AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder: COORDINATE-MDD consortium design and rationale.

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

HIV peripheral neuropathy-related degeneration of white matter tracts to sensorimotor cortex.

Human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) affects up to 50% of people with HIV and is associated with depression, unemployment, and generally worsened quality of life. Previous work on the cortical mechanism of HIV neuropathy found decreased gray matter volume in the bilateral midbrain, thalamus, and posterior cingulate cortex, but structural connectivity in this context remains under-studied. Here we examine alterations in white matter microstructure using diffusion imaging, hypothesizing that cortical white matter degeneration would be observed in continuation of the peripheral white matter atrophy previously observed in HIV-DSP. Male HIV seropositive patients (n = 57) experiencing varying degrees of HIV neuropathy underwent single-shell diffusion tensor imaging with 51 sampling directions. The scans were pooled using tractography and connectometry to create a quantitative map of white matter tract integrity, measured in generalized fractional anisotropy (GFA). The relationship between GFA and neuropathy severity was evaluated with linear regression. Correction for multiple comparisons was done using false discovery rate (FDR), a statistical method commonly used in genomics and imaging to minimize false positives when thousands of individual comparisons are made. Neuropathy severity was associated with decreased GFA along thalamocortical radiations leading along the lateral thalamus to sensorimotor cortex, with r = -0.405 (p < 0.001; FDR), as well as with the superior bilateral cingulum (r = -0.346 (p < 0.05; FDR)). Among a population of HIV neuropathy patients, greater neuropathy severity was correlated with lower white matter integrity running from midbrain to somatosensory cortex. This suggests ascending deafferentation extending from damaged peripheral nerves further downstream than seen previously, into the axons of third-order neurons. There is also evidence of cingulum degeneration, implying some more complex mechanism beyond the ascending atrophy observed here.

The Resurrection of Interdisciplinary Pain Rehabilitation: Outcomes Across a Veterans Affairs Collaborative.

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.

Anorexia nervosa, neuroimaging research, and the contextual salience of food cues: The food approach-avoidance conundrum.

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.

Association of Traumatic Brain Injury With Chronic Pain in Iraq and Afghanistan Veterans: Effect of Comorbid Mental Health Conditions.

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.

Pilot Study of Functional Magnetic Resonance Imaging Responses to Somatic Pain Stimuli in Youth With Functional and Inflammatory Gastrointestinal Disease.

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.

Evidence for acute central sensitization to prolonged experimental pain in posttraumatic stress disorder.

BACKGROUND: Post-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. METHODS: Ten 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. RESULTS: There 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. CONCLUSION: These 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.

Identification of group differences in predictive anticipatory biasing of pain during uncertainty: preparing for the worst but hoping for the best.

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.

Exploring the effects of fitbit incentive on treatment outcomes in veterans undergoing intensive pain rehabilitation program.

OBJECTIVE: This study compares clinical pain outcomes between patients in a pain treatment program that received a Fitbit, to patients that did not. We also explored: (1) cognitive, emotional, and psychological factors that may have impacted the decision to opt in to receiving a Fitbit; and (2) whether the choice to receive a Fitbit impacted changes in cognitive, emotional, and psychological factors following treatment. METHODS: Among 58 patients in a multidisciplinary pain treatment program at a Veterans Affairs Healthcare System hospital, 31 patients opted to receive a Fitbit as adjunct treatment, while 27 did not. This study utilized patient-reported and practitioner-collected data from the pain treatment program. RESULTS: Compared to the non-Fitbit group, the Fitbit group displayed a significant decrease in average pain intensity, however showed no correlation between Fitbit activity and average pain intensity. Additionally, treatment satisfaction was the only predictor of treatment group, when modeling pre- and post-treatment outcomes changes. CONCLUSION: The implementation of a Fitbit may lead to improved pain intensity. Initial evidence suggests that opting to receive a Fitbit during a pain treatment program indicates treatment engagement leading to greater treatment satisfaction. Future work is needed to verify and expand upon this potential mechanism.

Expectation of pain and relief: A dynamical model of the neural basis for pain-trauma co-morbidity.

Posttraumatic Stress Disorder (PTSD) is highly co-morbid with chronic pain conditions. When present, PTSD significantly worsens chronic pain outcomes. Likewise, pain contributes to a more severe PTSD as evidenced by greater disability, more frequent use of harmful opioid analgesics and increased pain severity. The biomechanism behind this comorbidity is incompletely understood, however recent work strongly supports the widely-accepted role of expectation, in the entanglement of chronic pain and trauma symptoms. This work has shown that those with trauma have a maladaptive brain response while expecting stress and pain, whereas those with chronic pain may have a notable impairment in brain response while expecting pain relief. This dynamical expectation model of the interaction between neural systems underlying expectation of pain onset (traumatic stress) and pain offset (chronic pain) is biologically viable and may provide a biomechanistic insight into pain-trauma comorbidity. These predictive mechanisms work through interoceptive pathways in the brain critically the insula cortex. Here we highlight how the neural expectation-related mechanisms augment the existing models of pain and trauma to better understand the dynamics of pain and trauma comorbidity. These ideas will point to targeted complementary clinical approaches, based on mechanistically separable neural biophenotypes for the entanglement of chronic pain and trauma symptoms.

