LSD increases sleep duration the night after microdosing.

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3-38.3 min) compared to placebo-with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ; ACTRN12621000436875.

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. Here, resting-state EEG was recorded in a group of 30 patients with major depressive disorder (MDD) at baseline and during a 0.44 mg/kg ketamine dose comprising a bolus and infusion. Fronto-parietal connectivity was assessed using dynamic causal modelling to fit a thalamocortical model to hierarchically connected nodes in the medial prefrontal cortex and superior parietal lobule. We found a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both parameter changes were correlated across participants with the antidepressant response to ketamine. Changes to the NMDA receptor time constant and inhibitory intraneuronal input into superficial pyramidal cells did not survive correction for multiple comparisons and were not correlated with the antidepressant response. These results provide evidence that the antidepressant effects of ketamine may be mediated by acute fronto-parietal connectivity and GABA receptor dynamics. Furthermore, it supports the large body of literature suggesting the acute mechanism underlying ketamine's antidepressant properties is related to GABA-A and AMPA receptors rather than NMDA receptor antagonism.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1).

BACKGROUND: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2). METHODS: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen. DISCUSSION: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial. TRIAL REGISTRATION: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

BACKGROUND: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. METHODS: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 µg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here. RESULTS: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points. CONCLUSIONS: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response.

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. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Association between caregiver opposition to topical fluoride and COVID-19 vaccines.

PURPOSE: Caregivers who oppose topical fluoride in dental settings may be opposed to other preventive health treatments, including COVID-19 vaccines. The study objective was to examine the association between caregiver opposition to topical fluoride and COVID-19 vaccines. METHODS: The study took place at the University of Washington in Seattle, WA. English-speaking caregivers of children aged < 18 years were eligible to participate. An 85-item REDCap survey was administered from February to September 2021. The predictor variable was topical fluoride opposition (no/yes). The outcome was COVID-19 vaccine opposition (no/yes). The models included the following covariates: child and caregiver age; caregiver race and ethnicity, education level, dental insurance type, parenting style, political ideology, and religiosity; and household income. Logistic regression models generated odds ratios (OR) and 95 % confidence intervals (α = 0.05). RESULTS: Six-hundred-fifty-one caregivers participated, and 403 caregivers with complete data were included in the final regression model. Mean child age was 8.5 years (SD 4.2), mean caregiver age was 42.1 years (SD 9.1), 53.0 % of caregivers were female, 57.3 % self-reported as white, and 65.5 % were insured by Medicaid. There was a significant positive association between topical fluoride and COVID-19 vaccine opposition (OR = 3.13; 95 % CI: 1.87, 5.25; p < 0.001). Other factors associated with COVID-19 vaccine opposition included conservative political views (OR = 2.77; 95 % CI: 1.26, 6.08; p < 0.011) and lower education (OR = 3.47; 95 % CI: 1.44, 8.38; p < 0.006). CONCLUSIONS: Caregivers opposed to topical fluoride in dental settings were significantly more likely to oppose COVID-19 vaccines for their child. Future research should identify ways to address both topical fluoride and vaccine opposition to prevent diseases in children.

The challenges ahead for psychedelic 'medicine'.

With the extensive public, commercial and scientific interest from what has been widely termed the psychedelic renaissance, it is important that the scientific practices and results obtained from its implementation into medicine are put under a critical microscope. While there are numerous works on the potential benefits and applications of psychedelics as medicines, relatively little has been written about the challenges this field will face when incorporated into modern medical practice. Indeed, as a new or at least revived area of investigation, psychedelic medicine has a particular set of challenges which need to be addressed. In this viewpoint, we identify a number of these challenges. First, challenges related to the design of individual research studies are discussed, particularly focusing on current practices surrounding blinding, expectancy, the use of therapy and sources of bias. Second, the broader context of the research environment is considered, including how medical science typically establishes evidence, funding bodies and the impact of psychedelics being scheduled at odds with their risk profile. Finally, we describe challenges relating to the implementation of psychedelic therapies into modern medicine, considering the social and economic context. Alongside, we provide suggestions for what could be included into current research protocols to mitigate these challenges.

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. 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.

Blinding and expectancy confounds in psychedelic randomized controlled trials.

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.

High-capacity multimodal anion-exchange membranes for polishing of therapeutic proteins.

This contribution reports on a study using Purexa™-MQ multimodal anion-exchange (AEX) membranes for protein polishing at elevated solution conductivities. Dynamic binding capacities (DBC10 ) of bovine serum albumin (BSA), human immunoglobulins, and salmon sperm DNA (ss-DNA) are reported for various salt types, salt concentrations, flowrates, and pH. Using 1 mg/ml BSA, DBC10 values for Purexa™-MQ were >90 mg/ml at conductivities up to 15 mS/cm. The membranes maintained a high, salt-tolerant BSA DBC10 of 89.8 ± 2.7 (SD) over the course of 100 bind-elute cycles. Polishing studies with acidic and basic monoclonal antibodies at >2 kg/L loads showed that Purexa™-MQ had higher clearance of host cell proteins and aggregate species at high conductivity (13 mS/cm) and in the presence of phosphate than other commercial AEX media. Purexa™-MQ also had a high ss-DNA DBC10 of 50 mg/ml at conductivities up to 15 mS/cm, markedly outperforming other commercial products. In addition to the effectiveness of Purexa™-MQ for protein polishing at elevated solution conductivities, its unusually high binding capacity for ss-DNA indicates potential applications for plasmid DNA purification.

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. 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 < 1.0 °C. Minimal differences between the two scan types were found in EEG channel variance and spectra. Expected decreases in MB4-fMRI tSNR were observed. In n-back task scans, little to no differences were detected in both EEG source analyses and fMRI local analyses for mixed effects. Resting-state posterior cingulate cortex seed-based analyses of the default mode network along with EEG-informed fMRI analysis of the occipital alpha anticorrelation effect showed improved statistical and spatial sensitivity at lower scan durations. Using EEG/MB4-fMRI for n-back tasks provided no statistical advantages nor disadvantages. However, for studying the resting-state, MB4-fMRI potentially allows for reduced scanning durations for equivalent statistical significance to be obtained or alternatively, larger effect sizes for the same scanning duration. As such, simultaneous EEG/MB4-fMRI is a viable alternative to EEG/SB-fMRI.

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. 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.

Simultaneous EEG/fMRI recorded during ketamine infusion in patients with major depressive disorder.

A single subanaesthetic dose of ketamine rapidly alleviates the symptoms of major depressive disorder (MDD). However, few studies have investigated the acute effects of ketamine on the BOLD pharmacological magnetic resonance imaging (phMRI) response and EEG spectra. In a randomised, double-blind, active placebo-controlled crossover trial, resting-state simultaneous EEG/fMRI was collected during infusion of ketamine or active placebo (remifentanil) in 30 participants with MDD. Montgomery-Asberg depression rating scale scores showed a significant antidepressant effect of ketamine compared to placebo (69% response rate). phMRI analyses showed BOLD signal increases in the anterior cingulate and medial prefrontal cortices and sensitivity of the decrease in subgenual anterior cingulate cortex (sgACC) BOLD signal to noise correction. EEG spectral analysis showed increased theta, high beta, low and high gamma power, and decreased delta, alpha, and low beta power with differing time-courses. Low beta and high gamma power time courses explained significant variance in the BOLD signal. Interestingly, the variance explained by high gamma power was significantly associated with non-response to ketamine, but significant associations were not found for other neurophysiological markers when noise correction was implemented. The results suggest that the decrease in sgACC BOLD signal is potentially noise and unrelated to ketamine's antidepressant effect, highlighting the importance of noise correction and multiple temporal regressors for phMRI analyses. The lack of effects significantly associated with antidepressant response suggests the phMRI methodology employed was unable to detect such effects, the effect sizes are relatively small, or that other processes, e.g. neural plasticity, underlie ketamine's antidepressant effect.

Adjunctive dental therapies in caries-active children: Shifting the cariogenic salivary microbiome from dysbiosis towards non-cariogenic health.

BACKGROUND: The oral microbiome is a complex assembly of microbial species, whose constituents can tilt the balance towards progression of oral disease or sustained health. Recently we identified sex-specific differences in the salivary microbiome contained within caries-active and caries-free children. In this study, we sought to ascertain if adjunctive dental therapies, including povidone iodine and chlorhexidine, were effective in shifting the cariogenic microbiome from dysbiosis to non-cariogenic health. DESIGN: We recruited young children (ages 2-12 years) to enter five enrollment groups, with each group (N = 9-30 participants/group) receiving caries restorative and/or adjunctive therapies, either singularly or in combination (OHSU IRB #6535). Saliva specimens were collected pre- and post-treatment (4-8 weeks) of caries preventive measures, and oral microbiota were identified using next generation sequencing (HOMINGS, Forsyth Institute, Cambridge, MA). RESULTS: With the use of multi-dimensional scaling plots, support vector machine learning, odds ratio analysis, and other statistical methods, we have determined that treatment with povidone iodine can shift the composition of the salivary cariogenic microbiome to include higher proportions of aerobic microorganisms, such as Stentrophomonas maltophila, as well as non-cariogenic, anaerobic microorganisms including Poryphyromonas and Fusobacterium species. CONCLUSION: We have identified microorganisms that are associated with caries-active children and have determined that povidone iodine is an effective adjunctive therapy that has the potential to shift the composition of the cariogenic microbiome to one more closely aligned with non-cariogenic health.

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. 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.

Sex-specific differences in the salivary microbiome of caries-active children.

