Elsevier

Neuroscience & Biobehavioral Reviews

Volume 47, November 2014, Pages 165-176
Neuroscience & Biobehavioral Reviews

Review
Updating freeze: Aligning animal and human research

https://doi.org/10.1016/j.neubiorev.2014.07.021Get rights and content

Highlights

  • Research on defense behavior profits from animal–human translations.

  • Core features of freezing: reduced mobility, bradycardia and increased muscle tonus.

  • Human and animal research should use the same definition of freezing.

  • Sympathetic and parasympathetic systems are active during freezing.

  • Viewing threatening stimuli in a laboratory setting elicits freezing-like responses in humans.

Abstract

Freezing is widely used as the main outcome measure for fear in animal studies. Freezing is also getting attention more frequently in human stress research, as it is considered to play an important role in the development of psychopathology. Human models on defense behavior are largely based on animal models. Unfortunately, direct translations between animal and human studies are hampered by differences in definitions and methods. The present review therefore aims to clarify the conceptualization of freezing. Neurophysiological and neuroanatomical correlates are discussed and a translational model is proposed. We review the upcoming research on freezing in humans that aims to match animal studies by using physiological indicators of freezing (bradycardia and objective reduction in movement). Finally, we set the agenda for future research in order to optimize mutual animal–human translations and stimulate consistency and systematization in future empirical research on the freezing phenomenon.

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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