Circadian Effects on Vascular Immunopathologies.

Circadian rhythms exert a profound impact on most aspects of mammalian physiology, including the immune and cardiovascular systems. Leukocytes engage in time-of-day-dependent interactions with the vasculature, facilitating the emigration to and the immune surveillance of tissues. This review provides an overview of circadian control of immune-vascular interactions in both the steady state and cardiovascular diseases such as atherosclerosis and infarction. Circadian rhythms impact both the immune and vascular facets of these interactions, primarily through the regulation of chemoattractant and adhesion molecules on immune and endothelial cells. Misaligned light conditions disrupt this rhythm, generally exacerbating atherosclerosis and infarction. In cardiovascular diseases, distinct circadian clock genes, while functioning as part of an integrated circadian system, can have proinflammatory or anti-inflammatory effects on these immune-vascular interactions. Here, we discuss the mechanisms and relevance of circadian rhythms in vascular immunopathologies.

Automated slice-specific z-shimming for functional magnetic resonance imaging of the human spinal cord.

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.

Parallel cortical-brainstem pathways to attentional analgesia.

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand.

Realization of thin-film m-plane InGaN laser diode fabricated by epitaxial lateral overgrowth and mechanical separation from a reusable growth substrate.

A nonpolar edge emitting thin film InGaN laser diode has been separated from its native substrate by mechanical tearing with adhesive tape, combining the benefits of Epitaxial Lateral Overgrowth (ELO) and cleavability of nonpolar GaN crystal. The essence of ELO is mainly to weakening strength between native substrate and the fabricated laser device on top of it. We report a 3 mm long laser bar removed from its native GaN substrate. We confirmed edge emitting lasing operation after cleaving facets on a separated thin bar. Threshold current density of the laser was measured to be as low as 2.15 kA/cm2.

Cardiopulmonary effects of reverse Trendelenburg position at 5° and 10° in sevoflurane-anesthetized steers.

OBJECTIVE: To assess the cardiopulmonary effects caused by reverse Trendelenburg position (RTP) at 5° and 10° in sevoflurane-anesthetized yearling steers. STUDY DESIGN: Prospective, experimental study. ANIMALS: Eight Holstein steers aged (mean ± standard deviation) 12 ± 2 months and weighing 145 ± 26 kg. METHODS: In the first phase of the study, the individual minimum alveolar concentration (MAC) of sevoflurane was determined using electrical stimulation. In the second phase, the effects of RTP were assessed. The animals were anesthetized on three separate events separated by ≥7 days in an incomplete crossover design: control treatment using a table without tilt (RTP0); treatment with the table at 5° RTP (RTP5) and table tilted 10° RTP (RTP10). Subjects were physically restrained in dorsal recumbency on the table, which was already tilted according to each treatment. Anesthesia was induced with sevoflurane at 8% in 5 L minute-1 oxygen via face mask followed by maintenance with sevoflurane at 1.3 MAC and spontaneous breathing. Cardiopulmonary variables were obtained immediately after instrumentation (T0) and then after 30, 60, 120 and 180 minutes (T30, T60, T120 and T180, respectively). RESULTS: The mean sevoflurane MAC for the eight steers was 2.12 ± 0.31%. Cardiac output was lower at all time points and the systemic vascular resistance index was higher at T120 and T180 in RTP10 compared with RTP0. Oxygen consumption was lower at T0 and at T180 in RTP10 compared with RTP0 and at all time points except T30 compared with RTP5. Oxygen extraction was lower at T0 in RTP10 compared with RTP0 and RTP5, and at T60 and T180 compared with RTP5. CONCLUSIONS AND CLINICAL RELEVANCE: RTP 5° and 10° did not improve ventilatory and oxygenation variables in sevoflurane-anesthetized steers when compared with no tilt, however the cardiovascular variables were adversely affected in RTP10.

Effects of dexmedetomidine combined with ropivacaine on sciatic and femoral nerve blockade in dogs.

