Inflammation induces α1-adrenoceptor expression in peripheral blood mononuclear cells of patients with complex regional pain syndrome.

Persistent regional and systemic inflammation may promote pain and hyperalgesia in complex regional pain syndrome (CRPS). In this study, we investigated whether stimulation of α1-adrenoceptors (α1-AR) on peripheral blood mononuclear cells (PBMC) might contribute to this inflammatory state. PBMC were isolated from venous blood collected from 21 CRPS patients and 21 sex and age-matched controls. Lipopolysaccharide (LPS), a bacterial toxin, was administered to cultured PBMC for 24 h to trigger inflammation. Exposure to LPS resulted in heightened gene expression of α1-AR subtype B (α1B-AR) in PBMC of CRPS patients relative to controls. Interleukin (IL)-1ß and IL-6 levels did not change when the α1-AR agonist phenylephrine was administered to naïve PBMC. However, α1-AR stimulation following LPS treatment increased IL-6 mRNA and protein levels in PBMC of patients and controls. To investigate the possible consequence of heightened IL-6 levels on immunoglobulin G antibody production, PBMC were stimulated with CD40 ligand and IL-21 to generate plasmablasts (B cells that secrete antibodies). This response was similar in patients and controls. Adding IL-6 to the cell culture medium increased plasmablast differentiation in controls and antibody production both in patients and controls. These findings suggest that the inflammatory cascade associated with elevated levels of IL-6 may generate α1B-AR expression in CRPS PBMC. A reciprocal interaction between heightened α1-AR expression in PBMC and IL-6 secretion may contribute to systemic inflammation and antibody production in CRPS.

Olfaction in Complex Regional Pain Syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is associated with a range of sensory disturbances on the symptomatic side of the body but whether this includes olfaction is uncertain. To clarify this, the aims of this study were to compare ratings of intensity and hedonic appeal of household odorants in CRPS patients and controls, and to determine whether ratings differed between the symptomatic and contralateral sides within the sample of patients. METHODS: Six odorants (vanilla, fish sauce, vinegar, eucalyptus, almond essence and acetone) were presented sequentially in random order on cottonwool buds held in the midline approximately 1 cm from both nostrils in 37 CRPS patients and 21 pain-free controls. Each odor was rated for intensity and hedonic appeal, and participants reported whether the odor was stronger and/or smelt different on one side than the other. RESULTS: The odorants smelt worse for patients than controls (P < .05 for the symptomatic and contralateral sides) but neither the intensity nor the unpleasantness of the odorants was greater on the symptomatic than contralateral side in the group as-a-whole. CONCLUSIONS: These findings suggest that the trigeminal component of olfaction interacts bilaterally with pain-sensitized circuits in the thalamus or higher cortical centers to distort odor perception in patients with CRPS. This aberrant process appears to differ from the mechanism that underlies hemilateral hyperalgesia in other sensory modalities.

A Macroscopic Quantum Three-Box Paradox: Finding Consistency with Weak Macroscopic Realism.

The quantum three-box paradox considers a ball prepared in a superposition of being in any one of three boxes. Bob makes measurements by opening either box 1 or box 2. After performing some unitary operations (shuffling), Alice can infer with certainty that the ball was detected by Bob, regardless of which box he opened, if she detects the ball after opening box 3. The paradox is that the ball would have been found with certainty by Bob in either box if that box had been opened. Resolutions of the paradox include that Bob's measurement cannot be made non-invasively or else that realism cannot be assumed at the quantum level. Here, we strengthen the case for the former argument by constructing macroscopic versions of the paradox. Macroscopic realism implies that the ball is in one of the boxes prior to Bob or Alice opening any boxes. We demonstrate the consistency of the paradox with macroscopic realism, if carefully defined (as weak macroscopic realism, wMR) to apply to the system at the times prior to Alice or Bob opening any boxes but after the unitary operations associated with preparation or shuffling. By solving for the dynamics of the unitary operations and comparing with mixed states, we demonstrate agreement between the predictions of wMR and quantum mechanics: the paradox only manifests if Alice's shuffling combines both local operations (on box 3) and nonlocal operations, on the other boxes. Following previous work, the macroscopic paradox is shown to correspond to a violation of a Leggett-Garg inequality, which implies failure of non-invasive measurability if wMR holds.

Phase-space simulations of feedback coherent Ising machines.

A new, to the best of our knowledge, technique is demonstrated for carrying out exact positive-P phase-space simulations of the coherent Ising machine quantum computer. By suitable design of the coupling matrix, general hard optimization problems can be solved. Here, computational quantum simulations of a feedback type of photonic parametric network are carried out, which is the implementation of the coherent Ising machine. Results for success rates are obtained using this scalable phase-space algorithm for quantum simulations of quantum feedback devices.

Painful diabetic peripheral neuropathy: Role of oxidative stress and central sensitisation.

AIMS: Diabetic peripheral neuropathy (DPN) occurs in about half of people with diabetes, of whom a quarter may develop chronic pain. Pain may remain for years yet be difficult to treat because the underlying mechanisms remain unclear. There is consensus that processing excessive glucose leads to oxidative stress, interfering with normal metabolism. In this narrative review, we argue that oxidative stress may also contribute to pain. METHODS: We reviewed literature in PubMed published between January 2005 and August 2021. RESULTS AND CONCLUSIONS: In diabetes, hyperglycaemia and associated production of reactive species can directly increase pain signalling and activate sensory neurons; or the effects can be indirect, mediated by mitochondrial damage and enhanced inflammation. Furthermore, pain processing in the central nervous system is compromised in painful DPN. This is implicated in central sensitisation and dysfunctional pain modulation. However, central pain modulatory function is understudied in diabetes. Future research is required to clarify whether central sensitisation and/or disturbances in central pain modulation contribute to painful DPN. Positive results would facilitate early detection and future treatment.

Co-morbidity between trigeminal autonomic cephalalgias and complex regional pain syndrome: Two case reports.

BACKGROUND: Trigeminal autonomic cephalalgias and complex regional pain syndrome are rare conditions, and their co-occurrence has not been reported previously.Clinical findings: In two patients, ipsilateral trigeminal autonomic cephalalgias developed after the onset of upper limb complex regional pain syndrome. Hyperalgesia to thermal and mechanical stimuli extended beyond the affected limb to encompass the ipsilateral forehead, and was accompanied by ipsilateral hyperacusis and photophobia. In addition, examination of the painful limb and bright light appeared to aggravate symptoms of trigeminal autonomic cephalalgias. Detailed examination of the association between facial and upper limb pain indicated that both sources of pain cycled together. Furthermore, in one case, stellate ganglion blockade inhibited pain for an extended period not only in the affected limb but also the face. CONCLUSIONS: These findings suggest some overlap in the pathophysiology of complex regional pain syndrome and trigeminal autonomic cephalalgias. Specifically, central sensitization and/or disruption of inhibitory pain modulation on the affected side of the body in complex regional pain syndrome might trigger ipsilateral cranial symptoms and increase vulnerability to trigeminal autonomic cephalalgias.

Modulation of the hypothalamic-pituitary-adrenal (HPA) axis by plants and phytonutrients: a systematic review of human trials.

INTRODUCTION: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response. Plants, herbs, spices, and plant-based nutrients may influence HPA-axis activity. OBJECTIVE: To evaluate randomised controlled, human trials assessing the effects of single plants or phytonutrients on HPA-axis related hormones. METHODS: A systematic review of PubMed, Cochrane library, and the Cumulative Index to Nursing and Allied Health Literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria comprised of human, randomised controlled studies with a control intervention examining the effects of a single herb, spice, plant, or extract on pre- and post-changes in blood, saliva, urine, or hair concentrations of cortisol, cortisone, corticotrophin-releasing hormone, or adrenocorticotropic hormone. Databases were searched from inception until October 2020. RESULTS: Fifty-two studies were identified examining the effects of ashwagandha, Korean ginseng, St John's Wort, cannabidiol, Rhodiola rosea, curcumin, cherry juice, asparagus, Jiaogulan, Black cohosh, Siberian ginseng, Bacopa monnieri, blueberries, green tea, Caralluma fimbriata, cashew apple juice, melon, American ginseng, Ginkgo biloba, grape juice, grapefruit juice, rosella, hops, mangosteen, holy basil, and pomegranate juice. Due to significant variability in study designs, the effect of phytonutrients on HPA-axis activity in humans was unclear. The most consistent finding was a morning, cortisol-lowering effect from ashwagandha supplementation. CONCLUSION: For most phytonutrients, the effects of supplementation on HPA-axis activity in humans is unclear. Before more definitive conclusions about the effects of phytonutrients on the HPA-axis can be made, further research is required.

Reduced SMA-M1 connectivity in older than younger adults measured using dual-site TMS.

With advancing age comes a decline in voluntary movement control. Growing evidence suggests that an age-related decline in effective connectivity between the supplementary motor area and primary motor cortex (SMA-M1) might play a role in an age-related decline of bilateral motor control. Dual-site transcranial magnetic stimulation (TMS) can be used to measure SMA-M1 effective connectivity. In the current study, we aimed to (1) replicate previous dual-site TMS research showing reduced SMA-M1 connectivity in older than younger adults and (2) examine whether SMA-M1 connectivity is associated with bilateral motor control in independent samples of younger (n = 30) and older adults (n = 30). SMA-M1 connectivity was measured using dual-site TMS with interstimulus intervals of 6, 7 and 8 ms, and bilateral motor control was measured using the Purdue Pegboard, Four Square Step Test and the Timed Up and Go task. Findings from this study showed that SMA-M1 connectivity was reduced in older than in younger adults, suggesting that the direct excitatory connections between SMA and M1 had reduced efficacy in older than younger adults. Furthermore, greater SMA-M1 connectivity was associated with better bimanual motor control in older adults. Thus, SMA-M1 connectivity in older adults might underpin, in part, the age-related decline in bilateral motor control. These findings contribute to our understanding of age-related declines in motor control and provide a physiological basis for the development of interventions to improve bimanual and bilateral motor control.

A positive feedback loop between alpha1-adrenoceptors and inflammatory cytokines in keratinocytes.

A positive feedback loop between inflammatory cytokines and alpha1-adrenoceptors (α1-AR) (a target of the sympathetic nervous system neurotransmitter norepinephrine) influences inflammatory responses in immune cells. This cross-talk between the sympathetic nervous system and immune system may play a role in promoting chronic inflammation. Emerging evidence shows that α1-AR interact with inflammatory cytokines in keratinocytes, and this epidermal adrenergic signalling may contribute to skin inflammatory responses following injury, disease or stress. In this study, utilizing an in vitro approach, we hypothesized that α1-AR interact in a positive feedback loop with inflammatory mediators in keratinocytes. The pro-inflammatory cytokine tumor necrosis factor α (TNFα) was used to induce an inflammatory state in cultured keratinocytes. TNFα increased interleukin (IL)-1ß, IL-6, IL-8 and nerve growth factor (NGF) production and gene expression levels of α1-AR subtype B (α1B-AR). Additional stimulation of α1-AR further increased IL-6 levels, while maintaining high levels of IL-8 and decreasing levels of IL-1ß and NGF. Our results suggest that reciprocal influences between α1-ARs and inflammatory cytokines may play a role in normal inflammatory responses. However, if unchecked, this cycle could contribute to pathology (e.g. chronic inflammatory diseases, chronic pain conditions, and stress-induced cancer progression).

Objective Quantum Fields, Retrocausality and Ontology.

We compare different approaches to quantum ontology. In particular, we discuss an interpretation of quantum mechanics that we call objective quantum field theory (OQFT), which involves retrocausal fields. Here, objective implies the existence of fields independent of an observer, but not that the results of conjugate measurements are predetermined: the theory is contextual. The ideas and analyses of Einstein and Bohr through to more recent approaches to objective realism are discussed. We briefly describe measurement induced projections, the guided wave interpretation, many-universes, consistent histories and modal theories. These earlier interpretations are compared with OQFT. We argue that this approach is compatible both with Bohr's quantum complementarity and Einstein's objective realism.

Tumor necrosis factor α induces α1B-adrenergic receptor expression in keratinocytes.

Keratinocytes produce cytokines and nerve growth factor (NGF) as part of a repair response to injury, disease or stress, and express alpha1-adrenoceptors (α1-AR). The expression of these receptors is elevated in some inflammatory diseases and chronic pain conditions. In this study, we investigated whether inflammatory signalling affects α1-AR expression in keratinocytes in vitro. Tumor necrosis factor α (TNFα) was administered to human keratinocytes, after which the levels of other key pro-inflammatory cytokines and NGF were measured. The production of these cytokines and NGF increased in cells treated with TNFα compared to untreated cells. Furthermore, exposure to TNFα increased gene expression of the α1-AR subtype B in keratinocytes. Our results suggest that inflammatory cytokines released during injury stimulate α1-AR expression in keratinocytes. The up-regulation of α1-AR may amplify the adrenergic sensitivity of these cells to catecholamines released during sympathetic nervous system activation after injury which, in turn, could heighten the inflammatory response.

Treatment Options for Fear of Blushing.

PURPOSE OF REVIEW: To review mechanisms of blushing and fear of blushing from physiological, neuropharmacological and psychological viewpoints, and to evaluate current forms of treatment for blushing-related fear. RECENT FINDINGS: Blushing appears to be driven primarily by sympathetic adrenomedullary and neural vasodilator discharge, possibly in association with secondary neurovascular inflammation. Psychological risk factors for fear of blushing include social anxiety, coupled with heightened self-focused attention and inflated beliefs about the likelihood and social costs of blushing. In addition, schemas of emotional inhibition, social isolation and alienation may underlie blushing-related fears. Established psychological treatments for fear of blushing include task concentration training, exposure, cognitive therapy, social skills training, psychoeducation and applied relaxation. More novel approaches include mindfulness and mindful self-compassion, video feedback and imagery rescripting. There are no established pharmacological treatments specifically for fear of blushing. However, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are effective treatments for social anxiety disorder and may thus help some patients manage their fear of blushing. A reactive sympathetic nervous system may interact with psychological predispositions to intensify fear of blushing. These physiological and psychological risk factors could be promising targets for treatment.

Expression of Cutaneous Beta-2 Adrenoceptors Is Similar in Patients with Complex Regional Pain Syndrome and Pain-Free Controls.

OBJECTIVE: Studies in rodents suggest that cutaneous beta-2 adrenoceptors (ß2-ARs) mediate inflammation and pain after tissue injury and that inflammation and peripheral nerve injury trigger increases in neuronal ß2-AR expression. Hence, the aim of this study was to investigate the expression of ß2-ARs on keratinocytes and dermal nerves in patients with complex regional pain syndrome (CRPS). DESIGN, SETTING, AND SUBJECTS: Fifty-eight patients with CRPS were recruited for this study. In addition, skin biopsies were obtained from 13 pain-free women and three pain-free men of similar age and sex distribution as the patients. METHODS: Quantitative sensory tests for assessing sensitivity to pressure, pinprick, light touch, heat, and cold were administered, and skin biopsies were obtained from the affected and contralateral limbs. Skin biopsies were also obtained from a similar site on the dorsal hand or foot of pain-free controls. Immunohistochemistry and confocal microscopy were used to identify ß2-ARs on keratinocytes, dermal nerves, and blood vessels in the skin samples. RESULTS: The distribution of ß2-ARs in keratinocytes and nerves was similar in the affected and contralateral limbs of patients and was similar for target cells in patients and controls. However, elevated ß2-AR expression in reticular nerve bundles was associated with heightened sensitivity to heat pain. CONCLUSIONS: These findings do not support a major role of cutaneous ß2-ARs in CRPS. However, activation of neuronal ß2-ARs may contribute to thermal hyperalgesia in a subgroup of patients. Whether activation of ß2-ARs on keratinocytes mediates inflammation early in the course of CRPS requires further investigation.

Herbal treatments for migraine: A systematic review of randomised-controlled studies.

Herbal treatments are often used as a treatment for migraine. Therefore, an evaluation of their safety and efficacy is important. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and Cochrane Collaboration's tool for assessing the risk of bias, a systematic literature review of randomised, controlled human trials assessing the effects of herbal treatments delivered as a single ingredient for the acute or prophylactic treatment of migraine were conducted. Studies were identified through electronic database searches on Medline (Pubmed), Cochrane Library, Scopus, and CINAHL. Nineteen studies were identified examining the effects on migraine of feverfew, butterbur, curcumin, menthol/peppermint oil, coriander, citron, Damask rose, chamomile, and lavender. Overall, findings on the efficacy of feverfew were mixed and there was positive, albeit limited evidence for butterbur. There were positive, preliminary findings on curcumin, citron, and coriander as a prophylactic treatment for migraine, and the use of menthol and chamomile as an acute treatment. However, the risk of bias was high for many studies. The results of this systematic review suggest that several herbal medicines, via their multifactorial physiological influences, present as potential options to enhance the treatment of migraine. However, further high-quality research is essential to examine their efficacy and safety as a treatment for migraine.

Reduction in Migraine and Headache Frequency and Intensity With Combined Antioxidant Prophylaxis (N-acetylcysteine, Vitamin E, and Vitamin C): A Randomized Sham-Controlled Pilot Study.

OBJECTIVE: To investigate the preventive effects of a combined antioxidant drug (N-acetylcysteine, vitamin E, and vitamin C [NEC]) on migraine outcomes. Migraine is characterized by increased oxidative stress and neurogenic inflammation in the brain; therefore, antioxidants may have a migraine preventive effect. DESIGN: Randomized, double-blind, sham-controlled pilot study. SETTING: Australian community. SUBJECTS: Adults reporting 2 to 8 migraines per month for at least a year. METHODS: After a 1-month baseline period, 35 subjects completed 3 months of treatment with NEC (n = 19) or sham (n = 16) capsules. The primary outcome was the difference in mean number of headaches per month between baseline and final month of the trial for NEC and sham groups; secondary outcomes are listed below. RESULTS: For NEC there was a significant decrease in mean number of headaches by 3.0 per month (P = 0.004) compared with 1.4 for sham (P = 0.073); there was no significant difference in these changes between the 2 groups (P = 0.052). Average monthly headache (P = 0.041) and migraine frequency (P = 0.018) were significantly less for NEC vs. sham. In NEC subjects, there was a significant decrease in average monthly migraine days (-3.1), moderate/severe headache days (-3.2), migraine duration, headache pain scores, and acute headache medication use. CONCLUSIONS: This is the first randomized controlled trial to find that combined antioxidant therapy with NEC reduces headaches and migraines in adult migraineurs. Given the limitations of this pilot study, an adequately powered randomized controlled trial is planned to further investigate antioxidant prophylaxis in migraine.

Quantum fidelity measures for mixed states.

Applications of quantum technology often require fidelities to quantify performance. These provide a fundamental yardstick for the comparison of two quantum states. While this is straightforward in the case of pure states, it is much more subtle for the more general case of mixed quantum states often found in practice. A large number of different proposals exist. In this review, we summarize the required properties of a quantum fidelity measure, and compare them, to determine which properties each of the different measures has. We show that there are large classes of measures that satisfy all the required properties of a fidelity measure, just as there are many norms of Hilbert space operators, and many measures of entropy. We compare these fidelities, with detailed proofs of their properties. We also summarize briefly the applications of these measures in teleportation, quantum memories and quantum computers, quantum communications, and quantum phase-space simulations.

Robustness of quantum Fourier transform interferometry.

We analyze the effect of decoherence and noise on quantum Fourier transform interferometry, in which a boson sampling photonic network is used to measure optical phase gradients. This novel type of metrology is shown to be robust against phase decoherence. One can also measure gradients using lower-order correlations without substantial degradation. Our results involve the estimation of up to a 100×100 matrix permanent.

Nonlocal Pair Correlations in a Higher-Order Bose Gas Soliton.

The truncated Wigner and positive-P phase-space representations are used to study the dynamics of a one-dimensional Bose gas. This allows calculations of the breathing quantum dynamics of higher-order solitons with 10^{3}-10^{5} particles, as in realistic Bose-Einstein condensation experiments. Although classically stable, these decay quantum mechanically. Our calculations show that there are large nonlocal correlations and nonclassical quantum entanglement.

Complex regional pain syndrome: a focus on the autonomic nervous system.

PURPOSE: Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance. METHODS: We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain. RESULTS: The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. CONCLUSIONS: We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.

Painful stimulation of a sensitized site in the forearm inhibits ipsilateral trigeminal nociceptive blink reflexes.

Exposure to moderate levels of ultraviolet B radiation (UVB) is painless but nevertheless induces an inflammatory response that sensitizes primary afferent nociceptors. Subsequently, heating the UVB-treated site can sensitize spinal nociceptors. We used a repeated-measures design to determine whether heating the UVB-treated site also triggers ipsilateral inhibitory controls. Specifically, a 2-cm diameter site on the forearm of 20 participants was exposed to UVB at twice the minimum erythema dose. 48 h later mechanical and thermal sensitivity had increased at the UVB-treated site, indicating primary hyperalgesia. In addition, sensitivity to blunt pressure had increased in the ipsilateral forehead, implying activation of an ipsilateral supra-spinal pro-nociceptive mechanism. Despite this, the area under the curve of the ipsilateral nociceptive blink reflex decreased when the UVB-treated site was heated to induce moderate pain. Together, these findings suggest that the UVB treatment sensitized primary nociceptive afferents and generated an ipsilateral supra-spinal pro-nociceptive mechanism. In addition, sensitization to heat induced by the UVB treatment strengthened an ipsilateral anti-nociceptive process elicited by heat-pain. Infrequent but enduring discharge of sensitized primary nociceptive afferents, driven by inflammation after UVB exposure, might initiate a lateralized supra-spinal pro-nociceptive influence that heightens awareness of impending harm on the sensitized side of the body. In addition, a lateralized anti-nociceptive response triggered by an intense barrage of nociceptive signals may help to differentiate stronger from weaker sources of pain.