Conscious State Research Articles

Adipocyte-Specific Disruption of the BBSome Causes Metabolic and Autonomic Dysfunction.

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of 8 conserved Bardet-Biedl Syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high fat & high sucrose diet (HFHSD). However, constitutive BBSome defiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific constitutive disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis, sympathetic traffic. The BBSome also contribute to baroreflex sensitivity under HFHSD, but not normal chow.

Interpreting Change in Disorders of Consciousness Using the Coma Recovery Scale-Revised.

The purpose of this study was to differentiate clinically meaningful improvement or deterioration from normal fluctuations in patients with disorders of consciousness (DoC) following severe brain injury. We computed indices of responsiveness for the Coma Recovery Scale-Revised (CRS-R) using data from a clinical trial of 180 participants with DoC. We used CRS-R scores from baseline (enrollment in a clinical trial) and a 4-week follow-up assessment period for these calculations. To improve precision, we transformed ordinal CRS-R total scores (0-23 points) to equal-interval measures on a 0-100 unit scale using Rasch Measurement theory. Using the 0-100 unit total Rasch measures, we calculated distribution-based 0.5 standard deviation (SD) minimal clinically important difference, minimal detectable change using 95% confidence intervals, and conditional minimal detectable change using 95% confidence intervals. The distribution-based minimal clinically important difference evaluates group-level changes, whereas the minimal detectable change values evaluate individual-level changes. The minimal clinically important difference and minimal detectable change are derived using the overall variability across total measures at baseline and 4 weeks. The conditional minimal detectable change is generated for each possible pair of CRS-R Rasch person measures and accounts for variation in standard error across the scale. We applied these indices to determine the proportions of participants who made a change beyond measurement error within each of the two subgroups, based on treatment arm (amantadine hydrochloride or placebo) or categorization of baseline Rasch person measure to states of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state). We compared the proportion of participants in each treatment arm who made a change according to the minimal detectable change and determined whether they also changed to another state of consciousness. CRS-R indices of responsiveness (using the 0-100 transformed scale) were as follows: 0.5SD minimal clinically important difference = 9 units, minimal detectable change = 11 units, and the conditional minimal detectable change ranged from 11 to 42 units. For the amantadine and placebo groups, 70% and 58% of participants showed change beyond measurement error using the minimal detectable change, respectively. For the unresponsive wakefulness syndrome and minimally conscious state groups, 54% and 69% of participants changed beyond measurement error using the minimal detectable change, respectively. Among 115 participants (64% of the total sample) who made a change beyond measurement error, 29 participants (25%) did not change state of consciousness. CRS-R indices of responsiveness can support clinicians and researchers in discerning when behavioral changes in patients with DoC exceed measurement error. Notably, the minimal detectable change can support the detection of patients who make a "true" change within or across states of consciousness. Our findings highlight that the continued use of ordinal scores may result in incorrect inferences about the degree and relevance of a change score.

Archetype symbols and altered consciousness: a study of shamanic rituals in the context of Jungian psychology

The alteration of consciousness during shamanic rituals is both a physical and mystical phenomenon. It involves psychological and spiritual experiences. Through ritual practices, shamans can connect with archetype within the collective unconscious, utilizing trance-inducing techniques for “hallucinatory exploration”. This study surveyed 75 participants to investigate the impact of prototype symbols in Shamanistic rituals on participants’ consciousness states focusing on Jungian psychology’s concept of archetype. The results indicate that archetype symbols in shamanic rituals can significantly influence participants’ conscious state, leading them to experience a conscious dissolution of the self. Furthermore, archetype symbols have different effects at the stages of consciousness change. In particular, during the “Visionary Restructuralization” stage, archetype symbols, such as patterns, masks, totems and music, brought participants’ consciousness to a peak and caused significant changes to it. These findings suggest that the metaphoric function of archetype symbols plays a crucial role in rituals. Archetype symbols connect the individual to the collective unconscious through visual images and symbolic imagery. They prompt the participants to experience emotional resonances that transcend individual experiences and affect their state of consciousness.

