Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD) by the release of pro‐inflammatory mediators that compromise neuronal ...function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti‐inflammatory effects of acetylcholine (ACh) or norepinephrine (NE), which mainly activates the β‐receptors on microglial cells. Non‐invasive vagus nerve stimulation (nVNS) is used in treatment of drug‐resistant depression, which is a risk factor for developing AD. The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM) and widely throughout the brain. Pilot studies showed first signs of cognitive‐enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280 min by 2‐photon laser scanning in vivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild‐type and amyloid precursor protein/presenilin‐1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS1 animals, whereas microglia from young animals were morphologically unaffected.
Microglia activation plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease and in acute brain trauma, including stroke and traumatic brain injury. Non‐invasive vagus nerve stimulation (nVNS) is able to revert the neuroinflammatory phenotype of microglia in a mouse model of AD. nVNS is thought to exert this effect by the release of norepinephrine and acetylcholine from the locus coeruleus and nucleus basalis of Meynert, respectively. nVNS may therefore provide a novel treatment paradigm for neurodegenerative diseases by inducing the neuroprotective action of microglia and suppressing the detrimental release of proinflammatory mediators.
Abstract Vagus nerve stimulation (VNS) has been reported to be effective in the abortive treatment of both migraine and cluster headache. Using validated animal models of acute dural-intracranial ...(migraine-like) and trigeminal-autonomic (cluster-like) head pain we tested whether VNS suppresses ongoing and nociceptive-evoked firing of trigeminocervical neurons to explain its abortive effects in migraine and cluster headache. Unilateral VNS was applied invasively via hook electrodes placed on the vagus nerve. A single dose of ipsilateral or contralateral VNS, to trigeminal recording and dural-stimulating side, suppressed ongoing spontaneous and noxious dural-evoked trigeminocervical neuronal firing. This effect was dose-dependent, with two doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing (maximally by ~ 60%) for up to three hours, and dural-evoked (Aδ-fiber; by ~ 22%, C-fiber: by ~ 55%) responses for at least two hours. Statistically, there was no difference between ipsilateral and contralateral groups. Two doses of VNS also suppressed superior salivatory nucleus-evoked trigeminocervical neuronal responses (maximally by ~ 22%) for 2.5 h, to model nociceptive activation of the trigeminal-autonomic pathway. VNS had no effect on normal somatosensory cutaneous facial responses throughout. These studies provide a mechanistic rationale for the observed benefits of VNS in the abortive treatment of migraine and cluster headache. In addition, they further validate these preclinical models as suitable approaches to optimize therapeutic efficacy, and provide an opportunity to hypothesize and dissect the neurobiological mechanisms of VNS in the treatment of primary headaches.
Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in ...a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) comprise the newest class of oral hypoglycemic agents approved for treating type II diabetes mellitus (DM-II). Their use, however, has been ...associated with the rare development of euglycemic diabetic ketoacidosis (euDKA). We present three cases of euDKA that occurred following elective coronary artery bypass grafting surgery. The role of the anesthesiologist in the prevention, diagnosis, and management of this complication is also discussed.
Clinical features
Three patients receiving chronic SGLT2i therapy for DM-II (discontinued one to two days preoperatively) underwent cardiac surgery. On the first postoperative day, each exhibited nausea, vomiting, and tachypnea. Although these nonspecific postoperative findings are common, our patients also exhibited anion gap metabolic acidosis (pH < 7.3, anion gap > 12 mmol·L
−1
) with lower than anticipated serum glucose levels of < 14 mmol·L
−1
. Serum and urine ketone analyses confirmed a diagnosis of euDKA. After insulin and dextrose infusions were initiated, rapid resolution of the metabolic abnormalities occured.
Conclusions
Anesthesiologists should recognize that patients receiving SGLT2i preoperatively are at risk of developing euDKA. Hence, based on the pharmacokinetics of SGLT2i, discontinuing the medication at least two days prior to surgery should minimize the risk. Diagnosing euDKA is challenging and often delayed because of its nonspecific signs and symptoms. When suspected, serum and urine ketones should be monitored to reduce the time to diagnosis and treatment.
The reduction of glutamate is identified as the mechanism of action of noninvasive vagus nerve stimulation for the treatment of trigeminal allodynia.
Implanted vagus nerve stimulation (VNS) has been ...used to treat seizures and depression. In this study, we explored the mechanism of action of noninvasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which led to chronic trigeminal allodynia. Administration of nVNS for 2minutes decreased periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5hours after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7±0.9-fold increase in extracellular glutamate in the TNC after i.p. administration of the chemical headache trigger glyceryl trinitrate (GTN; 0.1mg/kg). Allodynic rats that received nVNS had only a 2.3±0.4-fold increase in extracellular glutamate after GTN, similar to the response in control naive rats. When nVNS was delayed until 120minutes after GTN treatment, the high levels of glutamate in the TNC were reversed after nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia.
The primary objective of this study was to explore the impact of noninvasive Vagal Nerve Stimulation (nVNS) on brain electrophysiology, as assessed through spontaneous resting-state EEG and ...stimulus-driven event-related potentials (ERPs).
A hand-held transcutaneous stimulator was placed on the neck over the main branch of the left vagus (active condition) or more laterally over neck muscles (sham condition), with two 120-sec long bursts of stimulation applied over a five-minute period. For each of eight neurotypical subjects, prior to stimulation, and then again beginning at 15, 120, and 240 min post-stimulation, ten minutes of background EEG data were collected, along with a series of ERPs-N100 auditory sensory-gating; the N1/P2 loudness dependent auditory evoked responses (LDAER); mismatch negativity; P300a; and P300b. Each subject participated in active and sham stimulation sessions.
