Disruption in structural-functional network repertoire and time resolved subcortical-frontoparietal connectivity in disorders of consciousness

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, i.e. so-called eigenmodes, were supplemented as potential markers. By analysing time-resolved functional connectivity from fMRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and fronto-parietal subcortical network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the global neuronal workspace theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

Status Epilepticus

Status epilepticus (SE) is a medical and neurologic emergency defined as persistent seizure activity lasting more than 5 minutes or recurrent seizures without recovery of consciousness in between. When seizures persist despite adequate doses of first- and second-line antiepileptic agents, the condition is called refractory SE. Super-refractory SE occurs when seizure activity continues or recurs 24 hours after the initiation of therapy with anesthetic agents.

JUSTIFICATION FOR THE COMBINED USE OF PROPOFOL AND DEXMEDETOMIDINE IN ELECTIVE PROCEDURAL SEDATION

Procedural sedation (PS) is the technique of administering sedatives with or without analgesics to induce a condition in which the patient can tolerate unpleasant procedures while maintaining cardio-respiratory function. Planned PSs are performed with procedures of various invasiveness, painfulness and duration, but by definition, they do not reach the depth of general anesthesia and do not require the use of respiratory support or controlled mechanical ventilation, and even more – muscle relaxants. For effective PS, it is extremely important to establish verbal contact with the patient and achieve a stable emotional state of the patient and carefully explain to him the details of the PS. When choosing the depth of PS, it’s necessary to reach a compromise between the degree of anesthesia and amnesia, on the one hand, and the effectiveness of spontaneous breathing, as well as the possibility of an early recovery of consciousness, on the other. If possible, the problem of pain (when consciousness is partially preserved) or nociceptive stimuli (when the level of consciousness is reduced or absent) is solved separately through the use of local or regional anesthesia. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and some other drugs with analgesic properties are often used, and opioid analgesics are avoided or used in small or minimal doses. Unlike anesthesia, even deep sedation cannot and should not completely prevent the patient from moving during intense pain / nociceptive stimuli. If necessary, the problem of patient movements is solved not only and not so much by further deepening sedation, but precisely by improving analgesia and/or fixing the patient for the duration of short-term painful manipulations. To achieve these goals, PS is most often used propofol, or its dexmedetomidine or midazolam. This publication focuses on the advantages of using a multimodal approach for prolonged PS, which allows for a significant reduction in the dose of corresponding drugs and rate of complications in comparison with sedation with a single anaesthetic at significantly higher doses.

Location of Subcortical Microbleeds and Recovery of Consciousness After Severe Traumatic Brain Injury

Background:In patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (“arousal nuclei”) are implicated in coma pathogenesis and are compatible with coma recovery.Methods:We mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 Tesla susceptibility-weighted images (SWI) in twelve patients with acute severe TBI who presented in coma and recovered consciousness within six months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at six months.Results:There was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%) and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within non-arousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale-Extended scores.Conclusions:These results suggest resilience of arousal mechanisms in the human brain after severe TBI.

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.

Recovery of consciousness and cognition after general anesthesia in humans

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for three hours and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.

The Clinical Effect of Repetitive Transcranial Magnetic Stimulation on the Disturbance of Consciousness in Patients in a Vegetative State

ObjectiveTo explore the effect of combining repetitive transcranial magnetic stimulation (rTMS) and conventional rehabilitation on the recovery of consciousness in patients in a persistent vegetative state (PVS).MethodsA total of 48 patients in a PVS were randomly divided into a treatment and control group. Patients in the treatment group were treated with rTMS to stimulate the dorsolateral prefrontal cortex, and patients in the control group were treated with false stimulation. All patients were evaluated using scales and neuroelectrophysiological assessment before treatment, after 30 days of treatment, and following 60 days of treatment.ResultsBased on the Coma Recovery Scale-Revised (CRS-R) and electroencephalogram (EEG) grading indexes, the treatment group was significantly higher than those of the control group after 30 and 60 days of treatment. The average difference in the three measurements between the two groups before treatment, at 30 days, and 60 days was 0.04, 1.54, and 2.09 for CRS-R and 0.08, −0.83, and −0.62 for EEG indexes, respectively. The latency periods of each wave of the brainstem auditory evoked potentials (BAEPs) in the treatment group were shorter than those in the control group after 30 and 60 days of treatment. In both groups, the BAEP scores after 30 days of treatment were significantly higher than the scores before treatment, and the scores after 60 days of treatment were higher than the scores after 30 days.ConclusionIn patients in a PVS, rTMS assists in the recovery of consciousness function.