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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.

Objective Despite empirical support for interdisciplinary pain rehabilitation programs improving functioning and quality of life, access to this treatment approach has decreased dramatically over the last 20 years within the United States but has grown significantly in the Department of Veterans Affairs (VA). Between 2009 and 2019, VA pain rehabilitation programs accredited by the Commission on Accreditation of Rehabilitation Facilities increased 10-fold in the VA, expanding from two to 20. The aim of this collaborative observational evaluation was to examine patient outcomes across a subset of six programs at five sites. Methods Outcomes were assessed using agreed-upon measures of patient-reported pain intensity, pain interference across various domains, pain catastrophizing, and sleep. Results A total of 931 patients enrolled in the selected VA interdisciplinary pain programs, with 84.1% of participants completing the full course of treatment. Overall, all programs showed significant improvements from pretreatment to posttreatment in nearly all patient-reported outcomes. The effect sizes ranged from medium to large. Notably, the results demonstrate that positive outcomes were typical despite differences in structure and resources across programs. Conclusions The adverse impacts of opioid use have highlighted the importance of chronic pain treatment approaches that emphasize team-based care focused on functional improvements. This study represents the first and largest analysis of outcomes across chronic pain rehabilitation programs and demonstrates the need for increased access to similar comprehensive approaches to pain management across the health care system. Further, it suggests that a variety of structures may be effective, encouraging flexibility in adopting this interdisciplinary approach.

Prescription opioids are a primary driver of opioid-related deaths. Although craving is a substantial component of OUD, the degree to which craving leads to misuse among chronic pain patients on long-term prescription opioids is unknown. A clear understanding of the factors that lead to misuse in this vulnerable population is needed for the development of safe and effective practices for opioid taper. This narrative review summarizes the relevant literature on the role of craving in addiction and chronic pain through epidemiological and behavioral studies. The first part of this review examines the role of craving in predicting opioid use/misuse in individuals with chronic pain with and without OUD. The second part covers methods on how craving is evaluated experimentally using both subjective and objective measures and provides related findings. The overall goal of this review is to facilitate the development of a population-specific description of craving in those who use opioids to control chronic pain and to describe how it may be mechanistically linked to patterns of opioid (mis)use.

Anorexia nervosa (AN) is an often chronic and potentially lethal psychiatric disorder, for which the precise etiology remains elusive. While current treatment outcomes are modest at best, it is thought that the identification of translational mechanisms driving the psychopathology of AN will assist in the development and optimization of novel treatments. AN is a disorder characterized by fear and avoidance, hypervigilant scrutiny of one's body, and an unnatural fear of weight gain. Moreover, a suite of anxious traits and regimentation of behavior are atypically common well in advance of the onset of restrictive eating in those with AN. Here we consider the promise of shedding light on causal mechanisms of AN by interrogating the role of fear-related learning, deficits in discriminating safety cues, and extinction of acquired fear. We offer a translational rationale for this line of inquiry, and discuss the clinical implications of considering fear as a translational mechanism in the psychopathology of AN.

Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood, yet 40% of those with distal neuropathy (or 20% of all people with HIV) suffer from this debilitating condition. Central pain processing mechanisms are thought to contribute to the development of HIV neuropathic pain, yet studies investigating central mechanisms for HIV neuropathic pain are few. Considering the motivational nature of pain, we aimed to examine the degree to which expectation of pain onset and expectation of pain offset are altered in sixty-one male patients with HIV-related distal sensory polyneuropathy with (N = 30) and without (N = 31) chronic neuropathic pain. By contrasting painful (foot) and non-painful (hand) sites between those with and without neuropathic pain, we could identify unique neural structures that showed altered activation during expectation of pain offset or relief. Our results showed no evidence for peripheral mechanisms evidenced by lack of significant between group differences in thermo-sensation, subjective pain response or epidermal nerve fibre density. Likewise, we found no significant differences between groups in subjective or brain mechanisms underlying the expectation of pain onset. Conversely, we found significant interaction within right anterior insula during expectation of pain offset in our study in that individuals in the pain group compared to the no-pain group exhibited increased anterior insula activation on the painful compared to the non-painful site. Our findings are consistent with abnormal processing of expectation of pain offset or abnormal pain relief-related mechanisms potentially due to increased emotional distress regarding the experience of chronic endogenous pain., Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood. Using functional MRI, Strigo et al. show abnormal expectation of pain offset response in those who developed neuropathic pain potentially due to lack of pain relief regarding the experience of chronic endogenous pain., Graphical Abstract Graphical Abstract

