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DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in human cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement, and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements. In the brain cortex, loss of Pgbd5 leads to aberrant differentiation and gene expression of distinct neuronal populations, including specific types of glutamatergic neurons, which explains the features of PGBD5 deficiency in humans. Thus, PGBD5 might be a transposase-derived enzyme required for brain development in mammals., Competing Interests: Competing interests: Authors declare that they have no competing interests. AK is a consultant for Novartis, Rgenta, Blueprint, and Syndax. RR is a founder and a member of the SAB of Genotwin, and a member of the SAB of Diatech Pharmacogenetics. None of these activities are related to the work described in this manuscript.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness, suprathreshold stimuli evoke perceptions; under anesthesia, perceptions are abolished; and during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perceptions. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia as well as during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely, in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is reliably elicited by external visual stimuli., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females., Competing Interests: Competing interests statement:The authors declare no competing interest.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness stimuli evoke perceptions; under anesthesia perceptions are abolished; during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perception. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia and during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is elicited by specifically by external visual stimuli.

Background: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18-40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes., Methods: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation., Results: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [OR adjusted ]=2.7; 95% confidence interval [CI], 1.1-7.6; P=0.022) and was decreased with continuous anaesthesia before laryngoscopy (OR adjusted =0.43; 95% CI, 0.20-0.96; P=0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P=0.049)., Conclusions: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered to reduce the incidence of connected consciousness. Further research is required to understand sex-related differences in the risk of connected consciousness., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The relationship between neuronal activity and computations embodied by it remains an open question. We develop a novel methodology that condenses observed neuronal activity into a quantitatively accurate, simple, and interpretable model and validate it on diverse systems and scales from single neurons in C. elegans to fMRI in humans. The model treats neuronal activity as collections of interlocking 1-dimensional trajectories. Despite their simplicity, these models accurately predict future neuronal activity and future decisions made by human participants. Moreover, the structure formed by interconnected trajectories-a scaffold-is closely related to the computational strategy of the system. We use these scaffolds to compare the computational strategy of primates and artificial systems trained on the same task to identify specific conditions under which the artificial agent learns the same strategy as the primate. The computational strategy extracted using our methodology predicts specific errors on novel stimuli. These results show that our methodology is a powerful tool for studying the relationship between computation and neuronal activity across diverse systems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Brennan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most cognitive functions require the brain to maintain immediately preceding stimuli in working memory. Here, using a human working memory task with multiple delays, we test the hypothesis that working memories are stored in a discrete set of stable neuronal activity configurations called attractors. We show that while discrete attractor dynamics can approximate working memory on a single time scale, they fail to generalize across multiple timescales. This failure occurs because at longer delay intervals the responses contain more information about the stimuli than can be stored in a discrete attractor model. We present a modeling approach that combines discrete attractor dynamics with activity-dependent plasticity. This model successfully generalizes across all timescales and correctly predicts intertrial interactions. Thus, our findings suggest that discrete attractor dynamics are insufficient to model working memory and that activity-dependent plasticity improves durability of information storage in attractor systems.

The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called 'dissociated state' can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

During recovery from anesthesia, brain activity switches abruptly between a small set of discrete states. Surprisingly, this switching also occurs under constant doses of anesthesia, even in the absence of stimuli. These metastable states and the transitions between them are thought to form a "scaffold" that ultimately guides the brain back to wakefulness. The processes that constrain cortical activity patterns to these states and govern how states are coordinated between different cortical regions are unknown. If state transitions were driven by subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. Conversely, spatiotemporal heterogeneity would suggest that state transitions are coordinated through corticocortical interactions. To differentiate between these hypotheses, we quantified synchrony of brain states in male rats exposed to a fixed isoflurane concentration. States were defined from spectra of local field potentials recorded across layers of visual and motor cortices. A transition synchrony measure shows that most state transitions are highly localized. Furthermore, while most pairs of cortical sites exhibit statistically significant coupling of both states and state transition times, coupling strength is typically weak. States and state transitions in the thalamic input layer (L4) are particularly decoupled from those in supragranular and infragranular layers. This suggests that state transitions are not imposed on the cortex by broadly projecting modulatory systems. Although each pairwise interaction is typically weak, we show that the multitude of such weak interactions is sufficient to confine global activity to a small number of discrete states. SIGNIFICANCE STATEMENT The brain consistently recovers to wakefulness after anesthesia, but this process is poorly understood. Previous work revealed that, during recovery from anesthesia, corticothalamic activity falls into one of several discrete patterns. The neuronal mechanisms constraining the cortex to just a few discrete states remain unknown. Global states could be coordinated by fluctuations in subcortical nuclei that project broadly to the cortex. Alternatively, these states may emerge from interactions within the cortex itself. Here, we provide evidence for the latter possibility by demonstrating that most pairs of cortical sites exhibit weak coupling. We thereby lay groundwork for future investigations of the specific cellular and network mechanisms of corticocortical activity state coupling., (Copyright © 2022 Blackwood, Shortal et al.)

Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. Neuronal oscillations have been shown to mediate intercortical feedforward and feedback interactions. Yet, the macroscopic structure of the multitude of such oscillations remains unclear. Here, we show that simple visual stimuli reliably evoke two traveling waves with spatial wavelengths that cover much of the cerebral hemisphere in awake mice. 30-50 Hz feedforward waves arise in primary visual cortex (V1) and propagate rostrally, while 3-6 Hz feedback waves originate in the association cortex and flow caudally. The phase of the feedback wave modulates the amplitude of the feedforward wave and synchronizes firing between V1 and parietal cortex. Altogether, these results provide direct experimental evidence that visual evoked traveling waves percolate through the cerebral cortex and coordinate neuronal activity across broadly distributed networks mediating visual processing., (© 2022. The Author(s).)

Endogenous sleep and general anesthesia are distinct states that share similar traits. Of particular interest to neuroscience is the loss of consciousness that accompanies both states. Multiple lines of evidence demonstrate that general anesthetics can co-opt the neural circuits regulating arousal to produce unconsciousness. However, controversy remains as to whether the neural circuits and, more specifically, the same neurons shaping sleep and wakefulness actually do influence the anesthetic state in vivo. Hypothalamic preoptic area (POA) neurons are intimately involved in modulating spontaneous and anesthetic-induced changes in arousal. Nevertheless, recent work suggests that POA GABAergic or glutamatergic neurons capable of regulating endogenous sleep fail to influence the onset or dissipation of anesthesia. We hypothesized that the POA's broad neuronal diversity could mask convergent roles of a subset of neurons in regulating both arousal and anesthesia. Contrary to a previously published report, we show that chemogenetic activation of POA Tac1 neurons obliterates both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, strongly consolidating the waking state for hours, even during a period of elevated sleep drive. Moreover, chemogenetic activation of Tac1 POA neurons stabilizes the wake state against both isoflurane- and sevoflurane-induced unconsciousness. Tac1-activated mice display a partial resistance to entering isoflurane anesthesia and a more pronounced ability to exit both isoflurane- and sevoflurane-induced unconscious states. We conclude that POA Tac1 neurons can potently reinforce arousal both against endogenous and drug-induced unconscious states. POA Tac1 neurons thus add causal support for the involvement of arousal-regulating systems in the state of general anesthesia., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis., Methods: We constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models., Results: Our modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration., Conclusions: Effect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Recent studies point to a fundamental distinction between population-based and individual-based anaesthetic pharmacology. At the population level, anaesthetic potency is defined as the relationship between drug concentration and the likelihood of response to a stimulus. At the individual level, even when the anaesthetic concentration is held constant, fluctuations between the responsive and unresponsive states are observed. Notably, these spontaneous fluctuations exhibit resistance to state transitions R st . Therefore, the response probability in each individual depends not just upon the drug concentration, but also upon responses to previous stimuli. Here, we hypothesise that R st is distinct from drug potency and is differentially modulated by different anaesthetics., Methods: Adult (14-24 weeks old) C57BL/6J male mice (n=60) were subjected to repeated righting reflex (RR) assays at equipotent steady-state concentrations of isoflurane (0.6 vol%), sevoflurane (1.0 vol%), and halothane (0.4 vol%)., Results: Fluctuations in RR were observed for all tested anaesthetics. Analysis of these fluctuations revealed that R st was differentially modulated by different anaesthetics (F[2, 56.01]=49.59; P<0.0001). Fluctuations in RR were modelled using a stochastic dynamical system. This analysis confirmed that the amount of noise that drives behavioural state transitions depends on the anaesthetic agent (F[2, 42.86]=16.72; P<0.0001)., Conclusions: Whilst equipotent doses of distinct anaesthetics produce comparable population response probabilities, they engage dramatically different dynamics in each individual animal. This manifests as a differential aggregate propensity to exhibit state transitions. Thus, resistance to state transitions is a fundamentally distinct, novel measure of individualised anaesthetic pharmacology., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Previous research demonstrates that the underlying state of the brain influences how sensory stimuli are processed. Canonically, the state of the brain has been defined by quantifying the spectral characteristics of spontaneous fluctuations in local field potentials (LFP). Here, we utilized isoflurane and propofol anesthesia to parametrically alter the spectral state of the murine brain. With either drug, we produce slow wave activity, with low anesthetic doses, or burst suppression, with higher doses. We find that while spontaneous LFP oscillations were similar, the average visual-evoked potential (VEP) was always smaller in amplitude and shorter in duration under propofol than under comparable doses of isoflurane. This diminished average VEP results from increased trial-to-trial variability in VEPs under propofol. One feature of single trial VEPs that was consistent in all animals was visual-evoked gamma band oscillation (20-60 Hz). This gamma band oscillation was coherent between trials in the early phase (<250 ms) of the visual evoked potential under isoflurane. Inter trial phase coherence (ITPC) of gamma oscillations was dramatically attenuated in the same propofol anesthetized mice despite similar spontaneous oscillations in the LFP. This suggests that while both anesthetics lead to loss of consciousness (LOC), elicit slow oscillations and burst suppression, only the isoflurane permits phase resetting of gamma oscillations by visual stimuli. These results demonstrate that accurate characterization of a brain state must include both spontaneous as well as stimulus-induced perturbations of brain activity.

