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.anesthesia | state transitions | spectral analysis | emergence T he brain exhibits a remarkable ability to recover normal function associated with wakefulness, even after large perturbations to its activity. Two well-known examples of this are anesthesia and brain injury (1, 2). How the brain recovers from large perturbations currently is unknown. Given the number of neurons involved, the potential space of activity is huge. Thus, it is not clear how the brain samples the vast parameter space to discover patterns of activity that are consistent with consciousness after a large perturbation.The simplest possibility for the recovery of consciousness (ROC) is that, driven by noise inherent in many aspects of neuronal activity (3), the brain performs a random walk through the parameter space until it eventually enters the region that is consistent with consciousness. An alternative possibility is that although the motion through the parameter space is not random, the trajectory nonetheless is smooth. Lastly, it is possible that en route to ROC, the brain passes through a set of discrete metastable states-that is, a series of jumps between long-lived activity configurations.The utility of metastable intermediates to the problem of ROC is well illustrated by analogy with protein folding. Levinthal's paradox (4) refers to the implausibility of a denatured protein recovering its native fold conformation by random walk alone, as the time required to randomly explore the conformational space will rapidly exceed the age of the universe, even for a small number of residues. (ii), a "small-world" structure, in which most states are connected only locally whereas a few central hub states connect widely, allowing rapid long-distance travel through the network; and (iii) a lattice structure, in which all states have approximately the same connectivity, allowing multiple routes to ROC.In this report, we demonstrate that in rats under isoflurane anesthesia, ROC occurs after the brain traverses a series of metastable in...
It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer's disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients.
The central thalamus plays an important role in the regulation of arousal and allocation of attentional resources in the performance of even simple tasks. To assess the contribution of central thalamic neurons to short-term adjustments of attentional effort, we analyzed 166 microelectrode recordings obtained from two rhesus monkeys performing a visuomotor simple reaction time task with a variable foreperiod. Multiunit responses showed maintained firing rate elevations during the variable delay period of the task in ∼24% of recording sites. Simultaneously recorded local field potentials demonstrated significant decreases in power at ∼10-20 Hz and increases in power at 30-100 Hz during the delay period when compared against precue baselines. Comparison of the spectral power of local field potentials during the delay period of correct and incorrect trials showed that, during incorrect trials, similar, but reduced, shifts of spectral power occurred within the same frequency bands. Sustained performance of even simple tasks requires regulation of arousal and attention that combine in the concept of "attentional effort". Our findings suggest that central thalamic neurons regulate task performance through brief changes in firing rates and spectral power changes during task-relevant short-term shifts of attentional effort. Increases in attentional effort may be reflected in changes within the central thalamic local populations, where correct task performance associates with more robust maintenance of firing rates during the delay period. Such ongoing fluctuations of central thalamic activity likely reflect a mix of influences, including variations in moment-to-moment levels of motivation, arousal, and availability of cognitive resources.
Stochastic state switching accounts for all known features of neural inertia. More than two states are required to explain the consistent increase observed in variability of recovery from general anaesthesia. This model predicts that hysteresis should collapse with a time scale independent of anaesthetic drug pharmacokinetics.
The majority of 20th century investigations into anesthetic effects on the nervous system have used electrophysiology. Yet some fundamental limitations to electrophysiologic recordings, including the invasiveness of the technique, the need to place (potentially several) electrodes in every site of interest, and the difficulty of selectively recording from individual cell types, have driven the development of alternative methods for detecting neuronal activation. Two such alternative methods with cellular scale resolution have matured in the last few decades and will be reviewed here: the transcription of immediate early genes, foremost c-fos, and the influx of calcium into neurons as reported by genetically encoded calcium indicators, foremost GCaMP6. Reporters of c-fos allow detection of transcriptional activation even in deep or distant nuclei, without requiring the accurate targeting of multiple electrodes at long distances. The temporal resolution of c-fos is limited due to its dependence upon the detection of transcriptional activation through immunohistochemical assays, though the development of RT-PCR probes has shifted the temporal resolution of the assay when tissues of interest can be isolated. GCaMP6 has several isoforms that trade-off temporal resolution for signal to noise, but the fastest are capable of resolving individual action potential events, provided the microscope used scans quickly enough. GCaMP6 expression can be selectively targeted to neuronal populations of interest, and potentially thousands of neurons can be captured within a single frame, allowing the neuron-by-neuron reporting of circuit dynamics on a scale that is difficult to capture with electrophysiology, as long as the populations are optically accessible.
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