Impacts of early deprivation on behavioral and neural measures of executive function in early adolescence.

Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including executive function (EF). Changes in brain development are thought to contribute to these persistent EF challenges, but little research has used fMRI to investigate EF-related brain activity in children with a history of early deprivation. This study examined behavioral and neural data from a response conflict task in 12-14-year-olds who spent varying lengths of time in institutional care prior to adoption (N = 84; age at adoption - mean: 15.85 months, median: 12 months, range: 4-60 months). In initial analyses, earlier- and later-adopted (EA, LA) youth were compared to a group of children raised in their biological families (non-adopted, NA). NA youth performed significantly more accurately than LA youth, with EA youth falling in between. Imaging data suggested that previously institutionalized (PI) youth activated additional frontoparietal regions, including dorsolateral prefrontal cortex, as compared to NA youth. In addition, EA youth uniquely activated medial prefrontal regions, and LA uniquely activated parietal regions during this task. A separate analysis in a larger group of PI youth examined whether behavioral or brain measures of EF varied with the duration of deprivation experienced. Duration of deprivation was negatively associated with activation of default mode network (DMN) regions. Overall, results suggest that there are lasting effects of deprivation on EF, but that those who are removed from institutional care earlier may be able to recruit additional neural resources as a compensatory mechanism.

Age-related differences in resting-state functional connectivity from childhood to adolescence.

The human brain is active at rest, and spontaneous fluctuations in functional MRI BOLD signals reveal an intrinsic functional architecture. During childhood and adolescence, functional networks undergo varying patterns of maturation, and measures of functional connectivity within and between networks differ as a function of age. However, many aspects of these developmental patterns (e.g. trajectory shape and directionality) remain unresolved. In the present study, we characterised age-related differences in within- and between-network resting-state functional connectivity (rsFC) and integration (i.e. participation coefficient, PC) in a large cross-sectional sample of children and adolescents (n = 628) aged 8-21 years from the Lifespan Human Connectome Project in Development. We found evidence for both linear and non-linear differences in cortical, subcortical, and cerebellar rsFC, as well as integration, that varied by age. Additionally, we found that sex moderated the relationship between age and putamen integration where males displayed significant age-related increases in putamen PC compared with females. Taken together, these results provide evidence for complex, non-linear differences in some brain systems during development.

Graded Variation in T1w/T2w Ratio during Adolescence: Measurement, Caveats, and Implications for Development of Cortical Myelin.

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8-21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas, T1w/T2w ratio measures start at high levels at early ages, increase at a fast pace, and decelerate at later ages (18-21). In intermediate multimodal areas along the S-A axis, T1w/T2w starts at intermediate levels and increases linearly at an intermediate pace. In transmodal/paralimbic association areas, T1w/T2w starts at low levels and increases linearly at the slowest pace. These data provide evidence for graded variation of the T1w/T2w ratio along the S-A axis that may reflect cortical myelination changes during adolescence underlying the development of complex information processing and psychological functioning. We discuss the implications of these results as well as caveats in interpreting magnetic resonance imaging (MRI)-based estimates of myelination.SIGNIFICANCE STATEMENT Myelin is a lipid membrane that is essential to healthy brain function. Myelin wraps axons to increase neural signaling speed, enabling complex neuronal functioning underlying learning and cognition. Here, we characterize the developmental timing of myelination across the cerebral cortex during adolescence using a noninvasive proxy measure, T1w/T2w mapping. Our results provide new evidence demonstrating graded variation across the cortex in the timing of T1w/T2w changes during adolescence, with rapid T1w/T2w increases in lower-order sensory areas and gradual T1w/T2w increases in higher-order association areas. This spatial pattern of microstructural brain development closely parallels the sensorimotor-to-association axis of cortical organization and plasticity during ontogeny.

Testing the consequences of alcohol, cannabis, and nicotine use on hippocampal volume: a quasi-experimental cotwin control analysis of young adult twins.

BACKGROUND: Alcohol, cannabis, and nicotine use are highly comorbid and alarmingly prevalent in young adults. The hippocampus may be particularly sensitive to substance exposure. This remains largely untested in humans and familial risk may confound exposure effects. We extend prior work on alcohol and hippocampal volume in women by testing common and unique substance use effects and the potential moderating role of sex on hippocampal volume during emerging adulthood. A quasi-experimental cotwin control (CTC) design was used to separate familial risk from exposure consequences. METHODS: In a population-based sample of 435 24-year-old same-sex twins (58% women), dimensional measures (e.g. frequency, amount) of alcohol, cannabis, and nicotine use across emerging adulthood were assessed. Hippocampal volume was assessed using MRI. RESULTS: Greater substance use was significantly associated with lower hippocampal volume for women but not men. The same pattern was observed for alcohol, cannabis, and nicotine. CTC analyses provided evidence that hippocampal effects likely reflected familial risk and the consequence of substance use in general and alcohol and nicotine in particular; cannabis effects were in the expected direction but not significant. Within-pair mediation analyses suggested that the effect of alcohol use on the hippocampus may reflect, in part, comorbid nicotine use. CONCLUSIONS: The observed hippocampal volume deviations in women likely reflected substance-related premorbid familial risk and the consequences of smoking and, to a lesser degree, drinking. Findings contribute to a growing body of work suggesting heightened risk among women toward experiencing deleterious effects of substance exposure on the still-developing young adult hippocampus.

Impact of childhood maltreatment and resilience on behavioral and neural patterns of inhibitory control during emotional distraction.

Exposure to childhood maltreatment (CM) may disrupt typical development of neural systems underlying impulse control and emotion regulation. Yet resilient outcomes are observed in some individuals exposed to CM. Individual differences in adult functioning may result from variation in inhibitory control in the context of emotional distractions, underpinned by cognitive-affective brain circuits. Thirty-eight healthy adults with a history of substantiated CM and 34 nonmaltreated adults from the same longitudinal sample performed a Go/No-Go task in which task-relevant stimuli (letters) were presented at the center of task-irrelevant, negative, or neutral images, while undergoing functional magnetic resonance imaging. The comparison group, but not the maltreated group, made increased inhibitory control errors in the context of negative, but not neutral, distractor images. In addition, the comparison group had greater right inferior frontal gyrus and bilateral frontal pole activation during inhibitory control blocks with negative compared to neutral background images relative to the CM group. Across the full sample, greater adaptive functioning in everyday contexts was associated with superior inhibitory control and greater right frontal pole activation. Results suggest that resilience following early adversity is associated with enhanced attention and behavioral regulation in the context of task-irrelevant negative emotional stimuli in a laboratory setting.

Differential brain activity as a function of social evaluative stress in early adolescence: Brain function and salivary cortisol.

Understanding individual differences in neural responses to stressful environments is an important avenue of research throughout development. These differences may be especially critical during adolescence, which is characterized by opportunities for healthy development and increased susceptibility to the development of psychopathology. While the neural correlates of the psychosocial stress response have been investigated in adults, these links have not been explored during development. Using a new task, the Minnesota Imaging Stress Test in Children (MISTiC), differences in activation are found in fusiform gyrus, superior frontal gyrus, insula, and anterior cingulate cortex when comparing a stressful math task to a nonstressful math task. The MISTiC task successfully elicits cortisol responses in a similar proportion of adolescents as in behavioral studies while collecting brain imaging data. Cortisol responders and nonresponders did not differ in their perceived stress level or behavioral performance during the task despite differences in neuroendocrine function. Future research will be able to leverage the MISTiC task for many purposes, including probing associations between individual differences in stress responses with environmental conditions, personality differences, and the development of psychopathology.

Trait neuroticism and emotion neurocircuitry: Functional magnetic resonance imaging evidence for a failure in emotion regulation.

Though theory suggests that individual differences in neuroticism (a tendency to experience negative emotions) would be associated with altered functioning of the amygdala (which has been linked with emotionality and emotion dysregulation in childhood, adolescence, and adulthood), results of functional neuroimaging studies have been contradictory and inconclusive. We aimed to clarify the relationship between neuroticism and three hypothesized neural markers derived from functional magnetic resonance imaging during negative emotion face processing: amygdala activation, amygdala habituation, and amygdala-prefrontal connectivity, each of which plays an important role in the experience and regulation of emotions. We used general linear models to examine the relationship between trait neuroticism and the hypothesized neural markers in a large sample of over 500 young adults. Although neuroticism was not significantly associated with magnitude of amygdala activation or amygdala habituation, it was associated with amygdala-ventromedial prefrontal cortex connectivity, which has been implicated in emotion regulation. Results suggest that trait neuroticism may represent a failure in top-down control and regulation of emotional reactions, rather than overactive emotion generation processes, per se. These findings suggest that neuroticism, which has been associated with increased rates of transdiagnostic psychopathology, may represent a failure in the inhibitory neurocircuitry associated with emotion regulation.

