The impact of hypertonic saline on cerebrovascular reactivity and compensatory reserve in traumatic brain injury: an exploratory analysis.

BACKGROUND: Intravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI. METHODS: We retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA). RESULTS: Fifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration. CONCLUSIONS: The direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.

Alternative continuous intracranial pressure-derived cerebrovascular reactivity metrics in traumatic brain injury: a scoping overview.

BACKGROUND: Pressure reactivity index (PRx) has emerged as a means to continuously monitor cerebrovascular reactivity in traumatic brain injury (TBI). However, other intracranial pressure (ICP)-based continuous metrics exist, and may have advantages over PRx. The goal of this study was to perform a scoping overview of the literature on non-PRx ICP-based continuous cerebrovascular reactivity metrics in adult TBI. METHODS: We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019. Using a two-stage filtering of title/abstract, and then full manuscript, we identified pertinent articles. Data was abstracted to tables and each technique summarized, including pulse amplitude index (PAx), correlation between pulse amplitude of ICP and cerebral perfusion pressure (RAC), PRx55-15, and low-resolution metrics LAx and L-PRx. RESULTS: A total of 23 articles met the inclusion criteria, with the vast majority being retrospective in nature and based out of European centers. Sixteen articles focused on high-resolution metrics PAx, RAC, and PRx55-15, with 6 articles focusing on LAx and L-PRx. PAx may have a role in low ICP situations, where it appears to perform superior to PRx. RAC displays similar behavior to PRx, with a trend to stronger associations with favorable/unfavorable outcome at 6 months, and stronger parabolic relationship with CPP. PRx55-15 provides a focused assessment on the vasogenic frequency range associated with cerebral autoregulation, with preliminary data supporting a strong association with outcome in TBI. LAx and L-PRx display varying associations with 6-month outcome in TBI, depending on the window length of calculation, with shorter windows demonstrating stronger correlations with classical PRx. CONCLUSIONS: Non-PRx continuous ICP-based cerebrovascular reactivity metrics can be split into high-resolution and low-resolution measures. High-resolution indices include PAx, RAC, and PRx55-15, while low-resolution indices include L-PRx and LAx. The true role for these metrics beyond classic PRx remains unclear. Each displays situations where it may prove superior over PRx, given limitations with this currently widely accepted measure. Much future investigation into each of these alternative metrics is required prior to adoption into the clinical monitoring armamentarium in adult TBI.

Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation.

Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

Risk of recurrence of subdural hematoma after EMMA vs surgical drainage - Systematic review and meta-analysis.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common and debilitating neurological condition whose treatments, including burr hole drainage and craniotomy, suffer from high rates of recurrence and complication. Embolization of the middle meningeal artery (EMMA) is a promising minimally invasive approach to manage CSDH in a broad set of patients. METHODS: To evaluate the efficacy and safety of EMMA, a database search was conducted including the terms "subdural hematoma; embolization; embolized; middle meningeal" was performed and yielded a total of 260 results. Following exclusion based on predefined criteria, a total of four studies were identified and outcomes including recurrence rates and complication rates were extracted for analysis. RESULTS: Four studies including intervention and control groups were included with a total of n = 888 patients. The relative risk of CSDH recurrence in the EMMA (3.5%) compared to control group (23.5%) was significantly reduced when EMMA was performed (risk ratio = 0.17; 95% confidence interval (CI) 0.05-0.67). In addition, rates of complication were not significantly different between patients with conventional therapy and those who received EMMA (OR = 0.77; 95 confidence interval (CI) 0.3-1.99). CONCLUSION: Based on limited data, EMMA reduces the risk of recurrence by 20% compared to surgical treatment for CSDH.

Association Between Processed Electroencephalogram-Based Objectively Measured Depth of Sedation and Cerebrovascular Response: A Systematic Scoping Overview of the Human and Animal Literature.

