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Aberrant striatal dopamine links
topographically with cortico-thalamic
dysconnectivity in schizophrenia
Mihai Avram,
1,2,3,†
Felix Brandl,
1,2,4,†
Franziska Knolle,
1,2,5
Jorge Cabello,
3
Claudia Leucht,
4
Martin Scherr,
4
Mona Mustafa,
3
Nikolaos Koutsouleris,
6,7
Stefan Leucht,
4,8
Sibylle Ziegler
3,9
and Christian Sorg
1,2,4
†
These authors contributed equally to this work.
Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical net-
works and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological
link between these two alterations is suggested by theoretical models based on striatal dopamine’s topographic modulation of cor-
tico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links
topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC
between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the audi-
tory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19
age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-L-alanine PET (
18
F-DOPA-PET) and
resting state functional MRI (rs-fMRI). The influx constant k
icer
based on
18
F-DOPA-PET was used to measure striatal dopamine
synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were
used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis cap-
acity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both
patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum
dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus
iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links
topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and
cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic cir-
cuits in schizophrenia.
1 Department of Neuroradiology, Klinikum rechts der Isar, Technische Universita¨t Mu¨ nchen, Munich, 81675, Germany
2 TUM-NIC Neuroimaging Center, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Munich, 81675, Germany
3 Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universita¨t Mu¨ nchen, Munich, 81675, Germany
4 Department of Psychiatry, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Munich, 81675, Germany
5 Department of Psychiatry, University of Cambridge, Cambridge, UK
6 Department of Psychiatry, University Hospital, LMU Munich, Munich, 81377, Germany
7 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AB, UK
8 Department of Psychosis studies, King’s College London, UK
9 Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, 81377, Germany
Correspondence to: Mihai Avram
Department of Neuroradiology, Klinikum rechts der Isar, Technische Universita¨t Mu¨ nchen
Received April 23, 2020. Revised June 30, 2020. Accepted July 16, 2020. Advance access publication November 6, 2020
V
CThe Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For permissions, please email: journals.permissions@oup.com
doi:10.1093/brain/awaa296 BRAIN 2020: 143; 3495–3505 |3495
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Munich, 81675, Germany
E-mail: mihai.avram@tum.de
Keyword:
18
F-DOPA-PET; striatal dopamine synthesis capacity; resting-state fMRI; cortico-thalamic dysconnectivity
Abbreviations: ASM = auditory-sensorimotor network; CSPTC = cortico-striato-pallido-thalamo-cortical; DSC = dopamine syn-
thesis capacity; FD = framewise displacement; iFC = intrinsic functional connectivity; rs-fMRI = resting state functional MRI; SAL
= salience network
Introduction
Both aberrant dopamine transmission in the striatum
(Hietala et al.,1999;Howes et al.,2013;Jauhar et al.,
2017;Avram et al.,2019) and aberrant intrinsic functional
connectivity (iFC) between distinct cortical networks and
thalamic nuclei (Woodward et al.,2012;Anticevic et al.,
2015;Tu et al.,2015;Woodward and Heckers, 2016;
Avram et al.,2018) are among the most consistent large-
scale in vivo brain imaging findings in schizophrenia.
Concerning dopamine transmission, distinct aspects are
aberrant in schizophrenia, particularly presynaptic striatal
dopamine synthesis capacity (DSC) and dopamine release
(Hietala et al.,1999;Abi-Dargham et al.,2000,2009;
Kegeles et al., 2010;Howes et al.,2013;Jauhar et al.,2017;
Avram et al.,2019). The most consistent finding is aberrant
DSC in the ‘associative striatum’, with DSC being measured
by 6-
18
F-fluoro-3,4-dihydoxylphenyl-L-alanine PET (
18
F-
DOPA-PET) (McCutcheon et al.,2018,2020); the associa-
tive striatum mainly consists of the caudate nucleus; other
striatal subregions are the sensorimotor striatum (mostly
covering putamen) and the limbic striatum (mainly compris-
ing nucleus accumbens). In patients with schizophrenia and
current psychotic symptoms, striatal DSC is typically
increased (Hietala et al., 1999;Howes et al.,2009,2013;
Jauhar et al.,2017,2018). There is evidence, however, that
striatal DSC is not increased in patients with only mild
psychotic symptoms (Kim et al.,2017), and our group has
recently found decreased striatal DSC in patients with
schizophrenia during psychotic remission (Avram et al.,
2019). These last findings might reflect an effect of disorder
state (i.e. increased DSC during psychosis versus decreased
DSC during psychotic remission) and/or antipsychotic medi-
cation (Grunder and Cumming, 2019).