The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5-21 year olds.

Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5-21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9-17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset.

Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+ healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

Problematic alcohol use and hippocampal volume in a female sample: disentangling cause from consequence using a co-twin control study design.

BACKGROUND: Although there is extensive evidence that problematic alcohol use is associated with smaller hippocampal volume, the typical cross-sectional study design cannot determine whether hippocampal deviations reflect pre-existing liability toward problematic alcohol use or instead reflect an alcohol exposure-related effect. We used the co-twin control study design, which capitalizes upon differences within a twin pair in levels of drinking, to differentiate pre-existing liability from an effect of alcohol exposure. METHODS: The sample included 100 female twins, prospectively assessed from ages 11 to 24. Problematic alcohol use was assessed dimensionally and included indicators of quantity, frequency, and density of alcohol use and intoxication. Hippocampal volume was assessed using magnetic resonance imaging. RESULTS: Problematic alcohol use (proximal and cumulative) was associated with significantly smaller left and right hippocampal volume. Follow-up co-twin control analyses that partitioned individual-level alcohol effects into pre-existing, familial liability and non-shared alcohol exposure-related effects indicated that this association reflected alcohol exposure. Greater alcohol using twins had smaller hippocampal volume relative to lesser alcohol using co-twins, beyond effects of their shared genetic and environmental liability toward problematic alcohol use. Results held accounting for recent alcohol use, other substance use, externalizing and internalizing psychopathology, personality traits, trauma exposure, and menstrual phase. CONCLUSIONS: The association between problematic alcohol use and smaller hippocampal volume likely reflects an alcohol exposure-related effect. Differentiating pre-existing brain deviations that confer risk for problematic alcohol use from those that reflect effects of alcohol on the brain will inform etiological models of addiction and further prevention and intervention efforts.

To trust or not to trust: social decision-making in post-institutionalized, internationally adopted youth.

Chronic parental maltreatment has been associated with lower levels of interpersonal trust, and depriving environments have been shown to predict short-sighted, risk-averse decision-making. The present study examined whether a circumscribed period of adverse care occurring only early in life was associated with biases in trust behavior. Fifty-three post-institutionalized (PI) youth, adopted internationally on average by 1 year of age, and 33 never-institutionalized, non-adopted youth (Mage  = 12.9 years) played a trust game. Participants decided whether or not to share coins with a different anonymous peer in each trial with the potential to receive a larger number of coins in return. Trials were presented in blocks that varied in the degree to which the peers behaved in a trustworthy (reciprocal) or untrustworthy (non-reciprocal) manner. A comparison condition consisted of a computerized lottery with the same choices and probabilistic risk as the peer trials. Non-adopted comparison youth showed a tendency to share more with peers than to invest in the lottery and tended to maintain their level of sharing across trials despite experiencing trials in which peers failed to reciprocate. In contrast, PI children, particularly those who were adopted over 1 year of age, shared less with peers than they invested in the lottery and quickly adapted their sharing behavior to peers' responses. These results suggest that PI youth were more mistrusting, more sensitive to both defection and reciprocation, and potentially more accurate in their trusting decisions than comparison youth. Results support the presence of a sensitive period for the development of trust in others, whereby conditions early in life may set long-term biases in decision-making.

Hot executive function following moderate-to-late preterm birth: altered delay discounting at 4 years of age.

Interest in monitoring long-term neurodevelopmental outcomes of children born moderate-to-late preterm (32-36 weeks gestation) is increasing. Moderate-to-late preterm birth has a negative impact on academic achievement, which may relate to differential development of executive function (EF). Prior studies reporting deficits in EF in preterm children have almost exclusively assessed EF in affectively neutral contexts in high-risk preterm children (< 32 weeks gestation). Disrupted function in motivational or emotionally charged contexts (hot EF) following preterm birth remains uninvestigated, despite evidence that preterm children show differential development of neural circuitry subserving hot EF, including reduced orbitofrontal cortex volume. The present study is the first to examine whether low-risk, healthy children born moderate-to-late preterm exhibit impairments in the development of hot EF. Preterm children at age 4.5 years were less likely to choose larger, delayed rewards across all levels of reward magnitude on a delay discounting task using tangible rewards, but performed more similarly to their full-term peers on a delay aversion task involving abstract rewards and on measures of cool EF. The relationship between gestational age at birth and selection of delayed rewards extended across the entire gestational age range of the sample (32-42 weeks), and remained significant after controlling for intelligence and processing speed. Results imply that there is not a finite cut-off point at which children are spared from potential long-term neurodevelopmental effects of PT birth. Further investigation of reward processing and hot EF in individuals with a history of PT birth is warranted given the susceptibility of prefrontal cortex development to early environmental variations.

