Hypoxia modulates cholinergic but not opioid activation of G proteins in rat hippocampus

Intermittent hypoxia, such as that associated with obstructive sleep apnea, can cause neuronal death and neurobehavioral dysfunction. The cellular and molecular mechanisms through which hypoxia alter hippocampal function are incompletely understood. This study used in vitro [ 35 S]guanylyl-5′- O -(Γ-thio)-triphosphate ([ 35 S]GTPΓS) autoradiography to test the hypothesis that carbachol and DAMGO activate hippocampal G proteins. In addition, this study tested the hypothesis that in vivo exposure to different oxygen (O 2 ) concentrations causes a differential activation of G proteins in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus. G protein activation was quantified as nCi/g tissue in CA1, CA3, and DG from rats housed for 14 days under one of three different oxygen conditions: normoxic (21% O 2 ) room air, or hypoxia (10% O 2 ) that was intermittent or sustained. Across all regions of the hippocampus, activation of G proteins by the cholinergic agonist carbachol and the mu opioid agonist [D-Ala 2 , N-Met-Phe 4 , Gly 5 ] enkephalin (DAMGO) was ordered by the degree of hypoxia such that sustained hypoxia > intermittent hypoxia > room air. Carbachol increased G protein activation during sustained hypoxia (38%), intermittent hypoxia (29%), and room air (27%). DAMGO also activated G proteins during sustained hypoxia (52%), intermittent hypoxia (48%), and room air (43%). Region-specific comparisons of G protein activation revealed that the DG showed significantly less activation by carbachol following intermittent hypoxia and sustained hypoxia than the CA1. Considered together, the results suggest the potential for hypoxia to alter hippocampal function by blunting the cholinergic activation of G proteins within the DG. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57386/1/20312_ftp.pd

A roadmap to advance delirium research: recommendations from the NIDUS Scientific Think Tank

Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference “Advancing Delirium Research: A Scientific Think Tank” in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155509/1/alz12076_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155509/2/alz12076.pd

Recent Advances in Preventing and Managing Postoperative Delirium [version 1; peer review: 2 approved]

Postoperative delirium is a common and harrowing complication in older surgical patients. Those with cognitive impairment or dementia are at especially high risk for developing postoperative delirium; ominously, it is hypothesized that delirium can accelerate cognitive decline and the onset of dementia, or worsen the severity of dementia. Awareness of delirium has grown in recent years as various medical societies have launched initiatives to prevent postoperative delirium and alleviate its impact. Unfortunately, delirium pathophysiology is not well understood and this likely contributes to the current state of low-quality evidence that informs perioperative guidelines. Along these lines, recent prevention trials involving ketamine and dexmedetomidine have demonstrated inconsistent findings. Non-pharmacologic multicomponent initiatives, such as the Hospital Elder Life Program, have consistently reduced delirium incidence and burden across various hospital settings. However, a substantial portion of delirium occurrences are still not prevented, and effective prevention and management strategies are needed to complement such multicomponent non-pharmacologic therapies. In this narrative review, we examine the current understanding of delirium neurobiology and summarize the present state of prevention and management efforts

Dynamic Cortical Connectivity during General Anesthesia in Surgical Patients

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Functional connectivity across the cortex has been posited to be important for consciousness and anesthesia, but functional connectivity patterns during the course of surgery and general anesthesia are unknown. The authors tested the hypothesis that disrupted cortical connectivity patterns would correlate with surgical anesthesia. Methods Surgical patients (n = 53) were recruited for study participation. Whole-scalp (16-channel) wireless electroencephalographic data were prospectively collected throughout the perioperative period. Functional connectivity was assessed using weighted phase lag index. During anesthetic maintenance, the temporal dynamics of connectivity states were characterized via Markov chain analysis, and state transition probabilities were quantified. Results Compared to baseline (weighted phase lag index, 0.163, ± 0.091), alpha frontal–parietal connectivity was not significantly different across the remaining anesthetic and perioperative epochs, ranging from 0.100 (± 0.041) to 0.218 (± 0.136) (P &amp;gt; 0.05 for all time periods). In contrast, there were significant increases in alpha prefrontal–frontal connectivity (peak = 0.201 [0.154, 0.248]; P &amp;lt; 0.001), theta prefrontal–frontal connectivity (peak = 0.137 [0.091, 0.182]; P &amp;lt; 0.001), and theta frontal–parietal connectivity (peak = 0.128 [0.084, 0.173]; P &amp;lt; 0.001) during anesthetic maintenance. Additionally, shifts occurred between states of high prefrontal–frontal connectivity (alpha, beta) with suppressed frontal–parietal connectivity, and high frontal–parietal connectivity (alpha, theta) with reduced prefrontal–frontal connectivity. These shifts occurred in a nonrandom manner (P &amp;lt; 0.05 compared to random transitions), suggesting structured transitions of connectivity during general anesthesia. Conclusions Functional connectivity patterns dynamically shift during surgery and general anesthesia but do so in a structured way. Thus, a single measure of functional connectivity will likely not be a reliable correlate of surgical anesthesia. </jats:sec