Concerning cortico-thalamic iFC, dysconnectivity has been
observed in at-risk, first-episode, and chronic patients with
schizophrenia as well as first-degree relatives of patients
(Woodward et al.,2012;Anticevic et al.,2015;Lui et al.,
2015;Woodward and Heckers, 2016;Avram et al.,2018;
Brandl et al., 2019). Cortico-thalamic dysconnectivity
reflects aberrant coherence of infra-slow (50.1 Hz) fluctua-
tions of ongoing brain activity between distal regions, typic-
ally measured by correlated blood oxygenation fluctuations
in resting state functional MRI (rs-fMRI) (Biswal et al.,
1995). Brain-wide ongoing activity is organized by sets
of distinct iFC patterns, known as intrinsic brain
networks, such as the salience network (SAL) covering
cingulo-opercular-insular-mediofrontal cortices, or the audi-
tory-sensorimotor network (ASM) covering somatosensory/
motor and temporal cortices (Fox and Raichle, 2007;Yeo
et al., 2011). The most robust findings of aberrant iFC in
schizophrenia are, on the one hand, decreased iFC (‘hypo-
connectivity’) between frontal cortices of SAL and anterior/
mediodorsal thalamus, and on the other hand, increased iFC
(‘hyperconnectivity’) between primary auditory-sensorimotor
cortices of ASM and posterior/ventrolateral thalamus
(Woodward et al.,2012;Anticevic et al.,2015;Lui et al.,
2015;Woodward and Heckers, 2016;Avram et al.,2018;
Brandl et al.,2019).
It is, however, unclear whether aberrant striatal DSC and
altered cortico-thalamic iFC are related in schizophrenia.
Such a relationship has long been suggested based on ana-
tomical and physiological considerations (Swerdlow and
Koob, 1987), and partially explored via
18
F-deoxyglucose
PET in patients with schizophrenia (Wu et al.,1990): cor-
tico-thalamic iFC is part of largely parallel, topographically
organized cortico-striato-pallido-thalamo-cortical circuits,
which are modulated by midbrain dopaminergic neurons
projecting into the striatum (Fig. 1,top)(Alexander et al.,
1986;Haber, 2003;Hikosaka et al.,2006). In particular,
SAL-anterior/mediodorsal thalamus connectivity extends
topographically to dorsomedial parts of basal ganglia cir-
cuits (including associative striatum and corresponding mid-
brain dopaminergic projections)—we call it the SAL-centred
system. More posterior connections between ASM and pos-
terior/ventrolateral thalamus integrate dorsolateral parts of
the basal ganglia (including sensorimotor striatum and cor-
responding midbrain dopaminergic projections)—we call it
the ASM-centred system (Alcauter et al.,2014;Delevich
et al.,2015;Peters et al.,2016;Avram et al.,2018). In sup-
port of such relations, a recent study combining
18
F-DOPA-
PET and rs-fMRI investigated associations between striatal
DSC and iFC of different intrinsic brain networks, including
SAL and ASM, in healthy subjects (McCutcheon et al.,
2019). While no significant associations were reported be-
tween striatal DSC and iFC of the ASM, within-SAL-iFC
correlated significantly with striatal DSC (including associa-
tive striatum) (for similar findings see Cole et al.,2013;
Berry et al.,2018).
Thus, the question arises whether such topographic rela-
tionships can also be expected between aberrant striatal
DSC and aberrant cortico-thalamic iFC in schizophrenia.
To address this question, we carried out simultaneous
18
F-DOPA-PET and rs-fMRI using a hybrid PET/MRI
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scanner in healthy controls and patients with established
schizophrenia, i.e. with more than one psychotic episode.
We focused on patients during remission of psychotic symp-
toms to reduce heterogeneity of psychotic symptoms, which
seem to be linked with striatal DSC. We hypothesized specif-
ically that SAL-thalamic iFC is decreased and associated
with decreased associative striatum DSC, while ASM-thal-
amic iFC is increased and associated with decreased sensori-
motor striatum DSC (Fig. 1,bottom).
Materials and methods
Participants
Twenty-three patients with schizophrenia and 24 age- and sex-
comparable healthy controls participated in the study. PET data
from this sample have been used in a previous study, which
demonstrated decreased striatal DSC in schizophrenia during re-
mission of psychotic symptoms (Avram et al., 2019). Because of
excessive head motion during rs-fMRI, several subjects were
excluded, with 19 subjects remaining in each group for further
analyses (see below and Table 1).
