PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration.

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.

Structural brain differences in recovering and weight-recovered adult outpatient women with anorexia nervosa.

BACKGROUND: Anorexia nervosa is a complex psychiatric illness that includes severe low body weight with cognitive distortions and altered eating behaviors. Brain structures, including cortical thicknesses in many regions, are reduced in underweight patients who are acutely ill with anorexia nervosa. However, few studies have examined adult outpatients in the process of recovering from anorexia nervosa. Evaluating neurobiological problems at different physiological stages of anorexia nervosa may facilitate our understanding of the recovery process. METHODS: Magnetic resonance imaging (MRI) images from 37 partially weight-restored women with anorexia nervosa (pwAN), 32 women with a history of anorexia nervosa maintaining weight restoration (wrAN), and 41 healthy control women were analyzed using FreeSurfer. Group differences in brain structure, including cortical thickness, areas, and volumes, were compared using a series of factorial f-tests, including age as a covariate, and correcting for multiple comparisons with the False Discovery Rate method. RESULTS: The pwAN and wrAN cohorts differed from each other in body mass index, eating disorder symptoms, and social problem solving orientations, but not depression or self-esteem. Relative to the HC cohort, eight cortical thicknesses were thinner for the pwAN cohort; these regions were predominately right-sided and in the cingulate and frontal lobe. One of these regions, the right pars orbitalis, was also thinner for the wrAN cohort. One region, the right parahippocampal gyrus, was thicker in the pwAN cohort. One volume, the right cerebellar white matter, was reduced in the pwAN cohort. There were no differences in global white matter, gray matter, or subcortical volumes across the cohorts. CONCLUSIONS: Many regional structural differences were observed in the pwAN cohort with minimal differences in the wrAN cohort. These data support a treatment focus on achieving and sustaining full weight restoration to mitigate possible neurobiological sequela of AN. In addition, the regions showing cortical thinning are similar to structural changes reported elsewhere for suicide attempts, anxiety disorders, and autistic spectrum disorder. Understanding how brain structure and function are related to clinical symptoms expressed during the course of recovering from AN is needed.

Anorexia nervosa is a life-threatening mental illness defined in part by an inability to maintain a body weight in the normal range. Malnutrition and low weight are factors typically present in the anorexia nervosa and can affect brain structure. We conducted a detailed analysis of brain structure using Freesurfer, focusing on regional cortical thicknesses, areas, and volumes, in adult outpatient women with anorexia nervosa. The study included both a partially weight-restored cohort with anorexia nervosa, a cohort sustaining a healthy body weight with history of anorexia nervosa, and a healthy comparison cohort. Reduced cortical thicknesses were observed in eight regions, primarily in the frontal lobe and cingulate for the cohort recently with anorexia nervosa but only one frontal region in the weight-maintained cohort. These data emphasize the importance of sustained weight-restoration for adult women with anorexia nervosa. Further, the impacted neural regions have been associated with impulsivity, attention, self-regulation, and social interactions in other clinical cohorts, suggesting that these neuropsychological processes may warrant study in patients recovering from anorexia nervosa. Future work should consider whether these factors have clinical relevance in the outpatient treatment of adults with anorexia nervosa.

The Role of Expectations and Endogenous Opioids in Mindfulness-Based Relief of Experimentally Induced Acute Pain.

OBJECTIVE: Expectations contribute to cognitive pain modulation through opioidergically mediated descending inhibition. Mindfulness meditation reduces pain independent of endogenous opioids, engaging unique corticothalamocortical mechanisms. However, it remains unknown whether expectations for pain relief predict mindfulness-induced analgesia and if these expectations are modified by endogenous opioids. METHODS: In this secondary analysis of previously published work, 78 pain-free participants (mean age, 27 ± 7 years; 50% women) were randomized to a four-session mindfulness meditation or book listening regimen. Expectations for intervention-induced pain relief were assessed before and after each intervention. Pain ratings were examined after meditation or rest (control group) during noxious heat (49°C) and intravenous administration of saline placebo or the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg kg-1 h-1 infusion. RESULTS: Mindfulness significantly lowered pain during saline and naloxone infusion. Higher expected pain relief from mindfulness predicted lower pain intensity (r(40) = -0.41, p = .009). The relationship between meditation-related expectations and pain intensity reductions was exhibited during naloxone (r(20) = -0.76, p < .001) but not saline (r(20) = -0.22, p = .36). Expectations for book listening-based analgesia did not significantly predict pain changes during saline (r(20) = -0.37, p = .11) or naloxone (r(18) = 0.26, p = .30) in the control group. CONCLUSIONS: These novel findings demonstrate a significant role for expectations in mindfulness-based pain relief. However, this role was minimal during saline and stronger during opioid blockade, despite similar pain reductions. This supports growing evidence that mindfulness engages multiple mechanisms to reduce pain, suggesting that mindfulness might be an effective pain-reducing technique even for individuals with low expectations for pain relief.

