Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Placental genomic risk scores and early neurodevelopmental outcomes.

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.

A regional brain volume-based age prediction model for neonates and the derived brain maturation index.

OBJECTIVE: To develop a postmenstrual age (PMA) prediction model based on segmentation volume and to evaluate the brain maturation index using the proposed model. METHODS: Neonatal brain MRIs without clinical illness or structural abnormalities were collected from four datasets from the Developing Human Connectome Project, the Catholic University of Korea, Hammersmith Hospital (HS), and Dankook University Hospital (DU). T1- and T2-weighted images were used to train a brain segmentation model. Another model to predict the PMA of neonates based on segmentation data was developed. Accuracy was assessed using mean absolute error (MAE), root mean square error (RMSE), and mean error (ME). The brain maturation index was calculated as the difference between the PMA predicted by the model and the true PMA, and its correlation with postnatal age was analyzed. RESULTS: A total of 247 neonates (mean gestation age 37 ± 4 weeks; range 24-42 weeks) were included. Thirty-one features were extracted from each neonate and the three most contributing features for PMA prediction were the right lateral ventricle, left caudate, and corpus callosum. The predicted and true PMA were positively correlated (coefficient = 0.88, p < .001). MAE, RMSE, and ME of the external dataset of HS and DU were 1.57 and 1.33, 1.79 and 1.37, and 0.37 and 0.06 weeks, respectively. The brain maturation index negatively correlated with postnatal age (coefficient = - 0.24, p < .001). CONCLUSION: A model that calculates the regional brain volume can predict the PMA of neonates, which can then be utilized to show the brain maturation degree. CLINICAL RELEVANCE STATEMENT: A brain maturity index based on regional volume of neonate's brain can be used to measure brain maturation degree, which can help identify the status of early brain development. KEY POINTS: • Neonatal brain MRI segmentation model could be used to assess neonatal brain maturation status. • A postmenstrual age (PMA) prediction model was developed based on a neonatal brain MRI segmentation model. • The brain maturation index, derived from the PMA prediction model, enabled the estimation of the neonatal brain maturation status.

Influence of gonadal steroids on cortical surface area in infancy.

Sex differences in the human brain emerge as early as mid-gestation and have been linked to sex hormones, particularly testosterone. Here, we analyzed the influence of markers of early sex hormone exposure (polygenic risk score (PRS) for testosterone, salivary testosterone, number of CAG repeats, digit ratios, and PRS for estradiol) on the growth pattern of cortical surface area in a longitudinal cohort of 722 infants. We found PRS for testosterone and right-hand digit ratio to be significantly associated with surface area, but only in females. PRS for testosterone at the most stringent P value threshold was positively associated with surface area development over time. Higher right-hand digit ratio, which is indicative of low prenatal testosterone levels, was negatively related to surface area in females. The current work suggests that variation in testosterone levels during both the prenatal and postnatal period may contribute to cortical surface area development in female infants.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Proteobacteria abundance during nursing predicts physical growth and brain volume at one year of age in young rhesus monkeys.

Over the last decade, multiple studies have highlighted the essential role of gut microbiota in normal infant development. However, the sensitive periods during which gut bacteria are established and become associated with physical growth and maturation of the brain are still poorly defined. This study tracked the assembly of the intestinal microbiota during the initial nursing period, and changes in community structure after transitioning to solid food in infant rhesus monkeys (Macaca mulatta). Anthropometric measures and rectal swabs were obtained at 2-month intervals across the first year of life and bacterial taxa identified by 16S rRNA gene sequencing. At 12 months of age, total brain and cortical regions volumes were quantified through structural magnetic resonance imaging. The bacterial community structure was dynamic and characterized by discrete maturational phases, reflecting an early influence of breast milk and the later transition to solid foods. Commensal microbial taxa varied with diet similar to findings in other animals and human infants; however, monkeys differ in the relative abundances of Lactobacilli and Bifidobacteria, two taxa predominant in breastfed human infants. Higher abundances of taxa in the phylum Proteobacteria during nursing were predictive of slower growth trajectories and smaller brain volumes at one year of age. Our findings define discrete phases of microbial succession in infant monkeys and suggest there may be a critical period during nursing when endogenous differences in certain taxa can shift the community structure and influence the pace of physical growth and the maturational trajectory of the brain.

White Matter Development from Birth to 6 Years of Age: A Longitudinal Study.

