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

Abstract

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS Ϯ20%, Ϯ40%, and Ϯ60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

“…PTSD patients show reduced activation in these regions during threat processing and fear extinction (Milad et al , 2008; Hayes et al , 2012). Furthermore, recent studies show that in patients with generalized anxiety disorder, the vmPFC’s fear inhibition function is deficient, resulting in enhanced fear reactivity in the context of fear generalization (Greenberg et al , 2013b; Cha et al , 2014). Yet, whether the distinct vmPFC substructures, i.e.…”

“…The probabilistic Harvard–Oxford atlases (thresholded at 20%) were used for anatomic labeling and masking. The VTA was identified, based on previous literature (Cha et al , 2014), by a 4 mm radius sphere around MNI [3 −17 −12]. In these functional ROIs, we extracted percent signal change per stimulus type using FeatQuery.…”

COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume

“…70 Disturbances in this pathway have been linked to enhanced fear generalization in clinical samples. 71 One implication from these studies is that dopamine-associated hippocampal function is critical for the encoding of distinct memory representations. It is possible that higher dopamine degradationputatively associated with Val homozygosity -is a catalyst in dopaminergic pathway dysfunction that leads to difficulty in distinguishing related yet novel cues from the previously encoded trauma episode.…”

The left hemisphere learns what is right: Hemispatial reward learning depends on reinforcement learning processes in the contralateral hemisphere

“…the VTA) ROI, centre coordinates were obtained from a recent study [Ballard et al, 2011; left VTA x¼ À2 y¼ À15 z¼ À13; right VTA x¼3 y¼ À17 z¼ À12]. The VTA ROI was created by combining two spheres (radius¼ 4 mm) into one VTA mask, in accordance with a recently described procedure (Cha et al, 2014).…”

“…For the VTA, the obtained results are reported using a threshold of p o0.005 and a minimum cluster size of ten contiguous voxels (see Cha et al (2014)). Small volume corrections (SVC) using a threshold of p o0.05 Family-Wise Error Rate for multiple comparisons were obtained using the a priori ROIs described above.…”