OBJECTIVE: To evaluate motor and sensory blockade of combining dexmedetomidine with ropivacaine, administered perineurally or systemically, for femoral and sciatic nerve blocks in conscious dogs. STUDY DESIGN: Randomized, controlled, experimental study. ANIMALS: Seven healthy Beagle dogs, aged 3.3 ± 0.1 years and weighing 11.0 ± 2.4 kg. METHODS: Dogs were anesthetized with isoflurane on three separate occasions for unilateral femoral and sciatic nerve blocks and were administered the following treatments in random order: perineural ropivacaine 0.75% (0.1 mL kg-1) on each nerve and intramuscular (IM) saline (0.2 mL kg-1) (Gcon); perineural dexmedetomidine (1 µg mL-1) and ropivacaine 0.75% (0.1 mL kg-1) on each nerve and IM saline (0.2 mL kg-1) (GDPN); and perineural ropivacaine 0.75% (0.1 mL kg-1) on each nerve and IM dexmedetomidine (1 µg mL-1, 0.2 mL kg-1) (Gdim). Nerve blocks were guided by ultrasound and electrical stimulation and dogs were allowed to recover from general anesthesia. Sensory blockade was evaluated by response to clamp pressure on the skin innervated by the saphenous/ femoral, common fibular and tibial nerves. Motor blockade was evaluated by observing the ability to walk and proprioception. Sensory and motor blockade were evaluated until their full recovery. RESULTS: No significant differences in onset time to motor and sensory blockade were observed among treatments. Duration of motor blockade was not significantly different among treatments; however, duration of tibial sensory blockade was longer in the Gdpn than in the GDIM treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Although a longer duration of sensory blockade was observed with perineural dexmedetomidine, a significant increase compared with the control group was not established. Other concentrations should be investigated to verify if dexmedetomidine is a useful adjuvant to local anesthetics in peripheral nerve blocks in dogs.

Ultrasound-assisted periconal ocular blockade in rabbits.

OBJECTIVE: This study aimed to evaluate the benefit and specifically the feasibility of using ultrasound in ophthalmologic periconal block, and the occurrence of complications. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten healthy New Zealand White rabbits (6-8 months of age), weighing 2.0-3.5 kg. METHODS: Rabbits were anesthetized by intramuscular injection of acepromazine (1 mg kg(-1)), ketamine (30 mg kg(-1)) and xylazine (3 mg kg(-1)). Ultrasound-assisted periconal block with lidocaine was performed on 18 eyes. Intraocular pressure was measured by applanation tonometry whereas corneal sensitivity was assessed using an esthesiometer, before and after each periconal anesthesia. RESULTS: In all 18 eyes, it was possible to adequately visualize the needle shaft within the periconal space, as well as muscular cone, optic nerve and local anesthetic solution spread. Lidocaine 2% without epinephrine (0.79 ± 0.19 mL) was injected into the periconal space. There was no statistical difference between the intraocular pressure (mean ± SD) measured before (10.9 ± 2.9 mmHg) and after (11.9 ± 3.8 mmHg) the periconal anesthesia (p = 0.38). The effectiveness of the ultrasound-assisted technique was shown according to the values for corneal sensitivity, assessed before and after periconal anesthesia (p < 0.0001). Complications were not observed in this study. CONCLUSIONS: Eye ultrasonography allowed visualization of all anatomic structures necessary to perform a periconal block, as well as the needle insertion and anesthetic spread in real time. Further studies are required to prove the real potential of ultrasound for reducing the incidence of complications associated with ophthalmic blocks, especially when anatomic disorders of the eye could potentially increase the risk. CLINICAL RELEVANCE: Ultrasonography is a painless, noninvasive tool that may improve safety of ophthalmic regional blocks, potentially by reducing the prevalence of globe perforation or penetration of the optic nerve associated with the needle-based techniques.

Cardiovascular effects of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane.

