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A. Schmidt

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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Acute effects of methylphenidate, modafinil and MDMA on negative emotion processing

December 1, 2017 / MDMA, Papers, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
Stimulants such as methylphenidate (MPH) and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of MPH and modafinil on negative emotions in healthy subjects have been widely missing. The aim of this study was to compare the acute effects of MPH and modafinil on the neural correlates of fearful face processing using MDMA as a positive control.
METHODS:
Using a double-blind within-subject placebo-controlled cross-over design, 60 mg MPH, 600 mg modafinil, and 125 mg MDMA were administrated to 22 healthy subjects, while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings.
RESULTS:
Relative to placebo, modafinil, but not MPH or MDMA, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not MPH also increased amydgala responses to fearful faces compared with MDMA. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration.
CONCLUSIONS:
In spite of the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.
Schmidt, A., Müller, F., Dolder, P. C., Schmid, Y., Zanchi, D., Egloff, L., … & Borgwardt, S. (2017). Acute effects of methylphenidate, modafinil and MDMA on negative emotion processing. International Journal of Neuropsychopharmacology, pyx112. 10.1093/ijnp/pyx112
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Acute LSD effects on response inhibition neural networks

October 2, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:
Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.
METHODS:
In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.
RESULTS:
Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.
CONCLUSION:
Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.
Schmidt, A., Müller, F., Lenz, C., Dolder, P. C., Schmid, Y., Zanchi, D., … & Borgwardt, S. (2017). Acute LSD effects on response inhibition neural networks. Psychological Medicine, 1-13. 10.1017/S0033291717002914
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Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations

September 21, 2017 / LSD, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

OBJECTIVE:
It has been proposed that the thalamocortical system is an important site of action of hallucinogenic drugs and an essential component of the neural correlates of consciousness. Hallucinogenic drugs such as LSD can be used to induce profoundly altered states of consciousness, and it is thus of interest to test the effects of these drugs on this system.
METHOD:
100 μg LSD was administrated orally to 20 healthy participants prior to fMRI assessment. Whole brain thalamic functional connectivity was measured using ROI-to-ROI and ROI-to-voxel approaches. Correlation analyses were used to explore relationships between thalamic connectivity to regions involved in auditory and visual hallucinations and subjective ratings on auditory and visual drug effects.
RESULTS:
LSD caused significant alterations in all dimensions of the 5D-ASC scale and significantly increased thalamic functional connectivity to various cortical regions. Furthermore, LSD-induced functional connectivity measures between the thalamus and the right fusiform gyrus and insula correlated significantly with subjective auditory and visual drug effects.
CONCLUSION:
Hallucinogenic drug effects might be provoked by facilitations of cortical excitability via thalamocortical interactions. Our findings have implications for the understanding of the mechanism of action of hallucinogenic drugs and provide further insight into the role of the 5-HT2A -receptor in altered states of consciousness.
Mueller, F., Lenz, C., Dolder, P., Lang, U., Schmidt, A., Liechti, M., & Borgwardt, S. (2017). Increased thalamic resting‐state connectivity as a core driver of LSD‐induced hallucinations. Acta Psychiatrica Scandinavica. 10.1111/acps.12818
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The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

August 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

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 psilocybin’s 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.

Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H., Seifritz, E., & Vollenweider, F. X. (2015). The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical. https://dx.doi.org/10.1016/j.nicl.2015.08.009
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Spatiotemporal Brain Dynamics of Emotional Face Processing Modulations Induced by the Serotonin 1A/2A Receptor Agonist Psilocybin

July 16, 2013 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168–189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211–242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168–189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211–242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.

Bernasconi, F., Schmidt, A., Pokorny, T., Kometer, M., Seifritz, E., & Vollenweider, F. X. (2013). Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin. Cerebral Cortex, bht178. 10.1093/cercor/bht178
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Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors

December 19, 2012 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Background
Serotonin (5-HT) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders. These receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects. However, the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown.

Methods
In a randomized, double-blind study, 17 healthy human subjects received on 4 separate days placebo, psilocybin (215 g/kg), the preferential 5-HT2A antagonist ketanserin (50 mg), or psilocybin plus ketanserin. Mood states were assessed by self-report ratings, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues.

Results
Psilocybin enhanced positive mood and attenuated recognition of negative facial expression. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression.

Conclusions
This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. These findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin’s putative antidepressant effects.

Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., Seifritz, E., & Vollenweider, F. X. (2012). Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors. Biological Psychiatry, 72(11), 898-906. http://dx.doi.org/10.1016/j.biopsych.2012.04.005
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The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions

July 27, 2012 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Rationale
Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases.

Objectives
This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases.

Methods
S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP.

Results
Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces.

Conclusion
This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.

Schmidt, A., Kometer, M., Bachmann, R., Seifritz, E., & Vollenweider, F.X. (2012). The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. Psychopharmacology, 225(1), 227-239. http://dx.doi.org/doi:10.1007/s00213-012-2811-0
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