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Effects of LSD and music on brain activity



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LSD modulates music-induced imagery via
changes in parahippocampal connectivity
Mendel Kaelen
, Leor Roseman
, Joshua Kahan
Andre Santos-Ribeiro
, Csaba Orban
, Romy Lorenz
Frederick S. Barrett
, Mark Bolstridge
, Tim Williams
Luke Williams
, Matthew B. Wall
, Amanda Feilding
Suresh Muthukumaraswamy
, David J. Nutt
Robin Carhart-Harris
Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine,
Imperial College London, London W12, UK
The Computational, Cognitive and Clinical Neuroimaging Laboratory, The Centre for Neuroscience,
Division of Brain Sciences, Imperial College London, London W12, UK
Sobell Department of Motor Neuroscience & Movement Disorders, Institute of Neurology,
University College London, Queen Square, London WC1N 3BG, UK
Behavioral Pharmacology Research Unit, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA
Academic Unit of Psychiatry, University of Bristol, Bristol BS8 2BN, UK
Imanova Centre for Imaging Sciences, Hammersmith Hospital, London W12, UK
Clinical Psychopharmacology Unit, University College London, London UK
The Beckley Foundation, Beckley Park, Oxford OX3 9SY, UK
Schools of Pharmacy and Psychology, University of Auckland, Auckland 1142, New Zealand
Received 10 November 2015; received in revised form 15 February 2016; accepted 24 March 2016
Effective connectiv-
Mental imagery;
Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry
in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic
psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects,
while listening to music and being supervised by trained psychotherapists. In this context, music
is considered to be a key element in the therapeutic model; working in synergy with the drug to
evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms
involved in this process have, however, never been formally investigated. Here we studied the
interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-
controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers
received intravenously administered LSD (75 mg) and, on a separate occasion, placebo, before
0924-977X/&2016 Elsevier B.V. and ECNP. All rights reserved.
Correspondence to: Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London W12, UK.
E-mail address: (M. Kaelen).
European Neuropsychopharmacology (2016) 26, 10991109
being scanned under eyes-closed resting conditions with and without music-listening. The
parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion,
(2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on
changes in the connectivity prole of this particular structure. Results revealed increased PHC
visual cortex (VC) functional connectivity and PHC to VC information ow in the interaction
between music and LSD. This latter result correlated positively with ratings of enhanced eyes-
closed visual imagery, including imagery of an autobiographical nature. These ndings suggest a
plausible mechanism by which LSD works in combination with music listening to enhance certain
subjective experiences that may be useful in a therapeutic context.
&2016 Elsevier B.V. and ECNP. All rights reserved.
1. Introduction
Humans have chosen to alter their consciousness via psy-
chedelic drugs for millennia, and often in combination with
music (Nettl, 1956). In the 1950s and 1960s, psychedelic
drugs such as lysergic acid diethylamide (LSD) were used in
psychotherapy, and modern clinical trials are re-examining
their therapeutic potential (Bogenschutz et al., 2015;
Gasser et al., 2014;Grob et al., 2011;Johnson et al.,
2014). Since the inception of psychedelic-assisted psy-
chotherapy, music-listening has been considered an impor-
tant component in the therapeutic model (Bonny and
Pahnke, 1972). It is believed that music acts synergistically
with the drug to enhance emotionality, mental imagery, and
access to personal memories (Bonny and Pahnke, 1972;
Grof, 1980;Kaelen et al., 2015).
The main aim of the
present study was to investigate the brain mechanisms
underlying the effects of LSD and music on mental imagery.
The characteristic subjective effects of LSD and other
psychedelics such as psilocybin are thought to depend on
agonist actions at the serotonin 2A receptor (Glennon
et al., 1984;Vollenweider et al., 1998). The serotonin 2A
receptor is expressed on excitatorydeep layer pyramidal
cells, as well as on a smaller proportion of inhibitory
interneurons (Andrade, 2011;Celada et al., 2013). Its
activation depolarises the cell membrane of the host
neuron, increasing its likelihood of ring (Aghajanian and
Marek, 1999). Although expressed throughout the neo-
cortex (Pazosetal.,1987), the serotonin 2A receptor is
especially highly expressed in high-level association cor-
tices, including the anterior cingulate cortex (ACC), pos-
terior cingulate cortex (PCC) and insula, but also in the
visual cortex (VC) and, to a lesser extent, the entorhinal
cortex (Erritzoe et al., 2009;Ettrup et al., 2014;Pazos
et al., 1987). Not surprisingly, functional neuroimaging
studies revealed altered activity in these brain regions
during serotonin 2A receptor agonist-induced psychedelic
states (Carhart-Harris et al., 2012a;Muthukumaraswamy
et al., 2013;Riba et al., 2002;Vollenweider et al., 1997).
Of particular interest to the present study are the effects
of psychedelics and music-listening on activity in the
parahippocampal cortex (PHC). The PHC is an important
hub within the medial temporal lobe (MTL) (Burwell, 2000;
Eichenbaum and Lipton, 2008), and it's acute functioning is
appreciably altered by psychedelics as determined by fMRI
(Kometer et al., 2015;Tagliazucchi et al., 2014), depth EEG
(Monroe et al., 1957;Schwarz et al., 1956) and PET
(Vollenweider et al., 1997). Furthermore, attenuation of
the subjective and behavioural effects of LSD were observed
after resection of the MTLs in humans (Serafetinides, 1965)
and chimpanzees (Ramey and O'Doherty, 1960).
Activation of the PHC is found during spatial navigation
(Aguirre and DEsposito, 1999;Epstein, 2008), imagining
scenes (Spreng et al., 2009), emotional arousal (LaBar and
Cabeza, 2006;Smith et al., 2004) and personal memory
recall (Fink et al., 1996). Importantly, the PHC is also
implicated in music-evoked emotion (Baumgartner et al.,
2006;Gosselin et al., 2006;Koelsch, 2014) and music-evoked
personal memories (Janata, 2009). Damage to the PHC can
result in impaired music-evoked emotion (Gosselin et al.,
2006) and visual decits (Harding et al., 2002;Hensley-Judge
et al., 2013), whereas direct stimulation of the PHC can
producevisualhallucinationsofscenes(Mégevand et al.,
2014), autobiographical memories (Vignal et al., 2007)and
dream-like states (Bancaud et al., 1994;Barbeau et al.,
2005;Bartolomei et al., 2004), accompanied by enhanced
coupling between the PHC and the VC (Barbeau et al., 2005).
These insights motivated the present hypothesis that LSD,
in combination with music-listening, modulates PHC func-
tional connectivity. This hypothesis was tested using func-
tional magnetic resonance imaging (fMRI) and a balanced-
order, placebo-controlled design. Participants completed
ratings of eye-closed visual imagery and spontaneous auto-
biographical memory recollection. Acute changes in PHC
functional connectivity informed a subsequent Dynamic
Causal Modelling (DCM) analysis that assessed how music
and LSD interact to change the direction of information ow
between the PHC and the VC (i.e. effective connectivity).
By the late 1960s there existed, broadly speaking, two schools of thoughts around the therapeutic use of psychedelics and these differed
in the signicance they attributed to music. In the United States, higher dosages of psychedelics were administered, with the goal to
facilitate a peak- or mystical-type experience to promote long lasting change in personality traits and behaviour. Here, music was typically
played for the entire duration of the drug effects, with intermittent periods of silence. In Europe, psycholytic therapy became more widely
practiced. This method involved more frequent administration of lower dosages of a psychedelic, and with more interaction between
therapist and patient. Music was played for to help with relaxation, or to support intermittent periods of introspection.
M. Kaelen et al.1100
2. Experimental procedures
2.1. Approvals
This study was approved by the National Research Ethics
Service (NRES) committee London West London and was
conducted in accordance with the revised declaration of
Helsinki (2000), the International Committee on Harmonisa-
tion Good Clinical Practice guidelines and National Health
Service (NHS) Research Governance Framework. Imperial
College London sponsored the research which was con-
ducted under a Home Ofce license for research with
schedule I drugs.
2.2. Participants
Twenty participants (16 males and 4 females) were
recruited, carefully screened for physical and mental health
and provided written informed consent before participa-
tion. The screening for physical health included electro-
cardiogram (ECG), routine blood tests, and urine test for
recent drug use and pregnancy. A psychiatric assessment
was conducted and participants provided full disclosure of
their drug use history. Key exclusion criteria included: being
younger than 21 years of age, having a personal history of
diagnosed psychiatric illness, an immediate family history of
a psychotic disorder, an absence of previous experience
with a classic psychedelic drug (e.g. LSD, mescaline,
psilocybin or dimethyltryptamine (DMT), drug use within
6 weeks of the rst scanning day, a persistent adverse
reaction to a psychedelic drug, pregnancy, problematic
alcohol-use (i.e. 440 units consumed per week), and/or a
medically signicant condition rendering them unsuitable
for the study.
2.3. Study setting and overview
Screening took place at Imperial's clinical research facility
at the Hammersmith hospital campus. All study days were
performed at Cardiff University Brain Research Imaging
Centre (CUBRIC). Eligible participants attended two study
days that were separated by at least 14 days. LSD was
received on one of the study days, and placebo on the other.
The order of receipt of LSD was balanced across partici-
pants, and they were kept blind to this order but the
researchers were not.
On scanning days, volunteers arrived at the study centre
at 8:00 am, were given a detailed brief about the study day
schedule, gave a urine test for recent drug-use and preg-
nancy, and carried out a breathalyser test for recent
alcohol-use. A cannula was inserted into a vein in the
antecubital fossa by a medical doctor and secured. Partici-
pants were encouraged to close their eyes and relax in a
reclined position while the drug was administered. All
participants received 75 mg of LSD, administered intrave-
nously via a 10 ml solution infused over a two minute
period, followed by an infusion of saline. Dosing was
followed by an acclimatisation period of approximately
60 min, in which (for at least some of the time) participants
were encouraged to relax and lie with their eyes closed
inside a mock MRI scanner. This functioned to prepare the
participants for the subsequent (potentially anxiogenic
(Studerus et al., 2012)) MRI scanning experience.
Participants reported noticing subjective drug effects
between 5 and 15 min post-dosing, and these approached
peak intensity between 60 and 90 min post-dosing. The
duration of a subsequent plateau of drug effects varied
among individuals but was generally maintained for approxi-
mately four hours post-dosing. BOLD MRI scanning started
approximately 120 min post-dosing, and lasted for approxi-
mately 60 min. This included a structural scan, arterial spin
labelling (ASL) fMRI, and BOLD fMRI. After the MRI scanning,
magnetoencephalography (MEG) scanning was performed
but these ndings will be reported elsewhere. Once the
subjective effects of LSD had sufciently subsided, the
study psychiatrist assessed the participant's suitability for
3. Experimental design
Each fMRI scanning session involved three eyes-closed
resting state scans, each lasting seven minutes. After each
seven minute scan, visual analogue scale (VAS) ratings were
performed in the scanner via a response-box. The music-
listening scan always occurred after the rst resting state
(no music) scan and before a nal resting-state scan (no
music). The music itself was triggered by the rst TR, and
listened to via MRI compatible headphones (MR Confon).
Two seven-minute long excerpts (A and B) were selected
from the album Yearning, by ambient artist Robert Rich and
classical Indian musician Lisa Moskow. Pre-study assessments
conrmed the two excerpts to be balanced for their
emotional potency. Each participant listened to both sti-
muli, in a balanced order across conditions. Volume-
maximisation and broadband compression was carried out
using Ableton live 9 software.
Prior to each scan, participants were instructed via a
display screen to close their eyes and relax. Prior to the
music scan, the music volume was adjusted to a level that
was as loud as possible, without being unpleasantand
then maintained for each condition. When the music ended,
participants were instructed to open their eyes and rate the
degree of simple visual imagery (i.e. with my eyes closed I
saw colours or geometric patterns) and complex visual
imagery (i.e. with my eyes closed I saw complex visual
imagery) they experienced. Complex imagery was pre-
dened as: static or dynamic images of objects or entities
(e.g. plants, buildings, people or animals) and complex
scenes. Items were completed on a continuous visual
analogue scale from 0 (not at all)to20(extremely
intense). Soon after the MRI scanning session was com-
plete, participants rated some further VAS items that
assessed their subjective experience during scanning. The
VAS item I saw scenes from my pastwas selected for
special consideration because of personal memory recollec-
tion being consistently associated with PHC functioning
(Fink et al., 1996;Spreng et al., 2009), as well as a prior
hypothesis inspired by previous ndings (Carhart-Harris
et al., 2012b) that this would be modulated by the experi-
mental conditions.