Background: Current understanding of the impact that sedative agents have on neurovascular coupling, cerebral blood flow (CBF) and cerebrovascular response remains uncertain. One confounding factor regarding the impact of sedative agents is the depth of sedation, which is often determined at the bedside using clinical examination scoring systems. Such systems do not objectively account for sedation depth at the neurovascular level. As the depth of sedation can impact CBF and cerebral metabolism, the need for objective assessments of sedation depth is key. This is particularly the case in traumatic brain injury (TBI), where emerging literature suggests that cerebrovascular dysfunction dominates the burden of physiological dysfunction. Processed electroencephalogram (EEG) entropy measures are one possible solution to objectively quantify depth of sedation. Such measures are widely employed within anesthesia and are easy to employ at the bedside. However, the association between such EEG measures and cerebrovascular response remains unclear. Thus, to improve our understanding of the relationship between objectively measured depth of sedation and cerebrovascular response, we performed a scoping review of the literature. Methods: A systematically conduced scoping review of the existing literature on objectively measured sedation depth and CBF/cerebrovascular response was performed, search multiple databases from inception to November 2020. All available literature was reviewed to assess the association between objective sedation depth [as measured through processed electroencephalogram (EEG)] and CBF/cerebral autoregulation. Results: A total of 13 articles, 12 on adult humans and 1 on animal models, were identified. Initiation of sedation was found to decrease processed EEG entropy and CBF/cerebrovascular response measures. However, after this initial drop in values there is a wide range of responses in CBF seen. There were limited statistically reproduceable associations between processed EEG and CBF/cerebrovascular response. The literature body remains heterogeneous in both pathological states studied and sedative agent utilized, limiting the strength of conclusions that can be made. Conclusions: Conclusions about sedation depth, neurovascular coupling, CBF, and cerebrovascular response are limited. Much further work is required to outline the impact of sedation on neurovascular coupling.

Computer Vision for Continuous Bedside Pharmacological Data Extraction: A Novel Application of Artificial Intelligence for Clinical Data Recording and Biomedical Research.

Introduction: As real time data processing is integrated with medical care for traumatic brain injury (TBI) patients, there is a requirement for devices to have digital output. However, there are still many devices that fail to have the required hardware to export real time data into an acceptable digital format or in a continuously updating manner. This is particularly the case for many intravenous pumps and older technological systems. Such accurate and digital real time data integration within TBI care and other fields is critical as we move towards digitizing healthcare information and integrating clinical data streams to improve bedside care. We propose to address this gap in technology by building a system that employs Optical Character Recognition through computer vision, using real time images from a pump monitor to extract the desired real time information. Methods: Using freely available software and readily available technology, we built a script that extracts real time images from a medication pump and then processes them using Optical Character Recognition to create digital text from the image. This text was then transferred to an ICM + real-time monitoring software in parallel with other retrieved physiological data. Results: The prototype that was built works effectively for our device, with source code openly available to interested end-users. However, future work is required for a more universal application of such a system. Conclusion: Advances here can improve medical information collection in the clinical environment, eliminating human error with bedside charting, and aid in data integration for biomedical research where many complex data sets can be seamlessly integrated digitally. Our design demonstrates a simple adaptation of current technology to help with this integration.

Near-Infrared Cerebrovascular Reactivity for Monitoring Cerebral Autoregulation and Predicting Outcomes in Moderate to Severe Traumatic Brain Injury: Proposal for a Pilot Observational Study.

BACKGROUND: Impaired cerebrovascular reactivity after traumatic brain injury (TBI) in adults is emerging as an important prognostic factor, with strong independent association with 6-month outcomes. To date, it is unknown if impaired cerebrovascular reactivity during the acute phase is associated with ongoing impaired continuously measured cerebrovascular reactivity in the long-term, and if such measures are associated with clinical phenotype at those points in time. OBJECTIVE: We describe a prospective pilot study to assess the use of near-infrared spectroscopy (NIRS) to derive continuous measures of cerebrovascular reactivity during the acute and long-term phases of TBI in adults. METHODS: Over 2 years, we will recruit up to 80 adults with moderate/severe TBI admitted to the intensive care unit (ICU) with invasive intracranial pressure (ICP) monitoring. These patients will undergo high-frequency data capture of ICP, arterial blood pressure (ABP), and NIRS for the first 5 days of care. Patients will then have 30 minutes of noninvasive NIRS and ABP monitoring in the clinic at 3, 6, and 12 months post-injury. Outcomes will be assessed via the Glasgow Outcome Scale and Short Form-12 questionnaires. Various relationships between NIRS and ICP-derived cerebrovascular reactivity metrics and associated outcomes will be assessed using biomedical signal processing techniques and both multivariate and time-series statistical methodologies. RESULTS: Study recruitment began at the end of February 2020, with data collection ongoing and three patients enrolled at the time of writing. The expected duration of data collection will be from February 2020 to January 2022, as per our local research ethics board approval (B2018:103). Support for this work has been obtained through the National Institutes of Health (NIH) through the National Institute of Neurological Disorders and Stroke (NINDS) (R03NS114335), funded in January 2020. CONCLUSIONS: With the application of NIRS technology for monitoring of patients with TBI, we expect to be able to outline core relationships between noninvasively measured aspects of cerebral physiology and invasive measures, as well as patient outcomes. Documenting these relationships carries the potential to revolutionize the way we monitor patients with TBI, moving to more noninvasive techniques. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18740.

The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature.

Intravenous norepinephrine (NE) is utilized commonly in critical care for cardiovascular support. NE's impact on cerebrovasculature is unclear and may carry important implications during states of critical neurological illness. The aim of the study was to perform a scoping review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of NE. A search of MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019 was performed. All manuscripts pertaining to the administration of NE, in which the impact on CBF/cerebral vasculature was recorded, were included. We identified 62 animal studies and 26 human studies. Overall, there was a trend to a direct vasoconstriction effect of NE on the cerebral vasculature, with conflicting studies having demonstrated both increases and decreases in regional CBF (rCBF) or global CBF. Healthy animals and those undergoing cardiopulmonary resuscitation demonstrated a dose-dependent increase in CBF with NE administration. However, animal models and human patients with acquired brain injury had varied responses in CBF to NE administration. The animal models indicate an increase in cerebral vasoconstriction with NE administration through the alpha receptors in vessels. Global and rCBF during the injection of NE displays a wide variation depending on treatment and model/patient.

Cerebrovascular Response to Propofol, Fentanyl, and Midazolam in Moderate/Severe Traumatic Brain Injury: A Scoping Systematic Review of the Human and Animal Literature.

Intravenous propofol, fentanyl, and midazolam are utilized commonly in critical care for metabolic suppression and anesthesia. The impact of propofol, fentanyl, and midazolam on cerebrovasculature and cerebral blood flow (CBF) is unclear in traumatic brain injury (TBI) and may carry important implications, as care is shifting to focus on cerebrovascular reactivity monitoring/directed therapies. The aim of this study was to perform a scoping review of the literature on the cerebrovascular/CBF effects of propofol, fentanyl, and midazolam in human patients with moderate/severe TBI and animal models with TBI. A search of MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and the Cochrane Library from inception to May 2020 was performed. All articles were included pertaining to the administration of propofol, fentanyl, and midazolam, in which the impact on CBF/cerebral vasculature was recorded. We identified 14 studies: 8 that evaluated propofol, 5 that evaluated fentanyl, and 2 that evaluated midazolam. All studies suffered from significant limitations, including: small sample size, and heterogeneous design and measurement techniques. In general, there was no significant change seen in CBF/cerebrovascular response to administration of propofol, fentanyl, or midazolam during experiments where PCO2 and mean arterial pressure (MAP) were controlled. This review highlights the current knowledge gap surrounding the impact of commonly utilized sedative drugs in TBI care. This work supports the need for dedicated studies, both experimental and human-based, evaluating the impact of these drugs on CBF and cerebrovascular reactivity/response in TBI.

Cerebrovascular Response to Phenylephrine in Traumatic Brain Injury: A Scoping Systematic Review of the Human and Animal Literature.

Intravenous phenylephrine (PE) is utilized commonly in critical care for cardiovascular support. Its impact on the cerebrovasculature is unclear and its use may have important implications during states of critical neurological illness. The aim of this study was to perform a scoping review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of PE in traumatic brain injury (TBI), evaluating both animal models and human studies. We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and the Cochrane Library from inception to January 2020. We identified 12 studies with various animal models and 4 studies in humans with varying TBI pathology. There was a trend toward a consistent increase in mean arterial pressure (MAP) by the injection of PE systemically, and by proxy, an increase of the cerebral perfusion pressure (CPP). There was a consistent constriction of cerebral vessels by PE reported in the small number of studies documenting such a response. However, the heterogeneity of the literature on the CBF/cerebral blood volume (CBV) response makes the strength of the conclusions on PE limited. Studies were heterogeneous in design and had significant limitations, with most failing to adjust for confounding factors in cerebrovascular/CBF response. This review highlights the significant knowledge gap on the cerebrovascular/CBF effects of PE administration in TBI, calling for further study on the impact of PE on the cerebrovasculature both in vivo and in experimental settings.

The Impact of Vasopressor and Sedative Agents on Cerebrovascular Reactivity and Compensatory Reserve in Traumatic Brain Injury: An Exploratory Analysis.

The impact of vasopressor and sedative drugs on cerebrovascular reactivity in traumatic brain injury (TBI) remains unclear. The aim of this study was to evaluate the impact of changes of doses of commonly administered sedation (i.e., propofol, fentanyl, and ketamine) and vasopressor agents (i.e., norepinephrine [NE], phenylephrine [PE], and vasopressin[VSP]) on cerebrovascular reactivity and compensatory reserve in patients with moderate/severe TBI. Using the Winnipeg Acute TBI Database, we identified 38 patients with more than 1000 distinct changes of infusion rates and more than 500 h of paired drug infusion/physiology data. Cerebrovascular reactivity was assessed using pressure reactivity index (PRx) and cerebral compensatory reserve was assessed using RAP (the correlation [R] between pulse amplitude of intracranial pressure [ICP; A] and ICP [P]). We evaluated the data in two phases. First, we assessed the relationship between mean hourly dose of medication and its relation to both mean hourly index values, and time spent above a given index threshold. Second, we evaluated time-series data for each individual dose change per medication, assessing for a statistically significant change in PRx and RAP metrics. The results of the analysis confirmed that, overall, the mean hourly dose of sedative (propofol, fentanyl, and ketamine) and vasopressor (NE, PE, and VSP) agents does not impact hourly cerebrovascular reactivity or compensatory reserve measures. Similarly, incremental dose changes in these medications in general do not lead to significant changes in cerebrovascular reactivity or compensatory reserve. For propofol with incremental dose increases, in situations where PRx is intact (i.e., PRx <0 prior), a statistically significant increase in PRx was seen. However, this may not indicate deteriorating cerebrovascular reactivity as the final PRx (∼0.05) may still be considered to be intact cerebrovascular reactivity. As such, this finding with regards to propofol remains "weak." This study indicates that commonly administered sedative and vasopressor agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity or compensatory reserve in TBI. These results should be considered preliminary, requiring further investigation.

Conundrums of high-frequency oscillations (80-800 Hz) in the epileptic brain.

Pathological high-frequency oscillations (HFOs) (80-800 Hz) are considered biomarkers of epileptogenic tissue, but the underlying complex neuronal events are not well understood. Here, we identify and discuss several outstanding issues or conundrums in regards to the recording, analysis, and interpretation of HFOs in the epileptic brain to critically highlight what is known and what is not about these enigmatic events. High-frequency oscillations reflect a range of neuronal processes contributing to overlapping frequencies from the lower 80 Hz to the very fast spectral frequency bands. Given their complex neuronal nature, HFOs are extremely sensitive to recording conditions and analytical approaches. We provide a list of recommendations that could help to obtain comparable HFO signals in clinical and basic epilepsy research. Adopting basic standards will facilitate data sharing and interpretation that collectively will aid in understanding the role of HFOs in health and disease for translational purpose.

Identification of brain regions of interest for epilepsy surgery planning using support vector machines.

In patients with intractable epilepsy, surgical resection is a promising treatment; however, post surgical seizure freedom is contingent upon accurate identification of the seizure onset zone (SOZ). Identification of the SOZ in extratemporal epilepsy requires invasive intracranial EEG (iEEG) recordings as well as resource intensive and subjective analysis by epileptologists. Expert inspection yields inconsistent localization of the SOZ which leads to comparatively poor post surgical outcomes for patients. This study employs recordings from 6 patients undergoing resection surgery in order to develop an automated and scalable system for identifying regions of interest (ROIs). Leveraging machine learning techniques and features used for seizure detection, a classification system was trained and tested on patients with Engel class I to class IV outcomes, demonstrating superior performance in the class I patients. Further, classification using features based upon both high frequency and low frequency oscillations was best able to identify channels suited for resection. This study demonstrates a novel approach to ROI identification and provides a path for developing tools to improve outcomes in epilepsy surgery.

