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Neuroscience

The entropic brain – Revisited

March 13, 2018 / Neuroscience, Papers, Psychology, Publications / By /

Abstract

The entropic brain hypothesis proposes that within upper and lower limits, after which consciousness may be lost, the entropy of spontaneous brain activity indexes the informational richness of conscious states. Here the hypothesis is revisited four years on from its original publication. It is shown that the principle that the entropy of brain activity is elevated in the psychedelic state is increasingly well supported by separate and independent studies and analyses, and evidence for greater brain criticality under psychedelics is also highlighted. It is argued that heightened brain criticality enables the brain to be more sensitive to intrinsic and extrinsic perturbations which may translate as a heightened susceptibility to “set” and “setting”. This updated version of the original entropic brain hypothesis now offers more concrete information on specific measures of brain entropy and suggests new studies to scrutinise it further, as well as examine its utility for describing and informing the treatment of psychiatric and neurological conditions such as depression and disorders of consciousness.
Carhart-Harris, R. L. (2018). The entropic brain-Revisited. Neuropharmacology. 10.1016/j.neuropharm.2018.03.010
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MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?

March 7, 2018 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.

Feduccia, A. A., & Mithoefer, M. C. (2018). MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?. Progress in neuro-psychopharmacology and biological psychiatry. 10.1016/j.pnpbp.2018.03.003
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Altered network hub connectivity after acute LSD administration

March 7, 2018 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

LSD is an ambiguous substance, said to mimic psychosis and to improve mental health in people suffering from anxiety and depression. Little is known about the neuronal correlates of altered states of consciousness induced by this substance. Limited previous studies indicated profound changes in functional connectivity of resting state networks after the administration of LSD. The current investigation attempts to replicate and extend those findings in an independent sample. In a double-blind, randomized, cross-over study, 100 μg LSD and placebo were orally administered to 20 healthy participants. Resting state brain activity was assessed by functional magnetic resonance imaging. Within-network and between-network connectivity measures of ten established resting state networks were compared between drug conditions. Complementary analysis were conducted using resting state networks as sources in seed-to-voxel analyses. Acute LSD administration significantly decreased functional connectivity within visual, sensorimotor and auditory networks and the default mode network. While between-network connectivity was widely increased and all investigated networks were affected to some extent, seed-to-voxel analyses consistently indicated increased connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These latter observations are consistent with findings on the importance of hubs in psychopathological states, especially in psychosis, and could underlay therapeutic effects of hallucinogens as proposed by a recent model.
Müller, F., Dolder, P. C., Schmidt, A., Liechti, M. E., & Borgwardt, S. (2018). Altered network hub connectivity after acute LSD administration. NeuroImage: Clinical. 10.1016/j.nicl.2018.03.005
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Convergent Mechanisms Underlying Rapid Antidepressant Action

March 1, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018). Convergent mechanisms underlying rapid antidepressant action. CNS drugs, 1-31. 10.1007/s40263-018-0492-x
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Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats

March 1, 2018 / Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3 mg/kg), 25I-NBOMe (0.01-0.3 mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0 mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0 mg/kg) and DOI (0.03-1.0 mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl){1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.
Elmore, J. S., Decker, A. M., Sulima, A., Rice, K. C., Partilla, J. S., Blough, B. E., & Baumann, M. H. (2018). Comparative neuropharmacology of N-(2-methoxybenzyl)-2, 5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Neuropharmacology. 10.1016/j.neuropharm.2018.02.033
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Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature

February 20, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine’s mechanism may be elucidated in humans. Here, we review 47 articles of ketamine’s effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, may increase emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine’s mechanism of antidepressant action.
Ionescu, D. F., Felicione, J. M., Gosai, A., Cusin, C., Shin, P., Shapero, B. G., & Deckersbach, T. (2018). Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Harvard review of psychiatry. 10.1097/HRP.0000000000000179
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Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

February 14, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., & Hu, H. (2018). Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 554(7692), 317. 10.1038/nature25509
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The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes

February 11, 2018 / Iboga / Ibogaine, Neuroscience, Papers, Psychiatry & Medicine, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga. It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H2O2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H2O2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis.
Oreščanin-Dušić, Z., Tatalović, N., Vidonja-Uzelac, T., Nestorov, J., Nikolić-Kokić, A., Mijušković, A., … & Blagojević, D. (2018). The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes. Oxidative medicine and cellular longevity, 2018. 10.1155/2018/5969486
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Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice

February 6, 2018 / Neuroscience, Papers, Publications / By / , ,

Abstract

The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals’ response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2Aantagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
Buchborn, T., Lyons, T., & Knöpfel, T. (2018). Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice. Frontiers in Pharmacology, 9, 17. 10.3389/fphar.2018.00017
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A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

January 31, 2018 / Ayahuasca, Depressive Disorders, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized placebo-controlled trial supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients and in healthy volunteers. Subjects received a single dose of ayahuasca or placebo, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing) and 48h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients (DM), both with respect to healthy controls group (C). Salivary cortisol also was measured during dosing session and we observed a large increased for both C and DM that ingested ayahuasca, than placebo groups. After 48h of the dosing session (D2) with ayahuasca, awakening salivary cortisol response (for both sexes) of treated patients became similar to levels detected in controls. This was not observed in patients that ingested placebo. No changes in plasma cortisol were observed after 48 hours of ayahuasca or placebo ingestion for both groups and sexes. Therefore, these findings point to new evidence of modulation of ayahuasca on salivary cortisol levels, as cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes related to etiology of depression, this modulation could be an important part of the antidepressant effects observed with ayahuasca. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

Galvao, A. C. M., Almeida, R. N., dos Santos Silva, E. A., de Morais Freire, F. A., Palhano-Fontes, F., Onias, H., … & Galvao-Coelho, N. L. (2018). A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression. bioRxiv, 257238. 10.1101/257238
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