1101LSD modulates music-induced imagery via changes in parahippocampal connectivity
3.1. MRI scanner and data pre-processing
All imaging was performed on a 3T GE HDx system. For
registration and segmentation of functional images, an
initial 3D FSPGR anatomical scan was obtained in an axial
orientation, with eld of view=256 256 192 and
matrix=256 256 192 to yield 1-mm isotropic voxel reso-
lution (TR/TE=7.9/3.0 ms; inversion time=450 ms; ip
angle=201). Functional images were acquired using a
gradient echo planer imaging sequence, TR/TE=2000/
35 ms, eld-of-view =220 mm, 64 64 acquisition matrix,
parallel acceleration factor=2, 901ip angle. Thirty ve
oblique axial slices were acquired in an interleaved fashion,
each 3.4 mm thick with zero slice gap (3.4 mm isotropic
voxels). The precise length of each of the BOLD scans was
7:20 min.
Preprocessing utilised a combination of AFNI (Cox, 1996),
FSL (Smith et al., 2004b), Freesurfer (Dale et al., 1999) and
ANTS (Avants et al., 2011). After brain extraction (Free-
surfer), anatomical images were segmented into their three
underlying tissue types: cerebrospinal uid (CSF), grey
matter (GM) and white matter (WM) (fast, FSL) and regis-
tered to a 2 mm MNI152 template using afne (ANTS),
followed by non-linear transformation (SyN, ANTS). Anato-
mical images also underwent segmentation to dene sub-
cortical structures (Freesurfer).
One participant was excluded from analyses because of
early termination of the scanning due to him reporting
signicant anxiety. Three participants were excluded from
analyses due to technical problems with the sound delivery
and four more subjects were discarded from the group
analyses due to excessive head movement. This leaves a
total of twelve participants that entered the group ana-
lyses. Principally, motion was measured using frame-wise
displacement (FD) (Power et al., 2014). The criterion for
exclusion for excessive head movement was subjects dis-
playing higher than 15% scrubbed volumes when the scrub-
bing threshold is FD=0.5. After discarding these subjects,
we reduced the threshold to FD=0.4. The between-
condition difference in mean FD for the 4 subjects that
were discarded was 0.28670.185 and for the 12 subjects
that were used in the analysis the difference in mean FD
was 0.04970.029 (mean FD for placebo was 0.08570.028
and mean FD for LSD was 0.13470.037, p=0.0001).
Functional images were pre-processed according to the
following sequence: (1) Removal of rst three volumes (2)
de-spiking (3dDespike, AFNI), (3) slice time correction
(3dTshift, AFNI), (4) motion correction (3dvolreg, AFNI),
(5) brain extraction (bet, FSL), (6) rigid body registration to
anatomical scans (nine subjects with FSL's BBR, one subject
with Freesurfer's bbregister and two subjects manually),
(7) transformation of functional to MNI 2 mm space, using
previously calculated transformation matrix from the ana-
tomical scans, (8) motion scrubbing using an FD threshold of
0.4, and replacement with the mean of neighbouring
volumes (mean percentage of volumes scrubbed for placebo
and for LSD was 0.5%71 and 1.9%72.2, respectively.
Maximum volumes scrubbed for scan was 7.8%), (9) spatial
smoothing with a Gaussian kernel of 6 mm (FWHM) (3dBlur-
InMask, AFNI), (10) band-pass ltering between 0.01 and
0.08 Hz (3dFourier, AFNI), and (11) linear and quadratic
de-trending and regression of 9 nuisance parameters: 6
motion-related (3 translations, 3 rotations) and 3
The anatomically dened regressors consisted of Ventri-
cles (Freesurfer), Cerebrospinal uid (CSF) (FSL's FAST with
Freesurfer's Ventricles subtracted) and White matter (WM)
(FSL's FAST with Freesurfer's subcortical grey-matter sub-
tracted). All three masks were eroded to reduce partial
volume effects and were used to extract nuisance time-
series from an unsmoothed version of the pre-processed
functional data. The CSF and Venticles were used to extract
a single mean time-course for each mask, while WM mask
was used to produce a voxelwise regressor (3dLocalStat,
AFNI). Voxelwise WM regression has been found to outper-
form approaches using whole-brain averaged WM signal (Jo
et al., 2010,2013).
3.2. Subjective effects
A two-way repeated measures ANOVA with two factors (drug
condition and music condition) was performed to test for an
interaction between LSD and music on in-scanner ratings of
simple and complex hallucinations. A paired one-tailed t-
test was performed to examine between-condition differ-
ences in the post-scanner questionnaire item I saw scenes
from my past.
3.3. Seed-based functional connectivity analysis
A bilateral PHC region of interest (ROI) was acquired from
the Harvard anatomical atlas tool and used to extract PHC
time series for each subject. To begin with, a general linear
model (GLM) was used (FEAT, FSL) to model whole brain
resting state functional connectivity with the PHC seed,
with correction for autocorrelations (FILM, FSL) for each run
separately. Next, a xed-effects model was used to compare
music versus non-music runs for each subject, for LSD and
placebo separately. Finally, these drug effects (LSD versus
placebo) were fed into a higher-level mixed effects model
(FLAME1, FSL) to calculate the modulation of the effects of
music by LSD on PHC functional connectivity across the
brain (cluster correction threshold z42.3, po0.05).
