Figure 3. Contribution of prefrontal regions to fear regulation and expression.

A. Activation in the human brain during fear conditioning and extinction can be investigated in a Pavlovian fear conditioning and extinction paradigm. During conditioning, a conditioned stimulus (a colored light) is paired with a mild electric shock to the fingers in a particular context (context A). The acquisition of conditioned fear in this paradigm can be measured by the skin conductance response to the light. During extinction learning, the light is subsequently repeatedly presented without the shock in a different context (context B). This leads to extinction of the conditioned response. The next day, the light is again presented in the absence of the shock in Context B (extinction recall), and then again in Context A (fear renewal). Greater retention of extinction learning is associated with a lower fear response during extinction recall. Extinction retention is context-dependent: the hippocampus is thought to recognize whether a context is safe (B) or dangerous (A) and to communicate this information to other structures in the fear network.

B. fMRI studies have shown that activation of ventromedial prefrontal cortex (vmPFC, shown in green) during extinction recall is positively correlated with extinction retention,⁷⁰ whereas activation of dorsal anterior cingulate cortex (dACC, shown in red) is negatively correlated with extinction retention.⁷¹ Ventromedial PFC sends excitatory glutamatergic projections to gamma-aminobutyric acid (GABA) -ergic intercalated cells (ITC) in amygdala, which in turn inhibit the expression of the fear response by the amygdala’s central nucleus (Ce). In contrast, dACC sends excitatory glutamatergic projections to amygdala’s basolateral nucleus, which in turns activates the expression of the fear response by Ce. LA=lateral amygdala nucleus.

C. Non-PTSD subjects (left) have a relatively high vmPFC/dACC activation ratio during extinction recall, which tips the balance toward better extinction retention and less fear expression. By contrast, PTSD subjects (right) have a lower vmPFC/dACC activation ratio, which tips the balance toward less extinction retention and more fear expression.⁶⁸