Category: Neurology

Hot Topics: Stroke Care Affected by Traffic

Jackie Werner Hot Topics in Research, Neurology, Public Health

Rubber Meeting the Road: Access to Comprehensive Stroke Care in the Face of Traffic

Dworkis DA, Axeen S, Arora S. Rubber meeting the road: Access to comprehensive stroke care in the face of traffic. Acad Emerg Med. 2020. https://doi.org/10.1111/acem.13909.

Acute stroke is one of the leading causes of death in the United States, with an estimated annual cost of $34 billion and a death from stroke occurring approximately every 4 minutes. Early access to specialized stroke care is critically important in the treatment of suspected acute stroke, but access to dedicated stroke centers is unequal and varies geographically. Among the different levels of hospitals providing stroke care, the comprehensive stroke center (CSC) is the highest designation: CSCs utilize multidisciplinary stroke teams to provide the most advanced stroke care, including therapies like endovascular clot retrieval that are not available at most non‐CSC hospitals.

Hot Topics: Novel Target for Addiction Treatment

Jackie Werner Hot Topics in Research, Neurology, Pharmaceutical Sciences, Substance Use Disorders

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity

Corkrum M, Covelo A, Lines J, et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020. https://doi.org/10.1016/j.neuron.2019.12.026.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson’s disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

Hot Topics: Stroke Increases Risk of Heart Complications

Jackie Werner Cardiology, Hot Topics in Research, Neurology

First-Ever Ischemic Stroke and Incident Major Adverse Cardiovascular Events in 93,627 Older Women and Men

Sposato Luciano A, Melody L, Britney A, Shariff Salimah Z, Gustavo S. First-ever ischemic stroke and incident major adverse cardiovascular events in 93 627 older women and men. Stroke. https://doi.org/10.1161/STROKEAHA.119.028066.

Background and Purpose

Stroke risk is sex-specific, but little is known about sex differences of poststroke major adverse cardiovascular events (MACEs). Stroke-related brain damage causes autonomic dysfunction and inflammation, sometimes resulting in cardiac complications. Sex-specific cardiovascular susceptibility to stroke without the confounding effect of preexisting heart disease constitutes an unexplored field because previous studies focusing on sex differences in poststroke MACE have not excluded patients with known cardiovascular comorbidities. We therefore investigated sex-specific risks of incident MACE in a heart disease-free population-based cohort of patients with first-ever ischemic stroke and propensity-matched individuals without stroke.

Methods

We included Ontario residents ≥66 years, without known cardiovascular comorbidities, with first-ever ischemic stroke between 2002 and 2012 and propensity-matched individuals without stroke. We investigated the 1-year risk of incident MACE (acute coronary syndrome, myocardial infarction, incident coronary artery disease, coronary revascularization procedures, incident heart failure, or cardiovascular death) separately for females and males. For estimating cause-specific adjusted hazard ratios, we adjusted Cox models for variables with weighted standardized differences >0.10 or those known to influence MACE risk.

Results

We included 93 627 subjects without known cardiovascular comorbidities; 21 931 with first-ever ischemic stroke and 71 696 propensity-matched subjects without stroke. Groups were well-balanced on propensity-matching variables. There were 53 476 women (12 421 with and 41 055 without ischemic stroke) and 40 151 men (9510 with and 30 641 without ischemic stroke). First-ever ischemic stroke was associated with increased risk of incident MACE in both sexes. The risk was time-dependent, highest within 30 days (women: adjusted hazard ratio, 25.1 [95% CI, 19.3–32.6]; men: aHR, 23.4 [95% CI, 17.2–31.9]) and decreasing but remaining significant between 31 and 90 days (women: aHR, 4.8 [95% CI, 3.8–6.0]; men: aHR, 4.2 [95% CI, 3.3–5.4]), and 91 to 365 days (aHR, 2.1 [95% CI, 1.8–2.3]; men: aHR, 2.0 [95% CI, 1.7–2.3]).

Conclusions

In this large population-based study, ischemic stroke was independently associated with increased risk of incident MACE in both sexes.

Hot Topics: Exercise in Older Adults Boosts Memory

Jackie Werner Geriatrics, Hot Topics in Research, Memory Impairment

Semantic Memory Activation After Acute Exercise in Healthy Older Adults

Won J, Alfini AJ, Weiss LR, et al. Semantic memory activation after acute exercise in healthy older adults. Journal of the International Neuropsychological Society: 1-12. https://doi.org/10.1017/S1355617719000171.

