Early developmental changes in visual social engagement in infant rhesus monkeys.

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.

Chemogenetic Inhibition of the Amygdala Modulates Emotional Behavior Expression in Infant Rhesus Monkeys.

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.

Early amygdala damage alters the way rhesus macaques process species-specific audio-visual vocalizations.

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. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Longitudinal Anthropometric Assessment of Rhesus Macaque (Macaca mulatta) Model of Huntington Disease.

The neurodegeneration associated with Huntington disease (HD) leads to the onset of motor and cognitive impairment and their advancement with increased age in humans. In children at risk for HD, body measurement growth abnormalities include a reduction in BMI, weight, height, and head circumference. The transgenic HD NHP model was first reported in 2008, and progressive decline in cognitive behaviors and motor impairment have been reported. This study focuses on longitudinal body measurements in HD macaques from infancy through adulthood. The growth of HD macaques was assessed through head circumference, sagittal and transverse head, and crown-to-rump ('height') measurements and BMI. The animals were measured monthly from 0 to 72 mo of age and every 3 mo from 72 mo of age onward. A mixed-effect model was used to assess subject-specific effects in our nonlinear serial data. Compared with WT controls, HD macaques displayed different developmental trajectories characterized by increased BMI, head circumference, and sagittal head measurements beginning around 40 mo of age. The physiologic comparability between NHP and humans underscores the translational utility of our HD macaques to evaluate growth and developmental patterns associated with HD.

An MRI study of the corpus callosum in monkeys: Developmental trajectories and effects of neonatal hippocampal and amygdala lesions.

This study provides the first characterization of early developmental trajectories of corpus callosum (CC) segments in rhesus macaques using noninvasive MRI techniques and assesses long-term effects of neonatal amygdala or hippocampal lesions on CC morphometry. In Experiment 1, 10 monkeys (5 males) were scanned at 1 week-2 years of age; eight additional infants (4 males) were scanned once at 1-4 weeks of age. The first 8 months showed marked growth across all segments, with sustained, albeit slower, growth through 24 months. Males and females had comparable patterns of CC maturation overall, but exhibited slight differences in the anterior and posterior segments, with greater increases in the isthmus for males and greater increases in the rostrum for females. The developmental changes are likely a consequence of varying degrees of axonal myelination, redirection, and pruning. In Experiment 2, animals with neonatal lesions of the amygdala (n = 6; 3 males) or hippocampus (n = 6; 4 males) were scanned at 1.5 years post-surgery and compared to scans of six control animals from Experiment 1. Whereas amygdala damage yielded larger rostral and posterior body segments, hippocampal damage yielded larger rostrum and isthmus. These differences demonstrate that early perturbations to one medial temporal lobe structure may produce extensive and long-lasting repercussions in other brain areas. The current findings emphasize the complexity of neural circuitry putatively subserving neurodevelopmental disorders such as autism spectrum disorder and Williams syndrome, which are each characterized by malformations and dysfunction of complex neural networks that include regions of the medial temporal lobe.

Increased anxiety-like behaviors, but blunted cortisol stress response after neonatal hippocampal lesions in monkeys.

The hippocampus is most notably known for its role in cognition and spatial memory; however it also plays an essential role in emotional behaviors and neuroendocrine responses. The current study investigated the long-term effects of neonatal hippocampal lesions (Neo-Hibo) on emotional and hypothalamic-pituitary-adrenal (HPA) axis functioning. During infancy, unlike controls, Neo-Hibo monkeys exhibited enhanced expression of emotional behaviors (e.g. freezing, anxiety-like, and self-directed behaviors) when exposed to a human intruder (HI task). Upon reaching adulthood, they exhibited reduced freezing and hostility, but increased anxiety-like and self-directed behaviors during the HI task. Neo-Hibo monkeys behaved as if they systematically over-rated the risk inherent in the HI task, which supports Gray and McNaughton's septo-hippocampal theory of anxiety. Also, in adulthood, the increased levels of anxiety-like behaviors in Neo-Hibo monkeys were associated with a blunted cortisol response to the HI task. Examination of basal HPA axis function revealed that Neo-Hibo monkeys exhibited the typical diurnal cortisol decline throughout the day, but had lower cortisol concentrations in the morning as compared to controls. Taken together these data suggest that an intact hippocampus during development plays a larger role beyond that of inhibitory/negative feedback regulation of the HPA axis stress-activation, and may be critical for HPA axis basal functioning as well as for the stress response. The behavioral and neuroendocrine changes demonstrated in the current study are reminiscent of those seen in human or nonhuman primates with adult-onset hippocampal damage, demonstrating little functional compensation following early hippocampal damage.

UNC-Emory Infant Atlases for Macaque Brain Image Analysis: Postnatal Brain Development through 12 Months.

Computational anatomical atlases have shown to be of immense value in neuroimaging as they provide age appropriate reference spaces alongside ancillary anatomical information for automated analysis such as subcortical structural definitions, cortical parcellations or white fiber tract regions. Standard workflows in neuroimaging necessitate such atlases to be appropriately selected for the subject population of interest. This is especially of importance in early postnatal brain development, where rapid changes in brain shape and appearance render neuroimaging workflows sensitive to the appropriate atlas choice. We present here a set of novel computation atlases for structural MRI and Diffusion Tensor Imaging as crucial resource for the analysis of MRI data from non-human primate rhesus monkey (Macaca mulatta) data in early postnatal brain development. Forty socially-housed infant macaques were scanned longitudinally at ages 2 weeks, 3, 6, and 12 months in order to create cross-sectional structural and DTI atlases via unbiased atlas building at each of these ages. Probabilistic spatial prior definitions for the major tissue classes were trained on each atlas with expert manual segmentations. In this article we present the development and use of these atlases with publicly available tools, as well as the atlases themselves, which are publicly disseminated to the scientific community.

Alterations of hippocampal projections in adult macaques with neonatal hippocampal lesions: a Diffusion Tensor Imaging study.

Neuropsychological and brain imaging studies have demonstrated persistent deficits in memory functions and structural changes after neonatal neurotoxic hippocampal lesion in monkeys. However, the relevant microstructural changes in the white matter of affected brain regions following this early insult remain unknown. This study assessed white matter integrity in the main hippocampal projections of adult macaque monkeys with neonatal hippocampal lesions, using diffusion tensor imaging (DTI). Data analysis was performed using tract-based spatial statistics (TBSS) and compared with volume of interest statistics. Alterations of fractional anisotropy (FA) and diffusivity indices were observed in fornix, temporal stem, ventromedial prefrontal cortex and optical radiations. To further validate the lesion effects on the prefrontal cortex, probabilistic diffusion tractography was used to examine the integrity of the fiber connections between hippocampus and ventromedial prefrontal cortex, and alterations were found in these connections. In addition, increased radial diffusivity in the left ventromedial prefrontal cortex correlated negatively with the severity of deficits in working memory in the same monkeys. The findings revealed microstructural changes due to neonatal hippocampal lesion, and confirmed that neonatal neurotoxic hippocampal lesions resulted in significant and enduring functional alterations in the hippocampal projection system.

Crossmodal integration of conspecific vocalizations in rhesus macaques.

Crossmodal integration of audio/visual information is vital for recognition, interpretation and appropriate reaction to social signals. Here we examined how rhesus macaques process bimodal species-specific vocalizations by eye tracking, using an unconstrained preferential looking paradigm. Six adult rhesus monkeys (3M, 3F) were presented two side-by-side videos of unknown male conspecifics emitting different vocalizations, accompanied by the audio signal corresponding to one of the videos. The percentage of time animals looked to each video was used to assess crossmodal integration ability and the percentages of time spent looking at each of the six a priori ROIs (eyes, mouth, and rest of each video) were used to characterize scanning patterns. Animals looked more to the congruent video, confirming reports that rhesus monkeys spontaneously integrate conspecific vocalizations. Scanning patterns showed that monkeys preferentially attended to the eyes and mouth of the stimuli, with subtle differences between males and females such that females showed a tendency to differentiate the eye and mouth regions more than males. These results were similar to studies in humans indicating that when asked to assess emotion-related aspects of visual speech, people preferentially attend to the eyes. Thus, the tendency for female monkeys to show a greater differentiation between the eye and mouth regions than males may indicate that female monkeys were slightly more sensitive to the socio-emotional content of complex signals than male monkeys. The current results emphasize the importance of considering both the sex of the observer and individual variability in passive viewing behavior in nonhuman primate research.

Social communication in young children with traumatic brain injury: relations with corpus callosum morphometry.

The purpose of the present investigation was to characterize the relations of specific social communication behaviors, including joint attention, gestures, and verbalization, with surface area of midsagittal corpus callosum (CC) subregions in children who sustained traumatic brain injury (TBI) before 7 years of age. Participants sustained mild (n=10) or moderate-severe (n=26) noninflicted TBI. The mean age at injury was 33.6 months; mean age at MRI was 44.4 months. The CC was divided into seven subregions. Relative to young children with mild TBI, those with moderate-severe TBI had smaller surface area of the isthmus. A semi-structured sequence of social interactions between the child and an examiner was videotaped and coded for specific social initiation and response behaviors. Social responses were similar across severity groups. Even though the complexity of their language was similar, children with moderate-severe TBI used more gestures than those with mild TBI to initiate social overtures; this may indicate a developmental lag or deficit as the use of gestural communication typically diminishes after age 2. After controlling for age at scan and for total brain volume, the correlation of social interaction response and initiation scores with the midsagittal surface area of the CC regions was examined. For the total group, responding to a social overture using joint attention was significantly and positively correlated with surface area of all regions, except the rostrum. Initiating joint attention was specifically and negatively correlated with surface area of the anterior midbody. Use of gestures to initiate a social interaction correlated significantly and positively with surface area of the anterior and posterior midbody. Social response and initiation behaviors were selectively related to regional callosal surface areas in young children with TBI. Specific brainbehavior relations indicate early regional specialization of anterior and posterior CC for social communication.

Maturation of the hippocampal formation and amygdala in Macaca mulatta: a volumetric magnetic resonance imaging study.

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.

Treatment effects of methylphenidate on cognitive functioning in children with mental retardation and ADHD.

OBJECTIVE: Cognitive effects of stimulant medication were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Performance on tasks tapping sustained attention, visual and auditory selective attention, inhibition, and immediate memory was assessed for 24 children (mean age 10.9 years) during a placebo-controlled, double-blind, crossover treatment trial with 0.15, 0.30, and 0.60 mg/kg b.i.d. dosages of methylphenidate (MPH). RESULTS: Successively higher MPH doses were associated with consistent gains in cognitive task performance, with optimal performance noted at the highest dose. Analysis of dose-response curves revealed significant linear components of trend on measures tapping sustained attention, visual selective attention, auditory selective attention, as well as two tasks tapping inhibition/impulsivity: delay of gratification and match-to-sample. No evidence of a curvilinear dose-response relationship emerged for any measure. CONCLUSIONS: Inattention and disinhibition/impulsivity decline with MPH treatment in children with ADHD/MR, and consistent with the Multimodal Treatment Study of ADHD, higher MPH doses are most effective. These findings also suggest that cognitive testing, together with behavioral and medical assessment, can be an effective tool in assessing stimulant response in children with ADHD/MR.

Effects of methylphenidate treatment in children with mental retardation and ADHD: individual variation in medication response.

OBJECTIVE: Individual variation in cognitive and behavioral response to methylphenidate (MPH) was investigated in children with mental retardation and attention-deficit/hyperactivity disorder. METHOD: Twenty-four children (mean age 10.9 years, SD = 2.4) participated in a placebo-controlled, double-blind, crossover trial with 0.15-, 0.30-, and 0.60-mg/kg b.i.d. doses of MPH. Parent and teacher behavioral ratings, as well as cognitive task performance, were assessed at each dose. RESULTS: Relative to placebo, most children with attention-deficit/hyperactivity disorder and mental retardation showed some degree of behavioral and cognitive improvement with MPH treatment. However, fewer of these children made substantial gains (>30% improvement, relative to placebo) with MPH treatment. At the highest dose, 55% of the children showed substantial behavioral gains and 46% made substantial gains in cognitive task performance. However, there was substantial independence between changes in behavior and changes in cognitive performance. CONCLUSIONS: At the 0.60-mg/kg MPH dose, more children showed substantial cognitive and behavioral gains than those who showed substantial declines in a ratio of more than 5:1. However, it may be prudent to assess cognitive change as well as behavioral effects because improvements in the former do not necessarily forecast improvements in the latter in children with attention-deficit/hyperactivity disorder and mental retardation.