3.4. Dynamic causal modelling: background and
Dynamic Causal Modelling (DCM, as implemented in SPM12b)
was used to estimate changes in effective connectivity. DCM
is a biologically-informed modelling procedure that estimates
the causal interactions (i.e. effective connectivity) between
different pre-selected nodes of a network, and the changes in
coupling strength between and within those nodes (extrinsic
and intrinsic connections respectively) due to experimental
manipulations (Friston et al., 2003). The basic architecture of
amodelisdened by structurally plausible and functionally-
informed brain regions, whose connections are dened as
either bilinear (i.e. information ow between regions) or
non-linear (i.e. activity in one region modulating information
ow between regions). Typically, experimental manipulations
can directly affect activity in each node (as driving inputs)
M. Kaelen et al.1102
or alter the strength of coupling within or between nodes (as
modulatory inputs).
In the present study, all six scans were concatenated in
the following order: placebo no-music (NM), placebo music
(M), placebo NM, LSD NM, LSD M, LSD NM. The measured
BOLD time-series for the DCM were extracted as the rst
principal eigenvalue from a bilateral PHC and VC mask (The
PHC mask was dened by Harvard-Oxford atlas, and the VC
mask was dened by results of the PHC functional con-
nectivity analysis, i.e. the occipital cluster), and adjusted
for the effects of interest (i.e. main effect of music, main
effect of drug, and an interaction effect described below).
Between-node connections were dened as bilinear mean-
ing that information ow could be modulated in either
direction. Three experimental inputs entered the model as
modulatory inputs: a main drug effect, a main music effect,
and an interaction effect of music and drug (0.51 0.50.5 1
0.5). Due to the resting-state conditions of the scanning,
activity in the nodes was driven by stochastic (i.e. sponta-
neous) uctuations (Li et al., 2011).
3.5. Dynamic causal modelling: Bayesian model
In DCM, a series of plausible models, representing compet-
ing hypotheses, are specied. Each model corresponds to a
hypothesis about how observed changes in BOLD signal were
caused by changes in neural activity in each network node.
The different models can vary in terms of the position of
driving and modulatory inputs. DCM uses a biophysical
model of the hemodynamic response to predict the under-
ling neuronal activity and the underlying (changes in)
connectivity from the observed BOLD signal (see
Figure 2D). Model estimation, or inversion, returns condi-
tional estimates for the changes in connectivity and scores
the model in terms of its accuracy and complexity (using a
Free Energy bound on log model evidence). Bayesian Model
Selection (BMS) is used to compare different models to
identify the model with the greatest evidence i.e. the
model that offers the best explanation of the data. In the
present study, one full modelwas specied, with all three
experimental inputs modulating all extrinsic and intrinsic
connections. Following inversion of this full model, a post
hoc Bayesian model optimisation scheme was used to
identify the model structure with the greatest model
evidence (i.e. lowest free energy). This approach provides
an efcient scheme for scoring large numbers of competing
models (Friston and Penny, 2011). Optimal model structure
is usually determined by computing Bayes factors, as an
approximation of the model evidence. A Bayes factor of 20
corresponds to a belief of 95% in the statement that a
particular hypothesis (i.e. the proposed model) is true, and
therefore a p-value of 0.05. A Bayes factor higher than 150
corresponds to a belief of 99% in the hypothesis, and
equates a p-value smaller than 0.01. A Bayes factor higher
than 20 is therefore considered as strong evidence for the
proposed model (Penny et al., 2004). After model selection,
coupling parameters are analysed post-hoc to characterize
the size and direction of the changes in connection strength
caused by the experimental manipulations. Coupling para-
meters quantify the strength of the coupling in terms of the
rate (in Hz) at which a response is caused in a given region,
and modulation is expressed as either an increase or
decrease in this coupling measure.
3.6. Correlations with subjective effects
Following model selection, the hypothesis was tested that
the magnitude of the modulation in effective connectivity
by the music drug interaction would explain the observed
variance in participantssubjective responses to the music
under LSD. More specically, we asked whether the size of
the interaction effect as estimated by the DCM, correlated
with the magnitude of the enhancement of (1) eyes-closed
imagery and (2) visions of one's past (I saw scenes from my
past). A spearman's correlation was used due the non-
parametric nature of the data.
4. Results
4.1. Participant demographics
The data from twelve participants were found suitable for
data-analysis (2 female, mean age=3379 years, range 2247
years). All had at least one previous experience with a classic
psychedelic drug. Mean estimated lifetime LSD-use was
12715 (range=040). Self-estimates of other drug-use were
as follows (mean7SD, range): weekly alcohol units=878, 0
28; daily cigarettes=0; lifetime cannabis uses=6867625,
302000; lifetime MDMA uses=20718, 250; lifetime psilocy-
bin/magic mushroom uses=1079, 135; lifetime ayahuasca/
DMT uses=14721, 050; lifetime ketamine uses=376, 020;
lifetime cocaine uses=678, 020; lifetime amphetamine
uses=6711, 035; lifetime heroin uses=173, 010.
4.2. Subjective effects
A paired t-test revealed a signicant increase in personal
memory recollection under LSD (t=1.9, df=19, p=0.04).
For simple hallucinations, a two-way ANOVA revealed a
signicant drug effect (F=42.2, df=18, po0.001) but no
signicant effects were found for music (F=1.7, df=18,
p=0.2) or the interaction between music and LSD (F=1.1,
df =18, p=0.3). For complex hallucinations, a two-way
ANOVA revealed a signicant drug effect (F=24.7, df =18,
po0.001), a trend level effect of music (F=10.0, df=18,
p=0.09), but again, no signicant interaction effect for
music LSD (F=1.8, df=18, p=0.5). Drug effects on simple
and complex hallucinations survived multiple comparisons,
using Bonferroni adjusted alpha levels of 0.025 per test
4.3. Functional connectivity
Seed-based functional connectivity analysis of the bilateral
PHC showed a positive interaction between music and LSD
for the contrast LSD (music versus no music) versus placebo
(music versus no music), with increased coupling between
the PHC and two main clusters: One being the bilateral
visual cortex and the other being the left inferior frontal
gyrus (see Table 1 and Figure 1a). No decreases in PHC
1103LSD modulates music-induced imagery via changes in parahippocampal connectivity
functional connectivity were observed for this contrast. A
two-way repeated-measures ANOVA on z-scores for the VC
did not show a signicant effect of drug (F=0.49, df =11,
p=0.5) or music (F=2.27, df=11, p=0.16), but did reveal
an interaction effect of music and LSD (F=17.04, df =11,
p=0.002) (see Figure 1b. for a plot of the z-scores).