Psychedelics, the Bible, and the Divine

The current psychedelic renaissance intersects with Christian practices in two key ways. First, as psychedelic-assisted therapy (PAT) becomes more common, Christians undergoing therapeutic medical treatment may seek outside support for integrating into their religious lives mystical experiences that occur during psychedelic sessions. Second, with increasing legal access to psychedelics, more Christians may explore their spiritual potential outside of a medical context, either individually with spiritual guides or collectively in organized retreats. Many will have mystical encounters related to the Divine. Whether the experience involves the overwhelming presence or absence of the Divine, these Christians, too, will seek integration support. This essay argues that the Bible can serve as a rich source for such integration, because it contains significant material about mystical experiences marked by altered states of consciousness. First, I summarize the importance of the psychedelic renaissance, especially the scientific studies being conducted, as it relates to Christian practices of spiritual formation. Second, I explore new work being conducted by biblical scholars regarding embodied religious experiences with the Divine (and others), including mystical experiences. Third, I consider the Apostle Paul’s embodied mystical experience, with special attention to 2 Corinthians 12:1–10, as one example of biblical material that might intersect with or inform psychedelic mystical encounters that contemporary Christians might experience (whether in a medical therapeutic or non-medical spiritual formation setting). Finally, I indicate directions for further research and discussion.

Re-awakening the brain: Forcing transitions in disorders of consciousness by external in silico perturbation.

A fundamental challenge in neuroscience is accurately defining brain states and predicting how and where to perturb the brain to force a transition. Here, we investigated resting-state fMRI data of patients suffering from disorders of consciousness (DoC) after coma (minimally conscious and unresponsive wakefulness states) and healthy controls. We applied model-free and model-based approaches to help elucidate the underlying brain mechanisms of patients with DoC. The model-free approach allowed us to characterize brain states in DoC and healthy controls as a probabilistic metastable substate (PMS) space. The PMS of each group was defined by a repertoire of unique patterns (i.e., metastable substates) with different probabilities of occurrence. In the model-based approach, we adjusted the PMS of each DoC group to a causal whole-brain model. This allowed us to explore optimal strategies for promoting transitions by applying off-line in silico probing. Furthermore, this approach enabled us to evaluate the impact of local perturbations in terms of their global effects and sensitivity to stimulation, which is a model-based biomarker providing a deeper understanding of the mechanisms underlying DoC. Our results show that transitions were obtained in a synchronous protocol, in which the somatomotor network, thalamus, precuneus and insula were the most sensitive areas to perturbation. This motivates further work to continue understanding brain function and treatments of disorders of consciousness.

Contributions of Basal Ganglia Circuits to Perception, Attention, and Consciousness.

Research into ascending sensory pathways and cortical networks has generated detailed models of perception. These same cortical regions are strongly connected to subcortical structures, such as the basal ganglia (BG), which have been conceptualized as playing key roles in reinforcement learning and action selection. However, because the BG amasses experiential evidence from higher and lower levels of cortical hierarchies, as well as higher-order thalamus, it is well positioned to dynamically influence perception. Here, we review anatomical, functional, and clinical evidence to demonstrate how the BG can influence perceptual processing and conscious states. This depends on the integrative relationship between cortex, BG, and thalamus, which allows contributions to sensory gating, predictive processing, selective attention, and representation of the temporal structure of events.

Reduced processing of afforded actions while observing mental content as ongoing mental phenomena

While consciousness is typically considered equivalent to mental contents, certain meditation practices—including open monitoring (OM)—are said to enable a unique conscious state where meditators can experience mental content from a de-reified perspective as “ongoing phenomena.” Phenomenologically, such a state is considered as reduction of intentionality, the mental act upon mental content. We hypothesised that this de-reified state would be characterised by reduced mental actional processing of affording objects. We recruited two groups of participants, meditators with long-term experience in cultivating a de-reified state, and demographically-matched novice meditators. Participants performed a task with images in two configurations—where objects did (high-affordance) and did not imply actions (low-affordance)—following both a baseline and OM-induced de-reified state, along with EEG recordings. While long-term meditators exhibited preferential processing of high-affordance images compared to low-affordance images during baseline, such an effect was abolished during the OM state, as hypothesised. For novices, however, the high-affordance configuration was preferred over the low-affordance one both during baseline and OM. Perceptual durations of objects across conditions positively correlated with the degree of µ-rhythm desynchronization, indicating that neural processing of affordance impacted perceptual awareness. Our results indicate that OM styles of meditation may help in mentally decoupling otherwise automatic cognitive processing of mental actions by affording objects.

