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Importance: Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes., Objective: To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome., Design, Setting, and Participants: This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included., Exposures: Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases., Main Outcomes and Measures: Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score., Results: Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92)., Conclusions and Relevance: In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Objective: To describe the impact of COVID-19 on acute cerebrovascular disease care across 9 comprehensive stroke centers throughout Los Angeles County (LAC)., Methods: Volume of emergency stroke code activations, patient characteristics, stroke severity, reperfusion rates, treatment times, and outcomes from February 1 to April 30, 2020, were compared against the same time period in 2019. Demographic data were provided by each participating institution., Results: There was a 17.3% decrease in stroke code activations across LAC in 2020 compared to 2019 (1,786 vs. 2,159, respectively, χ2 goodness of fit test p < 0.0001) across 9 participating comprehensive stroke centers. Patients who did not receive any reperfusion therapy decreased by 16.6% in 2020 (1,527) compared to 2019 (1,832). Patients who received only intravenous thrombolytic (IVT) therapy decreased by 31.8% (107 vs. 157). Patients who received only mechanical thrombectomy (MT) increased by 3% (102 vs. 99). Patients who received both IVT and MT decreased by 31.8% (45 vs. 66). Recanalization treatment times in 2020 were comparable to 2019. CSCs serving a higher proportion of Latinx populations in the eastern parts of LAC experienced a higher incidence of MT in 2020 compared to 2019. Mild increase in stroke severity was seen in 2020 compared to 2019 (8.95 vs. 8.23, p = 0.046). A higher percentage of patients were discharged home in 2020 compared to 2019 (59.5 vs. 56.1%, p = 0.034), a lower percentage of patients were discharged to skilled nursing facility (16.1 vs. 20.7%, p = 0.0004), and a higher percentage of patients expired (8.6 vs. 6.3%, p = 0.008)., Conclusion: LAC saw a decrease in overall stroke code activations in 2020 compared to 2019. Reperfusion treatment times remained comparable to prepandemic metrics. There has been an increase in severe stroke incidence and higher volume of thrombectomy treatments in Latinx communities within LAC during the pandemic of 2020. More patients were discharged home, less patients discharged to skilled nursing facilities, and more patients expired in 2020, compared to the same time frame in 2019., (© 2021 S. Karger AG, Basel.)

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke., Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018., Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups., Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo., Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with a mild electric shock (the unconditioned stimulus, or US) delivered to one eyelid. After training, the CS elicited two different conditioned fear responses from rats: a passive freezing response, and an active turning response. The balance between these two modes of conditioned responding depended upon the rat's recent history of encounters with the US. If rats had not recently encountered the US, then they responded to the CS by freezing. But after recently encountering the US, rats exhibited CS-evoked turning responses that were always directed away from the trained eyelid, even if the US had recently been delivered to the opposite (untrained) eyelid. This post-encounter turning behavior was not observed in rats that had been trained with unpaired presentations of the CS and US, indicating that even though CS-evoked turning was selectively expressed after recent encounters with the US, it was nonetheless a conditioned Pavlovian fear response that depended upon a learned association between the CS and US. Further supporting this conclusion, pharmacological inactivation experiments showed that expression of both freezing and turning behaviors depended upon lateralized circuits in the amygdala and periaqueductal gray (PAG) that are known to support expression of Pavlovian fear responses. These findings indicate that even though the ability of a CS to elicit Pavlovian fear responses depend upon the long-term history of CS-US pairings, the mode of conditioned responding (freezing versus turning in the present experiments) can be modulated by short-term factors, such as the recent history of US encounters. We discuss neural mechanisms that might mediate such short-term transitions between different modes of defensive responding, and consider how dysregulation of such mechanisms might contribute to clinical anxiety disorders., ((c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

A form of aversively motivated learning called fear conditioning occurs when a neutral conditioned stimulus is paired with an aversive unconditioned stimulus (UCS). UCS-evoked depolarization of amygdala neurons may instruct Hebbian plasticity that stores memories of the conditioned stimulus-unconditioned stimulus association, but the origin of UCS inputs to the amygdala is unknown. Theory and evidence suggest that instructive UCS inputs to the amygdala will be inhibited when the UCS is expected, but this has not been found during fear conditioning. We investigated neural pathways that relay information about the UCS to the amygdala by recording neurons in the amygdala and periaqueductal gray (PAG) of rats during fear conditioning. UCS-evoked responses in both amygdala and PAG were inhibited by expectation. Pharmacological inactivation of the PAG attenuated UCS-evoked responses in the amygdala and impaired acquisition of fear conditioning, indicating that PAG may be an important part of the pathway that relays instructive signals to the amygdala.

We previously showed that when rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with a mild unilateral shock to the eyelid (the unconditioned stimulus, or US), conditioned freezing depended upon the amygdala contralateral but not ipsilateral from the US. It was proposed that convergent activation of amygdala neurons by the CS and US occurred mainly in the amygdala contralateral from US delivery, causing memories of the CS-US association to be stored primarily by that hemisphere. In the present study, we further tested this interpretation by administering unilateral infusions of U0126 (in 50% dimethyl sulfoxide (DMSO) vehicle) to block phosphorylation of extracellular signal-responsive kinase (ERK) in the amygdala prior to CS-US pairings. Conditioned freezing was impaired 24 h after training when U0126 was infused contralaterally-but not ipsilaterally-from the US, suggesting that fear memories were consolidated mainly by the contralateral amygdala. However, immunostaining experiments revealed that ERK phosphorylation was elevated in both hemispheres of the amygdale's lateral (LA) and centrolateral (CeL) nuclei after paired (but not unpaired (UNP)) presentations of the CS and US. Thus, fear acquisition induced ERK phosphorylation bilaterally in the amygdala, even though the ipsilateral hemisphere did not appear to participate in conditioned freezing. These findings suggest that associative plasticity may occur in both amygdala hemispheres even when only one hemisphere is involved in freezing behavior. Conditioning-induced ERK phosphorylation was identical in both hemispheres of LA, but was slightly greater in the contralateral than ipsilateral hemisphere of CeL. Hence, asymmetric induction of plasticity in CeL might help to explain why conditioned freezing depends preferentially upon the amygdala contralateral from the US in our fear conditioning paradigm.

Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2'-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N'-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNa(V)1.7 and hNa(V)1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 microM, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na+ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A- and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 microM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.

Pavlovian fear conditioning is an associative learning task in which subjects are trained to respond defensively to a neutral conditioned stimulus (CS) by pairing it with an aversive unconditioned stimulus (US). This type of learning depends critically on the amygdala, and evidence suggests that synaptic plasticity within the lateral nucleus of the amygdala (LA) may be responsible for storing memories of the CS-US association. In the present study, we trained rats to fear an auditory CS by pairing it with a shock US delivered to one eyelid. Conditioning was assessed by measuring freezing responses evoked by the CS during a subsequent test session. The amygdala was unilaterally inactivated during either the training or the testing session by intracranial infusions of muscimol into the LA. We found that both acquisition and expression of conditioned freezing to the CS depended on the amygdala contralateral but not ipsilateral from the eyelid where the shock US was delivered. To explain this surprising result, we propose that the shock US is relayed from the eyelid to the amygdala via lateralized nociceptive sensory pathways, which causes memories of the CS-US association to be stored by the amygdala contralateral but not ipsilateral from the shocked eyelid. Our results demonstrate that the fear-learning circuitry of the amygdala is functionally lateralized according to the anatomical source of predicted threats. In future studies, the cellular mechanisms of emotional memory storage might be pinpointed by identifying cellular processes that occur only in the amygdala contralateral but not ipsilateral from the US during lateralized fear conditioning.

One distinguishing feature of primary afferent neurons is their ability to bind the lectin IB(4). Previous work suggested that neurons in the inner part of lamina II (IIi), onto which IB(4)-positive sensory neurons project, facilitate nociceptive transmission following tissue or nerve injury. Using an IB(4)-saporin conjugate (IB(4)-SAP), we examined the contribution of IB(4)-positive neurons to nociceptive processing in rats with and without nerve injury. Intrasciatic injection of IB(4)-SAP (5 mug/5 mul) significantly decreased IB(4)-labeling and immunoreactive P(2)X(3) in the spinal cord and delayed the behavioral and neuroanatomical consequences of L5 spinal nerve ligation (SNL) injury. In the absence of injury, thermal and mechanical nociceptive thresholds increased 2 weeks post-treatment only in IB(4)-SAP-treated, but not control (saline or saporin only), rats. Acute NGF-induced hyperalgesia was also attenuated following IB(4)-SAP treatment. In the SNL model, mechanical allodynia failed to develop 1 and 2 weeks post-injury, but was fully established by 4 weeks. Moreover, neuropeptide Y immunoreactivity (NPY-ir), which increases in the spinal cord after nerve injury, was unchanged in IB(4)-SAP-treated animals whereas immunoreactive PKCgamma decreased 2, but not 4, weeks post-injury. Quantitative RT-PCR revealed a reduction in P(2)X(3) mRNA in L4 DRG of IB(4)-SAP-treated animals, but no change in TrkA expression. Our results suggest that IB(4)-positive neurons in L4 are required for the full expression of NGF-induced hyperalgesia and participate in the behavioral and anatomical consequences that follow injury to the L5 spinal nerve.