It is known that prenatal androgens are greatly responsible for phenotypic sexual dimorphism between the sexes by their influence on male sexual differentiation. Without androgens prenatally, the external genitalia will develop as female. However, evidence that prenatal and/or perinatal androgen exposure influences cognitive function is controversial, and the regional changes within the brain that may underlie such influences are not well understood. Our studies, using functional magnetic resonance imaging (fMRI), are designed to test the hypothesis that androgen exposure of the brain present in normal males during critical periods of differentiation and development leads to sexual dimorphism in brain function. We hypothesize that androgen exposure alters brain organization, and is responsible for sexual dimorphism between the sexes in areas of brain activation, resulting in sex differences in the performance of certain cognitive tasks as demonstrated by fMRI. The proposed studies will extend previous work on brain function organization in humans. They will address, for the first time, the issue of the androgen control of brain sexual dimorphism by studying control males and females as well as subjects with inherited disorders of androgen action, who have been characterized by molecular genetic analyses and biochemical studies. The two unique inherited conditions to be studies are complete androgen insensitivity and 5alpha-reductase deficiency. Our laboratory has been evaluating subjects with these inherited abnormalities for over twenty years. Thus, we are uniquely poised to do this study. The contrast of subjects with these conditions with each other, and with control males and females is particularly suited to dissecting out androgen effects on neurocognition. The fMRI activation methods and tasks employed have demonstrated significant sex differences in our pilot studies and will allow the more specific androgen-related hypotheses to be tested in these subject groups. These tasks include the Shepard Metzler Mental Rotation task (a visuo-spatial task), and a neutral and emotional word task, which demonstrate significant sexual dimorphism (see preliminary data). These unique studies will provide evidence for the androgen dependency of the sexually dimorphic organizational patterns of activity during the performance of certain cognitive tasks. Our studies are performed with the full fMRI resources and expertise of the Functional Neuroimaging Laboratory at Cornell, our molecular genetics laboratory, the expertise of the PI, and an experimental psychologist who has collaborated with us in the past.
