Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.

Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network.

Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans.

High Frequency Migraine Is Associated with Lower Acute Pain Sensitivity and Abnormal Insula Activity Related to Migraine Pain Intensity, Attack Frequency, and Pain Catastrophizing.

Migraine is a pain disorder associated with abnormal brain structure and function, yet the effect of migraine on acute pain processing remains unclear. It also remains unclear whether altered pain-related brain responses and related structural changes are associated with clinical migraine characteristics. Using fMRI and three levels of thermal stimuli (non-painful, mildly painful, and moderately painful), we compared whole-brain activity between 14 migraine patients and 14 matched controls. Although, there were no significant differences in pain thresholds nor in pre-scan pain ratings to mildly painful thermal stimuli, patients did have aberrant suprathreshold nociceptive processing. Brain imaging showed that, compared to controls, patients had reduced activity in pain modulatory regions including left dorsolateral prefrontal, posterior parietal, and middle temporal cortices and, at a lower-threshold, greater activation in the right mid-insula to moderate pain vs. mild pain. We also found that pain-related activity in the insula was associated with clinical variables in patients, including associations between: bilateral anterior insula and pain catastrophizing (PCS); bilateral anterior insula and contralateral posterior insula and migraine pain intensity; and bilateral posterior insula and migraine frequency at a lower-threshold. PCS and migraine pain intensity were also negatively associated with activity in midline regions including posterior cingulate and medial prefrontal cortices. Diffusion tensor imaging revealed a negative correlation between fractional anisotropy (a measure of white matter integrity; FA) and migraine duration in the right mid-insula and a positive correlation between left mid-insula FA and PCS. In sum, while patients showed lower sensitivity to acute noxious stimuli, the neuroimaging findings suggest enhanced nociceptive processing and significantly disrupted modulatory networks, particularly involving the insula, associated with indices of disease severity in migraine.

Ilaj bil hijamah (cupping therapy) in the Unani system of medicine: anecdotal practice to evidence based therapy.

BACKGROUND: Cupping (Hijamah) therapy is very well documented as a result of several thousand years of clinical experiences in Unani medicine. In this procedure, suction is created by various means either with or without bloodletting. Though this therapy is being widely practiced across the globe for treating many chronic and intractable ailments but many reports reveal its unscientific and improper practices which results in many complications. Therefore to develop standard operative procedures and to propose protocols of cupping therapy in various diseases is the need of hour. MATERIALS AND METHODS: A thorough literature review of relevant journals and textbooks was performed to gather the maximum available data on cupping therapy. CONCLUSION: This paper seeks to introduce the general concepts of cupping therapy in Unani medicine and other traditional systems of medicine, shortcomings and limitations of the currently published studies and suggest ways to improve these technical/methodological flaws. In addition, the authors have also attempted to provide the cupping related materials, hypotheses, observations which will provide the researchers the base for evaluating their usefulness in future clinical trials.

Altered cognition-related brain activity and interactions with acute pain in migraine.

Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain-cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain-task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.

Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study.

Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.

Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome.

Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel-based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC-Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC-Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain-related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS.

Comparison of surgical and endovascular approach in management of spinal dural arteriovenous fistulas: A single center experience of 27 patients.

BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) is a rare spinal vascular malformation with an annual incidence of 5-10 cases per million. The data on efficacy, recurrence rates and complications of endovascular versus surgical treatment of SDAVF is limited. METHODS: We conducted a retrospective chart review of 27 adult patients with a diagnosis of SDAVF and who underwent treatment at Duke University Hospital between January 1, 1993 and December 31, 2012. We compared the outcome measures by Aminoff-Logue score (ALS) in patients who underwent treatment with endovascular embolization versus surgical ligation of fistula. We compared complication rates, recurrence rates as well as data on long-term follow up in these patients. RESULTS: Out of 27 patients in the study, 10 patients underwent endovascular embolization (Onyx was used in 5 patients and NBCA in 5 patients) as the first line therapy. Seventeen patients underwent surgical ligation as initial therapeutic modality. Patients in both groups showed significant improvement in clinical status (ALS) after treatment. One patient in endovascular group developed spinal infarction due to accidental embolization of medullary artery. Three patients in embolization group had recurrence of fistula during the course of follow up requiring surgical ligation. Two patients in surgical group developed local wound infection. None of the patients in surgical group had recurrence of fistula during the course of follow up. CONCLUSIONS: Endovascular embolization and surgical ligation are effective treatment strategies for SDAVF. Our observations show that surgical ligation may offer permanent cure without any recurrence. Endovascular approach is associated with higher incidence of recurrence, especially with use of onyx.

