Slow-delta Oscillations Research Articles

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus.

Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism.

Modulatory dynamics mark the transition between anesthetic states of unconsciousness

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state-space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia.

γ-Aminobutyric Acid-Ergic Development Contributes to the Enhancement of Electroencephalogram Slow-Delta Oscillations Under Volatile Anesthesia in Neonatal Rats.

General anesthetics (eg, propofol and volatile anesthetics) enhance the slow-delta oscillations of the cortical electroencephalogram (EEG), which partly results from the enhancement of (γ-aminobutyric acid [GABA]) γ-aminobutyric acid-ergic (GABAergic) transmission. There is a GABAergic excitatory-inhibitory shift during postnatal development. Whether general anesthetics can enhance slow-delta oscillations in the immature brain has not yet been unequivocally determined. Perforated patch-clamp recording was used to confirm the reversal potential of GABAergic currents throughout GABAergic development in acute brain slices of neonatal rats. The power density of the electrocorticogram and the minimum alveolar concentrations (MAC) of isoflurane and/or sevoflurane were measured in P4-P21 rats. Then, the effects of bumetanide, an inhibitor of the Na+-K+-2Cl- cotransporter (NKCC1) and K+-Cl- cotransporter (KCC2) knockdown on the potency of volatile anesthetics and the power density of the EEG were determined in vivo. Reversal potential of GABAergic currents were gradually hyperpolarized from P4 to P21 in cortical pyramidal neurons. Bumetanide enhanced the hypnotic effects of volatile anesthetics at P5 (for MACLORR, isoflurane: 0.63% ± 0.07% vs 0.81% ± 0.05%, 95% confidence interval [CI], -0.257 to -0.103, P < .001; sevoflurane: 1.46% ± 0.12% vs 1.66% ± 0.09%, 95% CI, -0.319 to -0.081, P < .001); while knockdown of KCC2 weakened their hypnotic effects at P21 in rats (for MACLORR, isoflurane: 0.58% ± 0.05% to 0.77% ± 0.20%, 95% CI, 0.013-0.357, P = .003; sevoflurane: 1.17% ± 0.04% to 1.33% ± 0.04%, 95% CI, 0.078-0.244, P < .001). For cortical EEG, slow-delta oscillations were the predominant components of the EEG spectrum in neonatal rats. Isoflurane and/or sevoflurane suppressed the power density of slow-delta oscillations rather than enhancement of it until GABAergic maturity. Enhancement of slow-delta oscillations under volatile anesthetics was simulated by preinjection of bumetanide at P5 (isoflurane: slow-delta changed ratio from -0.31 ± 0.22 to 1.57 ± 1.15, 95% CI, 0.67-3.08, P = .007; sevoflurane: slow-delta changed ratio from -0.46 ± 0.25 to 0.95 ± 0.97, 95% CI, 0.38-2.45, P = .014); and suppressed by KCC2-siRNA at P21 (isoflurane: slow-delta changed ratio from 16.13 ± 5.69 to 3.98 ± 2.35, 95% CI, -18.50 to -5.80, P = .002; sevoflurane: slow-delta changed ratio from 0.13 ± 2.82 to 3.23 ± 2.49, 95% CI, 3.02-10.79, P = .003). Enhancement of cortical EEG slow-delta oscillations by volatile anesthetics may require mature GABAergic inhibitory transmission during neonatal development.

Development of NMDA receptors contributes to the enhancement of electroencephalogram oscillations under volatile anesthetics in rats.

Volatile anesthetics including sevoflurane and isoflurane enhance oscillations of cortical electroencephalogram (EEG), partly by their modulations on glutamate-mediated excitatory synaptic transmission. Expression of NMDA receptors is increased during neonatal development. However, how the development of NMDA receptors influences EEG under volatile anesthesia remains unclear. Expressions of NMDA receptor subtypes (NR1, NR2A, and NR2B) during neonatal development were measured by Western blotting. MAC (minimal alveolar concentration) of isoflurane and sevoflurane that inducing loss of righting reflex (LORR) and no response to tail-clamp (immobility) were measured to verify the effect of NR1 expression on anesthetic potency during neonatal development. Cortical electroencephalogram recording was used to examine the influence of NR1 expression on the power density of EEG. The expressions of GluNR1, GluNR2A and GluNR2B receptors were gradually increased during neonatal development in cortex, hippocampus and thalamus of rats. Knockdown of NR1 enhanced the sedative potency of volatile anesthetics but not on immobility potency in postnatal day 14 (P14)-P17 rats. For cortical EEG, along with the increased concentration of volatile anesthetics, cortical slow-delta oscillations of P5 rats were inhibited, theta and alpha oscillations were not changed significantly; while these oscillations were enhanced until high anesthetic concentrations in P21 rats. Knockdown of NR1 in forebrain suppressed the enhancement of cortical EEG oscillations in P21 rats. The development of NMDA receptors may contribute to the enhancement of cortical EEG oscillations under volatile anesthetics.

