A phenotype of early infancy predicts reactivity of the amygdala in male adults

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala has a central role in the processing of novelty and emotion in the brain. Although there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four-month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here, we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioral assessment made in the laboratory at 4 months of age. This is the earliest known human behavioral phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or 'endophenotypes') indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically defined disorder. As the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the 4-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.     

Interspecies Modeling and Prediction of Human Exenatide Pharmacokinetics

Purpose

To develop a model-based approach for interspecies scaling of the preclinical pharmacokinetics of exenatide and to predict concentration-time profiles in humans.

Methods

A target-mediated drug disposition (TMDD) model was simultaneously fit to concentration-time profiles of exenatide over a wide range of intravenous (IV) and subcutaneous (SC) doses obtained from mice, rats, and monkeys. Allometric relationships were incorporated into the model to scale parameters based on species body weight. Human pharmacokinetic profiles following IV and SC administration were simulated using the final model structure and parameter estimates and compared to clinical data.

Results

The final model provided a good simultaneous fit to all animal data and reasonable parameter estimates. Exenatide receptor binding affinity and baseline receptor concentrations were species-dependent. Absorption parameters from rat provided the best prediction of exenatide SC absorption in humans, but good predictions could also be obtained using allometric scaling of preclinical absorption parameters.

Conclusions

A TMDD model combined with allometric scaling was successfully used to simultaneously describe preclinical data for exenatide from three animal species following both IV and SC administration. The majority of model parameters could be shared among the animal species and further used for projecting exenatide behavior in humans.