Perioperative cardiac complications and 30-day mortality in patients undergoing intracranial aneurysmal surgery with adenosine-induced flow arrest: a retrospective comparative study.

BACKGROUND: Adenosine-induced flow arrest is a technique used to assist in the surgical clipping of complex aneurysms. OBJECTIVE: To assess the safety associated with adenosine-assisted intracranial aneurysm surgery. METHODS: Medical records of all patients presenting between January 1, 2009, and December 31, 2012, for intracranial aneurysm surgery were analyzed. Patients were divided into 2 groups based on the intraoperative administration of adenosine: the nonadenosine group (n = 262) and the adenosine group (n = 64). The primary outcome compared between groups included a composite of 30-day mortality and incidences of perioperative cardiac complications (perioperative myocardial infarction or perioperative cardiac arrhythmias). RESULTS: The study groups were statistically similar except for a difference in the size and location of cerebral aneurysms and the incidence of coronary artery disease. The primary composite outcome occurred in 4.6% and 9.4% of patients in the nonadenosine and adenosine groups, respectively (P = .13). After adjustment for differences in the incidence of coronary artery disease between the 2 groups, the odds of the primary outcome were not significantly different between the groups (adjusted odds ratio = 2.12; 95% confidence interval, 0.76-5.93; P = .15). There were also no significant differences in the durations of hospital and intensive care unit stay between the study groups. CONCLUSION: Our results suggest that adenosine-assisted intracranial aneurysm surgery is not associated with an increase in perioperative cardiac complications or mortality in patients with low risk of coronary artery disease and may be considered a safe technique to assist clipping of complex aneurysms.

Altered Brain Structure and Function Correlate with Disease Severity and Pain Catastrophizing in Migraine Patients.

To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.

Effect of 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride (Voluven®) on complications after subarachnoid hemorrhage: a retrospective analysis.

BACKGROUND: 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride (Voluven®; 6% HES 130/0.4) is a colloid often used for fluid resuscitation in patients with subarachnoid hemorrhage (SAH), despite a lack of safety data for this use. The purpose of our study was to evaluate the effect of 6% HES 130/0.4 on major complications associated with SAH. METHODS: Medical records of all patients presenting between May 2010 and September 2012 with aneurysmal SAH were analyzed. Patients were divided in two groups based on the administration of 6% HES 130/0.4; HES group (n=57) and Non-HES group (n=72). The primary outcome included a composite of three major complications associated with SAH: Delayed Cerebral Ischemia (DCI), Hydrocephalus (HCP) requiring cerebrospinal fluid (CSF) shunting, and Rebleeding. RESULTS: The study groups were similar with respect to most characteristics except the incidences of hypertension, ischemic heart disease, Fisher grade and lowest hemoglobin during stay. The odds of developing the primary composite outcome was higher in the HES group [OR= 3.1(1.30-7.36), p=0.01]. The patients in the HES group had a significantly longer median duration of hospital (19 vs 14 days) and Neurointensive Care Unit stay (14 vs 10 days) compared to the Non HES group. CONCLUSION: We observed increased complications after SAH with 6% HES 130/0.4 (Voluven®) administration. An adequately powered prospective randomized controlled trial into the safety of 6% HES 130/0.4 in this patient population is warranted.

Impaired Histatin-5 Levels and Salivary Antimicrobial Activity against C. albicans in HIV Infected Individuals.

HIV-infected individuals constitute a population highly susceptible to opportunistic infections, particularly oral candidiasis caused by the most pathogenic human fungal species Candida albicans. Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro. However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV-infected individuals to candidiasis has not been previously investigated. To that end, a novel immunoassay was used to demonstrate significant decrease in salivary Hst-5 levels in HIV+ individuals concomitant with enhanced candidal prevalence. Further, saliva's anti-candidal potency was found to be proportional to Hst-5 concentration and significantly compromised in HIV+ subjects compared to controls. The key role for Hst-5 was further confirmed upon exposure to the Hst-5-specific antibody where saliva's initial killing activity was substantially compromised. Combined, these findings identify Hst-5 as a key anti-candidal salivary component and demonstrate its decreased levels in HIV infection providing new insights into oral Innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis.

