Functional brain responses to emotional faces after three to five weeks of intake of escitalopram in healthy individuals: a double-blind, placebo-controlled randomised study.

Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3-5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen's D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3-5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen's D|< 0.2, PFWER = 1). Whole-brain, region-wise analyses revealed significant differences in frontal (|Cohen's D|< 0.6, PFWER < .01) and occipital regions (|Cohen's D|< 0.5, PFWER < .01). SSRI did not modulate correlations between amygdala responses to emotional faces and negative mood states. Our findings indicate that a 3-5 week SSRI intake impacts cortical responses to emotional stimuli, an effect possibly involved in SSRI's therapeutic efficacy.Trial registration Clinical Trials NCT04239339.

Genetic contributions to brain serotonin transporter levels in healthy adults.

The serotonin transporter (5-HTT) critically shapes serotonin neurotransmission by regulating extracellular brain serotonin levels; it remains unclear to what extent 5-HTT levels in the human brain are genetically determined. Here we applied [11C]DASB positron emission tomography to image brain 5-HTT levels and evaluated associations with five common serotonin-related genetic variants that might indirectly regulate 5-HTT levels (BDNF rs6265, SLC6A4 5-HTTLPR, HTR1A rs6295, HTR2A rs7333412, and MAOA rs1137070) in 140 healthy volunteers. In addition, we explored whether these variants could predict in vivo 5-HTT levels using a five-fold cross-validation random forest framework. MAOA rs1137070 T-carriers showed significantly higher brain 5-HTT levels compared to C-homozygotes (2-11% across caudate, putamen, midbrain, thalamus, hippocampus, amygdala and neocortex). We did not observe significant associations for the HTR1A rs6295 and HTR2A rs7333412 genotypes. Our previously observed lower subcortical 5-HTT availability for rs6265 met-carriers remained in the presence of these additional variants. Despite this significant association, our prediction models showed that genotype moderately improved prediction of 5-HTT in caudate, but effects were not statistically significant after adjustment for multiple comparisons. Our observations provide additional evidence that serotonin-related genetic variants modulate adult human brain serotonin neurotransmission.

Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.

BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. DISCUSSION: The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. TRIAL REGISTRATION: Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans: An open-label preliminary investigation.

Rationale: Psilocybin is a serotonergic psychedelic that has gained prominent attention recently as a potential therapeutic for neuropsychiatric disorders including Major Depressive Disorder. Pre-clinical and initial studies in humans suggest that serotonin 2A receptor agonists, including serotonergic psychedelics, have anti-inflammatory effects. This may contribute to its therapeutic effects as previous studies indicate a link between neuropsychiatric disorders and inflammatory processes. However, the effect of psilocybin on biomarkers of inflammation has not been evaluated in humans. Objectives: Investigate the effect of a single dose of psilocybin on peripheral biomarkers of inflammation in healthy humans. Methods: Blood samples were collected from 16 healthy participants before and one day after the administration of a single oral dose of psilocybin (mean dose: 0.22 mg/kg) and subsequently analyzed for concentrations of high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR). Change in inflammatory markers was evaluated using a paired t-test where p < 0.05 was considered statistically significant. Results: We did not observe statistically significant changes in any of the above biomarkers of inflammation (all Cohen's d ≤ 0.31; all p ≥ 0.23). Conclusions: Our data do not support that a single dose of psilocybin reduces biomarkers of inflammation in healthy individuals one day after administration. Nevertheless, we suggest that future studies consider additional markers of inflammation, including markers of neuroinflammation, and evaluate potential anti-inflammatory effects of psilocybin therapy in clinical cohorts where more prominent effects may be observable.

Psilocybin-assisted therapy for reducing alcohol intake in patients with alcohol use disorder: protocol for a randomised, double-blinded, placebo-controlled 12-week clinical trial (The QUANTUM Trip Trial).

