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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. Methods: In the current study, ketamine (0.44 mg/kg) was administered to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, in a magnetic resonance imaging (MRI) environment. The 11-dimension altered states of consciousness questionnaire and individual qualitative interviews were used to capture the acute psychedelic experience. The Montgomery-Asberg Depression Rating Scale and further interviewing explored lasting effects. The second qualitative interview took place ⩾3 weeks post-ketamine. Results: Greater antidepressant response (reduction in Montgomery-Asberg Depression Rating Scale at 24 h) correlated with the 11-dimension altered states of consciousness dimensions: spirituality, experience of unity, and insight. The first qualitative interview revealed that all participants experienced perceptual changes. Additional themes emerged including loss of control and emotional and mood changes. The final interview showed evidence of a psychedelic afterglow, and changes to perspective on life, people, and problems, as well as changes to how participants felt about their depression and treatments. Conclusions: The current study provides preliminary evidence for a role of the psychedelic experience and afterglow in ketamine’s antidepressant properties. Reflexive thematic analysis provided a wealth of information on participants’ experience of the study and demonstrated the psychedelic properties of ketamine are not fully captured by commonly used questionnaires. more...

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. We ascend through spatial scales starting with a complete review of the pharmacology of ketamine and then cover its effects onin vitroandin vivoelectrophysiology. We then summarise and critically evaluate studies using EEG/MEG and neuroimaging measures (MRI and PET), integrating across scales where possible. While a complicated and, at times, confusing picture of ketamine’s effects are revealed, we stress that much of this might be caused by use of different species, doses, and analytical methodologies and suggest strategies that future work could use to answer these problems. more...

Background Investigations of the electrophysiology of gaseous anesthetics xenon and nitrous oxide are limited revealing inconsistent frequency-dependent alterations in spectral power and functional connectivity. Here, the authors describe the effects of sedative, equivalent, stepwise levels of xenon and nitrous oxide administration on oscillatory source power using a crossover design to investigate shared and disparate mechanisms of gaseous xenon and nitrous oxide anesthesia. Methods Twenty-one healthy males underwent simultaneous magnetoencephalography and electroencephalography recordings. In separate sessions, sedative, equivalent subanesthetic doses of gaseous anesthetic agents nitrous oxide and xenon (0.25, 0.50, and 0.75 equivalent minimum alveolar concentration–awake [MACawake]) and 1.30 MACawake xenon (for loss of responsiveness) were administered. Source power in various frequency bands were computed and statistically assessed relative to a conscious/pre-gas baseline. Results Observed changes in spectral-band power (P < 0.005) were found to depend not only on the gas delivered, but also on the recording modality. While xenon was found to increase low-frequency band power only at loss of responsiveness in both source-reconstructed magnetoencephalographic (delta, 208.3%, 95% CI [135.7, 281.0%]; theta, 107.4%, 95% CI [63.5, 151.4%]) and electroencephalographic recordings (delta, 260.3%, 95% CI [225.7, 294.9%]; theta, 116.3%, 95% CI [72.6, 160.0%]), nitrous oxide only produced significant magnetoencephalographic high-frequency band increases (low gamma, 46.3%, 95% CI [34.6, 57.9%]; high gamma, 45.7%, 95% CI [34.5, 56.8%]). Nitrous oxide—not xenon—produced consistent topologic (frontal) magnetoencephalographic reductions in alpha power at 0.75 MACawake doses (44.4%; 95% CI [−50.1, −38.6%]), whereas electroencephalographically nitrous oxide produced maximal reductions in alpha power at submaximal levels (0.50 MACawake, −44.0%; 95% CI [−48.1,−40.0%]). Conclusions Electromagnetic source-level imaging revealed widespread power changes in xenon and nitrous oxide anesthesia, but failed to reveal clear universal features of action for these two gaseous anesthetics. Magnetoencephalographic and electroencephalographic power changes showed notable differences which will need to be taken into account to ensure the accurate monitoring of brain state during anaesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New more...

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. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting‐state networks. Independent components analysis (ICA)‐denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross‐modal comparisons of pharmacologically‐modulated functional connectivity. more...

