Ventromedial Prefrontal Cortex Reactivity Is Altered in Generalized Anxiety Disorder During Fear Generalization

Abstract

These findings suggest that deficits in fear regulation, rather than in the excitatory response itself, are more critical to the pathophysiology of GAD in the context of fear generalization.

Hyper-Reactive Human Ventral Tegmental Area and Aberrant Mesocorticolimbic Connectivity in Overgeneralization of Fear in Generalized Anxiety Disorder

“…This led to a significant group difference in the VTA fear generalization gradient: a linear increase in VTA reactivity with increase in perceptual similarity to the CS (threat) in healthy controls, but indiscriminately enhanced VTA activation, to all stimuli regardless of perceptual similarity to CS (threat), in individuals with GAD. This effect is well in line with the model of overgeneralization of conditioned fear in pathological anxiety (Jovanovic and Ressler, 2010;Britton et al, 2011;Kheirbek et al, 2012;Greenberg et al, 2013a). Furthermore, variability of the patient-specific VTA hyper-reactivity to the GS least similar to CS was correlated with individual differences in trait anxiety.…”

“…Regarding our previous reports on vmPFC dysfunction in individuals with GAD (Greenberg et al, 2013a;Cha et al, 2014), we examined the relationship between the fear generalization gradient in the vmPFC and the VTA. The vmPFC fear generalization gradient is the slope of the linear fit on the fear generalization reactivity gradient (as a function of cue similarity to CS); this measure did not show a correlation with the VTA fear generalization gradient in either the patient group or in healthy controls ( p Ͼ 0.52; nonparametric correlation).…”

“…Discrimination of threat and safety is an essential aspect of aversion processing for adaptive behavior. Deficits in this process lead to an overgeneralization of conditioned fear (Kheirbek et al, 2012;Greenberg et al, 2013b;Lissek et al, 2013b); indeed, recent human studies suggest that fear overgeneralization is an important pathogenic marker of anxiety disorders, including panic disorder and generalized anxiety disorder (GAD) (Greenberg et al, 2013a;Lissek et al, 2013a). Therefore, given the crucial role of the mesocorticolimbic dopamine system in negative motivation and the impact of stress on this system, it is reasonable to postulate that maladaptive aversion processing in this system is related to the overgeneralization of conditioned fear in clinical anxiety.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Mouse CSD resulted in excessive fear learning and memory of an aversive CS-US association, indicating that psychosocial stress induced generalized hyper-reactivity to aversion. Pavlovian fear learning-memory is an important translational readout for several reasons, including detailed knowledge of the neurobiology of adaptive fear learning-memory in healthy humans (Fullana et al, 2015) and mice (Duvarci and Pare, 2014;LeDoux, 2000;Wolff et al, 2014), and evidence for increased fear conditioning in MDD (Nissen et al, 2010) and GAD (Greenberg et al, 2013;Lissek et al, 2015). Repeated escitalopram reversed the increased fear expression, specifically, in CSD mice, indicating that the model has predictive validity.…”

“…The amygdala, specifically the basolateral complex and central nucleus, is essential for each of these stages (Duvarci and Pare, 2014;Kim and Jung, 2006;Maren and Quirk, 2004). In human, CS-US fear conditioning has been demonstrated to be increased in both MDD (Nissen et al, 2010) and GAD (Greenberg et al, 2013;Lissek et al, 2015).…”