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. This is typically evoked using a three-step noxious heat stimulus. In other clinical and laboratory settings, prior pain experience may increase pain intensity as well. Therefore, we hypothesized that even small increases in stimulus intensity within the noxious range would be accompanied by enhanced reported pain intensity. To test this possibility, we inverted the intensity order of the three-step stimulus, so that the same hot temperature is immediately preceded by an increase from a transiently lowered temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity during the novel, inverted, three-step stimulus. This disproportionate increase is similar in magnitude to that of offset analgesia. Control stimuli demonstrate that these changes in pain intensity are distinct from habituation. The magnitudes of offset analgesia and the disproportionate increase in pain intensity correlate with each other but not with the absolute noxious stimulus temperature. These observations suggest that the disproportionate increase in pain intensity represents an “onset hyperalgesia.” Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study finds that perceptual enhancement of noxious stimulus change occurs bidirectionally and that this depends on the intensity and direction of change of the immediately preceding stimulus.

Anorexia nervosa (AN) is characterized by an avoidance and marked apprehension around food intake, yet paradoxically, those with AN often display approach behaviors to food, engaging in food shopping or preparation activities which are described as rewarding. This approach–avoidance conundrum is of much importance as neuroimaging studies continue to probe mechanisms relating to core AN psychopathology. This Idea Worth Researching discusses the notion that neuroimaging studies relying on food cue presentation paradigms may be methodologically flawed without specifying the contextual salience of the food cues presented in paradigms. The appraisal of food cues may diverge as a function of one’s intent-to-eat, and thus, neuroimaging studies not specifying the contextual salience of food cues (i.e., intent-to-eat or not) may confound two distinctly different processes.

Objective To characterize the association between traumatic brain injury (TBI) and chronic pain and pain disability in the context of comorbid conditions, posttraumatic stress disorder (PTSD), and depression to better inform care of combat veterans. Design Retrospective cohort study. Setting Medical centers and community clinics. Participants Combat veterans (N=116,913) who received Veterans Affairs care between October 1, 2007 and March 31, 2015, completed a Comprehensive Traumatic Brain Injury Evaluation, and received a criterion standard diagnosis of TBI (none, mild, or moderate to severe). Interventions Not applicable. Main Outcome Measures Chronic pain defined as ≥2 of the same pain diagnoses ≥90 days apart and pain disability defined as self-reported pain causing moderate to very severe interference with daily functioning. Results Fifty-seven percent received ≥1 chronic pain diagnosis. Compared to those with no TBI, PTSD, or depression, there was an independent risk for chronic pain in veterans with mild TBI, which was higher in veterans with moderate to severe TBI. The risk of chronic pain was additive and highest when all 3 conditions—TBI, depression, and PTSD—were copresent (adjusted relative risk, 1.53 and 1.62 [95% confidence interval, 1.50–1.66] for mild and moderate or severe TBI, respectively, plus other diagnoses). The relation of pain disability to TBI, PTSD, and depression followed a similar additive pattern. Conclusions In combat veterans, chronic pain and pain disability are most commonly associated with TBI in conjunction with PTSD, depression, or both. Integrated models of care that simultaneously address pain in conjunction with TBI, PTSD, and depression will likely be the most clinically effective.

Background C-tactile (CT) afferents are unmyelinated low-threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation. Methods In total, 44 healthy volunteers experienced heat pain and CT optimal (slow brushing) and CT sub-optimal (fast brushing or vibration) stimuli. Three different experimental paradigms were used: Concurrent application of heat pain and tactile (slow brushing or vibration) stimulation; Slow brushing, applied for variable duration and intervals, preceding heat pain; Slow versus fast brushing preceding heat pain. Results Slow brushing was effective in reducing pain, whereas fast brushing or vibration was not. The reduction in pain was significant not only when the CT optimal touch was applied simultaneously with the painful stimulus but also when the two stimuli were separated in time. For subsequent stimulation, the pain reduction was more pronounced for a shorter time interval between brushing and pain. Likewise, the effect was more robust when pain was preceded by a longer duration of brush stimulation. Strong CT-related pain reduction was associated with low anxiety and high calmness scores obtained by a state anxiety questionnaire. Conclusions Slow brushing – optimal for CT activation – is effective in reducing pain from cutaneous heating. The precise mechanisms for the pain relief are as yet unknown but possible mechanisms include inhibition of nociceptive projection neurons at the level of the dorsal horn as well as analgesia through cortical mechanisms. Significance Slow brushing stimuli – optimal for activation of C-tactile fibres – can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation.

