Effective connectivity changes in LSD-induced altered states of consciousness in humans

This double-blind study (n=25) confirmed the hypothesis that LSD (100μg) acutely alters effective connectivity within CSTC pathways implicated in the gating of sensor and sensorimotor information to the cortex.

Abstract

“Introduction: Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico–striato–thalamo-cortical (CSTC) feedback loops.

Methods: To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex.

Results: Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation.

Discussion: Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.”

Authors: Katrin H. Preller, Adeel Razi, Peter Zeidman, Philipp Stämpfli, Karl J. Friston & Franz X. Vollenweider

Summary

Psychedelics exert unique effects on human consciousness. We used spectral dynamic causal modeling to study the connectivity between the thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex after acute administration of lysergic acid diethylamide (LSD) and after pretreatment with Ketanserin plus LSD.

causal modeling

Psychedelics induce an altered state of consciousness that offers the unique opportunity to investigate the neuropharmacological and mechanistic underpinnings of perception, thought, and consciousness.

Geyer and Vollenweider proposed that psychedelics cause psychotic symptoms by disrupting the cortico-striato-thalamo-cortical feedback loops. This model is supported by studies showing deficits in preattentive sensorimotor gating after the administration of psychedelics.

Thalamic gating has been suggested to be influenced by several neurotransmitter systems. The mesostriatal dopaminergic and serotoninrgic projections provide input to the striatum.

Significance

Using cutting-edge neuroimaging methods, we investigated directed connectivity within cortico-striato-thalamo-cortical pathways in humans after administration of LSD. Our results suggest that a disintegration of information processing within these loops is underlying the psychedelic state.

This article is a PNAS Direct Submission. The data for this article has been deposited in Bitbucket and the author can be reached at [email protected].

Pharmacological neuroimaging has the potential to address knowledge gaps by investigating the influence of psychedelics on cortico-striatal loops and elucidating specific receptor contributions. This study used LSD to investigate the role of 5-HT2A receptor stimulation by LSD in potentially altering the integration within and between key constituents of CTSC system.

This study capitalizes on recent advances in modeling the endogenous brain activity, which underlies resting-state fMRI data. It measures effective connectivity among brain regions and predicts that LSD induces changes in connectivity that are predominantly dependent on the 5-HT2A receptor.

Results

Subjective drug effects were assessed using the 5-Dimensions Altered States of Consciousness questionnaire (19). Ket blocked all LSD-induced subjective drug effects.

The contrast drug vs. placebo resulted in increased effective connectivity from the thalamus to the VS and the PCC to the VS, as well as decreased inhibitory self-connections from the PCC to the Temp.

5-HT2A Blockade increased effective connectivity from the thalamus to the VS, PCC, and Temp, and decreased self-inhibition of the Temp.

LSD increased effective connectivity from the thalamus to the PCC, decreased excitability in the Temp, increased effective connectivity from the PCC to the VS, and reduced self-inhibition of the PCC.

Discussion

Psychedelics induce an altered state of consciousness that mimics schizophrenia, but may have beneficial therapeutic effects in mood and anxiety disorders. The neurobiology and pharmacology of psychedelics is still poorly understood in humans.

Researchers used DCM to study the effects of LSD on CSTC pathways. They found that LSD increased connectivity from the thalamus to cortical areas and decreased connectivity from the VS to the thalamus.

The CSTC model by Geyer and Vollenweider (3) hypothesizes that psychedelics alter the capacity of the thalamus to control or gate the flow of information to the cortex. The thalamus is also a key part of various neurobiological theories of consciousness.

Here, we show that LSD increased the excitatory connection from the thalamus to the PCC, which is consistent with the CSTC model and with previous findings showing increased thalamo-cortical connectivity after LSD administration.

The precuneus is a core region in the default mode network (DMN), and is associated with arousal, awareness, and the control of the balance between internally and externally directed thought. It is also associated with increased excitability, decreased glutamate + glutamine, creatine, and N-acetylaspartate + N-acetylaspartylglutamate, and decreased -power.

LSD reduces effective connectivity from the ventral striatum to the thalamus, which opens the thalamic filter. LSD also increases effective connectivity from the thalamus to the PCC, but decreases effective connectivity from the thalamus to the temporal lobe.

The present study investigated acute alterations in connectivity between the thalamus and the temporal lobe, which might represent a neurobiological mechanism by which psychedelics potentially exert their antidepressive potential.

LSD causes an increased information flow to certain areas of the cortex while thalamic connectivity with other cortical areas is reduced in resting state. This might explain the seemingly paradoxical subjective effects often reported in psychedelic-induced altered states of consciousness.

The present study showed that the 5-HT2A receptor is involved in the thalamus-PCC connections and that the 5-HT2A receptor antagonist Ket blocked the thalamus-PCC connections, but not the thalamus-VS connections, suggesting that the VS connections were not affected by the 5-HT2A receptor. Previous animal studies suggested that dopamine D2 receptors play a role in the effects of LSD. However, the present study cannot conclusively answer questions regarding the role of other receptor systems beyond the 5-HT2A system in the neurobiological effects of LSD.

