ReviewThe structural and functional connectivity of the amygdala: From normal emotion to pathological 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).
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