Review articleMagnetic resonance imaging predictors of psychotherapy treatment response in post-traumatic stress disorder: A role for the salience network
Introduction
Early neurobiological models of post-traumatic stress disorder (PTSD) focused on abnormalities in the neuroendocrine systems involved in stress. These studies, which predated neuroimaging work, demonstrated abnormal glucocorticoid receptor (GR) sensitivity as evidenced by enhanced negative feedback inhibition of cortisol in regions comprising the hypothalamic-pituitary-adrenal (HPA) axis in PTSD (Szeszko et al., 2018, Yehuda, 2009). These findings were at first counter-intuitive. Under the influence of threat the release of cortisol permits the body to mobilize and respond accordingly. During this initial fight or flight increased cortisol production at the level of the pituitary and/or hypothalamus occurs in conjunction with the sympathetic nervous system (SNS). In PTSD, cortisol release appeared to be attenuated, possibly resulting from alterations in glucocorticoid receptor responsiveness (Yehuda, 2002). Early biological studies of PTSD found cortisol levels to either be normal or even lower than normal among individuals with PTSD compared to those without PTSD (Mason et al., 1986, Yehuda et al., 2006). While several follow-up studies examining the HPA axis eventually pointed to glucocorticoid receptor sensitivity as a potential culprit, it was not possible to truly understand the functional implications of these findings without examining cortisol effects in the brain.
The earliest studies to understand brain neuroendocrine changes in PTSD were conducted by Dr. Monte Buchsbaum (Yehuda et al., 2009) using positron emission tomography (PET). One of these studies examined glucocorticoid effects by measuring glucose metabolic rate in the hippocampus, amygdala, and anterior cingulate cortex (ACC) during a randomized, double-blind, placebo-controlled study of metabolic response to hydrocortisone using 2-Deoxy-2-[(18) F] PET. Findings indicated that among individuals with PTSD hydrocortisone administration was associated with the restoration of a normal inverse relationship between regions comprising the anterior cingulate cortex and amygdala, now referred to as the salience network. This work also demonstrated that glucocorticoids may have different effects in different brain regions. Importantly, hydrocortisone appeared to be associated with improved memory performance in PTSD (Yehuda et al., 2007), suggesting potential treatment applications of glucocorticoid administration in PTSD. This early PET work set the stage for subsequent magnetic resonance (MR) imaging studies that have identified abnormalities in brain regions comprising the salience network that play a role in PTSD neurobiology and treatment response.
This selective review of the literature provides an update and synthesis of the literature regarding the utility of MR imaging measures comprising the salience network to predict psychotherapy treatment response using cognitive-behavioral therapy (CBT) and prolonged exposure (PE) in PTSD. A role for the salience network, including the amygdala, anterior cingulate cortex and insula, in the neurobiology of PTSD is emphasized. Next, studies using baseline and longitudinal MR imaging measures (including brain structure and function) to predict symptom changes following psychotherapy are reviewed. The focus of this review will be on the use of CBT and PE as psychotherapeutic interventions given they are considered first-line treatments for PTSD. Lastly, an integrative model regarding how changes in brain regions comprising the salience network play a role in successful psychotherapy response in PTSD is described.
Section snippets
Salience in post-traumatic stress disorder and implications for treatment
The ability to quickly focus attention and initiate homeostatic mechanisms and concomitant motor functions in anticipation of threat is considered a critical survival function from an evolutionary perspective (Kotas and Medzhitov, 2015). These functions appear to be modulated, at least in part, by the salience network, which is primarily responsible for bottom-up processing, involving the integration of sensory information to inform behavior or cognition (Choi et al., 2018) and may be reliably
Amygdala
The amygdala sits in the anterior portion of the temporal lobe and is comprised of several individual nuclei that maintain afferent and efferent connections with other brain regions that play a role in fear regulation (Sah et al., 2003). Incoming information reaches the amygdala rapidly and well in advance of the cerebral cortex. The amygdala is biased for action and in PTSD (and other anxiety disorders) does not appear to be easily “turned off” once activated in response to feared stimuli that
Anterior cingulate cortex
The anterior cingulate cortex wraps around the corpus callosum and is considered to be a central hub for the integration of cognitive-behavioral, emotional-autonomic, and motor neural networks (Devinsky et al., 1995). The anterior cingulate cortex is known to be heterogeneous and there is evidence that it may be comprised of several cytoarchitecturally and functionally distinct regions (Bush et al., 2000, Devinsky et al., 1995). The region surrounding the genu contains afferent connections from
Insula
The insula plays an important role in monitoring internal body states and processing these states in the context of external emotional stimuli (Nicholson et al., 2016). The insula may be divided into a smaller posterior region that maintains connections with the somatosensory cortex and a larger anterior region that receives afferent and efferent connections to the amygdala (Craig, 2011) that are likely most relevant to PTSD phenomenology. In support of these connectivity patterns individuals
Summary and future directions
There is considerable heterogeneity in PTSD symptom presentation (Gilbertson et al., 2002) and no overarching model has been proposed to account for the complex symptom constellation of PTSD. With the advent of the DSM-V, there are now over 600,000 diagnostic permutations that could potentially yield a diagnosis of PTSD (Galatzer-Levy and Bryant, 2013). The use of MR imaging could provide quantitative biomarkers to conceptualize PTSD neurobiology and identify brain regions that play a role in
Disclaimer
The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Acknowledgement
This work was supported in part by Merit Award # 1‐I01‐CX‐001219‐01‐A1 from the United States (U.S.) Department of Veterans Affairs [Clinical Sciences Research and Development].
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