Logan Voss

Waikato Hospital · Anaesthesia

Despite 50 years of clinical use and experimental endeavor the anesthetic, analgesic, and psychomimetic effects of ketamine remain to be fully elucidated. While NMDA receptor antagonism has been long held as ketamine's fundamental molecular action, interrogation of bespoke ketamine analogs with known absent NMDA binding, yet profound anesthetic and...

The ex vivo cortical slice is an extremely versatile preparation, but its utility ultimately depends on understanding its limitations and functional constraints. A question for experimentalists new to the field of cortical slice electrophysiology might be — what are the different network dynamical states available to a cortical slice as a function...

Ketamine has been in clinical use for 50 years as an analgesic and anesthetic. In keeping with its unique clinical behavioral profile, the EEG patterns under ketamine anesthesia differ substantially from those seen with other classes of anesthetic drugs, making it something of an enigma in the field of anesthesiology. The EEG effects of anesthetic...

Quantification of plasma propofol (2,6-diisopropylphenol) in the context of clinical anaesthesia is challenging because of the need for offline blood sample processing using specialised laboratory equipment and techniques. In this study we sought to refine a simple procedure using solid phase extraction and colorimetric analysis into a benchtop pro...

The novel coronavirus SARS-CoV-2, responsible for the present COVID-19 global pandemic, is known to bind to the angiotensin converting enzyme-2 (ACE2) receptor in human cells. A possible treatment of COVID-19 could involve blocking ACE2 and/or disabling the spike protein on the virus. Here, molecular dynamics simulations were performed to test the...

Transcranial magnetic stimulation (TMS) is a technique used to treat different neurological disorders non-invasively. A pulsed current to a coil generates a magnetic field ( $B$ -field) which induces an electric field ( $E$ -field). Underlying biophysical effects of TMS are unclear. Therefore, animal experiments are needed; however, making small...

Hypoxic brain injury is a leading cause of loss of quality of life globally for which there are currently no effective treatments. There has been increasing interest in incorporating photosynthesising agents into hypoxic tissue as a mechanism for in situ oxygen delivery, independent of vascular perfusion. To date this has not been tested in the bra...

In brain slice experiments there’s currently no validated electrophysiological method for differentiating viability between GABAergic and glutamatergic cell populations. Here we investigated the neurophysiology of high frequency field potential activity — and its utility for probing the functional state of the GABAergic system in brain slices. Fiel...

Hypoxic-ischaemic brain injury is a major cause of morbidity and mortality internationally. Using an in vitro isolated cortex model, this study investigated the optimal cerebrospinal fluid oxygenation parameters for rescuing metabolically challenged cortical tissue. In particular, we asked whether maximizing oxygen content with oxygen nanobubbles c...

Ketamine is a common anaesthetic that reduces the excitatory action of glutamate and induces loss of consciousness. Importantly, it promotes analgesia, though it also induces undesirable effects, such as agitation, disorientation, hallucinations and nausea. Thus, there is an ongoing search for novel ketamine analogues that influence a similar reper...

The in vitro cortical slice preparation is a widely used tool for electrophysiological investigation of brain neurophysiology. However, slice quality can be highly variable despite attempts to standardise practice. The purpose of this study was to determine the extent to which this variability is due to sensitivity to aspects of the preparation met...

Regulation of synaptically located ionotropic receptors is thought to be the main mechanism by which anaesthetics cause unconsciousness. An alternative explanation, which has received much less attention, is that of primary anaesthetic disruption of brain metabolism via suppression of mitochondrial proteins. In this pilot study in mouse cortical sl...

One of the challenges for slice experimentalists is achieving optimal tissue oxygenation. One area that has not been addressed in submerged slices is the relationship between oxygenation of the artificial cerebrospinal fluid, slice depth and tissue performance. In this study we varied the depth of slice submersion, measured the oxygen profile in th...

A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily a...

