Multimodal assessment of recovery from coma in a rat model of diffuse brainstem tegmentum injury

Pais‐Roldán, Patricia; Edlow, Brian L.; Jiang, Yuanyuan; Stelzer, Johannes; Zou, Ming; Yu, Xin

doi:10.1016/j.neuroimage.2019.01.060

Cited by 27 publications

(14 citation statements)

References 136 publications

(140 reference statements)

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“…The marked hippocampal spectral differences in the Ictal and Postictal states compared to the Baseline and Recovery states, and the cortical low‐frequency oscillations seen in the Ictal and Postictal states suggest that the impairment arises from a broad network mechanism. This would be consistent with the known electrophysiological time course of emergence from other states of altered responsiveness, 39,47 and with spectral differences in the hippocampus and cortex specific to brain arousal state and behavior. The robust finding that cortical low‐frequency oscillations were associated with misses during the Ictal and Postictal periods makes a direct link between peri‐ictal behavioral impairment and remote cortical effects of limbic seizures, possibly mediated by changes in subcortical arousal state.…”

Section: Discussionsupporting

confidence: 85%

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

et al. 2021

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Objective Impairment in consciousness is a debilitating symptom during and after seizures; however, its mechanism remains unclear. Limbic seizures have been shown to spread to arousal circuitry to result in a "network inhibition" phenomenon. However, prior animal model studies did not relate physiological network changes to behavioral responses during or following seizures. Methods Focal onset limbic seizures were induced while rats were performing an operant conditioned behavioral task requiring response to an auditory stimulus to quantify how and when impairment of behavioral response occurs. Correct responses were rewarded with sucrose. Cortical and hippocampal electrophysiology measured by local field potential recordings was analyzed for changes in low‐ and high‐frequency power in relation to behavioral responsiveness during seizures. Results As seen in patients with seizures, ictal (p < .0001) and postictal (p = .0015) responsiveness was variably impaired. Analysis of cortical and hippocampal electrophysiology revealed that ictal (p = .002) and postictal (p = .009) frontal cortical low‐frequency 3–6‐Hz power was associated with poor behavioral performance. In contrast, the hippocampus showed increased power over a wide frequency range during seizures, and suppression postictally, neither of which were related to behavioral impairment. Significance These findings support prior human studies of temporal lobe epilepsy as well as anesthetized animal models suggesting that focal limbic seizures depress consciousness through remote network effects on the cortex, rather than through local hippocampal involvement. By identifying the cortical physiological changes associated with impaired arousal and responsiveness in focal seizures, these results may help guide future therapies to restore ictal and postictal consciousness, improving quality of life for people with epilepsy.

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Section: Discussionsupporting

confidence: 85%

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

et al. 2021

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“…They are located mainly in the medulla oblongata and pons Varolii (the caudal brainstem). The autonomic cardiorespiratory systems interact with the structures of the forebrain, and the functional significance of these connections is increasingly being explored [ 13 , 14 , 15 , 16 , 17 ]. Forebrain structures are the most unstable to ischaemic/hypoxic effects [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

et al. 2020

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(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

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“…Animal models that allow relevant direct measurements of such microscopic facets remain limited for coma [ 84 ] and fully absent for VS/UWS and MCS. The development of functionally relevant animal models will need to distinguish between the various neurological events (e.g., traumatic brain injury, anoxia, hypoxia among others) associated with DOC and the subsequent neurological syndromes of DOC (e.g., MCS, UWS/VS) [ 85 , 86 ] to characterize both etiology-specific and generalizable DOC mechanisms.…”

Section: Linking Micro- and Macroscalesmentioning

confidence: 99%

Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science

et al. 2021

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Aim In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. Methods To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. Results We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. Conclusion In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a “virtuous cycle,” leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.

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Multimodal assessment of recovery from coma in a rat model of diffuse brainstem tegmentum injury

Cited by 27 publications

References 136 publications

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science

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