An electroencephalogram biomarker of fentanyl drug effects.

Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects, including respiratory depression. At present, we do not have real-time clinical biomarkers of these brain effects. Here, we describe the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4 to 8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation. We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈1700-fold lower concentrations than those that produce sedation as measured by reaction time. The electroencephalogram biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.

Effects of Tai Chi Chuan on cortical sources of EEG rhythms in the resting state in elderly individuals: a cross-sectional study.

A standard low-resolution electromagnetic tomography (sLORETA) technique was used to observe the effect of long-term Tai Chi Chuan practice on the resting state of the brains of elderly individuals. Eyes-closed resting-state electroencephalography (EEG) signals were collected from 14 long-term Tai Chi Chuan (TCC) elderly practitioners, 14 demographically matched healthy controls (HCs) and 14 healthy young adults (HYs). The EEG rhythms of delta, theta, alpha 1, alpha 2, beta 1 and beta 2 were analyzed. The cortical sources of these EEG rhythms were estimated by sLORETA. The data showed that the theta and alpha 1 brain sources in the central, parietal and occipital regions displayed the pattern HY > TTC > HC (P < 0.01). However, the current density of the slow delta rhythm brain sources was significantly higher in HC than in TTC and HY (P < 0.05). The current density of the alpha 1 and alpha 2 rhythm cortical sources in the parietal and occipital cortices increased with an increase in TCC training experience, whereas the current density of the slow rhythm delta increased with an increase in age. Long-term TCC practice is related to cortical neural synchronization of alpha oscillations and the desynchronization of slow delta oscillations in the elderly and might delay physiologic aging effects on brain cognitive function.

A hidden Markov model reliably characterizes ketamine-induced spectral dynamics in macaque local field potentials and human electroencephalograms.

Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes high power gamma (25-50 Hz) oscillations alternating with slow-delta (0.1-4 Hz) oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human subjects. However, a detailed statistical analysis of these dynamics has not been reported. We characterize ketamine’s neural dynamics using a hidden Markov model (HMM). The HMM observations are sequences of spectral power in seven canonical frequency bands between 0 to 50 Hz, where power is averaged within each band and scaled between 0 and 1. We model the observations as realizations of multivariate beta probability distributions that depend on a discrete-valued latent state process whose state transitions obey Markov dynamics. Using an expectation-maximization algorithm, we fit this beta-HMM to LFP recordings from 2 NHPs, and separately, to EEG recordings from 9 human subjects who received anesthetic doses of ketamine. Our beta-HMM framework provides a useful tool for experimental data analysis. Together, the estimated beta-HMM parameters and optimal state trajectory revealed an alternating pattern of states characterized primarily by gamma and slow-delta activities. The mean duration of the gamma activity was 2.2s([1.7,2.8]s) and 1.2s([0.9,1.5]s) for the two NHPs, and 2.5s([1.7,3.6]s) for the human subjects. The mean duration of the slow-delta activity was 1.6s([1.2,2.0]s) and 1.0s([0.8,1.2]s) for the two NHPs, and 1.8s([1.3,2.4]s) for the human subjects. Our characterizations of the alternating gamma slow-delta activities revealed five sub-states that show regular sequential transitions. These quantitative insights can inform the development of rhythm-generating neuronal circuit models that give mechanistic insights into this phenomenon and how ketamine produces altered states of arousal.

Closed-Loop Acoustic Stimulation During Sedation with Dexmedetomidine (CLASS-D): Protocol for a Within-Subject, Crossover, Controlled, Interventional Trial with Healthy Volunteers.

IntroductionThe relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine.MethodsClosed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volunteers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation.ResultsThe primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep.DiscussionThis investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation.

