Rainer Kraehenmann

Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

Significance Social cognition critically impacts the development, progression, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. By applying a multimodal brain imaging strategy, the present study demonstrated the importance of the serotonin 2A/1A receptor system in the modulation of social exclusion processing. Understanding the biochemical underpinnings of the social rejection experience is important for increasing our knowledge about social/emotional processing and the related neural responses. The identification of relevant neural responses is in turn crucial for the efficacious management of disorders influenced by social factors. Our findings may help to diminish a knowledge gap that currently restrains the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders. Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybins effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Shared neural basis of social and non-social reward deficits in chronic cocaine users

Changed reward functions have been proposed as a core feature of stimulant addiction, typically observed as reduced neural responses to non-drug-related rewards. However, it was unclear yet how specific this deficit is for different types of non-drug rewards arising from social and non-social reinforcements. We used functional neuroimaging in cocaine users to investigate explicit social reward as modeled by agreement of music preferences with music experts. In addition, we investigated non-social reward as modeled by winning desired music pieces. The study included 17 chronic cocaine users and 17 matched stimulant-naive healthy controls. Cocaine users, compared with controls, showed blunted neural responses to both social and non-social reward. Activation differences were located in the ventromedial prefrontal cortex overlapping for both reward types and, thus, suggesting a non-specific deficit in the processing of non-drug rewards. Interestingly, in the posterior lateral orbitofrontal cortex, social reward responses of cocaine users decreased with the degree to which they were influenced by social feedback from the experts, a response pattern that was opposite to that observed in healthy controls. The present results suggest that cocaine users likely suffer from a generalized impairment in value representation as well as from an aberrant processing of social feedback.

Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation

Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N‐methyl‐d‐aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting‐state fMRI (rsfMRI), we assessed amygdalo‐hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo‐hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting‐state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate‐responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo‐hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941–1952, 2016.

Crowding Deficits in the Visual Periphery of Schizophrenia Patients

Accumulating evidence suggests that basic visual information processing is impaired in schizophrenia. However, deficits in peripheral vision remain largely unexplored. Here we hypothesized that sensory processing of information in the visual periphery would be impaired in schizophrenia patients and, as a result, crowding – the breakdown in target recognition that occurs in cluttered visual environments – would be stronger. Therefore, we assessed visual crowding in the peripheral vision of schizophrenia patients and healthy controls. Subjects were asked to identify a target letter that was surrounded by distracter letters of similar appearance. Targets and distracters were displayed at 8° and 10° of visual angle from the fixation point (eccentricity), and target-distracter spacing was 2°, 3°, 4°, 5°, 6°, 7° or 8° of visual angle. Eccentricity and target-distracter spacing were randomly varied. Accuracy was defined as the proportion of correctly identified targets. Critical spacing was defined as the spacing at which target identification accuracy began to deteriorate, and was assessed at viewing eccentricities of 8° and 10°. Schizophrenia patients were less accurate and showed a larger critical spacing than healthy individuals. These results indicate that crowding is stronger and sensory processing of information in the visual periphery is impaired in schizophrenia. This is in line with previous reports of preferential magnocellular dysfunction in schizophrenia. Thus, deficits in peripheral vision may account for perceptual alterations and contribute to cognitive dysfunction in schizophrenia.

Gender characteristics of cerebral hemodynamics during complex cognitive functioning.

Functional Transcranial Doppler sonography (fTCD) has been applied to assess peak mean cerebral blood flow velocity (MFV) with a high temporal resolution during cognitive activation. Yet, little attention has been devoted to gender-related alterations of MFV, including spectral analysis. In healthy subjects, fTCD was used to investigate a series of cerebral hemodynamic parameters in the middle cerebral arteries (MCA) during the Trail Making Tests (TMT), a means of selective attention and complex cognitive functioning. In females, there was a frequency peak at 0.375 Hz in both MCA, and we observed a dynamic shift in hemispheric dominance during that condition. Further, after the start phase, there was an MFV decline during complex functioning for the entire sample. These novel results suggest condition-specific features of cerebral hemodynamics in females, and it adds to the notion that gender is a fundamental confounder of brain physiology.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.

Neural underpinnings of prosexual effects induced by gamma-hydroxybutyrate in healthy male humans

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist currently used as treatment for narcolepsy but also as a drug of abuse. Non-medical GHB users have repeatedly reported prosexual effects including libido-enhancement and lowering of attractiveness standards for partner selection. Here, we examined the putative prosexual effects of oral GHB in healthy males in two experiments both employing randomized, placebo-controlled, double-blind, balanced, and cross-over study designs. In experiment I, subjective effects of 20 and 35mg/kg GHB vs. placebo were tested in 32 participants using the Sexual Arousal and Desire Inventory. In experiment II, brain reactivity towards erotic vs. neutral pictures was investigated in 15 participants using functional magnetic resonance imaging after 35mg/kg GHB vs. placebo. In experiment I, prosexual effects of GHB were shown by increased SADI ratings regarding physiological, evaluative, and motivational aspects of sexual arousal. In experiment II, erotic visual stimuli activated the bilateral insula, nucleus accumbens (NAcc), fusiform gyrus, thalamus, and left occipital pole under placebo. After GHB administration, even sexually neutral pictures of persons induced subjective sexual arousal and increased activation of the bilateral NAcc and right anterior cingulate cortex, which significantly correlated (left NAcc by trend). Moreover, a psychophysiological interaction analysis showed that GHB increased connectivity between NAcc and ventromedial prefrontal cortex during processing of visual erotic cues, i.e., in the condition in which subjective sexual arousal was highest. Our data show that GHB stimulates hedonic sexual functioning and lowers the threshold for erotic perception, which is related to increased susceptibility of mesolimbic reward pathways.

Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

Abstract Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo‐perfusion in various brain regions. In this placebo‐controlled, double‐blind study we used pseudo‐continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. We controlled for sex and age and used family‐wise error corrected p values in all neuroimaging analyses. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D‐ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations. HighlightsOral psilocybin decreases absolute cerebral blood flow in healthy participants.When evaluating relative changes, psilocybin produces hyperfrontal effects.Our results may clarify an existing discrepancy in the current literature.Our results highlight the importance of evaluating regional and global CBF.

LSD increases primary process thinking via serotonin 2A receptor activation

Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale. Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin. Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.