In daily life, in the operating room and in the laboratory, the operational way to assess wakefulness and consciousness is through responsiveness. A number of studies suggest that the awake, conscious state is not the default behavior of an assembly of neurons, but rather a very special state of activity that has to be actively maintained and curated to support its functional properties. Thus responsiveness is a feature that requires active maintenance, such as a homeostatic mechanism to balance excitation and inhibition. In this work we developed a method for monitoring such maintenance processes, focusing on a specific signature of their behavior derived from the theory of dynamical systems: stability analysis of dynamical modes. When such mechanisms are at work, their modes of activity are at marginal stability, neither damped (stable) nor exponentially growing (unstable) but rather hovering in between. We have previously shown that, conversely, under induction of anesthesia those modes become more stable and thus less responsive, then reversed upon emergence to wakefulness. We take advantage of this effect to build a single-trial classifier which detects whether a subject is awake or unconscious achieving high performance. We show that our approach can be developed into a means for intra-operative monitoring of the depth of anesthesia, an application of fundamental importance to modern clinical practice.

Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.

Electroencephalography (EEG) has a long history in neuroscience starting with its original description in humans by Hans Berger in 1929 (Berger, 1932). Investigations of EEG under anesthesia started soon after in the mid-1930s (Gibbs, 1937). No single methodology paper can credibly cover all of the issues relating to this rich field. The purpose of this chapter is to introduce some caveats that complicate and inform analysis of the EEG. Special emphasis will be given to common issues such as choice of reference electrode, filtering, artifact rejection, and spectral analysis. We will specifically emphasize high-density EEG recordings that have become the norm due to technological improvement in electrode and data acquisition design methods. In the last section we will discuss some applications of EEG analysis techniques to the study of the effects of anesthetics on the nervous system., (© 2018 Elsevier Inc. All rights reserved.)

The existence of a barrier between anesthetic behavioral state transitions has been observed across phyla, but demonstrating that such a barrier exists and is not a pharmacokinetic artifact has not yet been possible in humans. Such an investigation requires temporally precise information regarding the brain concentration of anesthetic in order to demonstrate the specific pharmacokinetic-pharmacodynamic mismatch that is hysteresis. We propose a method to noninvasively determine brain tissue anesthetic concentration using computerized tomography and the radiopaque gaseous anesthetic xenon. Such a technique can be used to investigate pharmacokinetic-pharmacodynamic mismatches in humans., (© 2018 Elsevier Inc. All rights reserved.)