A prominent model of pain as a predictive cue posits that anticipation shapes pain transmission and ultimately pain experience. Consistent with this model, the neural mechanisms underlying pain anticipation have the power to modulate pain experience thus understanding pain predictions, particularly during uncertainty, may allow us to ascertain measures indicative of intrinsic anticipation biases. Understanding such biases moves way to precision pain management, as it can guide the individualized treatment. To examine individual pain anticipation biases, we applied machine-learning-based neural decoding to functional magnetic resonance imaging (fMRI) data acquired during a pain-anticipation paradigm to identify individualized neural activation patterns differentiating two certain anticipatory conditions, which we then used to decode that individual’s uncertain anticipatory condition. We showed that neural patterns representative of the individualized response during certain anticipatory conditions were differentiable with high accuracy and, across individuals, most commonly involved neural activation patterns within anterior short gyrus of the insula and the nucleus accumbens. Using unsupervised clustering of individualized decodings of anticipatory responses during uncertain conditions, we identified three distinct response profiles representing subjects who, in uncertain situations, consistently anticipated high-pain (i.e., negative bias), subjects who consistently anticipated low-pain (i.e., positive bias), and subjects whose decoded anticipation responses were depended on the intensity of the preceding pain stimulus. The individualized decoded pain anticipation biases during uncertainty were independent of existence or type of diagnosed psychopathology, were stable over one year timespan and were related to underlying insula anatomy. Our results suggest that anticipation behaviors may be intrinsic, stable, and specific to each individual. Understanding individual differences in the neurobiology of pain anticipation has the potential to greatly improve the clinical pain management.

From the outside, it has been very common for clinicians to dismiss TMJ patients as “crazy,” “difficult,” or “high maintenance.” This sentiment conveyed both a lack of knowledge of TMJ pathology and mental illness on the part of the health professions. Fortunately, the true situation is gradually coming to light, and doctors are gaining an increased appreciation for how connected the mind and body really are. In fact, there is no true separation at all; it has always been something we created to make sense of a system we did not understand. Fortunately, our ideas of how the mind and body interact have evolved, and it is unmistakably critical to be able to assess both the mind and body together in order to ultimately make an ailing person whole again. This chapter is devoted to explaining how psychologists and psychiatrist evaluate, diagnose, and treat TMD/chronic pain patients.

Author(s): Huang, Jeannie S; Terrones, Laura; Simmons, Alan N; Kaye, Walter; Strigo, Irina | Abstract: BackgroundBrain-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).MethodsIBS 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.ResultsStudy 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.ConclusionsIBS 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.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n=15 sham and n=15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in nVNS group (p < .0005) in bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

Most neuroimaging studies of adolescent depression employ tasks not designed to engage brain regions necessary for the cognitive control of emotion, which is central to many behavioral therapies for depression. Depressed adults demonstrate less effective activation of these regions and greater amygdala activation during cognitive reappraisal; we examined whether depressed adolescents show similar patterns of brain activation.We collected functional magnetic resonance imaging (fMRI) data during cognitive reappraisal in 41 adolescents with major depressive disorder (MDD) and 34 matched controls (ages 13-17). We examined group differences in (1) activations associated with reappraisal and reappraisal success (i.e., negative affect reduction during reappraisal) using whole brain and amygdala region-of-interest analyses, and (2) functional connectivity of regions from the group-by-reappraisal success interaction.We found no significant group differences in whole brain or amygdala analyses during reappraisal. In the group-by-reappraisal success interaction, activations in the left dorsomedial prefrontal cortex (dmPFC) and left dorsolateral PFC (dlPFC) were associated with reappraisal success in healthy controls but not depressed adolescents. Depressed adolescents demonstrated reduced connectivity between the left dmPFC and the anterior insula/inferior frontal gyri bilaterally (AI/IFG) and between left dlPFC and left AI/IFG.Our results should be considered exploratory given our less conservative statistical threshold in the group-by-reappraisal interaction.We find preliminary evidence that depressed adolescents engage cognitive control regions less efficiently than healthy controls, suggesting delayed maturation of regulatory prefrontal cortex regions; more research is needed to determine whether cognitive therapies improve functioning of these regions in depressed youth.

