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

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  • Yale University/University of Zurich

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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. 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. 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. 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.
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Effective connectivity changes in LSD-induced altered
states of consciousness in humans
Katrin H. Preller
a,b,1,2
, Adeel Razi
b,c,d,e,1
, Peter Zeidman
b
, Philipp Stämpfli
f,g,h
, Karl J. Friston
b
,
and Franz X. Vollenweider
a
a
Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich,
8006 Zurich, Switzerland;
b
The Wellcome Centre for Human Neuroimaging, University College London, WC1N 3AR London, United Kingdom;
c
Monash
Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, 3168 VIC, Australia;
d
Monash Biomedical Imaging, Monash University,
Clayton, 3168 VIC, Australia;
e
Department of Electronic Engineering, NED University of Engineering and Technology, 75270 Karachi, Pakistan;
f
Department
of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, 8006 Zurich, Switzerland;
g
Medical Research Center of the
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, 8006 Zurich, Switzerland; and
h
Department of
Child and Adolescent Psychiatry, Psychiatric Hospital of the University of Zurich, 8006 Zurich, Switzerland
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 14, 2018 (received for review
September 1, 2018)
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 corticostriatothalamo-cortical
(CSTC) feedback loops. 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 treat-
ment condition to investigate the connectivity between the follow-
ing areas: thalamus, ventral striatum, posterior cingulate cortex, and
temporal cortex. Our results confirm major predictions proposed in
the CSTC model and provide evidence that LSD alters effective con-
nectivity 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. Together, these results advance our mecha-
nistic understanding of the action of psychedelics in health and
disease. This is important for the development of new pharmacolog-
ical therapeutics and also increases our understanding of the mech-
anisms underlying the potential clinical efficacy of psychedelics.
serotonin
|
LSD
|
fMRI
|
effective connectivity
|
spectral dynamic
causal modeling
Classic hallucinogens or psychedelics induce an altered state
of consciousness characterized by alterations in mood, sen-
sory perception, thought, and the sense of self (1). Psychedelics,
therefore, offer the unique opportunity to investigate the neu-
ropharmacological and mechanistic underpinnings of perception,
thought, and consciousness. However, despite renewed scientific
and clinical interest in these substances, there are still major gaps
in our knowledge regarding the effects of psychedelics on the
brain and their pharmacological mechanism of action (2).
Geyer and Vollenweider (3) proposed that key effects of
psychedelics may result from gating deficits, based on the dis-
integration of information processing of internal and external
stimuli within corticostriatothalamo-cortical (CSTC) feedback
loops. This CSTC model suggests that the thalamus (Thal) plays
a key role in controlling or gating information to the cortex and
is thereby critically involved in the regulation of consciousness
(3). Alterations beyond the normal range of thalamic gating of
information are suggested to result in an overload of the cortex,
with excessive exteroceptive and interoceptive stimuli that may
ultimately cause the sensory flooding, cognitive disruptions, and
ego dissolution seen in both naturally occurring psychoses and
drug-induced altered states of consciousness (3, 4). This thalamic-
gating model is supported by results obtained in schizophrenia
patients showing increased functional and effective connectivity
between the thalamus and specific cortical brain regions (5, 6)
and studies showing deficits in preattentive sensorimotor gating
after the administration of psychedelics (79).
Thalamic gating has been suggested to be influenced by sev-
eral neurotransmitter systems. Blockade of NMDA receptors,
increase of dopaminergic neurotransmission, or excessive stim-
ulation of serotonin (5-HT) 2A receptors could lead to a neu-
rotransmitter imbalance within CSTC loops, which results in an
opening of the thalamic filter. The mesostriatal dopaminergic
and serotonergic projections provide input to the striatum and
are thought to be counterbalanced by the glutamatergic input
Significance
Lysergic acid diethylamide (LSD) is a psychedelic drug that re-
liably induces an altered state of consciousness. Interest in
psychedelic compounds is growing due to their remarkable
potential for understanding altered neural states and potential
clinical applications. However, there are major knowledge gaps
regarding LSDs neuropharmacology. Using cutting-edge neu-
roimaging methods we investigated directed connectivity be-
tween corticostriatothalamo-cortical (CSTC) regions after
administration of LSD together with the specific role of the
serotonin 2A receptor. Our results provide evidence that LSD
alters directed connectivity within CSTC pathways in humans,
suggesting that a disintegration of information processing
within these loops is underlying the psychedelic state. These
results inform the neurobiology of altered states of con-
sciousness with critical implications for rational development
of novel treatments.
Author contributions: K.H.P . and F.X.V. designed research ; K.H.P. and P.S. performed
research; K.J.F. contributed new reagents/analytic tools; K.H.P., A.R., and P.Z. analyzed
data; and K.H.P., A.R., P.Z., P.S., K.J.F., and F.X.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This open access article is distributed under Creative Commons Attribution License 4.0
(CC BY).
Data deposition: The extracted time series for each ROI and each condition, as well as all
statistics applied to these data, have been deposited in Bitbucket (https://bitbucket.org/
katrinpreller/effective-connectivity-changes-in-lsd-induced-altered-states).
1
K.H.P. and A.R. contributed equally to this work.
2
To whom correspondence should be addressed. Email: preller@bli.uzh.ch.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1815129116/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1815129116 PNAS Latest Articles
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PHARMACOLOGY
derived from corticostriatal pathways. Alterations in these neu-
rotransmitter systems may result in a diminished influence of the
striatum on the thalamus and open the thalamic filter (3, 4).
However, so far this model and its underlying pharmacology
have never been tested in humans. Pharmacological neuro-
imaging offers the opportunity to address these knowledge gaps
by investigating the influence of psychedelics on CSTC loops and
elucidating specific receptor contributions. Lysergic acid dieth-
ylamide (LSD) is a prototypical psychedelic drug with predom-
inantly agonist activity at 5-HT-2A/C, -1A/B, -6, and -7, and
dopamine D2 and D1 receptors (10). In this study, administra-
tion of LSD with and without pretreatment with the selective
5-HT
2A
receptor antagonist Ketanserin (Ket) offered the unique
opportunity to investigate the role of 5-HT
2A
receptor stimula-
tion by LSD in potentially altering the integration within and
between key constituents of CTSC system: the thalamus, the
ventral striatum (VS), the posterior cingulate cortex (PCC), and
the superior temporal gyrus. The PCC and the temporal cortex
(Temp) are two cortical areas that have repeatedly been iden-
tified to play a major role in psychedelic-induced altered states
of consciousness, in particular in alterations of self-experience
(1114).