Patients had established schizophrenia according to DSM-IV
criteria, were in symptomatic remission of psychotic symptoms
(based on severity criteria by Andreasen et al.,2005) during the
study, and were all treated with antipsychotic medication
(Supplementary Table 1). The diagnosis of schizophrenia was
supported by the Structured Clinical Interview for DSM-IV
(First et al.,2002). Substance abuse, except nicotine, was an ex-
clusion criterion in both groups. Participants gave written
informed consent after receiving a complete description of the
study, which was approved by the Ethics Review Board of the
Technical University of Munich. Approval to administer radio-
tracers was obtained from the Administration of Radioactive
Substances (Bundesamt fu¨ r Strahlenschutz), Germany. For a
detailed participant description, including inclusion and exclu-
sion criteria, see the online Supplementary material or Avram
et al. (2019).
18
F-DOPA-PET data acquisition and preprocessing
18
F-DOPA-PET and MRI data were acquired simultaneously
with a hybrid whole-body mMR Biograph PET/MRI scanner
(Siemens-Healthineers). We used
18
F-DOPA-PET to measure the
influx constant k
icer
, a quantitative measure reflecting DSC, in
a voxel-wise manner with Gjedde–Patlak linear graphical
Figure 1 Research background and hypothesis. To p : Schematic depiction of cortico-thalamic connectivity and striatal circuits embedded in
larger CSPTC circuits, following Haber and McFarland (2001). Colour gradients across cortical and subcortical regions indicate the topographic,
parallel, but continuous organization of circuits, from which we derived the SAL-centred and ASM-centred systems. Note that these circuits re-
ceive dopaminergic modulation from ventral tegmentum and substantia nigra, pars compacta. Left: The SAL-centred system is depicted as an or-
ange ellipse. Reduced associative striatum DSC as well as reduced iFC between SAL (derived from Yeo et al., 2011) and the thalamic cluster that
was hypoconnected with SAL in our previous study (Avram et al., 2018) are graphically depicted (blue arrows). The grey arrow reflects our hy-
pothesis. Right: The ASM-centred system is depicted as a blue ellipse. Reduced sensorimotor striatum DSC as well as increased iFC between
ASM (derived from Ye o et al., 2011) and the thalamic cluster that was hyperconnected with ASM in our previous study (Avram et al., 2018)are
graphically depicted (blue and red arrows, respectively). The grey arrow reflects our hypothesis.
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analysis (Patlak et al.,1983), and compared averaged striatal
subdivisions’ k
icer
across groups with two-sample t-tests. The
same approach was was as in our previous study (Avram et al.,
2019)(Supplementary material).
Resting state functional MRI data acquisition and
preprocessing
Before rs-fMRI, participants were instructed to close their eyes
and to remain still, but stay awake. Rs-fMRI began simultan-
eously with the PET scan and lasted 20 min 8 s. Six hundred
volumes were acquired using T
2
-weighted echo-planar-imaging,
consisting of 35 axial slices (slice thickness = 3.0mm), field of
view (FoV) = 192 192 mm matrix (3.0 mm 3.0 mm in-
plane resolution), 90flip angle, repetition time = 2000 ms, and
echo time = 30 ms. Anatomical T
1
-weighted structural images
were obtained using gradient-echo imaging [repetition time/echo
time/flip angle: 2.300 ms/2.98 ms/9; 160 slices (gap 0.5 mm)
covering the whole brain; FoV: 256 mm; matrix size:
256 256; voxel size: 1.0 1.0 1.0 mm
3
].
MRI data were preprocessed with the Configurable Pipeline
for the Analysis of Connectomes (C-PAC, http://fcp-indi.github.
com). After removing the first five volumes, preprocessing
included image realignment, motion correction, scrubbing, in-
tensity normalization, nuisance signal regression [scanner drift,
head motion signals, and component-based noise correction
(Compcor) to remove physiological noise] (Behzadi et al.,
2007), bandpass filtering (0.01–0.1 Hz), registration to anatom-
ical space and normalization to MNI 2 mm
3
space with FSL
FLIRT/FNIRT. The Friston 24-parameter model was used to re-
gress out head motion effects (i.e. six head motion parameters,
six head motion parameters one time point before, and the 12
corresponding squared items). Because of excessive head mo-
tion, estimated with mean framewise displacement (FD) (Power
et al.,2012,2014), five healthy controls and four patients were
excluded (FD 40.2 mm). The remaining participants (19 per
group) did not differ in mean FD (P= 0.49), percentage of
frames deleted (P= 0.71), age (P= 0.27), and injected radioli-
gand dose (P= 0.91), as shown by t-tests, or sex (P= 0.73), as
shown by chi-squared test (Table 1).
We investigated cortico-thalamic iFC for SAL and ASM, re-
spectively, with seed-based iFC analysis. Cortical seeds were
derived from the 17-network cortical parcellation of Yeo et al.
(2011). The iFC analysis was restricted to the thalamus, with
thalamic target regions of interest based on thalamic clusters
from our previous study of SAL-/ASM-hypo-/hyperconnectivity
in a completely distinct, independent sample of patients with
schizophrenia (Avram et al.,2018). For SAL-iFC, we masked
the thalamus with the group-distinct cluster we previously
reported to be hypoconnected with SAL in patients (mainly cov-
ering mediodorsal and ventral anterior nuclei), and for ASM-
iFC, we used the analogous cluster previously reported to be
hyperconnected with ASM in patients (mainly covering ventral
and posterior thalamic nuclei). Correlating the time courses of
these seeds and target regions of interest, we generated z-maps
reflecting SAL-thalamic and ASM-thalamic iFC. Subsequently,
we extracted voxel-wise iFC values from the target regions of
interest, averaged them, and performed two-sample t-tests to
compare the resulting region of interest-wise iFC values between
groups.
Statistical analyses
Relationship between striatal dopamine synthesis
capacity and cortico-thalamic intrinsic functional
connectivity
To elucidate the physiological background of the relationship
between striatal DSC and cortico-thalamic iFC and to replicate
previous findings (McCutcheon et al.,2019), we initially investi-
gated this relationship in healthy controls, thereby bypassing
possible effects of the disorder and/or antipsychotic medication.
We used partial correlation analyses with age, sex, and head
motion (FD) as covariates of no interest to investigate relation-
ships within systems (i.e. associative striatum DSC and SAL-
thalamic iFC, and sensorimotor striatum DSC and ASM-thal-
amic iFC, respectively).
Next, to test our main hypothesis of a topographic associ-
ation between altered striatal DSC and cortico-thalamic dyscon-
nectivity in schizophrenia, we performed partial correlation
analyses in patients, with age, sex, FD, and chlorpromazine
equivalents (CPZ) as covariates of no interest.
Finally, we tested whether associations between striatal DSC
and cortico-thalamic iFC differed between patients and controls.
Table 1 Participant demographics and clinical-neuropsychological scores
Patients with schizophrenia Healthy controls P-value
Mean ±SD Mean ±SD
n19 19
Age, years 41.1 ±12.17 36.84 ±11.5 0.27
Females/males 7/12 6/13 0.73
FD, mm 0.12 ±0.03 0.11 ±0.03 0.49
Injected radioactivity, MBq 141.57 ±17.42 142.31 ±26.1 0.91
Illness duration, years 13.47 ±9NANA
Chlorpromazine equivalents, mg/day 492.15 ±380.04 NA NA
PANSS, a.u.
Positive 11.36 ±3.53 NA NA
Negative 14.31 ±6.36 NA NA
General 26.73 ±7.42 NA NA
Total 51.42 ±13.61 NA NA
Age, FD, injected radioactivity, and PANSS scores were compared with two-sample t-tests; gender was compared using chi-squared test. a.u. = arbitrary units; NA = not applicable;
PANSS = Positive and Negative Syndrome Scale; SD = standard deviation.
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To this end, we performed a multiple regression analysis with
cortico-thalamic iFC as dependent variable and striatal DSC,
group, and the interaction DSC group (our outcome of inter-
est) as independent variables, as well as age, sex, FD, and CPZ
as covariates of no interest.
Control analyses
We conducted several control analyses for potential confound-
ing effects such as choice of thalamic regions of interest for cor-
tico-thalamic iFC, motion-induced artefacts, or current
medication. Detailed descriptions of these analyses can be found
in the Supplementary material.
Data availability
The data that support the findings of this study are available on
request from the corresponding author. The data are not public-
ly available due to their containing information that could com-
promise the privacy of research participants.
Results
SAL-centred system
Associative striatum DSC and SAL-thalamic
intrinsic functional connectivity are decreased in
patients
Averaged associative striatum DSC values were significantly
reduced (P= 0.004) in patients (mean kcer
i=0.0129±0.001
min
–1
) compared to healthy controls (mean k
icer
=
0.0144 ±0.001 min
–1
)(Fig. 2A). Patients had reduced
(P= 0.04) SAL-mediodorsal/ventral-anterior-thalamus iFC
(mean z=0.07±0.04) compared to controls (mean
z=0.10±0.05) (Fig. 2B).Controlanalysesdidnotfindany
confounding effects of head motion (i.e. FD) or current
medication (i.e. CPZ) on group differences in associative stri-
atum DSC and SAL-thalamic iFC, respectively, suggesting
that decreased DSC and iFC values did not depend on mo-
tion artefacts or current medication (Supplementary
material).
Relationship between associative striatum DSC and
SAL-thalamic intrinsic functional connectivity in
controls
To elucidate the physiological background of the association
between associative striatum DSC (k
icer
) and SAL-thalamic
iFC (z-values), we studied this relationship in healthy con-
trols only, using partial correlation analysis with age, sex,
and FD as covariates of no interest. We found an ‘at trend
to significant’ correlation between associative striatum DSC
and SAL-thalamic iFC (r=0.38,P=0.07)(Fig. 2C). This re-
sult is in line with previous findings (McCutcheon et al.,
2019) and supports the idea of a physiological link between
striatal DSC and cortico-thalamic iFC in the SAL-centred
system.
Decreased associative striatum DSC is associated
with decreased SAL-thalamic intrinsic functional
connectivity in patients
To test our study’s hypothesis for the SAL-centred system,
we investigated the association between reduced associative
striatum DSC and SAL-thalamic iFC in patients with schizo-
phrenia via partial correlation analysis with age, sex, FD,
and CPZ as covariates of no interest. Similar to healthy con-
trols, we found a significant positive correlation between as-
sociative striatum DSC and SAL-thalamic iFC in patients
(r=0.51, P=0.02) (Fig. 2C). This association was not con-
founded by the choice of thalamic region of interest
(Supplementary material).
Associative striatum DSC and SAL-thalamic
intrinsic functional connectivity are related both in
patients and controls
Finally, we investigated whether schizophrenia significantly
modulates the relation between DSC and iFC in the SAL-
centred system. In more detail, we performed a multiple re-
gression analysis with interaction, using SAL-thalamic iFC
as dependent variable and associative striatum DSC, group,
and the interaction DSC group as independent variables
as well as age, sex, FD, and CPZ as covariates of no interest.
No significant interaction effect of ‘group associative stri-
atum DSC’ was found on SAL-thalamic iFC (P=0.8), indi-
cating that the positive correlation between striatal DSC and
cortico-thalamic iFC in the SAL-centred system reflects a
continuum across healthy controls and patients rather than
a group-specific characteristic. To estimate the effects of the
various covariates of no interest (age, sex, FD, CPZ) on the
associations between striatal DSC and cortico-thalamic iFC,
we computed several models (Supplementary Tables 2–4).
ASM-centred system
Sensorimotor striatum DSC is decreased and ASM-
thalamic intrinsic functional connectivity is
increased in patients
Averaged sensorimotor striatum DSC was significantly
reduced (P= 0.02) in patients (mean k
icer
=0.0135±0.002
min
–1
) compared to controls (mean k
icer
=0.0156±0.002
min
–1
)(Fig. 3A). Patients had increased (P=0.02)
ASM-ventral/posterior-thalamus iFC (mean z=0.05±0.035)
compared to controls (mean z=0.015±0.05) (Fig. 3B).
Control analyses did not find any confounding effects of
head motion (i.e. FD) or current medication (i.e. CPZ) on
group differences in sensorimotor striatal DSC and ASM-
thalamic iFC, respectively, suggesting that decreased DSC
and iFC values did not depend on head motion artefacts or
current medication (Supplementary material).
Relationship between sensorimotor striatum DSC
and ASM-thalamic intrinsic functional connectivity
in controls
To elucidate the physiological background of the association
between decreased sensorimotor striatum DSC (k
icer
)and
Dopamine and brain connectivity in schizophrenia BRAIN 2020: 143; 3495–3505 |3499
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increased ASM-thalamic iFC (z-values), we first studied this
relationship in healthy controls only, via partial correlation
analysis with age, sex, and FD as covariates of no interest.
In line with previous findings (McCutcheon et al.,2019), the
association was not significant (r=–0.23,P=0.18)
(Fig. 3C), suggesting that under physiological conditions, a
relationship between sensorimotor striatum DSC and ASM-
thalamic iFC is unlikely.
Decreased sensorimotor striatum DSC is associated
with increased ASM-thalamic intrinsic functional
connectivity in patients
To test our study’s hypothesis for the ASM-centred system,
we investigated the association between sensorimotor stri-
atum DSC and ASM-thalamic iFC in patients with schizo-
phrenia via partial correlation analysis with age, sex, FD,
and CPZ as covariates of no interest. In contrast to healthy
controls, we found a significant positive correlation between
sensorimotor striatum DSC and ASM-thalamic iFC in
patients (r=0.54, P=0.01) (Fig. 3C). This association was
not confounded by the choice of thalamic regions of interest
(Supplementary material).
Sensorimotor striatum DSC and ASM-thalamic
intrinsic functional connectivity are related only in
patients
Finally, we tested whether schizophrenia significantly modu-
lates the relationship between DSC and iFC in the ASM-cen-
tred system. We performed a multiple regression analysis
with interaction with ASM-thalamic iFC as dependent vari-
able and sensorimotor striatum DSC, group, and the inter-
action DSC group as independent variables, as well as
age, sex, FD, and CPZ as covariates of no interest. The
interaction ‘group sensorimotor striatum DSC’ was sig-
nificant (P= 0.04), suggesting that—for the ASM-centred
system—sensorimotor striatum DSC and ASM-thalamic iFC
are related in patients only.
