Linking and unlinking the paediatric brain: age-invariant neural correlates of general anaesthesia.

There is no single electroencephalographic metric for general anaesthesia that is validated for both children and adults. This is, in part, because of the changing electroencephalographic features associated with development. Here, we discuss how alterations in correlated brain activity during general anaesthesia advance our understanding of anaesthetic monitoring and the neurobiology of consciousness.

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 < 0.001) and theta connectivity (0.038 [0.029, 0.048] vs. 0.399 [0.254, 0.488]; P < 0.001), and decrease in parietal-occipital alpha connectivity (0.171 [0.145, 0.243] vs. 0.089 [0.055, 0.132]; P < 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.

Neurophysiologic Complexity in Children Increases with Developmental Age and Is Reduced by General Anesthesia.

BACKGROUND: Neurophysiologic complexity in the cortex has been shown to reflect changes in the level of consciousness in adults but remains incompletely understood in the developing brain. This study aimed to address changes in cortical complexity related to age and anesthetic state transitions. This study tested the hypotheses that cortical complexity would (1) increase with developmental age and (2) decrease during general anesthesia. METHODS: This was a single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists physical status I or II) children (n = 50) of age 8 to 16 undergoing surgery with general anesthesia at Michigan Medicine. This age range was chosen because it reflects a period of substantial brain network maturation. Whole scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Cortical complexity was measured using the Lempel-Ziv algorithm and analyzed during the baseline, premedication, maintenance of general anesthesia, and clinical recovery periods. The effect of spectral power on Lempel-Ziv complexity was analyzed by comparing the original complexity value with those of surrogate time series generated through phase randomization that preserves power spectrum. RESULTS: Baseline spatiotemporal Lempel-Ziv complexity increased with age (yr; slope [95% CI], 0.010 [0.004, 0.016]; P < 0.001); when normalized to account for spectral power, there was no significant age effect on cortical complexity (0.001 [-0.004, 0.005]; P = 0.737). General anesthesia was associated with a significant decrease in spatiotemporal complexity (median [25th, 75th]; baseline, 0.660 [0.620, 0.690] vs. maintenance, 0.459 [0.402, 0.527]; P < 0.001), and spatiotemporal complexity exceeded baseline levels during postoperative recovery (0.704 [0.642, 0.745]; P = 0.009). When normalized, there was a similar reduction in complexity during general anesthesia (baseline, 0.913 [0.887, 0.923] vs. maintenance 0.851 [0.823, 0.877]; P < 0.001), but complexity remained significantly reduced during recovery (0.873 [0.840, 0.902], P < 0.001). CONCLUSIONS: Cortical complexity increased with developmental age and decreased during general anesthesia. This association remained significant when controlling for spectral changes during anesthetic-induced perturbations in consciousness but not with developmental age.

Propofol versus dexmedetomidine during drug-induced sleep endoscopy (DISE) for pediatric obstructive sleep apnea.

PURPOSE: To test for differences in DISE findings in children sedated with propofol versus dexmedetomidine. We hypothesized that the frequency of ≥ 50% obstruction would be higher for the propofol than dexmedetomidine group at the dynamic levels of the airway (velum, lateral walls, tongue base, and supraglottis) but not at the more static adenoid level. METHODS: A single-center retrospective review was performed on children age 1-18 years with a diagnosis of sleep disordered breathing or obstructive sleep apnea (OSA) who underwent DISE from July 2014 to Feb 2019 scored by the Chan-Parikh scale sedated with either propofol or dexmedetomidine (with or without ketamine). Logistic regression was used to test for a difference in the odds of ≥ 50% obstruction (Chan-Parikh score ≥ 2) at each airway level with the use of dexmedetomidine vs. propofol, adjusted for age, sex, previous tonsillectomy, surgeon, positional OSA, and ketamine co-administration. RESULTS: Of 117 subjects, 57% were sedated with propofol and 43% with dexmedetomidine. Subjects were 60% male, 66% Caucasian, 31% obese, 38% syndromic, and on average 6.5 years old. Thirty-three percent had severe OSA and 41% had previous tonsillectomy. There was no statistically significant difference in the odds of ≥ 50% obstruction between the two anesthetic groups at any level of the airway with or without adjustment for potential confounders. CONCLUSION: We did not find a significant difference in the degree of upper airway obstruction on DISE in children sedated with propofol versus dexmedetomidine. Prospective, randomized studies would be an important next step to confirm these findings.