Comparison of electroencephalogram between propofol- and thiopental-induced anesthesia for awareness risk in pregnant women

There have been few comparative studies using electroencephalogram (EEG) spectral characteristics during the induction of general anesthesia for cesarean section. This retrospective study investigated the differences in the depth of anesthesia through EEG analysis between propofol- and thiopental-induced anesthesia. We reviewed data of 42 patients undergoing cesarean section who received either thiopental (5 mg/kg) or propofol (2 mg/kg). EEG data were extracted from the bispectral index (BIS) monitor, and 10-second segments were selected from the following sections: 1) Stage I, BIS below 60 after induction; 2) Stage II, after intubation completion; 3) Stage III, end-tidal sevoflurane above 0 vol%. The risk of awareness was represented by the BIS and entropy measures. In Stage III, the thiopental group (n = 20) showed significantly higher BIS value than the propofol group (n = 22) (67.9 [18.66] vs 44.5 [20.63], respectively, p = 0.002). The thiopental group had decreased slow-delta oscillations and increased beta-oscillations as compared to the propofol group in Stages II and III (p < 0.05). BIS, spectral entropy, and Renyi permutation entropy were also higher in the thiopental group at Stages II and III (p < 0.05). In conclusion, frontal spectral EEG analysis demonstrated that propofol induction maintained a deeper anesthesia than thiopental in pregnant women.

Dynamics of Ketamine-induced Loss and Return of Consciousness across Primate Neocortex.

Ketamine is a noncompetitive N-methyl-D-aspartate antagonist and is known for unique electrophysiologic profiles in electroencephalography. However, the mechanisms of ketamine-induced unconsciousness are not clearly understood. The authors have investigated neuronal dynamics of ketamine-induced loss and return of consciousness and how multisensory processing is modified in the primate neocortex. The authors performed intracortical recordings of local field potentials and single unit activity during ketamine-induced altered states of consciousness in a somatosensory and ventral premotor network. The animals were trained to perform a button holding task to indicate alertness. Air puff to face or sound was randomly delivered in each trial regardless of their behavioral response. Ketamine was infused for 60 min. Ketamine-induced loss of consciousness was identified during a gradual evolution of the high beta-gamma oscillations. The slow oscillations appeared to develop at a later stage of ketamine anesthesia. Return of consciousness and return of preanesthetic performance level (performance return) were observed during a gradual drift of the gamma oscillations toward the beta frequency. Ketamine-induced loss of consciousness, return of consciousness, and performance return are all identified during a gradual change of the dynamics, distinctive from the abrupt neural changes at propofol-induced loss of consciousness and return of consciousness. Multisensory responses indicate that puff evoked potentials and single-unit firing responses to puff were both preserved during ketamine anesthesia, but sound responses were selectively diminished. Units with suppressed responses and those with bimodal responses appeared to be inhibited under ketamine and delayed in recovery. Ketamine generates unique intracortical dynamics during its altered states of consciousness, suggesting fundamentally different neuronal processes from propofol. The gradually shifting dynamics suggest a continuously conscious or dreaming state while unresponsive under ketamine until its deeper stage with the slow-delta oscillations. Somatosensory processing is preserved during ketamine anesthesia, but multisensory processing appears to be diminished under ketamine and through recovery.

Dynamics of recovery from anaesthesia-induced unconsciousness across primate neocortex.

How the brain recovers from general anaesthesia is poorly understood. Neurocognitive problems during anaesthesia recovery are associated with an increase in morbidity and mortality in patients. We studied intracortical neuronal dynamics during transitions from propofol-induced unconsciousness into consciousness by directly recording local field potentials and single neuron activity in a functionally and anatomically interconnecting somatosensory (S1, S2) and ventral premotor (PMv) network in primates. Macaque monkeys were trained for a behavioural task designed to determine trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We found that neuronal dynamics were dissociated between S1 and higher-order PMv prior to return of consciousness. The return of consciousness was distinguishable by a distinctive return of interregionally coherent beta oscillations and disruption of the slow-delta oscillations. Clustering analysis demonstrated that these state transitions between wakefulness and unconsciousness were rapid and unstable. In contrast, return of pre-anaesthetic task performance was observed with a gradual increase in the coherent beta oscillations. We also found that recovery end points significantly varied intra-individually across sessions, as compared to a rather consistent loss of consciousness time. Recovery of single neuron multisensory responses appeared to be associated with the time of full performance recovery rather than the length of recovery time. Similar to loss of consciousness, return of consciousness was identified with an abrupt shift of dynamics and the regions were dissociated temporarily during the transition. However, the actual dynamics change during return of consciousness is not simply an inverse of loss of consciousness, suggesting a unique process.