Comparing Pain Outcomes and Treatment Adherence Between In-Person and Virtual Interdisciplinary Pain Rehabilitation Programs at the San Francisco VA Health Care System.

OBJECTIVE: This study compares clinical pain outcomes between patients in a pain treatment program that was conducted in-person, compared to a virtual program. METHODS: In-Person (N=127) and Virtual (N=101) pain treatment programs were compared based on patient-reported, practitioner-collected, and medical record data. The patients were measured at baseline and post treatment (week 12 for In-Person and week 8 for Virtual patients). We employed last observation carried forward (LOCF) to handle missing data. RESULTS: Both the In-Person and Virtual groups were similar in regard to all baseline outcomes, except the In-Person group having significantly more co-morbidities at baseline, with particularly more cases of mental, behavioral, or neurodevelopmental diseases. Both groups demonstrated significant improvements in the pain-related measurements of pain interference and pain catastrophizing thoughts, but neither group displayed a change in average pain across treatment. Further, both groups improved significantly on emotional well-being scores, but not on physical functioning scores. No significant differences existed between groups on outcomes, except for pain catastrophizing, which was higher in the Virtual group at both time points. The Virtual group had lower rates of dropouts compared to In-Person, while the In-Person group had a larger proportion reach a clinically meaningful change in pain-related outcomes, defined as a >30% improvement. DISCUSSION: While some changes were unique to the In-Person program, overall, patients in the Virtual program achieved similar treatment outcomes, suggesting that it can successfully treat Veterans seeking pain management, with less need for in-person facilities for both patients and clinicians.

Design of the COMEBACK and BACKHOME Studies, Longitudinal Cohorts for Comprehensive Deep Phenotyping of Adults with Chronic Low-Back Pain (cLBP): a part of the BACPAC Research Program.

Objective: The University of California, San Francisco (UCSF) Core Center for Patient-centric, Mechanistic Phenotyping in Chronic Low Back Pain (REACH) is one of the three NIH Back Pain Consortium (BACPAC) Research Programs Mechanistic Research Centers (MRCs). The goal of UCSF REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. The primary objective of this research project is to address the critical need for new diagnostic and prognostic markers, and associated patient classification protocols for chronic low back pain (cLBP) treatment. Design: To meet this objective, REACH is conducting two large investigator-initiated translational research cohort studies called: The Longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain (cLBP) Adults Study (comeBACK) and the Chronic Low-Back Pain (cLBP) in Adults Study (BACKHOME). Setting: comeBACK is a longitudinal multicenter in-person observational study of 450 adults with chronic low back pain designed to perform comprehensive deep phenotyping. While, the BACKHOME study is a site-less longitudinal observational e-cohort of approximately 3000 U.S. adults with cLBP. To our knowledge, BACKHOME is the largest prospective remote registry of nationwide adults with cLBP. Methods: Both the comeBACK and BACKHOME studies are collecting a robust and comprehensive set of risk factors, outcomes, and covariates in order to perform deep phenotyping of cLBP patients based on combined biopsychosocial variables to: define cLBP subtypes, establish phenotyping tools for routine clinical evaluation, and lead to improved cLBP outcomes in the future. The data from both studies will be used to establish techniques to develop a patient-centric definition of treatment success and to analyze cLBP patient traits to define clinically useful cLBP phenotypes, using a combination of traditional data analyses and deep learning methods. Conclusions: These 2 pivotal studies, in conjunction with the ancillary studies being performed in both comeBACK and BACKHOME, and the other BACPAC-consortium research projects, we will be able to address a number of diagnostic and therapeutic issues in this complex and diverse patient population with cLBP. These studies will help clarify biopsychosocial mechanisms of cLBP with the aim to provide a foundation to improve the evaluation of treatment effectiveness and to spur new avenues of therapeutic research, including personalized outcome measures that constitute a clinically meaningful treatment effect for individual cLBP patients.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (ß = -18.3, 95% CI (-34.3 to -2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.

Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder.

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.

Altered insula activation during pain anticipation in individuals recovered from anorexia nervosa: evidence of interoceptive dysregulation.

OBJECTIVE: Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in individuals with AN, such as the insula. METHOD: Functional magnetic resonance imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in 10 healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli. RESULTS: REC AN compared with CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN participants. DISCUSSION: REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from AN.