SummaryBackgroundUnderstanding the effects of anaesthetic drugs on cortical oscillations can help to elucidate the mechanistic link between receptor physiology and their clinical effects. Propofol produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing stimulus-onset-evoked responses) 1. Dexmedetomidine, an α2-adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deeper sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABAergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations.MethodsSixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visual and motor task.ResultsThe key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the M100 (27%) and M150 (52%) evoked responses, whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on motor GBR or movement related beta de-synchronisation (MRBD). However, dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%).ConclusionsDexmedetomidine and propofol, at equi-sedative doses, have contrasting effects on visual stimulus induced GBR, visual evoked responses and PMBR. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs and their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness. more...

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. In the main study, two thermometer probes were attached to 16 healthy individuals (ages 20–39, 9 females) whilst they completed two sets of 16-min resting-state and two sets of 9-min n-back task scans—each set consisting of one MB4 and one SB pulse sequence. No heating effects were reported and thermometer data showed mean increases of more...

Background Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine’s potential antidepressant effect remain unknown, such as its dose–response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood–brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine. Methods/Design A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 μg/kg) along with one glycopyrronium bromide 4 μg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery–Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants. Discussion This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose–response profile and washout period of scopolamine’s antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects. Trial registration The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019. more...

Background The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity. Methods The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery–Asberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine. Results Montgomery–Asberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10−11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation. Conclusions This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine. more...

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.In an open-label naturalistic study, resting-state fMRI was collected prior to and following a four-week course of rTMS in 24 participants with MDD and 2 with bipolar disorder. Montgomery-Asberg depression rating scale scores showed a response rate of 42%.Clinical response to rTMS was correlated with reduced functional connectivity from baseline to post-rTMS within the salience network (SN). This indicates SN connectivity may be functionally relevant to how rTMS produces antidepressant effects. In an exploratory inter-network analysis, connectivity between the SN and posterior default mode network (pDMN) was higher following treatment. However this difference was not correlated with the antidepressant response. Local BOLD activity within these networks was also assessed using the fractional amplitude of low-frequency fluctuations (fALFF) technique. Local activity increased in both the SN and pDMN following rTMS. However this increase was also not correlated with antidepressant response.The sample population was heterogeneous, continuing current use of medications, and the study lacked a healthy control or sham stimulation comparison group.Together, these results provide evidence for the involvement of the SN in the antidepressant response to rTMS treatment. more...

Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition, and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, for the first time, we empirically identify the specific critical point near which conscious cortical dynamics operate as the edge-of-chaos critical point, or the boundary between periodicity/stability and chaos/instability. We do so by applying the recently developed modified 0-1 chaos test to electrocorticography (ECoG) and magne-toencephalography (MEG) recordings from the cortices of humans and macaques across normal waking, generalized seizure, GABAergic anesthesia, and psychedelic states. Our evidence suggests that cortical information processing is disrupted during unconscious states because of a transition of cortical dynamics away from this critical point; conversely, we show that psychedelics may increase the information-richness of cortical activity by tuning cortical electrodynamics closer to this critical point. Finally, we analyze clinical electroencephalography (EEG) recordings from patients with disorders of consciousness (DOC), and show that assessing the proximity of cortical electrodynamics to the edge-of-chaos critical point may be clinically useful as a new biomarker of consciousness.Significance StatementWhat changes in the brain when we lose consciousness? One possibility is that the loss of consciousness corresponds to a transition of the brain’s electric activity away from edge-of-chaos criticality, or the knife’s edge in between stability and chaos. Recent mathematical developments have produced novel tools for testing this hypothesis, which we apply for the first time to cortical recordings from diverse brain states. We show that the electric activity of the cortex is indeed poised near the boundary between stability and chaos during conscious states and transitions away from this boundary during unconsciousness, and that this transition disrupts cortical information processing. more...

Introduction: 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.Areas covered: 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.Expert opinion: While psychedelic RCTs have generally shown promising results, with large effect sizes reported, we argue that treatment effect sizes in psychedelic RCTs are likely over-estimated due to de-blinding of participants and high levels of response expectancy. We suggest that psychedelic RCTs should routinely measure de-blinding and expectancy. Careful attention should be paid to clinical trial design and the instructions given to participants to allow these confounds to be reduced, estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs. more...

Background Regular ingestion of sub-hallucinogenic doses of psychedelics, referred to as “microdosing”, has gained increasing popularity and attention in the press and in online forums, with reported benefits across multiple cognitive and emotional domains. Rigorously controlled studies to date, however, have been limited in scope and have failed to produce results comparable to those reported in the grey literature. Methods Eighty healthy male participants will receive 14 doses of placebo or 10 μg lysergic acid diethylamide orally every 3rd day over a 6-week treatment protocol. A battery of personality, creativity, mood, cognition, and EEG plasticity measures, as well as resting-state fMRI imaging, will be administered at baseline and at the end of the protocol. Creativity, mood, and plasticity measures will additionally be assessed in the acute phase of the first dose. Daily functioning will be monitored with questionnaires and a wearable sleep and activity tracker. Discussion This study will rigorously examine the claims presented in the microdosing grey literature by pairing a comparable dosing protocol with objective measures. Potential therapeutic implications include future clinical trials to investigate microdosed psychedelics as a standalone treatment or as an augmentation of psychotherapy in the treatment of depression, addiction, eating disorders, obsessive-compulsive disorders, and palliative care. Trial registration ACTRN12621000436875. Registered on 19 February 2021 more...

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. Thirty participants were included in a placebo-controlled, three-way crossover design with ketamine and midazolam. Compared to placebo, ketamine administration attenuated theta power increases and alpha power decreases and midazolam attenuated low beta band decreases to increasing WM load. Additionally, ketamine caused larger blood-oxygen-dependent (BOLD) signal increases in the supplementary motor area and angular gyrus, and weaker deactivations of the default mode network (DMN), whereas no difference was found between midazolam and placebo. Ketamine administration caused positive temporal correlations between frontal-midline theta (fm-theta) power and the BOLD signal to disappear and attenuated negative correlations. However, the relationship between fm-theta and the BOLD signal from DMN areas was maintained in some participants during ketamine administration, as increasing theta strength was associated with stronger BOLD signal reductions in these areas. The presence of, and ability to manipulate, both positive and negative associations between the BOLD signal and fm-theta suggest the presence of multiple fm-theta components involved in WM processes, with ketamine administration disrupting one or more of these theta-linked WM strategies. more...

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes such as personality changes. These findings are particularly intriguing given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g. from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience, by studying participants under the effects of LSD or placebo, either with gross state changes (eyes closed vs. open) or different stimulus (no stimulus vs. music vs. video). Results show that while brain entropy increases with LSD in all the experimental conditions, it exhibits largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing video — potentially due to a “competition” between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence for the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment. Additionally, our findings put into question simplistic interpretations of brain entropy as a direct neural correlate of conscious level.Significance StatementThe effects of psychedelic substances on conscious experience can be substantially affected by contextual factors, which play a critical role in the outcomes of psychedelic therapy. This study shows how context can modulate not only psychological, but also neurophysiological phenomena during a psychedelic experience. Our findings reveal distinctive effects of having eyes closed after taking LSD, including a more pronounced change on the neural dynamics, and a closer correspondence between brain activity and subjective ratings. Furthermore, our results suggest a competition between external stimuli and internal psychedelic-induced imagery, which supports the practice of carrying out psychedelic therapy with patients having their eyes closed. more...

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 model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine’s ability to alter local coupling mediated by NMDA, AMPA and GABA-A. more...

