Development of Postanesthesia Care Unit Delirium Is Associated with Differences in Aperiodic and Periodic Alpha Parameters of the Electroencephalogram during Emergence from General Anesthesia: Results from a Prospective Observational Cohort Study.

BACKGROUND: Intraoperative alpha-band power in frontal electrodes may provide helpful information about the balance of hypnosis and analgesia and has been associated with reduced occurrence of delirium in the postanesthesia care unit. Recent studies suggest that narrow-band power computations from neural power spectra can benefit from separating periodic and aperiodic components of the electroencephalogram. This study investigates whether such techniques are more useful in separating patients with and without delirium in the postanesthesia care unit at the group level as opposed to conventional power spectra. METHODS: Intraoperative electroencephalography recordings of 32 patients who developed perioperative neurocognitive disorders and 137 patients who did not were considered in this post hoc secondary analysis. The power spectra were calculated using conventional methods and the "fitting oscillations and one over f" algorithm was applied to separate aperiodic and periodic components to see whether the electroencephalography signature is different between groups. RESULTS: At the group level, patients who did not develop perioperative neurocognitive disorders presented with significantly higher alpha-band power and a broadband increase in power, allowing a "fair" separation based on conventional power spectra. Within the first third of emergence, the difference in median absolute alpha-band power amounted to 8.53 decibels (area under the receiver operator characteristics curve, 0.74 [0.65; 0.82]), reaching its highest value. In relative terms, the best separation was achieved in the second third of emergence, with a difference in medians of 7.71% (area under the receiver operator characteristics curve, 0.70 [0.61; 0.79]). The area under the receiver operator characteristics curve values were generally lower toward the end of emergence with increasing arousal. CONCLUSIONS: Increased alpha-band power during emergence in patients who did not develop perioperative neurocognitive disorders can be traced back to an increase in oscillatory alpha activity and an overall increase in aperiodic broadband power. Although the differences between patients with and without perioperative neurocognitive disorders can be detected relying on traditional methods, the separation of the signal allows a more detailed analysis. This may enable clinicians to detect patients at risk for developing perioperative neurocognitive disorders in the postanesthesia care unit early in the emergence phase.

Electroencephalographic monitoring of anesthesia during surgical procedures in mice using a modified clinical monitoring system.

Monitoring brain activity and associated physiology during the administration of general anesthesia (GA) in mice is pivotal to guarantee postanesthetic health. Clinically, electroencephalogram (EEG) monitoring is a well-established method to guide GA. There are no established methods available for monitoring EEG in mice (Mus musculus) during surgery. In this study, a minimally invasive rodent intraoperative EEG monitoring system was implemented using subdermal needle electrodes and a modified EEG-based commercial patient monitor. EEG recordings were acquired at three different isoflurane concentrations revealing that surgical concentrations of isoflurane anesthesia predominantly contained burst suppression patterns in mice. EEG suppression ratios and suppression durations showed strong positive correlations with the isoflurane concentrations. The electroencephalographic indices provided by the monitor did not support online monitoring of the anesthetic status. The online available suppression duration in the raw EEG signals during isoflurane anesthesia is a straight forward and reliable marker to assure safe, adequate and reproducible anesthesia protocols.

Predictors of Low Risk for Delirium during Anesthesia Emergence.