Classification of Multiple Seizure-Like States in Three Different Rodent Models of Epileptogenesis.

Epilepsy is a dynamical disease and its effects are evident in over fifty million people worldwide. This study focused on objective classification of the multiple states involved in the brain's epileptiform activity. Four datasets from three different rodent hippocampal preparations were explored, wherein seizure-like-events (SLE) were induced by the perfusion of a low - Mg(2+) /high-K(+) solution or 4-Aminopyridine. Local field potentials were recorded from CA3 pyramidal neurons and interneurons and modeled as Markov processes. Specifically, hidden Markov models (HMM) were used to determine the nature of the states present. Properties of the Hilbert transform were used to construct the feature spaces for HMM training. By sequentially applying the HMM training algorithm, multiple states were identified both in episodes of SLE and nonSLE activity. Specifically, preSLE and postSLE states were differentiated and multiple inner SLE states were identified. This was accomplished using features extracted from the lower frequencies (1-4 Hz, 4-8 Hz) alongside those of both the low- (40-100 Hz) and high-gamma (100-200 Hz) of the recorded electrical activity. The learning paradigm of this HMM-based system eliminates the inherent bias associated with other learning algorithms that depend on predetermined state segmentation and renders it an appropriate candidate for SLE classification.

3-D flexible nano-textured high-density microelectrode arrays for high-performance neuro-monitoring and neuro-stimulation.

We introduce a new 3-D flexible microelectrode array for high performance electrographic neural signal recording and stimulation. The microelectrode architecture maximizes the number of channels on each shank and minimizes its footprint. The electrode was implemented on flexible polyimide substrate using microfabrication and thin-film processing. The electrode has a planar layout and comprises multiple shanks. Each shank is three mm in length and carries six gold pads representing the neuro-interfacing channels. The channels are used in recording important precursors with potential clinical relevance and consequent electrical stimulation to perturb the clinical condition. The polyimide structure satisfied the mechanical characteristics required for the proper electrode implantation and operation. Pad postprocessing technique was developed to improve the electrode electrical performance. The planar electrodes were used for creating 3-D "Waterloo Array" microelectrode with controlled gaps using custom designed stackers. Electrode characterization and benchmarking against commercial equivalents demonstrated the superiority of the Flex electrodes. The Flex and commercial electrodes were associated with low-power implantable responsive neuro-stimulation system. The electrodes performance in recording and stimulation application was quantified through in vitro and in vivo acute and chronic experiments on human brain slices and freely-moving rodents. The Flex electrodes exhibited remarkable drop in the electric impedance (100 times at 100 Hz), improved electrode-electrolyte interface noise (dropped by four times) and higher signal-to-noise ratio (3.3 times).

High-density intracortical microelectrode arrays with multiple metallization layers for fine-resolution neuromonitoring and neurostimulation.

Intracortical microelectrodes play a prominent role in the operation of neural interfacing systems. They provide an interface for recording neural activities and modulating their behavior through electric stimulation. The performance of such systems is thus directly meliorated by advances in electrode technology. We present a new architecture for intracortical electrodes designed to increase the number of recording/stimulation channels for a given set of shank dimensions. The architecture was implemented on silicon using microfabrication process and fabricated 3-mm-long electrode shanks with six relatively large (110 µm ×110 µm) pads in each shank for electrographic signal recording to detect important precursors with potential clinical relevance and electrical stimulation to correct neural behavior with low-power dissipation in an implantable device. Moreover, an electrode mechanical design was developed to increase its stiffness and reduce shank deflection to improve spatial accuracy during an electrode implantation. Furthermore, the pads were post-processed using pulsated low current electroplating and reduced their impedances by ≈ 30 times compared to the traditionally fabricated pads. The paper also presents microfabrication process, electrodes characterization, comparison to the commercial equivalents, and in vitro and in vivo validations.