Implications of the consciousness state on decannulation in patients with a prolonged Disorder of Consciousness

to prospectively investigate the evolution of the consciousness state and the cannula-weaning progression in patients with prolonged Disorders of Consciousness (pDoC). non-concurrent cohort study SETTING: rehabilitation unit of the Fondazione Don Gnocchi, Florence PARTICIPANTS: adult patients, with a pDoC following a sABI admitted between 06.2020 and 09.2022 INTERVENTIONS: not applicable MAIN OUTCOME MEASURES: consciousness state was assessed by repeated Coma Recovery Scale-Revised (CRS-R) administration at admission, and weekly afterwards. The dates of the first improvement of consciousness state and the achievement of decannulation were recorded. Decannulation followed an internal protocol of multi-professional rehabilitation. 144 patients were included: age: 69 years, 64 (44.4%) with hemorrhagic etiology, time post-onset: 40 days, CRS-R at admission: 9, median length of stay: 90 days. Seventy-three (50.7%) patients were decannulated. They showed a significantly higher CRS-R (p<0.001) and states of consciousness (p<0.001) at admission, at the first improvement of the consciousness state (p=0.003), and discharge (p<0.001), a lower severity in the Cumulative Illness Rating Scale at admission (p=0.01), and a lower rate of pulmonary infections with recurrence (p=0.021), compared to non-decannulated patients. Almost all decannulated patients (97.3%) improved their consciousness before decannulation. Consciousness states at decannulation were: Unresponsive wakefulness Syndrome: 0 (0%), Minimally conscious state (MCS) minus: 4 (5.5%), MCS plus: 7 (9.6%), Emergence from MCS: 62 (84.9%). Kaplan-Meier analysis showed a significant divergence between the curves with a higher probability of decannulation in patients who improved consciousness (p<0.001). This study showed that the presence of signs of consciousness, even subtle, is a necessary condition for decannulation, suggesting that consciousness may influence some of the components implied in the decannulation process.

Within-subject reliability of brain networks during advanced meditation: An intensively sampled 7 Tesla MRI case study.

Advanced meditation such as jhana meditation can produce various altered states of consciousness (jhanas) and cultivate rewarding psychological qualities including joy, peace, compassion, and attentional stability. Mapping the neurobiological substrates of jhana meditation can inform the development and application of advanced meditation to enhance well-being. Only two prior studies have attempted to investigate the neural correlates of jhana meditation, and the rarity of adept practitioners has largely restricted the size and extent of these studies. Therefore, examining the consistency and reliability of observed brain responses associated with jhana meditation can be valuable. In this study, we aimed to characterize functional magnetic resonance imaging (fMRI) reliability within a single subject over repeated runs in canonical brain networks during jhana meditation performed by an adept practitioner over 5 days (27 fMRI runs) inside an ultra-high field 7 Tesla MRI scanner. We found that thalamus and several cortical networks, that is, the somatomotor, limbic, default-mode, control, and temporo-parietal, demonstrated good within-subject reliability across all jhanas. Additionally, we found that several other relevant brain networks (e.g., attention, salience) showed noticeable increases in reliability when fMRI measurements were adjusted for variability in self-reported phenomenology related to jhana meditation. Overall, we present a preliminary template of reliable brain areas likely underpinning core neurocognitive elements of jhana meditation, and highlight the utility of neurophenomenological experimental designs for better characterizing neuronal variability associated with advanced meditative states.