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. We quantified whole brain activity and functional connectivity in discrete frequency bands. Drug-by-session (2 × 4) analysis of variance in connectivity revealed interaction and main effects. Post-hoc permutation testing of each post-drug recording vs. respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, across 1- 3- and 5- hour recordings following tiagabine only. The same analysis applied to activity revealed significant increases across frontal regions, coupled with reductions in posterior regions, across delta, theta, alpha and beta frequencies. Crucially, the spatial distribution of tiagabine-induced changes overlap with group-averaged maps of the distribution of GABAA receptors, from flumazenil (FMZ-VT) PET, demonstrating a link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. Our results indicate that the relationship between PET receptor distributions and MEG effects warrants further exploration, since elucidating the nature of this relationship may uncover electrophysiologically-derived maps of oscillatory activity as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging. more...

The non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a role for GABA in shaping the topography of functional activity and connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) through oral administration of the GABA transporter 1 (GAT1) blocker tiagabine (15 mg). We show that the spatial distribution of tiagabine-induced activity changes, across the brain, corresponds to group-average flumazenil PET maps of GABAA receptor distribution.In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using leakage-corrected amplitude envelope correlations (AECs), we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity across the brain.Analysis of variance in connectivity using a drug-by-session (2×4) design revealed interaction effects, accompanied by main effects of drug and session. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo.The same analysis applied to activity, across the brain, also revealed a significant interaction, with post-hoc permutation testing demonstrating significant increases in activity across frontal regions, coupled with reductions in activity in posterior regions, across the delta, theta, alpha and beta frequency bands.Crucially, we show that the spatial distribution of tiagabine-induced changes in oscillatory activity overlap significantly with group-averaged maps of the estimated distribution of GABAA receptors, derived from scaled flumazenil volume-of-distribution (FMZ-VT) PET, hence demonstrating a possible mechanistic link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. We therefore propose that electrophysiologically-derived maps of oscillatory connectivity and activity can be used as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging at the group level, providing direct measures of target engagement and pharmacodynamics. more...

The identification of biomarkers of drug action can be supported by non-invasive brain imaging techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), with simultaneous collection plausibly overcoming the limitations of either modality alone. Despite this, few studies have assessed the feasibility and utility of recording simultaneous EEG/fMRI in a drug study. We used simultaneous EEG/fMRI to assess the modulation of neural activity by ketamine and midazolam, in a placebo-controlled, single-blind, three-way cross-over design. Specifically, we analysed the sensitivity and direction of the spectral effects of each modality and the temporal correlations between the modulations of power of the common EEG bands and the blood-oxygen-level-dependent (BOLD) signal. Demonstrating feasibility, local spectral effects were similar to those found in previous non-simultaneous EEG and fMRI studies. Ketamine administration resulted in a widespread reduction of BOLD fractional amplitude of low frequency fluctuations (fALFF) and a diverse pattern of effects in the different EEG bands. Midazolam increased fALFF in occipital, parietal, and temporal areas, and frontal delta and beta EEG power. While EEG spectra were more sensitive to pharmacological modulations than the fALFF bands, there was no clear spatial relationship between the two modalities. Additionally, ketamine modulated the temporal correlation strengths between the theta EEG band and the BOLD signal, whereas midazolam altered temporal correlations with the alpha and beta bands. Taken together, these results demonstrate the utility of simultaneous recording: each modality provides unique insights, and combinatorial analyses elicit more information than separate recordings. more...

In healthy women, fluctuations in hormones including progesterone and oestradiol lead to functional changes in the brain over the course of each menstrual cycle. Though considerable attention has been directed towards understanding changes in human cognition over the menstrual cycle, changes in underlying processes such as neural plasticity have largely only been studied in animals. In this study we explored predictive coding and repetition suppression via the roving mismatch negativity paradigm as a model of short-term plasticity (Garrido, Kilner, Kiebel, et al., 2009), and Hebbian learning via visual sensory long-term potentiation (LTP) as a model of long-term plasticity (Teyler et al., 2005). Electroencephalography (EEG) was recorded in 20 females during their early follicular and mid-luteal phases. Event-related potential (ERP) analyses were complemented with dynamic causal modelling (DCM) to characterise changes in the underlying neural architecture. More sustained variability in the ERP response to a change in tone during the luteal phase are interpreted as a delayed habituation of the P3a component in the luteal relative to the follicular phase. The additional increased forward connection strength over tone repetitions compared to the follicular phase suggests that, in this phase, females may be less efficient when processing deviations from predicted sensory input (error). In contrast, there appears to be no reliable change in sensory LTP. This suggests that predictive coding, but not Hebbian plasticity is modified in the mid-luteal compared to the follicular phase, at least at the days of the menstrual cycle tested. This finding implicates the human menstrual cycle in complex changes in neural plasticity and provides further evidence for the importance of considering the menstrual cycle when including females in electrophysiological research. more...

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 (H1MRS) 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. H1 MRS measures were collected at baseline and after four weeks of daily treatment. GABA and Glx were measured from both the left DLPFC and a control region (right motor cortex). Twenty-seven participants completed the study and were included in the analysis. Contrary to previous studies, no difference in GABA was observed following treatment. Glx levels were found to significantly increase in both the left DLPFC and right motor cortex voxels but this increase did not correlate with antidepressant response. Glx levels were found to increase following rTMS, not only underlying the site of stimulation but also at a distant control voxel suggesting a degree of non-specificity in response to therapy. more...

Background:- \ud \ud Benign epilepsy with centro-temporal spikes (BECTS) is a common childhood epilepsy syndrome also known as Rolandic Epilepsy (RE). Neurocognitive phenotypes have been described with greater focus on attention, reading and language domains but there have been far fewer studies focusing on motor functioning. This study included measures of motor, language and cognition in order to investigate the range, degree and pattern of difficulties associated with BECTS in a case series of children, but with a particular emphasis on motor skills.\ud \ud Method:- \ud \ud Twenty-one children aged between 8 and 16 years with a diagnosis of BECTS were asked to complete standardized assessments for language, cognition, motor functioning and handwriting.\ud \ud Results:- \ud \ud When measuring across language, cognitive and motor domains, 19 (90.48%) of the twenty-one children with a diagnosis of BECTS showed some difficulties on at least one area of functioning using standardized assessment tests. Of particular note nearly half (47.62%) of the children had some difficulties in one or more areas of motor functioning.\ud \ud Discussion:- \ud \ud Children with BECTS have a heterogeneous pattern of neurocognitive impairments. The presence of motor difficulties (DCD) should be considered in all children routinely seen in clinical settings with BECTS and included in any screening processes. more...

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 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration. more...

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. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10−3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = −.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug. more...

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. Across 15 years of use and replication in humans several major paradigm variants for eliciting visual LTP have emerged. The application of different paradigms, and the broad implementation of visual LTP across different populations combines to provide a rich and sensitive account of Hebbian LTP, and potentially non-Hebbian plasticity mechanisms. This review will conclude with a discussion of how these findings have advanced existing theories of perceptual learning by positioning Hebbian learning both alongside and within other major theories such as Predictive Coding and The Free Energy Principle. more...

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness. more...

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. It is an intervention that requires daily visits to a clinic over a period of at least four weeks. This study aimed to investigate the effectiveness and acceptability of offering rTMS as a treatment for MDD in the setting of New Zealand healthcare systems.This was a naturalistic, open-label pilot study in which 30 patients with moderate-to-severe treatment-resistant MDD were treated with a course of rTMS (10 Hz) daily over the left dorsolateral prefrontal cortex for four weeks (20 sessions). Primary endpoint was response to treatment, stratified into non-responder, partial responder or responder based on the Montgomery-Åsberg Depression Rating Scale (MADRS) at the end of treatment compared to baseline (25% reduction, 25-50% reduction, and50% reduction respectively). Participant remission was also noted as reaching a score of ≤10.Thirty participants completed the full course of treatment (16 women, mean age 47y, range 19-77y), with a mean baseline MADRS of 32.0 (range 21-48). Twelve participants were classified as responders, six as partial responders, and 12 as non-responders. Of the responders, nine were in remission at the end of treatment. Minimal side effects were reported.Daily sessions of rTMS were successfully administered and were effective in treatment-resistant MDD. The treatment was accessible and well tolerated by the majority of the study participants and should be made available to MDD patients in New Zealand as a treatment option. more...