Objectives: A growing body of research suggests that regular participation in long-term exercise is associated with enhanced cognitive function. However, less is known about the beneficial effects of acute exercise on semantic memory. This study investigated brain activation during a semantic memory task after a single session of exercise in healthy older adults using functional magnetic resonance imaging (fMRI). Methods: Using a within-subjects counterbalanced design, 26 participants (ages, 55–85 years) underwent two experimental visits on separate days. During each visit, participants engaged in 30 min of rest or stationary cycling exercise immediately before performing a Famous and Non-Famous name discrimination task during fMRI scanning. Results: Acute exercise was associated with significantly greater semantic memory activation (Famous>Non-Famous) in the middle frontal, inferior temporal, middle temporal, and fusiform gyri. A planned comparison additionally showed significantly greater activation in the bilateral hippocampus after exercise compared to rest. These effects were confined to correct trials, and as expected, there were no differences between conditions in response time or accuracy. Conclusions: Greater brain activation following a single session of exercise suggests that exercise may increase neural processes underlying semantic memory activation in healthy older adults. These effects were localized to the known semantic memory network, and thus do not appear to reflect a general or widespread increase in brain blood flow. Coupled with our prior exercise training effects on semantic memory-related activation, these data suggest the acute increase in neural activation after exercise may provide a stimulus for adaptation over repeated exercise sessions.

Hot Topics: Parkinson Cases Point to Pandemic

Jackie Werner Hot Topics in Research, Neurology

The Emerging Evidence of the Parkinson Pandemic

Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of the parkinson pandemic. Journal of Parkinson’s Disease. 2018;8(s1):S8. http://dx.doi.org/10.3233/JPD-181474.

Neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson disease. From 1990 to 2015, the number of people with Parkinson disease doubled to over 6 million. Driven principally by aging, this number is projected to double again to over 12 million by 2040. Additional factors, including increasing longevity, declining smoking rates, and increasing industrialization, could raise the burden to over 17 million. For most of human history, Parkinson has been a rare disorder. However, demography and the by-products of industrialization have now created a Parkinson pandemic that will require heightened activism, focused planning, and novel approaches.

Hot Topics: Reward Behavior Provides Insights into Depression

Jackie Werner Hot Topics in Research, Mood Disorders, Neurology

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

LeGates TA, Kvarta MD, Tooley JR, et al. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses. Nature. 2018. https://doi.org/10.1038/s41586-018-0740-8.

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity1,2 and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Hot Topics: Chronic Pain Lessened by Stimulating the Brain

Jackie Werner Hot Topics in Research, Neurology, Substance Use Disorders

Patients’ Experience With Opioid Tapering: A Conceptual Model With Recommendations for Clinicians

Ahn S, Prim JH, Alexander ML, McCulloch KL, Fröhlich F. Identifying and engaging neuronal oscillations by transcranial alternating current stimulation in patients with chronic low back pain: A randomized, crossover, double-blind, sham-controlled pilot study. The Journal of Pain. . https://doi.org/10.1016/j.jpain.2018.09.004

Clinical guidelines discourage prescribing opioids for chronic pain, but give minimal advice about how to discuss opioid tapering with patients. We conducted focus groups and interviews involving 21 adults with chronic back or neck pain in different stages of opioid tapering. Transcripts were qualitatively analyzed to characterize patients’ tapering experiences, build a conceptual model of these experiences, and identify strategies for promoting productive discussions of opioid tapering. Analyses revealed 3 major themes. First, owing to dynamic changes in patients’ social relationships, emotional state, and health status, patients’ pain and their perceived need for opioids fluctuate daily; this finding may conflict with recommendations to taper by a certain amount each month. Second, tapering requires substantial patient effort across multiple domains of patients’ everyday lives; patients discuss this effort superficially, if at all, with clinicians. Third, patients use a variety of strategies to manage the tapering process (eg, keeping an opioid stash, timing opioid consumption based on planned activities). Recommendations for promoting productive tapering discussions include understanding the social and emotional dynamics likely to impact patients’ tapering, addressing patient fears, focusing on patients’ best interests, providing anticipatory guidance about tapering, and developing an individualized tapering plan that can be adjusted based on patient response.

Perspective: This study used interview and focus group data to characterize patients’ experiences with opioid tapering and identify communication strategies that are likely to foster productive, patient-centered discussions of opioid tapering. Findings will inform further research on tapering and help primary care clinicians to address this important, often challenging topic.