Constrained Functional Connectivity Dynamics in Pediatric Surgical Patients Undergoing General Anesthesia

Background Functional connectivity in cortical networks is thought to be important for consciousness and can be disrupted during the anesthetized state. Recent work in adults has revealed dynamic connectivity patterns during stable general anesthesia, but whether similar connectivity state transitions occur in the developing brain remains undetermined. The hypothesis was that anesthetic-induced unconsciousness is associated with disruption of functional connectivity in the developing brain and that, as in adults, there are dynamic shifts in connectivity patterns during the stable maintenance phase of general anesthesia. Methods This was a preplanned analysis of a previously reported single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists status I or II) children aged 8 to 16 yr undergoing surgery with general anesthesia (n = 50) at Michigan Medicine. Whole-scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Functional connectivity was measured using a weighted phase lag index, and discrete connectivity states were classified using cluster analysis. Results Changes in functional connectivity were associated with anesthetic state transitions across multiple regions and frequency bands. An increase in prefrontal–frontal alpha (median [25th, 75th]; baseline, 0.070 [0.049, 0.101] vs. maintenance 0.474 [0.286, 0.606]; P &amp;lt; 0.001) and theta connectivity (0.038 [0.029, 0.048] vs. 0.399 [0.254, 0.488]; P &amp;lt; 0.001), and decrease in parietal–occipital alpha connectivity (0.171 [0.145, 0.243] vs. 0.089 [0.055, 0.132]; P &amp;lt; 0.001) were among those with the greatest effect size. Contrary to the hypothesis, connectivity patterns during the maintenance phase of general anesthesia were dominated by stable theta and alpha prefrontal–frontal and alpha frontal–parietal connectivity and exhibited high between-cluster similarity (r = 0.75 to 0.87). Conclusions Changes in functional connectivity are associated with anesthetic state transitions but, unlike in adults, connectivity patterns are constrained during general anesthesia in late childhood and early adolescence. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New </jats:sec

Table_2_Age-Related Changes in Cortical Connectivity During Surgical Anesthesia.docx

An advanced understanding of the neurophysiologic changes that occur with aging may help improve care for older, vulnerable surgical patients. The objective of this study was to determine age-related changes in cortical connectivity patterns during surgical anesthesia. This was a substudy analysis of a prospective, observational study characterizing cortical connectivity during surgical anesthesia in adult patients (n = 45) via whole-scalp (16-channel) electroencephalography. Functional connectivity was estimated using a weighted phase lag index (wPLI), which was classified into a discrete set of states through k-means analysis. Temporal dynamics were quantified by occurrence rate and state transition probabilities. The mean global connectivity state transition probability [13.4% (±8.1)] was not correlated with age (ρ = 0.100, p = 0.513). Increasing age was inversely correlated with prefrontal-frontal alpha-beta connectivity (ρ = −0.446, p = 0.002) and positively correlated with frontal-parietal theta connectivity (ρ = 0.414, p = 0.005). After adjusting for anesthetic-related confounders, prefrontal-frontal alpha-beta connectivity remained significantly associated with age (β = −0.625, 95% CI −0.99 to −0.26; p = 0.001), while frontal-parietal theta connectivity was no longer significant (β = 0.436, 95% CI −0.03 to 0.90; p = 0.066). Specific transition states were also examined. Between frontal-parietal connectivity states, transitioning from theta-alpha to theta-dominated connectivity positively correlated with age (ρ = 0.545, p = 0.001). Dynamic connectivity states during surgical anesthesia, particularly involving alpha and theta bandwidths, maybe an informative measure to assess neurophysiologic changes that occur with aging.</p