BACKGROUND: Processed electroencephalography (EEG) is used to monitor the level of anesthesia, and it has shown the potential to predict the occurrence of delirium. While emergence trajectories of relative EEG band power identified post hoc show promising results in predicting a risk for a delirium, they are not easily transferable into an online predictive application. This article describes a low-resource and easily applicable method to differentiate between patients at high risk and low risk for delirium, with patients at low risk expected to show decreasing EEG power during emergence. METHODS: This study includes data from 169 patients (median age, 61 yr [49, 73]) who underwent surgery with general anesthesia maintained with propofol, sevoflurane, or desflurane. The data were derived from a previously published study. The investigators chose a single frontal channel, calculated the total and spectral band power from the EEG and calculated a linear regression model to observe the parameters' change during anesthesia emergence, described as slope. The slope of total power and single band power was correlated with the occurrence of delirium. RESULTS: Of 169 patients, 32 (19%) showed delirium. Patients whose total EEG power diminished the most during emergence were less likely to screen positive for delirium in the postanesthesia care unit. A positive slope in total power and band power evaluated by using a regression model was associated with a higher risk ratio (total, 2.83 [95% CI, 1.46 to 5.51]; alpha/beta band, 7.79 [95% CI, 2.24 to 27.09]) for delirium. Furthermore, a negative slope in multiple bands during emergence was specific for patients without delirium and allowed definition of a test for patients at low risk. CONCLUSIONS: This study developed an easily applicable exploratory method to analyze a single frontal EEG channel and to identify patterns specific for patients at low risk for delirium.

The Influence of Electromyographic on Electroencephalogram-Based Monitoring: Putting the Forearm on the Forehead.

BACKGROUND: Monitoring the electroencephalogram (EEG) during general anesthesia can help to safely navigate the patient through the procedure by avoiding too deep or light anesthetic levels. In daily clinical practice, the EEG is recorded from the forehead and available neuromonitoring systems translate the EEG information into an index inversely correlating with the anesthetic level. Electrode placement on the forehead can lead to an influence of electromyographic (EMG) activity on the recorded signal in patients without neuromuscular blockade (NMB). A separation of EEG and EMG in the clinical setting is difficult because both signals share an overlapping frequency range. Previous research showed that indices decreased when EMG was absent in awake volunteers with NMB. Here, we investigated to what extent the indices changed, when EEG recorded during surgery with NMB agents was superimposed with EMG. METHODS: We recorded EMG from the flexor muscles of the forearm of 18 healthy volunteers with a CONOX monitor during different activity settings, that is, during contraction using a grip strengthener and during active diversion (relaxed arm). Both the forehead and forearm muscles are striated muscles. The recorded EMG was normalized by z-scoring and added to the EEG in different amplification steps. The EEG was recorded during anesthesia with NMB. We replayed these combined EEG and EMG signals to different neuromonitoring systems, that is, bispectral index (BIS), CONOX with qCON and qNOX, and entropy module with state entropy (SE) and response entropy (RE). We used the Friedman test and a Tukey-Kramer post hoc correction for statistical analysis. RESULTS: The indices of all neuromonitoring systems significantly increased when the EEG was superimposed with the contraction EMG and with high EMG amplitudes, the monitors returned invalid values, representative of artifact contamination. When replaying the EEG being superimposed with "relaxed" EMG, the qCON and BIS showed significant increases, but not SE and RE. For SE and RE, we observed an increased number of invalid values. CONCLUSIONS: With our approach, we could show that EMG activity during contraction and resting state can influence the neuromonitoring systems. This knowledge may help to improve EEG-based patient monitoring in the future and help the anesthesiologist to use the neuromonitoring systems with more knowledge regarding their function.

Performance of the SEDLine Monitor: Age Dependency and Time Delay.