Hot Topics: Some Seizures Start After Brain Inhibition

Jackie Werner Biomedical Sciences, Hot Topics in Research, Neurology

Low‐Voltage Fast Seizures in Humans Begin with Increased Interneuron Firing

Elahian B, Lado NE, Mankin E, et al. Low-voltage fast seizures in humans begin with increased interneuron firing. Annals of Neurology. 2018. https://doi.org/10.1002/ana.25325

Objective
Intracellular recordings from cells in entorhinal cortex tissue slices show that low‐voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial–temporal LVF seizures recorded in patients.

Methods
The seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single‐unit activity during the onset of LVF seizures recorded from microelectrodes in mesial–temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K‐means clustering.

Results
From a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial–temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p < 0.01). Excitatory neuron firing rates peaked 10 seconds after the inhibitory neurons (p < 0.01). During LVF spread to the contralateral mesial temporal lobe, an increase in inhibitory neuron firing rate was also observed (p < 0.01).

Interpretation
Our results suggest that seizure generation and spread during spontaneous mesial–temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution.

Hot Topics: Anesthesiology Should Look to Neuroscience and Nociception

Jackie Werner Hot Topics in Research, Neurology, Surgery

Multimodal General Anesthesia: Theory and Practice

Brown EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: Theory and practice. Anesthesia & Analgesia. http://dx.doi.org/10.1213/ANE.0000000000003668

Balanced general anesthesia, the most common management strategy used in anesthesia care, entails the administration of different drugs together to create the anesthetic state. Anesthesiologists developed this approach to avoid sole reliance on ether for general anesthesia maintenance. Balanced general anesthesia uses less of each drug than if the drug were administered alone, thereby increasing the likelihood of its desired effects and reducing the likelihood of its side effects. To manage nociception intraoperatively and pain postoperatively, the current practice of balanced general anesthesia relies almost exclusively on opioids. While opioids are the most effective antinociceptive agents, they have undesirable side effects. Moreover, overreliance on opioids has contributed to the opioid epidemic in the United States. Spurred by concern of opioid overuse, balanced general anesthesia strategies are now using more agents to create the anesthetic state. Under these approaches, called “multimodal general anesthesia,” the additional drugs may include agents with specific central nervous system targets such as dexmedetomidine and ones with less specific targets, such as magnesium. It is postulated that use of more agents at smaller doses further maximizes desired effects while minimizing side effects. Although this approach appears to maximize the benefit-to-side effect ratio, no rational strategy has been provided for choosing the drug combinations. Nociception induced by surgery is the primary reason for placing a patient in a state of general anesthesia. Hence, any rational strategy should focus on nociception control intraoperatively and pain control postoperatively. In this Special Article, we review the anatomy and physiology of the nociceptive and arousal circuits, and the mechanisms through which commonly used anesthetics and anesthetic adjuncts act in these systems. We propose a rational strategy for multimodal general anesthesia predicated on choosing a combination of agents that act at different targets in the nociceptive system to control nociception intraoperatively and pain postoperatively. Because these agents also decrease arousal, the doses of hypnotics and/or inhaled ethers needed to control unconsciousness are reduced. Effective use of this strategy requires simultaneous monitoring of antinociception and level of unconsciousness. We illustrate the application of this strategy by summarizing anesthetic management for 4 representative surgeries.

Hot Topics: Dementia Risk Doubled After Stroke

Jackie Werner Dementia, Hot Topics in Research, Neurology

Stroke and dementia risk: A systematic review and meta-analysis

Kuźma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ. Stroke and dementia risk: A systematic review and meta-analysis. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. . https://doi.org/10.1016/j.jalz.2018.06.3061.

Introduction
Stroke is an established risk factor for all-cause dementia, though meta-analyses are needed to quantify this risk.

Methods
We searched Medline, PsycINFO, and Embase for studies assessing prevalent or incident stroke versus a no-stroke comparison group and the risk of all-cause dementia. Random effects meta-analysis was used to pool adjusted estimates across studies, and meta-regression was used to investigate potential effect modifiers.

Results
We identified 36 studies of prevalent stroke (1.9 million participants) and 12 studies of incident stroke (1.3 million participants). For prevalent stroke, the pooled hazard ratio for all-cause dementia was 1.69 (95% confidence interval: 1.49–1.92; P < .00001; I2 = 87%). For incident stroke, the pooled risk ratio was 2.18 (95% confidence interval: 1.90–2.50; P < .00001; I2 = 88%). Study characteristics did not modify these associations, with the exception of sex which explained 50.2% of between-study heterogeneity for prevalent stroke.

Discussion
Stroke is a strong, independent, and potentially modifiable risk factor for all-cause dementia.