Low-density EEG-based Functional Connectivity Discriminates Patients in a Minimally Conscious State plus from minus

Objective: Within the continuum of consciousness, patients in a Minimally Conscious State (MCS) may exhibit high-level behavioral responses (MCS+) or may not (MCS-). The evaluation of residual consciousness and related classification is crucial to propose tailored rehabilitation and pharmacological treatments, considering the inherent differences among groups in diagnosis and prognosis. Currently, differential diagnosis relies on behavioral assessments posing a relevant risk of misdiagnosis. In this context, EEG offers a non-invasive approach to model the brain as a complex network. The search for discriminating features could reveal whether behavioral responses in post-comatose patients have a defined physiological background. Additionally, it is essential to determine whether the standard behavioral assessment for quantifying responsiveness holds physiological significance. Methods: In this prospective observational study, we investigated whether low-density EEG-based graph metrics could discriminate MCS+/- patients by enrolling 57 MCS patients (MCS-: 30; males: 28). At admission to intensive rehabilitation, 30 minutes resting-state closed-eyes EEG recordings were performed together with consciousness diagnosis following international guidelines. After EEG preprocessing, graphs’ metrics were estimated using different connectivity measures, at multiple connection densities and frequency bands (α,θ,δ). Metrics were also provided to cross-validated ML models with outcome MCS+/-. Results: A lower level of brain activity integration was found in the MCS- group in the α band. Instead, in the δ band MCS- group presented an higher level of clustering (weighted clustering coefficient) respect to MCS+. The best-performing solution in discriminating MCS+/- through the use of ML was an Elastic-Net regularized logistic regression with a cross-validation accuracy of 79% (sensitivity and specificity of 74% and 85% respectively). Conclusion: Despite tackling the MCS+/- differential diagnosis is highly challenging, a daily-routine low-density EEG might allow to differentiate across these differently responsive brain networks. Significance: Graph-theoretical features are shown to discriminate between these two neurophysiologically similar conditions, and may thus support the clinical diagnosis.

Psychedelic-Assisted Therapy Training: An Argument in Support of Firsthand Experience of Nonordinary States of Consciousness in the Development of Competence

Psychedelic-Assisted Therapy Training: An Argument in Support of Firsthand Experience of Nonordinary States of Consciousness in the Development of Competence

Laying the foundations for a theory of consciousness: the significance of critical brain dynamics for the formation of conscious states.

Empirical evidence indicates that conscious states, distinguished by the presence of phenomenal qualities, are closely linked to synchronized neural activity patterns whose dynamical characteristics can be attributed to self-organized criticality and phase transitions. These findings imply that insight into the mechanism by which the brain controls phase transitions will provide a deeper understanding of the fundamental mechanism by which the brain manages to transcend the threshold of consciousness. This article aims to show that the initiation of phase transitions and the formation of synchronized activity patterns is due to the coupling of the brain to the zero-point field (ZPF), which plays a central role in quantum electrodynamics (QED). The ZPF stands for the presence of ubiquitous vacuum fluctuations of the electromagnetic field, represented by a spectrum of normal modes. With reference to QED-based model calculations, the details of the coupling mechanism are revealed, suggesting that critical brain dynamics is governed by the resonant interaction of the ZPF with the most abundant neurotransmitter glutamate. The pyramidal neurons in the cortical microcolumns turn out to be ideally suited to control this interaction. A direct consequence of resonant glutamate-ZPF coupling is the amplification of specific ZPF modes, which leads us to conclude that the ZPF is the key to the understanding of consciousness and that the distinctive feature of neurophysiological processes associated with conscious experience consists in modulating the ZPF. Postulating that the ZPF is an inherently sentient field and assuming that the spectrum of phenomenal qualities is represented by the normal modes of the ZPF, the significance of resonant glutamate-ZPF interaction for the formation of conscious states becomes apparent in that the amplification of specific ZPF modes is inextricably linked with the excitation of specific phenomenal qualities. This theory of consciousness, according to which phenomenal states arise through resonant amplification of zero-point modes, is given the acronym TRAZE. An experimental setup is specified that can be used to test a corollary of the theory, namely, the prediction that normally occurring conscious perceptions are absent under experimental conditions in which resonant glutamate-ZPF coupling is disrupted.

Neuropsychopharmacological Induction of (Lucid) Dreams: A Narrative Review

Lucid dreaming (LD) is a physiological state of consciousness that occurs when dreamers become aware that they are dreaming, and may also control the oneiric content. In the general population, LD is spontaneously rare; thus, there is great interest in its induction. Here, we aim to review the literature on neuropsychopharmacological induction of LD. First, we describe the circadian and homeostatic processes of sleep regulation and the mechanisms that control REM sleep with a focus on neurotransmission systems. We then discuss the neurophysiology and phenomenology of LD to understand the main cortical oscillations and brain areas involved in the emergence of lucidity during REM sleep. Finally, we review possible exogenous substances—including natural plants and artificial drugs—that increase metacognition, REM sleep, and/or dream recall, thus with the potential to induce LD. We found that the main candidates are substances that increase cholinergic and/or dopaminergic transmission, such as galantamine. However, the main limitation of this technique is the complexity of these neurotransmitter systems, which challenges interpreting results in a simple way. We conclude that, despite these promising substances, more research is necessary to find a reliable way to pharmacologically induce LD.

Expanding the scope of "trans-humanism": situating within the framework of life and death education - the importance of a "trans-mystical mindset".

Life and death education, as noted from the literatures, has been studied and researched extensively in China, Malaysia, and Taiwan. Our own research undertakings over the past several years, situated in different sociocultural settings have delved into aspects of life and death that could help advance theoretical understanding of the subject matters (e.g., does the meaning of "effective life functioning" connote differing interpretations for different cultural groups?). Situating within the framework of life and death education, we expand the study of trans-humanism by introducing an extended prefix or nomenclature known as "trans-mystical". Specifically, our philosophized concept of trans-mysticism considers a related concept, which we term as a "trans-mystical mindset". A trans-mystical mindset, differing from an ordinary mindset, from our philosophical rationalization, is defined as "a person's higher-order state of consciousness, espousing her perception, judgment, belief, and attempted interpretation of life and death phenomena that are mystifying and fall outside the ordinary boundaries of human psyche." Our focus of inquiry, as reported in the present article, seeks to advance our proposition: that a trans-mystical mindset, unlike an ordinary mindset, may help a person to rationalize, appreciate, and understand metaphysical contexts, mystical experiences, and the like. This focus, interestingly, serves to highlight an important discourse - namely, that there is a dichotomy in theoretical lenses (i.e., objective reality vs. individual subjectivity) that a person may use to rationalize the significance or non-significance of universal contexts, events, phenomena, etc. (e.g., a person's experience of "premonition"). As such, then, there is an important question that we seek to consider: whether philosophization, or the use of philosophical psychology, would yield perceived "scientific evidence" to support or to reject the study of metaphysicism, mysticism, and the like? For example, does our philosophization of an "equivalency" between a person's trans-mystical mindset and her experience of self-transcendence help to normalize and/or to scientize the subject matters of metaphysicism, mysticism, etc.?

Induction of altered states of consciousness during Floatation-REST is associated with the dissolution of body boundaries and the distortion of subjective time

Floatation-REST (Reduced Environmental Stimulation Therapy) minimizes stimulation of the nervous system by immersing subjects in an environment without sound or light while they effortlessly float in thermoneutral water supersaturated with Epsom salt. Here we investigated the relationship between altered states of consciousness (ASC) and its association with the affective changes induced by Floatation-REST. Using a within-subject crossover design, 50 healthy subjects were randomized to 60 min of Floatation-REST or 60 min of Bed-REST (an active control condition that entailed lying supine on a warm waterbed in a dark and quiet room). Following Floatation-REST, subjects felt significantly more relaxed, less anxious, and less tired than after Bed-REST. Floatation-REST also induced significantly more pronounced ASC characterized by the dissolution of body boundaries and the distortion of subjective time. The loss of body boundaries mediated the loss of anxiety, revealing a novel mechanism by which Floatation-REST exerts its anxiolytic effect.

A Birth–Death Toy Model for a Measure of Consciousness

The ancient Ouroboros symbolism (one who eats oneself) is here integrated into a simple birth–death clustering process that needed nothing but itself for a transition from indistinguishable phases to a sort of higher-level “conscious” phases. Birth and death coefficients are formulated in terms of odd and even exponentials used to represent a suitable form for conscious states via the internal transfer of information. This toy model may ideally quantify conscious states having inner causes via an Ouroboros index 0 &lt; [Formula: see text] &lt; 1. The value [Formula: see text] = 0 lends to infinite loops and the limiting values [Formula: see text] →1 disclose transformation into awareness. Relationships with physics theories of consciousness and the use of the Ouroboros index to discern about conscious-like states in Artificial Intelligence systems are discussed. Consciousness and freedom of will may go side-by-side in the model when [Formula: see text] is extended to be a complex number modulus.

Feasibility of an animal model for long-term mechanical circulatory support with Impella 5.5 implanted through carotid artery access in sheep.

Impella is a mechanical circulatory support device of a catheter-based intravascular microaxial pump for left ventricular support and unloading. However, nonclinical studies assessing the effects of the extended duration of left ventricular unloading on cardiac recovery are lacking. An animal model using Impella implanted with a less invasive procedure to enable long-term support is required. This study aimed to evaluate the feasibility of an animal model for long-term support with Impella 5.5 implanted through carotid artery access in sheep.Impella 5.5 was implanted in four sheep through the proximal region of the left carotid artery without a thoracotomy, and myocardial injuries were induced by coronary microembolization. Support by Impella 5.5 was maintained for 4 weeks, and the animals were observed. The position of Impella 5.5 and cardiac function was evaluated using cardiac computer tomography at 2 and 4 weeks after implantation.All four animals completed the 4-week study without major complications. The discrepancy in the Impella 5.5 flow rate between the conscious and anesthetized states was observed depending on the device's position. Animals in whom the inflow was above the left ventricular papillary muscle had a relatively high flow rate under the maximum performance level without a suction alarm during the conscious state. Pathological changes in the aortic valve were observed. Cardiac function under the minimum performance level was observed with no remarkable deterioration.The animal model with myocardial injuries supported for 4 weeks by Impella 5.5 implanted through carotid artery access in sheep was feasible.

Breakdown of effective information flow in disorders of consciousness: Insights from TMS-EEG

BackgroundThe complexity of the neurophysiological mechanisms underlying human consciousness is widely acknowledged, with information processing and flow originating in cortex conceived as a core mechanism of consciousness emergence. Combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is considered as a promising technique to understand the effective information flow associated with consciousness. ObjectivesTo investigate information flow with TMS-EEG and its relationship to different consciousness states. MethodsWe applied an effective information flow analysis by combining time-varying multivariate adaptive autoregressive model and adaptive directed transfer function on TMS-EEG data of frontal, motor and parietal cortex in patients with disorder of consciousness (DOC), including 14 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, 21 minimally conscious state (MCS) patients, and 22 healthy subjects. ResultsTMS in DOC patients, particularly VS/UWS, induced a significantly weaker effective information flow compared to healthy subjects. The bidirectional directed information flow was lost in DOC patients with TMS of frontal, motor and parietal cortex. The interactive ROI rate of the information flow network induced by TMS of frontal and parietal cortex was significantly lower in VS/UWS than in MCS. The interactive ROI rate correlated with DOC clinical scales. ConclusionsTMS-EEG revealed a physiologically relevant correlation between TMS-induced information flow and levels of consciousness. This suggests that breakdown of effective cortical information flow serves as a viable marker of human consciousness. SignificanceFindings offer a unique perspective on the relevance of information flow in DOC, thus providing a novel way of understanding the physiological basis of human consciousness.

Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants.

To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), in healthy participants. In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1-12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8-10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. NCT05347849.

Covert Consciousness in Acute Brain Injury Revealed by Automated Pupillometry and Cognitive Paradigms.

Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC. We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinicallylow-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks). We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsivepatients and 50.0% of clinically low-responsivepatients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation. Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC.