The relationship between the dopaminergic system and depressive symptoms in cervical dystonia
The relationship between the dopaminergic system and depressive symptoms in cervical dystonia
E. Zoons 0 1 2
J. Booij 0 1 2
M. A. J. Tijssen 0 1 2
Y. E. M. Dreissen 0 1 2
J. D. Speelman 0 1 2
M. Smit 0 1 2
0 Department of Nuclear Medicine, Academic Medical Centre , PO Box 22660, 1100 DD Amsterdam , The Netherlands
1 Department of Neurology, University Medical Centre , Groningen , The Netherlands
2 Department of Neurology, Academic Medical Centre , Amsterdam , The Netherlands
Purpose Cervical dystonia (CD) is associated with tremor/ jerks (50%) and psychiatric complaints (17-70%). The dopaminergic system has been implicated in the pathophysiology of CD in animal and imaging studies. Dopamine may be related to the motor as well as non-motor symptoms of CD. CD is associated with reduced striatal dopamine D2/3 (D2/3) receptor and increased dopamine transporter (DAT) binding. There are differences in the dopamine system between CD patients with and without jerks/ tremor and psychiatric symptoms. Methods Patients with CD and healthy controls underwent neurological and psychiatric examinations. Striatal DAT and D2/3 receptor binding were assessed using [123I]FP-CIT and [123I]IBZM SPECT, respectively. The ratio of specific striatal to non-specific binding (binding potential; BPND) was the outcome measure. Results Twenty-seven patients with CD and 15 matched controls were included. Nineteen percent of patients fulfilled the criteria for a depression. Striatal DAT BPND was significantly lower in depressed versus non-depressed CD patients. Higher DAT BPND correlated significantly with higher scores on the Unified Myoclonus Rating Scale (UMRS). The striatal D2/3 receptor BPND in CD patients showed a trend towards lower binding compared to controls. The D2/3 BPND was significantly lower in depressed versus non-depressed CD patients. A significant correlation between DAT and D2/3R BPND was found in both in patients and controls. Conclusions Alterations of striatal DAT and D2/3 receptor binding in CD patients are related mainly to depression. DAT BPND correlates significantly with scores on the UMRS, suggesting a role for dopamine in the pathophysiology of tremor/jerks in CD.
Cervical dystonia; SPECT; Dopamine D2/3 receptor; Dopamine transporter (DAT); Depression
Dystonia is characterized by sustained or intermittent muscle
contractions causing abnormal, often repetitive, movements,
postures, or both . Idiopathic cervical dystonia (CD; dystonia
of the neck) is the most common form . Approximately 50%
of CD patients suffer from myoclonus (jerks) or tremor of the
head. It has been hypothesized that patients with tremor/jerks
have a more severe phenotype, with segmental spreading of
dystonia and more often an underlying genetic cause . One
of the regions hypothesized to be involved in the
pathophysiology in tremor/jerks in dystonia is the nucleus of Cajal, which
obtains information projected from the substantia nigra pars
compacta, implicating the dopaminergic system .
Over the last few years, there has been increasing
awareness of non-motor symptoms in CD patients. Psychiatric
complaints, mainly depressive symptoms and anxiety disorders,
have been described in a significant number of patients with
dystonia (17–70%) [5–7]. Lifetime prevalence of up to 91.4%
has been reported . It is hypothesized that motor and
psychiatric symptoms have a common underlying biochemical
etiology [8, 9].
Several studies have implicated the dopaminergic system in
the pathophysiology of dystonia. A hyperdopaminergic system,
defined as an increased concentration of synaptic dopamine, is an
attractive hypothesis in dystonia. In animal models of inherited
forms such as myoclonus dystonia (M-D) and DYT1 dystonia, a
hyperdopaminergic system has been confirmed [10, 11].
