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Maturation of the Hippocampal Formation and Amygdala in Macaca mulatta: A Volumetric Magnetic Resonance Imaging Study
Abstract
Malformations of the hippocampal formation and amygdala have been implicated in several neurodevelopmental disorders; yet relatively little is known about their normal structural development. The purpose of this study was to characterize the early developmental trajectories of the hippocampus and amygdala in the rhesus macaques (Macaca mulatta) using noninvasive MRI techniques. T1-weighted structural scans of 22 infant and juvenile monkeys (11 male, 11 female) were obtained between 1 week and approximately 2 yrs of age. Ten animals (five males, five females) were scanned multiple times and 12 monkeys (six males, six females) were scanned once between 1 and 4 weeks of age. Both structures exhibited significant age-related changes throughout the first 2 yrs of life that were not explained by overall brain development. The hippocampal formation increased 117.05% in males and 110.86% in females. No sex differences were evident, but the left hemisphere was significantly larger than the right. The amygdala increased 86.49% in males and 72.94% in females with males exhibiting a larger right than left amygdala. For both structures, the most substantial volumetric increases were seen within the first month, but the hippocampal formation appeared to develop more slowly than the amygdala with the rate of hippocampal maturation stabilizing around 11 months and that of amygdala maturation stabilizing around 8 months. Differences in volumetric developmental trajectories of the hippocampal formation and amygdala largely mirror differences in the timing of the functional development of these structures. The current results emphasize the importance of including early postnatal ages when assessing developmental trajectories of neuroanatomical structures and reinforces the utility of nonhuman primates in the assessment of normal developmental patterns.
... A handful of neuroimaging studies have already shown that development of total brain volume (TBV), intracranial volume (ICV: GM+WM+cerebrospinal fluid -CSF-) and of cortical GM and WM volumes in rhesus monkeys follows similar patterns to those reported in humans. Similarities include rapid, exponential growth of GM in the first 3 months of life (roughly equivalent to the first year in humans), and a continuous, slower growth thereafter, up to puberty, whereas WM volume increases more slowly but continuously until young adulthood in both species (Malkova et al. 2006;Knickmeyer et al. 2010;Payne et al. 2010;Liu et al. 2015;Scott et al. 2016;Liu et al. 2019;Kim et al. 2020). ...
... The models that best fit the data were identified using several factors. Previous developmental studies in rhesus macaques have indicated global and regional brain growth are best characterized by nonlinear models and exhibit regional differences that reflect the unique GM and WM ratios and developmental timescale of each region (Payne et al. 2010;Payne et al. 2017). Given the early age range in this study, which has not previously been fully characterized using structural MRI in rhesus macaques, we took an iterative approach to assessing which parameters best characterized the regional data. ...
... Overall, the current findings parallel those of earlier studies revealing an expansion of total brain and cerebral lobe volumes from 2 to 6 months of age, but particularly fast during the first 12 postnatal weeks in rhesus macaques (Malkova et al. 2006;Payne et al. 2010;Scott et al. 2016;Liu et al. 2019;Kim et al. 2020). In addition, using a full longitudinal design with densely scan sampling at the earlier ages (2, 4, 8, 12 weeks), high resolution scan sequences and minimized artifacts, as well as age-specific infant atlases and processing pipelines that use both T1-and T2-weighted data in multi-modal fashion to optimize tissue segmentation and cortical parcellations at these early ages, our study provides novel findings demonstrating a substantial overall brain and cortical growth at the earliest ages between 1-4 weeks of age. ...
This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2–24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20–24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2–24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2–12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.
... They also exhibit a prolonged postnatal development which can make them particularly vulnerable to early central nervous system (CNS) insults, including ZIKV infection. Amygdala volume in RMs increases rapidly from birth to 8 months of age, but continues growing into adulthood 35,36 . Amygdala volumes were similar to controls at 3 and 6 months of age 31 ; however, ZIKVinfected RM infants exhibited smaller amygdala volume than controls at 12 months of age (Fig. 3d). ...
... Amygdala volumes were similar to controls at 3 and 6 months of age 31 ; however, ZIKVinfected RM infants exhibited smaller amygdala volume than controls at 12 months of age (Fig. 3d). Postnatal development of the hippocampus is more protracted than the amygdala, with the hippocampus doubling its volume between 1 week and 2 years of life in RMs 35 . Here, ZIKV-infected RM infants also exhibited smaller hippocampal volumes compared to controls at 12 months of life (Fig. 3e). ...
... Although no differences were detected in amygdala volume at 3 and 6 months of age, by 12 months RM infants exposed to ZIKV had much smaller amygdalae compared to controls. The rapid maturation of the amygdala seen in infant RMs may have precluded the detection of group differences in amygdala volume until after the rate of growth stabilized at around 8 months of age 35,36 . ZIKV-infected RMs also exhibited underdeveloped dendritic branching of immature amygdala neurons, likely limiting their ability to be incorporated into the neural network. ...
Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.
... However, this knowledge was gained from lesion studies in adults that have a fully developed amygdala and have already acquired the skills needed for threat detection and promoting emotional responses toward threats. Thus, considering the extended postnatal development of the amygdala, which in macaques reaches volumetric stability at roughly 8 months of age (Payne, Machado, Bliwise, & Bachevalier, 2010), it is important to understand how early damage may impact the development of threat detection and emotional responses toward a variety of threats. ...
... The development of threat detection and social competency in rhesus monkeys corresponds with postnatal growth of the amygdala that continues to develop from birth until 2 years of age (Chareyron, Lavenex, Amaral, & Lavenex, 2012;Payne et al., 2010). Previous studies have reported that early damage to the amygdala results in decreased emotional reactivity toward threatening object, including social (mammal like) and innate (snake) aversive objects (Bliss-Moreau, Bliss-Moreau, Toscano, Bauman, Mason, & Amaral, 2010. ...
... Animals in group Neo-C received a Fast Spin-Echo-Inversion Recovery (FSE-IR) series (TE ϭ 20 ms, TR ϭ 4500/250 ms, ETL ϭ 6, BW ϭ 32 kHz, contiguous 1.5 mm thick images, 12 cm FOV, 256 ϫ 256 matrix, 2 NEX). The latter series was used as part of a separate study to track the developmental trajectory of several brain structures (Payne, Cirilli, & Bachevalier, 2017;Payne et al., 2010). ...
The amygdala plays an essential role in evaluating social information, threat detection, and learning fear associations. Yet, most of that knowledge comes from studies in adult humans and animals with a fully developed amygdala. Given the considerable protracted postnatal development of the amygdala, it is important to understand how early damage to this structure may impact the long-term development of behavior. The current study examined behavioral responses toward social, innate, or learned aversive stimuli among neonatal amygdala lesion (Neo-Aibo; males = 3, females = 3) or sham-operated control (Neo-C; males = 3, females = 4) rhesus macaques. Compared with controls, Neo-Aibo animals exhibited less emotional reactivity toward aversive objects, including faster retrieval of food reward, fewer fearful responses, and more manipulation of objects. This lower reactivity was only seen in response to social and innate aversive stimuli, whereas Neo-Aibo animals had similar responses to controls for learned aversive stimuli. The current study also detected sex differences in behavioral response to aversive stimuli, such that, as compared with males, females took longer to retrieve the food reward across all aversive stimuli types, but only expressed more hostility and more coo vocalizations during learned aversive trials. Early amygdala damage impacted the expression of some, but not all, sex differences. For example, neonatal amygdala damage eliminated the sex difference in object manipulation. These findings add important information that broaden our understanding of the role of the amygdala in the expression of sexually dimorphic behaviors, as well as its role in learning fear associations and threat detection. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
... They also exhibit a prolonged postnatal development which can make them particularly vulnerable to early CNS insults, including ZIKV infection. Amygdala volume in RMs increases rapidly from birth to 8 months of age, but continues growing into adulthood [34][35][36][37][38] . Amygdala volumes were similar to controls at 3 and 6 months of age 31 ; however, ZIKV-infected RM infants exhibited smaller amygdala volume than controls at 12 months of age ( Fig 3D). ...
... Amygdala volumes were similar to controls at 3 and 6 months of age 31 ; however, ZIKV-infected RM infants exhibited smaller amygdala volume than controls at 12 months of age ( Fig 3D). Postnatal development of the hippocampus is more protracted than the amygdala, with the hippocampus doubling its volume between 1 week and 2 years of life in RMs 38 . Here, ZIKVinfected RM infants also exhibited smaller hippocampal volumes compared to controls at 12 months of life ( Fig 3E). ...
... Although no differences were detected in amygdala volume at 3 and 6 months of age, by 12 months RM infants exposed to ZIKV had much smaller amygdalae compared to controls. The rapid maturation of the amygdala seen in infant RMs may have precluded the detection of group differences in amygdala volume until after the rate of growth stabilized at around 8 months of age [34][35][36][37][38] . ZIKV-infected RMs also exhibited underdeveloped dendritic branching of immature amygdala neurons, likely limiting their ability to be incorporated into the neural network. ...
Considering the impact that Zika virus (ZIKV) infection has on the fetal nervous system and given that the postnatal period is also a time of rapid brain growth, it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Using a rhesus macaque (RM) model, we showed that postnatal ZIKV infection resulted in long-term behavioral changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant RMs had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior and cognitive function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection of infants in this model has long lasting neurodevelopmental consequences.
... basic cellular architecture of the amygdala and pathways of amygdalocortical connectivity appear to be well established at the time of birth (Bauman & Amaral, 2005;Emery & Amaral, 2000), both cytoarchitectural and magnetic resonance imaging (MRI) studies demonstrate rapid postnatal enlargement of the nonhuman primate amygdala between birth and 3 months of age (Chareyron, Lavenex, Amaral, & Lavenex, 2012;Payne, Machado, Bliwise, & Bachevalier, 2010). Surprisingly, cross-sectional MRI studies indicate that the human amygdala continues to undergo substantial postnatal growth throughout childhood and well into adolescence, increasing by approximately 40% from 5 to 18 years of age in males (Giedd, Castellanos, Rajapakse, Vaituzis, & Rapoport, 1997;J. ...
... To date, the only other semi-longitudinal MRI volumetric study to evaluate early development of the rhesus macaque amygdala was carried out by Payne et al. (2010), in which hippocampal, amygdala and total cerebral volumetric growth were evaluated in nursery-reared rhesus monkeys between 1 week and 2 years of age. Amygdala volume was calculated using 66 MRIs across 10 developmental time points, using a combination of longitudinal and cross-sectional subjects. ...
... The present experiment was conducted with rhesus macaques living in large troops in outdoor corrals that had a complex, speciestypical social structure and were reared by their mothers. In contrast, the primates studied by Payne et al. (2010) were nursery-reared by humans with more limited access to species-typical social stimuli. ...
Emerging evidence suggests that the human amygdala undergoes extensive growth through adolescence, coinciding with the acquisition of complex socioemotional learning. Our objective was to longitudinally map volumetric growth of the nonhuman primate amygdala in a controlled, naturalistic social environment from birth to adulthood. Magnetic resonance images were collected at 5 time-points in 24 male and female rhesus macaques from 6 months to adulthood at 5 years. We then compared amygdala growth to other brain regions, including newly collected isocortical gray and white matter volumes, and previously published data on the same cohort. We found that amygdala volume increases by nearly 50% from age 6 months to 5 years. This dramatic growth is in contrast to overall brain and hippocampal volume, which peak near 3 years, white matter, which slows from 3 to 5 years, and isocortical gray, which has a net decrease. Similar to isocortical gray and hippocampal volumes, amygdala volume is ~8% larger in males than females. Rate of growth does not differ by sex. Although the underlying neurobiological substrate for protracted amygdala growth into adulthood is unclear, we propose it may be due in part to the unique cellular development of immature neurons in paralaminar nucleus that mature in size and connectivity with age. Prolonged amygdala maturation raises the possibility that environmental and genetic perturbations that disrupt this trajectory may contribute to the emergence of psychiatric disorders, such as anxiety, depression, schizophrenia, and autism; all in which the amygdala is strongly implicated. This article is protected by copyright. All rights reserved.
... Rhesus macaques have a lifespan of about 25 years, and their developmental stages are 3-4 times faster than humans (Scott et al. 2016). Because rhesus macaques have neuroanatomy, social skills, and psychological characteristics similar to humans, they have been widely used in MRI studies to infer normal human brain development (Malkova et al. 2006;Payne et al. 2010;Shi et al. 2013;Scott et al. 2016;Meng et al. 2017), as well as developmental disorders (Braunschweig and Van de Water 2012;Bauman et al. 2013). In particular, NHP models are useful to investigate the effects of drug exposure and maternal environments on brain structural changes associated with development. ...
... Prior longitudinal MRI studies of rhesus monkey brain development have demonstrated relatively rapid volumetric increases over the first several months after birth, followed by stabilized growth patterns after infancy characterized by quadratic or cubic (Payne et al. 2010;Liu et al. 2015) curves. However, other recent longitudinal studies in NHPs (Malkova et al. 2006;Scott et al. 2016) have reported that intracranial volume (ICV) decreases slightly during late infancy (months 6-10), driven primarily by volumetric contractions of the occipital and parietal lobes, followed by an apparent rebound in ICV up to 3 years of age. ...
The typical developmental trajectory of brain structure among nonhuman primates (NHPs) remains poorly understood. In this study, we characterized the normative trajectory of developmental change among a cohort of rhesus monkeys (n = 28), ranging in age from 2 to 22 months, using structural MRI datasets that were longitudinally acquired every 3-4 months. We hypothesized that NHP-specific transient intracranial volume decreases reported during late infancy would be part of the typical developmental process, which is driven by volumetric contraction of gray matter in primary functional areas. To this end, we performed multiscale analyses from the whole brain to voxel level, characterizing regional heterogeneity, hemispheric asymmetry, and sexual dimorphism in developmental patterns. The longitudinal trajectory of brain development was explained by three different regional volumetric growth patterns (exponentially decreasing, undulating, and linearly increasing), which resulted in developmental brain volume curves with transient brain volumetric decreases. White matter (WM) fractional anisotropy increased with age, corresponding to WM volume increases, while mean diffusivity (MD) showed biphasic patterns. The longitudinal trajectory of brain development in young rhesus monkeys follows typical maturation patterns seen in humans, but regional volumetric and MD changes are more dynamic in rhesus monkeys compared with humans, with marked decreases followed by "rebound-like" increases.
... Brain development is a non-linear process (Goddings et al., 2014;Gogtay et al., 2004;Mills et al., 2016;Wierenga et al., 2014). Early in childhood the amygdala grows rapidly (Nordahl, 2012;Payne et al., 2010). Then, around age 10-12 amygdala growth peaks and subsequently stagnates with slower growth from adolescence into adulthood (Payne et al., 2010;Pechtel et al., 2014;Wierenga et al., 2014). ...
... Early in childhood the amygdala grows rapidly (Nordahl, 2012;Payne et al., 2010). Then, around age 10-12 amygdala growth peaks and subsequently stagnates with slower growth from adolescence into adulthood (Payne et al., 2010;Pechtel et al., 2014;Wierenga et al., 2014). The results of this study demonstrate that these developmental trajectories differ as a function of early temperament, with the negative reactive individuals showing a pattern of relatively little growth in the left amygdala during middle childhood. ...
The current study examined the link between temperamental reactivity in infancy and amygdala development in middle childhood. A sample (n = 291) of four-month-old infants was assessed for infant temperament, and two groups were identified: those exhibiting negative reactivity (n = 116) and those exhibiting positive reactivity (n = 106). At 10 and 12 years of age structural imaging was completed on a subset of these participants (n = 75). Results indicate that, between 10 and 12 years of age, left amygdala volume increased more slowly in those with negative compared to positive reactive temperament. These results provide novel evidence linking early temperament to distinct patterns of brain development over middle childhood.
... As with humans, longitudinal MRI analyses in macaques have found that total brain volume approaches two-thirds of full adult volume by 1 week of age, and follows a nonlinear trajectory over time with an initial rapid growth rate that slows from around 4 months onwards (Malkova et al. 2006;Payne et al. 2010;Scott et asl. 2016). ...
... In later childhood, the thalamus, pallidum and hippocampus increase in volume into adolescence before decreasing, whereas caudate and putamen volumes decrease from around the age of 5 onwards (Herting et al. 2018). In macaques, manual tracing of the hippocampus reveal a similar trajectory to that described in humans, peaking by 3 years of age before declining slightly (Payne et al. 2010;Hunsaker et al. 2014). In contrast, using cross-sectional data, Knickmeyer described linear increases of caudate, putamen and hippocampal volume between 10 and 64 months in the macaque (Knickmeyer et al. 2010). ...
Quantifying individual variation in postnatal brain development can provide insight into cognitive diversity within a population and the aetiology of common neuropsychiatric and neurodevelopmental disorders. Non-invasive studies of the non-human primate can aid understanding of human brain development, facilitating longitudinal analysis during early postnatal development when comparative human populations are difficult to sample. In this study, we perform analysis of a longitudinal MRI dataset of 32 macaques, each with up to five magnetic resonance imaging (MRI) scans acquired between 3 and 36 months of age. Using nonlinear mixed effects model we derive growth trajectories for whole brain, cortical and subcortical grey matter, cerebral white matter and cerebellar volume. We then test the association between individual variation in postnatal tissue volumes and birth weight. We report nonlinear growth models for all tissue compartments, as well as significant variation in total intracranial volume between individuals. We also demonstrate that regional subcortical grey matter varies both in total volume and rate of change between individuals and is associated with differences in birth weight. This supports evidence that birth weight may act as a marker of subsequent brain development and highlights the importance of longitudinal MRI analysis in developmental studies.
... As with humans, longitudinal MRI analyses in macaques have found that total brain volume approaches two-thirds of full adult volume by one week of age, and follows a nonlinear trajectory over time with an initial rapid growth rate that slows from around 4 months onwards (Malkova et al. 2006;Payne et al. 2010;Scott et al. 2016). In both species, total brain volume is, on average, larger in males, and postnatal growth is largest in frontal, parietal and temporal lobes with similar trajectories in subcortical and cerebellar volumes (Gilmore et al. 2012;Scott et al. 2016). ...
... In later childhood, the thalamus, pallidum and hippocampus increase in volume into adolescence before decreasing whereas caudate and putamen volumes decrease from around the age of 5 onwards (Herting et al. 2018). In macaques, manual tracing of the hippocampus reveal a similar trajectory to that described in humans, peaking by 3 years of age before declining slightly (Payne et al. 2010;Hunsaker et al. 2014). In contrast, using cross-sectional data, Knickmeyer described linear increases of caudate, putamen and hippocampal volume between 10 and 64 months in the macaque (Knickmeyer et al. 2010). ...
Quantifying individual variation in postnatal brain development can provide insight into cognitive diversity within a population and the aetiology of common neuropsychiatric and neurodevelopmental disorders that are associated with adverse conditions in early life. Non-invasive studies of the non-human primate can aid understanding of human brain development, facilitating longitudinal analysis during early postnatal development when comparative human populations are difficult to sample.
In this study, we perform analysis of a longitudinal MRI dataset of 32 macaques, each with up to five magnetic resonance imaging (MRI) scans acquired between 1 and 36 months of age. Using nonlinear mixed effects model we derive growth trajectories for whole brain, cortical and subcortical grey matter, cerebral white matter and cerebellar volume. We then test the association between individual variation in postnatal tissue volumes and birth weight.
We report nonlinear growth models for all tissue compartments, as well as significant variation in total intracranial volume between individuals. We also demonstrate that subcortical grey matter varies both in total volume and rate of change between individuals and is associated with differences in birth weight. This supports evidence that subcortical grey matter is specifically vulnerable to adverse conditions in utero and highlights the importance of longitudinal MRI analysis in developmental studies.
... The protracted postnatal development of brain areas important for socioemotional behavior may make infants particularly vulnerable to ZIKV infection early in life. The hippocampus is one of the brain regions with extended postnatal development, doubling its volume from 1 week to 2 years of age in RMs (32,33).Thus, the increase in total hippocampal volume between 3 and 6 months of age seen in the uninfected control infant RMs (Fig. 5B) is consistent with normative development in this species (18). However, ZIKV-infected infant RMs exhibited relatively blunted increases in hippocampal volume between 3 and 6 months of age (Fig. 5B). ...
... Data sets were processed using AutoSeg_3.3.2 segmentation package (87) to get the volumes of brain WM and GM, CSF, and cortical (temporal visual area, temporal auditory area, and prefrontal, frontal, parietal, and occipital lobes) and subcortical (hippocampus and amygdala) brain areas. Image processing steps included the following: (i) averaging T1 and T2 images to improve signal-to-noise ratio, (ii) intensity inhomogeneity correction, (iii) rigid-body registration of the subject MRI to the 3-or 6-month UNC-Emory infant RM atlases (36), (iv) tissue segmentation and skull stripping, (v) registration of the atlas to the subject's brain to generate cortical parcellations (affine followed by deformable SyN/ANTS registration), and (vi) manual editing of the amygdala and hippocampus done on all scans using previously published neuroanatomical boundaries (32). For more detailed description of the structural MRI analysis, see (87,88). ...
The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance
imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.
... In addition, Old World NHPs (such as baboons and macaques) share over 90% of the human genome [26]. Therefore, NHPs are being used frequently as excellent models in various studies on immunology [27], vaccines [28,29], neuroAIDS [30][31][32], and neuroscience research including stroke [33][34][35], drug abuse [36], autism [37,38], Huntington's disease [39,40], amygdala and hippocampal lesions [41][42][43], Alzheimer disease [44,45], and Parkinsonian disease [46,47]. ...
Non-human primates (NHPs) are the closest living relatives of the human and play a critical role in investigating the effects of maternal viral infection and consumption of medicines, drugs, and alcohol on fetal development. With the advance of contemporary fast MRI techniques with parallel imaging, fetal MRI is becoming a robust tool increasingly used in clinical practice and preclinical studies to examine congenital abnormalities including placental dysfunction, congenital heart disease (CHD), and brain abnormalities non-invasively. Because NHPs are usually scanned under anesthesia, the motion artifact is reduced substantially, allowing multi-parameter MRI techniques to be used intensively to examine the fetal development in a single scanning session or longitudinal studies. In this paper, the MRI techniques for scanning monkey fetal brains in utero in biomedical research are summarized. Also, a fast imaging protocol including T2-weighted imaging, diffusion MRI, resting-state functional MRI (rsfMRI) to examine rhesus monkey fetal brains in utero on a clinical 3T scanner is introduced.
... Evidence for the role of the hippocampus in emotional responses and HPA axis function thus far has largely been investigated using lesions acquired during adulthood when the hippocampus and neuroendocrine systems are already fully developed. Considering the prolonged maturation of the hippocampus (Payne et al., 2010), it is important to understand its contribution to the maturation of emotional regulation and neuroendocrine responses. ...
The hippocampus is important for long-term memory storage, but also plays a role in regulating the hypothalamic-pituitary-adrenal (HPA) axis and emotional behaviors. We previously reported that early hippocampal damage in monkeys result in increased anxious expression and blunted HPA responses to an acute stressor. Here, we further probe their responses toward aversive stimuli (conditioned and unconditioned) and evaluate HPA axis dysfunction. Responses toward social, innate, and learned aversive stimuli, fear potentiated acoustic startle, and pituitary-adrenal function were investigated in 13 adult rhesus monkeys with neonatal hippocampal lesions (Neo-Hibo=6) and controls (Neo-C=7). Neo-Hibo monkeys' responses depend on the type of unconditioned stimulus, with increased anxiety behaviors toward social and learned, but decreased reactivity toward innate stimuli. Neo-C and Neo-Hibo monkeys exhibited similar performance learning conditioned cues and safety signals. Neo-Hibo monkeys were less sensitive to HPA axis stimulation, potentially suggesting adrenal fatigue. Current findings suggest that the hippocampus plays a large role in regulating not only anxiety behaviors, but also the HPA-axis, a neural system crucial to regulate how we respond to the world around us. These data have important clinical significance considering that many developmental neuropsychiatric disorders exhibit altered hippocampal structure and function, emotional and HPA axis dysregulation.
... Neuroinflammation during mid-to late pregnancy can disrupt neuroapoptosis, myelination and the synaptic pruning and maturation of the ventral tegmental area (VTA), which is the site of dopaminergic neuron cell bodies that project to the frontal and prefrontal cortex (Donev and Thome, 2010;Gillies et al., 2014). Development of the amygdala, an area of the brain contributing to emotional processing where its reactivity has been linked to behavioral inhibition and fear in particular (Thomas et al., 2019), begins to develop later in pregnancy with rapid changes right after birth (Gilmore et al., 2012;Humphrey, 1968;Payne et al., 2010;Tottenham and Gabard-Durnam, 2017). Oxidative stress disrupts circuitry linked to anxiety behaviors (McCoy et al., 2019) and other evidence shows that boys may be more vulnerable to in utero oxidative stress compared to girls (Minghetti et al., 2013). ...
Background
Prenatal exposure to fine particulate matter with a diameter of ≤2.5 μm (PM2.5) has been linked to adverse neurodevelopmental outcomes in later childhood, while research on early infant behavior remains sparse.
Objectives
We examined associations between prenatal PM2.5 exposure and infant negative affectivity, a stable temperamental trait associated with longer-term behavioral and mental health outcomes. We also examined sex-specific effects.
Methods
Analyses included 559 mother-infant pairs enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. Daily PM2.5 exposure based on geocoded residential address during pregnancy was estimated using a satellite-based spatiotemporal model. Domains of negative affectivity (Sadness, Distress to Limitations, Fear, Falling Reactivity) were assessed using the Infant Behavior Questionnaire-Revised (IBQ-R) when infants were 6 months old. Subscale scores were calculated as the mean of item-specific responses; the global Negative Affectivity (NA) score was derived by averaging the mean of the four subscale scores. Bayesian distributed lag interaction models (BDLIMs) were used to identify sensitive windows for prenatal PM2.5 exposure on global NA and its subscales, and to examine effect modification by sex.
Results
Mothers were primarily racial/ethnic minorities (38% Black, 37% Hispanic), 40% had ≤12 years of education; most did not smoke during pregnancy (87%). In the overall sample, BDLIMs revealed that increased PM2.5 at mid-pregnancy was associated with higher global NA, Sadness, and Fear scores, after adjusting for covariates (maternal age, education, race/ethnicity, sex). Among boys, increased PM2.5 at early pregnancy was associated with decreased Fear scores, while exposure during late pregnancy was associated with increased Fear scores (cumulative effect estimate = 0.57, 95% CI: 0.03–1.41). Among girls, increased PM2.5 during mid-pregnancy was associated with higher Fear scores (cumulative effect estimate = 0.82, 95% CI: 0.05–1.91).
Conclusions
Prenatal PM2.5 exposure was associated with negative affectivity at age 6 months, and the sensitive windows may vary by subdomains and infant sex.
... For example, studies in which maternal care and responsiveness were manipulated showed that higher levels of stress due to neglecting maternal caring led to an increased amygdala volume that also persisted at latter developmental stages of life [52][53][54]. This may be due to the features of amygdala developmental trajectory that is characterized by a robust growth during the first few years of life, with a peak around the timing of preadolescence in non-human primates [55] as well as in healthy humans [56], highlighting how early environmental stressors may perturb a typical development in such an area. Similarly, animal and human studies showed that maternal care-related early life stress result in persistent alterations in the amygdala functional circuitry [53], with alterations in functional connectivity of the amygdala with the hippocampus [48,49,57], the medial prefrontal cortex [58] and the anterior cingulate cortex [59,60]. ...
Studies comparing organized (O) and unresolved/disorganized (UD) attachment have consistently shown structural and functional brain abnormalities, although whether and how attachment patterns may affect resting state functional connectivity (RSFC) is still little characterized. Here, we investigated RSFC of temporal and limbic regions of interest for UD attachment. Partic-ipants' attachment was classified via the Adult Attachment Interview, and all participants underwent clinical assessment. Functional magnetic resonance imaging data were collected from 11 UD individuals and seven matched O participants during rest. A seed-to-voxel analysis was performed , including the anterior and the posterior cingulate cortex, the bilateral insula, amygdala and hippocampus as seed regions. No group differences in the clinical scales emerged. Compared to O, the UD group showed lower RSFC between the left amygdala and the left cerebellum (lobules VIII), and lower functional coupling between the right hippocampus and the posterior portion of the right middle temporal gyrus. Moreover, UD participants showed higher RSFC between the right amygdala and the anterior cingulate cortex. Our findings suggest RSFC alterations in regions associated with encoding of salient events, emotion processing, memories retrieval and self-referential processing in UD participants, highlighting the potential role of attachment experiences in shaping brain abnormalities also in non-clinical UD individuals.
