Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

Abstract

Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and "personalized" interventions.

Figure 1

Neural circuits within the Basolateral Complex (BLC) of the Amygdala. Altered functioning within BLC circuits has been implicated in the Abnormal Fear Learning model of PTSD (see text). Interrupted lines represent distal inputs to and outputs from BLC.

Figure 2

Brain regions of the Salience Network. Abnormal function within Salience Network regions is implicated in the Exaggerated Threat Detection model of PTSD (see text).

Figure 3

Brain regions involved in executive function and emotional regulation. Abnormal function in these regions has been implicated in the Diminished Executive Function and Emotional Regulation model of PTSD (see text).

Figure 4

Brain circuits involved in contextual processing functions. Abnormal function within these circuits is implicated in the Deficient Contextual Processing model of PTSD (see text). Information flow in this circuit includes Locus Coeruleus (LC) adrenergic neurons (shown in schematic but not visible in depicted brain slices).

Figure 5

Contextual processing abnormalities in the Single Prolonged Stress animal model of PTSD (Panels A and B) and in PTSD patients (Panels C, D and E). Panel A – Schematic depiction of the SPS paradigm, which involves multiple stressors delivered sequentially in one day and then a 7 day “rest” period, followed by fear conditioning, extinction and renewal testing. Panel B – data using this paradigm show abnormal fear renewal in SPS animals (seen on the right, in line graph and summary bar graph). Panel C – Schematic depiction (including screen shots) of the paradigm used to examine fear conditioning, extinction, extinction recall and fear renewal in fMRI experiments with humans. Panels D and E – data using this paradigm with PTSD patients and combat control (CC) subjects show abnormal extinction recall (D) and abnormal fear renewal (E) in PTSD (skin conductance data shown on right in both panels). Differences in fMRI activations in PTSD compared to controls, in response to previously conditioned and then extinguished stimuli (CS+E), are shown on the left in both panels.