Depression Predicts Chronic Pain Interference in Racially Diverse, Income-Disadvantaged Patients.

BACKGROUND: Chronic pain is one of the most common reason adults seek medical care in the United States, with prevalence estimates ranging from 11% to 40%. Mindfulness meditation has been associated with significant improvements in pain, depression, physical and mental health, sleep, and overall quality of life. Group medical visits are increasingly common and are effective at treating myriad illnesses, including chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence based integrative medicine, and medical group visits and can be used as adjuncts to medications, particularly in diverse underserved populations with limited access to non-pharmacological therapies. OBJECTIVE AND DESIGN: The objective of the present study was to use a blended analytical approach of machine learning and regression analyses to evaluate the potential relationship between depression and chronic pain in data from a randomized clinical trial of IMGV in diverse, income-disadvantaged patients suffering from chronic pain and depression. METHODS: The analytical approach used machine learning to assess the predictive relationship between depression and pain and identify and select key mediators, which were then assessed with regression analyses. It was hypothesized that depression would predict the pain outcomes of average pain, pain severity, and pain interference. RESULTS: Our analyses identified and characterized a predictive relationship between depression and chronic pain interference. This prediction was mediated by high perceived stress, low pain self-efficacy, and poor sleep quality, potential targets for attenuating the adverse effects of depression on functional outcomes. CONCLUSIONS: In the context of the associated clinical trial and similar interventions, these insights may inform future treatment optimization, targeting, and application efforts in racialized, income-disadvantaged populations, demographics often neglected in studies of chronic pain.

Evidence of Altered Brain Responses to Nicotine in an Animal Model of Attention Deficit/Hyperactivity Disorder.

INTRODUCTION: Individuals with attention deficit/hyperactivity disorder (ADHD) are susceptible to earlier and more severe nicotine addiction. To shed light on the relationship between nicotine and ADHD, we examined nicotine's effects on functional brain networks in an animal model of ADHD. METHODS: Awake magnetic resonance imaging was used to compare functional connectivity in adolescent (post-natal day 44 ± 2) males of the spontaneously hypertensive rat (SHR) strain and two control strains, Wistar-Kyoto and Sprague-Dawley (n = 16 each). We analyzed functional connectivity immediately before and after nicotine exposure (0.4 mg/kg base) in naïve animals, using a region-of-interest approach focussing on 16 regions previously implicated in reward and addiction. RESULTS: Relative to the control groups, the SHR strain demonstrated increased functional connectivity between the ventral tegmental area (VTA) and retrosplenial cortex in response to nicotine, suggesting an aberrant response to nicotine. In contrast, increased VTA-substantia nigra connectivity in response to a saline injection in the SHR was absent following a nicotine injection, suggesting that nicotine normalized function in this circuit. CONCLUSIONS: In the SHR, nicotine triggered an atypical response in one VTA circuit while normalizing activity in another. The VTA has been widely implicated in drug reward. Our data suggest that increased susceptibility to nicotine addiction in individuals with ADHD may involve altered responses to nicotine involving VTA circuits. IMPLICATIONS: Nicotine addiction is more common among individuals with ADHD. We found that two circuits involving the VTA responded differently to nicotine in animals that model ADHD in comparison to two control strains. In one circuit, nicotine normalized activity that was abnormal in the ADHD animals, while in the other circuit nicotine caused an atypical brain response in the ADHD animals. The VTA has been implicated in drug reward. Our results would be consistent with an interpretation that nicotine may normalize abnormal brain activity in ADHD, and that nicotine may be more rewarding for individuals with ADHD.

Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model. Sarm1(-/-) mice developed fewer ß-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared to Sarm1(+/+) mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phophorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after traumatic brain injury. Strikingly, whereas wild-type mice exibited a number of behavioural deficits after traumatic brain injury, we observed a strong, early preservation of neurological function in Sarm1(-/-) animals. Finally, using in vivo proton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1(-/-) mice compared to controls immediately following traumatic brain injury. Our results indicate that the SARM1-mediated prodegenerative pathway promotes pathogenesis in traumatic brain injury and suggest that anti-SARM1 therapeutics are a viable approach for preserving neurological function after traumatic brain injury.

Effects of Recent Concussion on Brain Bioenergetics: A Phosphorus-31 Magnetic Resonance Spectroscopy Study.

BACKGROUND: Although clinical evaluations and neurocognitive assessments are commonly used to evaluate the extent of and recovery from concussion, brain bioenergetics could provide a more quantitative marker. The neurometabolic response to a concussion is thought to increase neuronal energy consumption and thus the demand for nucleoside triphosphate (NTP). OBJECTIVE: We investigated the possible disruption in high-energy metabolism within the prefrontal cortex of college athletes who had either had a concussion within the past 6 months (n=14) or had never had a concussion (n=13). We hypothesized that concussed athletes would have imbalanced brain bioenergetics resulting from increased NTP consumption, and these biochemical changes would correspond to impaired cognitive abilities. METHODS: We used phosphorus-31 magnetic resonance spectroscopy to quantify high-energy phosphates. We performed the neuroimaging in conjunction with neurocognitive assessments targeting prefrontal cortex-mediated tasks. RESULTS: Our results revealed significantly lower γ-NTP levels in the athletes after concussion. Although the concussed and non-concussed participants performed similarly in neurocognitive assessments, lower levels of γ-NTP were associated with worse scores on neurocognitive tasks. CONCLUSIONS: Our results support the concept of increased energy demand in the prefrontal cortex of a concussed brain, and we found that while neurocognitive assessments appear normal, brain energetics may be abnormal. A longitudinal study could help establish brain NTP levels as a biomarker to aid in diagnosis and to assess recovery in concussed patients.

A scoping review of interprofessional collaborative practice and education using the lens of the Triple Aim.

The Triple Aim unequivocally connects interprofessional healthcare teams to the provision of better healthcare services that would eventually lead to improved health outcomes. This review of the interprofessional education (IPE) and collaborative practice empirical literature from 2008 to 2013 focused on the impact of this area of inquiry on the outcomes identified in the Triple Aim. The preferred reporting items for systematic reviews and meta-analyses methodology were employed including: a clearly formulated question, clear inclusion criteria to identify relevant studies based on the question, an appraisal of the studies or a subset of the studies, a summary of the evidence using an explicit methodology and an interpretation of the findings of the review. The initial search yielded 1176 published manuscripts that were reduced to 496 when the inclusion criteria were applied to refine the selection of published manuscripts. Despite a four-decade history of inquiry into IPE and/or collaborative practice, scholars have not yet demonstrated the impact of IPE and/or collaborative practice on simultaneously improving population health, reducing healthcare costs or improving the quality of delivered care and patients' experiences of care received. We propose moving this area of inquiry beyond theoretical assumptions to systematic research that will strengthen the evidence base for the effectiveness of IPE and collaborative practice within the context of the evolving imperative of the Triple Aim.

Race-Based Differences in the Response to a Mindfulness Based Integrative Medical Group Visit Intervention for Chronic Pain.

Background: Chronic pain is one of the most common drivers of healthcare utilization and a marked domain for health disparities, as African American/Black populations experience high rates of chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence-based integrative medicine, and medical group visits. In a parent randomized controlled trial, this approach was tested as an adjunct treatment in a diverse, medically underserved population with chronic pain and depression. Objective: To determine race-based heterogeneity in the effects of a mindfulness based treatment for chronic pain. Methods: This secondary analysis of the parent trial assessed heterogeneity of treatment effects along racialized identity in terms of primary patient-reported pain outcomes in a racially diverse sample suffering from chronic pain and depression. The analytic approach examined comorbidities and sociodemographics between racialized groups. RMANOVAs examined trajectories in pain outcomes (average pain, pain severity, and pain interference) over three timepoints (baseline, 9, and 21 weeks) between participants identifying as African American/Black (n = 90) vs White (n = 29) across both intervention and control conditions. Results: At baseline, African American/Black participants had higher pain severity and had significantly different age, work status, and comorbidity profiles. RMANOVA models also identified significant race-based differences in the response to the parent IMGV intervention. There was reduced pain severity in African American/Black subjects in the IMGV condition from baseline to 9 weeks. This change was not observed in White participants over this time period. However, there was a reduction in pain severity in White participants over the subsequent interval from 9 to 21 week where IMGV had no significant effect in African American/Black subjects during this latter time period. Conclusion: Interactions between pain and racialization require further investigation to understand how race-based heterogeneity in the response to integrative medicine treatments for chronic pain contribute to the broader landscape of health inequity.