Brief nVNS had a significant (p < 0.05), and in some cases prolonged (>2 hours), impact on the spontaneous EEG (decreased theta and alpha, and increased beta and gamma), and on sensory gating, LDAER, and P300b evoked responses. Based on prior literature, these specific observations may reflect nVNS-induced modulation of particular neurotransmitter systems including those for GABA (gamma power and frequency); acetylcholine (sensory gating); serotonin (LDAER); and noradrenaline (P300b).
Brief nVNS leads to changes in a sub-set of resting-state and event-related electrophysiologic indices of brain activity. These changes are believed to be mediated by vagal afferent projections to the nucleus of the solitary tract, which in turn regulates several neurotransmitter systems through known direct and indirect neuroanatomic pathways.
To develop the first high-resolution, multi-scale model of cervical non-invasive vagus nerve stimulation (nVNS) and to predict vagus fiber type activation, given clinically relevant rheobase ...thresholds.
An MRI-derived Finite Element Method (FEM) model was developed to accurately simulate key macroscopic (e.g., skin, soft tissue, muscle) and mesoscopic (cervical enlargement, vertebral arch and foramen, cerebral spinal fluid CSF, nerve sheath) tissue components to predict extracellular potential, electric field (E-Field), and activating function along the vagus nerve. Microscopic scale biophysical models of axons were developed to compare axons of varying size (Aα-, Aβ- and Aδ-, B-, and C-fibers). Rheobase threshold estimates were based on a step function waveform.
Macro-scale accuracy was found to determine E-Field magnitudes around the vagus nerve, while meso-scale precision determined E-field changes (activating function). Mesoscopic anatomical details that capture vagus nerve passage through a changing tissue environment (e.g., bone to soft tissue) profoundly enhanced predicted axon sensitivity while encapsulation in homogenous tissue (e.g., nerve sheath) dulled axon sensitivity to nVNS.
These findings indicate that realistic and precise modeling at both macroscopic and mesoscopic scales are needed for quantitative predictions of vagus nerve activation. Based on this approach, we predict conventional cervical nVNS protocols can activate A- and B- but not C-fibers. Our state-of-the-art implementation across scales is equally valuable for models of spinal cord stimulation, cortex/deep brain stimulation, and other peripheral/cranial nerve models.
Background
The debilitating nature of migraine and challenges associated with treatment-refractory migraine have a profound impact on patients. With the need for alternatives to pharmacologic agents, ...vagus nerve stimulation has demonstrated efficacy in treatment-refractory primary headache disorders. We investigated the use of cervical non-invasive vagus nerve stimulation (nVNS) for the acute treatment and prevention of migraine attacks in treatment-refractory episodic and chronic migraine (EM and CM) and evaluated the impact of nVNS on migraine-associated sleep disturbance, disability, and depressive symptoms.
Methods
Twenty patients with treatment-refractory migraine were enrolled in this 3-month, open-label, prospective observational study. Patients administered nVNS prophylactically twice daily at prespecified times and acutely as adjunctive therapy for migraine attacks. The following parameters were evaluated: pain intensity (visual analogue scale VAS); number of headache days per month and number of migraine attacks per month; number of acutely treated attacks; sleep quality (Pittsburgh Sleep Quality Index PSQI); migraine disability assessment (MIDAS); depressive symptoms (Beck Depression Inventory® BDI); and adverse events (AEs).
Results
Of the 20 enrolled patients, 10 patients each had been diagnosed with EM and CM. Prophylaxis with nVNS was associated with significant overall reductions in patient-perceived pain intensity; median (interquartile range) VAS scores at baseline versus 3 months were 8.0 (7.5, 8.0) versus 4.0 (3.5, 5.0) points (
p
< 0.001). Baseline versus 3-month values (mean ± standard error of the mean) were 14.7 ± 0.9 versus 8.9 ± 0.8 (
p
< 0.001) for the number of headache days per month and 7.3 ± 0.9 versus 4.5 ± 0.6 (
p
< 0.001) for the number of attacks per month. Significant improvements were also noted in MIDAS (
p
< 0.001), BDI (
p
< 0.001), and PSQI global (
p
< 0.001) scores. No severe or serious AEs occurred.
Conclusion
In this study, treatment with nVNS was safe and provided clinically meaningful decreases in the frequency and intensity of migraine attacks in patients with treatment-refractory migraine. Improvements in migraine-associated disability, depression, and sleep quality were also noted.
The purpose of this manuscript is to establish a unified theory of porohyperelasticity with transport and growth and to demonstrate the capability of this theory using a finite element model ...developed in MATLAB. We combine the theories of volumetric growth and mixed porohyperelasticity with transport and swelling (MPHETS) to derive a new method that models growth of biological soft tissues. The conservation equations and constitutive equations are developed for both solid-only growth and solid/fluid growth. An axisymmetric finite element framework is introduced for the new theory of growing MPHETS (GMPHETS). To illustrate the capabilities of this model, several example finite element test problems are considered using model geometry and material parameters based on experimental data from a porcine coronary artery. Multiple growth laws are considered, including time-driven, concentration-driven, and stress-driven growth. Time-driven growth is compared against an exact analytical solution to validate the model. For concentration-dependent growth, changing the diffusivity (representing a change in drug) fundamentally changes growth behavior. We further demonstrate that for stress-dependent, solid-only growth of an artery, growth of an MPHETS model results in a more uniform hoop stress than growth in a hyperelastic model for the same amount of growth time using the same growth law. This may have implications in the context of developing residual stresses in soft tissues under intraluminal pressure. To our knowledge, this manuscript provides the first full description of an MPHETS model with growth. The developed computational framework can be used in concert with novel in-vitro and in-vivo experimental approaches to identify the governing growth laws for various soft tissues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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