OBJECTIVE: To assess the cardiovascular changes of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane during mechanical ventilation. STUDY DESIGN: Prospective, randomized, cross-over, experimental trial. ANIMALS: A total of eight, healthy, male Holstein calves, aged 10 ± 1 months and weighing 114 ± 11 kg were included in the study. METHODS: Calves were administered xylazine followed by ketamine and midazolam, orotracheal intubation and maintenance on isoflurane (1.3%) using mechanical ventilation. Forty minutes after induction, lidocaine (2 mg kg⁻¹ bolus) or an equivalent volume of saline (0.9%) was administered IV followed by a continuous rate infusion (100 µg kg⁻¹ minute⁻¹) of lidocaine (treatment L) or saline (treatment C). Heart rate (HR), systolic, diastolic and mean arterial pressures (SAP, DAP and MAP), central venous pressure (CVP), mean pulmonary arterial pressure (mPAP), pulmonary arterial occlusion pressure (PAOP), cardiac output, end-tidal carbon dioxide (Pe'CO2 ) and core temperature (CT) were recorded before lidocaine or saline administration (Baseline) and at 20-minute intervals (T20-T80). Plasma concentrations of lidocaine were measured in treatment L. RESULTS: The HR was significantly lower in treatment L compared with treatment C. There was no difference between the treatments with regards to SAP, DAP, MAP and SVRI. CI was significantly lower at T60 in treatment L when compared with treatment C. PAOP and CVP increased significantly at all times compared with Baseline in treatment L. There was no significant difference between times within each treatment and between treatments with regards to other measured variables. Plasma concentrations of lidocaine ranged from 1.85 to 2.06 µg mL⁻¹ during the CRI. CONCLUSION AND CLINICAL RELEVANCE: At the studied rate, lidocaine causes a decrease in heart rate which is unlikely to be of clinical significance in healthy animals, but could be a concern in compromised animals.

Electrocardiographic evaluation and degree of sedation with three doses of methadone in healthy dogs [corrected].

OBJECTIVE: The present study aimed to investigate the influence of methadone on cardiorespiratory parameters, electrocardiogram and clinical sedation in dogs. Further possible side effects are reported. STUDY DESIGN: Prospective experimental cross-over study. DOGS: Eight, 1-4-year-old, various breeds of dogs of both genders weighing 9-36 kg. METHODS: Each dog was treated three times: methadone 0.3 mg kg(-1) (M0.3), 0.5 mg kg(-1) (M0.5) and 1.0 mg kg(-1) (M1.0) intramuscularly. Respiratory rate, heart rate and arterial blood pressure were recorded as well as electrocardiographic evaluation of lead II. Clinical sedation in each treatment received a score (0-3) after drug administration and at 30 minute intervals until scores and measurements returned to baseline values. RESULTS: A significant decrease in heart rate was seen with each dose of methadone and bradycardia (HR<60 bpm) was noted in a few dogs at each dose. A clinically significant arrhythmia occurred in one dog at 1 mg kg(-1) that required reversal with butorphanol. There was no significant difference in SAP, MAP and DAP between treatments. Some side effects such as salivation, defecation, vocalization and panting, after administration of methadone were observed. There were no differences in mean values of heart rate, P-wave and QRS complex duration and QT interval between treatments. CONCLUSION AND CLINICAL RELEVANCE: Methadone administration was associated with panting and a decrease in heart rate at all doses tested in this study. The cardiac rhythm should be monitored carefully in dogs when methadone is administered on its own, especially at higher doses.

Tumescent local anesthesia with ropivacaine in different concentrations in bitches undergoing mastectomy: plasma concentration and post-operative analgesia.