The level of activity of many animals including humans rises and falls with a period of ~ 24 hours. The intrinsic biological oscillator that gives rise to this circadian oscillation is driven by a molecular feedback loop with an approximately 24 hour cycle period and is influenced by the environment, most notably the light:dark cycle. In addition to the circadian oscillations, behavior of many animals is influenced by multiple oscillations occurring at faster-ultradian-time scales. These ultradian oscillations are also thought to be driven by feedback loops. While many studies have focused on identifying such ultradian oscillations, less is known about how the ultradian behavioral oscillations interact with each other and with the circadian oscillation. Decoding the coupling among the various physiological oscillators may be important for understanding how they conspire together to regulate the normal activity levels, as well in disease states in which such rhythmic fluctuations in behavior may be disrupted. Here, we use a wavelet-based cross-frequency analysis to show that different oscillations identified in spontaneous mouse behavior are coupled such that the amplitude of oscillations occurring at higher frequencies are modulated by the phase of the slower oscillations. The patterns of these interactions are different among different individuals. Yet this variability is not random. Differences in the pattern of interactions are confined to a low dimensional subspace where different patterns of interactions form clusters. These clusters expose the differences among individuals-males and females are preferentially segregated into different clusters. These sex-specific features of spontaneous behavior were not apparent in the spectra. Thus, our methodology reveals novel aspects of the structure of spontaneous animal behavior that are not observable using conventional methodology., Competing Interests: The authors have declared that no competing interests exist.

What aspects of neuronal activity distinguish the conscious from the unconscious brain? This has been a subject of intense interest and debate since the early days of neurophysiology. However, as any practicing anesthesiologist can attest, it is currently not possible to reliably distinguish a conscious state from an unconscious one on the basis of brain activity. Here we approach this problem from the perspective of dynamical systems theory. We argue that the brain, as a dynamical system, is self-regulated at the boundary between stable and unstable regimes, allowing it in particular to maintain high susceptibility to stimuli. To test this hypothesis, we performed stability analysis of high-density electrocorticography recordings covering an entire cerebral hemisphere in monkeys during reversible loss of consciousness. We show that, during loss of consciousness, the number of eigenmodes at the edge of instability decreases smoothly, independently of the type of anesthetic and specific features of brain activity. The eigenmodes drift back toward the unstable line during recovery of consciousness. Furthermore, we show that stability is an emergent phenomenon dependent on the correlations among activity in different cortical regions rather than signals taken in isolation. These findings support the conclusion that dynamics at the edge of instability are essential for maintaining consciousness and provide a novel and principled measure that distinguishes between the conscious and the unconscious brain., Significance Statement: What distinguishes brain activity during consciousness from that observed during unconsciousness? Answering this question has proven difficult because neither consciousness nor lack thereof have universal signatures in terms of most specific features of brain activity. For instance, different anesthetics induce different patterns of brain activity. We demonstrate that loss of consciousness is universally and reliably associated with stabilization of cortical dynamics regardless of the specific activity characteristics. To give an analogy, our analysis suggests that loss of consciousness is akin to depressing the damper pedal on the piano, which makes the sounds dissipate quicker regardless of the specific melody being played. This approach may prove useful in detecting consciousness on the basis of brain activity under anesthesia and other settings., (Copyright © 2015 the authors 0270-6474/15/3510866-12$15.00/0.)

Background and Objectives: Ophthalmic arterial chemosurgery for retinoblastoma has been associated with intraoperative decreases in respiratory compliance. Through the analysis of data from computerized records, we objectively defined severe respiratory compliance events and correlated them with demographic and clinical information in patients undergoing this procedure., Methods: Data were collected from ophthalmic arterial chemosurgery cases from 2006 to 2013. Intraoperative PIP, PEEP, TV, SpO2 , and EtCO2 were analyzed. Compliance changes, desaturations, decreases in EtCO2 , and clinical outcomes were assessed., Results: Respiratory compliance decreases with a bimodal distribution. Severe events were defined as exhibiting a minimum compliance decrease of 40%. Seventy-eight of 122 children (64%) experienced a severe compliance event during at least one treatment, and it occurred in 137/468 cases (29%). A subset of 94 children had complete or at least the first three records. The incidence of a severe respiratory compliance event in this subgroup was 17/94 (18%) on the first and 84/261 (32%) on subsequent procedures. The probability of developing a severe respiratory compliance event on a subsequent procedure was 0.40 if the child developed it on the first procedure, 0.30 if he did not; this difference was not significant. The incidence of desaturation below 90% with severe respiratory compliance events was 0.20; the incidence of a 30% drop in EtCO2 was 0.34. No morbidity, no extended recovery, and no admissions were associated with intraoperative severe respiratory compliance events. We found no correlation between history, age, sex, weight or allergies, and intraoperative severe respiratory compliance events., Conclusions: Here, most patients experienced a severe respiratory compliance event during at least one of their procedures. Overall incidence was 29% and was more likely on subsequent procedures. A severe respiratory compliance event at the initial procedure was poorly predictive of its occurrence on subsequent procedures. No morbidity was associated with intraoperative severe respiratory compliance events., (© 2015 John Wiley & Sons Ltd.)

