NEURODEFENSE is a research program that is funded by the European Research Council by means of a starting grant (ERC-StG). The project aims to investigate defensive freeze-fight-flight reactions in humans by focusing on the neuroendocrine mechanisms underlying these defensive reactions in healthy and (aggressive and anxious) patient samples. Insight into these mechanisms is relevant to our understanding of how people can flexibly cope with acute stress and to provide starting points for early identification of risk factors for aggression and anxiety:

  • We explore the role of freezing in action preparation as well as perceptual preparedness during threat in healthy individuals.
  • In addition, we explore the effects of steroid hormones (testosterone) on these defensive stress-reactions in healthy participants and in patients with aggressive and social anxiety disorders.
  • Finally, we aim to investigate the role of defensive freeze-fight-flight responses in the development of aggression and anxiety. Therefore, adolescents have been tested at a critical transition stage in their lives (between age 14 and age 17), when most aggressive and anxiety symptoms develop.

The project has started in 2013 and will run until 2018.

The first results

  • The role of freezing in action- and perceptual preparedness

In an initial study, we found that freezing -characterized by decreased heart rate and immobility- is related to action preparation (Gladwin, Hashemi et al., 2015). It involves activation in the periaqueductal gray (PAG), an important structure in the human midbrain, that is implicated in heart rate deceleration via vagal efferents and in immobility via medullar-spinal projections (Hagenaars, Oitzl & Roelofs, 2014; Roelofs, 2017).MAria_3

The state of freezing is also associated with alterations in visual perception: It is accompanied by increased ability to detect coarse (low spatial frequency LSF) visual features at the expense of detailed (high spatial frequency HSF) visual information, (see picture from Lojowska et al., 2015). Furthermore, stronger decrease in heart rate, a parasympathetic physiological index of freezing, was linked to better LSF perception (Lojowska et al., 2015). Amygdala projections to V1 and periaqueductal gray (PAG) may underlie the increased visual preparedness during the state of freezing (Lojowska ea., in prep).

  • Steroid hormones (testosterone) and social psychopathologies

In terms of hormones, we have shown that testosterone plays an important role in how frontal-amygdala brain-structures regulate fight-flight tendencies in healthy individuals and in aggressive samples (Radke et al., 2014; Volman et al., 2016; Koch, Kaldewaij et al, in prep; Van Peer, Bramson et al, in prep).

In addition, testosterone administration in patients with social anxiety disorder –who are characterized by reduced testosterone levels- can alleviate social avoidance in these patients (Enter et al., 2015; 2016). Currently, we are investigating whether testosterone administration can boost effects of exposure therapy in patients with social anxiety disorder (Hutschemaekers, Kuilboer, in prep).

  • Development of control over defensive stress-reactions

Testosterone plays a role in the shift from subcortical to frontal control over automatic defensive reactions during puberty (Tyborowska ea, 2016). In addition, prolonged stress-induced freezing in adolescence is related to increased chance on internalizing symptoms (Niermann ea 2017).