OBJECTIVE: To compare two concentrations of ropivacaine administered for tumescent local anesthesia (TLA) in dogs undergoing mastectomy. STUDY DESIGN: Prospective randomized clinical study. ANIMALS: Seventeen bitches of various breeds, aged 12 ± 2 years and weighing 10 ± 6.5 kg requiring total unilateral or bilateral mastectomy. METHODS: Dogs were premedicated with acepromazine (0.04 mg kg(-1) ) and morphine (0.4 mg kg(-1) ) intramuscularly. Anesthesia was induced with propofol (2.5 mg kg(-1) ) and midazolam (0.2 mg kg(-1) ) intravenously, followed by intubation and maintenance with isoflurane and TLA. Dogs were randomly allocated to receive TLA either with 0.1% ropivacaine (group G1) or with 0.05% ropivacaine (group G05). TLA was performed by insertion of a multihole needle under the skin and infusion of ropivacaine and lactated Ringer's solution at a fixed volume of 15 mL kg(-1) . Ropivacaine concentrations in arterial blood were measured by high-performance liquid chromatography. Post-operative pain was assessed using two scales (University of Melbourne pain scale and a modified composite measure pain scale) and von Frey filaments, 4 hours after TLA and at 1 hour intervals until sensitivity was regained. A score above 30% of the maximum possible score was considered a positive indicator of pain. RESULTS: Peak plasma concentrations of ropivacaine were measured 240 minutes after TLA in G1. Low concentrations were measured in G05 for 60 minutes, with subsequent increase. Analgesic rescue and return of sensitivity occurred at 7 ± 2.3 and 7 ± 1.9 hours (mean ± SD) after TLA for G1 and G05, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Tumescent local anesthesia with ropivacaine provided satisfactory post-operative analgesia that lasted for several hours, with no difference in duration between the concentrations. No serious side effects were attributed to TLA. Results indicated that 0.05% ropivacaine provided adequate analgesia for mastectomy, however, more studies are required to support this conclusion.

Disentangling self from pain: mindfulness meditation-induced pain relief is driven by thalamic-default mode network decoupling.

ABSTRACT: For millenniums, mindfulness was believed to diminish pain by reducing the influence of self-appraisals of noxious sensations. Today, mindfulness meditation is a highly popular and effective pain therapy that is believed to engage multiple, nonplacebo-related mechanisms to attenuate pain. Recent evidence suggests that mindfulness meditation-induced pain relief is associated with the engagement of unique cortico-thalamo-cortical nociceptive filtering mechanisms. However, the functional neural connections supporting mindfulness meditation-based analgesia remain unknown. This mechanistically focused clinical trial combined functional magnetic resonance imaging with psychophysical pain testing (49°C stimulation and pain visual analogue scales) to identify the neural connectivity supporting the direct modulation of pain-related behavioral and neural responses by mindfulness meditation. We hypothesized that mindfulness meditation-based pain relief would be reflected by greater decoupling between brain mechanisms supporting appraisal (prefrontal) and nociceptive processing (thalamus). After baseline pain testing, 40 participants were randomized to a well-validated, 4-session mindfulness meditation or book-listening regimen. Functional magnetic resonance imaging and noxious heat (49°C; right calf) were combined during meditation to test study hypotheses. Mindfulness meditation significantly reduced behavioral and neural pain responses when compared to the controls. Preregistered (NCT03414138) whole-brain analyses revealed that mindfulness meditation-induced analgesia was moderated by greater thalamus-precuneus decoupling and ventromedial prefrontal deactivation, respectively, signifying a pain modulatory role across functionally distinct neural mechanisms supporting self-referential processing. Two separate preregistered seed-to-seed analyses found that mindfulness meditation-based pain relief was also associated with weaker contralateral thalamic connectivity with the prefrontal and primary somatosensory cortex, respectively. Thus, we propose that mindfulness meditation is associated with a novel self-referential nociceptive gating mechanism to reduce pain.

WITHDRAWN: I feel your pain: Higher empathy is associated with higher posterior default mode network activity.

The authors discovered an error in the primary analysis and have withdrawn the results from this version of the investigation.

The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial.

Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.Trial Registration: ClinicalTrials.gov identifier: NCT04034004.

Cardiopulmonary and analgesic effects of caudal epidurally administered ropivacaine in cattle.