Elemental distribution, solute solubility and defect free volume in nanocrystalline restricted-equilibrium Cu-Ag alloys.

In this article we study the elemental distribution and solute solubility in nanocrystalline alloys of immiscible components near restricted equilibrium for the case of the binary Cu-Ag system. As predicted from thermodynamic considerations, a grain boundary segregated monophase alloy is observed in the annealed mechanically alloyed state for low Ag content by using atom probe tomography. From the detected Ag solute grain boundary enrichment the segregation free enthalpy is estimated to range between -25 and -49 kJ mol(-1) following the McLean equation, in agreement with values reported for coarse-grained Cu-Ag. The extension of the alloying range is described by a two-domain thermodynamic model that considers the excess free volume in the grain boundaries and the strain in the grain interior on the basis of the universal equation of state at negative pressure. To access the grain boundary volumetric strain experimentally, a method based on a combination of density measurements and microscopical quantification of closed pore areas is presented. Moreover, we apply x-ray diffraction line broadening analysis to determine the local strain amplitude, which yields a root-mean-square microstrain of ~0.3% for a grain size of ~30 nm. It is shown that the grain boundary free volume represents the major origin for the global solubility enhancement in nanocrystalline Cu-Ag at 503 K.

A study of phase separated Ni66Nb17Y17 metallic glass using atom probe tomography.

Microstructural characterization of Ni(66)Nb(17)Y(17) as spun metallic glass ribbon was carried out using atom probe tomography. A comparison of different experimental conditions for pulsed laser and pulsed voltage field evaporation reveal that the laser pulsing can be optimized to avoid preferential evaporation of yttrium. Atom probe tomography measurements illustrate that the sample undergoes phase separation resulting in two interconnected phases during the process of vitrification. The yttrium-enriched phase was depleted in niobium and yttrium-depleted phase was enriched in niobium. Moreover, detailed analyses of the roller-contact and non-contact sides of the melt-spun ribbon show different wavelength of phase separated regions revealing that the degree of phase separation is directly associated with the cooling rate.

A systematic overview of the medicinal importance of sanguivorous leeches.

Leeches are a class of segmented invertebrates, known for their blood-feeding habits and used in phlebotomy to treat various ailments since antiquity. In Europe, medicinal leeches have recently been rediscovered and are used by maxillofacial and other microsurgeons to aid salvage of compromised venous engorged tissue and amputations, such as digits, ears, and nasal tips. Because of their important salivary components, blood-sucking (sanguivorous) leeches, such as Hirudo medicinalis and related species, have engendered great interest from pharmaceutical companies searching for anticoagulants to prevent blood clotting during microsurgeries. Scientific research reveals that the beneficial effects of leeching, in addition to decongestion, include injection of a cocktail of several medicinally useful bioactive molecules present in their saliva. Owing to its therapeutic potential, the research is continuing as many new salivary compounds are being isolated and synthesized.

Large aneurysmal bone cyst of iliac bone in a female child: a case report.

BACKGROUND: Symptomatic aneurysmal bone cysts in pediatric age group with an expansile lesion in ilium is a rare occurrence. CASE: An 11-year-old female presented with a swelling over her right iliac region and numbness along the medial aspect of thigh. Clinicoradiological diagnosis was aneurysmal bone cyst confirmed on fine needle aspiration cytology. Excision curettage (wide margin excision of the soft tissue tumor and intralesional curettage in the region of acetabulum) of the tumor was performed in view of proximity to acetabular roof and endangered hip stability. RESULT: At follow up of 18 months, the child has full painless range of movements in the hip joint with no recurrence. CONCLUSIONS: Pelvic aneurysmal bone cysts are distinctly rare in pediatric age. The lesion was associated with an atypical symptom of numbness along the femoral nerve distribution. Hip stability and range of movements were major concern in this patient. Although many treatment options are described, surgical excision still remains the mainstay. In our case, we performed excision curettage, with good outcome.