ReviewUpdating freeze: Aligning animal and human research
Introduction
Freezing behavior has been used as a main outcome measure for fear for decades in animal studies. It has been described as a highly heritable fear response that is relatively stable over time (De Castro Gomes and Landeira-Fernandez, 2008, Rogers et al., 2008). Human research has recently also recognized the importance of freezing as part of the human defense cascade (Hagenaars et al., 2012, Hermans et al., 2012, Lang et al., 1997, Lang et al., 2000, Marx et al., 2008, Mobbs et al., 2009). Knowledge about freezing in humans is of great importance, as freezing has been linked to the development of psychopathology. That is, freezing is considered to play a role in the etiology of threat-related disorders such as posttraumatic stress disorder (PTSD; e.g., Hagenaars et al., 2008, Rizvi et al., 2008) and social phobia (Buss et al., 2004).
Human defense-models are largely based on findings from animal studies (e.g., Lang et al., 1997). Unfortunately, definitions, instruments, and methods of animal and human studies vary, thereby hampering comparisons and mutual knowledge transfer, as well as empirical testing of animal models in humans. Also, although numerous animal studies have used freezing as an index of fear, research on the nature and phenomenology of freezing responses themselves is scarcer.
We therefore aim to clarify the conceptualization of freezing in order to optimize mutual translations. Several neurophysiological correlates are discussed and human research is reviewed that used the main objective indicator for freezing, similar to animal studies: bodily immobility. Finally, we aim to define gaps in our knowledge and point out directions for future research in order to align animal and human approaches and stimulate a systematic investigation of freezing behavior.
Section snippets
Definition and main characteristics
In the present review, we use the freezing definition that was originally referred to as crouching (Blanchard et al., 1968) and is widely used in animal research: a complete absence of movement, except for that associated with respiration, and a tense body posture (e.g., Fanselow, 1984, Kalin and Shelton, 1989). Note that a tense body posture implies increased muscle tonus. We extend this definition with a third characteristic: reduced heart rate (bradycardia). Bradycardia was found to be
Neural structures
Neurobiological findings have shed some light on the distinction between the different defense responses. Several brain structures have been implicated in freezing in animals. First, the amygdala plays an important role in the expression of freezing as part of the conditioned and unconditioned fear response (LeDoux, 2000). Lesions in the amygdala disrupt both autonomic and behavioral fear responses, including freezing (Blair et al., 2005). The CeA consists of several subnuclei that are involved
Objectively measured spontaneous freezing
Human studies that objectively assessed freezing generally define this response with reduced mobility and bradycardia (Azevedo et al., 2005, Bradley et al., 2001, Hagenaars et al., 2012, Roelofs et al., 2010). This seems a solid assumption given that these are two core features of freezing in animal research. The first general conclusion that can be drawn from these studies is that like in animals, freezing can be elicited in humans as well using experimental designs. Several authors have found
Reflections on animal and human models of freezing
Defense responses in animal models (Eilam, 2005, Fanselow, 1994) formed the basis for the development of human models of defense behavior, including freezing (Lang et al., 1997, Marx et al., 2008). These models are a good starting point for human research, and indeed explain several neurobiological findings. For example, during freezing, sympathetic activity has already started, but cannot be acted upon as a result of a PAG-directed inhibition of motor initiation. Current models indeed posit
Directions for future research
Animal research has directed and stimulated research on threat-related immobility responses in humans (Lang et al., 1997, Marx et al., 2008). Numerous areas still need to be covered though, in order to extend our understanding of the freezing response. First of all, investigation of the time course (intermitted or continuous) and duration (from seconds to 30 min) of freezing will allow distinctions between attentional and defensive immobility, and between the different defensive responses
Summary and conclusions
The definition of freezing is consistent in animal research and should also be used in human research. That is, although several other parameters may vary in presence and fluctuate over time, freezing can quite reliably be operationalized as a fear-related reduction in mobility, increase in muscle tonus and heart rate deceleration.
Brain structures relevant for freezing are those that are involved in fear processing, e.g., amygdala and prefrontal cortex. Moreover, distinct subnuclei of the
Acknowledgements
This work is supported by the Dutch Organization for Scientific Research (NWO): M.A. Hagenaars VENI Grant (#451-09-018), K. Roelofs VIDI Grant (#452-07-008), M.S. Oitzl Grant IRTG (#DN95-420) and Programme for Excellence: Brain&Cognition (#433-09-251).
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