... The developmental trajectories of the amygdala and the PFC suggest that there may be multiple windows of vulnerability during which these regions may be differentially sensitive to the effects of adversity. Structurally, the rate of volumetric growth in the amygdala is largest during the early postnatal years (Payne, Machado, Bliwise, & Bachevalier, 2010), increasing in volume by more than 100% during the first year of life (Gilmore et al., 2012). The PFC, however, continues to develop throughout childhood into adolescence and adulthood (Gogtay et al., 2004;Sowell et al., 2003). ...
Childhood adversity is thought to undermine youth socioemotional development via altered neural function within regions that support emotion processing. These effects are hypothesized to be developmentally specific, with adversity in early childhood sculpting subcortical structures (e.g., amygdala) and adversity during adolescence impacting later-developing structures (e.g., prefrontal cortex; PFC). However, little work has tested these theories directly in humans. Using prospectively collected longitudinal data from the Fragile Families and Child Wellbeing Study (FFCWS) ( N = 4,144) and neuroimaging data from a subsample of families recruited in adolescence ( N = 162), the current study investigated the trajectory of harsh parenting across childhood (i.e., ages 3 to 9) and how initial levels versus changes in harsh parenting across childhood were associated with corticolimbic activation and connectivity during socioemotional processing. Harsh parenting in early childhood (indexed by the intercept term from a linear growth curve model) was associated with less amygdala, but not PFC, reactivity to angry facial expressions. In contrast, change in harsh parenting across childhood (indexed by the slope term) was associated with less PFC, but not amygdala, activation to angry faces. Increases in, but not initial levels of, harsh parenting were also associated with stronger positive amygdala–PFC connectivity during angry face processing.
... Animal studies have demonstrated that limbic brain development and the HPA axis are highly coupled during development . Amygdala and hippocampus are rich with cortisol-binding receptors, particularly early in development (Avishai-Eliner et al., 1996;Gilmore et al., 2012;Payne et al., 2010;Vázquez et al., 2012), and they provide regulatory feedback to the HPA-axis . However, there is a paucity of human studies that examine how these systems interact during development. ...
Although decades of research have shown associations between early caregiving adversity, stress physiology and limbic brain volume (e.g., amygdala, hippocampus), the developmental trajectories of these phenotypes are not well characterized. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4-20 years old) completed 1-3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239) and structural MRI (N = 156). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Amygdala and hippocampal volumes were also prospectively associated with future morning cortisol in both groups. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.
... Neuroanatomical work suggests that these changes in behavior are associated with changes in subcortical regions, particularly the amygdala. For instance, in rhesus monkeys, the amygdala undergoes exponential developmental changes during the first months of life before stabilizing and displaying slower rates of change (Chareyron, Lavenex, Amaral, & Lavenex, 2012;Payne, Machado, Bliwise, & Bachevalier, 2010). Moreover, disruptions to the amygdala during this developmental period lead to abnormal threat detection and fear-related responses to strangers (Bauman, Lavenex, Mason, Capitanio, & Amaral, 2004;Raper, Wilson, Sanchez, Machado, & Bachevalier, 2013). ...
In the current chapter, we suggest that a neuroscientific approach provides a valuable perspective to the study of emotional development. We discuss how a neuroscientific approach offers unique contributions to notable practical and theoretical challenges in the study of the development of emotion and emotion regulation. We exemplify these contributions by reviewing the current knowledge on the development of the expression and regulation of fear and anxiety and their associated neural bases. The literature reviewed highlights the fact that a neuroscientific approach situates the study of emotional development in a larger biological and evolutionary framework facilitating the translation of research across species and providing an account for species-typical development as well as individual variation. A neuroscientific approach also provides methods that permit studying of emotional development across several levels of analyses, providing information on the similarity and/or differentiation between processes and mechanisms. We also cover literature that exemplifies how a neuroscientific approach can expand our understanding of how constitutional factors and experiences create the brain networks that support the expression and regulation of emotion across development. Finally, we discuss outstanding issues and future directions with the neuroscientific approach to the study of emotional development.
... Volume measurements were performed as described in Payne et al. (2010) . Briefly, two trained observers used the ITK-Snap software ( www.ITK-SNAP.org ...
The dorsolateral prefrontal cortex (DLPFC) and ventral lateral prefrontal cortex (VLPFC) play critical but different roles in working memory (WM) processes. Resting-state functional MRI (rs-fMRI) was employed to investigate the effects of neonatal hippocampal lesions on the functional connectivity (FC) between the hippocampus (H) and the DLPFC and VLPFC and its relation to WM performance in adult monkeys. Adult rhesus monkeys with neonatal H lesions (Neo-H, n = 5) and age- and gender- matched sham-operated monkeys (Neo-C, n = 5) were scanned around 10 years of age. The FC of H-DLPFC and H-VLPFC in Neo-H monkeys was significantly altered as compared to controls, but also switched from being positive in the Neo-C to negative in the Neo-H. In addition, the altered magnitude of FC between right H and bilateral DLPFC was significantly associated with the extent of the hippocampal lesions. In particular, the effects of neonatal hippocampal lesion on FC appeared to be selective to the left hemisphere of the brain (i.e. asymmetric in the two hemispheres). Finally, FC between H and DLPFC correlated with WM task performance on the SU-DNMS and the Obj-SO tasks for the control animals, but only with the H-VLPFC and SU-DNMS task for the Neo-H animals. In conclusion, the present rsfMRI study revealed that the neonatal hippocampal lesions significantly but differently altered the integrity in the functional connectivity of H-DLPFC and H-VLPFC. The similarities between the behavioral, cognitive and neural alterations in Neo-H monkeys and Schizophrenia (SZ) patients provide a strong translational model to develop new therapeutic tools for SZ.
... The amygdala matures very early on (some primates have some amygdala nuclei fully developed at birth) (Chareyron et al., 2012, Payne et al., 2010, and conditioned responses to stimuli are expected to be established at a very young age, dictating approach or avoidance behaviors to significant environmental elements. The hippocampus provides contextual and spatial data to these interactions with the environment (Tallot et al., 2016), and as episodic memory is established, there is a greater frame of reference which allows for the immediate salience-based response of the amygdala to be tuned down in light of the hippocampal contribution. ...
... Functional neuroimaging studies in infant rhesus macaques viewing faces have shown a robust early activation of the lateral geniculate nucleus as early as 1 week of age, suggesting an early reliance on subcortical visual processing Arcano & Livingstone, 2017, Arcano et al., 2017. In addition, sharp increase in amygdala volume, most likely resulting from increased interconnectivity of the amygdala with neocortical areas, occurs within the first six weeks of age in monkeys (Payne et al., 2010;Chareyon et al., 2012) and may help tag perceptual face processing with emotional content of a face. In contrast, the ventral temporal visual pathway involved in the perception of facial features and identity, the visual cortical areas located within the superior temporal sulcus important for the detection of facial movements and facial expressions, and the dorsal visual stream in the parietal cortex involved in spatial attentional processes are not fully developed at birth and have a more prolonged development throughout infancy (Webster et al., 1991;Webster et al., 1994;Rodman & Consuelos, 1994; J o u r n a l P r e -p r o o f Livingstone et al., 2017;Rodman et al., 1991;Rodman et al., 1993;Distler et al., 1996). ...
Impairments in social interaction in Autism Spectrum Disorder (ASD) differ greatly across individuals and vary throughout an individual’s lifetime. Yet, an important marker of ASD in infancy is deviations in social-visual engagement, such as the reliably detectable early deviations in attention to the eyes or to biological movement (Klin et al., 2015). Given the critical nature of these early developmental periods, understanding its neurobehavioral underpinnings by means of a nonhuman primate model will be instrumental to understanding the pathophysiology of ASD. Like humans, rhesus macaques 1) develop in rich and complex social behaviors, 2) progressively develop social skills throughout infancy, and 3) have high similarities with humans in brain anatomy and cognitive functions (Machado and Bachevalier, 2003). In this study, male infant rhesus macaques living with their mothers in complex social groups were eye-tracked longitudinally from birth to 6 months while viewing full-faced videos of unfamiliar rhesus monkeys differing in age and sex. The results indicated a critical period for the refinement of social skills around 4–8 weeks of age in rhesus macaques. Specifically, infant monkeys’ fixation to the eyes shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14–18 weeks, before increasing again. These results parallel the developmental trajectory of social visual engagement published in human infants (Jones & Klin, 2013) and suggest the presence of a switch in the critical networks supporting these early developing social skills that is highly conserved between rhesus macaque and human infant development.
... As study of Tottenham and Sheridan reports amygdala is more reactive in an early life than in the adulthood, but its extremum reaches in the adolescence (Tottenham, 2010). The most exponential rate of development was observed during the early postnatal period; therefore, it can be expected that amygdala is more susceptible for environmental factors in this stage (Payne et al., 2010;Tottenham, most widely distributed CaBPs in the nervous system are calbindin (CB), calretinin (CR) and parvalbumin (PV) and they occur in the various brain regions. These proteins are a very usable histochemical tools to mark specific neuronal cell groups (Foo et al., 2014) among other in amygdala. ...
Amygdala is a limbic structure involved in the stress response. The immunohistochemical and morphometric methods were used to examine whether the chronic mild psychological stress during the early postnatal period would change activation of amygdaloid nuclei in response to the same stressor in adult. In the study we focused on the role of neurons containing calbindin (CB), calretinin (CR), parvalbumin (PV) and nitric oxide synthase (NOS).
The rats were divided into three groups: control non-stressed animals and two experimental: EI consisted of animals that were exposed to acute stress in the high-light, open-field test (HL-OF) at P90 (P – postnatal day) and EII consisted of rats that were exposed to chronic stress in HL-OF, daily during the first 21 postnatal days and then once at P90.
The scheme of activation of amygdaloid nuclei under stress in EI and EII group was similar. The highest density of c-Fos-ir cells (c-Fos – a marker of neuronal activation) was demonstrated by the medial nucleus (Me) and bed nucleus of the accessory olfactory tract (BAOT). The amygdaloid nuclei diversity after HL-OF was determined by the high activation of the NOS-ir cells in the Me and NOS- and CR-ir cells in the BAOT. These are probably projection neurons involved in modulation of defensive, reproductive and autonomic behavior in stress response and creation/storage of aversive memory. However, in comparison with EI group, significant decrease in density of c-Fos-ir cells, in almost all amygdaloid nuclei of EII group was revealed. Particularly in BAOT and Me the strong decrease of activity of NOS- and CR-ir neurons was observed. It probably results in attenuation of stress responses what, depending on the circumstances, can be adaptive or maladaptive.
... A more direct pathway also exists and links ERh directly to the CA1 (10) (see detailed anatomical organization of the hippocampus in ref. 11). Recent longitudinal structural neuroimaging studies in monkeys revealed an increase in overall hippocampal volume, as well as changes in the ratio of hippocampal gray to white matter from birth to 2 y of age (12,13). These volumetric changes have been associated with significant microstructural and neurochemical changes, as well as fine tuning of intrinsic synaptic connections that span several years after birth (14)(15)(16). ...
Nonhuman primates provide highly valuable animal models that have significantly advanced our understanding of numerous behavioral and biological phenomena in humans. Here, we reviewed a series of developmental neuropsychological studies that informed us on the timing of development of the hippocampus and of hippocampal-dependent cognitive functions in primates. Data indicate that, in primates, the emergence of adult-like proficiency on behavioral tasks sensitive to hippocampal dysfunction is a stepwise process and reflects the gradual maturation of different hippocampal circuits and their connections with other neural structures. Profound and persistent memory loss resulting from insult to the hippocampus in infancy was absent in early infancy but became evident later in childhood and persisted in adulthood, indicating very little sparing or recovery of function. Finally, the early hippocampal insult resulted in both adaptive and maladaptive neuroplasticity: i.e., sparing contextual memory, but affecting working memory processes as well as emotional reactivity and hypothalamic–pituitary–adrenal (HPA) axis functioning. The results provide significant information on the emergence of hippocampal-dependent functions in humans, on the time course of memory impairment in human cases with early hippocampal insult, and on the clinical implication of the hippocampus in developmental neuropsychiatric disorders.
... These data shed light on the role of psychosocial stress and E2 on the functional plasticity of system-level emotional circuits of the brain using a highly translational model of female social subordination and provide insight into possible mechanisms of adaptation to these environments that may exacerbate risk of developing stress-related disorders in women. Amygdala Seed and Whole-brain FC. (A) Amygdala ROIs were derived from an automated pipeline (AutoSeg version 2.6.2, as described in (54,56,57)), and manually edited using published anatomical criteria for the macaque brain (58)(59)(60)94). ROIs were registered to the F99 atlas, resampled to EPI resolution (1.5mm 3 , blue/red), and eroded (green/yellow) to prevent overlap with regions of temporal lobe signal drop-out common in EPI scans. ...
Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behavior through the modification of amygdala and medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical to understanding the neurobiology underpinning vulnerability to stress-related disorders in women. Here, we used a well-validated rhesus monkey model of chronic psychosocial stress (subordinate social rank) to examine effects of E2 on subordinate (SUB) -high stress- and dominant (DOM) -low stress- female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviors, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate social rank alters amygdala FC and E2's impact on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.
... In the present study, we mainly focused on the effect of hormones on the adolescence period. Neuroscientists have begun to discover the substantial structural and functional remodelling of the brain, particularly in limbic and cortical regions, which occurs during adolescent development (Payne et al., 2010;Piekarski et al., 2017). Many studies have reported that EDCs might increase the risk of early neurodevelopmental disorders in children by interfering with the processes regulating endogenous hormones (Kim et al., 2011;Whyatt et al., 2012;Harley et al., 2013;Tewar et al., 2016). ...
17β-Trenbolone (17β-TBOH) is an endocrine disruptor that has been widely reported in aquatic organisms. However, little is known about the effect of 17β-TBOH on mammals, particularly on the development of adolescents. Through a series of behavioural experiments, exposure to at 80 μg kg -1 d -1 and 800 μg kg -1 d -1 17β-TBOH during puberty (from PND 28 to 56, male mice) increased anxiety-like behaviours. Exposure to the low dose of 80 μg kg -1 d -1 resulted in a clear social avoidance behaviour in mice. The two doses affected testicular development and endogenous androgen synthesis in male mice. In addition, 17β-TBOH exposure altered the differentiation of oligodendrocytes and the formation of the myelin sheath in the medial prefrontal cortex (mPFC). These results reveal the effects of 17β-TBOH on the behaviours, gonadal and neurodevelopment of adolescent mammals. In addition, the inhibition of the secretion of endogenous hormones and decrease in the formation of the myelin sheath in mPFC may be associated with the 17β-TBOH-induced behavioural changes in mice.
... This knowledge has largely come from research on adult humans and animals. Yet, the amygdala has a protracted postnatal development (Payne et al., 2010;Chareyron et al., 2012;Hunsaker et al., 2014), in which growth of the amygdala appears to coincide with the refinement of social and threat-detecting skills (Mendelson, 1982;Mendelson et al., 1982;Kalin et al., 1991). Investigations of how amygdala development contributes to these skills have largely used permanent lesion techniques, finding that damage to the amygdala during the early postnatal period contributes to life-long changes in social, emotional, and neuroendocrine function (Bauman et al., 2004;Bliss-Moreau et al., 2010, 2011a,b, 2017Raper et al., 2013bRaper et al., , 2014aStephens et al., 2015;Moadab et al., 2017). ...
Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low-dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eye-tracking task, compared with vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent amygdala lesions in infant monkeys, such that neonatal lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results may help support the notion that the more extensive behavior changes seen after early lesions are manifested from brain reorganization that occur after permanent damage. The current study provides a proof of principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior.
... These conditions exceed any normative range of expected caregiving (McLaughlin, Sheridan, & Nelson, 2017;Tottenham, 2012a), and therefore, act as a potent stressor on infant brain development (e.g., Gee et al., 2013;Gunnar, Frenn, Wewerka, & Van Ryzin, 2009;McLaughlin et al., 2015). Biological systems like the amygdala and hypothalamic-pituitary-adrenal axis (HPA) are particularly sensitive to such stressors due in part to their early development (Gilmore et al., 2012;Humphrey, 1968;Payne, Machado, Bliwise, & Bachevalier, 2010;Ulfig, Setzer, & Bohl, 2003) and to an abundance of stress hormone receptors, which animal models have shown are already present in early postnatal life (Avishai-Eliner, Yi, & Baram, 1996;Fenoglio, Brunson, Avishai-Eliner, Chen, & Baram, 2004). Moreover, administration of stress hormones has been causally linked to amygdala hyperactivity in the developing rodent (Baram, Hirsch, Snead, & Schultz, 1992). ...
Adverse caregiving, for example, previous institutionalization (PI), is often associated with emotion dysregulation that increases anxiety risk. However, the concept of developmental multifinality predicts heterogeneity in anxiety outcomes. Despite this well-known heterogeneity, more work is needed to identify sources of this heterogeneity and how these sources interact with environmental risk to influence mental health. Here, working memory (WM) was examined during late childhood/adolescence as an intra-individual factor to mitigate the risk for separation anxiety, which is particularly susceptible to caregiving adversities. A modified “object-in-place” task was administered to 110 youths (10–17 years old), with or without a history of PI. The PI youths had elevated separation anxiety scores, which were anticorrelated with morning cortisol levels, yet there were no group differences in WM. PI youths showed significant heterogeneity in separation anxiety symptoms and morning cortisol levels, and WM moderated the link between caregiving and separation anxiety and mediated the association between separation anxiety and morning cortisol in PI youth. Findings suggest that (a) institutional care exerts divergent developmental consequences on separation anxiety versus WM, (b) WM interacts with adversity-related emotion dysregulation, and (c) WM may be a therapeutic target for separation anxiety following early caregiving adversity.
... Like humans, the rhesus macaque brain undergoes protracted postnatal development and is not fully mature until 3-4 years of age (Knickmeyer et al., 2010;Málková, Heuer, & Saunders, 2006;Payne, Machado, Bliwise, & Bachevalier, 2010). Thus, the early timing of the lesions in our study (approximately 2 weeks of age) allows for the possibility of functional compensation by other brain regions. ...
Perceiving, integrating, and interpreting multimodal signals are essential for social success, but the neural substrates mediating these functions are not fully understood. This study examined the role of the amygdala in processing bimodal species-specific vocalizations using eye tracking in rhesus macaques. Looking behavior of 6 adult rhesus monkeys with neonatal amygdala lesions (Neo-Aibo; 3M, 3F) was compared with that of 6 sham-operated controls (Neo-C; 3M, 3F). Two side-by-side videos of unknown male conspecifics emitting different vocalizations were presented with the audio signal matching one video. The percentage of time spent looking at each video was used to assess crossmodal integration ability and the percentages of time spent looking at a priori regions of interest (ROIs; eyes, mouth, and rest of each video) were used to characterize scanning patterns. Both groups looked more to one video, indicating that early amygdalar damage did not impair crossmodal integration of complex social signals. However, scanning patterns differed across groups as a function of sex and stimulus parameter. Whereas Neo-C males exhibited differential viewing to the eye and mouth regions as a function of the relative identity of the stimulus animals and Neo-C females made similar distinctions as a function of the relative valence of the vocalizations in females, Neo-Aibo males and females scanned these regions similarly across all trial types. The results suggest that neonatal amygdala damage alters the ability to perceive the social relevance of stimulus features, and are consistent with a role of the amygdala in the recognition of the social salience of complex cues.
... This knowledge has largely come from research on adult humans and animals. Yet, the amygdala has a protracted postnatal development (Payne et al., 2010;Chareyron et al., 2012;Hunsaker et al., 2014), in which growth of the amygdala appears to coincide with refinement of social and threat detecting skills (Mendelson, 1982;Mendelson et al., 1982.;Kalin et al., 1991). ...
Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eyetracking task, compared to vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent lesions of the amygdala in infant monkeys, such that early amygdala lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results support the notion that early permanent damage leads to brain reorganization manifesting in a broader impact on behavior. The current study provides a proof-of-principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior.
Statement of Significance
Many neurodevelopmental disorders exhibit abnormal structural or functional amygdala development and alterations in socioemotional behavior. To date, developmental neuroscience studies have relied on permanent lesions techniques to investigate how atypical amygdala development impacts socioemotional behaviors, which may not adequately recapitulate the role of amygdala dysfunction in the manifestation of aberrant behavior. The present study sought to demonstrate that the DREADDs (designer receptors exclusively activated by designer drugs) chemogenetic tool could transiently inhibit amygdala activity in infant monkeys resulting in alterations in socioemotional behavior. This proof-of-principle study supports the use of chemogenetics for developmental neuroscience research, providing an opportunity to broaden our understanding of how changes in neuronal activity across early postnatal development influences behavior and clinical symptoms.
... First, from infancy to adolescence, hippocampal gray volume increases nonlinearly with its volume peaking from 9-11 years old (Raz et al., 2005;Uematsu et al., 2012;Voineskos et al., 2015). A similar pattern is observed for the amygdala with its volume peaking within the same age range (Payne, Machado, Bliwise, & Bachevalier, 2010;Uematsu et al., 2012). In more extreme cases of early adversity, such as maternal deprivation, amygdala functional connectivity to the prefrontal cortex has been shown to reach more mature, adult-like patterns earlier compared with children who had not experienced maternal deprivation (Gee et al., 2013). ...
Socioeconomic disadvantage is associated with higher rates of psychopathology as well as hippocampus, amygdala and prefrontal cortex structure. However, little is known about how variations in brain morphometry are associated with socio-emotional risks for mood disorders in children growing up in families experiencing low income. In the current study, using structural magnetic resonance imaging, we examined the relationship between socioeconomic disadvantage and gray matter volume in the hippocampus, amygdala, and ventrolateral prefrontal cortex in a sample of children (n = 34) in middle childhood. Using an affective dot probe paradigm, we examined the association between gray matter volume in these regions and attentional bias to threat, a risk marker for mood disorders including anxiety disorders. We found that lower income-to-needs ratio was associated with lower bilateral hippocampal and right amygdala volume, but not prefrontal cortex volumes. Moreover, lower attentional bias to threat was associated with greater left hippocampal volume. We provide evidence of a relationship between income-related variations in brain structure and attentional bias to threat, a risk for mood disorders. Therefore, these findings support an environment-morphometry-behavior relationship that contributes to the understanding of income-related mental health disparities in childhood.
... This anatomical refinement of connections, presumably due to experience, could increase the functional strength of remaining TE inputs to AMY neurons. Together with significant volumetric increase and morphological changesincluding myelinationwithin the AMY during the first 3 months postpartum in monkeys (Payne et al. 2010;Chareyron et al. 2012), the fine-tuning of TE-AMY connections may enable greater precision in the evaluation of social stimuli and faces in particular. ...
Early social interactions shape the development of social behavior, although the critical periods or the underlying neurodevelopmental processes are not completely understood. Here, we studied the developmental changes in neural pathways underlying visual social engagement in the translational rhesus monkey model. Changes in functional connectivity (FC) along the ventral object and motion pathways and the dorsal attention/visuo-spatial pathways were studied longitudinally using resting-state functional MRI in infant rhesus monkeys, from birth through early weaning (3 months), given the socioemotional changes experienced during this period. Our results revealed that (1) maturation along the visual pathways proceeds in a caudo-rostral progression with primary visual areas (V1-V3) showing strong FC as early as 2 weeks of age, whereas higher-order visual and attentional areas (e.g., MT-AST, LIP-FEF) show weak FC; (2) functional changes were pathway-specific (e.g., robust FC increases detected in the most anterior aspect of the object pathway (TE-AMY), but FC remained weak in the other pathways (e.g., AST-AMY)); (3) FC matures similarly in both right and left hemispheres. Our findings suggest that visual pathways in infant macaques undergo selective remodeling during the first 3 months of life, likely regulated by early social interactions and supporting the transition to independence from the mother.
... Although functional networks continue segregating through adolescence, these spatial patterns of connectivity suggest core network components differentiating the sub-regions are in place early. This set of findings is consistent with evidence that amygdala sub-regions segregate structurally early in development [Humphrey, 1968;Payne et al., 2010;Ulfig et al., 2003;Saygin et al., 2015]. Several patterns emerged across the sub-regions' connectivity in infancy and early childhood distinguishing this period from amygdala networks in later developmental periods. ...
Although the amygdala’s role in shaping social behavior is especially important during early post-natal development, very little is known of amygdala functional development before childhood. To address this gap, this study uses resting-state fMRI to examine early amygdalar functional network development in a cross-sectional sample of 80 children from 3-months to 5-years of age. Whole brain functional connectivity with the amygdala, and its laterobasal and superficial sub-regions, were largely similar to those seen in older children and adults. Functional distinctions between sub-region networks were already established. These patterns suggest many amygdala functional circuits are intact from infancy, especially those that are part of motor, visual, auditory and subcortical networks. Developmental changes in connectivity were observed between the laterobasal nucleus and bilateral ventral temporal and motor cortex as well as between the superficial nuclei and medial thalamus, occipital cortex and a different region of motor cortex. These results show amygdala-subcortical and sensory-cortex connectivity begins refinement prior to childhood, though connectivity changes with associative and frontal cortical areas, seen after early childhood, were not evident in this age range. These findings represent early steps in understanding amygdala network dynamics across infancy through early childhood, an important period of emotional and cognitive development.
Keywords
amygdala development early childhood resting-state functional connectivity infancy
... Child and adolescent development involve dynamic changes in frontoamygdala circuitry, which may contribute to heightened risk for anxiety at specific developmental stages. Cross-species evidence suggests that the amygdala matures earlier than the PFC (Chareyron, Lavenex, Amaral, & Lavenex, 2012;Lenroot & Giedd, 2006;Machado & Bachevalier, 2003;Payne, Machado, Bliwise, & Bachevalier, 2010). Children show robust amygdala reactivity to fearful faces and other emotional stimuli during typical development, with reactivity typically decreasing following childhood (Decety, Michalska, & Kinzler, 2012;Gee, Gabard-Durnam, et al., 2013;Gee, Humphreys, et al., 2013;Silvers, Shu, Hubbard, Weber, & Ochsner, 2015;Swartz, Carrasco, Wiggins, Thomason, & Monk, 2014;Vink, Derks, Hoogendam, Hillegers, & Kahn, 2014). ...
Anxiety disorders are among the most prevalent psychiatric disorders in youth; however, progress in treatment for childhood anxiety has stalled over the past decade. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) project represents a shift toward a dimensional and interdisciplinary approach to psychiatric disorders; this shift can reframe developmental psychopathology for childhood anxiety and facilitate novel advances in its classification and treatment. Here we highlight constructs in the Systems for Social Processes and the Negative Valence System domains of RDoC, as they relate to childhood anxiety disorders. Childhood anxiety relates to both RDoC domains. In terms of social processes, through natural reliance on parents to reduce children's fear, attachment represents one particular social process, which plays a central role in anxiety among youth. In terms of negative valence, considerable research links threat conditioning to pediatric anxiety. Finally, fronto-amygdala circuitry relates to all three entities, as it has been shown to underly both attachment processes and threat learning, while it also has been consistently implicated in anxiety disorders across development. Through integrative and translational approaches, RDoC provides unique opportunities and simultaneous challenges for advancing the understanding and treatment of childhood anxiety disorders.
... Second, our rearing protocol produces species-typical caregiver attachment and developmental pattern in emotional behavior on the HI task and cognitive skills similar to those reported in mother-reared monkeys (Goursaud & Bachevalier, 2007;Kalin et al., 1991;Raper et al., 2013b;Zeamer, Heuer, & Bachevalier, 2010). In addition, our developmental neuroimaging studies indicated that changes in hippocampal volume from infancy to two years of age are remarkably comparable in animals raised in our nursery-enriched protocol (Payne, Machado, Bliwise, & Bachevalier, 2010) and those raised by their mothers in a social group (Hunsaker, Scott, Bauman, Schumann, & Amaral, 2014). Finally, the Neo-Aibo and Neo-Hibo animals discussed earlier have been shown to have distinct and dissociable changes in emotional reactivity as compared to controls. ...
The medial temporal lobe (MTL) is a collection of brain regions best known for their role in perception, memory, and emotional behavior. Within the MTL, the perirhinal cortex (PRh) plays a critical role in perceptual representation and recognition memory, although its contribution to emotional regulation is still debated. Here, rhesus monkeys with neonatal perirhinal lesions (Neo-PRh) and controls (Neo-C) were tested on the Human Intruder (HI) task at 2 months, 4.5 months, and 5 years of age to assess the role of the PRh in the development of emotional behaviors. The HI task presents a tiered social threat to which typically developing animals modulate their emotional responses according to the level of threat. Unlike animals with neonatal amygdala or hippocampal lesions, Neo-PRh animals were not broadly hyper- or hyporesponsive to the threat presented by the HI task as compared with controls. Instead, Neo-PRh animals displayed an impaired ability to modulate their freezing and anxiety-like behavioral responses according to the varying levels of threat. Impaired transmission of perceptual representation generated by the PRh to the amygdala and hippocampus may explain the animals' inability to appropriately assess and react to complex social stimuli. Neo-PRh animals also displayed fewer hostile behaviors in infancy and more coo vocalizations in adulthood. Neither stress-reactive nor basal cortisol levels were affected by the Neo-PRh lesions. Overall, these results suggest that the PRh is indirectly involved in the expression of emotional behavior and that effects of Neo-PRh lesions are dissociable from neonatal lesions to other temporal lobe structures.
Early development of postnatal corticolimbic circuitry is vulnerable to challenges from the early environment. Prior work has shown hyper-innervation of glutamatergic basolateral amygdala (BLA) projections to the prefrontal cortex (PFC) in the adolescent timeperiod following rearing in an adverse early life environment, but how these ELA-induced connectivity changes alter the startle circuitry required to execute a startle response and whether the BLA-PFC pathway is responsible for previously reported blunted startle response remains unknown. We directly tested whether BLA activity during a discrete adolescent period altered later anxiety behaviors, and if behavioral changes were driven by altered PFC innervation. To test these questions, we exposed rat pups to an ELA model of maternal separation on postnatal days (P) 2-21. Rats then underwent an injection of an inhibitory DREADD in the BLA in order to silence the excitatory projections during the adolescent time period of P33-39. Finally, rats were tested in an acoustic startle paradigm in late adolescence to assess the effects of reduced BLA-PFC connectivity on the ELA-induced blunted startle response. Density, intensity, and volume of axonal boutons in the BLA projecting PFC neurons were then assessed to elucidate how BLA inhibition during adolescence affects innervation later in life. These results explore how altered early life environments may affect the development of anxiety-related circuitry and anxiety responses later in life, and how rescue of this maladaptive response may be sex and developmentally specific.
Depression is a serious public health problem, and adolescence is an ‘age of risk’ for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico‐amygdala circuit, lowers sensitivity to rewards in the cortico‐striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self‐medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress‐related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a ‘next generation’ of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents.
Zika virus (ZIKV) infection during infancy in a rhesus macaque (RM) model negatively impacts brain development resulting in long-term behavioral alterations. The current study investigated whether postexposure prophylaxis could alleviate these negative neurodevelopmental consequences. Three RM infants received a 14-day course of sofosbuvir (SOF; 15 mg/kg p.o.) treatment starting at 3 days post-infection with a Puerto Rican strain of ZIKV (PRVABC59) and were then monitored longitudinally for one year. In contrast to ZIKV-infected infant RMs who did not receive SOF, postexposure SOF treatment mitigated the neurodevelopmental, behavioral and cognitive changes seen after postnatal ZIKV infection even while not accelerating viral clearance from the blood. These data suggest that antiviral treatment may help ameliorate some, but not all, of the neurodevelopmental abnormalities associated with early postnatal ZIKV infection.
This study examined the role of male pubertal maturation on physical growth and development of neurocircuits that regulate stress, emotional and cognitive control using a translational nonhuman primate model. We collected longitudinal data from male macaques between pre- and peri-puberty, including measures of physical growth, pubertal maturation (testicular volume, blood testosterone -T- concentrations) and brain structural and resting-state functional MRI scans to examine developmental changes in amygdala (AMY), hippocampus (HIPPO), prefrontal cortex (PFC), as well as functional connectivity (FC) between those regions.Physical growth and pubertal measures increased from pre- to peri-puberty. The indexes of pubertal maturation -testicular size and T- were correlated at peri-puberty, but not at pre-puberty (23 months). Our findings also showed ICV, AMY, HIPPO and total PFC volumetric growth, but with region-specific changes in PFC. Surprisingly, FC in these neural circuits only showed developmental changes from pre- to peri-puberty for HIPPO-orbitofrontal FC. Finally, testicular size was a better predictor of brain structural maturation than T levels -suggesting gonadal hormones-independent mechanisms-, whereas T was a strong predictor of functional connectivity development. We expect that these neural circuits will show more drastic pubertal-dependent maturation, including stronger associations with pubertal measures later, during and after male puberty.
Adverse social experience during childhood and adolescence leads to developmental alterations in emotional and stress regulation and underlying neurocircuits. We examined the consequences of social subordination (low social rank) in juvenile female rhesus monkeys, as an ethologically valid model of chronic social stressor exposure, on brain structural and behavioral development through the pubertal transition. Adolescence is a developmental period of extensive brain remodeling and increased emotional and stress reactivity. Puberty-induced increases in gonadal hormones, particularly estradiol (E2), are likely involved due to its organizational effects on the brain and behavior. Thus, we also examined how experimentally delaying pubertal onset with Lupron (gonadotropin releasing hormone -GnRH- agonist used clinically to delay early puberty) interacted with social rank (dominant vs. subordinate) to affect brain and behavioral outcomes. Using a longitudinal experimental design, structural MRI (sMRI) scans were collected on socially housed juvenile female rhesus monkeys living in indoor-outdoor enclosures prior to the onset of puberty (18-25 months), defined as menarche or the initial occurrence of perineal swelling and coloration, and again at 29-36 months, when all control animals had reached puberty but none of the Lupron-treated had. We examined the effects of both social rank and pubertal delay on overall structural brain volume (i.e. intracranial, grey matter (GM) and white matter (WM) volumes), as well as on cortico-limbic regions involved in emotion and stress regulation: amygdala (AMYG), hippocampus (HC), and prefrontal cortex (PFC). Measures of stress physiology, social behavior, and emotional reactivity were collected to examine functional correlates of the brain structural effects. Apart from expected developmental effects, subordinates had bigger AMYG volumes than dominant animals, most notably in the right hemisphere, but pubertal delay with Lupron-treatment abolished those differences, suggesting a role of gonadal hormones potentiating the brain structural impact of social stress. Subordinates also had elevated baseline cortisol, indicating activation of stress systems. In general, Lupron-treated subjects had smaller AMYG and HC volume than controls, but larger total PFC (driven by bigger GM volumes), and different, region-specific, developmental patterns dependent on age and social rank. These findings highlight a region-specific effect of E2 on structural development during female adolescence, independent of those due to chronological age. Pubertal delay and AMYG volume, in turn, predicted differences in emotional reactivity and social behavior. These findings suggest that exposure to developmental increases in E2 modifies the consequences of adverse social experience on the volume of cortico-limbic regions involved in emotional and stress regulation during maturation. But, even more importantly, they indicate different brain structural effects of chronological age and pubertal developmental stage in females, which are very difficult to disentangle in human studies. These findings have additional relevance for young girls who experience prolonged pubertal delays or for those whose puberty is clinically arrested by pharmacological administration of Lupron.
Interactions between the amygdala and prefrontal cortex are fundamental to human emotion. Despite the central role of frontoamygdala communication in adult emotional learning and regulation, little is known about how top-down control emerges during human development. In the present cross-sectional pilot study, we experimentally manipulated prefrontal engagement to test its effects on the amygdala during development. Inducing dorsal anterior cingulate cortex (dACC) activation resulted in developmentally-opposite effects on amygdala reactivity during childhood versus adolescence, such that dACC activation was followed by increased amygdala reactivity in childhood but reduced amygdala reactivity in adolescence. Bayesian network analyses revealed an age-related switch between childhood and adolescence in the nature of amygdala connectivity with the dACC and ventromedial PFC (vmPFC). Whereas adolescence was marked by information flow from dACC and vmPFC to amygdala (consistent with that observed in adults), the reverse information flow, from the amygdala to dACC and vmPFC, was dominant in childhood. The age-related switch in information flow suggests a potential shift from bottom-up co-excitatory to top-down regulatory frontoamygdala connectivity and may indicate a profound change in the circuitry supporting maturation of emotional behavior. These findings provide novel insight into the developmental construction of amygdala-cortical connections and implications for the ways in which childhood experiences may influence subsequent prefrontal function.
The evolution of the human brain following the split from the last common ancestor of hominins and Pan has involved a substantial increase in size as well as modifications to the internal, cellular organization. These changes were likely achieved through modifications in the timing and rate of development during hominin evolution. The result of those changes is a uniquely derived developmental trajectory of the brain in humans compared to non-human primates, which includes an accelerated rate of growth prenatally and in infancy, prolonged development, and substantial postnatal plasticity. The outcome of these evolutionary modifications is significant brain growth and development occurring postnatally. This allows the brain to be shaped by the physical and social environment outside of the uterus to a greater degree than is seen in non-human primates, contributing to the cognitive flexibility, intelligence, and brain plasticity of humans.
Adversity early in life is common and is a major risk factor for the onset of psychopathology. Delineating the neurodevelopmental pathways by which early adversity affects mental health is critical for early risk identification and targeted treatment approaches. A rapidly growing cross-species literature has facilitated advances in identifying the mechanisms linking adversity with psychopathology, specific dimensions of adversity and timing-related factors that differentially relate to outcomes, and protective factors that buffer against the effects of adversity. Yet, vast complexity and heterogeneity in early environments and neurodevelopmental trajectories contribute to the challenges of understanding risk and resilience in the context of early adversity. In this overview, the author highlights progress in four major areas-mechanisms, heterogeneity, developmental timing, and protective factors; synthesizes key challenges; and provides recommendations for future research that can facilitate progress in the field. Translation across species and ongoing refinement of conceptual models have strong potential to inform prevention and intervention strategies that can reduce the immense burden of psychopathology associated with early adversity.
Pediatric traumatic brain injury (TBI) is a public health crisis, with neurobehavioral morbidity observed years after an injury associated with changes in related brain structures. A substantial literature base has established family environment as a significant predictor of neurobehavioral outcomes following pediatric TBI. The neural mechanisms linking family environment to neurobehavioral outcomes has however, received less empiric study in this population. In contrast, limbic structural differences as well as challenges with emotional adjustment and behavioral regulation in non-TBI populations have been linked to a multitude of family environmental factors, including family stress, parenting style, and adverse childhood experiences (ACEs). In this paper, we systematically reviewed the more comprehensive literature on family environment and neurobehavioral outcomes in pediatric TBI and leveraged the work in both TBI and non-TBI populations to expand our understanding of the underlying neural mechanisms. Thus, we summarize the extant literature on the family environment’s role in neurobehavioral sequelae in children with TBI and explore potential neural correlates by synthesizing the wealth of literature on family environment and limbic development, specifically related to the amygdala. This review underscores the critical role of environmental factors, especially those predating the injury, in modeling recovery outcomes post-TBI in childhood, and discusses clinical and research implications across pediatric populations. Given the public health crisis of pediatric TBI, along with the context of sparse available medical interventions, a broader understanding of factors contributing to outcomes is warranted to expand the range of intervention targets.
Fear and safety learning are necessary adaptive behaviors that develop over the course of maturation. While there is a large body of literature regarding the neurobiology of fear and safety learning in adults, less is known regarding safety learning during development. Given developmental changes in the brain, there are corresponding changes in safety learning that are quantifiable; these may serve to predict risk and point to treatment targets for fear and anxiety-related disorders in children and adolescents. For healthy, typically developing youth, the main developmental variation observed is reduced discrimination between threat and safety cues in children compared to adolescents and adults, while lower expression of extinction learning is exhibited in adolescents compared to adults. Such distinctions may be related to faster maturation of the amygdala relative to the prefrontal cortex, as well as incompletely developed functional circuits between the two. Fear and anxiety-related disorders, childhood maltreatment, and behavioral problems are all associated with alterations in safety learning for youth, and this dysfunction may proceed into adulthood with corresponding abnormalities in brain structure and function-including amygdala hypertrophy and hyperreactivity. As impaired inhibition of fear to safety may reflect abnormalities in the developing brain and subsequent psychopathology, impaired safety learning may be considered as both a predictor of risk and a treatment target. Longitudinal neuroimaging studies over the course of development, and studies that query change with interventions are needed in order to improve outcomes for individuals and reduce long-term impact of developmental psychopathology.
Early caregiving experiences play a central role in shaping corticolimbic development and emotional learning and regulation. Given dynamic changes in corticolimbic maturation, the effects of caregiving experiences are likely to depend on the developmental timing of exposure. Cross-species evidence has identified timing-related differences in the effects of caregiving adversity. However, the extent to which developmental differences in associations between caregiving adversity and corticolimbic circuitry align with a sensitive period model has remained unclear. Converging evidence from studies of caregiver deprivation points to a sensitive period for caregiving influences on corticolimbic circuitry and emotional development during infancy. By contrast, differential associations between maltreatment and corticolimbic circuitry at specific ages in childhood and adolescence may reflect experience-dependent mechanisms of plasticity. Delineating sensitive periods of development and the precise experience-related mechanisms by which caregiving experiences influence corticolimbic development is essential for refining conceptual models and understanding risk and resilience following early adversity.