INTRODUCTION: Alcohol use disorder is a difficult-to-treat psychiatric disorder and a major burden on public health. Existing treatment efficacy is moderate, and relapse rates are high. Preliminary findings suggest that psilocybin, a psychedelic compound, can safely and reliably occasion highly meaningful experiences that may spur a positive change in drinking behaviour when administered in a therapeutic context. However, the efficacy of a single psilocybin administration and its potential neurobiological underpinnings still remain unknown. METHODS AND ANALYSIS: To establish efficacy, we will investigate the effects of psilocybin-assisted therapy versus placebo in a randomised, double-blinded, placebo-controlled 12-week clinical trial. Ninety treatment-seeking patients, aged 20-70 years, diagnosed with alcohol use disorder will be recruited from the community via advertisement and referrals from general practitioners or specialised treatment units. The psilocybin or placebo will be administered in accordance with a protocol for psychological support before, during and after the dosing. Outcome assessments will be carried out 1, 4, 8 and 12 weeks postdosing. The primary outcome is reduction in the percentage of heavy drinking days from baseline to follow-up at 12 weeks. Key secondary outcomes are as follows: (1) total alcohol consumption, (2) phosphatidyl-ethanol, an objective biomarker for alcohol, (3) plasma psilocin, the active metabolite, to establish a possible therapeutic range, (4) the acute subjective drug experience as a possible predictor of treatment outcome and (5) neuronal response to alcohol cues and cognitive flexibility within corticostriatal pathways by use of functional MR brain imaging 1-week postdosing. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Committee on Health Research Ethics of the Capital Region of Denmark (H-20043832). All patients will be provided oral and written information about the trial before screening. The study results will be disseminated by peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: EudraCT 2020-000829-55 and NCT05416229.

Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals.

Background: Psilocybin-induced mystical-type experiences are associated with lasting positive psychological outcomes. Recent studies indicate that trait mindfulness is increased 3 months after psilocybin intake, preceded by decreases in neocortical serotonin 2A receptor (5-HT2AR) binding. However, the association between psilocybin-induced mystical-type experiences and subsequent changes in trait mindfulness remains unexplored, as does the association between pre-drug trait mindfulness and 5-HT2AR binding in the healthy brain. Aim: We evaluated whether psilocybin induced lasting increases in trait mindfulness in healthy volunteers, and whether the mystical-type experience was associated with this increase. We further examined the association between pre-drug trait mindfulness and 5-HT2AR binding in neocortex and selected frontolimbic regions. Materials and methods: Forty-six medium-high dose psilocybin sessions were conducted in 39 healthy individuals. The mystical-type experience was measured with the Mystical Experience Questionnaire (MEQ) at the end of the session. Trait mindfulness was measured using the Mindful Attention and Awareness Scale (MAAS) at baseline and 3 months after the psilocybin session. Thirty-two of the participants completed pre-drug [11C]-Cimbi-36 positron emission tomography (PET) to assess 5-HT2AR binding in neocortex and, post-hoc, in the frontolimbic regions amygdala, frontal cortex, and anterior cingulate cortex. Results: The MAAS score was significantly increased at 3-month follow-up (p = 3.24 × 10-6), a change positively associated with the MEQ score (p = 0.035). Although the association between pre-drug MAAS score and neocortex 5-HT2AR binding was not significant (p = 0.24), post-hoc analyses revealed a significant negative association between MAAS and right amygdala 5-HT2AR binding (pFWER = 0.008). Conclusion: We here show that lasting changes in trait mindfulness following psilocybin administration are positively associated with intensity of the mystical-type experience, suggesting that the acute phenomenology of psilocybin facilitates a shift in awareness conducive for mindful living. We furthermore show that higher pre-drug trait mindfulness is associated with reduced 5-HT2AR binding in the right amygdala.

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial.

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Effects of an Oral Contraceptive on Dynamic Brain States and Network Modularity in a Serial Single-Subject Study.

