Reading out a spatiotemporal population code by imaging neighbouring parallel fibre axons in vivo.

The spatiotemporal pattern of synaptic inputs to the dendritic tree is crucial for synaptic integration and plasticity. However, it is not known if input patterns driven by sensory stimuli are structured or random. Here we investigate the spatial patterning of synaptic inputs by directly monitoring presynaptic activity in the intact mouse brain on the micron scale. Using in vivo calcium imaging of multiple neighbouring cerebellar parallel fibre axons, we find evidence for clustered patterns of axonal activity during sensory processing. The clustered parallel fibre input we observe is ideally suited for driving dendritic spikes, postsynaptic calcium signalling, and synaptic plasticity in downstream Purkinje cells, and is thus likely to be a major feature of cerebellar function during sensory processing

Complexity of multi-dimensional spontaneous EEG decreases during propofol induced general anaesthesia

Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia

Critical Changes in Cortical Neuronal Interactions in Anesthetized and Awake Rats

Background: Neuronal interactions are fundamental for information processing, cognition and consciousness. Anesthetics reduce spontaneous cortical activity; however, neuronal reactivity to sensory stimuli is often preserved or augmented. How sensory stimulus-related neuronal interactions change under anesthesia has not been elucidated. Here we investigated visual stimulus-related cortical neuronal interactions during stepwise emergence from desflurane anesthesia. Methods: Parallel spike trains were recorded with 64-contact extracellular microelectrode arrays from the primary visual cortex of chronically instrumented, unrestrained rats (N=6) at 8%, 6%, 4%, 2% desflurane anesthesia and wakefulness. Light flashes were delivered to the retina by transcranial illumination at 5-15s randomized intervals. Information theoretical indices, integration and interaction complexity, were calculated from the probability distribution of coincident spike patterns and used to quantify neuronal interactions before and after flash stimulation. Results: Integration and complexity showed significant negative associations with desflurane concentration (N=60). Flash stimulation increased integration and complexity at all anesthetic levels (N=60); the effect on complexity was reduced in wakefulness. During stepwise withdrawal of desflurane, the largest increase in integration (74%) and post-stimulus complexity (35%) occurred prior to reaching 4% desflurane concentration – a level associated with the recovery of consciousness according to the rats\u27 righting reflex. Conclusions: Neuronal interactions in the cerebral cortex are augmented during emergence from anesthesia. Visual flash stimuli enhance neuronal interactions in both wakefulness and anesthesia; the increase in interaction complexity is attenuated as post-stimulus complexity reaches plateau. The critical changes in cortical neuronal interactions occur during transition to consciousness

A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans

During awake consciousness, the brain intrinsically maintains a dynamical state in which it can coordinate complex responses to sensory input. How the brain reaches this state spontaneously is not known. General anesthesia provides a unique opportunity to examine how the human brain recovers its functional capabilities after profound unconsciousness. We used intracranial electrocorticography and scalp EEG in humans to track neural dynamics during emergence from propofol general anesthesia. We identify a distinct transient brain state that occurs immediately prior to recovery of behavioral responsiveness. This state is characterized by large, spatially distributed, slow sensory-evoked potentials that resemble the K-complexes that are hallmarks of stage two sleep. However, the ongoing spontaneous dynamics in this transitional state differ from sleep. These results identify an asymmetry in the neurophysiology of induction and emergence, as the emerging brain can enter a state with a sleep-like sensory blockade before regaining responsivity to arousing stimuli.National Institutes of Health (U.S.) (Grant K99-MH111748)National Institutes of Health (U.S.) (Grant R00-NS080911)National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant S10-RR023401)National Institutes of Health (U.S.) (Grant R01- NS062092)National Institutes of Health (U.S.) (Grant R01AG056015)National Institutes of Health (U.S.) (Grant P01GM118269)National Institutes of Health (U.S.) (Grant R01-EB009282

Monitoring the Depth of Anaesthesia

One of the current challenges in medicine is monitoring the patients’ depth of general anaesthesia (DGA). Accurate assessment of the depth of anaesthesia contributes to tailoring drug administration to the individual patient, thus preventing awareness or excessive anaesthetic depth and improving patients’ outcomes. In the past decade, there has been a significant increase in the number of studies on the development, comparison and validation of commercial devices that estimate the DGA by analyzing electrical activity of the brain (i.e., evoked potentials or brain waves). In this paper we review the most frequently used sensors and mathematical methods for monitoring the DGA, their validation in clinical practice and discuss the central question of whether these approaches can, compared to other conventional methods, reduce the risk of patient awareness during surgical procedures

Functional integration in the cortical neuronal network of conscious and anesthetized animals

General anesthesia consists of amnesia, analgesia, areflexia and unconsciousness. How anesthetics suppress consciousness has been a mystery for more than one and a half centuries. The overall goal of my research has been to determine the neural correlates of anesthetic-induced loss of consciousness. I hypothesized that anesthetics induce unconsciousness by interfering with the functional connectivity of neuronal networks of the brain and consequently, reducing the brain\u27s capacity for information processing. To test this hypothesis, I performed experiments in which neuronal spiking activity was measured with chronically implanted microelectrode arrays in the visual cortex of freely-moving rats during wakefulness and at graded levels of anesthesia produced by the inhalational anesthetic agent desflurane. I then applied linear and non-parametric information-theoretic analyses to quantify the concentration-dependent effect of general anesthetics on spontaneous and visually evoked spike firing activity in rat primary visual cortex. Results suggest that desflurane anesthesia disrupts cortical neuronal integration as measured by monosynaptic connectivity, spike burst coherence and information capacity. This research furthers our understanding of the mechanisms involved with the anesthetic-induced LOC which may facilitate in the development of better anesthetic monitoring devices and the creation of effective anesthetic agents that will be free of unwanted side effects

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold

Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients

Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non-reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment

Characterization of response properties in the mouse lateral geniculate nucleus

The lateral geniculate nucleus (LGN) has been increasingly recognized to actively regulate information transmission to primary visual cortex (V1). Although efforts have been devoted to study its morphological and functional features, the full array of response characteristics in mouse LGN as well as their dependency on subjective state have been relatively unexplored. To address the question we recorded from mouse LGN with multisite-electrode-arrays (MEAs). From a dataset with 185 single units, our results revealed several exceptional response features in mouse LGN. We also demonstrated that subtypes, such as ON-/OFF-centre and transient/sustained cells exhibited functionally distinctive features, which might indicate parallel projections. To further compare response features from the full extent of mouse LGN, we developed a three-dimension (3D) LGN volume through histological approach. This volume explicitly captures morphological features of mouse LGN and provides the preciseness to classify location of single neuron into the anterior/middle/posterior LGN. Based on this categorization, we showed that response features were not regionally restricted within mouse LGN. We further examined neural activity with subjects in high or low isoflurane states. The distinct features in LFPs between the two states indicated that adjusting isoflurane concentration could provide a reliable and controllable experimental model to explore the state-dependent neural activity in mouse visual system. Subsequently, our results demonstrated that properties, including response latency, contrast sensitivity and spatial frequency properties were modulated by isoflurane concentration. Our current work suggests that mouse LGN can dynamically regulate information transmission to the cortex using numerous mechanisms, including responding mode, modulation of neuronal responses according to subjects’ states.Open Acces