Human studies have shown lower striatal dopamine D2/3
(D2/3) receptor binding in patients with CD, writer’s cramp
and M-D [12–15]. According to the competition model, this
decreased D2/3 receptor binding is compatible with higher
concentrations of synaptic dopamine and occupancy of more
postsynaptic D2/3 receptors, a reduced number of these receptors,
or a combination of both. Increased levels of synaptic dopamine
may lead to upregulation of the dopamine transporter (DAT) to
ensure greater reuptake of endogenous dopamine. However,
previous imaging studies investigating DAT binding found no
differences between dystonia patients and controls [8, 15].
Recent animal studies have shown that the dopaminergic tone
is probably regulated by the amount of DAT present at the
presynaptic cell membrane [16, 17]. This could explain the lack
of DAT binding abnormalities found despite indications of a
hyperdopaminergic system, i.e. more DAT are present, but they
are occupied by the higher level of intrasynaptic dopamine.
The dopaminergic system is also implicated in psychiatric
conditions, especially in major depression. Two positron
emission tomography (PET) studies found reduced striatal
DAT binding in patients with major depression [18, 19].
Striatal DAT binding is also negatively related to depressive
symptoms in patients with Parkinson’s disease . Previous
nuclear imaging studies in dystonia did not correct for
In the present study, to further establish the role of
dopamine in dystonia and comorbid psychiatric symptoms, we
imaged both the presynaptic striatal DAT and the postsynaptic
striatal D2/3 receptors in the same sample. We hypothesized
that CD is associated with reduced striatal D2/3 receptors and
increased striatal DAT binding. In addition, we investigated
whether there were differences in the dopamine system
between patients with and without jerks/tremor and between
patients with and without psychiatric symptoms.
Material and methods
We included patients who had been previously diagnosed with
idiopathic CD by an experienced neurologist. Neurological
examination and additional tests (laboratory tests, genetic tests
and conventional imaging) revealed no signs of acquired or
inherited dystonia (including dopa-responsive dystonia).
Inclusion criteria were as follows: CD that had been stable
according to the Tsui scale for at least 1 year during botulinum
neurotoxin (BoNT) treatment , and age of 35–80 years.
BoNT injections were administered on the day of
singlephoton emission computed tomography (SPECT) scanning or
a maximum of 7 days prior to/after scanning. This applied for
both scans. Scans were acquired within 3 to 7 days of each
other. Exclusion criteria were other relevant neurological
conditions at inclusion or in the past, treatment with deep brain
stimulation (DBS), use of antidepressants in the past 6 months,
symptomatic therapy for dystonia other than BoNT and low
dosages of benzodiazepines, use of medication with a known
dopaminergic or serotonergic effect , and pregnancy or
lactation. Patients were allowed to use other medications, e.g.
antihypertensive drugs. Healthy age- and sex-matched subjects
(recruited through flyers in the hospital) served as the control
group. Controls had a normal neurological examination and no
self-reported history or family history of dystonia, myoclonus
or psychiatric illness. Written informed consent was obtained
from all subjects, and the study was approved by the local
medical ethics committee.
Scoring neurological and psychiatric symptoms
The neurological examination of patients was videotaped and
blindly scored by two independent clinicians. Dystonic
symptoms were scored using the Toronto Western Spasmodic
Torticollis Rating Scale (TWSTRS)  and the Tsui scale
. Symptoms of myoclonus were scored using the Unified
Myoclonus Rating Scale (UMRS) . The independent scores
on the Tsui and TWSTRS revealed good agreement between
the two observers (>0.80 intraclass correlation coefficients,
two-way mixed, absolute agreement, average measures). The
independent scores on the UMRS had an intraclass correlation
coefficient of 0.73. The average scores of the two experts on the
Tsui, TWSTRS and UMRS were used in the statistical analysis.
Subjects completed several take-home questionnaires
concerning psychiatric symptoms. The psychiatric interview,
performed by a trained investigator (EZ, YD), consisted of
the Mini International Neuropsychiatric Interview
(MINI)Plus and several questionnaires concerning symptoms of
depression and anxiety. For this study we incorporated the results
of the Beck Depression Inventory (BDI; home questionnaire)
and Montgomery–Asberg Depression Rating Scale (MADRS;
incorporated in psychiatric interview) for depression and the
Liebowitz Social Anxiety Scale (LSAS; home questionnaire)
and the Beck Anxiety Inventory (BAI; home questionnaire) for
anxiety. Subjects were judged to have a depressive disorder
when they fulfilled the relevant criteria on the MINI and/or
had a MADRS score ≥ 20 points or BDI score ≥ 14 points.
