The role of puberty on physical and brain development: A longitudinal study in male Rhesus Macaques.

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.

Validation of the Social Responsiveness Scale (SRS) to screen for atypical social behaviors in juvenile macaques.

Primates form strong social bonds and depend on social relationships and networks that provide shared resources and protection critical for survival. Social deficits such as those present in autism spectrum disorder (ASD) and other psychiatric disorders hinder the individual's functioning in communities. Given that early diagnosis and intervention can improve outcomes and trajectories of ASD, there is a great need for tools to identify early markers for screening/diagnosis, and for translational animal models to uncover biological mechanisms and develop treatments. One of the most widely used screening tools for ASD in children is the Social Responsiveness Scale (SRS), a quantitative measure used to identify individuals with atypical social behaviors. The SRS has been adapted for use in adult rhesus monkeys (Macaca mulatta)-a species very close to humans in terms of social behavior, brain anatomy/connectivity and development-but has not yet been validated or adapted for a necessary downward extension to younger ages matching those for ASD diagnosis in children. The goal of the present study was to adapt and validate the adult macaque SRS (mSRS) in juvenile macaques with age equivalent to mid-childhood in humans. Expert primate coders modified the mSRS to adapt it to rate atypical social behaviors in juvenile macaques living in complex social groups at the Yerkes National Primate Research Center. Construct and face validity of this juvenile mSRS (jmSRS) was determined based on well-established and operationalized measures of social and non-social behaviors in this species using traditional behavioral observations. We found that the jmSRS identifies variability in social responsiveness of juvenile rhesus monkeys and shows strong construct/predictive validity, as well as sensitivity to detect atypical social behaviors in young male and female macaques across social status. Thus, the jmSRS provides a promising tool for translational research on macaque models of children social disorders.

Structural development of cortical lobes during the first 6 months of life in infant macaques.

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.

Early Developmental Trajectories of Functional Connectivity Along the Visual Pathways in Rhesus Monkeys.

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.

Automatic detection of trustworthiness of the face: a visual mismatch negativity study.

Recognizing intentions of strangers from facial cues is crucial in everyday social interactions. Recent studies demonstrated enhanced event-related potential (ERP) responses to untrustworthy compared to trustworthy faces. The aim of the present study was to investigate the electrophysiological correlates of automatic processing of trustworthiness cues in a visual oddball paradigm in two consecutive experimental blocks. In one block, frequent trustworthy (p = 0.9) and rare untrustworthy face stimuli (p = 0.1) were briefly presented on a computer screen with each stimulus consisting of four peripherally positioned faces. In the other block stimuli were presented with reversed probabilities enabling the comparison of ERPs evoked by physically identical deviant and standard stimuli. To avoid attentional effects participants engaged in a central detection task. Analyses of deviant minus standard difference waveforms revealed that deviant untrustworthy but not trustworthy faces elicited the visual mismatch negativity (vMMN) component. The present results indicate that adaptation occurred to repeated unattended trustworthy (but not untrustworthy) faces, i.e., an automatic expectation was elicited towards trustworthiness signals, which was violated by deviant untrustworthy faces. As an evolutionary adaptive mechanism, the observed fast detection of trustworthiness-related social facial cues may serve as the basis of conscious recognition of reliable partners.