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BACKGROUND: Evidence suggests that early life adversity is associated with maladaptive behaviors and is commonly an antecedent of stress-related psychopathology. This is particularly relevant to rearing in primate species as infant primates depend on prolonged, nurturant rearing by caregivers for normal development. To further understand the consequences of early life rearing adversity, and the relation among alterations in behavior, physiology and brain function, we assessed young monkeys that had experienced maternal separation followed by peer rearing with behavioral, endocrine and multimodal neuroimaging measures. METHODS: 50 young rhesus monkeys were studied, half of which were rejected by their mothers and peer reared, and the other half were reared by their mothers. Assessments were performed at approximately 1.8 years of age and included: threat related behavioral and cortisol responses, cerebrospinal fluid (CSF) measurements of oxytocin and corticotropin releasing hormone (CRH), and multimodal neuroimaging measures (anatomical scans, resting functional connectivity, diffusion tensor imaging, and threat-related regional glucose metabolism). RESULTS: The results demonstrated alterations across behavioral, endocrine, and neuroimaging measures in young monkeys that were reared without their mothers. At a behavioral level in response to a potential threat, peer reared animals engaged in significantly less freezing behavior (p = 0.022) along with increased self-directed behaviors (p

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

Intelligence (IQ) scores are used in educational and vocational planning for individuals with autism spectrum disorder (ASD) yet little is known about the stability of IQ throughout development. We examined longitudinal age-related IQ stability in 119 individuals with ASD (3-36 years of age at first visit) and 128 typically developing controls. Intelligence measures were collected over a 20-year period. In ASD, Full Scale (FSIQ) and Verbal (VIQ) Intelligence started lower in childhood and increased at a greater rate with age relative to the control group. By early adulthood, VIQ and working memory stabilized, whereas nonverbal and perceptual scores continued to change. Our results suggest that in individuals with ASD, IQ estimates may be dynamic in childhood and young adulthood.

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

BackgroundAnxious temperament (AT) is an early-life heritable trait that predisposes individuals to develop anxiety and depressive disorders. Our previous work in preadolescent children suggests alterations in the uncinate fasciculus (UF), the white matter tract that connects prefrontal with limbic regions, in boys with anxiety disorders. Here, using a nonhuman primate model of AT, we tested whether this sexually dimorphic finding is evolutionarily conserved and examined the extent to which heritable and environmental influences contribute to UF microstructure.MethodsDiffusion tensor images were collected in 581 young rhesus monkeys (1.89 ± 0.77 years old; 43.9% female). Using tract-based analyses, we assessed the relationship among AT, UF microstructure (as measured with fractional anisotropy), and sex. Heritability of tract microstructure was determined using oligogenic linkage analysis of this large multigenerational pedigree.ResultsWe predicted and found a negative relation between AT and UF fractional anisotropy in male but not female monkeys (AT × sex; p = .032, 1-tailed). Additionally, heritability analyses revealed that variation in UF fractional anisotropy was largely due to nonheritable factors (h2 = 0.185, p = .077).ConclusionsThese results demonstrate a cross-species, male-specific relation between UF microstructure and anxiety and provide a potential substrate for anxiety-related prefrontal-limbic dysregulation. The heritability analyses point to the importance of environmental influences on UF microstructure, which could be important in mediating the nonheritable components of pathological anxiety. These findings have the potential to guide new treatment strategies for childhood anxiety disorders and further support the use of nonhuman primates as a translational model to discover mechanisms underlying the development of anxiety.

BackgroundAn early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates.MethodsIn response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group).ResultsThis discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit.ConclusionsTogether, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

ObjectiveAnxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders.MethodsFA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects.ResultsTract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts.ConclusionsThese findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

OBJECTIVE:There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. METHODS:Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic field strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. RESULTS:Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. CONCLUSIONS:Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies.

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce-BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce-BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce-BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce-BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.