Hormonal contraceptive drugs are used by adolescent and adult women worldwide. Increasing evidence from human neuroimaging research indicates that oral contraceptives can alter regional functional brain connectivity and brain chemistry. However, questions remain regarding static whole-brain and dynamic network-wise functional connectivity changes. A healthy woman (23 years old) was scanned every day over 30 consecutive days during a naturally occurring menstrual cycle and again a year later while using a combined hormonal contraceptive. Here we calculated graph theory-derived, whole-brain, network-level measures (modularity and system segregation) and global brain connectivity (characteristic path length) as well as dynamic functional brain connectivity using Leading Eigenvector Dynamic Analysis and diametrical clustering. These metrics were calculated for each scan session during the serial sampling periods to compare metrics between the subject's natural and contraceptive cycles. Modularity, system segregation, and characteristic path length were statistically significantly higher across the natural compared to contraceptive cycle scans. We also observed a shift in the prevalence of two discrete brain states when using the contraceptive. Our results suggest a more network-structured brain connectivity architecture during the natural cycle, whereas oral contraceptive use is associated with a generally increased connectivity structure evidenced by lower characteristic path length. The results of this repeated, single-subject analysis allude to the possible effects of oral contraceptives on brain-wide connectivity, which should be evaluated in a cohort to resolve the extent to which these effects generalize across the population and the possible impact of a year-long period between conditions.

Psychedelic resting-state neuroimaging: A review and perspective on balancing replication and novel analyses.

Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic imaging researchers, review the 42 research articles published to date, based on the 17 unique studies evaluating psychedelic effects on rs-fMRI, focusing on methodological variation. Prominently, we observe that nearly all studies vary in data processing and analysis methodology, two datasets are the foundation of over half of the published literature, and there is lexical ambiguity in common outcome metric terminology. We offer guidelines for future studies that encourage coherence in the field. Psychedelic rs-fMRI will benefit from the development of novel methods that expand our understanding of the brain mechanisms mediating its intriguing effects; yet, this field is at a crossroads where we must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics.

Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report.

Psychedelic drugs such as psilocybin have shown substantial promise for the treatment of several psychiatric conditions including mood and addictive disorders. They also have the remarkable property of producing persisting positive psychological changes in healthy volunteers for at least several months. In this study (NCT03289949), 35 medium-high doses of psilocybin were administered to 28 healthy volunteers (12 females). By the end of the dosing day, participants reported the intensity of their acute experience using the 30-item Mystical Experience Questionnaire (MEQ) and an open-form qualitative report from home. Persisting psychological effects attributed to the psilocybin experience were measured using the Persisting Effects Questionnaire (PEQ) 3-months after administration. Using a linear latent-variable model we show that the MEQ total score is positively associated with the later emergence of positive PEQ effects (p = 3 × 10-5). Moreover, the MEQ subscales "Positive Mood" (pcorr = 4.1 × 10-4) and "Mysticality" (pcorr = 2.0 × 10-4) are associated with positive PEQ whereas the subscales "Transcendence of Time and Space" (pcorr = 0.38) and "Ineffability" (pcorr = 0.45) are not. Using natural language pre-processing, we provide the first qualitative descriptions of the "Complete Mystical Experience" induced by orally administered psilocybin in healthy volunteers, revealing themes such as a sense of connection with the Universe, familial love, and the experience of profound beauty. Combining qualitative and quantitative methods, this paper expands understanding of the acute psilocybin induced experience in healthy volunteers and suggests an importance of the type of experience in predicting lasting positive effects.

Reduced prefrontal cortex response to own vs. unknown emotional infant faces in mothers with bipolar disorder.

Motherhood involves functional brain adaptations within a broad neural network purported to underlie sensitive caregiving behavior. Bipolar disorder (BD) is associated with aberrant brain response to emotional faces within a similar network, which may influence BD mothers' sensitivity to infant faces. This functional magnetic resonance imaging (fMRI) study aimed to investigate whether mothers with BD display aberrant neural responses to own infant faces compared to healthy mothers. Twenty-six mothers with BD in remission and 35 healthy mothers underwent fMRI during which they viewed happy and distressed still facial photographs of their own and of unknown infants. After the scan, mothers viewed the pictures again on a computer screen and rated the intensity of infants' facial emotions and their own emotional response to infant face images. Mothers with BD displayed lower left dorsolateral prefrontal cortex (dlPFC) response compared to healthy mothers to own vs. unknown infant faces specifically and abnormal positive functional connectivity between the left and right amygdala and prefrontal regions. BD mothers further displayed stronger deactivation of precuneus and occipital regions to all happy vs. distressed infant faces. After the scan, they rated their infants' distress and own response to their infants' distressed faces less negatively than healthy mothers. Blunted dlPFC response and aberrant fronto-limbic connectivity while viewing own infant faces and less negative ratings of own infants' distress in BD mothers may affect their responses to their own infants in real-life mother-infant interactions.

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals.

BACKGROUND: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. AIM: Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. METHODS: Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. RESULTS: Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen's d = -1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months (r = -0.65). CONCLUSIONS: These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic 'afterglow' period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [11C]UCB-J and [18F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [11C]UCB-J binding and [18F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuit's cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [11C]UCB-J and [18F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

Affective episodes in recently diagnosed patients with bipolar disorder associated with altered working memory-related prefrontal cortex activity: A longitudinal fMRI study.

INTRODUCTION: Bipolar disorder (BD) is often accompanied by trait-related cognitive impairments, but it is unclear which neurocircuitry abnormalities give rise to these impairments and whether neurocircuitry differences are exacerbated with illness progression. This longitudinal fMRI study of recently diagnosed BD patients investigates whether aberrant working memory (WM) related activity in the cognitive control network is accentuated by new affective episodes. METHODS: Forty-seven recently diagnosed BD patients in full or partial remission and 38 healthy controls were assessed with neurocognitive tests and fMRI during the performance of a verbal n-back WM task at baseline and follow-up (15.4 months in average). RESULTS: Patients showed WM-related hypo-activity in dorsal prefrontal cortex (dPFC) and impaired cognitive function within attention and psychomotor speed, WM and executive function, and verbal learning and memory compared to controls at baseline. During the follow-up period, 26 patients experienced at least one affective episode (BD+), while 21 remained in remission (BD-). There was no deterioration in cognitive performance in BD+ compared to BD- patients. Nevertheless, BD+ displayed increased WM-related dPFC activity at follow-up compared with BD- patients. This change in dPFC response was independent of mood symptoms and medication. LIMITATIONS: The study did not account for type or frequency of affective episodes. CONCLUSION: The study identifies cognitive impairment and WM-related hypo-activity in dPFC early during the course of BD. Increased high-load WM related dPFC activity over the follow-up period in BD+ versus BD- patients in the absence of changes in cognitive performance may reflect an episode-related reduction in PFC efficiency.

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans.

BACKGROUND: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. AIMS: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. METHOD: Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. RESULTS: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. CONCLUSION: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Cognitive impairment and psychopathology in out-of-hospital cardiac arrest survivors in Denmark: The REVIVAL cohort study protocol.

INTRODUCTION: Cognitive impairment and psychopathology caused by brain hypoxia and the traumatic impact of critical illness are common in cardiac arrest survivors and can lead to negative consequences of everyday life functioning, and further impact mental health in relatives. Most studies have dealt with the mere survival rate after cardiac arrest and not with long-term consequences to mental health in cardiac arrest survivors. Importantly, we face a gap in our knowledge about suitable screening tools in the early post-arrest phase for long-term risk prediction of mental health problems. This study aims to evaluate the efficacy of a novel screening procedure to predict risk of disabling cognitive impairment and psychopathology 3 months after cardiac arrest. Furthermore, the study aims to evaluate long-term prevalence of psychopathology in relatives. METHODS AND ANALYSES: In this multicentre prospective cohort study, out-of-hospital cardiac arrest survivors and their relatives will be recruited. The post-arrest screening includes the Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HADS), the Impact of Event Scale-Revised (IES-R) and the Acute Stress Disorder Interview (ASDI) and is conducted during hospitalisation. In a subsample of the patients, functional MRI is done, and cortisol determination collected. At 3-month follow-up, the primary study outcomes for 200 survivors include the Danish Affective Verbal Learning Test-26 (VAMT-26), Delis-Kaplan Executive Function System tests (trail making, colour-word interference, word and design fluency), Rey's Complex Figure and Letter-number sequencing subtest of Wechsler Adult Intelligence Scale-IV, HADS and IES-R. For the relatives, they include HADS and IES-R. ETHICS AND DISSEMINATION: The study is approved by the local regional Research Ethics Committee (H-18046155) and the Danish Data Protection Agency (RH-2017-325, j.no.05961) and follows the latest version of the Declaration of Helsinki. The results will be published in peer-reviewed journals and may impact the follow-up of cardiac arrest survivors.

Visual stimuli induce serotonin release in occipital cortex: A simultaneous positron emission tomography/magnetic resonance imaging study.

Endogenous serotonin (5-HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5-HT levels in living humans. Here, we study the neural responses to a visual stimulus using simultaneous PET/MRI. In a cross-over design, 11 healthy individuals were PET/MRI scanned with the 5-HT1B receptor radioligand [11 C]AZ10419369, which is sensitive to changes in endogenous 5-HT. During the last part of the scan, participants either viewed autobiographical images with positive valence (n = 11) or kept their eyes closed (n = 7). The visual stimuli increased cerebral blood flow (CBF) in the occipital cortex, as measured with pseudo-continuous arterial spin labeling. Simultaneously, we found decreased 5-HT1B receptor binding in the occipital cortex (-3.6 ± 3.6%), indicating synaptic 5-HT release. Using a linear regression model, we found that the change in 5-HT1B receptor binding was significantly negatively associated with change in CBF in the occipital cortex (p = .004). For the first time, we here demonstrate how cerebral 5-HT levels change in response to nonpharmacological stimuli in humans, as measured with PET. Our findings more directly support a link between 5-HT signaling and visual processing and/or visual attention.

A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding.

A single dose of the serotonin 2A receptor (5-HT2AR) agonist psilocybin can have long-lasting beneficial effects on mood, personality, and potentially on mindfulness, but underlying mechanisms are unknown. Here, we for the first time conduct a study that assesses psilocybin effects on cerebral 5-HT2AR binding with [11C]Cimbi-36 positron emission tomography (PET) imaging and on personality and mindfulness. Ten healthy and psychedelic-naïve volunteers underwent PET neuroimaging of 5-HT2AR at baseline (BL) and one week (1W) after a single oral dose of psilocybin (0.2-0.3 mg/kg). Personality (NEO PI-R) and mindfulness (MAAS) questionnaires were completed at BL and at three-months follow-up (3M). Paired t-tests revealed statistically significant increases in personality Openness (puncorrected = 0.04, mean change [95%CI]: 4.2[0.4;∞]), which was hypothesized a priori to increase, and mindfulness (pFWER = 0.02, mean change [95%CI]: 0.5 [0.2;0.7]). Although 5-HT2AR binding at 1W versus BL was similar across individuals (puncorrected = 0.8, mean change [95%CI]: 0.007 [-0.04;0.06]), a post hoc linear regression analysis showed that change in mindfulness and 5-HT2AR correlated negatively (ß [95%CI] = -5.0 [-9.0; -0.9], pFWER= 0.046). In conclusion, we confirm that psilocybin intake is associated with long-term increases in Openness and - as a novel finding - mindfulness, which may be a key element of psilocybin therapy. Cerebral 5-HT2AR binding did not change across individuals but the negative association between changes in 5-HT2AR binding and mindfulness suggests that individual change in 5-HT2AR levels after psilocybin is variable and represents a potential mechanism influencing long-term effects of psilocybin on mindfulness.

Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study.

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5-HT2A R) agonist psilocybin. However, no studies have investigated whether 5-HT2A R availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5-HT2A R binding in neocortex imaged with [18 F]altanserin or [11 C]Cimbi-36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory-Revised. No significant associations between neocortical 5-HT2A R binding and trait Openness were found for [18 F]altanserin (p = 0.5) or [11 C]Cimbi-36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5-HT2A R availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5-HT2A R with compounds such as psilocybin may contribute to long-term changes in trait Openness, there is no evidence in favor of an association between 5-HT2A R and trait Openness.

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.