Magnetic resonance imaging predictors of psychotherapy treatment response in post-traumatic stress disorder: A role for the salience network

doi:10.1016/j.psychres.2019.02.005

Psychiatry Research

Volume 277, July 2019, Pages 52-57

https://doi.org/10.1016/j.psychres.2019.02.005 Get rights and content

Highlights

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Abnormalities in the salience network contribute to PTSD phenomenology.
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These brain regions include the amygdala, anterior cingulate cortex and insula.
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MR imaging can predict successful psychotherapy treatment response in PTSD.
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Downregulation of amygdala activity to trauma-related stimuli is important.

Abstract

The earliest neuroimaging studies in post-traumatic stress disorder (PTSD) utilized positron emission tomography (PET) to examine the brain's response to glucocorticoid administration given predominant neurobiological models of the stress response focusing on that neuroendocrine system. This work revealed that the anterior cingulate cortex and amygdala, which is now considered part of the salience network, play a role in treatment response, and set the stage for subsequent magnetic resonance (MR) imaging studies focused on understanding the role of the salience network in the neurobiology of treatment response in PTSD. This selective review discusses magnetic resonance (MR) imaging studies that have been used to predict treatment response to cognitive-behavioral therapy (CBT) or prolonged exposure (PE) in PTSD, which have demonstrated abnormalities in processing involving the salience network, including the amygdala, anterior cingulate cortex and insula. Increased attention to environmental cues may signal alarm resulting in hypervigilance and overactive action-monitoring for the detection of threatening stimuli and an inability to integrate concomitant emotional and sensory functions in PTSD. Successful psychotherapy treatment response in PTSD appears to involve the ability to downregulate amygdala activity to trauma-related stimuli through improved regulation of attention by the anterior cingulate cortex and concomitant internal emotional states mediated by the insula. In addition, the ability to better modulate (normalize) the salience network following psychotherapy in PTSD may be associated with better crosstalk between untargeted inner thought (i.e., task-negative network) and the ability to focus attention on stimulus-dependent demands (i.e., task positive 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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Published by Elsevier B.V.

Review articleMagnetic resonance imaging predictors of psychotherapy treatment response in post-traumatic stress disorder: A role for the salience network

Highlights

Abstract

Introduction

Section snippets

Salience in post-traumatic stress disorder and implications for treatment

Amygdala

Anterior cingulate cortex

Insula

Summary and future directions

Disclaimer

Acknowledgement

Psychiatry Res.

Psychiatry Res. Neuroimaging

Biol. Psychiatry

Trends Cogn. Sci.

Curr. Opin. Neurobiol.

J. Psychiatr. Res.

Neuroimage Clin.

Neuroimage Clin.

J. Anxiety Disorders

Cell

Biol. Psychiatry

Psychiatry Res. Neuroimaging

Psychiatry Res.

Neuron

Biol. Psychiatry

Neurosci. Biobehav. Rev.

J. Psychiatr. Res.

Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans

Cereb. Cortex

Toward discovery science of human brain function

Proc. Natl. Acad. Sci. U S A

Morphovolumetric changes after EMDR treatment in drug-naive PTSD patients

Riv. Psichiatr.

Learned predictions of error likelihood in the anterior cingulate cortex

Science

Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour therapy for post-traumatic stress disorder

Psychol. Med.

Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder

J. Psychiatry Neurosci.

The counting stroop: an interference task specialized for functional neuroimaging–validation study with functional MRI

Human Brain Mapping

Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder

Psychol. Med.

Significance of the insula for the evolution of human awareness of feelings from the body

Ann. N.Y. Acad. Sci.

Switching between executive and default mode networks in posttraumatic stress disorder: alterations in functional connectivity

J. Psychiatry Neurosci.

Contributions of anterior cingulate cortex to behaviour

Brain

Augmentation of fear extinction by transcranial direct current stimulation (tDCS)

Front. Behav. Neurosci.

Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder

Psychol. Sci.

PTSD psychotherapy outcome predicted by brain activation during emotional reactivity and regulation

Am. J. Psychiatry

Posttraumatic stress disorder under ongoing threat: a review of neurobiological and neuroendocrine findings

Eur. J. Psychotraumatol.

636,120 ways to have posttraumatic stress disorder

Perspect. Psychol. Sci.

Prefrontal-cingulate interactions in action monitoring

Nature Neurosci.

Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

Nature Neurosci.

Frequency specific resting state functional abnormalities in psychosis

Human Brain Mapping

Review article
Magnetic resonance imaging predictors of psychotherapy treatment response in post-traumatic stress disorder: A role for the salience network