Figure 2 Results for the salience network-centred system. (A)Top left: One-sample t-test parametric map of k
icer
(indicating DSC) in the
associative striatum (AST), based on
18
F-DOPA-PET and graphical Patlak analysis. Top right: Associative striatum region of interest from Oxford-
GSK-Imanova atlas. Bottom: Box plots depicting significant group differences in associative striatum DSC (averaged across the region of interest),
measured with a two-sample t-test. (B)Top left: Template of salience network (SAL) derived from Ye o et al. (2011).Top right: Thalamic region of
interest reflecting hypoconnectivity with SAL, derived from our previous study (Avram et al., 2018). Bottom: Box plots depicting group differences
in SAL-thalamic iFC (averaged across the thalamic region of interest), measured with a two-sample t-test. (C) Partial correlations (age, sex, FD,
and CPZ as covariates of no interest) between averaged associative striatum DSC and averaged SAL-thalamic iFC in patients with schizophrenia
(red line and dots) and healthy controls (blue line and dots). The interaction between group and associative striatum DSC is based on a multiple
regression analysis with SAL-thalamic iFC as dependent variable and associative striatum DSC, group, and the interaction DSC group as inde-
pendent variables (age, sex, FD, and CPZ as covariates of no interest). k
icer
= steady-state uptake rate constant of
18
F-DOPA-PET relative to
cerebellum; HC = healthy controls; SCZ = patients with schizophrenia.
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Discussion
Using simultaneous
18
F-DOPA-PET and rs-fMRI in patients
with schizophrenia during remission of psychotic symptoms,
we tested the hypothesis that reduced striatal dopamine links
topographically with cortico-thalamic dysconnectivity. We
found, on the one hand, for the SAL-centred system that
decreased DSC in the associative striatum was associated
with patients’ decreased SAL-thalamic iFC. On the other
hand, in the ASM-centred system, decreased sensorimotor
striatum DSC was associated with increased ASM-thalamic
iFC in patients. These findings demonstrate—to the best of
our knowledge for the first time—that aberrant striatal
dopamine links topographically with cortico-thalamic dys-
connectivity in schizophrenia. Data suggest that striatal
dopamine dysfunction and cortico-thalamic dysconnectivity
are pathophysiologically related.
SAL-centred system
Reduced associative striatum DSC links with
reduced SAL-thalamic intrinsic functional
connectivity
We found a trend for a positive correlation between associa-
tive striatum DSC and SAL-thalamic iFC in healthy controls.
Although only at-trend significant, this result is in line with
recent findings reported by McCutcheon et al. (2019),who
found a positive correlation between associative striatum
DSC and within-SAL iFC in healthy subjects. These observa-
tions suggest a physiological basis for the link between asso-
ciative striatum DSC and SAL-iFC.
Compared to healthy controls, patients with schizophre-
nia during psychotic remission had both reduced associa-
tive striatum DSC and reduced SAL-thalamic iFC, as
previously reported (Woodward and Heckers, 2016;
Avram et al., 2018,2019;Brandl et al., 2019). Critically,
Figure 3 Results for the auditory-sensorimotor network-centred system. (A)Top left: One-sample t-test parametric map of kcer
i
(DSC) in the sensorimotor striatum. Top right: Sensorimotor striatum region of interest from Oxford-GSK-Imanova atlas. Bottom: Box blots
depicting significant group differences in sensorimotor striatum DSC, measured with a two-sample t-test on average DSC values. (B)Top left:
Template of auditory-sensorimotor network (ASM) derived from Ye o et al. (2011) Top right: Thalamic region of interest reflecting hyperconnectiv-
ity with ASM, derived from our previous study (Avram et al., 2018). Bottom: Box blots depicting group differences in ASM-thalamic iFC, measured
with a two-sample t-test on average iFC values. (C) Partial correlations (age, sex, FD, and CPZ as covariates of no interest) between averaged
sensorimotor striatum (SMST) DSC and averaged ASM-thalamic iFC in patients with schizophrenia (red line and dots) and healthy controls (blue
line and dots). The interaction between group and sensorimotor striatum DSC is based on a multiple regression analysis with ASM-thalamic iFC
as dependent variable and sensorimotor striatum DSC, group, and the interaction DSC group as independent variables (age, sex, FD, and CPZ
as covariates of no interest). k
icer
= steady-state uptake rate constant of
18
F-DOPA-PET relative to cerebellum; HC = healthy controls; SCZ =
patients with schizophrenia.
