Brain activity patterns in deep anesthesia
|Advisor:||Parent, André; Amzica, Florin|
|Abstract:||The guiding question for our investigations was: How do modulations in excitatory and inhibitory signaling lead to changes in the state of consciousness in the brain - are wakefulness, sleep and coma only landmarks on a continuum ranging from predominance of excitation (during wakefulness) to an ultimate prevalence of inhibition (during coma)? We addressed this question by a multilayered approach including a) sub-cellular investigations of modulations of ionic concentrations, b) intracellular responsiveness to excitatory stimuli, and c) EEG measures of whole-brain activity. Our studies were carried out exclusively in acute in vivo experiments on deeply anesthetized rats and cats. Since one of the factors in modulating inhibition is the accessibility of chloride inside- and outside of nerve cells, we began our investigations by asking which influence the availability of this ion might have on inhibitory network responses. Chloride-based inhibitory signaling requires a certain electrochemical gradient between the cytoplasm and the extracellular space as a permissive prerequisite. Thus far, it is widely assumed that diffusion provides a sufficient driving force to evenly distribute Cl- within the extracellular space and that a small re-distribution takes place after strong network activity including inhibitory signaling. In contrast we show a significant difference in regional levels of available extracellular Cl- within our target structure, the hippocampal formation. These findings suggest that the brain might employ mechanisms to counteract diffusion processes and thus create region-specific accumulations of ions - most likely to support needs of supply and demand. In our model, the states of vigilance and consciousness were controlled by application of general anesthesia and by doing so we intentionally offset the balance of excitatory and inhibitory brain signaling mechanisms. Previous research has shown that isoflurane anesthesia induces unconsciousness by modulating thalamocortical neurons. These neurons act as a relay for afferent sensory signals en route to the cortex. Isoflurane hyperpolarizes the cell membrane of these neurons and thus reduces their responsiveness to excitatory synaptic signaling. At the same time it appears that most cortical neurons are not subjected to isoflurane modulation in the same way. On the contrary, we observed diminishing inhibitory responses to afferent stimuli in cortical neurons under increasing levels of isoflurane, especially during conditions producing anesthesia-induced coma. In addition to these micro dynamic mechanisms we also investigated global whole-brain processes pertaining to inhibition. Under conditions of deep anesthesia, we observed two novel phenomena: Firstly, we demonstrated that even during comatose states, subliminal stimulations can elicit brain bursting responses - however only during a certain window during the anesthesia-induced passage from sleep-like behaviors to coma. Therefore, synaptic responses can indeed be elicited even during comatose states. This finding may constitute a vital piece of the puzzle for clinicians working with comatose patients and trying to re-vitalize brain circuits. Secondly, we observed a novel brain activity pattern which emerges under extremely high applications of isoflurane anesthesia – beyond the levels required for induction of a continuously flat (isoelectric) EEG line. This surprising finding demonstrates the importance of the circuit-level balance between excitation and inhibition, as even though the isoelectric line might appear to pose the ultimate dominance of inhibition, some form of excitatory activity can emerge and re-vitalize brain circuits. We conclude that excitation and inhibition might not balance in an all-or-none fashion and that an increase in inhibition does not automatically cause sleep and/or coma. Rather, excitation and inhibition should be understood as very localized processes during which the activity of a few neurons can tip the balance between the states of consciousness.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||13 April 2018|
|Collection:||Thèses et mémoires|
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