These cut-off values correspond to moderate–severe
depression. Subjects were judged to have an anxiety disorder when
they fulfilled the relevant criteria on the MINI-Plus and/or had a
BAI score ≥ 16 points or LSAS score ≥ 30 points. These cut-off
values correspond to moderate–severe anxiety.
All participants received 300 mg potassium iodide to block
thyroid uptake of free radioactive iodide before administration
of the tracer. For the DAT study, subjects received a mean dose
of 100 MBq of [123I]FP-CIT intravenously (produced
according to good manufacturing practices [GMP] criteria by GE
Healthcare) as a bolus . Scans were performed 3 h after
bolus injection to visualize and quantify the specific DAT
binding in the striatum . For visualizing striatal D2/3 receptor
binding, subjects received a 56 MBq bolus of [123I]IBZM
intravenously (produced according to GMP criteria by GE
Healthcare) followed by continuous infusion of 14 MBq/h of
[123I]IBZM until the end of the scan to achieve unchanging
regional brain activity levels [27, 28]. Acquisition of the images
was started 2 h after the bolus injection [27, 29]. SPECT studies
were performed using a 12-detector single-slice brain-dedicated
scanner (Neurofocus 810 is an upgrade for the Strichman
Medical Equipment 810X camera) with a full-width at
halfmaximum resolution of approximately 6.5 mm throughout the
20-cm field of view. After positioning of the subjects with the
head parallel to the orbitomeatal line, axial slices parallel and
upward from the orbitomeatal line to the vertex were acquired
in 5-mm increments, with an average of 15 slices in a 64×64
matrix. Scanning time was 3.5 min per slice for [123I]FP-CIT
and 5 min per slice for [123I]IBZM SPECT. The energy window
was set at 140–178 keV. Images were reconstructed in 3-D
mode and analysed blindly by one observer (EZ). For the
[123I]FP-CIT SPECT images, fixed regions of interest (ROIs)
for caudate nucleus and putamen were positioned on the four
consecutive axial slices with highest striatal activity, as
described previously . The activity in the separate ROIs was
combined to reflect average activity in the caudate nucleus
(left + right), putamen (left + right) and whole striatum
bilaterally. The cerebellum was used as reference region by
positioning an ROI, as described previously . For the [123I]IBZM
images, fixed ROIs were positioned for the striatum, as
described previously . The four slices with the highest striatal
activity were pooled, and the average activity was calculated.
An ROI was positioned on the occipital cortex on the same four
slices as reference region for the IBZM tracer. For both scans,
ratios of specific to non-specific binding were calculated as
[(activity in ROI − activity in reference region)/activity in
reference region], representing the binding potential (BPND) .
BPND is a combined measure of the density of available
neuroreceptors and tracer affinity to the neuroreceptor.
The Mann–Whitney U test and Kruskal–Wallis test were used
to assess differences in receptor/transporter binding ratios
(BPND) between different groups of subjects. The Kruskal–
Wallis test was also used to assess differences in baseline
characteristics between patients with and without jerks/
tremor and controls. Chi-square and Fisher’s exact tests were
used to assess dichotomous variables.
Linear regression was used to determine whether differences
in baseline characteristics explained differences in BPND, both
between patients with and without jerks/tremor and between
dystonia patients and healthy controls. Linear regression was
also used for assessing relationships between BPND and motor
and psychiatric scores and between motor and psychiatric
scores. Multicollinearity among variables was avoided by
categorizing motor and psychiatric symptoms and not using more
than one such variable in the model. Analyses were carried out
using SPSS version 20 software (IBM Corp., Armonk, NY,
USA), and differences were considered significant at p < 0.05.
We included 27 patients with CD (15 with jerks/tremor and 12
without) and compared them to 15 age- and gender-matched
healthy controls. Due to technical difficulties, one
[123I]FPCIT SPECT scan of a control and three [123I]FP-CIT scans
and one [123I]IBZM scan of patients had to be excluded from
the analysis. Baseline characteristics are depicted in Table 1
for subjects in whom at least one scan was available for
analysis. Patients with jerks/tremor were slightly but not
significantly younger than patients without jerks/tremor and
controls. Tsui scores were slightly higher in patients with jerks/
tremor. UMRS scores were significantly higher in patients
with tremor/jerks, but even ten patients classified as having
no tremor/jerks occasionally exhibited myoclonus, with
UMRS scores around 1–2. Psychiatric comorbidity was
common in CD patients (17/27 patients; 63%). There was no
significant difference in psychiatric comorbidity between
patients with and without tremor/jerks. There was no correlation
between motor scores and psychiatric comorbidity, excluding
multicollinearity in further regression models. Two out of 14
controls (14%) fulfilled the criteria for a psychiatric diagnosis
(one for alcohol abuse in the past, and one scored 34 on the
LSAS, meeting the criteria for social anxiety disorder).
[123I]FP-CIT SPECT – dopamine transporter imaging
There was no difference between DAT BPND in the whole
striatum between CD patients (3.48; IQR 3.01–3.84) and
controls (3.64; IQR 3.33–3.99; p = 0.41) or in the caudate nucleus
(p = 0.58) or putamen (p = 0.38) separately. DAT BPND was
comparable between patients with and without jerks/tremor
for the whole striatum (p = 0.24), caudate nucleus (p = 0.33)
and putamen (p = 0.37). Neither Tsui (p = 0.86) nor TWSTRS
(p = 0.56) explained the variance in DAT BPND. However,
Table 1 Baseline characteristics
BAI Beck Anxiety Inventory, BDI Beck Depression Inventory, CD cervical dystonia, IQR interquartile range,
LSAS Liebowitz Social Anxiety Scale, MADRS Montgomery–Asberg Depression Rating Scale, n number,
TWSTRS Toronto Western Spasmodic Torticollis Rating Scale, UMRS Unified Myoclonus Rating Scale
UMRS scores contributed significantly to differences in DAT
BPND (p = 0.04, rs = 0.19).
CD patients with comorbid depression had lower DAT
BPND (3.02; IQR 2.51–3.39) in the whole striatum compared
to patients without depression (3.54; IQR 3.34–4.03; p =
0.05). This difference was also present in the caudate nucleus
(DAT BPND 3.00 [IQR 2.58–3.51] vs. 3.84 [IQR 3.51–4.24];
p = 0.02). DAT BPND was also lower in the putamen of
patients with a depression compared to patients without, but this
did not reach statistical significance (p = 0.14). There was no
significant difference in DAT BPND between CD patients
without comorbid depression and controls (DAT BPND 3.54
[3.34–4.03] vs. 3.64 [IQR 3.33–3.99]; p = 0.86 for whole
striatum). No differences were found between patients with and
without psychiatric co-morbidity and with and without an
anxiety disorder. Scores of CD patients on the BDI (p =
0.90), MADRS (0.29), LSAS (0.81) and BAI (0.44) did not
contribute to differences in DAT BPND in the whole striatum.
Since age and sex are known to have an effect on DAT BPND
as measured with [123I]FP-CIT SPECT [34–36], and age
differed slightly between groups, they could be potential
confounders. Therefore, we corrected for these factors for the
striatum as a whole, which did not change any of the results
(regression coefficients and p values are depicted in Table 2).
Correcting for the occurrence of depression changed the
correlation between DAT BPND and UMRS scores only slightly (p =
0.04 before correction and 0.06 after correction).
D2/3 receptor BPND between patients with and without jerks
(p = 0.54). Scores on the Tsui (p = 0.92), TWSTRS (p = 0.74)
and UMRS (p = 0.67) did not contribute to differences in D2/3
Patients with psychiatric symptoms did not differ in D2/3
receptor BPND from patients without (p = 0.20), nor did patients
with an anxiety disorder differ from patients without (p = 0.72).