O23 Characteristic slow gamma and delta frequency changes in the preictal EEG of partial epileptic patients

The preictal EEG has informations about the onset of the epileptic seizure. Authors aim was to find the characteristic EEG frequency changes which predict the launch of the seizure. Authors analysed the slow delta and gamma oscillations (0–100 Hz ) in the preictal scalp EEG of partial epileptic patients. The lower delta frequency was measured 0–2.5 Hz, and the lower gamma frequency was measured 35–100 Hz. It were applied the Main Dominant Frequency, the Median Frequency and the Relative Power frequency analysis methods. The Relative Power frequency analysis proportionated the results of the spectrum. They have been selected 12 electroclinical seizures from the presurgical video EEG monitorization of 5 patients The measurement was done from the 3 min long preictal EEG sample. There were not analysed the seizure EEG. Authors observed in the 3 min long examined EEG period, that for several seconds the frequency values of the electrodes time to time approach each other. This phenomenon was much more pronounced on the electrodes of the ictal hemisphere. There were specific moments (1 or 2 s) of the preictal EEG length, when the frequency values of the electrodes were almost the same. In the point of view of the brain network theory our results are the parameters of the synchronisation in the epileptic network. There are prognostical parameters in the frequency spectrum of the preictal 3 min long EEG period. The authors have been found characteristic frequency changes in the preictal EEG.

Sevoflurane Induces Coherent Slow-Delta Oscillations in Rats.

Although general anesthetics are routinely administered to surgical patients to induce loss of consciousness, the mechanisms underlying anesthetic-induced unconsciousness are not fully understood. In rats, we characterized changes in the extradural EEG and intracranial local field potentials (LFPs) within the prefrontal cortex (PFC), parietal cortex (PC), and central thalamus (CT) in response to progressively higher doses of the inhaled anesthetic sevoflurane. During induction with a low dose of sevoflurane, beta/low gamma (12–40 Hz) power increased in the frontal EEG and PFC, PC and CT LFPs, and PFC–CT and PFC–PFC LFP beta/low gamma coherence increased. Loss of movement (LOM) coincided with an abrupt decrease in beta/low gamma PFC–CT LFP coherence. Following LOM, cortically coherent slow-delta (0.1–4 Hz) oscillations were observed in the frontal EEG and PFC, PC and CT LFPs. At higher doses of sevoflurane sufficient to induce loss of the righting reflex, coherent slow-delta oscillations were dominant in the frontal EEG and PFC, PC and CT LFPs. Dynamics similar to those observed during induction were observed as animals emerged from sevoflurane anesthesia. We conclude that the rat is a useful animal model for sevoflurane-induced EEG oscillations in humans, and that coherent slow-delta oscillations are a correlate of sevoflurane-induced behavioral arrest and loss of righting in rats.

Lack of Responsiveness during the Onset and Offset of Sevoflurane Anesthesia Is Associated with Decreased Awake-Alpha Oscillation Power.

Anesthetic drugs are typically administered to induce altered states of arousal that range from sedation to general anesthesia (GA). Systems neuroscience studies are currently being used to investigate the neural circuit mechanisms of anesthesia-induced altered arousal states. These studies suggest that by disrupting the oscillatory dynamics that are associated with arousal states, anesthesia-induced oscillations are a putative mechanism through which anesthetic drugs produce altered states of arousal. However, an empirical clinical observation is that even at relatively stable anesthetic doses, patients are sometimes intermittently responsive to verbal commands during states of light sedation. During these periods, prominent anesthesia-induced neural oscillations such as slow-delta (0.1–4 Hz) oscillations are notably absent. Neural correlates of intermittent responsiveness during light sedation have been insufficiently investigated. A principled understanding of the neural correlates of intermittent responsiveness may fundamentally advance our understanding of neural dynamics that are essential for maintaining arousal states, and how they are disrupted by anesthetics. Therefore, we performed a high-density (128 channels) electroencephalogram (EEG) study (n = 8) of sevoflurane-induced altered arousal in healthy volunteers. We administered temporally precise behavioral stimuli every 5 s to assess responsiveness. Here, we show that decreased eyes-closed, awake-alpha (8–12 Hz) oscillation power is associated with lack of responsiveness during sevoflurane effect-onset and -offset. We also show that anteriorization—the transition from occipitally dominant awake-alpha oscillations to frontally dominant anesthesia induced-alpha oscillations—is not a binary phenomenon. Rather, we suggest that periods, which were defined by lack of responsiveness, represent an intermediate brain state. We conclude that awake-alpha oscillation, previously thought to be an idling rhythm, is associated with responsiveness to behavioral stimuli.

Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants.

Electroencephalogram (EEG) approaches may provide important information about developmental changes in brain-state dynamics during general anesthesia. We used multi-electrode EEG, analyzed with multitaper spectral methods and video recording of body movement to characterize the spatio-temporal dynamics of brain activity in 36 infants 0-6 months old when awake, and during maintenance of and emergence from sevoflurane general anesthesia. During maintenance: (1) slow-delta oscillations were present in all ages; (2) theta and alpha oscillations emerged around 4 months; (3) unlike adults, all infants lacked frontal alpha predominance and coherence. Alpha power was greatest during maintenance, compared to awake and emergence in infants at 4-6 months. During emergence, theta and alpha power decreased with decreasing sevoflurane concentration in infants at 4-6 months. These EEG dynamic differences are likely due to developmental factors including regional differences in synaptogenesis, glucose metabolism, and myelination across the cortex. We demonstrate the need to apply age-adjusted analytic approaches to develop neurophysiologic-based strategies for pediatric anesthetic state monitoring.

Nitrous oxide-induced slow and delta oscillations

ObjectivesSwitching from maintenance of general anesthesia with an ether anesthetic to maintenance with high-dose (concentration >50% and total gas flow rate >4liters per minute) nitrous oxide is a common practice used to facilitate emergence from general anesthesia. The transition from the ether anesthetic to nitrous oxide is associated with a switch in the putative mechanisms and sites of anesthetic action. We investigated whether there is an electroencephalogram (EEG) marker of this transition. MethodsWe retrospectively studied the ether anesthetic to nitrous oxide transition in 19 patients with EEG monitoring receiving general anesthesia using the ether anesthetic sevoflurane combined with oxygen and air. ResultsFollowing the transition to nitrous oxide, the alpha (8–12Hz) oscillations associated with sevoflurane dissipated within 3–12min (median 6min) and were replaced by highly coherent large-amplitude slow-delta (0.1–4Hz) oscillations that persisted for 2–12min (median 3min). ConclusionsAdministration of high-dose nitrous oxide is associated with transient, large amplitude slow-delta oscillations. SignificanceWe postulate that these slow-delta oscillations may result from nitrous oxide-induced blockade of major excitatory inputs (NMDA glutamate projections) from the brainstem (parabrachial nucleus and medial pontine reticular formation) to the thalamus and cortex. This EEG signature of high-dose nitrous oxide may offer new insights into brain states during general anesthesia.

CaMKIV over-expression boosts cortical 4-7 Hz oscillations during learning and 1-4 Hz delta oscillations during sleep

Mounting evidence suggests that neural oscillations are related to the learning and consolidation of newly formed memory in the mammalian brain. Four to seven Hertz (4-7 Hz) oscillations in the prefrontal cortex are also postulated to be involved in learning and attention processes. Additionally, slow delta oscillations (1-4 Hz) have been proposed to be involved in memory consolidation or even synaptic down scaling during sleep. The molecular mechanisms which link learning-related oscillations during wakefulness to sleep-related oscillations remain unknown. We show that increasing the expression of calcium/calmodulin dependent protein kinase IV (CaMKIV), a key nucleic protein kinase, selectively enhances 4-7.5 Hz oscillation power during trace fear learning and slow delta oscillations during subsequent sleep. These oscillations were found to be boosted in response to the trace fear paradigm and are likely to be localized to regions of the prefrontal cortex. Correlation analyses demonstrate that a proportion of the variance in 4-7.5 Hz oscillations, during fear conditioning, could account for some degree of learning and subsequent memory formation, while changes in slow delta power did not share this predictive strength. Our data emphasize the role of CaMKIV in controlling learning and sleep-related oscillations and suggest that oscillatory activity during wakefulness may be a relevant predictor of subsequent memory consolidation.

Interactions between cardiac, respiratory and EEG‐δ oscillations in rats during anaesthesia

We hypothesized that, associated with the state of anaesthesia, characteristic changes exist in both cardio-respiratory and cerebral oscillator parameters and couplings, perhaps varying with depth of anaesthesia. Electrocardiograms (ECGs), respiration and electroencephalograms (EEGs) were recorded from two groups of 10 rats during the entire course of anaesthesia following the administration of a single bolus of ketamine-xylazine (KX group) or pentobarbital (PB group). The phase dynamics approach was then used to extract the instantaneous frequencies of heart beat, respiration and slow delta-waves (within 0.5-3.5 Hz). The amplitudes of delta- and theta-waves were analysed by use of a time-frequency representation of the EEG signal within 0.5-7.5 Hz obtained by wavelet transformation, using the Morlet mother wavelet. For the KX group, where slow delta-waves constituted the dominant spectral component, the Hilbert transform was applied to obtain the instantaneous delta-frequency. The theta-activity was spread over too wide a spectral range for its phase to be meaningfully defined. For both agents, we observed two distinct phases of anaesthesia, with a marked increase in theta-wave activity occurring on passage from a deeper phase of anaesthesia to a shallower one. In other respects, the effects of the two anaesthetics were very different. For KX anaesthesia, the two phases were separated by a marked change in all three instantaneous frequencies: stable, deep, anaesthesia with small frequency variability was followed by a sharp transition to shallow anaesthesia with large frequency variability, lasting until the animal awoke. The transition occurred 16-76 min after injection of the anaesthetic, with simultaneous reduction in the delta-wave amplitude. For PB anaesthesia, the two epochs were separated by the return of a positive response to the pinch test at 53-94 min, following which it took a further period of 45-70 min for the animal to awaken. delta-Waves were not apparent at any stage of PB anaesthesia. We applied non-linear dynamics and information theory to seek evidence of causal relationships between the cardiac, respiratory and slow delta-oscillations. We demonstrate that, for both groups, respiration drives the cardiac oscillator during deep anaesthesia. During shallow KX anaesthesia the direction either reverses, or the cardio-respiratory interaction becomes insignificant; in the deep phase, there is a unidirectional deterministic interaction of respiration with slow delta-oscillations. For PB anaesthesia, the cardio-respiratory interaction weakens during the second phase but, otherwise, there is no observable change in the interactions. We conclude that non-linear dynamics and information theory can be used to identify different stages of anaesthesia and the effects of different anaesthetics.

Increased gamma- and decreased delta-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking interneurons.

Kv3.1 is a voltage-gated, fast activating/deactivating potassium (K(+)) channel with a high-threshold of activation and a large unit conductance. Kv3.1 K(+) channels are expressed in fast-spiking, parvalbumin-containing interneurons in cortex, hippocampus, striatum, the thalamic reticular nucleus (TRN), and in several nuclei of the brain stem. A high density of Kv3.1 channels contributes to short-duration action potentials, fast afterhyperpolarizations, and brief refractory periods enhancing the capability in these neurons for high-frequency firing. Kv3.1 K(+) channel expression in the TRN and cortex also suggests a role in thalamocortical and cortical function. Here we show that fast gamma and slow delta oscillations recorded from the somatomotor cortex are altered in the freely behaving Kv3.1 mutant mouse. Electroencephalographic (EEG) recordings from homozygous Kv3.1(-/-) mice show a three- to fourfold increase in both absolute and relative spectral power in the gamma frequency range (20-60 Hz). In contrast, Kv3.1-deficient mice have a 20-50% reduction of power in the slow delta range (2-3 Hz). The increase in gamma power is most prominent during waking in the 40- to 55-Hz range, whereas the decrease in delta power occurs equally across all states of arousal. Our findings suggest that Kv3. 1-expressing neurons are involved in the generation and maintenance of cortical fast gamma and slow delta oscillations. Hence the Kv3. 1-mutant mouse could serve as a model to study the generation and maintenance of fast gamma and slow delta rhythms and their involvement in behavior and cognition.