4.4. Dynamic causal modelling
Post-hoc model optimisation determined the optimal model
structure. The optimal model had a Bayes factor 344 higher
than the preceding model architecture. This equates, in a
frequentist statistical approach, to a p-value much smaller
than 0.01, and is therefore considered as strong evidence
for the model. The optimal model features a main effect of
drug and music modulating the intrinsic connections of both
nodes, and an interaction effect modulating the connection
from the PHC to the VC. Group averages for the posterior
estimates are 0.4170.05 Hz for drug effect on PHC,
0.4270.06 Hz for music effect on PHC, 0.3870.06 Hz
for drug effect on VC, and 0.4070.06 Hz for music effect
on VC. The group average of the posterior estimate for the
interaction effect is 0.0270.04 Hz (Table 2).
4.5. Correlations
A signicant positive correlation was found between the
interaction effect of LSD and music on PHC to VC effective
connectivity, and increases in the in-scanner ratings for
complex visual imagery (Spearman's ρ=0.71, with p=0.01,
and Pearson r=0.65, with p=0.03). A trend-level positive
correlation was found between the interaction effect of LSD
and music on PHC to VC, and the post-scanner questionnaire
item I saw scenes from my past(Spearman ρ=0.67, with
p=0.02, and Pearson r=0.69, with p=0.01). These tests
were conducted using Bonferroni adjusted alpha levels of
0.0167 per test (0.05/3) (see Figure 3).
5. Discussion
The present study has demonstrated that increased PHCVC
effective connectivity during music-listening under LSD
correlates with enhancements in eyes-closed mental-ima-
gery. These results are consistent with current thinking on
the role of the PHC in mental imagery, and provide new
insights into the brain mechanisms by which psychedelics
Table 1 Brain regions showing increased coupling with the parahippocampus.
Cluster Region Lateralization Size (mm) Peak z-score Peak coordinates (mm)
Occipital Calcarine ssure L 3722 4.02 8,76,8
Calcarine ssure R 4516 4.02 6,84,8
Cuneus L 4190 3.62 4,80,6
Cuneus R 2732 3.44 8, 88,10
Lingual cortex L 4600 3.29 6,78,4
Lingual cortex R 3052 3.28 6, 76,20
Superior occipital gyrus L 5036 3.07 26,78,2
Fusiform gyrus R 2848 2.74 12,70,22
Inferior frontal Middle frontal cortex L 3380 3.52 30,32, 8
Inferior frontal gyrus, opercular L 5058 3.47 44,36,22
Inferior frontal gyrus, triangularis L 9726 3.33 42,38,22
Precentral gyrus L 7052 3.28 56,2,28
Inferior frontal gyrus, orbitalis L 2076 3.27 44,12,18
Insula L 3716 3.11 32,22,14
Figure 1 Seed-based functional connectivity analysis of the bilateral parahippocampus. (A) Brain regions showing increased
coupling (displayed in yellow, cluster-corrected, Z42.3) with the bilateral PHC (displayed in red) for the contrast LSD (music4no
music)4placebo (music4no music) (the left side of the brain is shown on the right side of the brain in these images, as if the body is
being viewed through the soles of the feet). Signicant effects were observed in the primary visual cortex, left anterior insula, and
left inferior frontal cortex. (B) Coupling between the PHC and the visual cortex under LSD and placebo (NM=No Music, M=Music)
(For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article).
M. Kaelen et al.1104
may enhance some of the subjective effects of music-
The PHC is implicated in the generation of visual mental
imagery (Brewer et al., 1998;Epstein, 2008), personal
memory recollection (Fink et al., 1996;Spreng et al.,
2009) and music-evoked personal memories (Janata,
2009). Within the MTL system, the PHC primarily functions
to encode and retrieve context-related memory content
(Ranganath and Ritchey, 2012), which is consistent with
complex rather than simple visual imagery. Direct structural
(Catani et al., 2002) and functional (Libby et al., 2012;
Powell et al., 2004) connections between the PHC and the
VC have been detected, and increased information ow
from the PHC to the VC (i.e. effective connectivity) has
previously been found to occur during the construction of
visually imagined scenery (Chadwick et al., 2013). Interest-
ingly, direct stimulation of the PHC can produce visual
hallucinations of complex scenes (Mégevand et al., 2014)
and autobiographical memories (Bancaud et al., 1994;
Bartolomei et al., 2004), and there is evidence that this is
related to a strengthening of PHCVC coupling (Barbeau
et al., 2005). Damage to the PHC can result in visual neglect
(Hensley-Judge et al., 2013) visual hallucinations (Harding
et al., 2002) and hippocampal damage has been linked to an
impaired ability to imagine complex scenes (Cooper et al.,
In sum, these ndings suggest that PHCVC effective
connectivity constitutes an important pathway for the
construction of visual imagery (Chadwick et al., 2013;
Zeidman et al., 2014). Mechanistically, increased informa-
tion ow from the PHC to the visual cortex may correspond
to an increase in top-down (prior) information (instantiated
by PHC activity) being conferred on activity in the lower
levels of the visual system (that normally processes incom-
ing visual information) (Aguirre and DEsposito, 1999;Libby
et al., 2012;Summereld et al., 2006). The present study
has shown that the combination of LSD and music modulates
information ow from the PHC to the VC, and that the
Figure 2 Dynamic Causal Modelling. (A) Time series that enter the DCM are extracted as rst principal eigenvalues from the PHC
mask and the VC mask (the latter is dened by the seed-based functional connectivity result) (Dale et al., 1999). The full DCM that
enters the Bayesian model selection (BMS) after model estimation. The model has two nodes (PHC and VC) that are connected via
extrinsic bilinear connections, and each node has one intrinsic connection. Every connection has three modulatory effects: D=main
drug effect, M=main music effect, I=Interaction effect. The nodes are driven by stochastic uctuation. (C) Post-hoc model
optimisation determined the optimal model structure. Dashed lines indicate a negative connection or modulation, whereas normal
lines indicate a positive connection or modulation. This model has the main effect of drug and the main effect of music modulating
the intrinsic-connections of both nodes. The interaction effect has a modulatory effect on the connection from PHC to VC. (D) The
sum estimated neural activity in each node is convolved by the hemodynamic response function to yield a predicted BOLD response.
The predicted BOLD response is compared to the observed BOLD response to determine how well the model explains the data.
Displayed are predicted and observed time-series from one subject for illustration purposes. (E) Scatterplots illustrate model tby
correlation of predicted verses observed BOLD responses for both regions.
Table 2 Pearson correlation coefcients from all par-
ticipants for predicted versus observed BOLD signals for
visual cortex (VC) and parahippocampus (PHC).
Participant VC PHC
1 0.95 0.94
2 0.91 0.97
3 0.89 0.91
4 0.92 0.95
5 0.88 0.93
6 0.91 0.93
7 0.97 0.95
8 0.82 0.87
9 0.93 0.90
10 0.92 0.96
11 0.88 0.86
12 0.85 0.94
1105LSD modulates music-induced imagery via changes in parahippocampal connectivity
magnitude of this modulation predicts enhanced visual
imagery. Importantly, this correlation was only evident for
the complex visual imagery item (dened as the eyes-closed
hallucinations of objects, entities and scenes), and not for
simple imagery (dened as low-level visual features such as
colours and patterns). We therefore propose that the
experience of perceiving complex imagery whilst listening
to music under LSD may be the result of an enhanced gain
on circuits (such as the PHC to VC circuit) that normally
confer complex, top-down information about (a potential)
visual scene. Perceiving complex scenes in the absence of
visual input may therefore result from a ipin the normal
direction of information ow within the visual system such
that higher-level components of the system, responsible for
processing high-level features, take precedence over incom-
ing sensory information.
The PHC possesses high baseline connectivity with high-
level cortical regions such as those that make-up the so-
called default-mode network (Raichle et al., 2001;Ward
et al., 2014). Under normal conditions, the top-down inhibi-
tory control over PHC activity is provided by projections from
the posterior cingulate cortex (PCC), the retrosplenial cortex
(RSC) and the medial prefrontal cortex (mPFC), that termi-
nate on interneurons within the PHC (Mohedano-Moriano
et al., 2007;Morris et al., 1999;Vann et al., 2009). The
RSC, PCC and mPFC express notably high levels of serotonin
2A receptors (Erritzoe et al., 2009), and psychedelics have a
dysregulating effect on activity within these regions
(Carhart-Harris et al., 2012a;Muthukumaraswamy et al.,
2013). The dysregulating effect of psychedelics on activity in
these cortical regions may compromise their ability to
maintain top-down control over the PHC. Indeed, reduced
functional connectivity between the PHC and the RSC has
been observed after both psilocybin and LSD (Carhart-Harris
et al., 2014). Thus, the effects of psychedelics on the PHC's
inhibitory afferents may increase its sensitivity and respon-
siveness to stimuli that normally engage it, such as music
(Koelsch, 2014;Mitterschiffthaler et al., 2007;Tros t e t a l . ,
2012)orodour(Jung et al., 2006).
Effects of sound on eyes-closed visual experiences under
LSD have been reported since its discovery. Albert Hoffman,
who discovered the powerful psychoactive effects of LSD by
accidentally intoxicating himself, describes his experience
in his memoir (Hoffman, 1970): It was particularly remark-
able how every acoustic perception, such as the sound of a
door handle or a passing automobile, became transformed
into optical perceptions. Every sound generated a vividly
changing image, with its own consistent form and colour.
Such experiences are often compared to synaesthesia, a
neurological condition characterized by involuntarily sen-
sory experiences (for example seeing a colour) in response
to a different sensory stimulus (for example, hearing a
sound). Synaesthesia is characterized by responses that are
consistent to a specic stimulus (Ward, 2013), and it is
therefore not possible to say to what extent the audio-visual
experiences reported under LSD can be formally be termed
synestheticin the conventional sense. The present results
do, however, suggest a plausible mechanism via which such
experiences can arise, and highlight how psychedelics can
inform on the neuroscience of sensory processing.
5.1. Implications for psychedelic-assisted
Music is an effective medium for evoking emotion (Trost
et al., 2012) and autobiographical memories (Janata, 2009;
Janata et al., 2007) and these effects of music have been
therapeutically exploited (Castillo-Pérez et al., 2010;
Erkkilä et al., 2011). Music may serve to deepen the
psychedelic experience by enhancing emotional engage-
ment (Kaelen et al., 2015) and stimulating personally
meaningful mental imagery (Carhart-Harris et al., 2012b).
The ndings of the present study help to elucidate the
mechanisms by which music and psychedelics can do this
but further research is required to test its therapeutic value
5.2. Limitations
No interaction was found between LSD and music on in-
scanner subjective ratings, whereas connectivity analyses
did show a signicant interaction effect on PHCVC cou-
pling. Since enhanced PHCVC coupling via the interaction
between LSD and music correlated with complex mental
imagery, this could be explained by individual differences in
Figure 3 Correlation analyses suggest that the interaction between LSD and music induces certain subjective experiences via
increasing the inuence of PHC activity on VC activity. Changes in coupling parameters are displayed on the x-axis and are
signicantly correlated with: (A) increases in complex visual imagery (Y-axis) (i.e. music4rest for LSD4placebo) and (B) increases
in visions of one's personal past (Y-axis) (i.e. LSD4placebo).
M. Kaelen et al.1106
subjective response to LSD and music, and perhaps appraisal
of the subjective experience. For example, it may have
been the case that some participants disliked the genre of
music or were distracted by the considerable ambient noise
emitted by the MRI machinery. Some participants may also
have been emotionally relaxed by the particular music that
was chosen, rather than emotionally stimulated. Further
work is required to test these different hypotheses. For
example, a study could be designed that incorporates more
than one genre of music (e.g. emotionally relaxing music
versus emotionally evocative and/or arousing music).
