Whole-Brain Models to Explore Altered States of Consciousness from the Bottom Up.

The scope of human consciousness includes states departing from what most of us experience as ordinary wakefulness. These altered states of consciousness constitute a prime opportunity to study how global changes in brain activity relate to different varieties of subjective experience. We consider the problem of explaining how global signatures of altered consciousness arise from the interplay between large-scale connectivity and local dynamical rules that can be traced to known properties of neural tissue. For this purpose, we advocate a research program aimed at bridging the gap between bottom-up generative models of whole-brain activity and the top-down signatures proposed by theories of consciousness. Throughout this paper, we define altered states of consciousness, discuss relevant signatures of consciousness observed in brain activity, and introduce whole-brain models to explore the biophysics of altered consciousness from the bottom-up. We discuss the potential of our proposal in view of the current state of the art, give specific examples of how this research agenda might play out, and emphasize how a systematic investigation of altered states of consciousness via bottom-up modeling may help us better understand the biophysical, informational, and dynamical underpinnings of consciousness

Decreased directed functional connectivity in the psychedelic state

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data

A unified model of ketamine’s dissociative and psychedelic properties

OKKetamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as ‘dissociation’. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine’s multi-level effects – from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (‘minimal’ self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (‘biographical’ self), we propose that transitory SN desegregation and disintegration accounts for ketamine’s ‘dissociative’ state, while transitory DMN desegregation and disintegration accounts for ketamine’s ‘psychedelic’ state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.publishersversionepub_ahead_of_prin

RAPID-ACTING ANTIDEPRESSANT DRUGS: AN EMERGING APPROACH FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

In questa tesi viene proposta ed elaborata l'evoluzione terapeutica contro la depressione resistente ai trattamenti convenzionali, con un'attenzione maggiore a una nuova e promettente classe di farmaci denominata Rapid-Acting-Antidepressant. Inizialmente, viene offerta una presentazione in cui vengono definiti i vari tipi di depressione diagnosticabili, con le rispettive caratterizzazioni e sintomi, per poi delineare le terapie attualmente prescritte contro questa condizione. In seguito, viene introdotta una nuova ipotesi chiamata ipotesi glutammatergica, in quanto si ritiene che la presenza di un'aumentata concentrazione del neurotrasmettitore glutammato sia coinvolta nella manifestazione dei sintomi nei pazienti depressi. Questo neurotrasmettitore eccitatorio è il più abbondante nel sistema nervoso centrale dei mammiferi adulti e possiede un ruolo importante nell'neuroplasticità. In base alla neurotrasmissione, i recettori glutammatergici possono essere suddivisi in: metabotropici (mGluR), che sono recettori accoppiati a proteine G implicati nella plasticità sinaptica, nell'eccitabilità e nella connettività neuronale; e ionotropici (iGluR), che sono canali cationici dipendenti dal ligando. I recettori ionotropici sono proteine di membrana composte da quattro subunità che costituiscono il canale ionico che consente l'afflusso di cationi calcio in seguito al legame con il glutammato. Le subunità sono essenziali per la sinaptogenesi, il rimodellamento sinaptico che dipende dalle variazioni della potenza sinaptica. Nella depressione, vi è una sovrastimolazione di questi recettori causata da alte concentrazioni di glutammato che porta a una condizione di eccitotossicità. Le terapie farmacologiche basate su questa teoria mirano all'inibizione dei recettori N-metil-D-aspartato (NMDA). Il principale capostipite dal punto di vista farmacologico è la ketamina, diffusa come anestetico locale, che ha dimostrato un'attività antidepressiva rapida e prolungata. Tuttavia, la ketamina non può essere considerata un farmaco sicuro perché la sua somministrazione richiede un trattamento ambulatoriale del paziente, a causa della comparsa di effetti collaterali dissociativi e del potenziale di abuso. Per questo motivo, la ricerca si è concentrata sullo sviluppo di altri composti attivi. Oltre alla ketamina, altri antagonisti dei recettori NMDA sono: la memantina, un farmaco prescritto per la malattia di Alzheimer; la norketamina, un derivato della ketamina; l'MK-801, il destrometorfano, il destrometadone e la lanicemina. Tuttavia, esistono anche altri farmaci con un diverso meccanismo d'azione, come il rapastinel, un agonista parziale dei recettori NMDA. Oltre al sistema glutammatergico, negli ultimi anni è stato dimostrato il coinvolgimento di altri sistemi, tra cui il sistema serotoninergico, il sistema colinergico e l'asse ipotalamo-ipofisi-surrene. Ognuno di questi sistemi ha almeno un candidato farmaco in fase di sperimentazione clinica per il trattamento del disturbo depressivo maggiore. In conclusione, questo lavoro di tesi propone un confronto tra le terapie attualmente prescritte e i nuovi approcci terapeutici per la depressione, confrontandone le caratteristiche principali.In this thesis, therapeutic evolution against depression resistant to conventional treatment is proposed and elaborated with a greater focus on a new and promising class of drugs called Rapid-Acting-Antidepressant. Initially, a presentation is offered in which the various types of diagnosable depression are defined along with their respective characterizations and symptoms, and then the currently prescribed therapies against this condition are outlined. Continuing, a new hypothesis called the glutamatergic hypothesis is introduced as it is believed that the presence of increased concentration of the neurotransmitter glutamate is involved in the manifestation of symptoms in depressed patients. This excitatory neurotransmitter is the most abundant in the adult mammalian central nervous system and possesses an important role inneuroplasticity. Based on neurotransmission, glutamatergic receptors can be divided into: metabotropic (mGluR) which are G-protein-coupled receptors implicated in synaptic plasticity, excitability and neuronal connectivity; and ionotropic (iGluR) which are ligand-dependent cation channels. Ionotropic receptors are membrane proteins composed of four subunits that constitute the ion channel which allows the influx of calcium cations following glutamate binding. The subunits are essential for synaptogenesis, the synaptic remodeling dependent on changes in synaptic potency. In depression, there is overstimulation of these receptors caused by high concentrations of glutamate leading to an excitotoxic condition. Phamacological therapies based on this theory target N-methyl-D-aspartate (NMDA) receptor inhibition. The main progenitor from the pharmacological point of view is ketamine, widespread as a local anesthetic, which has shown rapid and sustained antidepressant activity. However, ketamine cannot be regarded as a safe drug because its administration requires ambulatory treatment of the patient, due to the occurrence of dissociative side effects and the potential for abuse. For this reason, research has focused on the development of other active compounds. In addition to ketamine, other NMDA receptor antagonists include: memantine, a drug prescribed for Alzheimer's disease; norketamine, a ketamine derivative; MK-801, dextromethorphan, dextromethadone, and lanicemine. However, there are also other drugs having different mechanism of action such as rapastinel, an NMDA receptor partial agonist. In addition to the glutamatergic system, the involvement of other systems including the serotonergic system, the cholinergic system, and the hypothalamic-pituitary-adrenal axis has been demonstrated in recent years. Each of these systems has at least one drug candidate in clinical trials for the treatment of major depressive disorder. In conclusion, this thesis work proposes a comparison of currently prescribed therapies and new therapeutic approaches for depression by comparing their main characteristics

The effects of DMT and associated psychedelics on the human mind and brain

This work presents seven investigations conducted with the aim to determine the effects of DMT (a compound which is able to cause remarkable effects in consciousness) and associated psychedelic drugs on the human brain and mind. Including a variety of neuroimaging (EEG, MEG and fMRI), phenomenological, psychometric and naturalistic research methods, these are the first controlled investigations of the impact of DMT in the human resting brain. Results revealed that DMT disrupted several brain mechanisms associated with top-down control (alpha power, integrity of high-level networks, modularity), increased measures related to entropy, or disorder (Lempel-Ziv complexity, novel pairwise connectivity) and immersive states of consciousness (delta/theta power), with some of these effects following the experiential trajectories of the DMT state. We also observed a significant temporal correlation between some of these effects (alpha power and default-mode network integrity fluctuations), which were supported by LSD effects of reduced feedback connectivity and neural adaption mechanisms. suggesting that the psychedelic brain state is one of reduced modularity, increased integration and functional plasticity. These findings were complemented by psychological studies showing that the DMT state is one of immersive visual imagery, intense somatic experiences and partial disconnection from the environment, which we found shared significant overlap with near- death experiences. DMT administration also resulted in positive mental health outcomes in healthy volunteers providing evidence for the first time that DMT may provide a useful alternative to currently- investigated psychedelic treatments. Finally, results from our last study performed in naturalistic environments revealed that psychedelics are able to have a transformative potential on core beliefs concerning the fundamental nature of reality and consciousness for up to 6 months, with important social and bioethical implications. Collectively these results attest to the strong impact that psychedelics have on varied human domains, which range experience, brain activity, mental health, intersubjectivity and beliefs.Open Acces

Computational modelling of EEG and fMRI paradigms indicates a consistent loss of pyramidal cell synaptic gain in schizophrenia

Background Diminished synaptic gain – the sensitivity of postsynaptic responses to neural inputs – may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. Methods Participants with schizophrenia diagnoses (PScz, n=108), their relatives (n=57), and controls (n=107) underwent three electroencephalography (EEG) paradigms – resting, mismatch negativity, and 40 Hz auditory steady-state response – and resting functional magnetic resonance imaging. Dynamic causal modelling was used to quantify synaptic connectivity in cortical microcircuits. Results Classic group differences in EEG features between PScz and controls were replicated, including increased theta and other spectral changes (resting EEG), reduced mismatch negativity, and reduced 40 Hz power. Across all four paradigms, characteristic PScz data features were all best explained by models with greater self-inhibition (decreased synaptic gain), in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in PScz, in three paradigms. Conclusions First, characteristic EEG changes in PScz in three classic paradigms are all attributable to the same underlying parameter change: greater self-inhibition in pyramidal cells. Second, psychotic symptoms in PScz relate to disinhibition in neural circuits. These findings are more commensurate with the hypothesis that in PScz, a primary loss of synaptic gain on pyramidal cells is then compensated by interneuron downregulation (rather than the converse). They further suggest that psychotic symptoms relate to this secondary downregulation

Modern patterns of use of selected non-traditional psychoactive substances

Východiska: Nástup nových syntetických drog spolu s rostoucím zájmem o nootropika, microdosing a netradiční přírodní i syntetické látky bez pochyby ovlivňuje vývoj novodobé drogové scény. Uvolnění represí ve vědeckém výzkumu zejména u psychedelik a získání nových informací o jejich potenciálním využití pro psychoterapii, léčbu závislostí, chronických bolestí, ale i osobnostní rozvoj navíc profiluje nový typ uživatele, který se snaží o vylepšení kognitivních, duchovních či intelektuálních funkcí, a to s minimálním dopadem na své fyzické i duchovní zdraví. Cíle: Cílem práce je popsat vzorce užívání vybraných netradičních psychoaktivních látek, které jsou za netradiční považovány vzhledem k tuzemské kultuře a kontextu, případně pak nootropik a fenoménu mikrodávkování. Specifickým cílem je nalézt motivaci uživatelů vybraných psychoaktivních látek k jejich aplikaci, porovnat následky jejich užití s typicky návykovými skupinami běžně zneužívaných látek jako jsou stimulanty a opiáty, následně pak popsat jejich případný vliv na konzumaci alkoholu a tabáku. Metody: Výzkum je kombinací kvantitativních a kvalitativních metod. Data byla sbírána pomocí anonymního dotazníku. Výzkumný soubor (n = 35) byl vybrán metodou účelového výběru v kombinaci s metodou sněhové koule. Každý respondent měl alespoň jednu...Background: The popularity of new synthetic drugs together with rising interest in nootropics, microdosing and untraditional natural or synthetic substances has been influencing the development of drug scene. Unleashing repression in scientific research of these substances together with new information about their potential usage in psychotherapy, treatment of substance abuse, chronic pain and personality development profiles a new type of user, who is seeking enhancement in his cognitive, spiritual or intellectual functions with minimal health risks. Aim: The aim of this thesis is to describe psychoactive substance patterns of use, which we consider untraditional given the current culture and context, eventually nootropics and microdosing phenomenon. Specific aim of this thesis is to find motivation behind using psychoactive substances, compare consequences of this use between commonly abused stimulants, opiates and describe the effect these substances have on alcohol and tobacco consumption. Methods: Quantitative and qualitative methods were used. Data was collected with anonymous questionnaire. Research file (n = 35) was chosen based on intended selection and snowball sampling methods. Every participant must had at least one experience with untraditional psychoactive substance which were chosen...Klinika adiktologie 1.LF UK a VFN v PrazeDepartment of Adictology First Faculty of Medicine and General University Hospital in PragueFirst Faculty of Medicine1. lékařská fakult

Spectral signatures of serotonergic psychedelics and glutamatergic dissociatives

Classic serotonergic psychedelics are remarkable for their capacity to induce reversible alterations in consciousness of the self and the surroundings, mediated by agonism at serotonin 5-HT2A receptors. The subjective effects elicited by dissociative drugs acting as N-methyl-D-aspartate (NMDA) antagonists (e.g. ketamine and phencyclidine) overlap in certain domains with those of serotonergic psychedelics, suggesting some potential similarities in the brain activity patterns induced by both classes of drugs, despite different pharmacological mechanisms of action. We investigated source-localized magnetoencephalography recordings to determine the frequency-specific changes in oscillatory activity and long-range functional coupling that are common to two serotonergic compounds (lysergic acid diethylamide [LSD] and psilocybin) and the NMDA-antagonist ketamine. Administration of the three drugs resulted in widespread and broadband spectral power reductions. We established their similarity by using different pairs of compounds to train and subsequently evaluate multivariate machine learning classifiers. After applying the same methodology to functional connectivity values, we observed a pattern of occipital, parietal and frontal decreases in the low alpha and theta bands that were specific to LSD and psilocybin, as well as decreases in the low beta band common to the three drugs. Our results represent a first effort in the direction of quantifying the similarity of large-scale brain activity patterns induced by drugs of different mechanism of action, confirming the link between changes in theta and alpha oscillations and 5-HT2A agonism, while also revealing the decoupling of activity in the beta band as an effect shared between NMDA antagonists and 5-HT2A agonists. We discuss how these frequency-specific convergences and divergences in the power and functional connectivity of brain oscillations might relate to the overlapping subjective effects of serotonergic psychedelics and glutamatergic dissociative compounds.Fil: Pallavicini, Carla. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Gonzalez Vilas, Martina. Max Planck Institute For Empirical Aesthetics; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Villarreal, Mirta Fabiana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zamberlan, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Muthukumaraswamy, Suresh D.. University of Auckland; Nueva ZelandaFil: Nutt, David. Center of Neuropsychopharmacology; Reino UnidoFil: Carhart Harris, Robin. Center of Neuropsychopharmacology; Reino UnidoFil: Tagliazucchi, Enzo Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentin