Unveiling age-independent spectral markers of propofol-induced loss of consciousness by decomposing the electroencephalographic spectrum into its periodic and aperiodic components

BackgroundInduction of general anesthesia with propofol induces radical changes in cortical network organization, leading to unconsciousness. While perioperative frontal electroencephalography (EEG) has been widely implemented in the past decades, validated and age-independent EEG markers for the timepoint of loss of consciousness (LOC) are lacking. Especially the appearance of spatially coherent frontal alpha oscillations (8–12 Hz) marks the transition to unconsciousness.Here we explored whether decomposing the EEG spectrum into its periodic and aperiodic components unveiled markers of LOC and investigated their age-dependency. We further characterized the LOC-associated alpha oscillations by parametrizing the adjusted power over the aperiodic component, the center frequency, and the bandwidth of the peak in the alpha range.MethodsIn this prospective observational trial, EEG were recorded in a young (18–30 years) and an elderly age-cohort (≥ 70 years) over the transition to propofol-induced unconsciousness. An event marker was set in the EEG recordings at the timepoint of LOC, defined with the suppression of the lid closure reflex. Spectral analysis was conducted with the multitaper method. Aperiodic and periodic components were parametrized with the FOOOF toolbox. Aperiodic parametrization comprised the exponent and the offset. The periodic parametrization consisted in the characterization of the peak in the alpha range with its adjusted power, center frequency and bandwidth. Three time-segments were defined: preLOC (105 – 75 s before LOC), LOC (15 s before to 15 s after LOC), postLOC (190 – 220 s after LOC). Statistical significance was determined with a repeated-measures ANOVA.ResultsLoss of consciousness was associated with an increase in the aperiodic exponent (young: p = 0.004, elderly: p = 0.007) and offset (young: p = 0.020, elderly: p = 0.004) as well as an increase in the adjusted power (young: p < 0.001, elderly p = 0.011) and center frequency (young: p = 0.008, elderly: p < 0.001) of the periodic alpha peak. We saw age-related differences in the aperiodic exponent and offset after LOC as well as in the power and bandwidth of the periodic alpha peak during LOC.ConclusionDecomposing the EEG spectrum over induction of anesthesia into its periodic and aperiodic components unveiled novel age-independent EEG markers of propofol-induced LOC: the aperiodic exponent and offset as well as the center frequency and adjusted power of the power peak in the alpha range

ECoG-based short-range recurrent stimulation techniques to stabilize tissue at risk of progressive damage: Theory based on clinical observations

We introduce theoretical concepts based on chaos control to stabilize in acute stroke the tissue at risk of progressive damage by preventing adverse effects of waves of mass neuronal depolarization. Moreover, we present clinical electrocorticography (ECoG) recordings of relevant signals suggested for the feedback control. The recordings are performed in combination with novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry in patients with aneurysmal subarachnoid haemorrhage (aSAH). In aSAH patients waves of spreading depolarization (SD) have a high incidence and cause hypoxia in tissue at risk, and, importantly, the haemodynamic response is the inverse of that seen in healthy tissue. In previous clinical studies, clusters of prolonged SDs have been measured in aSAH patients in close proximity to structural brain damage as assessed by neuroimaging, and, in theoretical studies, a mechanism was presented, suggesting how a failure of internal feedback could be a putative mechanism of such SD cluster patterns in acute stroke. 

This failing internal feedback control is now suggested to be replaced by ECoG-based short-range recurrent functional stimulation that initiates the normal hyperperfusion haemodynamic response in a demand-controlled way and stabilizes the tissue at risk during the critical phase of SD passage. The suggested method has three key features: (i) it is short-range, i.e., in the order of the distance of the ECoG electrode strip, (ii) it is demand-controlled, and (iii) it uses no prior knowledge of the target state, in particular, it adapts to conditions in the healthy physiological range. On-demand type stimulation provides minimal invasive feedback as the control force is off when the target state is reached, i.e., the tissue at risk is without SD or it is back to the physiological range (out of risk). These last two features (ii-iii) are shared with classical methods of chaos control, where major progress was made in the last years with respect to extensions for spatio-temporal wave patterns. A detailed bifurcation analysis of the nonlinear model is presented, in particular, the SD cluster forming cortical state is suggested to be caused by a delay-induced saddle-node bifurcation.
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Interactions between endocarditis-derived Streptococcus gallolyticus subsp. gallolyticus isolates and human endothelial cells

<p>Abstract</p> <p>Background</p> <p><it>Streptococcus gallolyticus </it>subsp. <it>gallolyticus </it>is an important causative agent of infective endocarditis (IE) but the knowledge on virulence factors is limited and the pathogenesis of the infection is poorly understood. In the present study, we established an experimental <it>in vitro </it>IE cell culture model using EA.hy926 and HUVEC cells to investigate the adhesion and invasion characteristics of 23 <it>Streptococcus gallolyticus </it>subsp. <it>gallolyticus </it>strains from different origins (human IE-derived isolates, other human clinical isolates, animal isolates). Adhesion to eight components of the extracellular matrix (ECM) and the ability to form biofilms <it>in vitro </it>was examined in order to reveal features of <it>S. gallolyticus </it>subsp. <it>gallolyticus </it>endothelial infection. In addition, the strains were analyzed for the presence of the three virulence factors <it>gtf</it>, <it>pilB</it>, and <it>fimB </it>by PCR.</p> <p>Results</p> <p>The adherence to and invasion characteristics of the examined <it>S. gallolyticus </it>subsp. <it>gallolyticus </it>strains to the endothelial cell line EA.hy926 differ significantly among themselves. In contrast, the usage of three different <it>in vitro </it>models (EA.hy926 cells, primary endothelial cells (HUVECs), mechanical stretched cells) revealed no differences regarding the adherence to and invasion characteristics of different strains. Adherence to the ECM proteins collagen I, II and IV revealed the highest values, followed by fibrinogen, tenascin and laminin. Moreover, a strong correlation was observed in binding to these proteins by the analyzed strains. All strains show the capability to adhere to polystyrole surfaces and form biofilms. We further confirmed the presence of the genes of two known virulence factors (<it>fimB</it>: all strains, <it>gtf</it>: 19 of 23 strains) and demonstrated the presence of the gene of one new putative virulence factor (<it>pilB</it>: 9 of 23 strains) by PCR.</p> <p>Conclusion</p> <p>Our study provides the first description of <it>S. gallolyticus </it>subsp. <it>gallolyticus </it>adhesion and invasion of human endothelial cells, revealing important initial information of strain variability, behaviour and characteristics of this as yet barely analyzed pathogen.</p

Oxygen-Induced and pH-Induced Direct Current Artifacts on Invasive Platinum/Iridium Electrodes for Electrocorticography

Background: Spreading depolarization (SD) and the initial, still reversible phase of neuronal cytotoxic edema in the cerebral gray matter are two modalities of the same process. SD may thus serve as a real-time mechanistic biomarker for impending parenchyma damage in patients during neurocritical care. Using subdural platinum/iridium (Pt/Ir) electrodes, SD is observed as a large negative direct current (DC) shift. Besides SD, there are other causes of DC shifts that are not to be confused with SD. Here, we systematically analyzed DC artifacts in ventilated patients by observing changes in the fraction of inspired oxygen. For the same change in blood oxygenation, we found that negative and positive DC shifts can simultaneously occur at adjacent Pt/Ir electrodes. Methods: Nurses and intensivists typically increase blood oxygenation by increasing the fraction of inspired oxygen at the ventilator before performing manipulations on the patient. We retrospectively identified 20 such episodes in six patients via tissue partial pressure of oxygen (p(ti)O(2)) measurements with an intracortical O-2 sensor and analyzed the associated DC shifts. In vitro, we compared Pt/Ir with silver/silver chloride (Ag/AgCl) to assess DC responses to changes in pO(2), pH, or 5-min square voltage pulses and investigated the effect of electrode polarization on pO(2)-induced DC artifacts. Results: Hyperoxygenation episodes started from a p(ti)O(2) of 37 (30-40) mmHg (median and interquartile range) reaching 71 (50-97) mmHg. During a total of 20 episodes on each of six subdural Pt/Ir electrodes in six patients, we observed 95 predominantly negative responses in six patients, 25 predominantly positive responses in four patients, and no brain activity changes. Adjacent electrodes could show positive and negative responses simultaneously. In vitro, Pt/Ir in contrast with Ag/AgCl responded to changes in either pO(2) or pH with large DC shifts. In response to square voltage pulses, Pt/Ir falsely showed smaller DC shifts than Ag/AgCl, with the worst performance under anoxia. In response to pO(2) increase, Pt/Ir showed DC positivity when positively polarized and DC negativity when negatively polarized. Conclusions: The magnitude of pO(2)-induced subdural DC shifts by approximately 6 mV was similar to that of SDs, but they did not show a sequential onset at adjacent recording sites, could be either predominantly negative or positive in contrast with the always negative DC shifts of SD, and were not accompanied by brain activity depression. Opposing polarities of pO(2)-induced DC artifacts may result from differences in baseline electrode polarization or subdural p(ti)O(2) inhomogeneities relative to subdermal p(ti)O(2) at the quasi-reference

Unveiling age-independent spectral markers of propofol-induced loss of consciousness by decomposing the electroencephalographic spectrum into its periodic and aperiodic components

Background: Induction of general anesthesia with propofol induces radical changes in cortical network organization, leading to unconsciousness. While perioperative frontal electroencephalography (EEG) has been widely implemented in the past decades, validated and age-independent EEG markers for the timepoint of loss of consciousness (LOC) are lacking. Especially the appearance of spatially coherent frontal alpha oscillations (8-12 Hz) marks the transition to unconsciousness.Here we explored whether decomposing the EEG spectrum into its periodic and aperiodic components unveiled markers of LOC and investigated their age-dependency. We further characterized the LOC-associated alpha oscillations by parametrizing the adjusted power over the aperiodic component, the center frequency, and the bandwidth of the peak in the alpha range. Methods: In this prospective observational trial, EEG were recorded in a young (18-30 years) and an elderly age-cohort (>= 70 years) over the transition to propofol-induced unconsciousness. An event marker was set in the EEG recordings at the timepoint of LOC, defined with the suppression of the lid closure reflex. Spectral analysis was conducted with the multitaper method. Aperiodic and periodic components were parametrized with the FOOOF toolbox. Aperiodic parametrization comprised the exponent and the offset. The periodic parametrization consisted in the characterization of the peak in the alpha range with its adjusted power, center frequency and bandwidth. Three time-segments were defined: preLOC (105 - 75 s before LOC), LOC (15 s before to 15 s after LOC), postLOC (190 - 220 s after LOC). Statistical significance was determined with a repeated-measures ANOVA. Results: Loss of consciousness was associated with an increase in the aperiodic exponent (young: p = 0.004, elderly: p = 0.007) and offset (young: p = 0.020, elderly: p = 0.004) as well as an increase in the adjusted power (young: p < 0.001, elderly p = 0.011) and center frequency (young: p = 0.008, elderly: p < 0.001) of the periodic alpha peak. We saw age-related differences in the aperiodic exponent and offset after LOC as well as in the power and bandwidth of the periodic alpha peak during LOC. Conclusion: Decomposing the EEG spectrum over induction of anesthesia into its periodic and aperiodic components unveiled novel age-independent EEG markers of propofol-induced LOC: the aperiodic exponent and offset as well as the center frequency and adjusted power of the power peak in the alpha range

Correlates of Spreading Depolarization, Spreading Depression, and Negative Ultraslow Potential in Epidural Versus Subdural Electrocorticography

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, neuronal oedema and activity loss (=depression). The SD extreme in ischemic tissue, termed ‘terminal SD,’ shows prolonged depolarization, in addition to a slow baseline variation called ‘negative ultraslow potential’ (NUP). The NUP is the largest bioelectrical signal ever recorded from the human brain and is thought to reflect the progressive recruitment of neurons into death in the wake of SD. However, it is unclear whether the NUP is a field potential or results from contaminating sensitivities of platinum electrodes. In contrast to Ag/AgCl-based electrodes in animals, platinum/iridium electrodes are the gold standard for intracranial direct current (DC) recordings in humans. Here, we investigated the full continuum including short-lasting SDs under normoxia, long-lasting SDs under systemic hypoxia, and terminal SD under severe global ischemia using platinum/iridium electrodes in rats to better understand their recording characteristics. Sensitivities for detecting SDs or NUPs were 100% for both electrode types. Nonetheless, the platinum/iridium-recorded NUP was 10 times smaller in rats than humans. The SD continuum was then further investigated by comparing subdural platinum/iridium and epidural titanium peg electrodes in patients. In seven patients with either aneurysmal subarachnoid hemorrhage or malignant hemispheric stroke, two epidural peg electrodes were placed 10 mm from a subdural strip. We found that 31/67 SDs (46%) on the subdural strip were also detected epidurally. SDs that had longer negative DC shifts and spread more widely across the subdural strip were more likely to be observed in epidural recordings. One patient displayed an SD-initiated NUP while undergoing brain death despite continued circulatory function. The NUP’s amplitude was -150 mV subdurally and -67 mV epidurally. This suggests that the human NUP is a bioelectrical field potential rather than an artifact of electrode sensitivity to other factors, since the dura separates the epidural from the subdural compartment and the epidural microenvironment was unlikely changed, given that ventilation, arterial pressure and peripheral oxygen saturation remained constant during the NUP. Our data provide further evidence for the clinical value of invasive electrocorticographic monitoring, highlighting important possibilities as well as limitations of less invasive recording techniques

Less-invasive subdural electrocorticography for investigation of spreading depolarizations in patients with subarachnoid hemorrhage

IntroductionWyler-strip electrodes for subdural electrocorticography (ECoG) are the gold standard for continuous bed-side monitoring of pathological cortical network events, such as spreading depolarizations (SD) and electrographic seizures. Recently, SD associated parameters were shown to be (1) a marker of early brain damage after aneurysmal subarachnoid hemorrhage (aSAH), (2) the strongest real-time predictor of delayed cerebral ischemia currently known, and (3) the second strongest predictor of patient outcome at 7 months. The strongest predictor of patient outcome at 7 months was focal brain damage segmented on neuroimaging 2 weeks after the initial hemorrhage, whereas the initial focal brain damage was inferior to the SD variables as a predictor for patient outcome. However, the implantation of Wyler-strip electrodes typically requires either a craniotomy or an enlarged burr hole. Neuromonitoring via an enlarged burr hole has been performed in only about 10% of the total patients monitored.MethodsIn the present pilot study, we investigated the feasibility of ECoG monitoring via a less invasive burrhole approach using a Spencer-type electrode array, which was implanted subdurally rather than in the depth of the parenchyma. Seven aSAH patients requiring extraventricular drainage (EVD) were included. For electrode placement, the burr hole over which the EVD was simultaneously placed, was used in all cases. After electrode implantation, continuous, direct current (DC)/alternating current (AC)-ECoG monitoring was performed at bedside in our Neurointensive Care unit. ECoGs were analyzed following the recommendations of the Co-Operative Studies on Brain Injury Depolarizations (COSBID).ResultsSubdural Spencer-type electrode arrays permitted high-quality ECoG recording. During a cumulative monitoring period of 1,194.5 hours and a median monitoring period of 201.3 (interquartile range: 126.1–209.4) hours per patient, 84 SDs were identified. Numbers of SDs, isoelectric SDs and clustered SDs per recording day, and peak total SD-induced depression duration of a recording day were not significantly different from the previously reported results of the prospective, observational, multicenter, cohort, diagnostic phase III trial, DISCHARGE-1. No adverse events related to electrode implantation were noted.DiscussionIn conclusion, our findings support the safety and feasibility of less-invasive subdural electrode implantation for reliable SD-monitoring