Patients with depression had a significantly lower D2/3 receptor
BPND (0.56, IQR 0.48–0.72) compared to patients without
(0.89; IQR 0.70–1.01; p = 0.008). There was no significant
difference in D2/3 receptor BPND between CD patients without
comorbid depression and controls (D2/3 receptor BPND 0.89
[IQR 0.70–1.00] vs. 0.91 [0.79–1.12]; p = 0.43). In CD
patients, scores on BDI (p = 0.25), MADRS (0.82), LSAS
(0.36) and BAI (0.70) did not contribute to D2/3 receptor BPND.
Since age and sex are known to have an effect on D2/3
receptor BPND , we corrected for these factors. This did
not change the result between patients and controls (p = 0.09
before and after correction) or between patients with and
without jerks (p = 0.66 before correction and 0.44 after correction).
Because of the surprising finding of a large difference in D2/3
receptor BPND between patients with and without comorbid
depression, we also separately corrected the D2/3 receptor BPND
for the occurrence of depression. Before correction, there was a
regression coefficient of −0.12 between patients and controls
(95% CI −0.25 to 0.02; p = 0.09), and after correction the
regression coefficient was −0.06 (95% CI −0.19 to 0.07; p = 0.34).
[123I]IBZM SPECT - dopamine D2/3 receptor imaging
DAT-D2/3 receptor ratio
There was a trend towards lower striatal D2/3 receptor BPND
in patients with CD (0.84; IQR 0.63–0.99) compared to
controls (0.91; 0.79–1.12; p = 0.14). There was no difference in
In patients with a lower striatal DAT BPND, there was a trend
towards a lower striatal D2/3 receptor BPND (regression
coefficient 0.93 [95% CI −0.30 to 2.14]; p = 0.13). The same trend
Regression analyses for DAT BPND corrected for age and sex
Regression coefficient for
DAT BPND before correction
was found in controls (regression coefficient 1.03 [95% CI
−0.55 to 2.61]; p = 0.18). When patients and controls were
combined, this resulted in a statistically significant correlation
between striatal DAT and D2/3 receptor BPND (regression
coefficient 0.98 [95% CI 0.12–1.84]; p = 0.03; Fig. 1). This
correlation was not caused by an age effect. When plotting the binding
potential and age in graphs, in both cases the fit lines are almost
horizontal but with a trend towards decreasing BPND at higher
age (R2 0.028 for D2/3 receptor and R2 0.015 for DAT).
This study showed a strong relation between depressive
symptoms and alterations in striatal DAT and D2/3 receptor binding
in patients with CD. In addition, the association between DAT
BPND and scores on the UMRS suggests a role for dopamine
in the pathophysiology of tremor/jerks in CD.
In line with previous studies, no difference in striatal DAT
binding was detected between patients and controls.
Differences in DAT binding are likely to be small, but can still
be clinically significant. The fact that we did not find a
difference in striatal DAT binding may be explained by various
factors. First, it might mean that there is no difference in the
number of DATs. Second, there could be a hyperdopaminergic
system that cannot be detected with DAT imaging. Two recent
animal studies hypothesized that dopaminergic tone is
Fig. 1 The correlation between DAT and D2/3 receptor BPND in both
patients (black circles) and controls (grey circles). The D2/3 receptor BPND is
shown on the x-axis, and the DAT BP is shown on the y-axis. Every black or
grey circle is an individual study subject. Values are depicted only for subjects
in which both a DAT and D2/3 receptor scan was performed
Regression coefficient for
DAT BPND corrected for
age and sex
regulated by the amount of DAT present at the presynaptic
cell membrane. More intrasynaptic dopamine would lead to
more DATs to bind dopamine. In that case, the amount of DAT
free to bind [123I]FP-CIT might be stable, and no difference
would be found in DAT BPND [16, 17]. Lastly, it could mean
that there is a difference in intrasynaptic dopamine, but
[123I]FP-CIT is less sensitive in detecting differences in
dopaminergic concentrations compared to [123I]IBZM.
We did find a strong trend towards reduced striatal D2/3
receptor binding in patients with idiopathic CD compared to
controls. This could be consistent with a hyperdopaminergic
state in the striatum and/or with a reduced number of D2/3
receptors. Previous reports have been ambiguous about D2/3
receptor binding in dystonia, although reduced binding has
been more commonly reported [13, 15, 37].
The existence of depressive symptoms within the group of
CD patients was associated with a significant difference in
striatal D2/3 receptor and DAT BPND. There was no significant
difference in DAT or D2/3 receptor BPND between
nondepressed CD patients and controls. Moreover, when we
corrected for comorbid depression, there was no longer a
difference in D2/3 receptor BPND between patients and controls,
indicating that changes in the dopamine system of CD patients
may correlate mainly with depressive symptoms and not with
dystonia per se. Psychiatric symptoms, more specifically
anxiety and depression, are common in dystonia. In our cohort,
63% of patients had psychiatric symptoms. This is on the high
end of the 17–70% range reported in observational cohort
studies in the literature [6, 7, 38, 39]. Molecular imaging studies in
depression and anxiety disorders have shown abnormalities in
both striatal DAT and D2/3 receptor binding. Most studies in
major depressive disorder (MDD) have reported decreased
striatal DAT binding compared to controls [40–42]. Reduced
DAT binding has also been described in anxiety disorders,
although less consistently [43, 44]. Results on striatal D2/
3 receptor binding in patients with depression and anxiety
have been ambiguous. Abnormalities have been found, but
differences with controls were smaller than observed in
studies on DAT binding, and both decreased and increased binding
have been described [45–47]. Reduced striatal DAT binding
has been found in Parkinson’s patients with depression
compared to non-depressed Parkinson’s patients, and binding
in the caudate nucleus was negatively related to the severity of
depressive symptoms in patients with Parkinson’s disease [20,
48]. We also observed that decreased DAT binding in the
caudate nucleus was related to depressive symptoms in CD.
Another recent study investigated striatal DAT
availability in different groups of patients with movement disorders
and found normal DAT binding in dystonia patients, with
an inverse correlation between DAT availability in the left
putamen and severity of both anxiety and depression .
The authors hypothesized that dysfunction of the basal
ganglia-thalamocortical circuits underlies both motor and
psychiatric manifestations in movement disorders . We
hypothesize that the differences we found in striatal DAT
and D2/3R binding are mainly driven by the psychiatric
symptoms in dystonia. However, an effect of motor
symptoms cannot be completely ruled out, especially since a
recent study found differences in spatial reorganization of
putaminal D2/3 receptor binding between patients with
blepharospasm and hand dystonia . We were unable to
measure spatial redistribution due to the limited spatial
resolution of SPECT imaging. We can say, however, that
psychiatric symptoms play an important role in abnormalities
in the dopamine system of patients with CD and should be
taken into account in future imaging studies. It could be that
patients who suffer from both motor and psychiatric
symptoms have a more severe phenotype in which dopamine
plays a more important role.
There was no difference in D2/3 receptor or DAT
binding between CD patients with and without tremor or jerks,
although DAT binding did correlate with scores on the
UMRS . This is probably because most patients
classified as having no jerks (10/12) did have some mild jerks or
tremor. As stated above, the nucleus of Cajal, which
receives input from the substantia nigra pars compacta, has
been hypothesized to play a role in the occurrence of tremor
and jerks in dystonia. Biochemical changes in this region
may lead to changes in DAT binding and tremor or jerks in
CD patients . However, this area is too small to assess
in vivo in humans.
The other interesting finding is the positive correlation
between DAT and D2/3 receptor binding. This is not consistent
with the competition model. It is likely that the competition
model applies only to acute interventions and not to chronic
disease conditions such as dystonia. The relation between
DAT and D2/3 receptor binding has not been studied
extensively in healthy controls or in different conditions, although a
recent study showed a significant positive correlation between
striatal DAT and D2/3 receptor binding in healthy controls
, using the same radiotracers we used.
