Abstract
Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning.
Highlights
The experience of a dangerous or harmful situation often results in the implicit association of a neutral stimulus with the fear experience
Skin conductance responses revealed a recovery of fear to both the CS+ (P < 0.001) and the CS− (P < 0.001), suggesting that fear recovery generalized to both conditions across all participants
GABA concentrations appear to influence the recovery of fear through modulation of amygdala responsivity, indicating that high baseline GABA levels are associated to increased fear recovery as suggested by both skin conductance responses and BOLD data
Summary
The experience of a dangerous or harmful situation often results in the implicit association of a neutral stimulus with the fear experience. Despite shortterm benefits of exposure therapy, relapse into fear is a common problem in the treatment of anxiety disorders such as posttraumatic stress disorder (PTSD) (Durham et al, 2005; Milad et al, 2008; Duits et al, 2015) This phenomenon is known as the spontaneous recovery of fear and is highly variable between individuals (Pavlov, 1927; Milad and Quirk, 2002; Bush et al, 2007). Theoretical accounts posit that spontaneous recovery is the consequence of reduced inhibition of conditioned responses (Rescorla, 2004), and pharmacological studies in rodents point to a key role of the primary inhibitory neurotransmitter γaminobutyric acid (GABA) in the acquisition and maintenance of fear inhibition These studies indicate that increased GABAergic neurotransmission during extinction training initially reduces fear expression. Increasing GABAergic neurotransmission disrupts the consolidation of the acquired extinction memory which leads to stronger recovery of fear (Bindra et al, 1965; Bouton et al, 1990; McGaugh et al, 1990; Makkar et al, 2010)
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