Background Transcranial Magnetic Stimulation (TMS) is a technique used to treat different neurological disorders non-invasively. A pulsed current to a coil induces an E -field. Underlying biophysical effects of TMS are unclear. Therefore, animal experiments are needed; however, making small TMS coils suitable for mice is difficult because their fie...

Background: Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010,...

Background: EEG activity in the extended alpha frequency range (7–17 Hz) during maintenance of general anaesthesia is primarily determined by effect-site concentrations of the hypnotic and analgesic drugs used. Intermittent alpha loss during surgery, unexplained by changes in anaesthetic or opioid concentrations, could represent arousal of the cort...

Background Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared acr...

Background Postoperative delirium may manifest in the immediate post-anaesthesia care period. Such episodes appear to be predictive of further episodes of inpatient delirium and associated adverse outcomes. Frontal electroencephalogram (EEG) findings of suppression patterns and low proprietary index values have been associated with postoperative de...

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine's psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic link...

General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine an...

Spinodal decomposition is a well-known pattern-forming mechanism in metallurgic alloys, semiconductor crystals, and colloidal gels. In metallurgy, if a heated sample of a homogeneous Zn-Al alloy is suddenly quenched below a critical temperature, then the sample can spontaneously precipitate into inhomogenous textures of Zn- and Al-rich regions with...

Background: Assessment of patients for delirium in the Post Anesthesia Care Unit (PACU) is confounded by the residual effects of the varied anesthetic and analgesic regimens employed during surgery and by the physiological consequences of surgery such as pain. Nevertheless, delirium diagnosed at this early stage has been associated with adverse cli...

Objective. Significant spectral characteristics of electroencephalogram (EEG) patterns exist in individual patients during re-establishing consciousness after general anesthesia. However, these EEG patterns cannot be quantitatively identified using commercially available depth of anesthesia (DoA) monitors. This study proposed an effective classific...

Background: Ketamine is a general anesthetic thought to act by antagonizing N-methyl-D-aspartate receptors. However, ketamine acts on multiple channels, many of which are potential targets-including hyperpolarization-activated cyclic nucleotide-gated and potassium channels. In this study we tested the hypothesis that potassium leak channels contri...

During emergence from anesthesia patients regain their muscle tone (EMG). In a typical population of surgical patients the actual volatile gas anesthetic concentrations in the brain (CeMAC) at which EMG activation occurs remains unknown, as is whether EMG activation at higher CeMACs is correlated with subsequent severe pain, or with cortical activa...

Oscillations in the electroencephalogram (EEG) at the alpha frequency (8–12 Hz) are thought to be ubiquitous during surgical anesthesia, but the details of how this oscillation responds to ongoing changes in volatile anesthetic concentration have not been well characterized. It is not known how often alpha oscillations are absent in the clinical co...

Example data from four additional patients (A–D) showing spectrograms and the relation between anesthetic concentration and peak alpha frequency. Note that for ease of viewing anesthetic concentration has been inverted on the y-axis. Patients (A–C) show clear relationships between anesthetic concentration and frequency, but patient (D) does not.

Power spectra for six example patients (A–F) showing median power (thick blue line) from a 60 s period following cessation of surgery.

Astrocytes have been promoted as a possible mechanistic target for anaesthetic hypnosis. The aim of this study was to explore this using the neocortical brain slice preparation. The methods were in two parts. Firstly, multiple general anaesthetic compounds demonstrating varying in vivo hypnotic potency were analysed for their effect on "zero-magnes...

Modeling the effects of anesthetic drugs on brain activity is very helpful in understanding anesthesia mechanisms. The aim of this study was to set up a combined model to relate actual drug levels to EEG dynamics and behavioral states during propofol-induced anesthesia. We proposed a new combined theoretical model based on a pharmacokinetics (PK) m...