Furthermore, the present study capitalizes on recent advances
in modeling the endogenous brain activity, which underlies
resting-state fMRI data. We characterized each subjects dis-
tributed neuronal dynamics using spectral dynamic causal mod-
eling (DCM) (15), which rests on a generative model of how
interacting neural populations cause fMRI time series, which in
turn give rise to functional connectivity measures (i.e., correlated
hemodynamic fluctuations) (Fig. 1). DCM provides estimates of
parameters quantifying the strength of directed connections be-
tween regions. We estimated these parameters at the between-
condition level using a Bayesian model (parametric empirical
Bayes, PEB) (16), enabling us to test for between-session (i.e.,
drug) effects. Compared with functional connectivity approaches,
which provide measures of correlation that cannot be used to
infer causality, spectral DCM quantifies (directed) effective
connectivity among brain regions. This aspect is crucial for
testing the thalamic-gating model, which predicts LSD-induced
increase in connectivity from the thalamus to cortical regions
and decreased connectivity from the VS to the thalamus.
This study, therefore, constitutes an investigation of fMRI
effective resting-state connectivity within the CTSC loops, its
alterations by LSD, and the underlying receptor pharmacology.
We hypothesized LSD-induced changes of effective connectivity
in accordance with the predictions of the thalamic-gating model.
Furthermore, we previously reported that psychedelic effects in
humans could be blocked by 5-HT2A receptor antagonism (17,
18). Therefore, we hypothesized that LSD-induced connectivity
changes are predominantly dependent on the 5-HT2A receptor.
Results
Subjective Drug Effects. Subjective drug effects were assessed us-
ing the 5-Dimensions Altered States of Consciousness (5D-ASC)
questionnaire (19). Detailed results are reported elsewhere (17).
In brief, all LSD-induced subjective drug effects were blocked by
Ket. No significant differences were found between the placebo
(Pla) and the Ket +LSD conditions (SI Appendix, Fig. S1).
Drugs vs. Placebo. The contrast drug vs. placebo [Pla <(LSD +
[Ket +LSD])] resulted in increased effective connectivity from
the thalamus to the VS and the PCC to the VS. Furthermore,
decreases in effective connectivity were found: from the thala-
mus to the Temp, the VS to thalamus, the VS to PCC, and the
VS to Temp. Regarding inhibitory self-connections, which con-
trol the regionsgain or sensitivity to inputs, there was reduced
self-inhibition (i.e., disinhibition) of PCC due to the drug. These
results are shown in Fig. 2A.
5-HT2A Blockade. The contrast Ket +LSD <LSD revealed in-
creased effective connectivity from the thalamus to the VS and
PCC, and from the VS to the Temp. Decreased effective con-
nectivity was found from the PCC to the thalamus. Furthermore,
we found an increase in self-inhibition of the Temp. These re-
sults are shown in Fig. 2B.
An additional advantage of DCM is the possibility to deter-
mine the valence of the connections: that is, define whether they
are excitatory or inhibitory in nature. See Table 1 for the sum-
mary of the signed connectivity parameters and SI Appendix,
Table S1 for parameter estimates (mean and variance).
In sum, our analyses showed that LSD increased effective
connectivity from the thalamus to the PCC, whereas the reciprocal
connection from the PCC to the thalamus had reduced effective
connectivity. Furthermore, we also found decreased excitability
(i.e., increased self-inhibition) in the Temp. These alterations
seem to be driven by 5-HT
2A
receptor stimulation by LSD because
they were blocked by Ket. Furthermore, we found that LSD de-
creased effective connectivity from the VS to the thalamus and the
PCC, from the thalamus to the Temp, increased effective con-
nectivity from the PCC to the VS, and reduced self-inhibition of
the PCC. These LSD-induced changes were not blocked by Ket.
Discussion
Psychedelics induce an altered state of consciousness that, on the
one hand, mimics predominantly positive symptoms of schizo-
phrenia, but on the other hand, may have beneficial therapeutic
effects in mood and anxiety disorders (20). The history of re-
search on psychedelics is also intertwined with the investigation
of the role of the serotonergic system in cognition and behavior
in health and psychiatric disorders (3). However, the neurobi-
ology and pharmacology of psychedelics, in particular LSD, is
still poorly understood in humans. Geyer and Vollenweider (3)
Fig. 1. Four nodes of the DCM. The model includes the following nodes: VS,
Thal, Temp, and PCC. The associated time series were used to invert the
spectral DCM with a fully connected architecture.
Fig. 2. Connectivity changes for (A)Pla<[LSD +(LSD +Ket)] and (B) (LSD +
Ket) <LSD. n=25.
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proposed that key effects of psychedelics may result from the
disintegration of information processing of internal and external
stimuli within CSTC feedback loops. In this work we sought to
mechanistically test this hypothesis by leveraging the recent ad-
vances in modeling endogenous activity using DCM for resting-
state fMRI (15) with the administration of LSD and Ket, a
5-HT
2A
receptor antagonist. Investigating effective (resting-
state) connectivity in LSD-induced states, the present study
closes critical knowledge gaps by showing that LSD alters con-
nectivity within CSTC pathways. In particular, LSD increases
effective connectivity from the thalamus to cortical areas, via
agonistic activity on the 5-HT
2A
receptor, and decreases effec-
tive connectivity from the VS to the thalamus independently of
5-HT
2A
receptor stimulation.
At the core of the CSTC model by Geyer and Vollenweider
(3) is the hypothesis that psychedelics alter the capacity of the
thalamus to control or gate the flow of information to the cortex.
The thalamus is the central part of the diencephalon containing
relay cells that project to the cortex (21). The thalamus also gates
the main input to the cortex from subcortical areas and likely
all regions of the cortex receive input from the thalamus (21). It
also plays a key role in various neurobiological theories of con-
sciousness, suggesting that neural activity in thalamo-cortical
loops gives rise to conscious experience (22, 23). During sleep,
sedation, and anesthesia, thalamo-cortical connectivity is de-
creased, while information transfer from the thalamus to the
cortex is highest during states requiring high levels of sustained
attention (2429). Alterations in thalamo-cortical connectivity
are also crucial features of various psychiatric disorders, pre-
dominantly schizophrenia (6, 3034), and also depression and
obsessive-compulsive disorder (35).
Here, we show that, in line with the CSTC model, LSD in-
creased the excitatory connection from the thalamus to the PCC.
This finding is particularly interesting in light of predictive cod-
ing formulations of the CSTC model, where filtering or gating is
implemented via changes in the precision of ascending pre-
diction errors. Much neurobiological evidence points to the
thalamus as a key source of the requisite neuromodulation (36).
This result is also consistent with a previous study showing in-
creased functional thalamo-cortical connectivity after LSD ad-
ministration (37). Furthermore, LSD increased excitability of the
PCC and reduced effective connectivity from the PCC to the
thalamus. The PCC has repeatedly been shown to be involved in
the effects of psychedelics. For example, decreased functional
connectivity between the PCC and frontal brain areas has been
reported after psilocybin and LSD administration (12, 14), as
well as decreased global brain connectivity after LSD adminis-
tration (38). Furthermore, at a postacute assessment 24 h after
ayahuasca intake, functional connectivity was increased be-
tween the PCC and the anterior cingulate cortex and reductions
in glutamate +glutamine, creatine, and N-acetylaspartate +
N-acetylaspartylglutamate in the PCC were measured (39). Our
study showing increased excitability of the PCC is also in line
with previous results reporting LSD, psilocybin, and ayahuasca-
induced decreases in α-power (13, 4042), as decreases in
α-oscillations have been reported to reflect a state of enhanced
cortical excitability (43). Specifically, reductions in α-power in
the PCC assessed with magnetoencephalography after psilocybin
and LSD administration correlated with self-report question-
naire items indicating psilocybin-induced alterations in self-
processing and ego-integration (13). This is in line with current
theories of the role of the PCC in cognitive functioning, which
associate the PCC with arousal and awareness as well as the
control of the balance between internally and externally directed
thought (44). The interaction of the PCC with other brain net-
works is therefore considered to be important for conscious
awareness and the failure to suppress PCC activity to be asso-
ciated with the intrusion of internal mentation (44). Previous
effective connectivity studies using the spectral DCM have con-
sistently shown the PCC, which is a core region in the default
mode network (DMN), to be a robustly driven hub receiving
information from other core regions of the DMN: that is, the
medial prefrontal cortex and bilateral angular gyrus (4547).
The CSTC model also proposes that the gating capacities of
the thalamus are controlled by the striatum (4). Vollenweider
and Geyer hypothesized that increasing serotonergic activation
by psychedelics reduces the influence of the striatum on the
thalamus, which leads to opening the thalamic filter. The present
data show that LSD indeed reduces effective connectivity from
the VS to the thalamus, therefore corroborating the assumption
that alterations in striatalthalamic interaction are important
mechanisms underlying psychedelic states.
In contrast to LSD-induced increases in effective connectivity
from the thalamus to the PCC, excitatory connectivity from the
thalamus to the Temp was decreased and the inhibitory self-
connection of the Temp was increased by LSD. Previous studies
showed that: (i) decreases in functional connectivity between the
Temp and other cortical regions after LSD and psilocybin ad-
ministration (11, 12), and (ii) alterations in lagged phase syn-
chronization of δ-oscillations after psilocybin administration
(42), both correlating with subjective drug-induced effects. The
temporal lobe is associated with processing emotional and social
Table 1. Summary of results
Connection
Connectivity: =increased,
=decreased
Valence: +=excitatory,
=inhibitory
Effect size (typical effect
size is 0.1 Hz)
Contrast 1: Placebo <[LSD +(Ket +LSD)]
Thal VS +0.088
PCC VS +0.047
Thal Temp +0.275
VS Thal +0.184
VS PCC +0.139
VS Temp 0.325
PCC PCC 0.091
Contrast 2: (Ket +LSD) <LSD
Thal VS +0.143
Thal PCC +0.276
VS Temp 0.169
PCC Thal 0.098
Temp Temp 0.18
n=25.
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information (48), both of which are altered in psychedelic states
(4951) and is implicated in the pathophysiology of schizophre-
nia (52). Because it has been reported that patients suffering
from major depression disorder show increased thalamo-temporal
connectivity (53), attenuating effective connectivity from the
thalamus to the Temp might additionally represent a neurobio-
logical mechanism by which psychedelics potentially exert their
antidepressive potential (54). However, because the present
study investigated acute alterations in connectivity, further studies
are needed to clarify whether these results translate into long-term
therapeutic effects.
The present results therefore show that while the thalamus
indeed decreases information gating and therefore increases
bottom-upinformation flow to certain cortical areas as well as
the VS in accordance with the CSTC model, LSD does not cause
an undifferentiated cortical inundation as first hypothesized in
the model, but rather leads to a pattern of increased information
flow to particular 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 that are
characterized by increased arousal as well as a dreamlike experi-
ence, impaired cognition but at the same time reported perceived
mental clarity, and psychosis-like effects combined with blissful
experiences (55). Therefore, psychedelics states differ from pre-
viously investigated states like anesthesia, sleep, or cognitively
demanding situations (2428).
The design of the present study also involved the pretreatment
of LSD with the 5-HT
2A
receptor antagonist Ket and therefore
allowed for investigation of the role of this specific receptor
system in LSD-induced alterations in effective connectivity.
While we have previously shown that Ket blocked all subjective
and most neural effects of LSD (17, 38), the present analysis
showed particular alterations in the thalamusPCC connections,
dependent on the 5-HT
2A
receptor. This is in line with a previous
study showing that PCC desynchronization under the influence
of psilocybin can be explained by increased excitability of 5-
HT2A receptor-rich deep-layer pyramidal neurons (13). In our
study, Ket blocked increased effective connectivity from the
thalamus to the PCC and reduced connectivity from the PCC to
the thalamus, as well as increased inhibition of the Temp. On the
other hand, mostly connections involving the VS were not
blocked by Ket: decreased effective connectivity from the VS to
the thalamus and the PCC, from the thalamus to the Temp, in-
creased effective connectivity from the PCC to the VS, and re-
duced inhibition of the PCC, suggesting that these LSD-induced
alterations are probably not attributable to LSDs agonistic action
on the 5-HT
2A
receptor. Previous animal studies suggested that, in
addition to, 5-HT2A receptors, dopamine D2 receptors play a role
in the effects of LSD (56, 57). Considering that the effects not
blocked by Ket mostly involve the VS and that the striatum is a key
structure in dopaminergic pathways, the involvement of the do-
pamine system in LSD-induced alterations in brain connectivity
seems likely. However, the present study cannot conclusively an-
swer questions regarding the role of other receptor systems beyond
the 5-HT
2A
system in the neurobiological effects of LSD, and
therefore further studies are warranted to test the specific con-
tributions of other receptors, for example, by pretreatment with
dopamine-antagonists. However, considering that Ket normalized
all subjective effects, it is, on the one hand, possible that alter-
ations induced by LSDs action on other receptors only provoke
noticeable subjective effects when 5-HT
2A
receptors are stimu-
lated concurrently. On the other hand, it is possible that higher
doses of LSD are needed to produce noticeable subjective effects
even when the 5-HT
2A
receptor is blocked. Future studies could
therefore test the effects of multiple (and higher) doses of LSD.
Beyond the CSTC model, several authors have proposed ad-
ditional theories to explain the biological underpinnings of
alterations in consciousness experienced following the adminis-
tration of psychedelics. An early psychophysiological model by
Fischer proposed that shifts in the ratio of sensory-to-motor
activity could explain subjective symptoms (58). More recent
evidence from human studies suggests that psychedelic-induced
alterations in consciousness are related to increased entropy in
the brain, leading to disorganization of brain activity and more
flexible cognition (entropic brain hypothesis) (59). This model
has been corroborated with studies showing that psilocybin
produces an increase in blood-oxygen level-dependent (BOLD)
signal variance and decreased connectivity within the DMN (60,
61). These models are not mutually exclusive, and focus on
complementary correlates of altered states of consciousness.
While this is beyond the scope of the present study, a unifying
framework should be developed and tested in future studies.