Pain-related opioidergic and dopaminergic neurotransmission: Dual meta-Analyses of PET radioligand studies.

Molecular mechanisms of the interaction between opioidergic and dopaminergic processing during pain-related experiences in the human brain are still incompletely understood. This is partially due to the invasive nature of the available techniques to visualize and measure metabolic activity. Positron Emission Tomography (PET) radioligand studies using radioactive substances are still the only available modality to date that allows for the investigation of the molecular mechanisms in the human brain. The most commonly studied PET radiotracers are [11C]-carfentanil (CFN) and [11C]- or [18F]-diprenorphine (DPN), which bind to opioid receptors, and [11C]-raclopride (RAC) and [18F]-fallypride (FAL) tracers, which bind to dopamine receptors. The current meta-analysis examines pain-related studies that used aforementioned opioid and dopamine radioligands in an effort to consolidate the available data into the most likely activated regions. Our primary goal was to identify regions of shared opioid/dopamine neurotransmission during pain-related experiences using within-subject approach. Seed-based d Mapping (SDM) analysis of previously published voxel coordinate data showed that opioidergic activations were strongest in the bilateral caudate, thalamus, right putamen, cingulate gyrus, midbrain, inferior frontal gyrus, and left superior temporal gyrus. The dopaminergic studies showed that the bilateral caudate, thalamus, right putamen, cingulate gyrus, and left putamen had the highest activations. We were able to see a clear overlap between opioid and dopamine activations in a majority of the regions during pain-related experiences, though there were some unique areas of dopaminergic activation such as the left putamen. Regions unique to opioidergic activation included the midbrain, inferior frontal gyrus, and left superior temporal gyrus. Here we provide initial evidence for the functional overlap between opioidergic and dopaminergic processing during aversive states in humans.

Unsupervised learning for prognostic validity in patients with chronic pain in transdisciplinary pain care.

Chronic pain is not a singular disorder and presents in various forms and phenotypes. Here we show data from a cohort of patients seeking treatment in a transdisciplinary pain clinic. Patients completed a multidimensional patient-reported battery as part of routine initial evaluation at baseline and at each of the four subsequent visits over 1-year follow-up (0, 1, 3, 6, 12 months). The goal of this work was to use unsupervised modeling approach to identify whether patients with chronic pain undergoing transdisciplinary intensive rehabilitation treatment: (1) can be derived based upon self-reported outcome measures at baseline (or before treatment initiation), (2) are clinically validated based on their clinical diagnosis and medication use, and (3) differ in treatment trajectories over 1 year of transdisciplinary treatment. We applied unsupervised clustering on baseline outcomes using nine patient-reported symptoms and examined treatment trajectories. The three-cluster solution was internally validated. Psychiatric diagnosis, chronic back pain-related disability and symptoms severity determined cluster assignment and treatment prognosis. Conversely, clinical pain severity had lesser effect. Furthermore, clusters showed stability over time despite symptoms improvement. The accurate and meaningful subgrouping of the underlying chronic pain phenotypes would greatly enhance treatment and provide personalized and effective pain management.

Combat-exposed war veterans at risk for suicide show hyperactivation of prefrontal cortex and anterior cingulate during error processing.

OBJECTIVE: Suicide is a significant public health problem. Suicidal ideation (SI) increases the risk for completed suicide. However, the brain basis of SI is unknown. The objective of this study was to examine the neural correlates of self-monitoring in individuals at risk for suicide. We hypothesized that combat veterans with a history of SI relative to those without such a history would show altered activation in the anterior cingulate cortex and related circuitry during self-monitoring. METHODS: Two groups of combat-exposed war veterans (13 men with and 13 men without history of SI) were studied. Both the SI and non-SI participants had two or more of the following: a) current major depressive disorder, b) current posttraumatic stress disorder, and c) history of mild traumatic brain injury, and each subject performed a validated stop task during functional magnetic resonance imaging. Error-related activation was compared between the SI and non-SI groups. RESULTS: The SI group demonstrated more error-related activation of the anterior cingulate (8256 mm(3), t = 2.51) and prefrontal cortex (i.e., clusters >2048 mm(3), voxelwise p < .05). The SI and non-SI participants showed similar behavioral task performance (i.e., mean error rate, F values < 0.63, p values > .43; and mean reaction times, F = 0.27, p = .61). CONCLUSIONS: These findings suggest neural correlates of altered self-monitoring in individuals with a history of SI and may further suggest that functional magnetic resonance imaging could be used to identify individuals at risk for suicide before they engage in suicidal behavior.

Understanding Pain and Trauma Symptoms in Veterans From Resting-State Connectivity: Unsupervised Modeling.

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.

Learning from addiction: Craving of prescription opioids in chronic pain sufferers.

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.