Trauma-related disorders of affect and cognition (TRACs) are associated with a high degree of diagnostic comorbidity, which may suggest that these disorders share a set of underlying neural mechanisms. TRACs are characterized by aberrations in functional and structural circuits subserving verbal memory and affective anticipation. Yet, it remains unknown how the neural circuitry underlying these multiple mechanisms contribute to TRACs. Here, in a sample of 47 combat Veterans, we measured affective anticipation using functional magnetic resonance imaging (fMRI), verbal memory with fluorodeoxyglucose positron emission tomography (FDG-PET), and grey matter volume with structural magnetic resonance imaging (sMRI). Using a voxel-based multimodal canonical correlation analysis (mCCA), the set of neural measures were statistically integrated, or fused, with a set of TRAC symptom measures including mild traumatic brain injury (mTBI), posttraumatic stress, and depression severity. The first canonical correlation pair revealed neural convergence in clusters encompassing the middle frontal gyrus and supplemental motor area, regions implicated in top-down cognitive control and affect regulation. These results highlight the potential of leveraging multivariate neuroimaging analysis for linking neurobiological mechanisms associated with TRACs, paving the way for transdiagnostic biomarkers and targets for treatment. Keywords: Trauma, TBI, PTSD, Multimodal imaging, Canonical correlation

Objective. Chronic pain conditions are prominent among Veterans. To leverage the biopsychosocial model of pain and comprehensively serve Veterans with chronic pain, the San Francisco Veterans Affairs Healthcare System has implemented the interdisciplinary pain rehabilitation program (IPRP). This study aims to (1) understand initial changes in treatment outcomes following IPRP, (2) investigate relationships between psychological factors and pain outcomes, and (3) explore whether changes in psychological factors predict changes in pain outcomes. Methods. A retrospective study evaluated relationships between clinical pain outcomes (pain intensity, pain disability, and opioid use) and psychological factors (depressive symptoms, catastrophizing, and “acceptable” level of pain) and changes in these outcomes following treatment. Multiple regression analysis explored whether changes in psychological variables significantly predicted changes in pain disability. Results. Catastrophizing and depressive symptoms were positively related to pain disability, while “acceptable” level of pain was idiosyncratically related to pain intensity. Pain disability and psychological variables showed significant changes in their expected directions. Regression analysis indicated that only changes in depressive symptoms significantly predicted changes in pain disability. Conclusion. Our results are consistent with evidence-based clinical practice guidelines for the management of chronic pain in Veterans. Further investigation of interdisciplinary treatment programs in Veterans is warranted.

Patients with eating disorders (EDs) often present with psychiatric comorbidity, and functional and/or organic gastrointestinal (GI) symptomatology. Such multidiagnostic presentations can complicate diagnostic practice and treatment delivery. Here we describe an adolescent patient who presented with mixed ED, depressive, and GI symptomatology, who had received multiple contrasting diagnoses throughout treatment. We used a novel machine learning approach to classify (i) the patient's functional brain imaging during an experimental pain paradigm, and (ii) patient self-report psychological measures, to categorize the diagnostic phenotype most closely approximated by the patient. Specifically, we found that the patient's response to pain anticipation and experience within the insula and anterior cingulate cortices, and patient self-report data, were most consistent with patients with GI pain. This work is the first to demonstrate the possibility of using imaging data, alongside supervised learning models, for purposes of single patient classification in those with ED symptomatology, where diagnostic comorbidity is common.

Author(s): Moeller-Bertram, Tobias; Strigo, Irina A; Simmons, Alan N; Schilling, Jan M; Patel, Piyush; Baker, Dewleen G | Abstract: BackgroundPost-traumatic stress disorder (PTSD) and pain have a well-documented high comorbidity; however, the underlying mechanisms of this comorbidity are currently poorly understood. The aim of this psychophysical study was to investigate the behavioral response to a prolonged suprathreshold pain stimulus in subjects with combat-related PTSD and combat controls (CC) for clinical evidence of central sensitization.MethodsTen male subjects with current PTSD related to combat and 11 CC male subjects underwent baseline quantitative sensory testing (QST), temporal pain summation, and psychological profiling followed by an intramuscular injection of capsaicin into the quadriceps muscle.ResultsThere was no significant between-group difference for the initial maximal pain response or an initial pain reduction for the first 15 minutes postinjection on QST or pain ratings. However, we observed significantly higher scores in the PTSD group for the second 15 minutes postinjection on both pain intensity and pain unpleasantness ratings. Assessment of temporal summation to repetitive pressure stimuli showed significantly higher subjective pain in the PTSD group.ConclusionThese findings are consistent with a significantly higher degree of acute central sensitization in individuals with PTSD. Increased acute central sensitization may underlie increased vulnerability for developing pain-related conditions following combat trauma.