Attention to breath sensations does not engage endogenous opioids to reduce pain.

The endogenous opioidergic system is critically involved in the cognitive modulation of pain. Slow-breathing-based techniques are widely used nonpharmacological approaches to reduce pain. Yet, the active mechanisms of actions supporting these practices are poorly characterized. Growing evidence suggest that mindfulness-meditation, a slow-breathing technique practiced by nonreactively attending to breathing sensations, engages multiple unique neural mechanisms that bypass opioidergically mediated descending pathways to reduce pain. However, it is unknown whether endogenous opioids contribute to pain reductions produced by slow breathing. The present double-blind, placebo-controlled crossover study examined behavioral pain responses during mindfulness-meditation (n = 19), sham-mindfulness meditation (n = 20), and slow-paced breathing (n = 20) in response to noxious heat (49°C) and intravenous administration (0.15 mg/kg bolus + 0.1 mg/kg/hour maintenance infusion) of the opioid antagonist, naloxone, and placebo saline. Mindfulness significantly reduced pain unpleasantness ratings across both infusion sessions when compared to rest, but not pain intensity. Slow-paced breathing significantly reduced pain intensity and unpleasantness ratings during naloxone but not saline infusion. Pain reductions produced by mindfulness-meditation and slow-paced breathing were insensitive to naloxone when compared to saline administration. By contrast, sham-mindfulness meditation produced pain unpleasantness reductions during saline infusion but this effect was reversed by opioidergic antagonism. Sham-mindfulness did not lower pain intensity ratings. Self-reported "focusing on the breath" was identified as the operational feature particularly unique to the mindfulness-meditation and slow paced-breathing, but not sham-mindfulness meditation. Across all individuals, attending to the breath was associated with naloxone insensitive pain-relief. These findings provide evidence that slow breathing combined with attention to breath reduces pain independent of endogenous opioids.

Assessing the Effect of Clinical Trial Evidence and Anecdote on Caregivers' Willingness to Use Corticosteroids: A Randomized Controlled Trial [Formula: see text].

BACKGROUND: Treatment of childhood atopic dermatitis (AD) is hindered by nonadherence, but caregiver reassurance may help overcome this hurdle. OBJECTIVES: To assess caregivers' willingness to treat childhood AD with a corticosteroid when presented with clinical trial evidence, anecdote, or both. METHODS: A total of 476 caregivers were recruited through a dermatology clinic and online crowdsourcing platform. Subjects were randomized to receive clinical trial evidence, anecdote, or both, using either the term "medication" or "topical steroid." Additional caregivers were queried about their willingness to treat with the doctor's recommendation or without knowledge of its safety information. Responses were recorded on a 10-point Likert scale. RESULTS: Caregivers' willingness to treat was higher in all information assignment groups compared to those not provided with safety information: clinical trial evidence of a "medication" (P = .003; Cohen's d = 0.83) or "topical steroid" (P = .030; d = 0.55), anecdote of a "medication" (P < .0001; d = 1.37) or "topical steroid" (P < .0001; d = 0.85), both clinical trial evidence and anecdote of a "medication" (P < .0001; d = 1.00) or "topical steroid" (P = .000; d = 0.89), and simply the doctor's recommendation (P < .0001; d = 0.92). Significance was corrected for multiple comparisons to 0.0018. There were no differences between caregivers of children with and without AD (P = .36). CONCLUSIONS: Providing anecdotal reassurance, even in the setting of reported high willingness to treat with the doctor's recommendation, may be an effective strategy to improve caregivers' perceptions of starting new medications.

The Role of Heart Rate Variability in Mindfulness-Based Pain Relief.

Mindfulness meditation is a self-regulatory practice premised on sustaining nonreactive awareness of arising sensory events that reliably reduces pain. Yet, the specific analgesic mechanisms supporting mindfulness have not been comprehensively disentangled from the potential nonspecific factors supporting this technique. Increased parasympathetic nervous system (PNS) activity is associated with pain relief corresponding to a number of cognitive manipulations. However, the relationship between the PNS and mindfulness-based pain attenuation remains unknown. The primary objective of the present study was to determine the role of high-frequency heart rate variability (HF HRV), a marker of PNS activity, during mindfulness-based pain relief as compared to a validated, sham-mindfulness meditation technique that served as a breathing-based control. Sixty-two healthy volunteers (31 females; 31 males) were randomized to a 4-session (25 min/session) mindfulness or sham-mindfulness training regimen. Before and after each group's respective training, participants were administered noxious (49°C) and innocuous (35°C) heat to the right calf. HF HRV and respiration rate were recorded during thermal stimulation and pain intensity and unpleasantness ratings were collected after each stimulation series. The primary analysis revealed that during mindfulness meditation, higher HF HRV was more strongly associated with lower pain unpleasantness ratings when compared to sham-mindfulness meditation (B = -.82, P = .04). This finding is in line with the prediction that mindfulness-based meditation engages distinct mechanisms from sham-mindfulness meditation to reduce pain. However, the same prediction was not confirmed for pain intensity ratings (B = -.41). Secondary analyses determined that mindfulness and sham-mindfulness meditation similarly reduced pain ratings, decreased respiration rate, and increased HF HRV (between group ps < .05). More mechanistic work is needed to reliably determine the role of parasympathetic activation in mindfulness-based pain relief as compared to other meditative techniques. Perspective: Mindfulness has been shown to engage multiple mechanisms to reduce pain. The present study extends on this work to show that higher HRV is associated with mindfulness-induced reductions in pain unpleasantness, but not pain intensity ratings, when compared to sham-mindfulness meditation. These findings warrant further investigation into the mechanisms engaged by mindfulness as compared to placebo.

Complementary and Integrative Therapies for Childhood Atopic Dermatitis.

BACKGROUND: Childhood atopic dermatitis is a chronic inflammatory skin condition that causes significant psychological and financial costs to the individual and society. Treatment regimens may require long-term medication adherence and can be associated with poor patient satisfaction. There is considerable interest in complementary and integrative medicine (CIM) approaches for childhood atopic dermatitis. OBJECTIVE: To assess the effects of CIM approaches on childhood atopic dermatitis outcomes as defined by randomized, controlled clinical trials. METHODS: A PubMed review of CIM-related treatments for pediatric atopic dermatitis was performed, and data related to age, study population, efficacy, treatment regimen, length of treatment, and sample size were included. RESULTS: The search yielded 20 trials related to probiotic/prebiotic treatments for atopic dermatitis, three on the effects of vitamins on children with atopic dermatitis, and two on the effects of Chinese herbal treatments for atopic dermatitis in children and adolescents. The strongest evidence was for supplementation with the probiotics L. fermentum and L. plantarum. CONCLUSIONS: Certain strains of probiotics, specifically L. plantarum and L. fermentum, may improve clinical severity scores in children with atopic dermatitis. However, additional trials are needed to more thoroughly delineate the effects of additional integrative therapies on childhood atopic dermatitis.

Topical and Oral Therapies for Childhood Atopic Dermatitis and Plaque Psoriasis.

BACKGROUND: Treatment of atopic dermatitis and psoriasis in children is difficult due to lack of standardized treatment guidelines and few FDA-approved treatment options. Treatments approved for adults may be used off-label in pediatric patients. OBJECTIVE: This review evaluates the topical and oral treatment options available, including off-label uses, and provides a basic therapeutic guideline for pediatric atopic dermatitis and psoriasis. METHODS: A PubMed review of topical and systemic treatments for pediatric psoriasis and atopic dermatitis with information regarding age, efficacy, dosing, contra-indications, adverse events, and off-label treatments. RESULTS: The search identified seven topical and five systemic treatments that are routinely employed to treat pediatric atopic dermatitis and psoriasis. LIMITATIONS: Standardized guidelines regarding treatment choice, dosing, and long-term safety are scarce. Reviews may be subject to ascertainment bias. CONCLUSIONS: Current treatment guidelines are based on clinical experience and expert advice with few treatments officially approved for atopic dermatitis and psoriasis in children.

Brain moderators supporting the relationship between depressive mood and pain.

Pain and depressive mood commonly exhibit a comorbid relationship. Yet, the brain mechanisms that moderate the relationship between dysphoric mood and pain remain unknown. An exploratory analysis of functional magnetic resonance imaging, behavioral, and psychophysical data was collected from a previous study in 76 healthy, nondepressed, and pain-free individuals. Participants completed the Beck Depression Inventory-II (BDI), a measure of negative mood/depressive symptomology, and provided pain intensity and pain unpleasantness ratings in response to noxious heat (49°C) during perfusion-based, arterial spin-labeled functional magnetic resonance imaging. Moderation analyses were conducted to determine neural mechanisms involved in facilitating the hypothesized relationship between depressive mood and pain sensitivity. Higher BDI-II scores were positively associated with pain intensity (R = 0.10; P = 0.006) and pain unpleasantness (R = 0.12; P = 0.003) ratings. There was a high correlation between pain intensity and unpleasantness ratings (r = 0.94; P < 0.001); thus, brain moderation analyses were focused on pain intensity ratings. Individuals with higher levels of depressive mood exhibited heightened sensitivity to experimental pain. Greater activation in regions supporting the evaluation of pain (ventrolateral prefrontal cortex; anterior insula) and sensory-discrimination (secondary somatosensory cortex; posterior insula) moderated the relationship between higher BDI-II scores and pain intensity ratings. This study demonstrates that executive-level and sensory-discriminative brain mechanisms play a multimodal role in facilitating the bidirectional relationship between negative mood and pain.

Neural mechanisms supporting the relationship between dispositional mindfulness and pain.

Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo analgesia, we sought to determine whether dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six meditation-naive and healthy volunteers completed the Freiburg Mindfulness Inventory and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher Freiburg Mindfulness Inventory ratings were associated with lower pain intensity (P = 0.005) and pain unpleasantness ratings (P = 0.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies.

Mindfulness Meditation for Fibromyalgia: Mechanistic and Clinical Considerations.

PURPOSE OF REVIEW: Fibromyalgia is a disorder characterized by widespread pain and a spectrum of psychological comorbidities, rendering treatment difficult and often a financial burden. Fibromyalgia is a complicated chronic pain condition that requires a multimodal therapeutic approach to optimize treatment efficacy. Thus, it has been postulated that mind-body techniques may prove fruitful in treating fibromyalgia. Mindfulness meditation, a behavioral technique premised on non-reactive sensory awareness, attenuates pain and improves mental health outcomes. However, the impact of mindfulness meditation on fibromyalgia-related outcomes has not been comprehensively characterized. The present review delineates the existing evidence supporting the effectiveness and hypothesized mechanisms of mindfulness meditation in treating fibromyalgia-related outcomes. RECENT FINDINGS: Mindfulness-based interventions premised on cultivating acceptance, non-attachment, and social engagement may be most effective in decreasing fibromyalgia-related pain and psychological symptoms. Mindfulness-based therapies may alleviate fibromyalgia-related outcomes through multiple neural, psychological, and physiological processes. Mindfulness meditation may provide an effective complementary treatment approach for fibromyalgia patients, especially when combined with other reliable techniques (exercise; cognitive behavioral therapy). However, characterizing the specific analgesic mechanisms supporting mindfulness meditation is a critical step to fostering the clinical validity of this technique. Identification of the specific analgesic mechanisms supporting mindfulness-based pain relief could be utilized to better design behavioral interventions to specifically target fibromyalgia-related outcomes.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT: Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.