BACKGROUND: Devices monitoring the hypnotic component of general anesthesia can help to guide anesthetic management. The main purposes of these devices are the titration of anesthesia dose. While anesthesia at low doses can result in awareness with intraoperative memory formation, excessive administration of anesthetics may be associated with an increased risk of postoperative neurocognitive disorder. We have previously shown for various indices that they are significantly influenced by the patient's age and that the monitors have a significant time delay. Here, we evaluated the influence of patient's age and time delay on the patient state index (PSI) of the SEDLine monitor. METHODS: To analyze the influence of the patient's age, we replayed 2 minutes of electroencephalography (EEG) of 141 patients (19-88 years, ASA I-IV) undergoing general anesthesia maintained with desflurane, sevoflurane, or propofol to the SEDLine monitor. We extracted the PSI as well as the spectral edge frequency (SEF) and performed a linear regression analysis. For evaluation of the time delay, we replayed 5 minutes of EEG of stable episodes of adequate anesthesia (PSI between 25 and 50) or light sedation/wake (PSI >70) in different orders to the SEDLine to simulate sudden changes between the states. Time delays were defined as the required time span of the monitor to reach the stable target index. RESULTS: PSI and SEF increased significantly with the patient's age. These findings did not depend on the administered anesthetic. The evaluation of the correlation between SEF and PSI showed a strong correlation with Spearman's correlation coefficient of ρ = 0.86 (0.82; 0.89). The time delays depended on the type of transition. We found a median time delay of 54 (Min: 46; Max: 61) seconds for the important transition between adequate anesthesia and awake and 55 (Min: 50; Max: 67) seconds in the other direction. CONCLUSIONS: With our analyses, we show that the indices presented on the SEDLine display, the PSI and the SEF, increase with age for patients under general anesthesia. Additionally, a delay of the PSI to react to sudden neurophysiologic changes due to dose of the maintenance anesthetic is of a time course that is clinically significant. These factors should be considered when navigating anesthesia relying on only the proprietary index for the SEDLine monitor.

Associations of an eye-tracking task and pupillary metrics with age and ASA physical status score in a preoperative cohort.

Advanced age, American Society of Anesthesiologists physical status (ASA) classification and the presence of cognitive impairment are associated with an elevated risk of postoperative morbidity and mortality. The visual paired comparison (VPC) task, which relies on recognition of novel images, examines declarative memory. VPC scores have demonstrated the ability to detect mild cognitive impairment and track progression of neurodegenerative disease. Quantitative pupillometry may have similar value. We evaluate for associations between these variables of interest and the feasibility of performing these tests in the preoperative clinic. Prospective data from 199 patients seen in the preoperative clinic at a tertiary academic center were analyzed. A 5 min VPC task (Neurotrack Technologies, Inc, Redwood City, CA) was administered during their scheduled preoperative clinic visit. Pupillary light reflexes were measured at the same visit (PLR-3000™, Neuroptics Corp, Irvine, California).Thirty-four percent of patients were categorized as ASA 2 and 58% as ASA 3. Median age was 57 (IQR: 44-69). Associations were demonstrated between age and ASA physical status (Mann-Whitney U Test, p < 0.0001), maximum pupil size (Spearman Rank Correlation, r = - 0.40, p < 0.0001), and maximum constriction velocity (Spearman Rank Correlation, r = - 0.39, p < 0.0001). Our data also revealed an association between VPC score and age (Spearman Rank Correlation, p = 0.0016, r = - 0.21) but not ASA score (Kruskal-Wallis Test, p = 0.14). When compared to a nonsurgical cohort with no history of memory impairment, our population scored worse on the VPC task (Mann-Whitney U Test, p = 0.0002). A preoperative 5 min VPC task and pupillometry are feasible tests in the preoperative setting and may provide a valuable window into an individual's cognition prior to elective surgery.

Ketamine-Associated Intraoperative Electroencephalographic Signatures of Elderly Patients With and Without Preoperative Cognitive Impairment.

