Elsevier

Behavioural Brain Research

Volume 223, Issue 2, 1 October 2011, Pages 403-410
Behavioural Brain Research

Review
The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety

https://doi.org/10.1016/j.bbr.2011.04.025Get rights and content

Abstract

The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala–mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala–mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety.

Highlights

Amygdala is extensively interconnected with the medial prefrontal cortex ► Amygdala-prefrontal circuitry is critical in top-down and bottom-up processes ► Stronger amygdala-prefrontal connectivity predicts lower levels of anxiety ► Stronger amygdala-prefrontal connectivity predicts effective emotion regulation.

Introduction

Accurate evaluation of and response to potentially life threatening or sustaining events are hallmarks of biologically relevant learning in animals and humans. In response to cues of threat, rodents exhibit a distinctive “freezing” or somatomotor arrest behavior. This behavior is critical in a natural environment in which movement may attract a predator to its location. Humans show a similar freezing response to a potentially threatening situation [1]. Rather than having to avoid predators, humans might more ordinarily show such a response when having to speak in front of a large audience. In such threatening instances, performance would be facilitated if able to override the initial freezing behavior.

In psychological terms, instinctive reactions to threat and subsequent regulatory responses are often referred to as bottom-up and top-down processes, respectively. The interplay between these two processes is exemplified by the following example: upon encountering a snake at a zoo, an initial reaction is driven by its appearance (i.e., bottom-up saliency), but the response is then implicitly controlled by the determination that the snake presents no immediate danger because it is behind a sheet of Plexiglas (i.e., top-down control). Of course, the context is critical since the same snake encountered in a field would evoke an initial freezing response followed by a very different type of top-down control in the form of running (or screaming in some cases). Thus, interactions between bottom-up and top-down processes will determine the adaptiveness of behavior in a given situation.

This conceptualization may be directly applicable to clinical research, as the interaction between these bottom-up and top-down processes is hypothesized to be impaired in psychiatric illnesses – and here we will focus on the anxiety disorders. For example, in specific phobias, perhaps a failure to employ top-down control mechanisms allows initial bottom-up responses to intrude on normal cognitive functioning. Alternatively, it may be the case that the initial bottom-up reactions are so potent and exaggerated that even a normally functioning top-down regulatory system cannot keep these responses in check. Individual differences in the function and structure of this circuitry can also explain differences in normal levels of anxiety.

Numerous studies have highlighted the critical role of the amygdala and the mPFC in behavioral phenomena that involve competition between bottom-up and top-down processes, including fear conditioning and extinction [2], [3], [4]. Critically, it is believed that the mPFC regulates and controls amygdala output and the accompanying behavioral phenomena [2], [3], [4]. The reciprocal relationship between the amygdala and the mPFC strongly suggests the need to investigate these brain regions as one circuit, rather than studying them separately. That is, while numerous studies have assessed the separate contributions that the amygdala and mPFC make to reactivity and regulation, respectively [5], [6], [7], [8], more recent studies suggest that the structural and functional connectivity between these two regions is a better predictor of these outcomes than the activity of either region alone [9], [10], [11]. The idea here is that the stronger the coupling between the amygdala and the mPFC, the better the behavioral outcome in terms of reported anxiety.

Section snippets

Structural neuroanatomy of amygdala–mPFC circuitry

The amygdala is an almond-shaped brain structure that resides in the medial temporal lobe of the brain [12], [13]. Its structure is comprised of many subnuclei, including the basolateral nuclei (BLA) and the central nucleus (Ce), which have distinct anatomical connections with other brain regions that serve different functions. Comprehensive descriptions of the anatomical connections of the amygdala exist elsewhere [14], [15]. Here, we focus on the connectivity between the amygdala and the

Amygdala-prefrontal circuitry and fear conditioning and extinction

Studies of the non-human animal amygdala have shown that sensory information received by the BLA is then passed to the Ce [45]. Though outputs exist at the level of the BLA, a majority of outputs originate from the Ce [46]. The Ce projects directly to the hypothalamus and brain stem nuclei that drive autonomic and somatomotor responding [47]. The Ce also projects to all major neuromodulatory systems including dopaminergic, cholinergic, serotonergic and noradrenergic systems [46]. Thus, while

Amygdala-prefrontal circuitry and emotion regulation

The ability to regulate our emotions is essential in our everyday lives, and successful emotion regulation begets beneficial outcomes in many social situations. Emotion regulation is a classic example of how top-down and bottom-up processes compete and interact to produce optimal (or counterproductive) behavioral outcomes. For example, one's instinctive reaction to a frightening scene in a horror movie may include an urge to scream and/or run out of the room. Normally, this bottom-up reaction

Amygdala-prefrontal circuitry and the interpretation of emotionally ambiguous facial expressions

In humans, patients with selective amygdala lesions have displayed deficits in processing the facial expressions of fear [80], leading to numerous functional neuroimaging studies using presentations of fearful faces to probe amygdala activity [10], [81], [82], [83], [84], [85], [86]. These studies have shown that the amygdala is particularly responsive to fearful faces compared to other expressions [87], including angry, happy, and neutral [10], [81], [82], [84], [85], [86], except for one

Amygdala-prefrontal circuitry and anxiety within the normal range

Anxiety is characterized by chronic, nonspecific apprehension and arousal related to the potential occurrence of future threat [93], [94]. Neurobiological theories of anxiety have highlighted the central role of the amygdala in the generation and experience of the fear that can give rise to anxiety [48], [49], and fear extinction investigations in animals support such theories [48], [49]. Similar to the inhibition of previously conditioned fear responses during fear extinction, reduced anxiety

Amygdala-prefrontal circuitry and pathological anxiety

Taking individual differences in normal fluctuations in anxiety as our starting point, disrupted bottom-up and top-down emotional and cognitive processes are thought to be a crucial component of symptomology in pathological anxiety. This model suggests an imbalance between the amygdala and the prefrontal cortex, which is typically characterized by hyperactivity of the amygdala and hypoactivity of the prefrontal cortex [104], [105].

Conclusions

From normal emotion to pathological anxiety, an organism's reaction to biologically relevant stimuli and the regulation of these responses can be usefully conceived as a constant struggle between bottom-up and top-down brain processes. A wealth of animal and human neuroimaging studies has shown that the amygdala and the prefrontal cortex, particularly the medial regions, are central to these processes. Investigating the connectivity between the amygdala and the prefrontal cortex has provided a

Acknowledgements

Supported by the National Institute of Mental Health grants to MJK (F31 MH090672) and PJW (R01 MH080716).

References (126)

  • K.J. Friston et al.

    Psychophysiological and modulatory interactions in neuroimaging

    Neuroimage

    (1997)
  • K.J. Friston et al.

    Dynamic causal modelling

    Neuroimage

    (2003)
  • D.S. Margulies et al.

    Mapping the functional connectivity of anterior cingulate cortex

    Neuroimage

    (2007)
  • A.K. Roy et al.

    Functional connectivity of the human amygdala using resting state fMRI

    Neuroimage

    (2009)
  • A.M. Kelly et al.

    Competition between functional brain networks mediates behavioral variability

    Neuroimage

    (2008)
  • M. Davis et al.

    The amygdala

    Curr Biol

    (2000)
  • G. Holstege et al.

    The emotional motor system

    Prog Brain Res

    (1996)
  • G.J. Quirk et al.

    Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat

    Neuron

    (1995)
  • M.S. Fanselow et al.

    Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala

    Neuron

    (1999)
  • M.R. Delgado et al.

    Neural circuitry underlying the regulation of conditioned fear and its relation to extinction

    Neuron

    (2008)
  • M.R. Milad et al.

    Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert

    Biol Psychiatry

    (2007)
  • E.A. Phelps et al.

    Extinction learning in humans: role of the amygdala and vmPFC

    Neuron

    (2004)
  • A.R. Hariri et al.

    Neocortical modulation of the amygdala response to fearful stimuli

    Biol Psychiatry

    (2003)
  • K.L. Phan et al.

    Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study

    Biol Psychiatry

    (2005)
  • T.D. Wager et al.

    Prefrontal-subcortical pathways mediating successful emotion regulation

    Neuron

    (2008)
  • E.M. Drabant et al.

    Individual differences in typical reappraisal use predict amygdala and prefrontal responses

    Biol Psychiatry

    (2009)
  • M.M. Botvinick et al.

    Conflict monitoring and anterior cingulate cortex: an update

    Trends Cogn Sci

    (2004)
  • T.F. Heatherton et al.

    Cognitive neuroscience of self-regulation failure

    Trends Cogn Sci

    (2011)
  • H. Breiter et al.

    Response and habituation of the human amygdala during visual processing of facial expression

    Neuron

    (1996)
  • D.A. Fitzgerald et al.

    Beyond threat: amygdala reactivity across multiple expressions of facial affect

    Neuroimage

    (2006)
  • T.A. Hare et al.

    Biological substrates of emotional reactivity and regulation in adolescence during an emotional go-nogo task

    Biol Psychiatry

    (2008)
  • E.W. Dickie et al.

    Amygdala responses to unattended fearful faces: interaction between sex and trait anxiety

    Psychiatry Res

    (2008)
  • A. Etkin et al.

    Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces

    Neuron

    (2004)
  • L.H. Somerville et al.

    Human amygdala responses during presentation of happy and neutral faces: correlations with state anxiety

    Biol Psychiatry

    (2004)
  • K. Roelofs et al.

    Facing freeze: social threat induces bodily freeze in humans

    Psychol Sci

    (2010)
  • S. Bishop et al.

    Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli

    Nat Neurosci

    (2004)
  • A. Simmons et al.

    Anxiety vulnerability is associated with altered anterior cingulate response to an affective appraisal task

    Neuroreport

    (2008)
  • J.R. Simpson et al.

    Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety

    Proc Natl Acad Sci USA

    (2001)
  • L. Pezawas et al.

    5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

    Nat Neurosci

    (2005)
  • M.J. Kim et al.

    The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety

    J Neurosci

    (2009)
  • Kim MJ, Gee DG, Loucks RA, Davis FC, Whalen PJ. Anxiety dissociates dorsal and ventral medial prefrontal cortex...
  • P.J. Whalen et al.

    The human amygdala

    (2009)
  • D.G. Amaral et al.

    Anatomical organization of the primate amygdaloid complex

  • J.L. Freese et al.

    Neuroanatomy of the primate amygdala

  • S.T. Carmichael et al.

    Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys

    J. Comp. Neurol.

    (1995)
  • L. Stefanacci et al.

    Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study

    J Comp Neurol

    (2002)
  • D.G. Amaral et al.

    Amygdalo-cortical projections in the monkey (Macaca fascicularis)

    J Comp Neurol

    (1984)
  • H. Barbas et al.

    Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey

    J Comp Neurol

    (1990)
  • J.E. LeDoux

    The emotional brain

    (1996)
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