This study was limited to brain regions implicated by the
CSTC model, which have been shown empirically to be sensitive
to the effects of psychedelics in previous studies, as well as within
the current participants (3, 4, 1114, 17, 62). Clearly, testing
additional models in future studies has the potential to extend
our knowledge about the effects of LSD on effective connectivity
among more distributed brain regions, in particular, additional
hubs of the CSTC model such as the medial prefrontal cortex.
Furthermore, future analyses using smaller regions-of-interest
(ROIs) could reveal differential effects of subregions of the
current ROIs. Additionally, to focus on drug effects using effi-
cient estimates of the cross-spectral density (CSD), we concat-
enated time-series data over subjects. This precluded analysis
between subject effects; for example, we were unable to relate
connectivity parameters to subjective effects. We will address
this limitation in the future using (hierarchical) PEB. Although a
previous study has shown that Ket does not induce an altered
state of consciousness or affect sensorimotor gating (8), the lack
of a Ket +Pla condition represents a further limitation of this
study. This suggests that future studies will be needed to char-
acterize the influence of Ket alone on effective connectivity.
In sum, the present results confirm major predictions pro-
posed 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: LSD diminishes the influence of the striatum on
the thalamus and opens the thalamic filter, but selectively: only
to certain areas of the cortex. In particular, the present results
pinpoint the role of the thalamusPCC connection for the effects
of psychedelics. Additionally, the present results enhance our
knowledge about the contribution of the serotonin system to the
functional organization of the brain in LSD-induced states. Fi-
nally, the present study showcases the newly developed spectral
DCM approachcoupled with modeling using the PEB frame-
workto testing hypotheses in resting-state pharmacological
fMRI at the group level. Taken together, the results deepen our
knowledge about the mechanism of action of psychedelics rele-
vant for health and disease and important for the development
of new pharmacological therapeutics.
Methods
Participants. The data analyzed in this paper were collected as part of a larger
study, which is reported in refs. 17 and 38. The present characterization of
these data extends the analysis presented in Preller et al. (38). Participants
were recruited through advertisements placed in local universities. All par-
ticipants underwent a screening visit before inclusion in the study. All included
participants were healthy according to medical history, physical examination,
blood analysis, and electrocardiography. The Mini-International Neuropsy-
chiatric Interview (MINI-SCID) (63), the Diagnostic and Statistical Manual of
Mental Disorders, fourth edition self-rating questionnaire for Axis-II per-
sonality disorders (SCID-II) (64), and the Hopkins Symptom Checklist (SCL-90-R)
(65) were used to exclude subjects with present or previous psychiatric dis-
orders or a history of major psychiatric disorders in first-degree relatives.
Participants were asked to abstain from the use of any prescription or illicit
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drugs for a minimum of 2 wk before the first test day and for the duration of
the entire study, and to abstain from drinking alcohol for at least 24 h be-
fore test days. Urine tests and self-report questionnaires were used to verify
the absence of drug and alcohol use. Participants were required to abstain
from smoking for at least 60 min before MRI assessment and from drinking
caffeine during the test day. Urine tests were also used to exclude preg-
nancy. Further exclusion criteria included left-handedness, poor knowledge
of the German language, cardiovascular disease, history of head injury or
neurological disorder, history of alcohol or illicit drug dependence, MRI
exclusion criteria, including claustrophobia, and previous significant adverse
reactions to a hallucinogenic drug.
Twenty-five participants took part in the study (n=19 males and 6
females; mean age =25.24 y; SD =3.72 y; range =2034 y). All participants
provided written informed consent statements in accordance with the
declaration of Helsinki before participation in the study. Subjects received
written and oral descriptions of the study procedures, as well as details
regarding the effects and possible risks of LSD and Ket treatment. The
Swiss Federal Office of Public Health, Bern, Switzerland, authorized the
use of LSD in humans, and the study was approved by the Cantonal Ethics
Committee of Zurich. The study was registered at ClinicalTrials.gov
(NCT02451072).
Study Design. In a double-blind, randomized, cross-over design, subjects re-
ceived either: (i)Pla+Pla condition: Pla (179 mg Mannitol and Aerosil 1 mg
orally) after pretreatment with Pla (179 mg Mannitol and Aerosil 1 mg
orally); (ii)Pla+LSD condition: LSD (100 μg orally) after pretreatment with
Pla (179 mg Mannitol and Aerosil 1 mg orally); or (iii ) Ket +LSD (Ket +LSD)
condition: LSD (100 μg po) after pretreatment with the 5-HT2A antagonist
Ket (40 mg orally) at three different occasions 2 wk apart. Pretreatment with
Pla or Ket occurred 60 min before treatment with Pla or LSD to allow for Ket
to reach peak plasma levels (66). The resting-state scans (10 min) were ac-
quired twice: 75 min (session 1) and 300 min (session 2) after treatment
administration. The 5D-ASC (a retrospective self-report questionnaire) (19)
was administered to participants 720 min after drug treatment to assess
subjective experience after drug intake. Ninety-four items are answered on
visual analog scales. Scores were calculated for 11 validated scales (67): ex-
perience of unity, spiritual experience, blissful state, insightfulness, disembodi-
ment, impaired control and cognition, anxiety, complex imagery, elementary
imagery, audiovisual synesthesia, and changed meaning of percepts. The 5D-ASC
score was analyzed using a repeated-measures ANOVA with drug condition
(Pla, LSD, and Ket +LSD) and scale as within-subject factors.
MRI Data Acquisition and Preprocessing. MRI data were acquired on a Philips
Achieva 3.0T whole-body scanner. A 32-channel receive head coil and
MultiTransmit parallel radio frequency transmission was used. Images were
acquired using a whole-brain gradient-echo planar imaging (EPI) sequence
(repetition time, 2,500 ms; echo time, 27 ms; slice thickness, 3 mm; 45 axial
slices; no slice gap; field of view, 240 ×240 mm
2
;in-planeresolution,3×3mm;
sensitivity-encoding reduction factor, 2.0). Additionally, high-resolution an-
atomical images (voxel size, 0.7 ×0.7 ×0.7 mm) were acquired using a
standard T1-weighted 3D magnetization prepared rapid-acquisition gradi-
ent echo sequence. The acquired images were analyzed using SPM12
(https://www.fil.ion.ucl.ac.uk). The preprocessing steps of the images con-
sisted of slice time correction, realignment, spatial normalization to the
standard EPI template of the Montreal Neurological Institute (MNI), and
spatial smoothing using a Gaussian kernel of 6-mm full-width half-
maximum. We investigated for any excessive head motion but head move-
ment did not exceed 3 mm in any participant.
ROI Selection and Time-Series Extraction. This study aims at investigating the
effect of LSD on the integration within and between key constituents of CTSC
system. For this purpose, ROIs were identified as key nodes for effective
connectivity analysis, based on previous literature that considered: (i)the
thalamic gating model (3, 4); (ii) psychedelic-induced modulations of brain
activity and functional connectivity (1114, 62) in independent participant
cohorts; and (iii) LSD-induced alterations in BOLD signal in the current co-
hort of participants, using (independent) task-based data (17, 18). The CTSC
loop was comprised of the thalamus, the VS, the PCC, and the temporal
gyrus. ROIs were masked by an 8-mm radius sphere centered on previously
reported MNI coordinates of these regions. These MIN coordinates were
derived from LSD-induced alterations in BOLD signal, in the same cohort of
participants, using task-based data (17, 18): thalamus: x=15, y=8, z=1;
VS: x=9, y=8, z=8; PCC: x=3, y=46, z=31; Temp: x=56, y=54,
z=8. These ROIs are shown in Fig. 1. Time series from the four ROIs were
corrected for head motion and physiological noise. For this purpose, the
nuisance regressors included the six head-motion parameters, cerebrospinal
fluid (extracted from left ventricle using a 4-mm sphere), and white matter
(extracted from pons using a 4-mm sphere) regressors. Low-frequency signal
drifts were filtered using a 128-s high-pass filter.
Dynamic Causal Modeling. The spectral DCM analyses were conducted using
DCM12 (revision 6759) implemented in the SPM12 (revision 12.2). In brief, we
concatenated the time series over subjects for each region, drug condition,
and session. This enabled us to focus on the difference between drug con-
ditions using more efficient estimates of the CSD. However, this precluded
analysis of between-subject effects, such as subjective effects. These estimates
were then taken to the between-condition level and modeled with two
orthogonal contrasts of condition-specific effects; namely, Pla vs. drug con-
ditions with and without Ket. This was repeated for both (early and late)
sessions. In detail, for each drug condition and session, a fully connected
model was created to compare all possible nested models of between- and
within-region interactions (16). DCM was estimated using spectral DCM,
which fits the complex cross-spectral density using a (parameterized) power-
law model of endogenous neuronal fluctuations (15, 47). For more details,
see the SI Appendix. This analysis provides measures of causal interactions
between regions, as well as the amplitude of endogenous neuronal fluctu-
ations within each region (47). Because the main effect of drug did not differ
between sessions, we focus on the first (early) session. To investigate the (i)
effect of drug and (ii) influence of the 5-HT
2A
blockade by Ket, the following
two orthogonal contrasts of effects (at the between-subject level) were
modeled: Pla <[LSD +(Ket +LSD)] and (Ket +LSD) <LSD. To report im-
portant effects, we used model comparisons (using free energy) with and
without each effect and then calculated the posterior probability for each
model, which is simply a softmax function of the log Bayes factor. We only
report effects (i.e., changes in directed connectivity) that have a posterior
probability >0.95 (SI Appendix, Table S1).
Data Availability. The extracted time series for each ROI and each condition, as
well as all statistics applied to these data, have been deposited in Bitbucket (68).
ACKNOWLEDGMENTS. We thank Dr. A. Anticevic (Yale University) and
Dr. G. Repovs (University of Ljubljana) for providing the fMRI sequence.
This research was financially supported by Swiss National Science Foun-
dation Grant 1270 P2ZHP1_161626, (to K.H.P.), Swiss Neuromatrix Foun-
dation Grant 2015-0103 (to F.X.V.), and Usona Institute Grant 2015-2056
(to F.X.V.). A.R. is funded by the Australian Research Council Discovery
Early Career Research Award Fellowship (DE170100128) and the Wellcome
Trust. K.J.F. is funded by a Wellcome Trust Principal Research Fellowship
(088130/Z/09/Z).
1. Preller KH, Vollenweider FX (2016) Phenomenology, structure, and dynamic of
psychedelic states. Curr Top Behav Neurosci 36:221256, and erratum (2018)
36:1.
2. Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff AV (2017) Psychedelic drugs
in biomedicine. Trends Pharmacol Sci 38:9921005.
3. Geyer MA, Vollenweider FX (2008) Serotonin research: Contributions to under-
standing psychoses. Trends Pharmacol Sci 29:445453.
4. Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: In-
tegrating natural and drug-induced psychoses. Brain Res Bull 56:495507.
5. Schlösser R, Gesierich T, Kaufmann B, Vucurevic G, Stoeter P (2003) Altered effective
connectivity in drug free schizophrenic patients. Neuroreport 14:22332237.
6. Anticevic A, et al. (2014) Characterizing thalamo-cortical disturbances in schizophre-
nia and bipolar illness. Cereb Cortex 24:31163130.
7. Schmid Y, et al. (2015) Acute effects of lysergic acid diethylamide in healthy subjects.
Biol Psychiatry 78:544553.
8. Quednow BB, Kometer M, Geyer MA, Vollenweider FX (2012) Psilocybin-induced
deficits in automatic and controlled inhibition are attenuated by ketanserin in
healthy human volunteers. Neuropsychopharmacology 37:630640.
9. Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB (2007) The effects of
the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy
human volunteers depend on interstimulus interval. Neuropsychopharmacology 32:
18761887.
10. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131181.
11. Lebedev AV, et al. (2015) Finding the self by losing the self: Neural correlates of ego-
dissolution under psilocybin. Hum Brain Mapp 36:31373153.
12. Carhart-Harris RL, et al. (2016) Neural correlates of the LSD experience revealed by
multimodal neuroimaging. Proc Natl Acad Sci USA 113:48534858.
13. Muthukumaraswamy SD, et al. (2013) Broadband cortical desynchronization underlies
the human psychedelic state. J Neurosci 33:1517115183.
14. Carhart-Harris RL, et al. (2012) Neural correlates of the psychedelic state as de-
termined by fMRI studies with psilocybin. Proc Natl Acad Sci USA 109:21382143.
Preller et al. PNAS Latest Articles
|
5of6
PHARMACOLOGY
15. Friston KJ, Kahan J, Biswal B, Razi A (2014) A DCM for resting state fMRI. Neuroimage
94:396407.
16. Friston KJ, et al. (2016) Bayesian model reduction and empirical Bayes for group
(DCM) studies. Neuroimage 128:413431.
17. Preller KH, et al. (2017) The fabric of meaning and subjective effects in LSD-induced
states depend on serotonin 2A receptor activation. Curr Biol 27:451457.
18. Preller KH, et al. (2018) Role of the 5-HT
2A
receptor in self- and other-initiated social
interaction in lysergic acid diethylamide-induced states: A pharmacological fMRI
study. J Neurosci 38:36033611.
19. Dittrich A, Lamparter D, Maurer M (2006) 5D-ABZ: Fragebogen zur Erfassung Aus-
sergewöhnlicher Bewusstseinszustände. Eine kurze Einführung.[5D-ASC: Question-
naire for the Assessment of Altered States of Consciousness. A Short Introduction].
(PSIN Plus Publications, Zurich). German.
20. Vollenweider FX, Kometer M (2010) The neurobiology of psychedelic drugs: Impli-
cations for the treatment of mood disorders. Nat Rev Neurosci 11:642651.
21. Sherman SM (2017) Functioning of circuits connecting thalamus and cortex. Compr
Physiol 7:713739.
22. Tononi G, Edelman GM (1998) Consciousness and complexity. Science 282:18461851.
23. Ward LM (2011) The thalamic dynamic core theory of conscious experience. Conscious
Cogn 20:464486.
24. Picchioni D, et al. (2014) Decreased connectivity between the thalamus and the
neocortex during human nonrapid eye movement sleep. Sleep (Basel) 37:387397.
25. White NS, Alkire MT (2003) Impaired thalamocortical connectivity in humans during
general-anesthetic-induced unconsciousness. Neuroimage 19:402411.
26. Liu X, Lauer KK, Ward BD, Li SJ, Hudetz AG (2013) Differential effects of deep se-
dation with propofol on the specific and nonspecific thalamocortical systems: A
functional magnetic resonance imaging study. Anesthesiology 118:5969.
27. Akeju O, et al. (2014) Disruption of thalamic functional connectivity is a neural cor-
relate of dexmedetomidine-induced unconsciousness. eLife 3:e04499.
28. Huang Z, et al. (2014) Altered temporal variance and neural synchronization of
spontaneous brain activity in anesthesia. Hum Brain Mapp 35:53685378.
29. Bolkan SS, et al. (2017) Thalamic projections sustain prefrontal activity during work-
ing memory maintenance. Nat Neurosci 20:987996.
30. Anticevic A, et al. (2015) Association of thalamic dysconnectivity and conversion to
psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72:
882891.
31. Ramsay IS, Nienow TM, MacDonald AW, 3rd (2017) Increases in intrinsic thalamo-
cortical connectivity and overall cognition following cognitive remediation in chronic
schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging 2:355362.
32. Guller Y, Tononi G, Postle BR (2012) Conserved functional connectivity but impaired
effective connectivity of thalamocortical circuitry in schizophrenia. Brain Connect 2:
311319.
33. Woodward ND, Heckers S (2016) Mapping thalamocortical functional connectivity in
chronic and early stages of psychotic disorders. Biol Psychiatry 79:10161025.
34. Anticevic A (2017) Understanding the role of thalamic circuits in schizophrenia neu-
ropathology. Schizophr Res 180:13.
35. Chen Y, et al. (2016) Abnormal resting-state functional connectivity of the left cau-
date nucleus in obsessive-compulsive disorder. Neurosci Lett 623:5762.
36. Kanai R, Komura Y, Shipp S, Friston K (2015) Cerebral hierarchies: Predictive pro-
cessing, precision and the pulvinar. Philos Trans R Soc Lond B Biol Sci 370:20140169.
37. Müller F, et al. (2017) Increased thalamic resting-state connectivity as a core driver of
LSD-induced hallucinations. Acta Psychiatr Scand 136:648657.
38. Preller KH, et al. (2018) Changes in global and thalamic brain connectivity in LSD-
induced altered states of consciousness are attributable to the 5-HT2A receptor. eLife
7:e35082.
39. Sampedro F, et al. (2017) Assessing the psychedelic after-glowin ayahuasca users:
Post-acute neurometabolic and functional connectivity changes are associated with
enhanced mindfulness capacities. Int J Neuropsychopharmacol 20:698711.
40. Kometer M, Schmidt A, Jäncke L, Vollenweider FX (2013) Activation of serotonin 2A
receptors underlies the psilocybin-induced effects on αoscillations, N170 visual-
evoked potentials, and visual hallucinations. J Neurosci 33:1054410551.
41. Valle M, et al. (2016) Inhibition of alpha oscillations through serotonin-2A receptor ac-
tivationunderlies the visualeffects of ayahuascain humans. Eur Neuropsychopharmacol
26:11611175.
42. Kometer M, Pokorny T, Seifritz E, Volleinweider FX (2015) Psilocybin-induced spiritual
experiences and insightfulness are associated with synchronization of neuronal os-
cillations. Psychopharmacology (Berl) 232:36633676.
43. Müller N, et al. (2013) You cant stop the music: Reduced auditory alpha power and
coupling between auditory and memory regions facilitate the illusory perception of
music during noise. Neuroimage 79:383393.
44. Leech R, Sharp DJ (2014) The role of the posterior cingulate cortex in cognition and
disease. Brain 137:1232.
45. Sharaev MG, Zavyalova VV, Ushakov VL, Kartashov SI, Velichkovsky BM (2016) Ef-
fective connectivity within the default mode network: Dynamic causal modeling of
resting-state fMRI data. Front Hum Neurosci 10:14.
46. Zhou Y, et al. (2018) The hierarchical organization of the default, dorsal attention
and salience networks in adolescents and young adults. Cereb Cortex 28:726737.
47. Razi A, Kahan J, Rees G, Friston KJ (2015) Construct validation of a DCM for resting
state fMRI. Neuroimage 106:114.
48. Carter RM, Huettel SA (2013) A nexus model of the temporal-parietal junction. Trends
Cogn Sci 17:328336.
49. Preller KH, et al. (2016) Effects of serotonin 2A/1A receptor stimulation on social
exclusion processing. Proc Natl Acad Sci USA 113:51195124.
50. Kometer M, et al. (2012) Psilocybin biases facial recognition, goal-directed behavior,
and mood state toward positive relative to negative emotions through different
serotonergic subreceptors. Biol Psychiatry 72:898906.
51. Pokorny T, Preller KH, Kometer M, Dziobek I, Vollenweider FX (2017) Effect of psi-
locybin on empathy and moral decision-making. Int J Neuropsychopharmacol 20:
747757.
52. Mwansisya TE, et al. (2017) Task and resting-state fMRI studies in first-episode
schizophrenia: A systematic review. Schizophr Res 189:918.
53. Brown EC, Clark DL, Hassel S, MacQueen G, Ramasubbu R (2017) Thalamocortical
connectivity in major depressive disorder. J Affect Disord 217:125131.
54. Carhart-Harris RL, et al. (2016) Psilocybin with psychological support for treatment-
resistant depression: An open-label feasibility study. Lancet Psychiatry 3:619627.
55. Carhart-Harris RL, et al. (2016) The paradoxical psychological effects of lysergic acid
diethylamide (LSD). Psychol Med 46:13791390.
56. Marona-Lewicka D, Thisted RA, Nichols DE (2005) Distinct temporal phases in the
behavioral pharmacology of LSD: Dopamine D2 receptor-mediated effects in the rat
and implications for psychosis. Psychopharmacology (Berl) 180:427435.
57. Marona-Lewicka D, Nichols DE (2007) Further evidence that the delayed temporal
dopaminergic effects of LSD are mediated by a mechanism different than the first
temporal phase of action. Pharmacol Biochem Behav 87:453461.
58. Fischer R (1971) A cartography of the ecstatic and meditative states. Science 174:
897904.
59. Carhart-Harris RL, et al. (2014) The entropic brain: A theory of conscious states in-
formed by neuroimaging research with psychedelic drugs. Front Hum Neurosci 8:20.
60. Tagliazucchi E, et al. (2016) Increased global functional connectivity correlates with
LSD-induced ego dissolution. Curr Biol 26:10431050.
61. Tagliazucchi E, Carhart-Harris R, Leech R, Nutt D, Chialvo DR (2014) Enhanced rep-
ertoire of brain dynamical states during the psychedelic experience. Hum Brain Mapp
35:54425456.
62. Lewis CR, et al. (2017) Two dose investigation of the 5-HT-agonist psilocybin on rel-
ative and global cerebral blood flow. Neuroimage 159:7078.
63. Sheehan DV, et al. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.):
The development and validation of a structured diagnostic psychiatric interview for
DSM-IV and ICD-10. J Clin Psychiatry 59:2233, quiz 3457.
64. Fydrich T, Renneberg B, Schmitz B, Wittchen H-U (1997) SKID-II Strukturiertes Kli-
nisches Interview für DSM-IV, Achse II: Persönlichkeitsstörungen [SCID-II Structured
Cinical Interview for DSM-IV, Axis II: Personality Disorders]. (Hogrefe, Goettingen,
Germany). German.
65. Franke G (1995) Die Symptom-Check-Liste von DerogatisDeutsche Version (Beltz Test
Gesellschaft, Göttingen, Germany).
66. Persson B, Pettersson A, Hedner T (1987) Pharmacokinetics of ketanserin in patients
with essential hypertension. Eur J Clin Pharmacol 32:259265.
67. Studerus E, Gamma A, Vollenweider FX (2010) Psychometric evaluation of the altered
states of consciousness rating scale (OAV). PLoS One 5:e12412.
68. Preller KH, et al. (2019) data from Effective connectivity changes in LSD-induced
altered states of consciousness in humans.Bitbucket. Available at https://bitbucket.
org/katrinpreller/effective-connectivity-changes-in-lsd-induced-altered-states. Deposited
January 9 , 2019.
6of6
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www.pnas.org/cgi/doi/10.1073/pnas.1815129116 Preller et al.
... Ego dissolution, or the shift in sense of self and dissolution of boundary between the self and world (Lebedev et al., 2015;Millière, 2017), has been validated as a measurable construct on the Ego Dissolution Inventory 1 (Nour et al., 2016), with evidence suggesting that therapeutic outcomes are tied to its occurrence 2 Majic et al., 2015;Carhart-Harris and Goodwin, 2017;Roseman et al., 2018;Yaden and Griffiths, 2020). Ego dissolution and all subjective effects from classic psychedelics originate from the binding kinetics of the 5-HT2A receptor to psychedelic compounds (Quednow et al., 2012;Preller et al., 2019) with other 5-HT receptors and is suggested to mediate psychedelic experiences (Vollenweider and Preller, 2020). The 5-HT2A is a serotonergic receptor involved in attention, especially in the prediction of the cause of sensory impressions and the consequences of selfinitiated actions (Picard and Friston, 2014). ...
... Research applying dynamic causal modeling, which estimates effective connectivity between brain regions, suggest freer interactions may relate to reduced thalamic filtration of neural signals to the cortex under LSD. Recent research demonstrated increased effective connectivity from the thalamus to the posterior cingulate cortex under LSD (Preller et al., 2019) which may indicate the selection processes of attention that constrain the contents reaching consciousness become disinhibited by psychedelics (Carhart-Harris and Preller et al., 2019). Functional MRI observations of freer interactions are also identified in the medial temporal lobe and are associated to heightened responses to sensory stimuli under psychedelics (Carhart-Harris et al., 2014a,b;Kaelen et al., 2016;Carhart-Harris, 2018). ...
... Research applying dynamic causal modeling, which estimates effective connectivity between brain regions, suggest freer interactions may relate to reduced thalamic filtration of neural signals to the cortex under LSD. Recent research demonstrated increased effective connectivity from the thalamus to the posterior cingulate cortex under LSD (Preller et al., 2019) which may indicate the selection processes of attention that constrain the contents reaching consciousness become disinhibited by psychedelics (Carhart-Harris and Preller et al., 2019). Functional MRI observations of freer interactions are also identified in the medial temporal lobe and are associated to heightened responses to sensory stimuli under psychedelics (Carhart-Harris et al., 2014a,b;Kaelen et al., 2016;Carhart-Harris, 2018). ...
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... Removing analyses that did not include resting-state fMRI resulted in a total of 34 publications: (Atasoy et al., 2017;Barrett, Doss, et al., 2020a;Barrett, Krimmel, et al., 2020;Bershad et al., 2020;, 2016Carhart-Harris et al., 2013Deco et al., 2018;Jobst et al., 2021;Kaelen et al., 2016;Kringelbach et al., 2020;Lebedev et al., 2015Lebedev et al., , 2016Lord et al., 2019; J o u r n a l P r e -p r o o f Luppi et al., 2021;Mason et al., 2020;McCulloch et al., 2021;Müller et al., 2017Müller et al., , 2018Palhano-Fontes et al., 2015;Pasquini et al., 2020;Preller et al., 2018aPreller et al., , 2019Preller et al., , 2020Roseman et al., 2016;Sampedro et al., 2017;Smigielski et al., 2019;Speth et al., 2016;Tagliazucchi et al., 2014Tagliazucchi et al., , 2016Varley et al., 2020;Viol et al., 2017). Four additional papers did not appear in our search but were identified as relevant and added Mason et al., 2021;Petri et al., 2014;Roseman et al., 2014). ...
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... The burgeoning interest in characterising brain mechanisms underlying psychedelic effects has facilitated the application of novel neurocomputational models to these unique datasets. Ten studies focus on examples of these neurocomputational frameworks, including: dynamic causal modelling (Preller et al., 2019), temporal variability , homological scaffolds (Petri et al., 2014), gradient-based connectivity (Girn et al., 2021), retinotopic coordination (Roseman et al., J o u r n a l P r e -p r o o f 2016), whole-brain functional connectivity dynamics (Deco et al., 2018;Kringelbach et al., 2020), connectome-harmonic decomposition (Atasoy et al., 2017;Luppi et al., 2021), and leading eigenvector dynamic analysis (Lord et al., 2019). It is a benefit to the field of psychedelic imaging and functional brain imaging analysis as a whole to apply these models. ...
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Rationale LSD is the prototypical psychedelic. Despite a clear central role of the 5HT2a receptor in its mechanism of action, the contributions of additional receptors for which it shows affinity and agonist activity remain unclear. Objectives We employed receptor-enriched analysis of functional connectivity by targets (REACT) to explore differences in functional connectivity (FC) associated with the distributions of the primary targets of LSD—the 5HT1a, 5HT1b, 5HT2a, D1 and D2 receptors. Methods We performed secondary analyses of an openly available dataset (N = 15) to estimate the LSD-induced alterations in receptor-enriched FC maps associated with these systems. Principal component analysis (PCA) was employed as a dimension reduction strategy for subjective experiences associated with LSD captured by the Altered States of Consciousness (ASC) questionnaire. Correlations between these principal components as well as VAS ratings of subjective effects with receptor-enriched FC were explored. Results Compared to placebo, LSD produced differences in FC when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. Altered receptor-enriched FC showed relationships with the subjective effects of LSD on conscious experience, with serotonergic and dopaminergic systems being predominantly associated with perceptual effects and perceived selfhood as well as cognition respectively. These relationships were dissociable, with different receptors showing the same relationships within, but not between, the serotonergic and dopaminergic systems. Conclusions These exploratory findings provide new insights into the pharmacology of LSD and highlight the need for additional investigation of non-5HT2a-mediated mechanisms.
