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

Abstract

Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.

Neurobehavioural mechanisms of threat generalization moderate the link between childhood maltreatment and psychopathology in emerging adulthood

“…19,22 The dACC and anterior insula are known for their respective roles in the expression of fear responses 23 and interoceptive awareness, 24 with increasing activation along the similarity continu um to the CS. 25,26 The hippocampus and vmPFC have been implicated in stimulus discrimination and safety processing, 27,28 respectively, with decreasing activation along the similarity continuum. 25,26 Overall, the results therefore seem to indicate reduced threat-safety discrimination on a neural level in patients with anxiety and PTSD.…”

“…25,26 The hippocampus and vmPFC have been implicated in stimulus discrimination and safety processing, 27,28 respectively, with decreasing activation along the similarity continuum. 25,26 Overall, the results therefore seem to indicate reduced threat-safety discrimination on a neural level in patients with anxiety and PTSD. 19,22 Furthermore, generalization gradients in the vmPFC have been associated with symptoms of both anxiety and depression in those with GAD.…”

“…Threat generalization was assessed using a validated functional MRI (fMRI) paradigm 25 (adapted from Lissek and colleagues 26 ), measuring both the affective expression (i.e., fear) and the cognitive expression of threat processing (i.e., expectancy of an aversive unconditioned stimulus [US]; US expectancy) as well as neural generalization responses (see Appendix 1, Fig. S1 for more details).…”

Neuronal activity in sensory cortex predicts the specificity of learning

“…Here we find that the present state of each individual brain, in terms of neural discrimination of stimuli, is predictive of the future generalization of fear in the subject. This suggests that a way to prevent generalization of dangerous and safe sounds is to improve neural discrimination of potentially threatening stimuli (Ginat-Frolich et al, 2017;Lange et al, 2017;Roesmann et al, 2020;Tuominen et al, 2019). Further work in this area can lead to a deeper understanding how genetic and social factors, as well early life experiences, shape cortical activity in this common and devastating disorder (Mahan and Ressler, 2012;Roesmann et al, 2020).…”

Peer Review #1 of "Post-traumatic stress symptoms are associated with better performance on a delayed match-to-position task (v0.1)"

“…Recent research utilizing a go/no go task measuring inhibitory processes reported that not only were patients with PTSD more likely to make inhibition-related errors than participants without trauma, but the process of inhibition relied on different brain networks such that controls relied on a right-lateralized cortical network while the PTSD participants activated only on the left-lateral frontal cortex during inhibition (Falconer et al, 2008). Additionally, recent research examining the relationship between fear generalization and behavioral pattern separation reports brain areas involved in inhibition and safety processing play a role in behavioral pattern separation including the subcallosal cortex, orbitofrontal cortex, and ventromedial prefrontal cortex (Lange et al, 2017). This is in line with recent work using rat models of PTSD which further implicate the prefrontal cortex as a key region leading to deficits in cognitive flexibility and inhibitory responses (George et al, 2015).…”