The ability to anticipate and respond appropriately to the challenges and opportunities present in our environments is critical for adaptive behavior. Recent methodological innovations have led to substantial advances in our understanding of the neurocircuitry supporting such motivated behavior in adulthood. However, the neural circuits and cognitive processes that enable threat- and reward-motivated behavior undergo substantive changes over the course of development, and these changes are less well understood. In this article, we highlight recent research in human and animal models demonstrating how developmental changes in prefrontal-subcortical neural circuits give rise to corresponding changes in the processing of threats and rewards from infancy to adulthood. We discuss how these developmental trajectories are altered by experiential factors, such as early-life stress, and highlight the relevance of this research for understanding the developmental onset and treatment of psychiatric disorders characterized by dysregulation of motivated behavior.
Adolescence is a critical period for postnatal brain maturation and a time during which there is increased susceptibility to developing emotional and cognitive-related disorders. Exercise during adulthood has been shown to increase hippocampal plasticity and enhance cognition. However, the impact of exercise initiated in adolescence, on brain and behaviour in adulthood is not yet fully explored or understood. The aim of this study was to compare the impact of voluntary exercise that was initiated either during adolescence or early adulthood on cognitive performance in hippocampal and amygdala-dependent fear conditioning tasks in adulthood. Adult (eight weeks old) and adolescent (four weeks old) male Sprague Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for seven weeks. Adult-initiated exercise enhanced both contextual and cued fear conditioning, while conversely, exercise that began in adolescence did not affect performance in these tasks. These behaviours were accompanied by differential expression of plasticity-related genes in the hippocampus and amygdala in adulthood. Specifically, adolescent-initiated exercise increased the expression of an array of plasticity related genes in the hippocampus including BDNF, synaptophysin, Creb, PSD-95, Arc, TLX and DCX, while adult-initiated exercise did not affect hippocampal plasticity related genes. Together results show that exercise initiated during adolescence has a differential effect on hippocampal and amygdala-dependent behaviour and neuronal plasticity compared to when exercise was initiated in adulthood. These findings reinforce adolescence as a period during which environmental influences have a distinct impact on neuronal plasticity and cognition.
This article is part of the Special Issue entitled “Neurobiology of Environmental Enrichment”.
Confusion endures as to the exact role of the amygdala in relation to autism. To help resolve this we turned to the NIMH's Research Domain Criteria (RDoC) which provides a classification schema that identifies different categories of behaviors that can turn pathologic in mental health disorders, e.g. autism. While RDoC incorporates all the known neurobiological substrates for each domain, this review will focus primarily on the amygdala. We first consider the amygdala from an anatomical, historical, and developmental perspective. Next, we examine the different domains and constructs of RDoC that the amygdala is involved in: Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Social Processes, and Arousal and Regulatory Systems. Then the evidence for a dysfunctional amygdala in autism is presented with a focus on alterations in development, prenatal valproic acid exposure as a model for ASD, and changes in the oxytocin system therein. Finally, a synthesis of RDoC, the amygdala, and autism is offered, emphasizing the task of disambiguation and suggestions for future research.
Brain development involves spatiotemporally complex microstructural changes. A number of neuropsychiatric disorders are linked to the neural processes of development and aging. Thus, it is important to understanding the typical developmental patterns of various brain structures, which will help to define critical periods of vulnerability for neural maturation, as well as anatomical mechanisms of brain structure-related neuropathology. In this study, we used magnetic resonance imaging to assess development of the orbitofrontal cortex, cingulate cortex, amygdala, and hippocampus in a non-human primate species, the common marmoset (Callithrix jacchus). We collected a total of 114 T2-weighted and 91 diffusion-weighted scans from 23 animals from infancy to early adulthood. Quantitative and qualitative evaluation of age-related brain growth patterns showed non-linear structural developmental changes in all measured brain regions, consistent with reported human data. Overall, robust volumetric growth was observed from 1 to 3 months of age (from infancy to the early juvenile period). This rapid brain growth was associated with the largest decrease in mean, axial, and radial diffusivities of diffusion tensor imaging in all brain regions, suggesting an increase in the number and size of cells, dendrites, and spines during this period. After this developmental period, the volume of various brain regions steadily increased until adolescence (7-13 months of age, depending on the region). Further, structural connectivity derived from tractography data in various brain regions continuously changed from infancy to adolescence, suggesting that the increase in brain volume was related to continued axonal myelination during adolescence. Thereafter, the volume of the cortical regions decreased considerably, while there was no change in subcortical regions. Familial factors, rather than sex, contributed the development of the front-limbic brain regions. Overall, this study provides further data on the factors and timing important for normal brain development, and suggest that the common marmoset is a useful animal model for human neural development.
Children and adults were tested on 3 place learning tasks. Children under the age of 7 were inferior to older subjects in solving the tasks by using spatial relational solutions, but subjects of all ages were equally proficient in solving the task by using simple stimulus–reward associations (cued solutions). Accurate performance on the cued versions suggests that neither the general response demands nor the large size of testing environments rendered the tasks differentially inappropriate for young children. Instead, the nature of the cognitive demands were responsible for different levels of performance across the age groups. Because, in animal studies, spatial relational solutions but not cued solutions of these tests require mature and undamaged medial temporal lobe structures, the results suggest that these systems are not fully developed in humans before approximately 7 years of age.
Morphological studies suggest that the primate hippocampus develops extensively before birth, but little is known about its functional development. Patch-clamp recordings of hippocampal neurons and reconstruction of biocytin-filled pyramidal cells were performed in slices of macaque cynomolgus fetuses delivered by cesarean section. We found that during the second half of gestation, axons and dendrites of pyramidal cells grow intensively by hundreds of micrometers per day to attain a high level of maturity near term. Synaptic currents appear around midgestation and are correlated with the level of morphological differentiation of pyramidal cells: the first synapses are GABAergic, and their emergence correlates with the growth of apical dendrite into stratum radiatum. A later occurrence of glutamatergic synaptic currents correlates with a further differentiation of the axodendritic tree and the appearance of spines. Relying on the number of dendritic spines, we estimated that hundreds of new glutamatergic synapses are established every day on a pyramidal neuron during the last third of gestation. Most of the synaptic activity is synchronized in spontaneous slow ( approximately 0.1 Hz) network oscillations reminiscent of the giant depolarizing potentials in neonatal rodents. Epileptiform discharges can be evoked by the GABA(A) receptor antagonist bicuculline by the last third of gestation, and postsynaptic GABA(B) receptors contribute to the termination of epileptiform discharges. Comparing the results obtained in primates and rodents, we conclude that the template of early hippocampal network development is conserved across the mammalian evolution but that it is shifted toward fetal life in primate.
Brain development in the first 2 years after birth is extremely dynamic and likely plays an important role in neurodevelopmental disorders, including autism and schizophrenia. Knowledge regarding this period is currently quite limited. We studied structural brain development in healthy subjects from birth to 2. Ninety-eight children received structural MRI scans on a Siemens head-only 3T scanner with magnetization prepared rapid gradient echo T1-weighted, and turbo spin echo, dual-echo (proton density and T2 weighted) sequences: 84 children at 2-4 weeks, 35 at 1 year and 26 at 2 years of age. Tissue segmentation was accomplished using a novel automated approach. Lateral ventricle, caudate, and hippocampal volumes were also determined. Total brain volume increased 101% in the first year, with a 15% increase in the second. The majority of hemispheric growth was accounted for by gray matter, which increased 149% in the first year; hemispheric white matter volume increased by only 11%. Cerebellum volume increased 240% in the first year. Lateral ventricle volume increased 280% in the first year, with a small decrease in the second. The caudate increased 19% and the hippocampus 13% from age 1 to age 2. There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth. In contrast, white matter growth was much slower. Cerebellum volume also increased substantially in the first year of life. These results suggest the structural underpinnings of cognitive and motor development in early childhood, as well as the potential pathogenesis of neurodevelopmental disorders.
The emergence of stereotypies was examined in juvenile rhesus monkeys (Macaca mulatta) who, at 2 weeks of postnatal age, received selective bilateral ibotenic acid lesions of the amygdala (N = 8) or hippocampus (N = 8). The lesion groups were compared to age-matched control subjects that received a sham surgical procedure (N = 8). All subjects were maternally reared for the first 6 months and provided access to social groups throughout development. Pronounced stereotypies were not observed in any of the experimental groups during the first year of life. However, between 1 to 2 years of age, both amygdala- and hippocampus-lesioned subjects began to exhibit stereotypies. When observed as juveniles, both amygdala- and hippocampus-lesioned subjects consistently produced more stereotypies than the control subjects in a variety of contexts. More interesting, neonatal lesions of either the amygdala or hippocampus resulted in unique repertoires of repetitive behaviors. Amygdala-lesioned subjects exhibited more self-directed stereotypies and the hippocampus-lesioned subjects displayed more head-twisting. We discuss these results in relation to the neurobiological basis of repetitive stereotypies in neurodevelopmental disorders, such as autism.
The nature of proliferative cells in the subgranular zone (SGZ) of the hippocampal region and the fate of their progeny was analyzed by 3H-thymidine (3H-TdR) autoradiography combined with immunocytochemistry at the light and electron microscopic levels in 18 rhesus monkeys ranging in age from late gestation to 17 years. Our analysis indicates that, during the last quarter of gestation and the first 3 postnatal months, the SGZ produces both glial and neuronal cells. These 2 major classes of cells originate from the 2 precursor lines and, following their mitotic division, migrate to the granular layer. During the juvenile period (4-6 months of age), neuronal production tapers off and most postmitotic cells remaining within the SGZ differentiate into glial elements. In postpubertal animals (3 years and older), the 3H-TdR-labeled cells in the dentate gyrus belong to several non-neuronal classes. The largest group was immunoreactive to the glial fibrillary acidic protein (GFAP) at both the light and electron microscopic levels, indicating their astrocytic nature. The remaining 3H-TdR-labeled, GFAP-negative cells had ultra-structural characteristics of either microglia, oligodendroglia, or their progenitory stem cells. Therefore, there is a continuing addition and/or turnover of the glial cells in the dentate gyrus of sexually mature monkeys, but, in contrast to the massive neurogenesis reported in adult rodents, the production of new neurons could not be detected after puberty. The significance of a stable population of neurons in the hippocampal formation of mature primates is discussed in relation to its possible function in memory.
Structural brain-imaging measurements based on computed tomography (CT) or magnetic resonance imaging (MRI) are often corrected or adjusted for normal variation in head size. Some methods of head-size correction, such as the ventricle-brain ratio (VBR), are based on taking the brain structure size as a proportion of the estimated head size, while other methods have used a regression model to obtain head-size residualized structure measures. Recently, head-size correction was shown to result in less reliable volumetric measures of brain structures (Arndt et al., 1991). In the present study, MRI was used to examine the effects of head-size correction on the interrater reliability of volumetric measures of gray matter, white matter, and cerebrospinal fluid. Four raters independently scored MRI brain images from 26 subjects, generating separate estimates of head size and region of interest (ROI) size. Two methods were used to correct MRI values for differences in head size, one based on proportions and the other based on linear regression. Results confirmed that head-size correction did produce measures with lower reliability; however, further analysis based on classical measurement theory showed that the lower reliability was attributable not only to increased measurement error variance, but also to reduced true score variance. Subsequent analyses of criterion validity compared the raw (uncorrected) and head-size-corrected ROI measures in terms of their correlations with age in a sample of 43 normal control subjects, and in terms of their ability to differentiate schizophrenic patients (n = 22) from normal control subjects (n = 20). Results indicated that head-size correction often improved criterion validity, producing higher correlations with age and with diagnostic status than those produced by the raw measures. These findings suggest that head-size correction removes irrelevant true-score variance which reduces reliability yet improves the correlations with validity criteria such as age and diagnostic status.
Volumetric magnetic resonance image (MRI)-based morphometry was performed on the brains of 30 normal children (15 males and 15 males) with a mean age of 9 years (range 7-11 years). This age range lies in a late but critical phase of brain growth where not volumetric increment will be small but when the details of brain circuity are being fine-tuned to support the operations of the adult brain. The brain at this age is 95% the volume of the adult brain. The brain of the female child is 93% the volume of the male child. For more than 95% of brain structures, the volumetric differences in male and female child brain are uniformly scaled to the volume difference of the total brain in the two sexes. Exceptions to this pattern of uniform scaling are the caudate, hippocampus and pallidum, which are disproportionately larger in female than male child brain, and the amygdala, which is disproportionately smaller in the female child brain. The patterns of uniform scaling are generally sustained during the final volumetric increment in overall brain size between age 7-11 and adulthood. There are exceptions to this uniform scaling of child to adult brain, and certain of these exceptions are sexually dimorphic. Thus, with respect to major brain regions, the cerebellum in the female but not the male child is already at adult volume while the brainstem in both sexes must enlarge more than the brain as a whole. The collective subcortical gray matter structures of the forebrain of the female child are already at their adult volumes. The volumes of these same structures in the male child, by contrast, are greater than their adult volumes and, by implication, must regress in volume before adulthood. The volume of the central white matter, on the other hand, is disproportionately smaller in female than male child brain with respect to the adult volumes of cerebral central white matter. By implication, relative volumetric increase of cerebral central white matter by adulthood must be greater in the female than male brain. The juxtaposed progressive and regressive patterns of growth of brain structures implied by these observations in the human brain have a soundly established precedent in the developing rhesus brain. There is emerging evidence that sexually dimorphic abnormal regulation of these terminal patterns of brain development are associated with gravely disabling human disorders of obscure etiology.
Rhesus monkeys with neonatal aspiration lesions of the hippocampal formation or the amygdaloid complex were tested on concurrent discrimination learning (24-hr intertrial interval [ITI]) at 3 months, on object recognition memory (delayed nonmatching-to-sample [DNMS]) at 10 months, and retested on both tasks at 6–7 years of age. Neonatal amygdaloid damage mildly impaired acquisition at the 24-hr ITI and the performance test of DNMS at both ages. In contrast, early hippocampal lesions impaired performance only on the longest lists of 10 items in DNMS in adult monkeys. Thus, early amygdala lesions appeared to have resulted in a greater object memory loss than early hippocampal lesions. However, in light of recent findings from lesion studies in adult monkeys, the object memory impairment after early amygdaloid lesions is better accounted for by damage to the entorhinal and perirhinal cortex than by damage to the amygdaloid nuclei. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.