Dopamine and brain connectivity in schizophrenia BRAIN 2020: 143; 3495–3505 |3501
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we found that the two measures correlated significantly in
patients. Furthermore, a multiple regression analysis dem-
onstrated that the association between associative stri-
atum DSC and SAL-thalamic iFC was not distinct for the
two groups as the interaction effect of group and associa-
tive striatum DSC on SAL-thalamic iFC was not signifi-
cant. This suggests that the association between
associative striatum DSC and SAL-thalamic iFC reflects a
continuum across subjects rather than a characteristic that
is specific for schizophrenia. Furthermore, this finding is
congruent with general evidence that the dopaminergically
modulated basal ganglia interact with cortico-thalamic
connectivity (Carlsson et al.,2001;Haber and Calzavara,
2009;Bell and Shine, 2016) through parallel, topograph-
ically organized cortico-striato-pallido-thalamo-cortical
circuits (CSPTC) (Hikosaka et al.,2014;Grillner and
Robertson, 2016;Shepherd and Grillner, 2018).
Particularly, associative cortices including frontal/SAL
regions (i.e. opercular-insula, dorsal anterior cingulate)
form, together with the associative striatum and medio-
dorsal nucleus, parts of the associative CSPTC circuit
(Alexander et al., 1986;Parent and Hazrati, 1995). The
circuit is modulated by dopaminergic projections from
substantia nigra pars compacta, which projects topo-
graphically to cortical and subcortical areas, including
dorsal striatum and mediodorsal nucleus (Joel and
Weiner, 2000;McFarland and Haber, 2002;Haber and
Knutson, 2010;Varela, 2014). In such a framework,
changes in both associative striatum DSC and SAL-thal-
amic iFC might contribute to CSPTC circuit aberrances.
Below, we discuss which of both changes, reduced striatal
DSC or SAL-thalamic iFC, might be primary, i.e. drive
changes in the other measure.
ASN-centred system
Reduced sensorimotor striatum DSC links with
increased ASM-thalamic intrinsic functional
connectivity
Sensorimotor striatum DSC and ASM-thalamic iFC were
not significantly correlated in healthy controls, which indi-
cates that under physiological conditions, a relationship be-
tween the two measures is unlikely. This result is in line with
a previous report in which a significant association between
striatal DSC and iFC of the sensorimotor network was ab-
sent (McCutcheon et al.,2019).
Compared to healthy controls, patients had decreased sen-
sorimotor striatum DSC and increased ASM-thalamic iFC,
in line with previous findings (Woodward et al.,2012;
Avram et al.,2018,2019;Brandl et al.,2019). Furthermore,
supporting our hypothesis, the two measures were positively
correlated. A multiple regression analysis demonstrated a
significant interaction effect of group and sensorimotor stri-
atum DSC on ASM-thalamic iFC, suggesting that the associ-
ation between sensorimotor striatum DSC and ASM-
thalamic iFC was specific for schizophrenia. However, as
the patients recruited for this study received antipsychotic
medication, it was not possible to disentangle disorder
effects from medication effects. Specifically, both striatal
DSC and antipsychotic medication are thought to affect
postsynaptic dopaminergic receptors (McCutcheon et al.,
2020); therefore, putative downstream effects of dopamine
on neural circuits (i.e. on SAL-thalamic iFC) could be related
to disorder-specific alterations (e.g. pathologically reduced/
elevated striatal DSC) and/or effects of antipsychotic medica-
tion (e.g. by blocking dopaminergic receptors). In addition
to potential anti-dopaminergic effects of antipsychotics (and
adjunctive psychotropic medication) (see Avram et al., 2019
for discussion), anticholinergic burden of medication might
confound our results. Previous studies have demonstrated
that functional MRI-based blood oxygenation signals are
influenced by acetylcholine levels (Zaldivar et al.,2018).
However, a recent study demonstrated that although acetyl-
choline levels change the global blood oxygenation signal
(i.e. the averaged grey matter signal of blood oxygenation),
they do not seem to affect iFC of intrinsic networks such as
SAL (Turchi et al.,2018). Nevertheless, we cannot complete-
ly exclude anticholinergic effects on our findings of altered
iFC in patients, which should therefore be evaluated careful-
ly with respect to the anticholinergic burden of medication
(see Supplementary Table 1 for anticholinergic side effects of
medication in patients). Future studies could elucidate this
issue by investigating this link in unmedicated patients with
schizophrenia.