Background Traumatic brain injury (TBI) is common in military personnel and associated with high rates of posttraumatic stress disorder (PTSD). TBI impacts widely-distributed neural patterns, some of which influence affective processing. Better understanding how TBI and PTSD/TBI alters affective neural activity may improve our understanding of comorbidity mechanisms, but to date the neural correlates of emotional processing in these groups has been relatively understudied. Methods Military controls, military personnel with a history of TBI, and military personnel with both TBI and PTSD (N = 53) completed an emotional face processing task during fMRI. Whole-brain activation and functional connectivity during task conditions were compared between groups. Results Few whole-brain group differences emerged in planned pairwise contrasts, though the TBI group showed some areas of hypoactivation relative to other groups during processing of faces versus shapes. The PTSD/TBI group compared to the control and TBI groups demonstrated greater connectivity between the amygdala and insula seed regions and a number of prefrontal and posterior cingulate regions. Limitations Generalizability to other patient groups, including those with only PTSD, has not yet been established. Conclusion TBI alone was associated with hypoactivation during a condition processing faces versus shapes, but PTSD with TBI was associated altered functional connectivity between amygdala and insula regions and cingulate and prefrontal areas. Altered connectivity patterns across groups suggests that individuals with PTSD/TBI may need to increase frontal connectivity with the insulae in order to achieve similar task-based activity.

Exposure to psychological stress during combat can lead to posttraumatic stress disorder (PTSD). Anticipation of aversive events is often associated with an intense emotional state in individuals with PTSD. Both the valence (i.e., positive or negative) of the anticipated event and the degree of temporal predictability (i.e., one's ability to predict when an event will occur) have profound effects on an individual's emotional experience. This investigation tested the hypothesis that individuals with combat-related PTSD would show increased activation in the insula and related emotion-processing circuitry when anticipating emotionally significant events such as portrayed in combat-related images, and this heighted response within the insula would be particularly enhanced during temporal unpredictability.About 15 male veterans with PTSD and 15 male veterans with combat-exposure but no current or lifetime history of PTSD (combat exposed controls/CEC) performed a temporal unpredictability anticipation task of unpleasant (combat-related) and pleasant images during fMRI.As expected, greater activation in the bilateral anterior insulae was observed in the PTSD versus the CEC subjects during anticipation of combat-related images when the anticipatory period was of uncertain duration (p0.05). Furthermore, activation in the right anterior insula was related to greater perceived threat in the CEC group (ρ=0.619).The current study looks only at combat-related PTSD in a modest preliminary sized sample.These findings suggest that an excessive anticipatory reaction in individuals with PTSD to temporally unpredictable aversive stimulus may relate to greater perceived threat. These findings are concordant with psychological models of PTSD that focus on the association of PTSD with the experience of decreased predictability and control.

Background: Prolonged exposure (PE) therapy is the first-line treatment for posttraumatic stress disorder (PTSD) in combat veterans. The underlying brain changes of treatment effect in PTSD are currently unknown. Methods: A total of 31 veterans with PTSD completed an fMRI scan performing an affective anticipation task at baseline and were enrolled in PE therapy. Of these, 7 prematurely terminated therapy, while 24 individuals completed PE therapy and an identical follow-up fMRI scan. At follow-up, 15 of the 24 completers still had diagnosable PTSD (NR-PTSD) and 9 of the 24 completers showed complete remission from PTSD (R-PTSD), i.e. they did not meet diagnostic criteria for PTSD. Results: The left anterior insula showed a significant group by scan session interaction. Specifically, the R-PTSD group showed decreased activation during anticipation of negative images from pre- to posttreatment scans, while the NR-PTSD group showed increased activation during anticipation of positive images in this region. Furthermore, the change in functional activation in the insula co-occurred with increased connectivity between this insular region and the right cingulate and right mid-posterior insular region in R-PTSD. Conclusions: These findings suggest that the capacity to effectively remit from PTSD symptoms after PE treatment requires the ability to connect with physiological signals and moderate the discomfort of anticipatory anxiety of exposure therapy. These processes appear to be controlled by a network where the anterior insula is connected with the cingulate and the mid-posterior insula.

We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions . We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

OBJECTIVE: The detection of malingering in cognitive performance is a challenge in clinical and legal environments. Neuroimaging may provide an objective method for delineation of malingering. METHOD: A heterogeneous with concern of gender and racial-ethnic identity of 22 healthy volunteers completed the Tombaugh Test of Memory Malingering during an fMRI scan. Subjects were either instructed to perform optimally (not feigning) or to perform "as if they had a mild traumatic brain injury with memory impairment" (feigning). RESULTS: A voxel-based multiple regression analysis revealed that during correct responses there was greater activation in the superior and medial prefrontal cortex during the feigning versus the not-feigning responses. CONCLUSIONS: This finding suggests that falsified memory performance requires greater activation of cognitive control networks to determine a correct selection. (PsycINFO Database Record Language: en

The effects on the human brain of mild traumatic brain injury (mTBI), which is defined as a brief alteration (AOC) or loss of consciousness (LOC), are incompletely understood. Major psychiatric illnesses such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are common after mTBI. Prior research suggests that individuals who develop MDD after blast-related mTBI versus those who do not show significant white matter disruption and higher rates of LOC, suggesting that LOC might be uniquely associated with brain changes that increase the risk of developing mental illness after neurotrauma. Therefore, the objective of this study was to examine the effects of LOC, MDD, and PTSD on white matter integrity in individuals who reported experiencing mTBI during combat in Operations Enduring and Iraqi Freedom. We hypothesized that LOC would be associated with significant disruption of white matter, above and beyond putative effects of MDD and PTSD. To test this hypothesis, 46 individuals who experienced blast-related mTBI underwent a detailed clinical assessment and diffusion tensor imaging. As hypothesized, LOC versus AOC individuals displayed significantly lower fractional anisotropy (FA) in 14 regions, which included the superior longitudinal fasciculus and corpus callosum. No regions of significant FA difference were identified between individuals with and without PTSD, or between individuals with and without MDD. These preliminary results show that LOC is associated with detectable alterations in brain microstructure and may suggest a brain basis for psychiatric symptoms and mental illness after mTBI.

Individuals who perform optimally in extreme conditions, such as elite military warriors, can provide valuable insight into the neurobehavioral mechanisms underlying extraordinary performance. In the current study, we examined the degree to which Navy SEALs, when compared with healthy volunteers, could show more right anterior insula activation when shifting from anticipating one emotion to another during functional MRI. Consistent with our hypothesis, SEALs showed attenuated insula activation to negative image relative to positive image anticipation and greater right anterior insula activation during affective set-shifting. These findings suggest that elite warriors show combined (a) minimal reactivity during negative stimuli and (b) an enhanced ability to efficiently change their physiological state. These neural changes may underlie their ability to perform well in stressful situations.

Pain and Post Traumatic Stress Disorder (PTSD) are highly comorbid conditions. Patients with chronic pain have higher rates of PTSD. Likewise, patients with PTSD are often diagnosed with numerous chronic pain conditions. Despite the high pain-PTSD comorbidity, the neurobehavioral mechanisms underlying this phenomenon are incompletely understood and only recently researchers have started investigating it using experimental models. In this article, we systematically review the substantial clinical evidence on the co-occurrence of pain and PTSD, and the limited experimental evidence of pain processing in this disorder. We provide a detailed overview of the psychophysical and brain imaging experiments that compared somatosensory and pain processing in PTSD and non-PTSD populations. Based on the presented evidence, an extensive body of literature substantiates the clinical coexistence of pain and PTSD in patients but the limited experimental data show inconsistent results highlighting the need for well-controlled future studies. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Major Depressive Disorder (MDD) is among the top causes of disability worldwide and many patients with depression experience pain symptoms. Little is known regarding what makes depressed persons feel like they are in pain. An increasing number of neuroimaging studies show that both physical pain and depression involve the insular cortex. The present study aimed to investigate whether emotional processing in MDD patients is topologically shifted towards the insular area(s) involved in pain processing in healthy individuals. To achieve this aim, we investigated the functional organization of the insula by conducting meta-analyses of previously published neuroimaging studies on: (1) emotion in patients with MDD, (2) emotion in healthy subjects, and (3) physical pain in healthy subjects. Our results show that the dorsal part of the insula is reproducibly activated during experimental pain in healthy individuals, with multiple separate pain-related areas aligned along its dorsal border. Regions with maximal pain-related activation likelihood estimate (ALE) were located in the posterior (left) and dorsal mid-anterior insula (left and right). Furthermore, emotion-related peaks in healthy subjects were found both in its ventral (as shown in a previous meta-analysis) and dorsal anterior part. Importantly, emotion-related peaks in depressed patients were shifted to the dorsal anterior insula, where regions related to physical pain in healthy subjects are located. This shift was reflected in the observation that median z-coordinates of emotion-related responses in the left hemisphere were significantly larger in depressed patients than in healthy controls. This shift of emotion-related responses to the dorsal insula, i.e., where pain-processing takes place in healthy subjects, may play a role in "emotional allodynia" - a notion that individuals with MDD experience pain in response to stimuli that are normally not painful.

