Trauma and posttraumatic stress are highly comorbid with chronic pain and are often antecedents to developing chronic pain conditions. Pain and trauma are associated with greater utilization of medical services, greater use of psychiatric medication, and increased total cost of treatment. Despite the high overlap in the clinic, the neural mechanisms of pain and trauma are often studied separately. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) scans were completed among a diagnostically heterogeneous sample of veterans with a range of back pain and trauma symptoms. Using Group Iterative Multiple Model Estimation (GIMME), an effective functional connectivity analysis, we explored an unsupervised model deriving subgroups based on path similarity in a priori defined regions of interest (ROIs) from brain regions implicated in the experience of pain and trauma. Three subgroups were identified by patterns in functional connection and differed significantly on several psychological measures despite similar demographic and diagnostic characteristics. The first subgroup was highly connected overall, was characterized by functional connectivity from the nucleus accumbens (NAc), the anterior cingulate cortex (ACC), and the posterior cingulate cortex (PCC) to the insula and scored low on pain and trauma symptoms. The second subgroup did not significantly differ from the first subgroup on pain and trauma measures but was characterized by functional connectivity from the ACC and NAc to the thalamus and from ACC to PCC. The third subgroup was characterized by functional connectivity from the thalamus and PCC to NAc and scored high on pain and trauma symptoms. Our results suggest that, despite demographic and diagnostic similarities, there may be neurobiologically dissociable biotypes with different mechanisms for managing pain and trauma. These findings may have implications for the determination of appropriate biotype-specific interventions that target these neurological systems.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) commonly co-occur in general and military populations and have a number of overlapping symptoms. While research suggests that TBI is risk factor for PTSD and that PTSD may mediate TBI-related outcomes, the mechanisms of these relationships are not well understood. Neuroimaging may help elucidate patterns of neurocircuitry both specific and common to PTSD and TBI and thus help define the nature of their interaction, refine diagnostic classification, and may potentially yield opportunities for targeted treatments. In this review, we provide a summary of some of the most common and the most innovative neuroimaging approaches used to characterize the neural circuits associated with PTSD, TBI, and their comorbidity. We summarize the state of the science for each disorder and describe the few studies that have explicitly attempted to characterize the neural substrates of their shared and dissociable influence. While some promising targets in the medial frontal lobes exist, there is not currently a comprehensive understanding of the neurocircuitry mediating the interaction of PTSD and TBI. Future studies should exploit innovative neuroimaging approaches and longitudinal designs to specifically target the neural mechanisms driving PTSD-TBI-related outcomes.

Objectives

While preliminary evidence suggests that noninvasive vagal nerve stimulation (nVNS) may enhance cognition, to our knowledge, no study has directly assessed the effects of nVNS on brain function and cognitive performance in healthy individuals. The aim of this study was therefore to assess whether nVNS enhances complex visuospatial problem solving in a normative sample. Functional magnetic resonance imaging (fMRI) was used to examine underlying neural substrates.

Material and methods

Participants received transcutaneous cervical nVNS (N = 15) or sham (N = 15) stimulation during a 3 T fMRI scan. Stimulation lasted for 2 min at 24 V for nVNS and at 4.5 V for sham. Subjects completed a matrix reasoning (MR) task in the scanner and a forced-choice recognition task outside the scanner. An analysis of variance (ANOVA) was used to assess group differences in cognitive performance. And linear mixed effects (LMEs) regression analysis was used to assess main and interaction effects of experimental groups, level of MR task difficulty, and recall accuracy on changes in blood oxygen level-dependent (BOLD) signal.

Results

Subjects who received nVNS showed higher accuracy for both easy (p = 0.017) and hard (p = 0.013) items of the MR task, slower reaction times for hard items (p = 0.014), and fewer false negative errors during the forced-choice recognition task (p = 0.047). MR task difficulty related to increased activation in frontoparietal regions (p < 0.001). No difference between nVNS and sham stimulation was found on BOLD response during performance of the MR task.

Conclusions

We hypothesize that nVNS increased attention compared to sham, and that this effect led to enhanced executive functions, and consequently to better performance on visuospatial reasoning and recognition tasks. Results provide initial support that nVNS may be a low risk, low-cost treatment for cognitive disorders.

Abstract

Pain anticipation during conditions of uncertainty can unveil intrinsic biases, and understanding these biases can guide pain treatment interventions. This study used machine learning and functional magnetic resonance imaging to predict anticipatory responses in a pain anticipation experiment. One hundred forty-seven participants that included healthy controls (n = 57) and individuals with current and/or past mental health diagnosis (n = 90) received cues indicating upcoming pain stimuli: 2 cues predicted high and low temperatures, while a third cue introduced uncertainty. Accurate differentiation of neural patterns associated with specific anticipatory conditions was observed, involving activation in the anterior short gyrus of the insula and the nucleus accumbens. Three distinct response profiles emerged: subjects with a negative bias towards high pain anticipation, those with a positive bias towards low pain anticipation, and individuals whose predictions during uncertainty were unbiased. These profiles remained stable over one year, were consistent across diagnosed psychopathologies, and correlated with cognitive coping styles and underlying insula anatomy. The findings suggest that individualized and stable pain anticipation occurs in uncertain conditions.

Implicit social-affective biases-reflected in a propensity to approach positive and avoid negative stimuli-have been documented in humans with paradigms, such as the Approach-Avoidance Task (AAT). However, the degree to which preemptively engaging cognitive control can help to down-regulate those behavioral tendencies remains poorly understood. While undergoing functional magnetic resonance imaging (fMRI), 24 healthy participants completed a cued version of the AAT, in which they responded to pictures of happy or angry faces by pulling a joystick toward themselves (approach) or pushing the joystick away (avoidance) based on the color of the stimulus frame. On some trials, they were cued to reverse the frame color/joystick action instructions. Before stimulus onset, a reverse cue was associated with deactivation of a visuo-spatial and motor planning network and subsequent slowing down in response to stimuli. During the stimulus phase, a reverse cue was associated with a) activation of cognitive control areas, including the right inferior frontal gyrus (IFG) and right inferior parietal lobule (IPL); and b) reduced right precentral gyrus activation when having to push (avoid) a happy face. Overall, these results suggest that proactively engaging cognitive control can help fine-tune behavioral and neural adjustment to emotionally incongruent behavioral conditions.

Posttraumatic stress disorder (PTSD) is associated with inhibitory control dysfunction that extends beyond difficulties inhibiting trauma-related intrusions. Inhibitory learning has been proposed as a potential mechanism of change underlying the effectiveness of extinction-based therapies such as prolonged exposure (PE), a first-line treatment for PTSD. To identify neurocognitive markers of change in inhibitory learning associated with PE, we applied a Bayesian learning model to the analysis of neuroimaging data collected during an inhibitory control task, both before and after PE treatment. Veterans (N = 20) with combat-related PTSD completed a stop-signal task (SST) while undergoing fMRI at time points immediately before and after PE treatment. Participants exhibited a small, significant improvement in performance on the SST, as demonstrated by longer reaction times and improved inhibition accuracy. Amplitude of neural activation associated with a signed prediction error (SPE; i.e., the discrepancy between actual outcome and model-based expectation of needing to stop) in the right caudate decreased from baseline to posttreatment assessment. Change in model-based activation was modulated by performance accuracy, with a decrease in positive SPE activation observed on successful trials, d = 0.79, and a reduction in negative SPE activation on error trials, d = 0.74. The decrease in SPE-related activation on successful stop trials was correlated with PTSD symptom reduction. These results are consistent with the notion that PE may help broadly strengthen inhibitory learning and the development of more accurate model-based predictions, which may thus facilitate change in cognitions in response to trauma-related cues and help reduce PTSD symptoms.

The extent to which one can use cognitive resources to keep information in working memory is known to rely on (1) active maintenance of target representations and (2) downregulation of interference from irrelevant representations. Neurobiologically, the global capacity of working memory is thought to depend on the prefrontal and parietal cortices; however, the neural mechanisms involved in controlling interference specifically in working memory capacity tasks remain understudied. In this study, 22 healthy participants completed a modified complex working memory capacity task (Reading Span) with trials of varying levels of interference control demands while undergoing functional MRI. Neural activity associated with interference control demands was examined separately during encoding and recall phases of the task. Results suggested a widespread network of regions in the prefrontal, parietal, and occipital cortices, and the cingulate and cerebellum associated with encoding, and parietal and occipital regions associated with recall. Results align with prior findings emphasizing the importance of frontoparietal circuits for working memory performance, including the role of the inferior frontal gyrus, cingulate, occipital cortex, and cerebellum in regulation of interference demands.

Objective

The aim of this study was to examine the effect of Posttraumatic Stress Disorder (PTSD) and childhood adversity on brain structure. We assessed hippocampal and amygdala shape in veterans with varying levels of PTSD symptom severity and exposure to early life stressors (ELS).

Methods

A total of 70 male veterans, who were deployed to a combat area during OIF/OEF/OND and who had been exposed to trauma during deployment, were included in the study. We applied a vertex-wise shape analysis of 3T MRI scans to measure indentation or expansion in hippocampal and amygdala shape.

Results

Analyses showed a positive correlation between number of ELS and vertices in the right amygdala and the right hippocampus, as well as a positive correlation between PTSD symptom severity and right hippocampal vertices. There were no significant interactions between PTSD symptoms, ELS, and brain shape.

Discussion

Results indicate a relationship between exposure to more childhood adversity and expansion in amygdala and hippocampal shape as well as between more severe PTSD symptoms and expansion in hippocampal shape. These findings may have important implications for the pathophysiology of trauma-related disorders.

Abstract

The United States faces a crisis because of the high prevalence of chronic pain, concurrent opioid use disorder, and overdose deaths. Prescription opioids remain a primary driver of opioid-related deaths. Craving is a core symptom of addiction, yet the degree to which craving plays a role in prescription opioid use among patients with chronic pain is unknown. Understanding the degree to which craving should be considered in patients with chronic pain is critical for developing effective interventions for supporting patients through opioid tapering. The current work combines data collected from (1) 2152 veterans screened for eligibility at a pain specialty care clinic at the San Francisco VA Health Care System and (2) medical records obtained from the VA Corporate Data Warehouse. We found that prescription opioid craving among veterans with chronic pain was low, with 66.4% of the sample reporting no craving and 33.6% reporting craving. We also found that craving had a small association with morphine equivalent daily dose and pain severity but was more strongly associated with depression. Craving of prescription opioids among veterans with chronic pain is complex. Findings are discussed in relation to chronic pain symptoms, psychiatric comorbidities, and demographics.

Background

Brain-gut axis signaling modifies gastrointestinal symptomatology. Altered neural processing of intestinal pain signals involves interoceptive brain regions in adults with functional and inflammatory gastrointestinal disorders. Although these disorders frequently present in childhood, there are no published studies in youth. We determined whether neural processing of somatic pain stimuli differs in adolescents and young adults (AYA) with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), as compared to healthy controls (HC).

Methods

IBS and IBD AYA (16-20 years) underwent anticipated and thermal pain stimuli of low and high intensity on their forearm and simultaneous blood oxygen level-dependent functional magnetic resonance imaging. Data from adult HC were used for comparison. Subjects answered surveys evaluating alexithymia, anxiety, depression, and pain catastrophizing. Group data were compared using linear mixed effects and analysis of variance.

Results

Study groups were similar by sex but not age. Significant group by pain condition interactions were observed in interoceptive brain regions during pain anticipation, and within perceptual brain regions during perceived pain. Higher activation within interoceptive brain regions during anticipated pain was observed in IBS compared with IBD and HC subjects. IBD patients demonstrated increased activation in perceptual brain regions during experienced pain as compared to IBS and HC.

Conclusions

IBS and IBD AYA demonstrate altered neural processing of somatic pain compared with each other and with HC. Our results suggest that neuromodulatory interventions targeting interoceptive brain circuits in IBS and perceptual brain regions in IBD may be effective.