Human white matter development in the first years of life is rapid, setting the foundation for later development. Microstructural properties of white matter are linked to many behavioral and psychiatric outcomes; however, little is known about when in development individual differences in white matter microstructure are established. The aim of the current study is to characterize longitudinal development of white matter microstructure from birth through 6 years to determine when in development individual differences are established. Two hundred and twenty-four children underwent diffusion-weighted imaging after birth and at 1, 2, 4, and 6 years. Diffusion tensor imaging data were computed for 20 white matter tracts (9 left-right corresponding tracts and 2 commissural tracts), with tract-based measures of fractional anisotropy and axial and radial diffusivity. Microstructural maturation between birth and 1 year are much greater than subsequent changes. Further, by 1 year, individual differences in tract average values are consistently predictive of the respective 6-year values, explaining, on average, 40% of the variance in 6-year microstructure. Results provide further evidence of the importance of the first year of life with regard to white matter development, with potential implications for informing early intervention efforts that target specific sensitive periods.

Exposure to prenatal maternal distress and infant white matter neurodevelopment.

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother-infant dyads. Prenatal distress was assessed at 17 and 29 weeks' gestational age (GA). Infant structural data were collected via diffusion tensor imaging at 42-45 weeks' postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks' GA was associated with increased fractional anisotropy (b = .283, t(64) = 2.319, p = .024) and with increased axial diffusivity (b = .254, t(64) = 2.067, p = .043) within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks' GA, nor earlier in gestation.

The UNC/UMN Baby Connectome Project (BCP): An overview of the study design and protocol development.

The human brain undergoes extensive and dynamic growth during the first years of life. The UNC/UMN Baby Connectome Project (BCP), one of the Lifespan Connectome Projects funded by NIH, is an ongoing study jointly conducted by investigators at the University of North Carolina at Chapel Hill and the University of Minnesota. The primary objective of the BCP is to characterize brain and behavioral development in typically developing infants across the first 5 years of life. The ultimate goals are to chart emerging patterns of structural and functional connectivity during this period, map brain-behavior associations, and establish a foundation from which to further explore trajectories of health and disease. To accomplish these goals, we are combining state of the art MRI acquisition and analysis techniques, including high-resolution structural MRI (T1-and T2-weighted images), diffusion imaging (dMRI), and resting state functional connectivity MRI (rfMRI). While the overall design of the BCP largely is built on the protocol developed by the Lifespan Human Connectome Project (HCP), given the unique age range of the BCP cohort, additional optimization of imaging parameters and consideration of an age appropriate battery of behavioral assessments were needed. Here we provide the overall study protocol, including approaches for subject recruitment, strategies for imaging typically developing children 0-5 years of age without sedation, imaging protocol and optimization, a description of the battery of behavioral assessments, and QA/QC procedures. Combining HCP inspired neuroimaging data with well-established behavioral assessments during this time period will yield an invaluable resource for the scientific community.

Walking, Gross Motor Development, and Brain Functional Connectivity in Infants and Toddlers.

Infant gross motor development is vital to adaptive function and predictive of both cognitive outcomes and neurodevelopmental disorders. However, little is known about neural systems underlying the emergence of walking and general gross motor abilities. Using resting state fcMRI, we identified functional brain networks associated with walking and gross motor scores in a mixed cross-sectional and longitudinal cohort of infants at high and low risk for autism spectrum disorder, who represent a dimensionally distributed range of motor function. At age 12 months, functional connectivity of motor and default mode networks was correlated with walking, whereas dorsal attention and posterior cingulo-opercular networks were implicated at age 24 months. Analyses of general gross motor function also revealed involvement of motor and default mode networks at 12 and 24 months, with dorsal attention, cingulo-opercular, frontoparietal, and subcortical networks additionally implicated at 24 months. These findings suggest that changes in network-level brain-behavior relationships underlie the emergence and consolidation of walking and gross motor abilities in the toddler period. This initial description of network substrates of early gross motor development may inform hypotheses regarding neural systems contributing to typical and atypical motor outcomes, as well as neurodevelopmental disorders associated with motor dysfunction.

A deep neural network to assess spontaneous pain from mouse facial expressions.

Grimace scales quantify characteristic facial expressions associated with spontaneous pain in rodents and other mammals. However, these scales have not been widely adopted largely because of the time and effort required for highly trained humans to manually score the images. Convoluted neural networks were recently developed that distinguish individual humans and objects in images. Here, we trained one of these networks, the InceptionV3 convolutional neural net, with a large set of human-scored mouse images. Output consists of a binary pain/no-pain assessment and a confidence score. Our automated Mouse Grimace Scale integrates these two outputs and is highly accurate (94%) at assessing the presence of pain in mice across different experimental assays. In addition, we used a novel set of "pain" and "no pain" images to show that automated Mouse Grimace Scale scores are highly correlated with human scores (Pearson's r = 0.75). Moreover, the automated Mouse Grimace Scale classified a greater proportion of images as "pain" following laparotomy surgery when compared to animals receiving a sham surgery or a post-surgical analgesic. Together, these findings suggest that the automated Mouse Grimace Scale can eliminate the need for tedious human scoring of images and provide an objective and rapid way to quantify spontaneous pain and pain relief in mice.

Joint Attention and Brain Functional Connectivity in Infants and Toddlers.

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

Development of cortical shape in the human brain from 6 to 24months of age via a novel measure of shape complexity.

The quantification of local surface morphology in the human cortex is important for examining population differences as well as developmental changes in neurodegenerative or neurodevelopmental disorders. We propose a novel cortical shape measure, referred to as the 'shape complexity index' (SCI), that represents localized shape complexity as the difference between the observed distributions of local surface topology, as quantified by the shape index (SI) measure, to its best fitting simple topological model within a given neighborhood. We apply a relatively small, adaptive geodesic kernel to calculate the SCI. Due to the small size of the kernel, the proposed SCI measure captures fine differences of cortical shape. With this novel cortical feature, we aim to capture comparatively small local surface changes that capture a) the widening versus deepening of sulcal and gyral regions, as well as b) the emergence and development of secondary and tertiary sulci. Current cortical shape measures, such as the gyrification index (GI) or intrinsic curvature measures, investigate the cortical surface at a different scale and are less well suited to capture these particular cortical surface changes. In our experiments, the proposed SCI demonstrates higher complexity in the gyral/sulcal wall regions, lower complexity in wider gyral ridges and lowest complexity in wider sulcal fundus regions. In early postnatal brain development, our experiments show that SCI reveals a pattern of increased cortical shape complexity with age, as well as sexual dimorphisms in the insula, middle cingulate, parieto-occipital sulcal and Broca's regions. Overall, sex differences were greatest at 6months of age and were reduced at 24months, with the difference pattern switching from higher complexity in males at 6months to higher complexity in females at 24months. This is the first study of longitudinal, cortical complexity maturation and sex differences, in the early postnatal period from 6 to 24months of age with fine scale, cortical shape measures. These results provide information that complement previous studies of gyrification index in early brain development.

Altered corpus callosum morphology associated with autism over the first 2 years of life.

Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology.

A diffusion tensor MRI atlas of the postmortem rhesus macaque brain.

The rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate for modeling the structure and function of the brain. Brain atlases, and particularly those based on magnetic resonance imaging (MRI), have become important tools for understanding normal brain structure, and for identifying structural abnormalities resulting from disease states, exposures, and/or aging. Diffusion tensor imaging (DTI)-based MRI brain atlases are widely used in both human and macaque brain imaging studies because of the unique contrasts, quantitative diffusion metrics, and diffusion tractography that they can provide. Previous MRI and DTI atlases of the rhesus brain have been limited by low contrast and/or low spatial resolution imaging. Here we present a microscopic resolution MRI/DTI atlas of the rhesus brain based on 10 postmortem brain specimens. The atlas includes both structural MRI and DTI image data, a detailed three-dimensional segmentation of 241 anatomic structures, diffusion tractography, cortical thickness estimates, and maps of anatomic variability among atlas specimens. This atlas incorporates many useful features from previous work, including anatomic label nomenclature and ontology, data orientation, and stereotaxic reference frame, and further extends prior analyses with the inclusion of high-resolution multi-contrast image data.

Investigating the tradeoffs between spatial resolution and diffusion sampling for brain mapping with diffusion tractography: time well spent?

Interest in mapping white matter pathways in the brain has peaked with the recognition that altered brain connectivity may contribute to a variety of neurologic and psychiatric diseases. Diffusion tractography has emerged as a popular method for postmortem brain mapping initiatives, including the ex-vivo component of the human connectome project, yet it remains unclear to what extent computer-generated tracks fully reflect the actual underlying anatomy. Of particular concern is the fact that diffusion tractography results vary widely depending on the choice of acquisition protocol. The two major acquisition variables that consume scan time, spatial resolution, and diffusion sampling, can each have profound effects on the resulting tractography. In this analysis, we determined the effects of the temporal tradeoff between spatial resolution and diffusion sampling on tractography in the ex-vivo rhesus macaque brain, a close primate model for the human brain. We used the wealth of autoradiography-based connectivity data available for the rhesus macaque brain to assess the anatomic accuracy of six time-matched diffusion acquisition protocols with varying balance between spatial and diffusion sampling. We show that tractography results vary greatly, even when the subject and the total acquisition time are held constant. Further, we found that focusing on either spatial resolution or diffusion sampling at the expense of the other is counterproductive. A balanced consideration of both sampling domains produces the most anatomically accurate and consistent results.