Change is constant in everyday life. Infants crawl and then walk, children learn to read and write, teenagers mature in myriad ways, and the elderly become frail and forgetful. Beyond these natural processes and events, external forces and interventions instigate and disrupt change: test scores may rise after a coaching course, drug abusers may remain abstinent after residential treatment. By charting changes over time and investigating whether and when events occur, researchers reveal the temporal rhythms of our lives. This book is concerned with behavioral, social, and biomedical sciences. It offers a presentation of two of today's most popular statistical methods: multilevel models for individual change and hazard/survival models for event occurrence (in both discrete- and continuous-time). Using data sets from published studies, the book takes you step by step through complete analyses, from simple exploratory displays that reveal underlying patterns through sophisticated specifications of complex statistical models.
We present evidence for continuous generation of neurons, oligodendrocytes, and astrocytes in the hippocampal dentate gyrus of adult macaque monkeys, using immunohistochemical double labeling for bromodeoxyuridine and cell-type-specific markers. We estimate that the relative rate of neurogenesis is approximately 10 times less than that reported in the adult rodent dentate gyrus. Nevertheless, the generation of these three cell types in a discreet brain region suggests that a multipotent neural stem cell may be retained in the adult primate hippocampus. This demonstration of adult neurogenesis in nonhuman Old World primates-with their phylogenetic proximity to humans, long life spans, and elaborate cognitive abilities-establishes the macaque as an unexcelled animal model to experimentally investigate issues of neurogenesis in humans and offers new insights into its significance in the adult brain.
The superior efficiency of systematic sampling at all levels in stereological studies is emphasized and various commonly used ways of implementing it are briefly described. Summarizing recent theoretical and experimental studies a set of very simple estimators of efficiency are presented and illustrated with a variety of biological examples. In particular, a nomogram for predicting the necessary number of points when performing point counting is provided. The very efficient and simple unbiased estimator of the volume of an arbitrary object based on Cavalieri's principle is dealt with in some detail. The efficiency of the systematic fractionating of an object is also illustrated.
The superior efficiency of systematic sampling at all levels in stereological studies is emphasized and various commonly used ways of implementing it are briefly described. Summarizing recent theoretical and experimental studies a set of very simple estimators of efficiency are presented and illustrated with a variety of biological examples. In particular, a nomogram for predicting the necessary number of points when performing point counting is provided. The very efficient and simple unbiased estimator of the volume of an arbitrary object based on Cavalieri's principle is dealt with in some detail. The efficiency of the systematic fractionating of an object is also illustrated.
Explored the role of the hippocampus in impaired spatial representational abilities in persons with Down syndrome (DS). Mental retardation from DS usually arises as a result of the triplication (trisomy) of chromosome 21. Presumably, deficient neural development has a detrimental impact on adaptive and intellectual functioning. It is hypothesized that the ability to represent objects and events in the environment is a prerequisite skill for knowledge acquisition. Neurobiological, neuropsychological, and behavioral evidence indicates that individuals with DS have impaired spatial representational abilities. Although the responsible neural loci are difficult to pinpoint, it is argued that the hippocampus may be implicated. in addition, diffuse language lateralization is likely to be a contributor to poor visuospatial performance. Task analyses that take into account attentional and behavioral requirements could aid neuropsychological test administration and interpretation.
Article abstract—Objective: To quantify,developmental,abnormalities,in cerebral,and,cerebellar,volume,in autism. Methods: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed,and,scanned,when,5 years,or older. The other,30 were,scanned,when,2 through,4 years,of age,and,then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Results: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 6 1.3 cm versus clinical norms: 34.6 6 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI‐VII than normal controls. Conclusions: Abnormal,regulation,of brain,growth,in autism,results,in early,overgrowth,followed,by,abnormally,slowed,growth. Hyperplasia,was,present,in cerebral,gray,matter,and,cerebral,and,cerebellar,white,matter,in early life in patients,with autism. NEUROLOGY 2001;57:245‐254 Little is known,about,the neuroanatomic,abnormali-
The volume of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus was quantified from magnetic images of the brains of 99 healthy children and adolescents aged 4–18 years. Variability in volume was high for all structures examined. When adjusted for a 9% larger total cerebral volume in males, there were no significant volume differences between sexes. However, sex-specific maturational changes were noted in the volumes of medial temporal structures, with the left amygdala increasing significantly only in males and with the right hippocampus increasing significantly only in females. Right-greater-than-left laterality effects were found for temporal lobe, superior temporal gyrus, amygdala, and hippocampal volumes. These results are consistent with previous preclinical and human studies that have indicated hormonal responsivity of these structures and extend quantitative morphologic findings from the adult literature. In addition to highlighting the need for large samples and sex-matched controls in pediatric neuroimaging studies, the information from this understudied age group may be of use in evaluating developmental hypotheses of neuropsychiatric disorders. © 1996 Wiley-Liss, Inc.†
Many scientists and colony managers assume that social housing is a beneficial living condition for all captive primates. Several older studies of primate development question the generality of this assumption. We recently tested this assumption by comparing the social development of pigtailed macaque infants raised in pairs and those that were raised in individual cages. All animals received 30 min of daily socialization in a playroom. Infants paired from postnatal week 3 through month 4 developed a playroom behavioral repertoire consisting largely of mutual clinging, fear, and social withdrawal. This was especially true of females. Unlike the singly caged infants, pair-reared monkeys did not successfully adapt to living in a large social group at 8–10 months of age. In this situation, pair-reared infants were subordinate and spent almost all of their time huddling on the pen floor. It was concluded that rearing macaque infants in pairs produces a behavioral repertoire that is maladaptive with respect to social development.
Behavioral and learning disturbances have been found in mice with partial trisomy 16, a new model for Down syndrome. Basal production of cyclic AMP in the hippocampus of trisomic mice was shown to be impaired. In addition, the responses of adenylyl cyclase to the stimulation of β-adrenoceptors with isoprenaline and of the catalytic subunit with forskolin were both severely depressed.
1.1. Sexual dimorphism of human brain anatomy has not been well-studied between 4 and 18 years of age, a time of emerging sex differences in behavior and the sexually specific hormonal changes of adrenarche (the predominantly androgenic augmentation of adrenal cortex function occurring at approximately age 8) and puberty.2.2. To assess sex differences in brain structures during this developmental period volumes of the cerebrum, lateral ventricles, caudate, putamen, globus pallidus temporal lobe, amygdala, and hippocampus, and midsagittal area measurements of the corpus callosum were quantified from brain magnetic resonance images of 121 healthy children and adolescent and examined in relation to age and sex.3.3. Males had a 9% larger cerebral volume. When adjusted for cerebral volume by ANCOVA only the basal ganglia demonstrated sex differences in mean volume with the caudate being relatively larger in females and the globus pallidus being relatively larger in males. The lateral ventricles demonstrated a prominent sex difference in brain maturation with robust increases in size in males only. A piecewise-linear model revealed a significant change in the linear regression slope of lateral ventricular volume in males after age 11 that was not shared by females at that or other ages.4.4. Amygdala and hippocampal volume increased for both sexes but with the amygdala increasing significantly more in males than females and hippocampal volume increasing more in females.5.5. These sexually dimorphic patterns of brain development may be related to the observed sex differences in age of onset, prevalence, and symptomatology seen in nearly all neuropsychiatrie disorders of childhood.
The differentiation of granule cell dendrites in the dentate gyrus of the hippocampal region was studied in a series of developing fetal and postnatal rhesus monkeys whose brains were processed by the rapid Golgi method. The total combined lengths of dendrites, the total number of dendritic spines, and their density on the proximal, middle, and distal thirds of the dendritic shafts were determined at embryonic days 58, 95, 120, 153, term (165), postnatal days 3, 20, 60, 150, 365, and adults. At all ages examined, granule cells exhibited various levels of maturation with the more differentiated cells being situated in the superficial strata of the granular layer and the less mature cells lying in progressively deeper positions, thus conforming to the outside-to-inside spatiotemporal gradient of their genesis. Quantitative analysis shows that, in this primate, hippocampal granule cells differentiate mainly in the second half of gestation with all measured parameters attaining mature values by the time of birth. However, the analysis also reveals a transient phase of exuberant postnatal development which involves excessive dendritic branching, regional changes in dendritic length, overproduction of dendritic spines, and redistribution of spines within the molecular layer. After reaching peak values around the middle of the first year of life, these parameters decrease and in adult monkeys fall back to the neonatal level
We compared the effects of bilateral amygdala, hippocampal or orbital frontal cortex lesions on emotional and hormonal reactivity in rhesus monkeys (Macaca mulatta). Experiment 1 measured behavioral reactivity to an unfamiliar human intruder before and after surgery. Animals with amygdala lesions demonstrated decreases in one passive defensive behavior (freezing), whereas animals with hippocampal lesions showed decreases in a more stimulus-directed defensive behavior (tooth grinding). Orbital frontal cortex lesions also reduced these two defensive behaviors, as well as decreased cage-shaking dominance displays. Animals with amygdala, hippocampal or sham lesions also demonstrated increased tension-related behaviors after surgery, but those with orbital frontal lesions did not. Finally, all three lesions diminished the operated animals' ability to modulate tension-related behaviors depending on the magnitude of threat posed by the human intruder. Experiment 2 measured circulating levels of cortisol and testosterone when a subset of these same animals was at rest and following physical restraint, temporary isolation, exposure to threatening objects and social interactions with an unfamiliar conspecific. None of the lesions impacted on testosterone levels in any condition. Amygdala or orbital frontal lesions blunted cortisol reactivity during isolation from peers, but not during any other condition. Hippocampal lesions did not alter circulating levels of cortisol under any condition. These results indicate that the amygdala, hippocampus and orbital frontal cortex play distinct, yet complimentary roles in coordinating emotional and hormonal reactivity to threat.
The presence of the neuropathological alterations of Alzheimer's disease (AD) in essentially all older Down syndrome (DS) patients suggests that the examination of younger DS patients may clarify the early pathological progression of AD. We examined the hippocampus and parahippocampal-inferior temporal gyri of 42 DS patients (ages 4 days to 38 years) for the deposition of amyloid beta protein (Abeta) using both a modified Bielschowsky stain and immunohistochemistry for Abeta protein. The parahippocampal and inferior temporal gyri demonstrated Abeta staining in cases as young as 8 years of age. As age and degree of Abeta deposition increased, staining included the CA-1/subiculum and dentate molecular layer followed then by the remainder of the CA hippocampal regions. The first neuritic plaques were observed in the CA-1/subiculum, despite this being a later region of Abeta deposition. Although Abeta staining increased with age, there was substantial variability in the severity of Abeta deposition within age groups. These results suggest that within the hippocampal/parahippocampal region there is a progressive stereotypic deposition of Abeta. The variable severity of Abeta deposition within age groups suggests that other factors, besides DS, may be contributing to the timing and severity of Abeta deposition.
Hippocampi are asymmetrical in children and adults, where the right hippocampus is larger. To date, no literature has confirmed that hippocampal asymmetry is evident at birth. Furthermore, gender differences have been observed in normal hippocampal asymmetry, but this has not been examined in neonates. Stress, injury, and lower IQ have been associated with alterations to hippocampal asymmetry. These same factors often accompany preterm birth. Therefore, prematurity is possibly associated with altered hippocampal asymmetry. There were three aims of this study: First, we assessed whether hippocampi were asymmetrical at birth, second whether there was a gender effect on hippocampal asymmetry, and third whether the stress of preterm birth altered hippocampal asymmetry. This study utilized volumetric magnetic resonance imaging to compare left and right hippocampal volumes in 32 full-term and 184 preterm infants at term. Full-term infants demonstrated rightward hippocampal asymmetry, as did preterm infants. In the case of preterm infants, hippocampal asymmetry was proportional to total hemispheric asymmetry. This study is the first to demonstrate that the normal pattern of hippocampal asymmetry is present this early in development. We did not find gender differences in hippocampal asymmetry at term. Preterm infants tended to have less asymmetrical hippocampi than full-term infants, a difference which became significant after correcting for hemispheric brain tissue volumes. This study may suggest that hippocampal asymmetry develops in utero and is maintained into adulthood in infants with a normal neurological course.
The dorsolateral prefrontal cortex of rhesus monkeys was functionally inactivated by local hypothermia as the monkeys performed spatial delayed-response and spatial delayed-alternation tasks at different stages of postnatal development. Cryogenic depression of prefrontal cortex at a temperature sufficient to induce 21--25% decrements in delayed-response performance in 34--36-month-old-monkeys, produced deficits of only 7--8% in 19--31-month-old and no detectable loss in younger monkeys, 9--16 months of age. Delayed-alternation performance was impaired by local hypothermia as early as 8.5 months of age, but maximal cooling-induced deficits on this task were not observed before 33 months of age. Thermal gradients mapped in representative monkeys at different stages of development were remarkable similar, indicating that the age-dependent differences in behavior were not attributable to technical factors. The results obtained in the present study on normal developing monkeys confirm the interpretation of previous research on brain-damaged infants that functional maturation of the dorsolateral prefrontal cortex is protracted over several years of postnatal life, and extends the earlier studies by indicating that the lower limit for maturity of dorsolateral function is close to puberty in this species. Further, the present study revealed that delayed-response and delayed-alternation performance are dissociable dorsolateral functions which achieve maturity at different rates. The convergence of evidence from reversible neural depression and permanent lesion methods provides strong validation for neurobehavioral analysis as a general approach to the study of regional maturation of the brain.
The postnatal generation, dendritic development and morphological variability of granule cells were studied in the monkey and human dentate gyrus. Granule cells are mainly formed prenatally in primates with an approximate 4- to 6-month postnatal generation time in humans. Dendritic development of individual granule cells appears to be prolonged over a long period of time. Immature granule cells were observed as late as in 15-month-old children. The morphological variability of granule cells is similar in monkeys and humans. Both display granule cells with basal dendrites as well as granule cells with different dendritic lengths and spine densities. The prolonged development of the spine structure of the human mossy cells suggests that synaptic connections between granule cells and their postsynaptic target neurons develop through a long postnatal period of time that may last as long as 5 years postnatally. The morphological variability of granule cells in primates should be considered when drawing conclusions about hippocampal neuropathology. The prolonged development of the neurons and neuronal circuitries in the human dentate gyrus may cause the lack of adult-like memory formation in early childhood resulting in the phenomenon of 'infantile amnesia'.
Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer's disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.
Quantitative electron microscopy was used to study synapse formation in the molecular layer of the dentate gyrus in rhesus monkeys ranging in age from embryonic day 62 to adult. Four to eight radial probes, consisting of a series of overlapping electronmicrographs and extending across the full thickness of the molecular layer were made in each specimen. Synaptic density (normalized to volume of neuropil) increased significantly during the last half of gestation, reaching adult levels at the time of birth. However, new synapses were added during infancy, resulting in an apparent peak in density at between 4 and 5 months of age. This increase was followed by a decline in the synaptic density over the next 5 months, to levels comparable to that of the newborn. In addition to synaptic density, synapse type (symmetric, asymmetric), location (on dendritic shafts or spines), and laminar distribution in the developing molecular layer was determined. The decrease in synaptic density is unlikely to be due to 'dilution' caused by an increase in molecular layer volume since no increase in the volume of the dentate gyrus could be detected during this period. Our calculations suggest that a selective overproduction of asymmetrical, axo-spinous synapses occurs during infancy. Finally, synaptic density was significantly greater in the middle third of the molecular layer suggesting that synaptic exuberance may be related to entorhinal input.
For quantification of brain structures from MR scans, a novel, powerful stereologic tool known as Cavalieri's principle was applied. This tool enables an objective estimation of volume. The method was applied to detect differences in various brain structures between persons with Down syndrome and control subjects. On the basis of absolute values, smaller volumes for the whole brain, cerebral cortex, white matter, and cerebellum were seen in persons with Down syndrome. Similar results were observed when a normalization procedure, based on the volume of cranial cavity, was used. Stereologic determinations of the volumes of brain structures from MR images can reliably identify volume differences between persons with Down syndrome and control subjects.
Ratio measures, such as the ventricle-brain ratio (VBR) based on computed tomography or magnetic resonance imaging, are widely used in psychiatric research in studies of brain function and morphology. While imaging techniques have advanced considerably, the form of the index of a structure's size has remained the same--a proportion based on an estimate of the structure's size divided by a like estimate of the whole brain size. We demonstrate that ratio and similar indices can suffer greatly in reliability when compared with simple volume measures. This loss of reliability is related to the relation of a structure's size and whole brain size. We review various methods for measuring the size of structures and discuss their strengths and limitations in terms of reliability and validity. In many instances, other methods of "correcting" for brain size (e.g., regression or covariance) may yield measurements that are more appropriate than ratios.
Lesion studies in adult monkeys have suggested that an experience can enter into memory in two ways: as cognitive information stored in a cortico-limbo-thalamocortical system (involving the higher order sensory areas of cortex, the amygdala, hippocampus, and entorhinal cortex, the medial thalamic nuclei, or ventromedial prefrontal cortex, and the basal forebrain) and as a habit stored perhaps in a cortico-striatal system (involving the sensory cortical areas and the caudate and putamen). Our studies of behavioral development in infant monkeys as well as those in human infants provide complementary evidence by suggesting that these two systems are developmentally dissociable, in that the cognitive memory system, assessed by the delayed non-matching to sample task, appears to mature considerably more slowly than the habit system, assessed by the concurrent visual discrimination task, a notion that has also been discussed recently by others (Nadel & Zola-Morgan, 1984; Rose, 1980). Furthermore, despite the late development of the cortico-limbo-diencephalic memory system, this chapter has presented evidence that some limbic-dependent memory processes, such as those required for success on the visual paired comparison task, develop extremely early. The notion that at least one type of recognition process mediated by the limbic system is present neonatally provides new insight into the normal development of memory processes and indicates the need to identify further the memory processes and substrates that become available to an infant at different time points during maturation. Such studies will help one day to determine the immaturity of structure or function that is responsible for the intriguing phenomenon of infantile amnesia, that is, the inability to recall the stimuli or events experienced in the first few years of life.
The aim of the present investigation was to detect differences between the left and right hemispheres at a macroscopical level using morphometric procedures. The volume fraction and the surface area of the different brain structures have been calculated from the profile area by stereological procedures. The volume, the relative volume fraction, the folded surface area as well as the mean cortical thickness were evaluated by stereology. Although some constant differences in the arrangement of sulci and their depth can be observed at a descriptive level, the quantitative morphological comparison between both hemispheres however only showed slight differences. The results are discussed with regard to the differences published up to the present. The morphometric methods will be discussed in detail.
The superior efficiency of systematic sampling at all levels in stereological studies is emphasized and various commonly used ways of implementing it are briefly described. Summarizing recent theoretical and experimental studies a set of very simple estimators of efficiency are presented and illustrated with a variety of biological examples. In particular, a nomogram for predicting the necessary number of points when performing point counting is provided. The very efficient and simple unbiased estimator of the volume of an arbitrary object based on Cavalieri's principle is dealt with in some detail. The efficiency of the systematic fractionating of an object is also illustrated.
Early infantile autism is a behaviorally defined syndrome that is often associated with abnormalities on neurologic examination and seizures. We report on the brain of a 29-year-old autistic man as compared with that of an age- and sex-matched normal control, using gapless sections of whole brain. Abnormalities were found in the hippocampus, subiculum, entorhinal cortex, septal nuclei, mamillary body, selected nuclei of the amygdala, neocerebellar cortex, roof nuclei of the cerebellum, and inferior olivary nucleus.
A comparison of the age and season at first parturition was made for spring-born female rhesus monkeys and for females born in the fall to mothers who had been laboratory-housed before being transferred outdoors. Females (N = 9) born during the fall had first parturition during the spring and summer, as did all spring-born females (N = 68), and not during the fall as would be predicted if age were the determining factor. A separate analysis of post-menarchial, spring-born females (N = 5) beginning in September at 29 months of age revealed that the ensuing 12 months were characterized by low serum levels of oestradiol (less than 50 pg/ml), progesterone (less than 1.0 ng/ml), LH (less than 7.0 ng/ml), and FSH (less than 5.50 micrograms/ml). First ovulation subsequently occurred in the fall in all subjects at a mean age of 41.9 +/- 0.1 months, and was preceded by significant elevations in basal LH and FSH, coincident in time with the transition of summer to fall (September). Female copulatory behaviour was restricted to the period surrounding first ovulation, beginning some 2 weeks before and ceasing within 3 days after the oestradiol peak. The most rapid gain in weight occurred during the summer months before first ovulation, and was associated with significant elevations in serum GH and prolactin. These data suggest that season may influence the timing of sexual maturation in rhesus monkeys kept outside in such a way that the occurrence of first ovulation is restricted to the fall and winter months.
The time of origin of neurons in the hippocampal region was determined in a series of rhesus monkeys, each of which had been exposed to a pulse of tritiated thymidine (³H-TdR) at a different time during ontogeny and sacrificed between the second and fifth month after birth. No heavily labeled cells were found in the hippocampal region of animals exposed to ³H-TdR before embryonic day 33 (E33). Exposure to ³H-TdR given at E36 labels a few neurons in the deepest layers of the entorhinal area, and ³H-TdR given at E38 labels a small number of neurons in all hippocampal subdivisions. Although the first neurons are generated almost simultaneously throughout the hippocampal region, the proliferation ceases at a different time in each subdivision. The last neurons destined for the entorhinal area and presubiculum are generated between E70 and E75, whereas the last parasubicular neurons are generated between E75 and E80. The production of neurons that form the subiculum ends about two weeks earlier, between E56 and E65. Within the hippocampus, genesis of pyramidal cells ends between E70 and E80 in area CA1, between E56 and E65 in area CA2, between E65 and E70 in area CA3, and between E75 and E80 in area CA4. In contrast, the genesis of granule cells of the fascia dentata is considerably prolonged. It continues throughout the second half of gestation, declines steadily in the course of the first postnatal month, and tapers off during the next 2 months.
The site of origin and route and rate of migration of neurons in the developing hippocampal region of the rhesus monkey were studied with tritiated thymidine (³H-TdR) autoratiography. Analysis of specimens sacrificed approximately 1 hour after exposure to ³H-TdR shows that the neurons destined for the hippocampus and subiculum are generated exclusively in the ventricular zone lining the medial wall of the lateral cerebral ventricle. In contrast, neurons of the parahippocampal formation are generated in two proliferative zones: The majority of neurons destined for the lamina principalis interna arise from the ventricular zone, whereas most of those destined for the lamina principalis externa originate from the subventricular zone. The neurons of the dentate gyrus are also generated in two locations: in the ventricular zone (between E38 and E85) and within the prospective hilus of the dentate gyrus (from E58 up to approximately 3 months after birth).
Morphometric analysis was performed on three-dimensional MRI scans of 10 male and 10 female young adults with four principal
objectives: (1) to characterize in vivo volumes of whole brain and substructures, (2) to explore volumetric symmetry in bilateral structures, (3) to consider the
extent to which volumetric measures are dimorphic in the male and female brain, and (4) to provide a normal volumetric database
for the young adult brain. Total brain volumes ranged between 1173 and 1626 cm3. All bilateral structures were symmetric or nearly symmetric in volume, with the exception of a slightly larger right neocortex
and amygdala, and larger left lateral ventricle. Male brains were larger in volume than female brains, a difference that reached
significance for cerebellar but not for cerebral hemisphere volume. In females, there was less cerebral white matter while
caudate volume was larger than in the male brains. The proportions of caudate and hippocampus relative to total cerebral volumes
were larger in females than in males. These four measures accurately predicted gender in 85% of the subjects by discriminant
analysis. No gender differences were noted in the structural symmetry analysis. These results represent the first step in
establishing a comprehensive database of morphometric parameters, with unexpected findings relative to brain symmetry and
sexual dimorphism.
Although substantive understanding of brain dysfunction in autism remains meager, clinical evidence as well as animal brain research on the effects of early damage to selective brain system have now yielded enough knowledge that some provisional hypotheses concerning the etiology of autism can be generated. Basically, the underlying premise of this review is that a major dysfunction of the autistic brain resides in neural mechanisms of the structures in the medial temporal lobe, and, perhaps, more specifically the amygdaloid complex. This review begins with a summary of clinical evidence of the involvement of the medial temporal lobe structures in autism. The major behavioral disturbances seen in monkeys that had received neonatal lesions of the medial temporal lobe structures are then described. From this survey it can be seen that distinct patterns of memory losses and socioemotional abnormalities emerge as a result of extent of damage to the medial temporal lobe structures. The potential value of the experimental findings for an understanding of neural dysfunction in autism as well as directions of future research are discussed in the final section of the review.
Elemental associations permit subjects to solve problems when the significance of the relevant stimulus elements are consistent from trial to trial but do not allow subjects to solve problems that require them to construct and use representations of stimulus conjunctions or configurations to guide their behavior. Recent research with brain-damaged and developing animals has led several theorists to propose that elemental and configural associations depend on different neural systems. Some evidence suggests that changes in children's learning that occur when they are about 4.5 years old may be partially due to developmental differences in access to the elemental and configural association systems. Two experiments are reported that support this hypothesis. Children at least 4.5 years old were able to solve the transverse patterning problem and a conditional discrimination, two problems that require configural association solutions. Younger children did not solve these problems but were able to solve problems constructed from the same stimulus materials that permitted an elemental association solution. These results suggest that children may not gain access to the configural association system until they are about 4.5 years old and support the hypothesis that the configural association system depends on different, later developing neural structures than does the elemental association system.
To characterize better the process of anatomic development of the human hippocampus, we studied the cytoarchitecture, myeloarchitecture, and neuronal morphology in human fetal and postnatal hippocampi. Twenty cases were studied in which the ages ranged from 9 weeks gestation through 62 years. Fixed, paraffin-embedded, hippocampal sections were stained with cresyl violet for Nissl substance and immunolabeled for myelin basic protein. The hippocampal region at 9 weeks contains 4 layers: a ventricular zone, an intermediate zone, a homogeneous-appearing hippocampal plate comprised of bipolar-shaped neurons, and a wide marginal zone. At 15-19 weeks, individual subfields can be distinguished. A distal-to-proximal gradient of cytoarchitectural and neuronal morphologic maturity is seen, with the subiculum appearing more developed than the ammonic subfields and the dentate gyrus appearing least mature. Within each subfield, an "inside-out" gradient of maturity is also evident. By 32-34 weeks gestational age, neurons in CA2 and CA3 have undergone rapid enlargement and morphologic maturation, surpassing CA1, which still contains some immature neurons. The dentate gyrus is the latest area to develop, only assuming a mature cytoarchitecture after 34 weeks. The essential cytoarchitectural appearance of the hippocampal subfields is stable after birth, although there is progressive neuronal enlargement and a decrease in neuronal density throughout childhood into adulthood. Myelination is first evident near term, with strong myelin basic protein immunoreactivity present in the angular bundle, alveus, and fimbria and relatively scant immunoreactivity in the nascent perforant pathway. Myelination in the hippocampus increases in childhood until adolescence, after which the pattern remains unchanged. These studies delineate normal neuroanatomic development and can be used to understand better the mechanisms underlying human neurodevelopmental and neurodegenerative disorders of the hippocampal formation.
Autism is a behaviorally defined syndrome in which neuropathological abnormalities have been identified in the limbic system and cerebellum. The morphology of hippocampal neurons in two cases of infantile autism was studied and compared to age-matched controls. CA4 neurons in autistic children were smaller in perikaryon area and dendritic branching of both CA4 and CA1 neurons was less than in controls. These findings are consistent with previous studies and suggest a curtailment in maturation in the pathogenesis of autism.
Children and adults were tested on 3 place learning tasks. Children under the age of 7 were inferior to older subjects in solving the tasks by using spatial relational solutions, but subjects of all ages were equally proficient in solving the task by using simple stimulus-reward associations (cued solutions). Accurate performance on the cued versions suggests that neither the general response demands nor the large size of testing environments rendered the tasks differentially inappropriate for young children. Instead, the nature of the cognitive demands were responsible for different levels of performance across the age groups. Because, in animal studies, spatial relational solutions but not cued solutions of these tests require mature and undamaged medial temporal lobe structures, the results suggest that these systems are not fully developed in humans before approximately 7 years of age.