressors may be necessary to increase the personal resources of ELBW participants for managing stress as they transition to adulthood.

Autonomic Functioning in Young Adults Born at Extremely Low Birth Weight.

Autonomic functioning is altered in infants born at extremely low birth weight (ELBW; <1000 g), but we know little about how such alterations manifest in adulthood. We examined associations between birth weight and resting heart rate (R-R interval), high-frequency (HF) and low-frequency (LF) heart rate variability, and systolic (SBP) and diastolic (DBP) blood pressure, in 60 participants (ages 22-26) born at ELBW and free of major neurosensory impairment, and 79 controls born at normal birth weight (NBW; >2500 g). HF in the smallest-born ELBW participants was significantly lower than in NBW controls. In both groups, greater birth weight was associated with higher HF. Among ELBW survivors, lower birth weight predicted faster heart rate and higher DBP, but neither heart rate nor DBP appeared to be well-coordinated with baroreflex activity (LF), the principal mechanism for short-term blood pressure regulation. Adult autonomic regulation may be significantly altered in those born extremely preterm.

Reduced respiratory sinus arrhythmia in adults born at extremely low birth weight: evidence of premature parasympathetic decline?

Individuals born at extremely low birth weight (ELBW; <1000 g) are exposed to early adversity in multiple forms. Given that substantial development of the autonomic nervous system (ANS) occurs during the third trimester of gestation, ANS functioning may be altered in adults who were born before reaching 28 weeks of gestational age. The aims of the study were to: (1) determine whether two indices of ANS functioning [resting heart period (HP) and respiratory sinus arrhythmia (RSA)], differed between adult ELBW survivors and normal birth weight (NBW) controls, and (2) ascertain whether ANS functioning was differentially vulnerable to age-related decline in the ELBW participants. Resting HP and RSA (reflecting cardiac efficiency and responsive cardiac control, respectively) were assessed in 30 non-impaired ELBW survivors and 47 NBW controls at ages 22-26 and again at 30-35 years. At each assessment, resting RSA was significantly lower in the ELBW group than in the NBW comparison group. In addition, individual differences in RSA within the ELBW group were poorly preserved over time. These findings are suggestive of a premature decline in parasympathetic functioning in some adult ELBW survivors.