BACKGROUND: Ketamine is typically used by anesthesiologists as an adjunct for general anesthesia and as a nonopioid analgesic. It has been explored for prevention of postoperative delirium, although results have been contradictory. In this study, we investigated the association of ketamine with postoperative delirium and specific encephalographic signatures. Furthermore, we examined these associations in the context of baseline neurocognition as measured by a validated assessment. METHODS: We conducted a prospective observational study from January 2019 to December 2020. Ninety-eight patients aged ≥65 years and undergoing spine surgery scheduled for ≥3 hours were included in the study. All participants who completed the University of California San Francisco (UCSF) Brain Health Assessment preoperatively and postoperatively were assessed with the confusion assessment method for intensive care unit (CAM-ICU) and/or the Nursing Delirium Screening Scale (NuDESC). Patients had frontal electroencephalogram (EEG) recordings (SedLine Root, Masimo, Corp) quantitatively analyzed. We used 60 seconds of artifact-free EEG (without burst suppression) extracted from the middle of the maintenance period to calculate the normalized power spectral density (PSD). Comparisons were made between those who did or did not receive ketamine and according to results from neurocognitive assessments. RESULTS: Ninety-eight patients (of a total of 155, enrolled and consented) had EEG of sufficient quality for analysis (42 women). Overall, we found a significant increase in the EEG power in the moderate frequency range (10-20 Hz) in patients that received ketamine. When the patients were divided by their preoperative cognitive status, this result in the ketamine group only held true for the cognitively normal patients. Patients that were cognitively impaired at baseline did not demonstrate a significant change in EEG characteristics based on ketamine administration, but impaired patients that received ketamine had a significantly higher rate of postoperative delirium (52% ketamine versus 20% no ketamine) (odds ratio [OR], 4.36; confidence interval [CI], 1.02-18.22; P = .048). In patients determined to be preoperatively cognitively normal, the incidence of postoperative delirium was not significantly associated with ketamine administration (19% ketamine versus 17% no ketamine) (OR, 1.10; CI, 0.30-4.04; P = .5833). CONCLUSIONS: Ketamine-related changes in EEG are observed in a heterogeneous group of patients receiving spine surgery. This result was driven primarily by the effect of ketamine on cognitively normal patients and not observed in patients that were cognitively impaired at baseline. Furthermore, patients who were cognitively impaired at baseline and who had received ketamine were more likely to develop postoperative delirium, suggesting that cognitive vulnerability might be predicted by the lack of a neurophysiologic response to ketamine.

The First Derivative of the Electroencephalogram Facilitates Tracking of Electroencephalographic Alpha Band Activity During General Anesthesia.

BACKGROUND: Intraoperative neuromonitoring can help to navigate anesthesia. Pronounced alpha oscillations in the frontal electroencephalogram (EEG) appear to predict favorable perioperative neurocognitive outcomes and may also provide a measure of intraoperative antinociception. Monitoring the presence and strength of these alpha oscillations can be challenging, especially in elderly patients, because the EEG in these patients may be dominated by oscillations in other frequencies. Hence, the information regarding alpha oscillatory activity may be hidden and hard to visualize on a screen. Therefore, we developed an effective approach to improve the detection and presentation of alpha activity in the perioperative setting. METHODS: We analyzed EEG records of 180 patients with a median age of 60 years (range, 18-90 years) undergoing noncardiac, nonneurologic surgery under general anesthesia with propofol induction and sevoflurane maintenance. We calculated the power spectral density (PSD) for the unprocessed EEG as well as for the time-discrete first derivative of the EEG (diffPSD) from 10-second epochs. Based on these data, we estimated the power-law coefficient κ of the PSD and diffPSD, as the EEG coarsely follows a 1/fκ distribution when displayed in double logarithmic coordinates. In addition, we calculated the alpha (7.8-12.1 Hz) to delta (0.4-4.3 Hz) ratio from the PSD as well as diffPSD. RESULTS: The median κ was 0.899 [first and third quartile: 0.786, 0.986] for the unaltered PSD, and κ = -0.092 [-0.202, -0.013] for the diffPSD, corresponding to an almost horizontal PSD of the differentiated EEG. The alpha-to-delta ratio of the diffPSD was strongly increased (median ratio = -8.0 dB [-10.5, -4.7 dB] for the unaltered PSD versus 30.1 dB [26.1, 33.8 dB] for the diffPSD). A strong narrowband oscillatory alpha power component (>20% of total alpha power) was detected in 23% using PSD, but in 96% of the diffPSD. CONCLUSIONS: We demonstrated that the calculation of the diffPSD from the time-discrete derivative of the intraoperative frontal EEG is a straightforward approach to improve the detection of alpha activity by eliminating the broadband background noise. This improvement in alpha peak detection and visualization could facilitate the guidance of general anesthesia and improve patient outcome.