Transmitter-mediated homosynaptic potentiation is generally implemented by the same transmitter that mediates the excitatory postsynaptic potentials (EPSPs), e.g., glutamate. When a presynaptic neuron contains more than one transmitter, however, potentiation can in principle be implemented by a transmitter different from that which elicits the EPSPs. Neuron B20 in Aplysia contains both dopamine and GABA. Although only dopamine acts as the fast excitatory transmitter at the B20-to-B8 synapse, GABA increases the size of these dopaminergic EPSPs. We now provide evidence that repeated stimulation of B20 potentiates B20-evoked dopaminergic EPSPs in B8 apparently via a postsynaptic mechanism, and short-term potentiation of this synapse is critical for the establishment and maintenance of an egestive network state. We show that GABA can act postsynaptically to increase dopamine currents that are elicited by direct applications of dopamine to B8 and that dopamine is acting on a 5-HT3-like receptor. This potentiation is mediated by GABAB-like receptors as GABAB-receptor agonists and antagonists, respectively, mimicked and blocked the potentiating actions of GABA. The postsynaptic actions of GABA rely on a G protein-mediated activation of PKC. Our results suggest that the postsynaptic action of cotransmitter-mediated potentiation may contribute to the maintenance of the egestive state of Aplysia feeding network and, in more general terms, may participate in the plasticity of networks that mediate complex behaviors., (Copyright © 2014 the American Physiological Society.)

It is not clear how, after a large perturbation, the brain explores the vast space of potential neuronal activity states to recover those compatible with consciousness. Here, we analyze recovery from pharmacologically induced coma to show that neuronal activity en route to consciousness is confined to a low-dimensional subspace. In this subspace, neuronal activity forms discrete metastable states persistent on the scale of minutes. The network of transitions that links these metastable states is structured such that some states form hubs that connect groups of otherwise disconnected states. Although many paths through the network are possible, to ultimately enter the activity state compatible with consciousness, the brain must first pass through these hubs in an orderly fashion. This organization of metastable states, along with dramatic dimensionality reduction, significantly simplifies the task of sampling the parameter space to recover the state consistent with wakefulness on a physiologically relevant timescale.

In this work we analyze electro-corticography (ECoG) recordings in human subjects during induction of anesthesia with propofol. We hypothesize that the decrease in responsiveness that defines the anesthetized state is concomitant with the stabilization of neuronal dynamics. To test this hypothesis, we performed a moving vector autoregressive analysis and quantified stability of neuronal dynamics using eigenmode decomposition of the autoregressive matrices, independently fitted to short sliding temporal windows. Consistent with the hypothesis we show that while the subject is awake, many modes of neuronal activity oscillations are found at the edge of instability. As the subject becomes anesthetized, we observe statistically significant increase in the stability of neuronal dynamics, most prominently observed for high frequency oscillations. Stabilization was not observed in phase randomized surrogates constructed to preserve the spectral signatures of each channel of neuronal activity. Thus, stability analysis offers a novel way of quantifying changes in neuronal activity that characterize loss of consciousness induced by general anesthetics.

Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarization-activated, cyclic nucleotide-regulated (HCN)-mediated IH pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-di-iso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA(A) receptor (GABA(A)-R) potentiation, and general anesthesia. Thus, 2,6- and 2,4-di-tertbutylphenol (2,6- and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6- and 2,4-di-sec-butylphenol (2,6- and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA(A)-R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA(A)-R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

Typically one expects that the intervals between consecutive occurrences of a particular behavior will have a characteristic time scale around which most observations are centered. Surprisingly, the timing of many diverse behaviors from human communication to animal foraging form complex self-similar temporal patterns reproduced on multiple time scales. We present a general framework for understanding how such scale invariance may arise in nonequilibrium systems, including those that regulate mammalian behaviors. We then demonstrate that the predictions of this framework are in agreement with detailed analysis of spontaneous mouse behavior observed in a simple unchanging environment. Neural systems operate on a broad range of time scales, from milliseconds to hours. We analytically show that such a separation between time scales could lead to scale-invariant dynamics without any fine tuning of parameters or other model-specific constraints. Our analyses reveal that the specifics of the distribution of resources or competition among several tasks are not essential for the expression of scale-free dynamics. Rather, we show that scale invariance observed in the dynamics of behavior can arise from the dynamics intrinsic to the brain.