Duration of early adversity and structural brain development in post-institutionalized adolescents.

For children reared in institutions for orphaned or abandoned children, multiple aspects of the early environment deviate from species-typical experiences, which may lead to alterations in neurobehavioral development. Although the effects of early deprivation and early life stress have been studied extensively in animal models, less is known about implications for human brain development. This structural neuroimaging study examined the long-term neural correlates of early adverse rearing environments in a large sample of 12-14 year old children (N = 110) who were internationally adopted from institutional care as young children (median age at adoption = 12 months) relative to a same age, comparison group reared with their biological families in the United States. History of institutional rearing was associated with broad changes in cortical volume even after controlling for variability in head size. Results suggested that prefrontal cortex was especially susceptible to early adversity, with significant reductions in volume (driven primarily by differences in surface area rather than cortical thickness) in post-institutionalized youth. Hippocampal volumes showed an association with duration of institutional care, with later-adopted children showing the smallest volumes relative to non-adopted controls. Larger amygdala volumes were not detected in this sample of post-institutionalized children. These data suggest that this temporally discrete period of early deprivation is associated with persisting alterations in brain morphology even years after exposure. Furthermore, these alterations are not completely ameliorated by subsequent environmental enrichment by early adolescence.

Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity.

Childhood maltreatment is a serious individual, familial, and societal threat that compromises healthy development and is associated with lasting alterations to emotion perception, processing, and regulation (Cicchetti & Curtis, 2005; Pollak, Cicchetti, Hornung, & Reed, 2000; Pollak & Tolley-Schell, 2003). Individuals with a history of maltreatment show altered structural and functional brain development in both frontal and limbic structures (Hart & Rubia, 2012). In particular, previous research has identified hyperactive amygdala responsivity associated with childhood maltreatment (e.g., Dannlowski et al., 2012). However, less is known about the impact of maltreatment on the relationship between the amygdala and other brain regions. The present study employed an emotion processing functional magnetic resonance imaging task to examine task-based activation and functional connectivity in adults who experienced maltreatment as children. The sample included adults with a history of substantiated childhood maltreatment (n = 33) and comparison adults (n = 38) who were well matched on demographic variables, all of whom have been studied prospectively since childhood. The maltreated group exhibited greater activation than comparison participants in the prefrontal cortex and basal ganglia. In addition, maltreated adults showed increased amygdala connectivity with the hippocampus and prefrontal cortex. The results suggest that the intense early stress of childhood maltreatment is associated with lasting alterations to frontolimbic circuitry.

Adolescent drinking and motivated decision-making: a cotwin-control investigation with monozygotic twins.

The present study used a monozygotic (MZ) cotwin-control (CTC) design to investigate associations between alcohol use and performance on the Iowa gambling task (IGT) in a sample of 96 adolescents (half female). The MZ CTC design is well suited to shed light on whether poor decision-making, as reflected on IGT performance, predisposes individuals to abuse substances or is a consequence of use. Participants completed structural MRI scans as well, from which we derived gray matter volumes for cortical and subcortical regions involved in IGT performance and reduced in adolescents with problematic alcohol use. Drinking was associated with poorer task performance and with reduced volume of the left lateral orbital-frontal cortex. CTC analyses indicated that the former was due to differences between members of twin pairs in alcohol use (suggesting a causal effect of alcohol), whereas the latter was due to factors shared by twins (consistent with a pre-existing vulnerability for use). Although these preliminary findings warrant replication, they suggest that normative levels of alcohol use may diminish the quality of adolescent decision-making and thus have potentially important public health implications.

Contributions of COMT Val¹58 Met to cognitive stability and flexibility in infancy.