Raspberry Pi-Based Data Archival System for Electroencephalogram Signals From the SedLine Root Device.

BACKGROUND: The retrospective analysis of electroencephalogram (EEG) signals acquired from patients under general anesthesia is crucial in understanding the patient's unconscious brain's state. However, the creation of such database is often tedious and cumbersome and involves human labor. Hence, we developed a Raspberry Pi-based system for archiving EEG signals recorded from patients under anesthesia in operating rooms (ORs) with minimal human involvement. METHODS: Using this system, we archived patient EEG signals from over 500 unique surgeries at the Emory University Orthopaedics and Spine Hospital, Atlanta, for about 18 months. For this, we developed a software package that runs on a Raspberry Pi and archives patient EEG signals from a SedLine Root EEG Monitor (Masimo) to a secure Health Insurance Portability and Accountability Act (HIPAA) compliant cloud storage. The OR number corresponding to each surgery was archived along with the EEG signal to facilitate retrospective EEG analysis. We retrospectively processed the archived EEG signals and performed signal quality checks. We also proposed a formula to compute the proportion of true EEG signal and calculated the corresponding statistics. Further, we curated and interleaved patient medical record information with the corresponding EEG signals. RESULTS: We retrospectively processed the EEG signals to demonstrate a statistically significant negative correlation between the relative alpha power (8-12 Hz) of the EEG signal captured under anesthesia and the patient's age. CONCLUSIONS: Our system is a standalone EEG archiver developed using low cost and readily available hardware. We demonstrated that one could create a large-scale EEG database with minimal human involvement. Moreover, we showed that the captured EEG signal is of good quality for retrospective analysis and combined the EEG signal with the patient medical records. This project's software has been released under an open-source license to enable others to use and contribute.

Effects of noxious stimulation on the electroencephalogram during general anaesthesia: a narrative review and approach to analgesic titration.

Electroencephalographic (EEG) activity is used to monitor the neurophysiology of the brain, which is a target organ of general anaesthesia. Besides its use in evaluating hypnotic states, neurophysiologic reactions to noxious stimulation can also be observed in the EEG. Recognising and understanding these responses could help optimise intraoperative analgesic management. This review describes three types of changes in the EEG induced by noxious stimulation when the patient is under general anaesthesia: (1) beta arousal, (2) (paradoxical) delta arousal, and (3) alpha dropout. Beta arousal is an increase in EEG power in the beta-frequency band (12-25 Hz) in response to noxious stimulation, especially at lower doses of anaesthesia drugs in the absence of opioids. It is usually indicative of a cortical depolarisation and increased cortical activity. At higher concentrations of anaesthetic drug, and with insufficient opioids, delta arousal (increased power in the delta band [0.5-4 Hz]) and alpha dropout (decreased alpha power [8-12 Hz]) are associated with noxious stimuli. The mechanisms of delta arousal are not well understood, but the midbrain reticular formation seems to play a role. Alpha dropout may indicate a return of thalamocortical communication, from an idling mode to an operational mode. Each of these EEG changes reflect an incomplete modulation of pain signals and can be mitigated by administration of opioid or the use of regional anaesthesia techniques. Future studies should evaluate whether titrating analgesic drugs in response to these EEG signals reduces postoperative pain and influences other postoperative outcomes, including the potential development of chronic pain.

Repetitive Anodal Transcranial Direct Current Stimulation Hastens Isoflurane-Induced Emergence and Recovery and Enhances Memory in Healthy Rats.

BACKGROUND: Attaining a rapid and smooth return to consciousness after general anesthesia is a goal for clinical anesthesiologists. This study aimed to investigate the effects of repeated anodal transcranial direct current stimulation (atDCS) on emergence and recovery from isoflurane anesthesia in rats. METHODS: Four days after surgery for atDCS socket implantation, rats received either sham stimulation or repetitive anodal direct electrical current of 0.2 mA intensity applied to the right motor cortex for 20 minutes/d for 10 consecutive days. Isoflurane potency and emergence and recovery from a 2-hour isoflurane challenge were evaluated 24 hours after the last atDCS session. Cognitive performance on novel object recognition and spontaneous alternation Y-maze tests were measured 48 hours after the last atDCS session. Locomotor activity was assessed via automated counting of electric infrared beam crossings. RESULTS: Data are expressed as mean ± standard error of mean (SEM). Isoflurane potency was not affected by atDCS (sham: 1.69% ± 0.06%, transcranial direct current stimulation [tDCS]: 1.73% ± 0.11%, mean difference [MD]: 0.045, 95% confidence interval [CI]: -0.22 to 0.30; P = .72). However, the time to appearance of emergence behavioral marker (eg, return of righting reflex) was hastened in rats receiving atDCS (sham: 486 ± 31 seconds, tDCS: 330 ± 45 seconds, MD: 157, 95% CI: 30-284; P = .008). Similarly, time to acknowledgment of adhesive tape ("sticky dot" applied while anesthetized) was also decreased in atDCS-treated rats as compared to sham (sham: 1374 ± 179 seconds, tDCS: 908 ± 151 seconds, MD: 466, 95% CI: 73-858; P = .015), indicating a faster recovery of isoflurane anesthesia. Rats treated with atDCS spent more time exploring the novel object and environment when compared to sham without affecting activity cycles, indicating visual and working memory can be enhanced by atDCS. CONCLUSIONS: Taken together, our findings suggest that atDCS over cortical areas might hasten recovery from isoflurane anesthesia and could potentially be used as a preventative strategy for disruptions in higher order functions related to sedation/anesthesia.

Spectral and Entropic Features Are Altered by Age in the Electroencephalogram in Patients under Sevoflurane Anesthesia.

BACKGROUND: Preexisting factors such as age and cognitive performance can influence the electroencephalogram (EEG) during general anesthesia. Specifically, spectral EEG power is lower in elderly, compared to younger, subjects. Here, the authors investigate age-related changes in EEG architecture in patients undergoing general anesthesia through a detailed examination of spectral and entropic measures. METHODS: The authors retrospectively studied 180 frontal EEG recordings from patients undergoing general anesthesia, induced with propofol/fentanyl and maintained by sevoflurane at the Waikato Hospital in Hamilton, New Zealand. The authors calculated power spectral density and normalized power spectral density, the entropic measures approximate and permutation entropy, as well as the beta ratio and spectral entropy as exemplary parameters used in current monitoring systems from segments of EEG obtained before the onset of surgery (i.e., with no noxious stimulation). RESULTS: The oldest quartile of patients had significantly lower 1/f characteristics (P < 0.001; area under the receiver operating characteristics curve, 0.84 [0.76 0.92]), indicative of a more uniform distribution of spectral power. Analysis of the normalized power spectral density revealed no significant impact of age on relative alpha (P = 0.693; area under the receiver operating characteristics curve, 0.52 [0.41 0.63]) and a significant but weak effect on relative beta power (P = 0.041; area under the receiver operating characteristics curve, 0.62 [0.52 0.73]). Using entropic parameters, the authors found a significant age-related change toward a more irregular and unpredictable EEG (permutation entropy: P < 0.001, area under the receiver operating characteristics curve, 0.81 [0.71 0.90]; approximate entropy: P < 0.001; area under the receiver operating characteristics curve, 0.76 [0.66 0.85]). With approximate entropy, the authors could also detect an age-induced change in alpha-band activity (P = 0.002; area under the receiver operating characteristics curve, 0.69 [0.60 78]). CONCLUSIONS: Like the sleep literature, spectral and entropic EEG features under general anesthesia change with age revealing a shift toward a faster, more irregular, oscillatory composition of the EEG in older patients. Age-related changes in neurophysiological activity may underlie these findings however the contribution of age-related changes in filtering properties or the signal to noise ratio must also be considered. Regardless, most current EEG technology used to guide anesthetic management focus on spectral features, and improvements to these devices might involve integration of entropic features of the raw EEG.

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on the Role of Neuromonitoring in Perioperative Outcomes: Electroencephalography.

Electroencephalographic (EEG) monitoring to indicate brain state during anesthesia has become widely available. It remains unclear whether EEG-guided anesthesia influences perioperative outcomes. The sixth Perioperative Quality Initiative (POQI-6) brought together an international team of multidisciplinary experts from anesthesiology, biomedical engineering, neurology, and surgery to review the current literature and to develop consensus recommendations on the utility of EEG monitoring during anesthesia. We retrieved a total of 1023 articles addressing the use of EEG monitoring during anesthesia and conducted meta-analyses from 15 trials to determine the effect of EEG-guided anesthesia on the rate of unintentional awareness, postoperative delirium, neurocognitive disorder, and long-term mortality after surgery. After considering current evidence, the working group recommends that EEG monitoring should be considered as part of the vital organ monitors to guide anesthetic management. In addition, we encourage anesthesiologists to be knowledgeable in basic EEG interpretation, such as raw waveform, spectrogram, and processed indices, when using these devices. Current evidence suggests that EEG-guided anesthesia reduces the rate of awareness during total intravenous anesthesia and has similar efficacy in preventing awareness as compared with end-tidal anesthetic gas monitoring. There is, however, insufficient evidence to recommend the use of EEG monitoring for preventing postoperative delirium, neurocognitive disorder, or postoperative mortality.

Propofol Affects Cortico-Hippocampal Interactions via ß3 Subunit-Containing GABAA Receptors.

BACKGROUND: General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABAA receptors, especially the type with ß3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABAA receptors with ß3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions. METHODS: We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and ß3(N265M) knock-in mice. In the ß3(N265M) mice, the action of propofol via ß3subunit containing GABAA receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2-16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions. RESULTS: Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the ß3(N265M) mutant. Propofol strongly decreased phase locking of 6-12 Hz oscillations in wild-type mice. This decrease was attenuated in the ß3(N265M) mutant. Finally, propofol reduced the mutual information between 6-16 Hz in wild-type mice, but only between 6 and 8 Hz in the ß3(N265M) mutant. CONCLUSIONS: GABAA receptors containing ß3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol.

Sleep/Wake Behavior and EEG Signatures of the TgF344-AD Rat Model at the Prodromal Stage.

Transgenic modification of the two most common genes (APPsw, PS1ΔE9) related to familial Alzheimer's disease (AD) in rats has produced a rodent model that develops pathognomonic signs of AD without genetic tau-protein modification. We used 17-month-old AD rats (n = 8) and age-matched controls (AC, n = 7) to evaluate differences in sleep behavior and EEG features during wakefulness (WAKE), non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) over 24-h EEG recording (12:12h dark-light cycle). We discovered that AD rats had more sleep-wake transitions and an increased probability of shorter REM and NREM bouts. AD rats also expressed a more uniform distribution of the relative spectral power. Through analysis of information content in the EEG using entropy of difference, AD animals demonstrated less EEG information during WAKE, but more information during NREM. This seems to indicate a limited range of changes in EEG activity that could be caused by an AD-induced change in inhibitory network function as reflected by increased GABAAR-ß2 expression but no increase in GAD-67 in AD animals. In conclusion, this transgenic rat model of Alzheimer's disease demonstrates less obvious EEG features of WAKE during wakefulness and less canonical features of sleep during sleep.

The RNA-binding protein, ZC3H14, is required for proper poly(A) tail length control, expression of synaptic proteins, and brain function in mice.

A number of mutations in genes that encode ubiquitously expressed RNA-binding proteins cause tissue specific disease. Many of these diseases are neurological in nature revealing critical roles for this class of proteins in the brain. We recently identified mutations in a gene that encodes a ubiquitously expressed polyadenosine RNA-binding protein, ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), that cause a nonsyndromic, autosomal recessive form of intellectual disability. This finding reveals the molecular basis for disease and provides evidence that ZC3H14 is essential for proper brain function. To investigate the role of ZC3H14 in the mammalian brain, we generated a mouse in which the first common exon of the ZC3H14 gene, exon 13 is removed (Zc3h14Δex13/Δex13) leading to a truncated ZC3H14 protein. We report here that, as in the patients, Zc3h14 is not essential in mice. Utilizing these Zc3h14Δex13/Δex13mice, we provide the first in vivo functional characterization of ZC3H14 as a regulator of RNA poly(A) tail length. The Zc3h14Δex13/Δex13 mice show enlarged lateral ventricles in the brain as well as impaired working memory. Proteomic analysis comparing the hippocampi of Zc3h14+/+ and Zc3h14Δex13/Δex13 mice reveals dysregulation of several pathways that are important for proper brain function and thus sheds light onto which pathways are most affected by the loss of ZC3H14. Among the proteins increased in the hippocampi of Zc3h14Δex13/Δex13 mice compared to control are key synaptic proteins including CaMK2a. This newly generated mouse serves as a tool to study the function of ZC3H14 in vivo.

Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures.

BACKGROUND: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. METHOD: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. RESULTS: While both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p < 0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p < 0.05, Kolmogorov-Smirnov test). CONCLUSION: Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABAA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.

Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations.

General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

Transient electroencephalographic alpha power loss during maintenance of general anaesthesia.

BACKGROUND: EEG activity in the extended alpha frequency range (7-17 Hz) during maintenance of general anaesthesia is primarily determined by effect-site concentrations of the hypnotic and analgesic drugs used. Intermittent alpha loss during surgery, unexplained by changes in anaesthetic or opioid concentrations, could represent arousal of the cortex as a result of increased surgical stimulation. METHODS: A generalised linear model was fitted to alpha power recorded from patients undergoing general anaesthesia from induction until waking using three explanatory variables: age-adjusted volatile anaesthetic effect-site concentration, and estimated effect-site propofol and opioid concentrations. Model residuals were decomposed into uncorrelated white noise and a fluctuating auto-correlated trend. Deviations of this local trend were classified as 'unexpected alpha dropout events'. To investigate whether these alpha dropouts might be explained by the effect of noxious stimulation, we related their occurrence to whether a patient was undergoing surgery involving the body cavity or not. RESULTS: Alpha power dropouts occurred in 73 of the 237 patients included in the final analysis (31%, median amplitude of -3.5 dB, duration=103 s). They showed a bimodal or broadly skewed distribution, being more probable soon after initial incision (32%), dropping to around 10% at 1 h, and then again increasing to >30% in operations lasting >3 h. Multivariate analysis showed that alpha dropouts were significantly associated with body cavity surgery (P=0.003) and with longer operations (P<0.001). CONCLUSIONS: A loss of alpha power, unexplained by changes in anaesthetic or opioid concentrations, is suggestive of thalamocortical depolarisation induced by body cavity noxious stimuli, and could provide a measure of nociception during surgery.

Escape From Oblivion: Neural Mechanisms of Emergence From General Anesthesia.

The question of how general anesthetics suppress consciousness has persisted since the mid-19th century, but it is only relatively recently that the field has turned its focus to a systematic understanding of emergence. Once assumed to be a purely passive process, spontaneously occurring as residual levels of anesthetics dwindle below a critical value, emergence from general anesthesia has been reconsidered as an active and controllable process. Emergence is driven by mechanisms that can be distinct from entry to the anesthetized state. In this narrative review, we focus on the burgeoning scientific understanding of anesthetic emergence, summarizing current knowledge of the neurotransmitter, neuromodulators, and neuronal groups that prime the brain as it prepares for its journey back from oblivion. We also review evidence for possible strategies that may actively bias the brain back toward the wakeful state.