To generate adaptive behavior, the nervous system is coupled to the environment. The coupling constrains the dynamical properties that the nervous system and the environment must have relative to each other if adaptive behavior is to be produced. In previous computational studies, such constraints have been used to evolve controllers or artificial agents to perform a behavioral task in a given environment. Often, however, we already know the controller, the real nervous system, and its dynamics. Here we propose that the constraints can also be used to solve the inverse problem--to predict from the dynamics of the nervous system the environment to which they are adapted, and so reconstruct the production of the adaptive behavior by the entire coupled system. We illustrate how this can be done in the feeding system of the sea slug Aplysia. At the core of this system is a central pattern generator (CPG) that, with dynamics on both fast and slow time scales, integrates incoming sensory stimuli to produce ingestive and egestive motor programs. We run models embodying these CPG dynamics--in effect, autonomous Aplysia agents--in various feeding environments and analyze the performance of the entire system in a realistic feeding task. We find that the dynamics of the system are tuned for optimal performance in a narrow range of environments that correspond well to those that Aplysia encounter in the wild. In these environments, the slow CPG dynamics implement efficient ingestion of edible seaweed strips with minimal sensory information about them. The fast dynamics then implement a switch to a different behavioral mode in which the system ignores the sensory information completely and follows an internal "goal," emergent from the dynamics, to egest again a strip that proves to be inedible. Key predictions of this reconstruction are confirmed in real feeding animals.

When sustained firing of a neuron is similar in different types of motor programs, its role in the generation of these programs is often similar. We investigated whether this is also the case for neurons involved in phase transition. In the Aplysia feeding central pattern generator (CPG), identified interneuron B64 starts firing at the transition between the protraction and the retraction phases of all types of motor programs, and its firing is sustained during the retraction phase. It was thought that B64 functions as a protraction terminator as it provides strong inhibitory input to protraction interneurons and motoneurons. Furthermore, premature activation of B64 can lead to premature termination of the protraction phase. Indeed, as we show here, B64 can terminate the protraction phase regardless of the type of motor program. However, B64 actually only functions as a protraction terminator in ingestive-like but not in egestive-like programs. This differential role of B64 results from a differential timing of the initiation of B64 spiking in the two types of programs. In turn, this differential timing of the initiation of B64 firing is determined by the internal state of the CPG. Thus, this study indicates the importance of the timing of initiation of firing in determining the functional role of a neuron and demonstrates that this role depends on the activity-dependent state of the network.

In Aplysia, mutually antagonistic ingestive and egestive behaviors are produced by the same multifunctional central pattern generator (CPG) circuit. Interestingly, higher-order inputs that activate the CPG do not directly specify whether the resulting motor program is ingestive or egestive because the slow dynamics of the network intervene. One input, the commandlike cerebral-buccal interneuron 2 (CBI-2), slowly drives the motor output toward ingestion, whereas another input, the esophageal nerve (EN), drives the motor output toward egestion. When the input is switched from EN to CBI-2, the motor output does not switch immediately and remains egestive. Here, we investigated how these slow dynamics are implemented on the interneuronal level. We found that activity of two CPG interneurons, B20 and B40, tracked the motor output regardless of the input, whereas activity of another CPG interneuron, B65, tracked the input regardless of the motor output. Furthermore, we show that the slow dynamics of the network are implemented, at least in part, in the slow dynamics of the interaction between the input-representing and the output-representing neurons. We conclude that 1) a population of CPG interneurons, recruited during a particular motor program, simultaneously encodes both the input that is used to elicit the motor program and the output elicited by this input; and 2) activity of the input-representing neurons may serve to bias the future motor programs.

Aplysia feeding behavior is highly variable from cycle to cycle. In some cycles, when the variability causes a mismatch between the animal's movements and the requirements of the feeding task, the variability makes the behavior unsuccessful. We propose that the behavior is variable nevertheless because the variability serves a higher-order functional purpose. When the animal is faced with a new and only imperfectly known feeding task in each cycle, the variability implements a trial-and-error search through the space of possible feeding movements. Over many cycles, this may be the animal's optimal strategy in an uncertain and changing feeding environment.

The Aplysia feeding system is advantageous for investigating the role of neuropeptides in behavioral plasticity. One family of Aplysia neuropeptides is the myomodulins (MMs), originally purified from one of the feeding muscles, the accessory radula closer (ARC). However, two MMs, MMc and MMe, are not encoded on the only known MM gene. Here, we identify MM gene 2 (MMG2), which encodes MMc and MMe and four new neuropeptides. We use matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to verify that these novel MMG2-derived peptides (MMG2-DPs), as well as MMc and MMe, are synthesized from the precursor. Using antibodies against the MMG2-DPs, we demonstrate that neuronal processes that stain for MMG2-DPs are found in the buccal ganglion, which contains the feeding network, and in the buccal musculature including the ARC muscle. Surprisingly, however, no immunostaining is observed in buccal neurons including the ARC motoneurons. In situ hybridization reveals only few MMG2-expressing neurons that are mostly located in the pedal ganglion. Using immunohistochemical and electrophysiological techniques, we demonstrate that some of these pedal neurons project to the buccal ganglion and are the likely source of the MMG2-DP innervation of the feeding network and musculature. We show that the MMG2-DPs are bioactive both centrally and peripherally: they bias egestive feeding programs toward ingestive ones, and they modulate ARC muscle contractions. The multiple actions of the MMG2-DPs suggest that these peptides play a broad role in behavioral plasticity and that the pedal-buccal projection neurons that express them are a novel source of extrinsic modulation of the feeding system of Aplysia.

The multitasking central pattern generator (CPG) that drives consummatory feeding behaviors of Aplysia can produce ingestive, egestive, and intermediate motor programs. External stimuli trigger the programs but, remarkably, do not directly specify which type of program is produced. Rather, recent work has proposed, the type of program is determined by the internal network state of the CPG that has developed in response to the previous history of the stimulation. Here we have tested a key prediction of this network-state hypothesis. If the network state has a real existence and governs real functional behavior, changes in the state should be seen as coherent, coordinated changes along many dimensions of interneuron and motor neuron activity, muscle contraction, and ultimately movement, that underlie functional behavior. In reduced neuromuscular preparations, we elicited repetitive motor programs by continued stimulation of the esophageal nerve while recording the firing of motor neurons B8, B15, B16, B4/5, and B48, and contractions of the accessory radula closer and I7-I10 muscles that respectively close and open the animal's food-grasping organ, the radula. Using sonomicrometric techniques, we similarly recorded the movement of the radula in the complete buccal mass. Successive esophageal nerve programs indeed exhibited clear progressive changes in motor neuron firing, muscle contractions, and the phasing of radula movements within each cycle, from an initially intermediate or even ingestive character to a strongly egestive character. We conclude that the Aplysia feeding CPG really has a coherent internal network state whose dynamics are likely to be reflected in the real behavior of the animal.

Aplysia consummatory feeding behavior, a rhythmic cycling of biting, swallowing, and rejection movements, is often said to be stereotyped. Yet closer examination shows that cycles of the behavior are very variable. Here we have quantified and analyzed the variability at several complementary levels in the neuromuscular system. In reduced preparations, we recorded the motor programs produced by the central pattern generator, firing of the motor neurons B15 and B16, and contractions of the accessory radula closer (ARC) muscle while repetitive programs were elicited by stimulation of the esophageal nerve. In other similar experiments, we recorded firing of motor neuron B48 and contractions of the radula opener muscle. In intact animals, we implanted electrodes to record nerve or ARC muscle activity while the animals swallowed controlled strips of seaweed or fed freely. In all cases, we found large variability in all parameters examined. Some of this variability reflected systematic, slow, history-dependent changes in the character of the central motor programs. Even when these trends were factored out, however, by focusing only on the differences between successive cycles, considerable variability remained. This variability was apparently random. Nevertheless, it too was the product of central history dependency because regularizing merely the high-level timing of the programs also regularized many of the downstream neuromuscular parameters. Central motor program variability thus appears directly in the behavior. With regard to the production of functional behavior in any one cycle, the large variability may indicate broad tolerances in the operation of the neuromuscular system. Alternatively, some cycles of the behavior may be dysfunctional. Overall, the variability may be part of an optimal strategy of trial, error, and stabilization that the CNS adopts in an uncertain environment.

Selection of behavioral responses to external stimuli is strongly influenced by internal states, such as intentions and expectations. These internal states are often attributed to higher-order brain functions. Yet here we show that even in the simple feeding network of Aplysia, external stimuli do not directly specify which motor output is expressed; instead, the motor output is specified by the state of the network at the moment of stimulation. The history-dependence of this network state manifests itself in the same way as do intentions and expectations in the behavior of higher animals. Remarkably, we find that activity-dependent plasticity of a synapse within the network itself, rather than some higher-order network, mediates one important aspect of the change in the network state. Through this mechanism, changes in the network state become an automatic consequence of the generation of behavior. Altogether, our findings suggest that intentions and expectations may emerge within behavior-generating networks themselves from the plasticity of the very processes that generate the behavior.

Aplysia feeding is striking in that it is executed with a great deal of plasticity. At least in part, this flexibility is a result of the organization of the feeding neural network. To illustrate this, we primarily discuss motor programs triggered via stimulation of the command-like cerebral-buccal interneuron 2 (CBI-2). CBI-2 is interesting in that it can generate motor programs that serve opposing functions, i.e., programs can be ingestive or egestive. When programs are egestive, radula-closing motor neurons are activated during the protraction phase of the motor program. When programs are ingestive, radula-closing motor neurons are activated during retraction. When motor programs change in nature, activity in the radula-closing circuitry is altered. Thus, CBI-2 stimulation stereotypically activates the protraction and retraction circuitry, with protraction being generated first, and retraction immediately thereafter. In contrast, radula-closing motor neurons can be activated during either protraction or retraction. Which will occur is determined by whether other cerebral and buccal neurons are recruited, e.g. radula-closing motor neurons tend to be activated during retraction if a second CBI, CBI-3, is recruited. Fundamentally different motor programs are, therefore, generated because CBI-2 activates some interneurons in a stereotypic manner and other interneurons in a variable manner., (Copyright 2004 S. Karger AG, Basel)

During rhythmic behaviors, sensori-motor transmission is often regulated so that there are phasic changes in afferent input to follower neurons. We study this type of regulation in the feeding circuit of Aplysia. We characterize effects of the B4/5 interneurons on transmission from the mechanoafferent B21 to the radula closer motor neuron B8. In quiescent preparations, B4/5-induced postsynaptic potentials (PSPs) can block spike propagation in the lateral process of B21 and inhibit afferent transmission. B4/5 are, however, active during the retraction phase of motor programs, i.e., when mechanoafferent transmission to B8 presumably occurs. To determine whether mechanoafferent transmission is necessarily inhibited when B4/5 are active, we characterize the B4/5 firing frequency during retraction and show that, for the most part, it is low (below 15 Hz). There is, therefore, a low probability that spike propagation will be inhibited. The relative ineffectiveness of low frequency activity is not simply a consequence of insufficient PSP magnitude, because a single PSP can block spike propagation. Instead, it is related to the fact that PSPs have a short duration. When B4/5 fire at a low frequency, there is therefore a low probability that afferent transmission in the lateral process of B21 can be inhibited. In conclusion, we demonstrate that afferent transmission will not always be affected when a neuron that exerts inhibitory effects is active. Although a cell may be ineffective when it fires at a low frequency, ineffectiveness is not necessarily a consequence of spike frequency per se. Instead it may be due to spike timing.

Improvement of behavioral responses to expected stimuli has been attributed to a change in the preparatory state. In this study, we take advantage of the accessibility of the nervous system of Aplysia and develop an in vitro analog of the preparatory state for feeding behaviors. We provide evidence that the change in the preparatory state may be elicited initially by activity of identified serotonergic metacerebral cells (MCCs). We demonstrate, however, that the preparatory state is maintained through MCC-independent repetition priming that is embedded in the properties of the behavior-generating network. Both MCC-dependent and MCC-independent processes converge on the same site in the behavior-generating network to mediate the change in the preparatory state. Thus, we propose a model of how multiple neuronal structures interact to elicit and maintain changes in the preparatory states in the CNS.