Introduction to the special issue on evaluator education.

After years in preparation, we are pleased to introduce this special issue of Evaluation and Program Planning that focuses on evaluator education, a topic that we believe is of considerable importance to the field's future. Before describing the issue's content, let us ground the articles in two ways: by examining the larger context within which evaluator education finds itself, and by briefly explaining who we are and describing how the issue came into being.

Effects of the Mindfulness-Based Blood Pressure Reduction (MB-BP) program on depression and neural structural connectivity.

BACKGROUND: Hypertension-related illnesses are a leading cause of disability and death in the United States, where hypertension prevalence in adults is 46%, with only half of those afflicted having it under control. Due to the significant challenges in long-term efficacy and adverse effects associated with pharmacological interventions, there is an eminent need for complimentary approaches for treating hypertension. Although initial studies of the Mindfulness-Based Blood Pressure Reduction program (MB-BP) indicate that this novel 8-week intervention is effective at inducing lasting decreases in blood pressure, the neural correlates are unknown. METHODS: The objectives of this study were to identify structural neural correlates of MB-BP using diffusion tensor magnetic resonance imaging (DTI) and assess potential correlations with key clinical outcomes. RESULTS: In a subset of participants (14 MB-BP, 22 controls) from a larger stage IIa randomized controlled trial, MB-BP participants exhibited increased interoception and decreased depressive symptoms compared to controls. Analyses of DTI data revealed significant group differences in multiple white matter neural tracts associated with the limbic system and/or blood pressure. Specific changes in neural structural connectivity were significantly associated with measures of interoception and depression. LIMITATIONS: Limitations include small sample size (leading to insufficient power in the analysis of blood pressure) and the study duration (3 months). The main MRI limitation is suboptimal resolution in areas of extensive neural tract crossings. CONCLUSIONS: It is concluded that MB-BP induces alterations in brain structural connectivity which could mediate beneficial changes in depression and interoceptive awareness in individuals with hypertension.

Latent Factor Decomposition Model: Applications for Questionnaire Data.

The analysis of clinical questionnaire data comes with many inherent challenges. These challenges include the handling of data with missing fields, as well as the overall interpretation of a dataset with many fields of different scales and forms. While numerous methods have been developed to address these challenges, they are often not robust, statistically sound, or easily interpretable. Here, we propose a latent factor modeling framework that extends the principal component analysis for both categorical and quantitative data with missing elements. The model simultaneously provides the principal components (basis) and each patients' projections on these bases in a latent space. We show an application of our modeling framework through Irritable Bowel Syndrome (IBS) symptoms, where we find correlations between these projections and other standardized patient symptom scales. This latent factor model can be easily applied to different clinical questionnaire datasets for clustering analysis and interpretable inference.

Keeping weight off: Mindfulness-Based Stress Reduction alters amygdala functional connectivity during weight loss maintenance in a randomized control trial.

Obesity is associated with significant comorbidities and financial costs. While behavioral interventions produce clinically meaningful weight loss, weight loss maintenance is challenging. The objective was to improve understanding of the neural and psychological mechanisms modified by mindfulness that may predict clinical outcomes. Individuals who intentionally recently lost weight were randomized to Mindfulness-Based Stress Reduction (MBSR) or a control healthy living course. Anthropometric and psychological factors were measured at baseline, 8 weeks and 6 months. Functional connectivity (FC) analysis was performed at baseline and 8 weeks to examine FC changes between regions of interest selected a priori, and independent components identified by independent component analysis. The association of pre-post FC changes with 6-month weight and psychometric outcomes was then analyzed. Significant group x time interaction was found for FC between the amygdala and ventromedial prefrontal cortex, such that FC increased in the MBSR group and decreased in controls. Non-significant changes in weight were observed at 6 months, where the mindfulness group maintained their weight while the controls showed a weight increase of 3.4% in BMI. Change in FC at 8-weeks between ventromedial prefrontal cortex and several ROIs was associated with change in depression symptoms but not weight at 6 months. This pilot study provides preliminary evidence of neural mechanisms that may be involved in MBSR's impact on weight loss maintenance that may be useful for designing future clinical trials and mechanistic studies.

Altered neural networks and cognition in a hereditary colon cancer.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Putting evaluation capacity building in context: Reflections on the Ontario Brain Institute's Evaluation Support Program.