The detailed description of the neural mass model and the computational process of EEG-like data. (PDF)

The general anesthetic propofol has been in clinical use for more than 30 years and has become the agent of choice for rapid intravenous induction. While its hypnotic and anti-convulsant properties are well known, the propensity for propofol to promote seizure activity is less well characterised. Electroencephalogram-confirmed reports of propofol-i...

Monitoring the brain state in anaesthesia is crucial for clinical doctors. In this study, we propose a novel nonlinear method, the permutation Lempel-Ziv complexity (PLZC) index, which describes the complexity in the electroencephalographic (EEG) signal to quantify the effect of GABAergic anaesthetics on brain activities.We applied the PLZC to two...

Despite their ubiquitous use for rendering patients unconscious for surgery, our understanding of how general anesthetics cause hypnosis remains rudimentary at best. Recent years have seen increased interest in "top-down" cortico-centric theories of anesthetic action. The aim of this study was to explore this by investigating direct cortical effect...

Background: Ketamine is a rapidly acting dissociative anaesthetic drug with additional sympathomimetic, analgesic, and antidepressant properties. Despite these advantages, clinical use is curtailed by prolonged psychomimetic effects apparent over the entire dose spectrum. In this study, we report on the hypnotic potency of SN 35210, the first keta...

Electroencephalogram (EEG) synchronization is becoming an essential tool to describe neurophysiological mechanisms of communication between brain regions under general anesthesia. Different synchronization measures have their own properties to reflect the changes of EEG activities during different anesthetic states. However, the performance charact...

Ketamine is a well-established, rapidly acting dissociative anesthetic. Clinical use is limited by prolonged psychotomimetic phenomena on emergence, often requiring the coadministration of additional hypnotic drugs. We hypothesized that the development of ketamine ester analogs with ultrashort offset times might markedly reduce the dysphoric emerge...

Highlights: ► Twelve entropy indices were systematically compared in monitoring depth of anesthesia and detecting burst suppression.► Renyi permutation entropy performed best in tracking EEG changes associated with different anesthesia states.► Approximate Entropy and Sample Entropy performed best in detecting burst suppression. Objective: Entro...

The electroencephalogram (EEG) during the re-establishment of consciousness after general anesthesia and surgery varies starkly between patients. Can the EEG during this emergence period provide a means of estimating the underlying biological processes underpinning the return of consciousness? Can we use a model to infer these biological processes...

Ketamine has been in clinical use for over half a century, yet its precise mechanisms of action remain mysterious for the large part. Its hypnotic effects appear to be largely mediated by blockade of NMDA and HCN1 receptors, but cholinergic, aminergic, and opioid systems appear to play both a positive and negative modulatory role in both sedation a...

Burst suppression is a unique electroencephalogram (EEG) pattern commonly seen in cases of severely reduced brain activity such as overdose of general anesthesia. It is important to detect burst suppression reliably during the administration of anesthetic or sedative agents, especially for cerebral-protective treatments in various neurosurgical dis...

General anesthetics are hypothesised to cause unconsciousness by interrupting communication pathways within the cerebral cortex. A correlate of this has been demonstrated in mouse neocortical slices, where anesthetics disrupt the spread of population field potential activity - resulting in a "decoupling" of activity recorded across spatial location...

The electrical impedance of samples of mouse brain cortex has been measured between 4.7 kHz and 2.0 MHz. Brain slices of thickness 400 μm were prepared from two mice. Each slice was placed in either normal artificial cerebrospinal fluid or magnesium-free artificial cerebrospinal fluid; the latter induces seizure-like electrical behaviour. A total o...

The electroencephalogram (EEG) has been widely applied in the assessment of depth of anesthesia (DoA). Recent research has found that multi-scale EEG analysis describes brain dynamics better than traditional non-linear methods. In this study, we have adopted a modified sample entropy (MSpEn) method to analyze anesthetic EEG series as a measure of D...

Low-magnesium hippocampal seizure-like events (hSLE) are well-known in vitro animal models of epilepsy. Although there has been extensive amount of study on the function of ionic channels, single neurons and their communications during hSLEs, less is done about describing these bursts using concepts from dynamical systems. Investigating the applica...

In cortical and hippocampal brain slice experiments, the viability of processed tissue is usually judged by the amplitude of extracellularly-recorded seizure-like event (SLE) activity. Surprisingly, the suitability of this approach for evaluating slice quality has not been objectively studied. Furthermore, a method for gauging the viability of quie...

Brain injury in the premature infant is associated with a high risk of neurodevelopmental disability. Previous small-animal models of brain injury attributable to extreme prematurity typically fail to generate a spectrum of pathology and behavior that closely resembles that observed in humans, although they provide initial answers to numerous cellu...

A series of aliphatic esters of the non-opioid anaesthetic/analgesic ketamine were prepared and their properties as shorter-acting analogues of ketamine itself were explored in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. The potency of t...

The electrical conductivity of small samples of mouse cortex (in vitro) has been measured at 10 kHz through the four-electrode method of van der Pauw. Brain slices from three mice were prepared under seizing and non-seizing conditions by changing the concentration of magnesium in the artificial cerebrospinal fluid used to maintain the tissue. These...

Monitoring depth of anesthesia using the Electroencephalogram (EEG) is a major ongoing challenge for anesthetists. The EEG is the recording of brain electrical activity and it contains valuable information related to the different physiological states of the brain. This paper proposes a novel automated method for assessing the anesthesia depth leve...

Background: The exact neurophysiological mechanisms of anesthetic-induced unconsciousness are not yet fully elucidated. The cortical information integration theory hypothesizes that loss of consciousness during general anesthesia is associated with breakdown of long-distance cortical connectivity across multiple brain regions. However, what is the...

Objective: The dynamic change of brain activity in anesthesia is an interesting topic for clinical doctors and drug designers. To explore the dynamical features of brain activity in anesthesia, a permutation auto-mutual information (PAMI) method is proposed to measure the information coupling of electroencephalogram (EEG) time series obtained in a...

Pharmacological brain slice experiments are complicated by the need to ensure adequate drug delivery deep into the healthy layers of the tissue. Because tissue slices have no blood supply, this is achieved solely by passive drug diffusion. The aim of this study was to determine whether pharmacokinetic/pharmacodynamic (PKPD) modeling could be adapte...

General anaesthetics have been hypothesised to ablate consciousness by decoupling intracortical neural connectivity. We explored this by investigating the effect of etomidate and ketamine on coupling of neural population activity using the low magnesium neocortical slice model. Four extracellular electrodes (50 μm) were positioned in mouse neocorti...

The Hurst exponent (HE) is a nonlinear method measuring the smoothness of a fractal time series. In this study we applied the HE index, extracted from electroencephalographic (EEG) recordings, as a measure of anesthetic drug effects on brain activity. In 19 adult patients undergoing sevoflurane general anesthesia, we calculated the HE of the raw EE...

Monitoring the effect of anesthetic drugs on the neural system is a major ongoing challenge for anesthetists. During the past few years, several electroencephalogram (EEG)-based methods such as the response entropy (RE) as implemented in the Datex-Ohmeda M-Entropy Module have been proposed. In this paper, sample entropy is used to quantify the pred...

This paper presents an alternative method, called as parallel factor analysis (PARAFAC) with a continuous wavelet transform, to analyze of brain activity in patients with chronic pain in the time-frequency-channel domain and quantifies differences between chronic pain patients and controls in these domains. The event related multiple EEG recordings...

Monitoring the effect of anesthetic drugs on the central nervous system is a major ongoing challenge in anesthesia research. A number of electroencephalogram (EEG)-based monitors of the anesthetic drug effect such as the bispectral (BIS) index have been proposed to analyze the EEG signal during anesthesia. However, the BIS index has received some c...