Although the exact number of affected individuals is unknown, it has been estimated that approximately 20% of U.S. veterans of Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF) have experienced mild traumatic brain injury (mTBI) (i.e., concussion), which is defined as a brief loss or alteration of consciousness from a blow or jolt to the head. Blast exposure is among the most common causes of concussion in OEF-OIF warriors. Although the mechanism is unknown, major depressive disorder (MDD) after head injury is common. The purpose of this study was to use diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to examine the structural and functional neural correlates of MDD in OEF-OIF combat veterans with a self-reported history of blast-related concussion. We hypothesized that subjects in the MDD group (i.e., individuals with a history of blast-related concussion who were experiencing current MDD) relative to individuals in the non-MDD group (i.e., individuals with a history of blast-related concussion but no current or lifetime history of MDD) would show amygdala hyperactivity and disruption of white matter tracts connecting prefrontal and limbic brain regions. To test these hypotheses, 11 MDD and 11 non-MDD individuals underwent DTI and performed a validated emotional face matching task during fMRI. MDD relative to non-MDD individuals showed greater activity during fear matching trials in the amygdala and other emotion processing structures, lower activity during fear matching trials in emotional control structures such as the dorsolateral prefrontal cortex and lower fractional anisotropy (FA) in several white matter tracts including the superior longitudinal fasciculus (SLF). Greater depressive symptom severity correlated negatively with FA in the SLF. These results suggest a biological basis of MDD in OEF-OIF veterans who have experienced blast-related concussion, and may contribute to the development of treatments aimed at improving the clinical care of this unique population of wounded warriors.

In this investigation, 27 individuals who experienced blast-related concussion, i.e., brief loss (LOC) or alteration (AOC) of consciousness, performed a stop task during functional magnetic resonance imaging. LOC versus AOC subjects displayed altered ventromedial prefrontal cortex activity, which correlated with somatic symptom severity-findings which may suggest a neural correlate of impaired self awareness after LOC.

Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.

Objective: It is well known that individuals with anorexia nervosa (AN) are inhibited and over-controlled. This study investigated a prefrontal-cingulate network that is involved in inhibitory control. To avoid the confounds of malnutrition, 12 recovered (RAN) subjects were compared to 12 matched control women (CW) using a validated inhibition task (i.e., a stop signal task) during functional magnetic resonance imaging. Results: Consistent with the a priori hypothesis, RAN subjects showed altered task-related activation in the medial prefrontal cortex (mPFC), a critical node of the inhibitory control network. Specifically, whereas RAN and CW showed similar mPFC acitivity during trials when inhibitory demand was low (i.e., easy trials), RAN relative to CW showed significantly less mPFC activation as inhibition trials became more difficult (i.e., hard trials), suggesting a demand-specific modulation of inhibitory control circuitry in RAN. Discussion: These findings support a neural basis for altered impulse control symptoms in AN V C 2010 by Wiley Periodicals, Inc.

Medial cortex is critically involved in self-referential processing. Little is known about how selective serotonin reuptake inhibitors (SSRIs) affect medial cortical activity during self-assessment. We hypothesized that a 3-week oral course of escitalopram,10 mg/day, would alter activity related to self-referential processing in medial cortex. Fifteen healthy females performed a self-assessment task during functional magnetic resonance imaging on two occasions--once after 3 weeks of placebo and once at the end of 3 weeks of escitalopram. Task conditions involved responding "yes" or "no" to whether various positive and negative adjectives described the subject (i.e., "self" evaluation trials) or the subject's best friend (i.e., "other" evaluation trials), whereas the comparison condition involved responding whether the valence of various adjectives was positive or negative (i.e., "word" evaluation trials). Behaviorally after escitalopram, subjects less frequently endorsed that negative adjectives described themselves. Three main neuroimaging results were observed: (1) increased activation in medial prefrontal cortex and posterior cingulate related to self minus word evaluation trials, (2) increased activation in posterior cingulate related to escitalopram minus placebo for self and word evaluation trials, and (3) drug by task interactions in the insula, cerebellum and prefrontal cortex. These results show that SSRIs change medial cortical activity and may alter self-evaluation.

Objective Functional neuroimaging studies have led to a significantly deeper understanding of the underlying neural correlates and the development of several mature models of depression in adults. In contrast, our current understanding of the underlying neural substrates of adolescent depression is very limited. Although numerous studies have consistently demonstrated a hyperactive amygdala in depressed adults, the few published pediatric studies have reported opposite results in the amygdala. Thus, the main purpose of this study was to further our knowledge of the underlying neural substrates of adolescent depression by examining the bilateral amygdala specifically and the whole brain in depressed adolescents compared to healthy controls. Method Twelve unmedicated adolescents diagnosed with current major depressive disorder without a comorbid psychiatric disorder and 12 well-matched controls ages 13 to 17 years performed a facial-emotion matching task during functional magnetic resonance imaging at 3 T. Results Region-of-interest analyses demonstrated: (1) significant bilateral amygdala activation in depressed and healthy adolescents, and (2) significantly greater left amygdala activation in depressed adolescents compared to controls. Whole-brain analysis revealed areas of significantly different brain activity in depressed adolescents compared to controls. Conclusions These results suggest that (1) depressed adolescents without a comorbid psychiatric disorder exhibit an abnormally hyperactive amygdala compared to healthy controls; (2) models of adult depression might be extended to include depressed adolescents; and (3) neuropsychiatric interventions that have been developed in depressed adults should be further examined in adolescents.

OBJECTIVE Interoception is the sense of one's internal physiological, sensory, and emotional status. Extensive evidence supports a link between interoception and subjective experience. An altered ability to monitor or modulate interoception as it relates to subjective experience may provide a mechanistic explanation for the development of some forms of psychiatric illness. METHODS We investigated which neural networks are activated when anticipating a change in affective (and thus interoceptive) state, which we term "affective set-shifting," in 15 women with posttraumatic stress disorder (PTSD) related to intimate partner violence, and in 15 nontraumatized healthy volunteers. RESULTS Although both groups activated the dorsolateral prefrontal cortex during affective set shifting, the PTSD group showed significantly less activation in the right anterior insula than did the controls. CONCLUSIONS These findings may suggest that although individuals with PTSD are cognitively aware of the impending shift in interoceptive state, they fail to appropriately activate neural circuitry involved in modulating interoceptive responses.

To examine the hypothesis that young adults with major depressive disorder (MDD) would show increased affective bias to painful and nonpainful experimental heat stimuli, as evidenced by an increased responsiveness to warm and hot temperatures. Pain and depression often occur together. Pain is both a sensation and an affective experience. Similarly, depression is associated frequently with somatic symptoms as well as emotional dysphoria. Existing evidence indicates that MDD may be associated with altered pain processing. However, the extent to which alterations in experimentally controlled heat pain sensations are related to increased affective bias in MDD is unknown.Graded nonnoxious and noxious heat stimuli were delivered randomly with a thermode applied to the volar surface of the left arm of 15 unmedicated subjects with current MDD and 15 age- and gender-matched healthy comparison subjects. MDD and non-MDD subjects rated the intensity and unpleasantness of all stimuli.Two main results were observed. First, MDD relative to non-MDD subjects showed decreased heat pain thresholds. Second, a significantly increased affective bias (unpleasantness/intensity) was observed in subjects with MDD, particularly over the range of nonnoxious heat stimuli. This bias was independent of the change in sensory pain thresholds.These findings represent corroborative evidence of abnormal affective heat pain processing in young adults with MDD, and suggest that MDD is associated with "emotional allodynia," a qualitatively altered negative emotional response to normally nonaversive thermal stimuli.

Interference processing requires increased focus on relevant dimensions of environmental stimuli and selective allocation of attentional resources, in order to filter extraneous information and inhibit non-adaptive responses. This process is important in everyday life and is necessary for responding to novel and challenging situations. Dorsal anterior cingulate cortex (dACC) is involved in this process, and behavioral twin studies indicate that performance on interference processing tasks is highly heritable. However, the extent to which dACC activation related to such tasks is influenced by genetic factors has not been reported. In the current study, 10 pairs of monozygotic and 10 pairs of dizygotic female twins performed a validated interference processing task during fMRI. There were three main results: (1) increased dACC activation for incongruent (INC) minus congruent (CON) trials was observed; (2) dACC activation for INC minus CON trials was both moderately heritable and significantly correlated with the difference in reaction time (RT) between INC and CON trials; (3) RT for INC trials was moderately heritable. RT for CON trials and the latency difference between INC and CON trials were not influenced significantly by genetic factors. The current study provides the first functional imaging evidence that dACC activation during interference processing is significantly influenced by genes. These results suggest an endophenotype that may be applied to various psychiatric disorders that are both highly heritable and associated with altered dACC function.