A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials

Sutton, J. A.; Clauss, R.P.

doi:10.1080/02699052.2017.1300836

Cited by 41 publications

(36 citation statements)

References 33 publications

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“…Are some patients just below this critical threshold? Different interventions, such as zolpidem or amantadine administration 65 , 66 , thalamic stimulation with deep brain stimulation 62 or low-intensity focused ultrasound pulsation 63 , transcranial direct current stimulation 67 , and vagal nerve stimulation 68 have demonstrated significant behavioral improvements in individual patients but a reliable read-out and interpretation of their end-point effects at the level of cortical circuits is still lacking. In the view of the present results, detecting the presence of cortical sleep-like bistability and tracking its evolution over time, may offer an objective reference to devise, guide, and titrate therapeutic strategies aimed at restoring consciousness.…”

Section: Discussionmentioning

confidence: 99%

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients

et al. 2018

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Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tendency of cortical circuits to fall into silence (OFF-period) upon receiving an input, a behavior typically observed during sleep. Spectral and phase domain analysis of EEG responses to transcranial magnetic stimulation reveals the occurrence of OFF-periods in the cortex of UWS patients (N = 16); these events never occur in healthy awake individuals (N = 20) but are similar to those detected in healthy sleeping subjects (N = 8). Crucially, OFF-periods impair local causal interactions, and prevent the build-up of global complexity in UWS. Our findings link potentially reversible local events to global brain dynamics that are relevant for pathological loss and recovery of consciousness.

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Section: Discussionmentioning

confidence: 99%

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients

et al. 2018

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“…Are some patients just below this critical threshold? Different interventions (73), such as zolpidem or amantadine administration(74,75), thalamic stimulation with Deep Brain Stimulation(69,76) or low-intensity focused ultrasound pulsation(70), transcranial direct current stimulation(77,78) and vagal nerve stimulation(79) have demonstrated significant behavioural improvements in individual patients but a reliable read--out and interpretation of their end--point effects at the level of cortical circuits is still lacking. To the extent that sleep--like bistability represents the common functional endpoint of loss of complexity in severely brain--injured brains, detecting…”

mentioning

confidence: 99%

Sleep-like bistability, loss of causality and complexity in the brain of Unresponsive Wakefulness Syndrome patients

Rosanova

Fecchio

Casarotto

et al. 2018

Preprint

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Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) also reveals preserved cortical reactivity, but in most cases, the residual thalamocortical circuits fail to engage complex causal interactions, as assessed by the perturbational complexity index (PCI).Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is physiological non-rapid eye movement (NREM) sleep. The underlying mechanism is bistability: the tendency of cortical neurons to fall into a silent period (OFF-period) upon receiving an input.Here we tested whether a pathological form of bistability may be responsible for loss of brain complexity in UWS patients. Time-frequency decomposition analysis of TMS/EEG responses in UWS patients revealed the occurrence of OFF-periods (detected as a transient suppression of high-frequency oscillations in the EEG) similar to the ones evoked by TMS in the cortex of healthy sleeping subjects. Pathological OFF-periods were detected in any cortical area, significantly impaired local causal interactions (as measured by PLF) and prevented the buildup of global complexity (as measured by PCI) in the brain of UWS patients.Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. To the extent that sleep-like bistability represents the common functional endpoint of loss of complexity, detecting its presence and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.

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“…Awakening, a temporary revival of patients who have been akinetic, apathic and with no reaction for years following a large brain damage, has been observed after administration of drugs even if the mechanisms underlying them remain unknown. Although rare, the awakenings produced briefly by "sleeping pills" are now well documented [1][2][3]. Arnst et al recently reported spectacular effects of Benzodiazepines (BZDs) on a 29 years old patient after a severe hypoxic-ischemic brain injury and following a history of alcohol abuse [4].…”

Section: Introductionmentioning

confidence: 99%

Is the awakening produced by benzodiazepines due to excitatory actions of GABA?

Ben-Ari

2021

transl med commun

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Benzodiazepines (BZDs) such as Zolpidem can produce a temporary revival of patients who have been akinetic and apathic for years. The mechanisms underlying this “awakening” reaction are suggested globally to be related to an activation of gamma-aminobutyric acid (GABA) inhibitory systems. However, brain trauma or cerebro-vascular infarcts, like many other pathological insults, are associated with a shift of the polarity of GABA from inhibition to excitation consequently to an increase of intracellular chloride concentration ([Cl−]i) levels. Experimental and clinical observations suggest that BZDs generate paradoxical reactions in these conditions, hence the transient “awakening”. The NKCC1 (Na-K-2Cl co-transporter isoform 1) chloride importer antagonist Bumetanide restores low [Cl−]i levels and an efficient inhibitory drive. It is therefore suggested that the administration of Bumetanide might provide a persistent “awakening” by shifting GABAergic actions from excitation to inhibition and attenuating the mechanism underlying the apathic/akinetic state.

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A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials

Cited by 41 publications

References 33 publications

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients

Sleep-like bistability, loss of causality and complexity in the brain of Unresponsive Wakefulness Syndrome patients

Is the awakening produced by benzodiazepines due to excitatory actions of GABA?

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