Background and Objectives: Dental caries is a chronic disease affecting young children and has multi-factorial risk factors. The purpose of this work was to identify sex-specific differences in the salivary microbiota within caries-active children. Design: Saliva specimens were collected from 85 children (boys: 41; girls: 44) between the ages of 2-12 years. Salivary microbial DNA was subjected to PCR amplification using V3-V4 16S rDNA-specific primers and next-generation sequencing. Results: Significant sex differences in salivary microbiota were found between caries-active boys versus caries-active girls. Neisseria flavescens, Rothia aeria, and Haemophilus pittmaniae were found at significantly higher levels in caries-active boys. In contrast, Lactococcus lactis, Selenomonas species HOT 126, Actinobaculum species HOT 183, Veillonella parvula, and Alloprevotella species HOT 473 were found at significantly higher levels in caries-active girls. Conclusion: We have found the acid-generating, cariogenic Lactococcus lactis to be much more abundant in caries-active girls than caries-active boys, indicating that this microorganism may play a more significant role in shaping the cariogenic microbiome in girls. In addition, in caries-active girls, Alloprevotella species HOT 473 was the only species that exhibited both significant sex differences (4.4-fold difference; p=0.0003) as well as high abundance in numbers (1.85% of the total microbial population).

Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: A simultaneous EEG/fMRI study.

BACKGROUND: Pharmacological magnetic resonance imaging has been used to investigate the neural effects of subanaesthetic ketamine in healthy volunteers. However, the effect of ketamine has been modelled with a single time course and without consideration of physiological noise. AIMS: This study aimed to investigate ketamine-induced alterations in resting neural activity using conventional pharmacological magnetic resonance imaging analysis techniques with physiological noise correction, and a novel analysis utilising simultaneously recorded electroencephalography data. METHODS: Simultaneous electroencephalography/functional magnetic resonance imaging and physiological data were collected from 30 healthy male participants before and during a subanaesthetic intravenous ketamine infusion. RESULTS: Consistent with previous literature, we show widespread cortical blood-oxygen-level dependent signal increases and decreased blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex following ketamine. However, the latter effect was attenuated by the inclusion of motion regressors and physiological correction in the model. In a novel analysis, we modelled the pharmacological magnetic resonance imaging response with the power time series of seven electroencephalography frequency bands. This showed evidence for distinct temporal time courses of neural responses to ketamine. No electroencephalography power time series correlated with decreased blood-oxygen-level dependent signal in the subgenual anterior cingulate cortex. CONCLUSIONS: We suggest the decrease in blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex typically seen in the literature is the result of physiological noise, in particular cardiac pulsatility. Furthermore, modelling the pharmacological magnetic resonance imaging response with a single temporal model does not completely capture the full spectrum of neuronal dynamics. The use of electroencephalography regressors to model the response can increase confidence that the pharmacological magnetic resonance imaging is directly related to underlying neural activity.

Constrained temporal parallel decomposition for EEG-fMRI fusion.

OBJECTIVE: Multimodal neuroimaging has become a common practice in neuroscience research. Simultaneous EEG-fMRI is a popular multimodal recording approach due to the complementary spatiotemporal relationship between the two modalities. Several data fusion techniques have been proposed in the literature for EEG-fMRI fusion, including joint-ICA and parallel-ICA frameworks. Previous EEG-fMRI fusion approaches have used sensor-level EEG features. Recently, we introduced source-space ICA for EEG-MEG source reconstruction and component identification, which was shown to be a superior alternative to sensor-space ICA. APPROACH: Here, we extend source-space ICA to the fusion of EEG-fMRI data. Additionally, we incorporate the use of a paradigm signal (constrained) and a lag-based signal decomposition approach to accommodate recent findings demonstrating the potentially variable lag structure between electrophysiological and BOLD signals. We evaluated this method on simulated concurrent EEG-fMRI during a boxcar task design, as well as real concurrent EEG-fMRI data from three participants performing an N-Back working memory task. The block diagram of the algorithm and corresponding source codes are provided. MAIN RESULTS: Based on the results of the real working memory task, for all three subjects, one frontal theta component, and one right posterior alpha component had the highest contribution coefficients (~0.5) to the paradigm-related fused component. There were also two more alpha band components with contribution coefficients of 0.3. The highest contributing fMRI component (~0.8) was one known in the literature to be related to the attention network. The second fMRI component was related to the well-known default mode network, with a contribution coefficient of 0.3. SIGNIFICANCE: The proposed EEG-fMRI fusion approach, is capable of estimating the brain maps of the EEG and fMRI for the fused components and account for the variable lag structure between electrophysiological and BOLD signals.

Comparison of local spectral modulation, and temporal correlation, of simultaneously recorded EEG/fMRI signals during ketamine and midazolam sedation.

RATIONALE AND OBJECTIVES: 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. METHODS: 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. RESULTS AND CONCLUSIONS: 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.

Cerebral blood flow predicts differential neurotransmitter activity.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.