Preoperative Predictors of Severe Respiratory Events After Tonsillectomy: Consideration for Pediatric Intensive Care Admission.

OBJECTIVE: Few data are available to guide postadenotonsillectomy (AT) pediatric intensive care (PICU) admission. The aim of this study of children with a preoperative polysomnogram (PSG) was to assess whether preoperative information may predict severe respiratory events (SRE) after AT. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary center. METHODS: Children aged 6 months to 17 years who underwent AT with preoperative polysomnography (2012-2018) were identified by billing codes. Data were extracted from medical records. SRE were defined as any 1 or more of desaturations <80% requiring intervention; newly initiated positive airway pressure; postoperative intubation; pneumonia/pneumonitis; respiratory code, cardiac arrest, or death. We hypothesized that SRE would be associated with age <24 months, major medical comorbidity, obesity (>95th percentile), apnea-hypopnea index (AHI) ≥ 30, and O2 nadir <70% on PSG. Analysis was performed with multivariable logistic regression. RESULTS: Of 1774 subjects, 28 (1.7%) experienced SRE. Compared to those without, children with SRE were on average younger (3 vs 5 years, p < .01) with a greater probability of medical comorbidities (59% vs 18%, p < .001). After adjustment for sex, black race, obesity, and age <24 months, children with major medical comorbidity were more likely than other children to have SRE (odds ratio [OR]: 14.2; 95% confidence interval [CI]: [5.7, 35.2]), as were children with AHI ≥ 30 (OR: 7.7 [3.0, 19.9]), or O2 nadir <70% (OR 6.1 [2.1, 17.9]). Age, obesity, sex, and black race did not independently predict SRE. CONCLUSION: PICU admission may be most prudent for children with complex medical co-morbidities, high AHI (>30), and/or low O2 nadir (<70%).

Neurobiological antecedents of multisite pain in children.

ABSTRACT: Altered brain structure and function is evident in adults with multisite chronic pain. Although many such adults trace their pain back to childhood, it has been difficult to disentangle whether central nervous system alterations precede or are consequences of chronic pain. If the former is true, aberrant brain activity may identify children vulnerable to developing chronic pain later in life. We examined structural and functional brain magnetic resonance imaging metrics in a subset of children from the first 2 assessments of the Adolescent Brain and Cognitive Development Study. Children (aged 9-10) who were pain free at baseline and then developed multisite pain 1 year later (n = 115) were matched to control children who were pain free at both timepoints (n = 230). We analyzed brain structure (cortical thickness and gray matter volume) and function (spontaneous neural activity and functional connectivity). Results were deemed significant at the cluster level P < 0.05 false discovery rate corrected for multiple comparisons. At baseline, children who subsequently developed multisite pain had increased neural activity in superior parietal /primary somatosensory and motor cortices and decreased activity in the medial prefrontal cortex. They also exhibited stronger functional connectivity between the salience network, somatosensory, and default mode network regions. No significant differences in the brain structure were observed. Increased neural activity and functional connectivity between brain regions, consistent to that seen in adults with chronic pain, exist in children before developing multisite pain. These findings may represent a neural vulnerability to developing future chronic pain.

Cortical Oscillations and Connectivity During Postoperative Recovery.

