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Impaired Pain Processing at a Brainstem Level Is Involved in Maladaptive Neuroplasticity in Patients with Chronic Complex Regional Pain Syndrome.

Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen's d: 1.3; = 0.012) and the non-stimulated side (Cohen's d: 1.1; = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis.

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Keloid disease: Review with clinical atlas. Part I: Definitions, history, epidemiology, clinics and diagnosis.

Keloids are chronic progressive dermal pseudo-tumors that can grow considerably in volume and surface area but do not invade other tissues. They are usually triggered by dermal injury or inflammation, but they are not scars in the normal sense of the word, since they enlarge and progress over decades. The phenomenon usually referred to as "hypertrophic scars" represents a kind of keloidal process that does not extend beyond the initial site of injury and spontaneously regresses in 12-24 months. The multiplication of keloids and hypertrophic scars in a single patient is known as keloid disease. Keloid disease is due to a familial predisposition (autosomal dominant) that preferentially affects people of non-European ancestry, especially those of sub-Saharan African descent. Keloid disease has a deep impact on quality of life, not only because of disfiguring lesions, but also because of the frequency of associated intense neurogenic pruritus and pain, as well as recurrent bouts of suppuration. Diagnosis relies primarily on a good knowledge of the clinical characteristics of keloids, thus warranting the inclusion of a clinical atlas in the first part of the review. The second part will deal with the pathology, pathophysiology and treatment of keloid disease.

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Resting-state Quantitative EEG Spectral Patterns in Migraine During Ictal Phase Reveal Deviant Brain Oscillations: .

Migraine headache may have a substantial bearing on the brain functions and rhythms. Electrophysiological methods can detect changes in brain oscillation. The present work examined the frequency band power through quantitative electroencephalogram (qEEG) and density spectral array (DSA) to elucidate the resting state neuronal oscillations in migraine. Clinical details were inquired, and EEG was recorded in migraineurs and healthy controls. The acquired data were analyzed to determine power spectral density values and obtain DSA graphs. The absolute and relative powers for the alpha, theta, and delta frequencies in frontocentral, parieto-occipital, and temporal regions were determined. A correlation of significant EEG findings with clinical features of migraine was sought. Forty-five participants were enrolled in the study. The spectrum analysis revealed an increase in the relative theta power ( < .001) and a reduction in relative alpha power ( < .001) in the observed cortical areas among the migraineurs as compared to the healthy controls. Relative delta power was increased over the frontocentral region ( = .001), slightly more on the symptomatic side of the head. In addition, frontocentral delta power had a moderate positive correlation (r = .697, n = 22,  = .000) with migraine severity. The study supports the evidence of a neuronal dysfunction existing in the resting state during the ictal phase of migraine. qEEG can reveal these aberrant oscillations. Utility of DSA to depict the changes in brain activity in migraine is a potential area for research. The information can help formulate new therapeutic strategies towards alteration in cortical excitability using brain stimulation techniques.

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Emodin Alleviates Arthritis Pain through Reducing Spinal Inflammation and Oxidative Stress.

Chronic pain is the predominant problem for rheumatoid arthritis patients, and negatively affects quality of life. Arthritis pain management remains largely inadequate, and developing new treatment strategies are urgently needed. Spinal inflammation and oxidative stress contribute to arthritis pain and represent ideal targets for the treatment of arthritis pain. In the present study, collagen-induced arthritis (CIA) mouse model was established by intradermally injection of type II collagen (CII) in complete Freund's adjuvant (CFA) solution, and exhibited as paw and ankle swelling, pain hypersensitivity and motor disability. In spinal cord, CIA inducement triggered spinal inflammatory reaction presenting with inflammatory cells infiltration, increased IL-1β expression, and up-regulated NLRP3 and cleaved caspase-1 levels, elevated spinal oxidative level presenting as decreased Nrf2 expression and SOD activity. To explore potential therapeutic options for arthritis pain, emodin was intraperitoneally injected for three days on CIA mice. Emodin treatment statistically elevated mechanical pain sensitivity, suppressed spontaneous pain, recovered motor coordination, decreased spinal inflammation scores and expression levels of IL-1β, increased spinal Nrf2 expression and SOD activity. Further, AutoDock data showed that emodin bind to AMPK through two electrovalent bonds. And emodin treatment increased the phosphorylated AMPK at threonine 172. In summary, emodin treatment activates AMPK, suppresses NLRP3 inflammasome response, elevates antioxidant response, inhibits spinal inflammatory reaction and alleviates arthritis pain.

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Association of pain and quality of life among middle-aged and older adults of India.

India is passing through a phase of demographic and epidemiological transition where ageing and chronic morbidities are being more common. Though studies have examined the prevalence and risk factors of pain and other chronic morbidities, nationally representative research examining the association of pain and quality of life (QoL) is limited in India. This study examines the association between pain and QoL among middle-aged and older adults in India.

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Exploring combat stress exposure effects on burn pain in a female rodent model.

In the military, constant physiological and psychological stress encountered by Soldiers can lead to development of the combat and operational stress reaction (COSR), which can effect pain management. Similar effects are seen in other populations subjected to high levels of stress. Using a model of COSR, our lab recently showed that four weeks of stress prior to an injury increases pain sensitivity in male rats. With the roles of women in the military expanding and recent studies indicating sex differences in stress and pain processing, this study sought to investigate how different amounts of prior stress exposure affects thermal injury-induced mechanosensitivity in a female rat model of COSR. Adult female Sprague Dawley rats were exposed to the unpredictable combat stress (UPCS) procedure for either 2 or 4 weeks. The UPCS procedure included exposure to one stressor each day for four days. The stressors include: (1) sound stress for 30 min, (2) restraint stress for 4 h, (3) cold stress for 4 h, and (4) forced swim stress for 15 min. The order of stressors was randomized weekly. Mechanical and thermal sensitivity was tested twice weekly. After the UPCS procedure, a sub-set of rats received a thermal injury while under anesthesia. The development of mechanical allodynia and thermal hyperalgesia was examined for 14 days post-burn. UPCS exposure increased mechanosensitivity after two weeks. Interestingly, with more stress exposure, females seemed to habituate to the stress, causing the stress-induced changes in mechanosensitivity to decrease by week three of UPCS. If thermal injury induction occurred during peak stress-induced mechanosensitivity, after two weeks, this resulted in increased mechanical allodynia in the injured hind paw compared to thermal injury alone. This data indicates a susceptibility to increased nociceptive sensitization when injury is sustained at peak stress reactivity. Additionally, this data indicates a sex difference in the timing of peak stress. Post-mortem examination of the prefrontal cortex (PFC) showed altered expression of p-TrkB in 4-week stressed animals given a thermal injury, suggesting a compensatory mechanism. Future work will examine treatment options for preventing stress-induced pain to maintain the effectiveness and readiness of the Warfighter.

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Microbiota-Pain Association; Recent Discoveries and Research Progress.

The relationship between gut microbiota and pain, such as visceral pain, headaches (migraine), itching, prosthetic joint infection (PJI), chronic abdominal pain (CAP), joint pain, etc., has received increasing attention. Several parts of the evidence suggest that microbiota is one of the most important pain modulators and they can regulate pain in the central and peripheral nervous systems. Any alteration in microbiota by diet or antibiotics mediation may characterize a novel therapeutic strategy for pain management. The present study includes the most up-to-date and influential scientific findings on the association of microbiota with pain, despite the fact that the underlying mechanism is not identified in most cases. According to recent research, identifying the molecular mechanisms of the microbiota-pain pathway can have a unique perspective in treating many diseases, even though there is a long way to reach the ideal point. This study will stress the influence of microbiota on the common diseases that can stimulate the pain with a focus on underlying mechanisms.

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Melancholia as psychalgia: the integration of psychophysiological theory and psychopathologic observation in the mid-19th century.

While sufferers of major depression to the present day sometimes describe their experience as "mental pain," limited attention has been given to one of the major etiologic theories of 19th century psychiatry: melancholia as psychalgia. I illustrate the development of this theory, which arose in the context of the early phases of the application of psychophysiology to mental illness, through German, French, and English psychiatric texts from the 1830-1870s. As clinical pathological correlation became a dominant paradigm in early 19th medicine, nervous diseases stood out as potential exceptions, sometimes demonstrating "pain without lesions" or neuralgia. Tic Douloureux was a paradigmatic example. The first descriptions of reflex actions in the spinal cord in the early 19th century resulted in a range of theories of reflexes in brain that expanded to include "ganglia" that could react to diverse complex social and mental stimuli, and whose actions could impact key mental functions including mood. Theories of neuralgia included a constitutional predisposition and an acute physical trauma producing a hypersensitivity so that normal stimuli (e.g., touch) were misinterpreted as excruciating pain. A parallel framework was conceptualized in the brain to produce psychalgia. A predisposition combined with a mental trauma could produce hypersensitivity in key brain ganglia. This psychophysiological framework explained how normal social and introspective experiences would, in melancholic patients, be interpreted in a distorted manner, reinforcing themes of inadequacy, failure, and worthlessness, and produce a sustained mood state of intense mental pain or psychalgia. I illustrate the development of this theory, which integrated brain and mind-based perspectives on mental illness, through the writings of four major 19th alienists: Guislain, Griesinger, Maudsley, and Krafft-Ebing.

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Atraumatic spinal needle indicates correct CSF opening pressure.

The accurate assessment of cerebrospinal fluid opening pressure during spinal puncture provides important medical information in diagnosis, prognosis and therapy of several neurological conditions. However, purpose-specific spinal needle choice is debated. While atraumatic needles are associated with lower incidence of post-puncture headache and re-hospitalisation, some clinicians believe that they lack in accuracy of CSF opening pressure assessment. Our primary objective was to investigate different needle types on correctly assessing CSF opening pressure. We compared typical clinically utilised traumatic (0.9 mm outer diameter) and atraumatic (0.7 mm; 0.45 mm) spinal needles with regards to the assessment of the opening pressure in an experimental spinal puncture model testing experimental and cerebrospinal fluids in predefined pressures. Our goal was to measure the time until indicated pressure levels were correctly shown. Atraumatic needles of at least 0.7 mm diameter had a similar accuracy as traumatic needles without significant differences in time-to-equilibrium. These results were independent of protein and glucose concentration and the presence of haemoglobin. This study demonstrates that atraumatic needles can be used to accurately measure CSF opening pressure. This knowledge might guide clinicians in their choice of needle and help to reduce post-puncture headaches and re-hospitalisation.

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Function of excitatory periaqueductal grey synapses in the ventral tegmental area following inflammatory injury.

Manipulating the activity of ventral tegmental area dopamine (VTA DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal grey (PAG), a nexus of ascending pain information. We tested whether PAG-VTA synapses undergo functional plasticity in response to a pain model using optical stimulation in conjunction with slice electrophysiology. We found that acute carrageenan inflammation does not significantly affect the strength of excitatory PAG synapses onto VTA DA neurons. However, at the PAG synapses on VTA GABA neurons, the subunit composition of NMDA receptors is altered; the complement of NR2D subunits at synaptic sites appears to be lost. Thus, our data support a model in which injury initially alters synapses on VTA GABA neurons. Over time, these alterations may increase tonic inhibition of VTA DA neurons leading to their reduced firing.Following a focal injury, the firing rate of dopamine neurons of the ventral tegmental area (VTA) decreases, despite a lack of direct innervation from the periphery. Here we assess the functional changes between a primary node of nociceptive output, the periaqueductal gray (PAG), and the VTA after peripheral inflammation. We find that synaptic strength at PAG-to-VTA dopamine neuron synapses is unaffected following inflammatory injury, but find a change in subunit composition of NMDARs at PAG synapses on the inhibitory neurons of the VTA.

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