This article, in three parts, reflects on the content of the six articles included in the forum. It begins with a description of the Evaluation Support Program, emphasizing its key attributes. Next, it raises two points regarding ECB theory: (1) the need to become clearer about the concepts and terms used to describe and study this phenomenon, and (2) the potential value of social science theory to understand ECB and improve its practice. The article concludes with practical ideas for improving ECB: (1) framing it as an educative act, which assigns the evaluator the critical role of evaluation teacher/coach; and (2) the importance of never assuming that an ECB effort begins in unchartered territory, but rather that it builds on people's knowledge, skills, attitudes, and previous experiences.

What do we know about evaluator education? A review of peer-reviewed publications (1978-2018).

This article reviews peer-reviewed writings on evaluator education from 1978 to 2018. Despite the topic's presumed importance, scholars to date have not extensively addressed it in peer-reviewed publications. The article first describes the methods used to select articles and the conceptual framework for their analysis. It then presents the content of 64 articles selected for review, divided into two major categories: research studies, and reflective case narratives. We further divide research studies into program directories and empirical studies; the case narratives provide information on programs, curriculum, and instruction and minimally on students/faculty. The article concludes with thoughts on next steps for research on evaluator education.

Robustness of sex-differences in functional connectivity over time in middle-aged marmosets.

Nonhuman primates (NHPs) are an essential research model for gaining a comprehensive understanding of the neural mechanisms of neurocognitive aging in our own species. In the present study, we used resting state functional connectivity (rsFC) to investigate the relationship between prefrontal cortical and striatal neural interactions, and cognitive flexibility, in unanaesthetized common marmosets (Callithrix jacchus) at two time points during late middle age (8 months apart, similar to a span of 5-6 years in humans). Based on our previous findings, we also determine the reproducibility of connectivity measures over the course of 8 months, particularly previously observed sex differences in rsFC. Male marmosets exhibited remarkably similar patterns of stronger functional connectivity relative to females and greater cognitive flexibility between the two imaging time points. Network analysis revealed that the consistent sex differences in connectivity and related cognitive associations were characterized by greater node strength and/or degree values in several prefrontal, premotor and temporal regions, as well as stronger intra PFC connectivity, in males compared to females. The current study supports the existence of robust sex differences in prefrontal and striatal resting state networks that may contribute to differences in cognitive function and offers insight on the neural systems that may be compromised in cognitive aging and age-related conditions such as mild cognitive impairment and Alzheimer's disease.

Chronic alcohol-induced liver injury correlates with memory deficits: Role for neuroinflammation.

Alcohol use disorder (AUD) affects over 15 million adults over age 18 in the United States, with estimated costs of 220 billion dollars annually - mainly due to poor quality of life and lost productivity, which in turn is intricately linked to cognitive dysfunction. AUD-induced neuroinflammation in the brain, notably the hippocampus, is likely to contribute to cognitive impairments. The neuroinflammatory mechanisms mediating the impact of chronic alcohol on the central nervous system, specifically cognition, require further study. We hypothesized that chronic alcohol consumption impairs memory and increases the inflammatory cytokines TNFα, IL6, MCP1, and IL1ß in the hippocampus and prefrontal cortex regions in the brain. Using the chronic-binge Gao-NIAAA alcohol mouse model of liver disease, representative of the drinking pattern common to human alcoholics, we investigated behavioral and neuroinflammatory parameters. Our data show that chronic alcohol intake elevated peripheral and brain alcohol levels, induced serum alanine aminotransferase (ALT, a marker of liver injury), impaired memory and sensorimotor coordination, and increased inflammatory gene expression in the hippocampus and prefrontal cortex. Interestingly, serum ALT and hippocampal IL6 correlated with memory impairment, suggesting an intrinsic relationship between neuroinflammation, cognitive decline, and liver disease. Overall, our results point to a likely liver-brain functional partnership and suggest that future strategies to alleviate hepatic and/or neuroinflammatory impacts of chronic AUD may result in improved cognitive outcomes.

Altered Resting State Brain Networks and Cognition in Familial Adenomatous Polyposis.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

The current state of evaluator education: A situation analysis and call to action.

