The Neurocircuitry of Fear, Stress, and Anxiety Disorders

Department of Psychology, Tufts University, Medford, MA 02155, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 08/2009; 35(1):169-91. DOI: 10.1038/npp.2009.83
Source: PubMed


Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

Download full-text


Available from: Israel Liberzon,
1 Follower
86 Reads
    • "Fear, anxiety, and pain are all conditions of negative affect that afflict women to a higher degree than men (Bartley and Fillingim, 2013; McLean and Anderson, 2009). The neural substrates of these conditions, which include the amygdala, anterior cingulate cortex (ACC), insula, periaqueductal grey, and prefrontal cortex (Linnman et al., 2012; May, 2007; Shin and Liberzon, 2010; Simons et al., 2014), overlap with and subserve extinction of conditioned fear (Milad and Quirk, 2012). These regions also demonstrate sex differences related to negative affect (Donner and Lowry, 2013; Lebron-Milad and Milad, 2012; Stevens and Hamann, 2012), and we have reported sex differences in the task-related functional activation of parts of this network during acute pain (Linnman et al., 2012), fear conditioning, and fear extinction (Lebron-Milad et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.
    Psychoneuroendocrinology 09/2015; 63:34-42. DOI:10.1016/j.psyneuen.2015.09.012 · 4.94 Impact Factor
  • Source
    • "In addition to the bidirectional beta correlations observed, PCL score was highly correlated with SAL network gamma synchrony, a network that includes the bilateral anterior cingulate cortex and insula. Abnormal activation in this network is noted in a number of psychiatric disorders (Menon, 2011; Palaniyappan and Liddle, 2012), as well as PTSD (Sripada et al., 2012), with increases in insula activation consistent with elevated levels of interception and awareness of arousal which could be related to symptoms of PTSD such as withdrawn and hypervigilant states (Shin and Liberzon, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Soldiers with post-traumatic stress disorder (PTSD) exhibit elevated gamma-band synchrony in left fronto-temporal cortex, and connectivity measures in these regions correlate with comorbidities and PTSD severity, which suggests increased gamma synchrony is related to symptomology. However, little is known about the role of intrinsic, phase-synchronised networks in the disorder. Using magnetoencephalography (MEG), we characterised spectral connectivity in the default-mode, salience, visual, and attention networks during resting-state in a PTSD population and a trauma-exposed control group. Intrinsic network connectivity was examined in canonical frequency bands. We observed increased inter-network synchronisation in the PTSD group compared with controls in the gamma (30-80 Hz) and high-gamma range (80-150 Hz). Analyses of connectivity and symptomology revealed that PTSD severity was positively associated with beta synchrony in the ventral-attention-to-salience networks, and gamma synchrony within the salience network, but also negatively correlated with beta synchrony within the visual network. These novel results show that frequency-specific, network-level atypicalities may reflect trauma-related alterations of ongoing functional connectivity, and correlations of beta synchrony in attentional-to-salience and visual networks with PTSD severity suggest complicated network interactions mediate symptoms. These results contribute to accumulating evidence that PTSD is a complicated network-based disorder expressed as altered neural interactions.
    Psychiatry Research: Neuroimaging 09/2015; DOI:10.1016/j.pscychresns.2015.09.002 · 2.42 Impact Factor
    • "A number of psychiatric disorders include symptoms of inappropriate or impaired attention towards salient emotional stimuli. For example, individuals with autism spectrum disorder (ASD) show reduced attentional bias to faces (Riby et al., 2012), while those with anxiety disorders or depression are more attentive towards negative emotional cues (Peckham et al., 2010; Shin and Liberzon, 2010). The hypothalamic neuropeptide oxytocin (OXT) has been reported to improve attention towards salient facial cues such as the eyes in individuals with ASD (Auyeung et al., 2015; Guastella et al., 2010), and to reduce attentional bias for emotional faces in individuals with high social anxiety (Clark-Efford et al., 2014) or for masked angry faces in those with high trait depression (Ellenbogen et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in altering attentional bias towards emotional social stimuli in psychiatric disorders. However, it is still unclear whether oxytocin primarily influences attention towards positive or negative valence social stimuli. Here in a double-blind, placebo controlled, between subject design experiment in 60 healthy male subjects we have used the highly sensitive dual-target rapid serial visual presentation (RSVP) paradigm to investigate whether intranasal oxytocin (40IU) treatment alters attentional bias for emotional faces. Results show that oxytocin improved recognition accuracy of neutral and happy expression faces presented in the second target position (T2) during the period of reduced attentional capacity following prior presentation of a first neutral face target (T1), but had no effect on recognition of negative expression faces (angry, fearful, sad). Oxytocin also had no effect on recognition of non-social stimuli (digits) in this task. Recognition accuracy for neutral faces at T2 was negatively associated with autism spectrum quotient (ASQ) scores in the placebo group, and oxytocin's facilitatory effects were restricted to a sub-group of subjects with higher ASQ scores. Our results therefore indicate that oxytocin primarily enhances the allocation of attentional resources towards faces expressing neutral or positive emotion and does not influence that towards negative emotion ones or non-social stimuli. This effect of oxytocin is strongest in healthy individuals with higher autistic trait scores, thereby providing further support for its potential therapeutic use in autism spectrum disorder.
    Psychoneuroendocrinology 09/2015; 62. DOI:10.1016/j.psyneuen.2015.09.002 · 4.94 Impact Factor
Show more