Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.

Introduction: Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).

Methods: This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety).

Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine.

Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms-it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion.

Resting-state EEG connectivity recorded before and after rTMS treatment in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy and tolerability in Major Depressive Disorder (MDD). However, the underlying mechanisms of its antidepressant effects remain unclear. This open-label study investigated electroencephalography (EEG) functional connectivity markers associated with response and the antidepressant effects of rTMS.

Overcoming blinding confounds in psychedelic randomized controlled trials using biomarker driven causal mediation analysis.

Introduction: There is great interest in the use of psychedelic-assisted therapies to treat a range of mental health conditions and initial randomized controlled trials (RCTs) have generated positive results. However, the effect sizes reported in psychedelic RCTs are likely inflated due to expectancy effects due to the de-blinding of both participants and study personnel to treatment allocation caused by the distinctive psychoactive effects of psychedelic drugs.

Areas Covered: An introduction to causal inference for RCTs, the underlying assumptions, and potential confounders along with graphical illustrations is provided.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls.

A Randomized Controlled Trial of Intravenous Scopolamine Versus Active-Placebo Glycopyrrolate in Patients With Major Depressive Disorder.

To investigate scopolamine's rapid-acting antidepressant effects using an active placebo comparator. Most prior intravenous scopolamine studies reduced depressive symptomatologies compared to saline placebo infusions within 3 days. However, the confounding effect of placebo is unknown given that only saline placebo has been used in prior studies.

Decreased salience network fMRI functional connectivity following a course of rTMS for treatment-resistant depression.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a treatment shown to be effective in treating major depressive disorder (MDD). However, the effect of rTMS therapy on functional connectivity within the brains of patients being treated for MDD remains poorly understood. Few studies have investigated the effects of a course of rTMS on resting-state network activity.

A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects.

Effects of Ketamine and Midazolam on Simultaneous EEG/fMRI Data During Working Memory Processes.

Reliable measures of cognitive brain activity from functional neuroimaging techniques may provide early indications of efficacy in clinical trials. Functional magnetic resonance imaging and electroencephalography provide complementary spatiotemporal information and simultaneous recording of these two modalities can remove inter-session drug response and environment variability. We sought to assess the effects of ketamine and midazolam on simultaneous electrophysiological and hemodynamic recordings during working memory (WM) processes.

Effect of rTMS on GABA and glutamate levels in treatment-resistant depression: An MR spectroscopy study.

Alterations in levels of neurotransmitters γ-aminobutyric acid (GABA) and glutamate may underlie the mechanism by which repetitive transcranial magnetic stimulation (rTMS) has efficacy as a treatment for major depressive disorder (MDD). This study used proton magnetic resonance spectroscopy (HMRS) to investigate the effect of rTMS on levels of GABA and combined glutamate/glutamine measure (Glx). Treatment-resistant, currently depressed individuals participated in a naturalistic open-label study with rTMS treatment administered at 10 Hz and 120% of resting motor threshold to the left dorsolateral prefrontal cortex (DLPFC) for 20 sessions.

Blinding and expectancy confounds in psychedelic randomized controlled trials.

: There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat several mental health disorders, with a growing number of randomized controlled trials (RCTs) being conducted to investigate the therapeutic effectiveness of psychedelics.: We review previous literature on expectancy effects and blinding in the context of psychedelic RCTs - literature which strongly suggest that psychedelic RCTs might be confounded by de-blinding and expectancy. We conduct systematic reviews of psychedelic RCTs using Medline, PsychInfo and EMBASE (Jan 1990 - Nov 2020) and show that currently reported psychedelic RCTs have generally not reported pre-trial expectancy, nor the success of blinding procedures.

Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions.

As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) plays a crucial role in shaping the frequency and amplitude of oscillations, which suggests a role for GABA in shaping the topography of functional connectivity and activity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) using the GABA transporter 1 (GAT1) blocker, tiagabine (15 mg). In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo.

A qualitative and quantitative account of patient's experiences of ketamine and its antidepressant properties.

Background: Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression. Limited research has indicated that the psychedelic properties of ketamine may play a role in its antidepressant effects.

Aim: The aim of the current study was to explore the psychedelic experiences and sustained impact of ketamine in major depressive disorder.

Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors.

Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM.

The role of Hebbian learning in human perception: a methodological and theoretical review of the human Visual Long-Term Potentiation paradigm.

Long-term potentiation (LTP) is one of the most widely studied forms of neural plasticity, and is thought to be the principle mechanism underlying long-term memory and learning in the brain. Sensory paradigms utilising electroencephalography (EEG) and sensory stimulation to induce LTP have allowed translation from rodent and primate invasive research to non-invasive human investigations. This review focusses on visual sensory LTP induced using repetitive visual stimulation, resulting in changes in the visually evoked response recorded at the scalp with EEG.

The neurophysiology of ketamine: an integrative review.

The drug ketamine has been extensively studied due to its use in anaesthesia, as a model of psychosis and, most recently, its antidepressant properties. Understanding the physiology of ketamine is complex due to its rich pharmacology with multiple potential sites at clinically relevant doses. In this review of the neurophysiology of ketamine, we focus on the acute effects of ketamine in the resting brain.

Juvenile myoclonic epilepsy shows increased posterior theta, and reduced sensorimotor beta resting connectivity.

Background: Widespread structural and functional brain network changes have been shown in Juvenile Myoclonic Epilepsy (JME) despite normal clinical neuroimaging. We sought to better define these changes using magnetoencephalography (MEG) and source space connectivity analysis for optimal neurophysiological and anatomical localisation.

Methods: We consecutively recruited 26 patients with JME who underwent resting state MEG recording, along with 26 age-and-sex matched controls.

On the Quality, Statistical Efficiency, and Safety of Simultaneously Recorded Multiband fMRI/EEG.

The recent development of multiband functional magnetic resonance imaging (MB-fMRI) allows for the reduction of sampling period by simultaneously exciting multiple slices-the number of which is referred to as the multiband factor. Simultaneously recorded electroencephalography (EEG)/MB-fMRI has yet to be validated for data quality against conventional single band (SB)-fMRI. Pilot scans were conducted on phantoms twice and on a healthy volunteer to ensure no heating effects.

Decreased directed functional connectivity in the psychedelic state.

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine.

Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam.

The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood-oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo-controlled, three-way crossover design with ketamine and midazolam.

Evidence that alpha blocking is due to increases in system-level oscillatory damping not neuronal population desynchronisation.

The attenuation of the alpha rhythm following eyes-opening (alpha blocking) is among the most robust features of the human electroencephalogram with the prevailing view being that it is caused by changes in neuronal population synchrony. To further study the basis for this phenomenon we use theoretically motivated fixed-order Auto-Regressive Moving-Average (ARMA) time series modelling to study the oscillatory dynamics of spontaneous alpha-band electroencephalographic activity in eyes-open and eyes-closed conditions and its modulation by the NMDA antagonist ketamine. We find that the reduction in alpha-band power between eyes-closed and eyes-open states is explicable in terms of an increase in the damping of stochastically perturbed alpha-band relaxation oscillatory activity.

An open-label feasibility study of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression in the New Zealand healthcare context.

Aim: Major depressive disorder (MDD) poses a significant and growing burden on the New Zealand population. It is a leading cause of disability, and resistance to currently offered treatments is common. Repetitive transcranial magnetic stimulation (rTMS) is a treatment offered internationally demonstrating good efficacy and few reports of side effects.

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia.

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam.