Freeze for action: neurobiological mechanisms in animal and human freezing

Abstract

Upon increasing levels of threat, animals activate qualitatively different defensive modes, including freezing and active fight-or-flight reactions. Whereas freezing is a form of behavioural inhibition accompanied by parasympathetically dominated heart rate deceleration, fight-or-flight reactions are associated with sympathetically driven heart rate acceleration. Despite the potential relevance of freezing for human stress-coping, its phenomenology and neurobiological underpinnings remain largely unexplored in humans. Studies in rodents have shown that freezing depends on amygdala projections to the brainstem (periaqueductal grey). Recent neuroimaging studies in humans have indicated that similar brain regions may be involved in human freezing. In addition, flexibly shifting between freezing and active defensive modes is critical for adequate stress-coping and relies on fronto-amygdala connections. This review paper presents a model detailing these neural mechanisms involved in freezing and the shift to fight-or-flight action. Freezing is not a passive state but rather a parasympathetic brake on the motor system, relevant to perception and action preparation. Study of these defensive responses in humans may advance insights into human stress-related psychopathologies characterized by rigidity in behavioural stress reactions. The paper therefore concludes with a research agenda to stimulate translational animal-human research in this emerging field of human defensive stress responses.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Keywords: defence cascade; freeze-fight-flight; freezing; neural fear and defence circuits; parasympathetic and sympathetic autonomic nervous system.

Figure 1.

Schematic of routes of defensive behaviour (adapted from Hagenaars et al. [15]). (Online version in colour.)

Figure 2.

Schematic of brain structures involved in the control of freezing and fight-or-flight reactions to threat. When threat is processed in the basolateral (BLA) parts of the amygdala, direct connections from the central nucleus of the amygdala (CE) to the ventrolateral periaqueductal grey (vlPAG) mediate freezing by (i) activating the vagal pathway, which in turn regulates parasympathetic (parasymp) heart rate deceleration and (ii) by regulating muscular activity by at least two routes: vlPAG activation (i) inhibits activation of fight-or-flight responses by the dorsolateral (dl)PAG and (ii) modulates premotor neurons projecting to the spinal cord via the rostral ventral medulla. Preservation of muscle tone during freezing is enabled by projections to the lateral hypothalamus. This area also controls sympathetic visceral reactions and activates the pituitary as part of the hypothalamus–pituitary–adrenal (HPA) axis. Shifting between passive and active defensive modes is implemented by the ventromedial prefrontal cortex (vmPFC) and, in particular, the anterior cingulate cortex (ACC), which in turn projects to the CE of the amygdala and to the vlPAG.

Figure 3.

(b) Stabilometric force platform registering body sway in terms of displacements in the centre of pressure during picture-viewing. (a) Example of time series of body sway displacements (in millimetres in the anterior–posterior as well as lateral dimensions) in response to angry, neutral and happy faces (adapted from Roelofs et al. [1]).