A psychophysiological model of psychedelic use proposes that shifts in sensory-to-motor activity and increased entropy in the brain may explain subjective symptoms. A neuroimaging study suggests that psilocybin increases BOLD signal variance and decreases connectivity within the DMN.

This study was limited to brain regions implicated by the CSTC model, and used time-series data over subjects to focus on drug effects. It also did not include a Ket + Pla condition, which suggests that future studies will be needed to characterize the influence of Ket alone on effective connectivity.

The present results confirm major predictions of the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways, enhancing our knowledge about the role of the serotonin system in psychedelic-induced states.

Methods

Participants were recruited through advertisements placed in local universities. They underwent a screening visit before inclusion in the study, and were healthy according to medical history, physical examination, blood analysis, and electrocardiography. Participants were asked to abstain from drug and alcohol use for 2 weeks, from smoking for 60 minutes before the MRI assessment, and from drinking caffeine during the test day.

Twenty-five participants took part in the study. They provided written informed consent statements and received written and oral descriptions of the study procedures and possible risks of LSD and Ket treatment.

In a double-blind, randomized, cross-over design, subjects received either Pla (179 mg Mannitol and Aerosil 1 mg orally), LSD (100 g po), or Ket (40 mg orally) after pretreatment with Pla (179 mg Mannitol and Aerosil 1 mg orally) at three different occasions 2 wk apart.

MRI data were acquired on a Philips Achieva 3.0T whole-body scanner using a 32-channel receive head coil and MultiTransmit parallel radio frequency transmission. High-resolution anatomical images were acquired using a standard T1-weighted 3D magnetization prepared rapid-acquisition gradient echo sequence.

This study aimed at investigating the effect of LSD on the integration within and between key constituents of the CTSC system. Four regions of interest (ROIs) were identified based on previous literature, and time-series were extracted using a 128-s high-pass filter.

Dynamic Causal Modeling (DCM) was conducted using DCM12 (revision 6759) implemented in the SPM12 (revision 12.2). This analysis provides measures of causal interactions between regions, as well as the amplitude of endogenous neuronal fluctuations within each region. We focused on the first (early) session to investigate the effects of drug and the influence of the 5-HT2A blockade by Ket. We reported important effects that had a posterior probability >0.95.

Psychedelic drugs in biomedicine: A systems model of altered consciousness integrating natural and drug-induced psychoses, and altered effective connectivity in drug-free schizophrenic patients.

Psilocybin induces deficits in automatic and controlled inhibition in healthy human volunteers, which are attenuated by ketanserin. The effects of psilocybin on prepulse inhibition of startle depend on interstimulus interval.

LSD induces subjective effects that depend on serotonin 2A receptor activation. The 5-HT2A receptor plays a role in self- and other-initiated social interaction. The thalamus and the cortex are connected by circuits, and the thalamus is the center of conscious experience. The connectivity between the thalamus and the cortex is decreased during nonrapid eye movement sleep. Thalamic functional connectivity is disrupted in anesthesia, dexmedetomidine induces unconsciousness, Huang Z, et al. (2014) altered temporal variance and neural synchronization of spontaneous brain activity in anesthesia, Bolkan SS, et al. (2017) association of thalamic dysconnectivity and conversion to psychosis in youth and young adults. In schizophrenia, thalamocortical circuitry has conserved functional connectivity but impaired effective connectivity, and in obsessive-compulsive disorder, there is abnormal resting-state functional connectivity of the left caudate nucleus. LSD induces increased thalamic resting-state connectivity, which is a core driver of hallucinations. Ayahuasca users exhibit post-acute neurometabolic and functional connectivity changes that are associated with enhanced mindfulness capacities. Psilocybin induces spiritual experiences and insightfulness through synchronization of neuronal oscillations, and ayahuasca induces visual hallucinations through inhibition of alpha oscillations.

Müller N, et al. (2013) and Leech R, Sharp DJ (2014) studied how the posterior cingulate cortex influences music perception. Several studies have shown that the default mode network is organized hierarchically in adolescents and young adults, and that serotonin 2A/1A receptor stimulation influences social exclusion processing, goal-directed behavior, and mood state toward positive relative to negative emotions. Psilocybin and psychological support for treatment-resistant depression: An open-label feasibility study. Lysergic acid diethylamide (LSD) induces paradoxical psychological effects, including increased global functional connectivity, ego dissolution, and increased cerebral blood flow. 63. Sheehan DV, et al. (1998), Fydrich T, Renneberg B, Schmitz B, Wittchen H-U (1997), Studerus E, Gamma, Vollenweider FX (2010), and Preller KH, et al. (2019) published data on effective connectivity changes in LSD-induced altered states of consciousness in humans.