Dysmorphogenic effects of first trimester-equivalent ethanol exposure in mice: a magnetic resonance microscopy-based study.

BACKGROUND: The first trimester of human development and the equivalent developmental period in animal models is a time when teratogenic ethanol (EtOH) exposure induces the major structural birth defects that fall within fetal alcohol spectrum disorder (FASD). Previous FASD research employing an acute high dose maternal intraperitoneal EtOH treatment paradigm has identified sensitive periods for a number of these defects. Extending this work, this investigation utilized high resolution magnetic resonance microscopy (MRM)-based analyses to examine the dysmorphology resulting from maternal dietary EtOH intake occurring during selected first trimester-equivalent time periods. METHODS: Female C57Bl/6J mice were acclimated to a liquid 4.8% EtOH (v/v)-containing diet, then bred while on standard chow. Dams were again provided the EtOH-containing liquid diet for a period that extended either from the beginning of gestational day (GD) 7 to the end of GD 11 or from the beginning of GD 12 to the end of GD 16. On GD 17, a subset of fetuses was selected for MRM-based analyses. Group comparisons were made for litter characteristics and gross dysmorphology, as well as whole and regional brain volumes. RESULTS: EtOH-induced stage of exposure-dependent structural brain abnormalities were observed. The GD 7 to 11 EtOH-exposed group presented with a significant decrease in cerebellar volume and an increase in septal volume, while GD 12 to 16 EtOH treatment resulted in a reduction in right hippocampal volume accompanied by enlarged pituitaries. Additionally, the GD 12 to 16 EtOH exposure caused a high incidence of edema/fetal hydrops. CONCLUSIONS: These results illustrate the teratogenic impact of maternal dietary EtOH intake occurring at time periods approximately equivalent to weeks 3 through 6 (GD 7 to 11 in mice) and weeks 7 through 12 (GD 12 to 16 in mice) of human gestation, further documenting EtOH's stage of exposure-dependent neuroteratogenic end points and highlighting the vulnerability of selected brain regions during the first trimester. Additionally they suggest that clinical attention should be paid to fetal hydrops as a likely component of FASD.

Diffusion tensor imaging-based characterization of brain neurodevelopment in primates.

Primate neuroimaging provides a critical opportunity for understanding neurodevelopment. Yet the lack of a normative description has limited the direct comparison with changes in humans. This paper presents for the first time a cross-sectional diffusion tensor imaging (DTI) study characterizing primate brain neurodevelopment between 1 and 6 years of age on 25 healthy undisturbed rhesus monkeys (14 male, 11 female). A comprehensive analysis including region-of-interest, voxel-wise, and fiber tract-based approach demonstrated significant changes of DTI properties over time. Changes in fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity (RD) exhibited a heterogeneous pattern across different regions as well as along fiber tracts. Most of these patterns are similar to those from human studies yet a few followed unique patterns. Overall, we observed substantial increase in FA and AD and a decrease in RD for white matter (WM) along with similar yet smaller changes in gray matter (GM). We further observed an overall posterior-to-anterior trend in DTI property changes over time and strong correlations between WM and GM development. These DTI trends provide crucial insights into underlying age-related biological maturation, including myelination, axonal density changes, fiber tract reorganization, and synaptic pruning processes.

Early adverse experience increases emotional reactivity in juvenile rhesus macaques: relation to amygdala volume.

This study investigated the impact of infant maltreatment on juvenile rhesus monkeys' behavioral reactivity to novel stimuli and its associations with amygdala volume. Behavioral reactivity to novel stimuli of varying threat intensity was measured using Approach/Avoidance (AA) and Human Intruder (HI) tasks. In vivo magnetic resonance imaging (MRI) was used to measure amygdala volume. Interestingly, group behavioral differences were context-dependent. When exposed to a human intruder, maltreated subjects displayed more anxious behaviors than controls; however, when presented with fear-evoking objects, maltreated animals exhibited increased aggression and a shorter latency to inspect the objects. Finally, under testing conditions with the lowest levels of threat (neutral novel objects) maltreated animals also showed shorter latencies to inspect objects, and reduced avoidance and increased exploration compared to controls. This suggests alterations in threat assessment and less behavioral inhibition in animals with early adverse experience compared to controls. Some of these behavioral responses were associated with amygdala volume, which was positively correlated with abuse rates received during infancy, particularly reflecting a relationship with exploration, consistent with previous studies.