Education is critically important for the maintenance and growth of programme evaluation and its emergence as a profession. This position paper presents evaluator education as an initiative and provides a foundation for its evaluation. In it, the authors use Stufflebeam's Context, Input, Process, and Product (CIPP) model to frame a review of the literature and practice. We follow this analysis of the current state of evaluator education in formal settings, with discussion of its implications, and directions for future research and action. Our analysis suggests that there is much work to be done to understand the needs for evaluator education, to delineate standards for quality in both education and practice, to identify the inputs and processes most effective for addressing those needs, and to document its ultimate impacts. The paper provides a call to action for improving the quality, consistency, and integrity of this important work.

The role of 5-HT1A receptors in the behavioral responses associated with innate fear.

Fear is a response induced by threatening stimuli and represents an important adaptive system. The serotonin (5-HT) system has been shown to be involved in the modulation of fear responses and anxiety disorders. In preclinical studies, it has been demonstrated that R (+)-8-hydroxy-dipropylaminotetralin (8-OHDPAT), a 5-HT1A agonist, has anxiolytic properties. However, 8-OHDPATs potential role in unconditioned fear has yet to be elucidated. The current study was designed to investigate the effects of 8-OHDPAT on behavioral and HPA axis function in response to an innate fear-inducing stimulus. Pretreatment with 8-OHDPAT resulted in a significant decrease in freezing grooming, and climbing and caused a significant increase in approach after exposure to an extract from fox feces, 2,5-dihyrdo-2,4,5-trimethylthiazoline (TMT), an unconditioned fear-inducing stimulus. Furthermore, 8-OHDPAT pretreatment also resulted in a significant decrease in blood corticosterone levels, a marker of HPA activation. Taken together, these results suggest an additional anxyolitic-like effect of 8-OHDPAT in innate fear paradigms.

Imaging brain activation in nicotine-sensitized rats.

Our purpose was to determine if sensitization to nicotine could be assessed using functional magnetic resonance imaging (fMRI) with BOLD contrast. Sensitization describes a phenomenon whereby subsequent doses of a drug produce greater responses than the initial dose. Robust locomotor sensitization was demonstrated in adult male Sprague-Dawley rats by the daily administration of nicotine 0.4 mg/kg over 5 days. In parallel experiments, brain activity was monitored using fMRI in animals receiving their first dose (acute) or fifth dose of nicotine (sensitized) and appropriate saline controls. Compared to the acute nicotine animals, brain activity in the sensitized animals demonstrated prolonged BOLD activation in response to nicotine in the hippocampus, nucleus accumbens, prefrontal cortex, ventral pallidum and ventral tegmentum, and more intense peak activation in the hippocampus, prefrontal cortex and ventral tegmentum. In addition, sensitization was associated with a relative decrease in activation in the anterior cingulate gyrus. Furthermore, despite the rich endowment of nicotinic receptors in the visual cortex there was no change in activation with sensitization, thus establishing the specificity of the observed pattern of regional activation and inhibition. Taken together, the current studies support the premise that nicotine sensitization is accompanied by changes in brain activation including a sensitized BOLD response in the extended limbic system that may subserve the process of dependence.

Glutamine/glutamate (Glx) concentration in prefrontal cortex predicts reversal learning performance in the marmoset.

This study used Magnetic Resonance Spectroscopy (MRS) to identify potential neurometabolitic markers of cognitive performance in male (n = 7) and female (n = 8) middle-aged (∼5 years old) common marmosets (Callithrix jacchus). Anesthetized marmosets were scanned with a 4.7 T/40 cm horizontal magnet equipped with 450 mT/m magnetic field gradients and a 20 G/cm magnetic field gradient insert, within 3 months of completing the CANTAB serial Reversal Learning task. Neurometabolite concentrations of N-Acetyl Asparate, Myo-Inositol, Choline, Phosphocreatine + creatine, Glutamate and Glutamine were acquired from a 3 mm3 voxel positioned in the Prefrontal Cortex (PFC). Males acquired the reversals (but not simple discriminations) faster than the females. Higher PFC Glx (glutamate + glutamine) concentration was associated with faster acquisition of the reversals. Interestingly, the correlation between cognitive performance and Glx was significant in males, but not in females. These results suggest that MRS is a useful tool to identify biochemical markers of cognitive performance in the healthy nonhuman primate brain and that biological sex modulates the relationship between neurochemical composition and cognition.