Topographic relations between
reduced striatal DSC and
cortico-thalamic dysconnectivity in
schizophrenia
In summary, our results provide evidence that decreased
striatal DSC and cortico-thalamic dysconnectivity are
topographically linked in schizophrenia: (i) within the
SAL-centred system, reduced associative striatum DSC
correlates with reduced SAL-thalamic iFC; and (ii) within
the ASM-centred system, reduced sensorimotor striatum
DSC correlates with increased ASM-thalamic iFC. We in-
terpret our findings in the framework of largely parallel
but interacting CSPTC circuits and midbrain dopamin-
ergic projections, which are both organized topographical-
ly (Alexander et al.,1986;Haber, 2003;Hikosaka et al.,
2014). Remarkably, a link integrating aberrant dopamine
transmission with CSPTC dysconnectivity in schizophre-
nia has long been proposed by theoretical models
(Swerdlow and Koob, 1987).Ourfindingsprovideempir-
ical support for such models.
However, the inherent limitations of our outcome
measures and the cross-sectional design of the study
make the translation of these statistical findings into a
full pathophysiological model difficult. First, it remains
unclear which of the two measures has a causal role in
eliciting changes in the other measure, as the direction of
influence (i.e. striatal DSC changes lead to cortico-
3502 |BRAIN 2020: 143; 3495–3505 M. Avram et al.
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thalamic iFC alterations or vice versa) cannot be estab-
lished here, and both options seem plausible. For in-
stance, there is evidence that experimental manipulation
of dopamine transmission via pharmacological manipula-
tion influences iFC in both SAL and ASM (Cole et al.,
2013;Esposito et al., 2013;Shafiei et al., 2019).
Likewise, an influence in the other direction is also pos-
sible: cortico-thalamic iFC might alter striatal dopamine
transmission, for example via CSPTC circuits and direct
striato-nigral projections (Hikosaka et al., 2014;Haber,
2016). Therefore, a further specification of our findings
in terms of such a causal pathophysiological model
would be highly speculative. For instance, some models
propose that certain structures convey the effects of aber-
rant striatal dopamine on CSPTC circuits (e.g. ventral
pallidum) (Swerdlow and Koob, 1987); however, we are
unable to identify such possible effects with the measures
used in this study.
Second, concerning the reduction of striatal DSC under
conditions of psychotic remission, it remains unclear how
this reduction comes about—i.e. is it an effect of disorder
state or rather of antipsychotic medication, or both?
Correspondingly, although we have controlled for effects of
current medication by statistical methods, we cannot exclude
long-/mid-term effects of medication on both measures and
their relationship. Longitudinal studies investigating this re-
lationship in both medicated and unmedicated patients are
necessary to disentangle these effects.
Strengths and limitations
The current study is the first to investigate the relationship
between striatal DSC and cortico-thalamic iFC with simul-
taneous
18
F-DOPA-PET and rs-fMRI, avoiding temporal
confounds of sequential assessment. We recruited a well-
defined, homogeneous sample of patients, reducing con-
founds of symptomatic variance (i.e. psychosis); and our
results support long-established theoretical models, based on
the well-established physiological framework of CSPTC cir-
cuits. Particularly, our findings integrate two largely inde-
pendent lines of findings in schizophrenia: striatal dopamine
dysfunction and cortico-thalamic dysconnectivity. In terms
of limitations of our study, the sample size was relatively
modest, therefore findings are not definitive and have to be
evaluated carefully. Most patients were medicated, potential-
ly confounding the study’s results (Supplementary material).
For detailed discussion of this point see above. Both striatal
DSC and blood oxygenation-based cortico-thalamic iFC are
indirect measures of brain activity averaged over several
minutes and reflect mixed signals. Therefore, we are only
able to examine relatively coarse relations and we might
have missed fast-occurring effects (e.g. phasic dopaminergic
transmission).
Conclusion
Cortico-thalamic dysconnectivity links topographically with
reduced striatal dopamine in schizophrenia. Data suggest
that aberrant striatal dopamine and cortico-thalamic dyscon-
nectivity are pathophysiologically related within dopamine-
modulated cortico-basal ganglia-thalamic circuits in
schizophrenia.
Acknowledgements
We thank Sylvia Schachoff and Anna Winter for their tech-
nical assistance during PET/MRI measurements. Particularly,
we thank all subjects for participating in the study.
Funding
This work has been supported by the European Union 7th
Framework Programme, TRIMAGE, a dedicated trimodality
(PET/MR/EEG) imaging tool for schizophrenia (Grant no.
602621). F.B. was supported by the Hans und Klementia
Langmatz Stiftung. F.K. received funding from the European
Union’s Horizon 2020 (Grant number 754462).
Competing interests
The authors report no conflict of interest relating to this
work. S.L. has received honoraria for consulting or lectures
from LB Pharma, Lundbeck, Otsuka, TEVA, LTS Lohmann,
Geodon Richter, Recordati, Boehringer Ingelheim, Sandoz,
Janssen, Lilly, SanofiAventis, Servier, and Sunovion.
Supplementary material
Supplementary material is available at Brain online.
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