NEURODEFENSE

Neural control of human freeze-fight-flight

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'This study investigates the mechanistic bases of human freeze-fight-flight reactions. The ability to control our social behavior is essential for almost every social interaction. It frequently fails in challenging situations when people fall back on basic defensive „freeze-fight-flight‟ (FFF) reactions. It chronically fails in social motivational disorders, with social anxiety as one extreme, and aggression as another. Such disorders are notoriously resistant to therapy. Accordingly, it is essential that we obtain mechanistic insight into the psychological and neurobiological control of human FFF behavior. Upon a social challenge, an automatic attentive immobility, the freeze reaction, serves fast risk-assessment, needed to optimize subsequent fight-or-flight responses. Precise temporal tuning of FFF responses is critical to adequate coping with social challenges. It is orchestrated by complex neuroendocrine systems, utilizing the steroid hormone testosterone. Imbalances in the temporal dynamics and associated neuroendocrine control of FFF behaviors are highly predictive of animal fear and aggression. Testing these mechanisms in humans is critical to advance mechanistic insight in human FFF control, but has as of yet been foreclosed in the absence of the requisite tools to objectively measure human FFF. Recent innovations have enabled us to demonstrate that human freeze reactions to social threat mimic animal freeze responses (bodily immobility and fear bradycardia). These findings open up paths toward investigating the role of FFF reactions in social motivational disorders. The major aim of the proposed research program is to reveal the mechanistic basis of human FFF regulation through the use of three cutting-edge methods: First I intend to integrate body-postural and electroencephalographic measures to detect, for the first time, the temporal dynamics and neuroendocrine control of the full FFF sequence in healthy individuals and patients with social anxiety and aggressive disorders. Second, I will apply hormonal and neural interventions to directly manipulate human FFF control using testosterone administration and transcranial magnetic stimulation. Third, and most crucially, I will validate the predictive value of basic FFF tendencies prospectively in a large longitudinal study. I will test adolescents in a critical transition phase (age 14-17) when they are most vulnerable to social and hormonal influences and when most symptoms develop. The projected findings will advance core theoretical knowledge of the mechanistic basis of human emotion regulation. Moreover they are of critical importance for clinical treatment and society, breaking the grounds for early symptom detection and (preventive) intervention into social anxiety and aggressive disorders that form an ever-growing burden for society.'