Adaptive behavior requires focusing on relevant tasks while remaining sensitive to novel information. In adult studies of cognitive control, cognitive stability involves maintaining robust cognitive representations while cognitive flexibility involves updating of representations in response to novel information. Previous adult research has shown that the Met allele of the COMT Val(158) Met gene is associated with enhanced cognitive stability whereas the Val allele is associated with enhanced cognitive flexibility. Here we propose that the stability/flexibility framework can also be applied to infant research, with stability mapping onto early indices of behavioral regulation and flexibility mapping onto indices of behavioral reactivity. From this perspective, the present study examined whether COMT genotype was related to 7-month-old infants' reactivity to novel stimuli and behavioral regulation. Cognitive stability and flexibility were assessed using (1) a motor approach task, (2) a habituation task, and (3) a parental-report measure of temperament. Val carriers were faster to reach for novel toys during the motor approach task and received higher scores on the temperament measure of approach to novelty. Met carriers showed enhanced dishabituation to the novel stimulus during the habituation task and received higher scores on the temperament measures of sustained attention and behavioral regulation. Overall, these results are consistent with adult research suggesting that the Met and Val alleles are associated with increased cognitive stability and flexibility, respectively, and thus suggest that COMT genotype may similarly affect cognitive function in infancy.

Multilevel assessment of the neurobiological threat system in depressed adolescents: interplay between the limbic system and hypothalamic-pituitary-adrenal axis.

Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12-19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

The impact of late preterm birth on executive function at preschool age.

OBJECTIVE: Very preterm birth (< 32 weeks' gestation) affects cognitive development. The impact of late preterm birth (34 to 36 weeks' gestation) on cognition, specifically executive function, is not fully characterized. The aim of this study was to assess whether late preterm children demonstrate impaired executive function compared with full-term children (38 to 42 weeks' gestation). STUDY DESIGN: This was a prospective cohort study of 4-year-old children. Preterm (n = 39) and full-term children (n = 44) completed a battery of executive function tasks and the Peabody Picture Vocabulary Test-4. Parents completed the Behavior Rating Inventory of Executive Function-Preschool version. RESULTS: Preterm children performed worse on the verbal inhibitory control (p = 0.02) and short-term verbal memory (p = 0.01) tasks. Gestational age predicted performance on the verbal inhibitory control (p = 0.02) and short-term verbal memory (p = 0.04) tasks. There was no group difference in nonverbal inhibitory control (p = 0.45) or spatial memory (p = 0.60). Parents of preterm and full-term children rated their children's behavior similarly (p = 0.79). CONCLUSION: Late preterm children demonstrated compromised verbal inhibitory control and short-term verbal memory compared with full-term peers. Late preterm children may not be spared from altered brain development. Further research is indicated to determine whether to screen late preterm children for executive function deficits.

Inhibitory control during emotional distraction across adolescence and early adulthood.

This study investigated the changing relation between emotion and inhibitory control during adolescence. One hundred participants between 11 and 25 years of age performed a go-nogo task in which task-relevant stimuli (letters) were presented at the center of large task-irrelevant images depicting negative, positive, or neutral scenes selected from the International Affective Picture System. Longer reaction times for negative trials were found across all age groups, suggesting that negative but not positive emotional images captured attention across this age range. However, age differences in accuracy on inhibitory trials suggest that response inhibition is more readily disrupted by negative emotional distraction in early adolescence relative to late childhood, late adolescence, or early adulthood.

Reduced Hippocampal Volumes in Children with History of Hypoxic Ischemic Encephalopathy after Therapeutic Hypothermia.

Hypoxic ischemic encephalopathy (HIE) remains a significant cause of disability despite treatment with therapeutic hypothermia (TH). Many survive with more subtle deficits that affect daily functioning and school performance. We have previously shown an early indication of hippocampal changes in infants with HIE despite TH. The aim of this study was to evaluate the hippocampal volume via MRI and memory function at 5 years of age. A cohort of children followed from birth returned for a 5-year follow-up (n = 10 HIE treated with TH, n = 8 healthy controls). The children underwent brain MRI and neurodevelopmental testing to assess their brain volume, general development, and memory function. Children with HIE had smaller hippocampal volumes than the controls despite no differences in the total brain volume (p = 0.02). Children with HIE generally scored within the average range on developmental testing. Though there was no difference in the memory scores between these groups, there was a positive within-group correlation between the hippocampal volume and memory scores in children with HIE (sentence recall r = 0.66, p = 0.038). There was no relationship between newborn memory function and 5-year hippocampal size. Children with HIE treated with TH experienced significant and lasting changes to the hippocampus despite improvements in survival and severe disability. Future studies should target diminishing injury to the hippocampus to improve overall outcomes.