This study has several limitations. The use of dopaminergic
or serotonergic medication  was an exclusion criterion in
our study, which could have excluded patients with severe
psychiatric complaints, leading to an underestimation of the
effect of psychiatric symptoms on DAT and D2/3 receptor
binding. Patients in our study did receive BoNT injections
and were allowed to use low dosages of benzodiazepines.
Furthermore, since subjects were on average 50–60 years of
age, most of them used medication for other conditions. BoNT
is a locally acting neurotoxin without systemic effects, and its
effect is noticeable after 1 week . Both scans were
performed before this effect could occur; thus it is unlikely that
BoNT had a direct effect on striatal DAT or D2/3 binding
ratios. We cannot rule out a placebo effect of the BoNT
injections, and such an effect has not been investigated to date.
There are some indications that benzodiazepines have an
effect on D2/3 receptor binding in the striatum and dorsolateral
prefrontal cortex. However, this has been investigated only
with lorazepam doses sufficient to cause sedation [51, 52].
Patients in our study used a low dosage of oxazepam or
clonazepam. Therefore, we do not believe that this influenced our
results significantly. [123I]FP-CIT is derived from cocaine and
metabolized by cytochrome P450 type 3A (CYP3A) in the
liver . The same enzyme also metabolizes most drugs.
Therefore, at least theoretically, many drugs might influence
[123I]FP-CIT metabolism and possibly striatal DAT binding.
For most drugs, potential effects have not been investigated.
The only potential influence we found was codeine, which
was used by one of our patients in a combination drug with
acetaminophen to treat pain (acetaminophen 500 mg +
codeine 10 mg three times daily). Opioid abuse, including abuse
of codeine, has been associated with lower DAT binding in the
striatum. In one study, DAT binding correlated with the
amount of opioids used [53–56]. It is unlikely that a low
dosage of codeine in one patient influenced our results. Even less
is known about interactions between drugs and [123I]IBZM
Another potential weakness of this study is the fact that we
did not correct for other factors that might influence the
dopamine system, e.g. smoking, season and amount of sunlight
exposure [57, 58]. All of these factors have been
hypothesized to influence the dopamine system, although the
relationship is still under debate, for example, with smoking .
Our study group was too small to correct for every factor that
could potentially influence the dopamine system. Also, with
the technique we used, it is only possible to adequately
measure DAT and D2/3 receptors in the striatum. Therefore, we
cannot exclude dopaminergic changes elsewhere in the brain.
Lastly, the significant number of scans that had to be
excluded from the analysis is a limitation. We had some technical
difficulties during the course of this study, leading to poor
scan quality. Even taking this into account, ours is still the
largest SPECT imaging study in patients with dystonia thus
far, and was the first to find that depressive symptoms likely
explain differences in striatal DAT and D2/3 receptor BPND
between CD patients and controls.
Author Contributions E. Zoons: conception, organization and
execution of the research project and statistical analysis, writing of the
M.A.J. Tijssen and J. Booij: conception of the research project, review
and critique of the statistical analysis and manuscript.
Y.E.M. Dreissen: execution of the research project and review and
critique of the manuscript.
J.D. Speelman: execution of the research project and review and
critique of the manuscript.
M. Smit: execution of the research project and review and critique of
the statistical analysis and manuscript.
Compliance with ethical standards This study was funded by the
Graduate School of the AMC via a personal scholarship for E. Zoons
and by the ONWAR Imaging Fund. M.A.J. Tijssen received grants from
Fonds Nuts-Ohra, Prinses Beatrix Fonds, Gossweiler foundation,
Stichting wetenschapsfonds dystonie vereniging, Fonds Psychische
gezondheid, Phelps Stichting, Beatrix kinderziekenhuis fonds, and the
Healthy Ageing Fund UMCG; unrestricted grants from Actelion, Merz,
Ipsen, Allergan and Medtronic; and an honorarium from the Merz expert
meeting Paris January 2016. The other authors report no conflicts of
All procedures performed in studies involving human participants
were in accordance with the ethical standards of the institutional and/or
national research committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included
in the study.
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