BACKGROUND: The objective of this study was to test whether postoperative electroencephalographic (EEG) biomarkers, parietal alpha power and frontal-parietal connectivity, were associated with measures of clinical recovery in adult surgical patients. METHODS: This is a secondary analysis of a prospective cohort study that analyzed intraoperative connectivity patterns in adult surgical patients (N=53). Wireless, whole-scalp EEG data were collected in the postanesthesia care unit and assessed for relevance to clinical and neurocognitive recovery. Parietal alpha power and frontal-parietal connectivity (estimated by weighted phase lag index) were tested for associations with postanesthesia care unit discharge readiness and University of Michigan Sedation Scale scores upon postoperative admission. Bivariable correlation and regression models were constructed to test for unadjusted associations, then multivariable regression models were constructed to adjust for confounding. RESULTS: Postoperative EEG patterns were characterized by a predominance of alpha parietal power and frontal-parietal connectivity. Neither relative parietal alpha power (% alpha, -0.25; 95% confidence interval [CI], -1.41 to 0.90; P=0.657) nor alpha frontal-parietal connectivity (weighted phase lag index, -82; 95% CI, -237 to 73; P=0.287) were associated with time until postanesthesia discharge criteria were met. Furthermore, neither alpha power (-0.03; 95% CI, -0.07 to 0.01; P=0.206) nor alpha frontal-parietal connectivity (-4.2; 95% CI, -11 to 2.6; P=0.226) were associated with sedation scores upon initial assessment. CONCLUSIONS: In a pragmatic study investigating clinically relevant endpoints of postoperative recovery, we found no correlation with surrogate measures of brain neurodynamics. These data contribute to the overall impetus of developing anesthetic-invariant and generalizable markers of brain recovery.

Ethanol acutely inhibits ionotropic glutamate receptor-mediated responses and long-term potentiation in the developing CA1 hippocampus.

BACKGROUND: Developmental ethanol (EtOH) exposure damages the hippocampus, causing long-lasting alterations in learning and memory. Alterations in glutamatergic synaptic transmission and plasticity may play a role in the mechanism of action of EtOH. This signaling is fundamental for synaptogenesis, which occurs during the third trimester of human pregnancy (first 12 days of life in rats). METHODS: Acute coronal brain slices were prepared from 7- to 9-day-old rats. Extracellular and patch-clamp electrophysiological recording techniques were used to characterize the acute effects of EtOH on alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated responses and long-term potentiation (LTP) in the CA1 hippocampal region. RESULTS: Ethanol (40 and 80 mM) inhibited AMPAR- and NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs). EtOH (80 mM) also reduced AMPAR-mediated fEPSPs in the presence of an inhibitor of Ca2+ permeable AMPARs. The effect of 80 mM EtOH on NMDAR-mediated fEPSPs was significantly greater in the presence of Mg2+. EtOH (80 mM) neither affected the paired-pulse ratio of AMPAR-mediated fEPSPs nor the presynaptic volley. The paired-pulse ratio of AMPAR-mediated excitatory postsynaptic currents was not affected either, and the amplitude of these currents was inhibited to a lesser extent than that of fEPSPs. EtOH (80 mM) inhibited LTP of AMPAR-mediated fEPSPs. CONCLUSIONS: Acute EtOH exposure during the third-trimester equivalent of human pregnancy inhibits hippocampal glutamatergic transmission and LTP induction, which could alter synapse refinement and ultimately contribute to the pathophysiology of fetal alcohol spectrum disorder.

Loss of Corneal Reflex in Children Undergoing Spinal Anesthesia: A Case Series.

Spinal anesthesia is administered for select procedures in the pediatric population and offers a safe alternative to general anesthesia. In this case series, we report loss of corneal and eyelash reflexes in 4 children who underwent spinal anesthesia for lower abdominal procedures. While initially thought to be the result of higher-than-intended spinal anesthesia, the observation that gentle stimulation produced vigorous phonation, orbicularis oculi constriction, and upper extremity movement suggests an alternative mechanism. This finding highlights a potential gap in knowledge related to the effect spinal anesthesia has on brain dynamics in children.

Focus on: neurotransmitter systems.

Neurotransmitter systems have been long recognized as important targets of the developmental actions of alcohol (i.e., ethanol). Short- and long-term effects of ethanol on amino acid (e.g., γ-aminobutyric acid and glutamate) and biogenic amine (e.g., serotonin and dopamine) neurotransmitters have been demonstrated in animal models of fetal alcohol spectrum disorders (FASD). Researchers have detected ethanol effects after exposure during developmental periods equivalent to the first, second, and third trimesters of human pregnancy. Results support the recommendation that pregnant women should abstain from drinking-even small quantities-as effects of ethanol on neurotransmitter systems have been detected at low levels of exposure. Recent studies have elucidated new mechanisms and/or consequences of the actions of ethanol on amino acid and biogenic amine neuro-transmitter systems. Alterations in these neurotransmitter systems could, in part, be responsible for many of the conditions associated with FASD, including (1) learning, memory, and attention deficits; (2) motor coordination impairments; (3) abnormal responsiveness to stress; and (4) increased susceptibility to neuropsychiatric disorders, such as substance abuse and depression, and also neurological disorders, such as epilepsy and sudden infant death syndrome. However, future research is needed to conclusively establish a causal relationship between these conditions and developmental dysfunctions in neurotransmitter systems.

Repeated third trimester-equivalent ethanol exposure inhibits long-term potentiation in the hippocampal CA1 region of neonatal rats.

Developmental ethanol exposure damages the hippocampus, causing long-lasting learning and memory deficits. Synaptic plasticity mechanisms (e.g., long-term potentiation [LTP]) contribute to synapse formation and refinement during development. We recently showed that acute ethanol exposure inhibits glutamatergic synaptic transmission and N-methyl-d-aspartate receptor (NMDAR)-dependent LTP in the CA1 hippocampal region of postnatal day (P)7-9 rats. The objective of this study was to further characterize the effect of ethanol on LTP in the developing CA1 hippocampus during the third trimester equivalent. To more closely model human ethanol exposure during this period, rat pups were exposed to ethanol vapor (2 or 4.5 g/dL in air, serum ethanol concentrations=96.6-147.2 or 322-395.6 mg/dL) from P2-9 (4h/d). Brain slices were prepared immediately after the end of the 4-h exposure on P7-9 and extracellular electrophysiological recordings were performed 1-7h later under ethanol-free conditions to model early withdrawal. LTP was not different than group-matched controls in the 96.6-147.2mg/dL group; however, it was impaired in the 322-395.6 mg/dL group. Neither alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)/NMDAR function nor glutamate release were affected in the 322-395.6 mg/dL ethanol exposure group. These data suggest that repeated in vivo exposure to elevated ethanol doses during the third trimester-equivalent period impairs synaptic plasticity, which may alter maturation of hippocampal circuits and ultimately contribute to the long-lasting cognitive deficits associated with fetal alcohol spectrum disorders.

AMPAR-mediated synaptic transmission in the CA1 hippocampal region of neonatal rats: unexpected resistance to repeated ethanol exposure.

Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamatergic receptors (AMPAR) mediate most of the fast excitatory synaptic transmission in mature neurons. In contrast, a number of developing synapses do not express AMPARs; these are gradually acquired in an activity-driven manner during the first week of life in rats, which is equivalent to the third trimester of human pregnancy. Neuronal stimulation has been shown to drive high conductance Ca(2+)-permeable AMPARs into the synapse, strengthening glutamatergic synaptic transmission. Alterations in this process could induce premature stabilization or inappropriate elimination of newly formed synapses and contribute to the hippocampal abnormalities associated with fetal alcohol spectrum disorder. Previous studies from our laboratory performed with hippocampal slices from neonatal rats showed that acute ethanol exposure exerts potent stimulant effects on CA1 and CA3 neuronal networks. However, the impact of these in vitro actions of acute ethanol exposure is unknown. Here, we tested the hypothesis that repeated in vivo exposure to ethanol strengthens AMPAR-mediated neurotransmission in the CA1 region by means of an increase in synaptic expression of Ca(2+)-permeable AMPARs. We exposed rats to ethanol vapor (serum ethanol concentration approximately 40 mM) or air for 4h/day from postnatal day (P) 2-6. In brain slices prepared at P4-6, we found no significant effect of ethanol exposure on input-output curves for AMPAR-mediated field excitatory postsynaptic potentials (fEPSPs), the contribution of Ca(2+)-permeable AMPARs to these fEPSPs, or the acute effect of ethanol on fEPSP amplitude. These results suggest that homeostatic plasticity mechanisms act to maintain glutamatergic synaptic strength and ethanol sensitivity in response to repeated developmental ethanol exposure.