Structural imaging results revealed conflicting reports of increased volume in SAD,66 no difference in SP,67 and decreased volume in SAD46 and PTSD68–70 compared with controls.
Recent functional imaging studies revealed insula hyper- activation to threat in patients with SP,27–29,71 SAD,36,50,52,65,72,73 and PTSD30,54,74–77 compared with controls. The degree of insula hyperactivation was positively correlated with symp- tom severity in SAD.72 Both medication and psychotherapy have been shown to decrease insula hyperactivation from pre- to posttreatment in SAD.31,58,78 In contrast, one study found that patients with dental phobia did not show hyperactivation in insula during exposure to phobic stimuli compared with healthy controls.29
Dorsal anterior cingulate cortex
Literature suggests decreased dACC gray matter and white matter volume in PD,40 SP,79 and PTSD80–82 compared with healthy controls. In contrast, some studies have reported increased volume in dACC in SAD66 and GAD.43
Functional imaging studies reported dACC hyperac- tivation to threat in SP,26–29,71 SAD,24,50,83 and PTSD.30,84–86 Increased dACC activation was correlated with greater autonomic arousal29 and subjective anxiety levels26,71 in SP. Cognitive behavioral therapy was found to decrease ACC activation in SP,71 and pretreatment ACC activation pre- dicted positive treatment response in patients with GAD.61 Despite relatively consistent findings of hyperactivation in dACC, some idiosyncrasies exist in the literature. In contrast to other types of phobia, patients with dental phobia26 and blood-injection-injury phobia29 did not exhibit increased ACC activation to phobic stimuli relative to healthy controls, suggesting dACC may not be involved in threat processing in some anxiety symptom presentations. Moreover, one study reported that dACC was less active to threat in SAD compared with healthy controls.87
Emotion modulation regions
Regions involved in regulating threat responding are particu- larly important in anxiety, as they can decrease activation in threat-processing regions such as the amygdala, insula, and dACC. These have been identified using basic science models and human imaging studies. The mPFC, hippocampus, dorsolateral prefrontal cortex (dlPFC), and rACC have been implicated in modulating fear responding. Although the mPFC10,33,34,88 and rACC89 are primarily involved in modulating emotion, the dlPFC89 has been implicated in both emotion modulation and attention control. The hippocampus
is primarily involved in encoding contextual information and modulating fear responding within the context of threat and safety signals.11 As such, these regions underlie differ- ent functions that may work in concert to modulate threat response. Evidence reported before the scope of the current review13 suggests hyperactivation in the hippocampus in PD and PTSD but little evidence for hippocampus involvement in other anxiety disorders. Hypoactivation in the mPFC has been reported in PTSD and GAD, with less consistent results seen in PD, SP, and SAD. Evidence for dlPFC and rACC is less consistent and less studied, with both hyper- and hypo- activation reported in PD, SP, SAD, and PTSD.
Medial prefrontal cortex
Structural imaging studies report differences in mPFC, with increased volume in SAD,90 decreased volume in PTSD,77,80 and no difference in GAD,91 with decreased volume associ- ated with greater symptom severity in PTSD.92,93
Functional imaging studies, including two recent meta- analyses and a literature review,30,76,94 primarily report decreased mPFC activation in PTSD compared with healthy controls. Some other studies of PTSD patients reported increased mPFC activation in response to fearful faces.74,75,95 Similar findings are reported in SAD, with both increased96 and decreased97 mPFC activation in response to threat and social tasks. Results are somewhat more consistent in GAD, with the majority reporting decreased mPFC activation.62,98–100 It has been suggested that hyperactivation and hypoactiva- tion in mPFC may be associated with different symptom profiles.101 It is also possible that although hypoactivation indicates a deficit in emotion regulation, hyperactivation indi- cates an overcompensatory response in an effort to decrease excessive fear responding. Regardless of these discrepancies, the treatment literature is quite consistent, suggesting that both pharmacotherapy and psychotherapy produce increases in mPFC activation in SAD57,58,102,103 and PTSD,59 which is related to symptom improvements.
Hippocampus
Although the hippocampus is often considered part of the limbic system responsible for fear generation, the majority of evidence in rodent and human models examining hippocampal function suggests its primary role is in context learning and fear modulation in the presence of safety and threat contexts.11 Structural imaging studies of the hippocampus suggest decreased volume and density in PD,38,40 SAD,45,104,90, GAD,106 and PTSD. There is also evidence for increased hippocampal volume after treatment with selective serotonin reuptake inhibitors in PTSD.107 However, findings are somewhat mixed, with studies also reporting no differences46 and larger47,108 hippocampal volume in SAD compared with healthy controls.