Finally, the present results cannot be extrapolated to a
patient population, in which the music psychedelic inter-
action is thought to be especially important (Bonny and
Pahnke, 1972;Kaelen et al., 2015). Subsequent work is
therefore needed to further our understanding of how music
and psychedelics interact and how this may be useful for
psychedelic-assisted therapy.
6. Conclusions
The present study revealed a positive interaction between
LSD and music on PHC functional and effective connectivity.
More specically, a modulation of PHC to VC connectivity
was observed that correlated positively with eyes-closed
visual imagery, and particularly imagery of a complex and
autobiographical nature. These results extend our under-
standing of circuitry involved in visual imagery and suggest
how LSD and music can work in synergy to enhance this
phenomenon. The present results provide the beginnings of
a mechanistic explanation for the role of music listening in
psychedelic drug-assisted psychotherapy; however, a large
amount of work is required to develop our understanding of
whether and how psychedelic-assisted psychotherapy can
be effective.
Role of funding source
The Beckley Foundation provided nancial and intellectual support,
and the study was conducted as part of a wider Beckley-Imperial
research programme. The researchers also received nancial sup-
port from the crowd-funding campaign. The report
presents independent research carried out at the NIHR/Wellcome
Trust Imperial Clinical Research Facility. The Beckley Foundation
and the Walacea crowd-funding campaign had no further role in
study design; in the collection, analysis and interpretation of data;
in the writing of the report; and in the decision to submit the paper
for publication.
MK designed and coordinated the study, carried out data collection,
undertook data analyses and wrote the rst draft of the manuscript.
LR, JK, ASR, CO and RL undertook data analyses. MB, TW and LW
carried out data collection. FSB, MBW, AF helped designing the
study.SM and DJN helped designing and coordinating the study. RCH
designed and coordinated the study, and carried out data collection
and writing of the manuscript. All authors contributed to and have
approved the nal manuscript.
Conict of interest
Author MBW's primary employer is Imanova Ltd., a private company
that performs contract research work for the pharmaceutical and
biotechnology industries. All other authors declare that they have
no conicts of interest.
This research received nancial and intellectual support from the
Beckley Foundation (Grant number: P41825) and was conducted as
part of a wider Beckley-Imperial research programme. The
researchers would like to thank supporters of the
crowd-funding campaign who played a crucial role in securing funds
to complete the study.
Appendix A. Supplementary material
Supplementary data associated with this article can be
found in the online version at
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1109LSD modulates music-induced imagery via changes in parahippocampal connectivity
... Research on the psychedelics influence on resting-state found that they can modulate the exploration of the brain's repertoire of functional network states (Lord et al. 2019;Tagliazucchi et al. 2014), alter their segregation and integration (Luppi et al. 2021;Preller et al. 2020), increase wholebrain between-network functional connectivity (Mason et al. 2020), decrease modularity of large-scale brain networks (Lebedev et al. 2015), and support formation of new local-range connections (Petri et al. 2014). In terms of specific brain subsystems, studies report an decrease in activity in medial prefrontal cortex, a key region in default mode network (DMN) (Carhart-Harris et al. 2012a;Palhano-Fontes et al. 2015), along with decreased functional connectivity within DMN (Carhart-Harris et al. 2012a;Carhart-Harris et al. 2016a). Even though studies have shown evidence for recurrent states in resting state (Cabral et al. 2017;Cornblath et al. 2020;Vidaurre et al. 2017), it was Singleton et al. (2022) who also showed that the brain manifests recurrent states of brain network activity under LSD influence. ...
... Music can deeply affect human cognition; therefore, its potential to contribute to the positive outcomes of the psychedelic-assisted therapy should not be underestimated Barrett et al. 2018b). Indeed, recent studies confirm that music supports the beneficial effect of psychedelics on mental imagery ), emotion processing (Carbonaro et al. 2018;Kaelen et al. 2015;Kaelen et al. 2016a), meaning making , and openness . However, most studies focus on the psychological aspect of using music in psychedelic therapy, rather than investigate its impact on the brain network organization and fluctuations of brain activity in time. ...
... Specifically, we expect to observe different patterns of brain states dynamics for the two resting-state runs. Psychedelics are known to enhance sensory (Aday et al. 2021;Carhart-Harris et al. 2012a;Carhart-Harris et al. 2016a;Császár-Nagy et al. 2019), emotional (Grimm et al. 2018;Kometer et al. 2012;Kraehenmann et al. 2015), and self-related processing (Smigielski et al. 2020); therefore, in both cases, we hypothesize that besides music, LSD may be also an important factor in affecting the brain states dynamics. LSD was reported to have an effect on the brain entropy by increasing it in the sensory and higher networks (Lebedev et al. 2016) and here its effects could be manifested by making the states' transitions more irregular and frequent. ...
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Rationale Psychedelics are getting closer to being widely used in clinical treatment. Music is known as a key element of psychedelic-assisted therapy due to its psychological effects, specifically on the emotion, meaning-making, and sensory processing. However, there is still a lack of understanding in how psychedelics influence brain activity in experimental settings involving music listening. Objectives The main goal of our research was to investigate the effect of music, as a part of “setting,” on the brain states dynamics after lysergic acid diethylamide (LSD) intake. Methods We used an open dataset, where a group of 15 participants underwent two functional MRI scanning sessions under LSD and placebo influence. Every scanning session contained three runs: two resting-state runs separated by one run with music listening. We applied K-Means clustering to identify the repetitive patterns of brain activity, so-called brain states. For further analysis, we calculated states’ dwell time, fractional occupancy and transition probability. Results The interaction effect of music and psychedelics led to change in the time-varying brain activity of the task-positive state. LSD, regardless of the music, affected the dynamics of the state of combined activity of DMN, SOM, and VIS networks. Crucially, we observed that the music itself could potentially have a long-term influence on the resting-state, in particular on states involving task-positive networks. Conclusions This study indicates that music, as a crucial element of “setting,” can potentially have an influence on the subject’s resting-state during psychedelic experience. Further studies should replicate these results on a larger sample size.
... One of the interesting findings of psychedelic neuroscience, is the ability of such compounds to collapse the neural hierarchies associated with the adult default mode network configuration. More specifically, psychedelics are believed reduce activity in this network, which seems to be associated with increased connectivity between primary and secondary cognitive systems while enhancing cross modular connectivity-which may account for the increased sensitivity to visual and aural phenomena in the psychedelic state (Carhart- Harris, et al. 2016;Kaelen, et al. 2017;Petri, et al. 2014;Tagliazucchi, et al. 2016). Decreased activity in this network, and the attendant transition from secondary to primary consciousness, has been found to correlate with the experience of 'ego dissolution' (Muthukumaraswamy et al. 2013;Carhart-Harris et al. 2016) as well as alteration in the processing of the relation between self and other resulting in reduced egocentric socio-cognitive bias (Pokorny, et al. 2017;Preller, et al. 2016). ...
In this essay, I outline an approach to analytical psychology based on the emerging disciplines of psychedelic neuroscience and psychedelic assisted therapies. During the 1950s Jung made brief comments on the use of psychedelics in traditional cultures and therapeutic contexts. I analyse these comments in the light of consequent research in the field. Contemporary psychedelic researchers are achieving impressive results in the treatment of mental illness and various forms of existential distress. A number of theories have been proposed to explain these results. In this essay, I will explore the idea that psychedelics facilitate a transition from our recently evolved secondary consciousness associated with the default mode network, to a more affect-based form of primary consciousness. I will also apply these findings to ethnographic accounts of traditional psychedelic use in Africa and Latin America, highlighting the usefulness of a Jungian approach to this material informed by psychedelic and evolutionary neuroscience.
... Switching out Black Sabbath's 'Paranoid', for The Orb's 'Slug Dub' may go much further than effecting the enjoyment of the soundtrack which accompanies their trip. Visual perception, mood, and indeed the character of the entire experience may be fundamentally altered for the better or worse depending solely on audition [47,48,89]. ...
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In this paper our aim is to examine whether research conducted on human participants with LSD-25 (lysergic acid diethylamide) raises unique research ethical questions or demands particular concerns with regard to the design, conduct and follow-up of these studies, and should this be the case, explore and describe those issues. Our analysis is based on reviewing publications up to date which examine the clinical, research and other uses of LSD and those addressing ethical and methodological concerns of these applications, just as some historical examinations of this subject. The first chapters of the paper give an overview regarding the history of LSD-research with human participants, healthy volunteers and patients alike. The remaining chapters have a focus on questions regarding the potential ethical issues of such human trials in the contemporary research ethics framework. We also consider briefly political and regulatory issues regarding this substance that possibly affect its clinical and research applications.
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There is renewed interest in the therapeutic potential of psychedelic drugs such as lysergic acid diethylamide (LSD). LSD was used extensively in the 1950s and 1960s as an adjunct in psychotherapy, reportedly enhancing emotionality. Music is an effective tool to evoke and study emotion and is considered an important element in psychedelic-assisted psychotherapy; however, the hypothesis that psychedelics enhance the emotional response to music has yet to be investigated in a modern placebo-controlled study. The present study sought to test the hypothesis that music-evoked emotions are enhanced under LSD. Ten healthy volunteers listened to five different tracks of instrumental music during each of two study days, a placebo day followed by an LSD day, separated by 5-7 days. Subjective ratings were completed after each music track and included a visual analogue scale (VAS) and the nine-item Geneva Emotional Music Scale (GEMS-9). Results demonstrated that the emotional response to music is enhanced by LSD, especially the emotions "wonder", "transcendence", "power" and "tenderness". These findings reinforce the long-held assumption that psychedelics enhance music-evoked emotion, and provide tentative and indirect support for the notion that this effect can be harnessed in the context of psychedelic-assisted psychotherapy. Further research is required to test this link directly.
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During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown. To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals. In this double-blind, placebo-controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness. Psilocybin decreased the current source density of neuronal oscillations at 1.5-20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5-4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area. These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience.
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Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.
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In recent years, evidence has accumulated to suggest the hippocampus plays a role beyond memory. A strong hippocampal response to scenes has been noted, and patients with bilateral hippocampal damage cannot vividly recall scenes from their past or construct scenes in their imagination. There is debate about whether the hippocampus is involved in the online processing of scenes independent of memory. Here, we investigated the hippocampal response to visually perceiving scenes, constructing scenes in the imagination, and maintaining scenes in working memory. We found extensive hippocampal activation for perceiving scenes, and a circumscribed area of anterior medial hippocampus common to perception and construction. There was significantly less hippocampal activity for maintaining scenes in working memory. We also explored the functional connectivity of the anterior medial hippocampus and found significantly stronger connectivity with a distributed set of brain areas during scene construction compared with scene perception. These results increase our knowledge of the hippocampus by identifying a subregion commonly engaged by scenes, whether perceived or constructed, by separating scene construction from working memory, and by revealing the functional network underlying scene construction, offering new insights into why patients with hippocampal lesions cannot construct scenes. © The Author 2014. Published by Oxford University Press.
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Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.
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[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68.
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In recent years, functional neuroimaging has disclosed a network of cortical areas in the basal temporal lobe that selectively respond to visual scenes, including the parahippocampal place area (PPA). Beyond the observation that lesions involving the PPA cause topographic disorientation, there is little causal evidence linking neural activity in that area to the perception of places. Here, we combined functional magnetic resonance imaging (fMRI) and intracranial EEG (iEEG) recordings to delineate place-selective cortex in a patient implanted with stereo-EEG electrodes for presurgical evaluation of drug-resistant epilepsy. Bipolar direct electrical stimulation of a cortical area in the collateral sulcus and medial fusiform gyrus, which was place-selective according to both fMRI and iEEG, induced a topographic visual hallucination: the patient described seeing indoor and outdoor scenes that included views of the neighborhood he lives in. By contrast, stimulating the more lateral aspect of the basal temporal lobe caused distortion of the patient's perception of faces, as recently reported (Parvizi et al., 2012). Our results support the causal role of the PPA in the perception of visual scenes, demonstrate that electrical stimulation of higher order visual areas can induce complex hallucinations, and also reaffirm direct electrical brain stimulation as a tool to assess the function of the human cerebral cortex.
The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in `magic mushrooms`) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behaviour in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.