OBJECTIVE: To assess cardiopulmonary and analgesic effects after administration of ropivacaine into the caudal epidural space of cattle. STUDY DESIGN: Prospective, single-dose trial. ANIMALS: Eight healthy mixed breed cows aged 8 ± 5 years and weighing 507 ± 112 kg. METHODS: Caudal epidural anesthesia was produced in cows with 0.75% ropivacaine (0.11 mg kg(-1)). Onset time, duration and cranial spread of analgesia were recorded. Heart rate (HR), respiratory rate (f(R)), rectal temperature (RT), and mean arterial blood pressure (MAP) were measured prior to epidural administration (T(0) ) and at 15, 30, 60, 120, 180 and 240 minutes after epidural administration (T(15), T(30), T(60) , T(120) , T(180) and T(240) ). Arterial blood acid-base balance (pH, standard bicarbonate and base excess), gas tension (PaO(2), PaCO(2), SaO(2)) and electrolytes (Na(+), K(+), iCa(2+),Cl(-)) were recorded at T(0), T(30), T(60), T(120), T(180) and T(240). Ataxia was evaluated at T(0), T(30), T(60), T(120), T(180) and T(240) and at 1 hour intervals thereafter until analgesia was no longer present in each animal. RESULTS: Epidurally administered ropivacaine induced variable analgesia extending bilaterally from the coccyx to S3. Time to onset of analgesia and mean duration in the perineal area were 15 ± 4 and 359 ± 90 minutes, respectively. Respiratory rate and RT increased from T(120) to T(240) when compared to the value at T(0) . Ionized calcium and chloride concentrations increased at T(180) and T(240) when compared to T(0). The other variables were not significantly different from baseline values (p > 0.05). Four animals were mildly ataxic. CONCLUSION AND CLINICAL RELEVANCE: Ropivacaine (0.75%, 0.11 mg kg(-1)) can be administered by caudal epidural injection to produce prolonged bilateral perineal analgesia with minimal ataxia and cardiopulmonary changes in standing cattle.

Control of lymph node activity by direct local innervation.

The nervous system detects environmental and internal stimuli and relays this information to immune cells via neurotransmitters and neuropeptides. This is essential to respond appropriately to immunogenic threats and to support system homeostasis. Lymph nodes (LNs) act as sentinels where adaptive immune responses are generated. They are richly innervated by peripheral sympathetic and sensory nerves, which are responsible for the local secretion of neurotransmitters by sympathetic fibers, such as norepinephrine, and neuropeptides by sensory fibers, including calcitonin gene-related peptide (CGRP) and substance P. Additionally, time-of-day-dependent oscillations in nerve activity are associated with differential immune responses, suggesting a potential role for neuroimmune interactions in coordinating immunity in a circadian fashion. Here, we discuss how LN activity is controlled by local innervation.

Central pain modulatory mechanisms of attentional analgesia are preserved in fibromyalgia.

ABSTRACT: Fibromyalgia is a prevalent pain condition that is associated with cognitive impairments including in attention, memory, and executive processing. It has been proposed that fibromyalgia may be caused by altered central pain processing characterised by a loss of endogenous pain modulation. We tested whether attentional analgesia, where cognitive engagement diminishes pain percept, was attenuated in patients with fibromyalgia (n = 20) compared with matched healthy controls (n = 20). An individually calibrated, attentional analgesia paradigm with a 2 × 2 factorial design was used with brain and brainstem-focussed functional magnetic resonance imaging. Patients with fibromyalgia had both lower heat pain thresholds and speeds in a visual attention task. When this was taken into account for both attentional task and thermal stimulation, both groups exhibited an equivalent degree of attentional analgesia. Functional magnetic resonance imaging analysis showed similar patterns of activation in the main effects of pain and attention in the brain and brainstem (with the sole exceptions of increased activation in the control group in the frontopolar cortex and the ipsilateral locus coeruleus). The attentional analgesic effect correlated with activity in the periaqueductal gray and rostral ventromedial medulla. These findings indicate that patients with fibromyalgia can engage the descending pain modulatory system if the attentional task and noxious stimulus intensity are appropriately titrated.

The Effects of Mindfulness-Based Stress Reduction on Trauma in Victims of Gun Violence: a Pilot Study.

Objectives: Gun violence is a significant problem in the United States of America. Gun violence produces lifelong psychological adversity, trauma, and grief. In the face of this epidemic, efficacious therapies that assuage gun violence-based trauma and negative health are lacking. Methods: The proposed, longitudinal pilot experiment examined the effects of an 8-week mindfulness-based stress reduction (MBSR) program on traumatized individuals as a direct consequence of gun violence. Twenty-four victims of gun violence (median age = 53 years; 21 female) completed measures of the primary outcome: trauma. Secondary outcomes were characterized as grief, depression, sleep quality, life satisfaction, and mindfulness. All assessments were administered before, after 5, and 8 weeks of MBSR training. It was hypothesized that trauma and other comorbidities would improve following MBSR. It was also predicted that outcomes would be significantly stronger from baseline to 5 weeks of MBSR training than from 5 to 8 weeks of training. Results: Before MBSR, volunteers exhibited high levels of trauma, depression, sleep difficulty, and grief. Participation in MBSR was associated with improved trauma, depression, sleep difficulty, and life satisfaction. The most pronounced improvements in psychological disposition were exhibited within the first 5 weeks of MBSR. However, these benefits were largely preserved after completion of the course. Importantly, increases in dispositional mindfulness predicted lower trauma, complicated grief, and sleep difficulties. Conclusions: The present findings should be interpreted with caution because they were derived from an uncontrolled, non-randomized trial. However, said findings suggest that MBSR may reduce trauma and improve overall well-being in gun violence victims.

Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia.

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.

Effect of lidocaine on the minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To investigate the effects of a low-dose constant rate infusion (LCRI; 50 microg kg(-1) minute(-1)) and high-dose CRI (HCRI; 200 microg kg(-1) minute(-1)) lidocaine on arterial blood pressure and on the minimum alveolar concentration (MAC) of sevoflurane (Sevo), in dogs. STUDY DESIGN: Prospective, randomized experimental design. ANIMALS: Eight healthy adult spayed female dogs, weighing 16.0 +/- 2.1 kg. METHODS: Each dog was anesthetized with sevoflurane in oxygen and mechanically ventilated, on three separate occasions 7 days apart. Following a 40-minute equilibration period, a 0.1-mL kg(-1) saline loading dose or lidocaine (2 mg kg(-1) intravenously) was administered over 3 minutes, followed by saline CRI or lidocaine LCRI or HCRI. The sevoflurane MAC was determined using a tail clamp. Heart rate (HR), blood pressure and plasma concentration of lidocaine were measured. All values are expressed as mean +/- SD. RESULTS: The MAC of Sevo was 2.30 +/- 0.19%. The LCRI reduced MAC by 15% to 1.95 +/- 0.23% and HCRI by 37% to 1.45 +/- 0.21%. Diastolic and mean pressure increased with HCRI. Lidocaine plasma concentration was 0.84 +/- 0.18 for LCRI and 1.89 +/- 0.37 microg mL(-1) for HCRI. Seventy-five percent of HCRI dogs vomited during recovery. CONCLUSION AND CLINICAL RELEVANCE: Lidocaine infusions dose dependently decreased the MAC of Sevo, did not induce clinically significant changes in HR or arterial blood pressure, but vomiting was common during recovery in HCRI.

Interplay of prefrontal cortex and amygdala during extinction of drug seeking.

Extinction of Pavlovian conditioning is a complex process that involves brain regions such as the medial prefrontal cortex (mPFC), the amygdala and the locus coeruleus. In particular, noradrenaline (NA) coming from the locus coeruleus has been recently shown to play a different role in two subregions of the mPFC, the prelimbic (PL) and the infralimbic (IL) regions. How these regions interact in conditioning and subsequent extinction is an open issue. We studied these processes using two approaches: computational modelling and NA manipulation in a conditioned place preference paradigm (CPP) in mice. In the computational model, NA in PL and IL causes inputs arriving to these regions to be amplified, thus allowing them to modulate learning processes in amygdala. The model reproduces results from studies involving depletion of NA from PL, IL, or both in CPP. In addition, we simulated new experiments of NA manipulations in mPFC, making predictions on the possible results. We searched the parameters of the model and tested the robustness of the predictions by performing a sensitivity analysis. We also present an empirical experiment where, in accord with the model, a double depletion of NA from both PL and IL in CPP with amphetamine impairs extinction. Overall the proposed model, supported by anatomical, physiological, and behavioural data, explains the differential role of NA in PL and IL and opens up the possibility to understand extinction mechanisms more in depth and hence to aid the development of treatments for disorders such as addiction.