... Within the Active Inference Framework (AIF), the most well-known (non-mutually exclusive) models of psychedelic action are the "thalamic gating" and "RElaxed Beliefs Under pSychedelics" (REBUS) models (Carhart-Harris and Preller et al., 2019). With thalamic gating, psychedelics have the effects of reducing top-down filtering of sense data and altering normal modes of synchronous binding, so allowing new patterns to make their way through the "doors of perception" with creative combinations. ...
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Across times and cultures, humans constantly and intentionally tried to 'lose' or to 'escape' their familiar, ordinary self, to 'self-detach' and to radically change the ways of perceiving oneself and the world. In this paper we explore the contrast between the feeling of 'losing' the sense of familiarity with one's self and body in Depersonalisation experiences (DP) and psychedelics (with some consideration of meditative experiences). We explore these radical changes in self-experiences through the lens of Active Inference Framework (AIF). AIF is a process theory aiming to capture the capacity of biological organisms (e.g. living human bodies) to survive and thrive in volatile and uncertain environments. In line with previous work on depersonalisation and psychedelic mechanisms, we suggest that such experiences can involve a stance with radically altered prior expectations, so providing opportunities for flexibly modulating self-and world models. Specifically, we suggest that controlled acquisition of new self-and world models may enhance the plasticity of one's perceptual and sensorimotor experiences. This new gained flexibility, we claim, may allow the individual to 'leave behind' certain habits, perceptual rigidities that holds him/her 'stuck' in certain behavioural patterns. And to open to new ways of perceiving and integrating self-and world-related information. By contrast, depersonalisation experiences point to a uncontrolled phenomenon of non-flexible (rigid) (dis)integration of ordinary/habitual self-models, and a consequent feeling of being 'stuck' in one's mind. While controlled (dis)integration of habitual self-experiences and consequent reintegration may have positive effect, uncontrolled (dis)integration of habitual self-experiences triggered by unpredictable life events may be overwhelming and lead to self-detachment and potentially adverse clinical outcomes. Contrasting these two modes of alteration will allow us to outline the importance of the controlled ability to flexibly integrate, disintegrate and reintegrate multisensory bodily signals, and its impact on the human sense of self and agency. 2
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When we talk about consciousness, it can be a funny thing. It provides us to live a strange experience, like when entering sleep or getting up in the morning, and sometimes it leaves us wondering who is really in control. The altered states of consciousness are a critical topic because it interferes with the individual’s psychological status.
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Background Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity (iFC) as measured by resting-state functional magnetic resonance imaging (rs-fMRI). Specifically, thalamic iFC is increased with sensorimotor cortices (hyperconnectivity) and decreased with prefrontal-limbic cortices (hypoconnectivity). Intriguingly, psychedelics such as lysergic acid diethylamide (LSD) elicit similar thalamocortical-hyperconnectivity with sensorimotor areas in healthy volunteers. It is unclear whether LSD also induces thalamocortical-hypoconnectivity with prefrontal-limbic cortices as current findings are equivocal. Notably, thalamocortical-hyperconnectivity was associated with psychotic symptoms in patients and substance-induced altered states of consciousness in healthy volunteers. Thalamocortical dysconnectivity is likely evoked by altered neurotransmission, e.g., via dopaminergic excess in psychotic disorders and serotonergic agonism in psychedelic-induced states. It is unclear whether thalamocortical dysconnectivity is also elicited by amphetamine-type substances, broadly releasing monoamines (i.e., dopamine, norepinephrine) but producing fewer perceptual effects than psychedelics. Methods We administrated LSD, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers and investigated their effects on thalamic iFC with two brain networks (auditory-sensorimotor (ASM) and salience (SAL) – corresponding to sensorimotor and prefrontal-limbic cortices, respectively), using a double-blind, placebo-controlled, cross-over design. Results All active substances elicited ASM-thalamic-hyperconnectivity compared to placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD-induced effects correlated with subjective changes in perception, indicating a link between hyperconnectivity and psychedelic-type perceptual alterations. Unlike d-amphetamine and MDMA, which induced hypoconnectivity with SAL, LSD elicited hyperconnectivity. D-amphetamine and MDMA evoked similar thalamocortical dysconnectivity patterns. Conclusions Psychedelics, empathogens, and psychostimulants evoke thalamocortical-hyperconnectivity with sensorimotor areas, akin to findings in patients with psychotic disorders.
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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.
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Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 μg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 μg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HTR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HTR stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HTR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders. Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the "social brain". Furthermore, these alterations are attributable to 5-HT receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.
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Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100μg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 μg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSDinduced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the “social brain” can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.
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Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
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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. For all neuroimaging analyses we controlled for sex and age and used family-wise error corrected p values. 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 hippocampus. 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.
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Background: Impaired empathic abilities lead to severe negative social consequences and influence the development and treatment of several psychiatric disorders. Furthermore, empathy has been shown to play a crucial role in moral and prosocial behaviour. Although the serotonin (5-HT) system has been implicated in modulating empathy and moral behaviour, the relative contribution of the various 5-HT receptor subtypes is still unknown. Methods: We investigated the acute effect of psilocybin (0.215mg/kg p.o.) in healthy human subjects on different facets of empathy and hypothetical moral decision-making using the Multifaceted Empathy Test (MET) (n=32) and the Moral Dilemma Task (MDT) (n=24). Results: Psilocybin significantly increased emotional, but not cognitive empathy compared to placebo, and the increase in implicit emotional empathy was significantly associated with psilocybin-induced changed meaning of percepts. In contrast, moral decision-making remained unaffected by psilocybin. Conclusions: These findings provide first evidence that psilocybin has distinct effects on social cognition by enhancing emotional empathy but not moral behaviour. Furthermore, together with previous findings psilocybin appears to promote emotional empathy presumably via activation of 5-HT2A/1A receptors suggesting that targeting 5-HT2A/1A receptors has implications for potential treatment of dysfunctional social cognition.
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The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC), and decreased MD-PFC connectivity is observed in schizophrenia patients. Patients also display cognitive deficits including impairments in working memory, but a mechanistic link between thalamo-prefrontal circuit function and working memory is missing. Using pathway-specific inhibition, we found directional interactions between mouse MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially tuned neurons, and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea, we found that enhancing MD excitability was sufficient to enhance task performance.