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Two interesting articles from Harvard University investigators in this issue of Biological Psychiatry challenge us to reconsider and re-think the complexities of the underlying neurobiology of posttraumatic stress disorder (PTSD). We will refer to these articles with a view to highlighting their unique contributions to the literature and the new directions they motivate for translational research in PTSD and other anxiety disorders.
Milad and colleagues (1) used an operant conditioning paradigm to show that patients with PTSD have deficient extinction retention relative to trauma-exposed controls who had not developed PTSD. They further demonstrate, using functional MRI (fMRI), that this reduced extinction retention is related to less activation in the hippocampus and bilateral ventromedial prefrontal cortex in patients with PTSD. This paper underscores our growing appreciation that PTSD is characterized by dysfunction of “unlearning” within fear circuitry, and the findings should motivate clinical research to enhance extinction retention through pharmacological and other means. Such approaches, in parallel with those aimed at the disruption of the consolidation of fear memories, are among the most promising translational leads for PTSD therapeutics (2).
In contrast to the aforementioned study which adds important information to the burgeoning literature on abnormal fear circuitry and deficient fear extinction mechanisms in PTSD, the paper by Elman and colleagues (3) delves into a much neglected area: the study of reward processing in PTSD. Consistent with a previous report of altered processing in the reward circuitry of patients with PTSD (4), these investigators found less striatal activation to monetary gains versus losses in PTSD in association with more self-reported motivational and social deficit. These observations can be considered complementary to those that find alterations in fear-motivated systems that underlie behavioral avoidance in PTSD (and, possibly, other anxiety disorders) in that they point to dysfunction in brain systems that underlie deficient approach behaviors. Reward circuitry has been largely neglected in the study of PTSD, and this paper (3) should be considered a call to action to intensify research on this topic. What can be gained by integrating investigation of reward systems in PTSD?
It has long been recognized that individuals balance the approach system, which is closely related to reward processes with the avoidance system, which focuses on fear-related processes (5). Nearly all research to date on PTSD has been focused on fear, therein ignoring the “ying-yang” of approach-avoidance that underlies all anxiety disorders, including PTSD. We would suggest that PTSD is a disorder characterized by imbalance of approach-avoidance systems. By considering both aspects when conceptualizing the dysfunctions observed in individuals with PTSD, one can generate new hypotheses and foster new insights with the potential to advance the field.
A critical assumption in this conceptualization is the notion that PTSD emerges as the individual's brain attempts to establish a new homeostatic steady state following the exposure to a trauma that has altered the approach/avoidance system. It is surprising that given the extensive literature on stress and homeostatic dysfunction (6), that homeostatic imbalance has not figured prominently in the conceptualization of PTSD. In comparison, its psychological analog, coping, has been widely used. Put differently, coping is the individual's attempt to reestablish homeostasis which, in large part, involves a decision to either approach or avoid.
Dopamine and norepinephrine have been implicated as key modulatory neurotransmitter systems in reward and fear-related processes, respectively. In particular, different personality characteristics have been related to these systems and to the degree to which individuals deploys actions to approach or avoid, respectively (7). If one assumes that an external trauma modulates the existing balance between approach and avoidance by up or down-regulating the sensitivity of neural substrates that process reward or fear, one can begin to conceptualize PTSD as an altered homeostatic balance between approach and avoidance (Figure 1). Moreover, the emerging symptoms can be understood as thoughts, feelings, or actions that result from the instability of this homeostatic balance.
In particular, some of the key symptoms of PTSD that are readily associated with alterations in the approach/avoidance systems are:
An obvious advantage of this conceptualization is that it permits – indeed, it requires that– PTSD be considered as an imbalance disorder involving failure to successfully adapt of several brain systems. Conversely, it discourages an approach to understanding (and treating) PTSD as a unitary, homogenous disorder. For example, this conceptualization:
Taken together, these two articles bring us a step closer to viewing PTSD as an imbalance state involving the dynamical adjustment of both approach and avoidance systems – and the multiple neurotransmitter systems that modulate these systems – toward an altered homeostatic steady state (Figure 2). In short, individuals with PTSD face a multi-systems imbalance and will require integrated pharmacological and behavioral interventions targeted at up/down-regulating approach and avoidance processes.
Dr. Stein reports that in the past 3 years he has been a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, Hoffmann-La Roche, Jazz Pharmaceuticals, Johnson & Johnson, Pfizer, Sepracor, and Transcept Pharmaceuticals; and he has received research funding from Eli Lilly, GlaxoSmithKline, and Hoffmann-La Roche. Dr. Paulus reports research funding from GlaxoSmithKline, Hoffmann-La Roche, and Sepracor.
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