1 Serotonin and Neuroplasticity – investigated in vivo by Positron Emission Tomography and structural Magnetic Resonance Imaging Doctoral thesis at the Medical University of Vienna in the program Clinical Neurosciences for obtaining the academic degree Doctor of Medical Science submitted by Christoph Kraus, MD Supervision by Rupert Lanzenberger, Assoc. Prof. PD MD NEUROIMAGING LABs (NIL) - PET & MRI & EEG & Chemical Lab Department of Psychiatry and Psychotherapy Medical University of Vienna Waehringer Guertel 18-20, 1090 Vienna, Austria http://www.meduniwien.ac.at/neuroimaging/ Vienna, July 2015
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1
Serotonin and Neuroplasticity – investigated in vivo by
Positron Emission Tomography and structural
Magnetic Resonance Imaging
Doctoral thesis at the Medical University of Vienna
in the program Clinical Neurosciences
for obtaining the academic degree
Doctor of Medical Science
submitted by
Christoph Kraus, MD
Supervision by
Rupert Lanzenberger, Assoc. Prof. PD MD
NEUROIMAGING LABs (NIL) - PET & MRI & EEG & Chemical Lab
Department of Psychiatry and Psychotherapy
Medical University of Vienna
Waehringer Guertel 18-20, 1090 Vienna, Austria
http://www.meduniwien.ac.at/neuroimaging/
Vienna,
July 2015
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I. Table of Contents
II. Declaration ................................................................................................................ 3
III. Abstract ..................................................................................................................... 4
IV. Kurzfassung .............................................................................................................. 5
V. List of Publicaitons .................................................................................................... 6
VI. Abbreviations ............................................................................................................. 7
VII. Acknowledgements and Project Funding ................................................................... 8
I. BACKGROUND ........................................................................................................... 9
1.1 General introduction .................................................................................................. 9
1.2 The role of neuroplasticity in health and disease ..................................................... 10
http://www.pmod.com) and applying the two-parameter linearized reference tissue model
(MRTM2) (Ichise et al., 2003). Compared to other models such as the simplified reference
tissue model (SRTM), MRTM2 leads to lower BPND bias and hence a better signal-to-noise-
ratio, especially for whole-brain voxel-by-voxel analysis. We modeled 5-HT1A BPND as
previously described by our group using the insula and the cerebellum taken from an
automated anatomical labeling-based (AAL) region of interest (ROI) (Tzourio-Mazoyer et al.,
2002) atlas, as receptor-rich and receptor-poor region, respectively. The cerebellum
excluding cerebellar vermis served as reference region. This was done for the voxel-by-voxel
analysis as well as the ROI-based multimodal analysis.
Image Co-Registration for Multimodal Data Analysis
We combined the advantages of PET in quantifying receptors at the molecular level with
structural MRI, which provides data on brain structure such as cortical folding, regional
cortical thickness and volume or gray/white matter contrast. This was achieved by co-
registration of each individual’s PET image to the corresponding structural MRI image. We
used SPM8 to apply the transformation matrix of the structural scans obtained during
normalization to the PETADD images. As the structural scans were already normalized to
standard MNI space, this step also brought the PET data to MNI space resulting in whole-
brain dynamic [carbonyl-11C]WAY-100635 maps co-registered to the structural MRI images.
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Quantification of 5-HT1A Receptor Binding Potential in Anatomical Regions of Interest
With this post-hoc analysis we aimed to investigate the area-specific relationship between 5-
HT1A and GMV to further confirm our primary voxel-by-voxel results using a different
approach. The ROI-based analysis also served to test, whether there exists a network
association between 5-HT1A receptors and gray matter in the projection areas of the one of
the main raphe nuclei, the dorsal raphe nucleus. For the ROI-based network analysis the
DRN was manually delineated on an averaged PETADD image in PMOD 3.1. Our DRN ROI
consisted of a sphere, 4 mm in diameter, comprising three slices on the averaged PETADD
image. Each individual’s 5-HT1A BPND value in the DRN was then obtained from individual
time-activity curves averaged across subjects (again using cerebellar gray matter as
reference). For further post-hoc analysis we quantified 5-HT1A receptor BPND values and
GMV values in MNI standard space in 48 ROIs, taken from the AAL atlas covering a broad
range of brain regions as previously shown (Stein et al., 2008). A ratio between GMV and
rescaled 5-HT1A BPND values was calculated by dividing the first through the latter.
Statistical analyses
Demographics
Sex differences in biological demographical and radiochemical variables were calculated to
assess study sample characteristics with either independent sample t-tests or Mann-Whitney
U tests where appropriate, using IBM SPSS Statistics (v19.0, 2010, SPSS, Inc., an IBM
Company, Chicago, United States of America) assuming a significance level of α = 0.05.
Multimodal Analysis
Multimodal image analysis was divided into two parts: we calculated regional voxel-by-voxel
associations between 5-HT1A receptor distribution and gray matter in the whole-brain.
Second, we assessed the associations between 5-HT1A receptor binding in a single area, the
DRN, and GMV in projection sites of the DRN. The DRN was chosen because of its central
role in the regulation of serotonergic firing and neurotransmission.
We thus calculated a multiple linear regression model with 5-HT1A receptor BPND values as
independent and GMV values as dependent variable for every voxel in the entire gray matter.
In this regression model age, sex and total GMV served as controlling variables. This was
done to adjust for age related gray matter alteration, varying brain sizes, and sex differences
(as outlined in Table 1) for. In two further models, we also considered the two radiochemical
variables specific activity (SA) and injected dose (ID) as factors. However, given that the
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number of control variables should not exceed n/10 and the results (data not shown) were
virtually identical with the primary model, we did not include SA and ID in our further
analyses. The voxel-by-voxel regression model was set up in the Biological Parametric
Mapping (BPM) toolbox for SPM8 (Casanova et al., 2007), which is designed to calculate
voxel-by-voxel statistics for multiple imaging modalities. More precisely, multiple regression
was calculated in each voxel (average voxel number across all subjects = 216,741.2) with
one value for GMV and one for 5-HT1A BPND (in arbitrary units). We used 0.1 as absolute
threshold and a level of statistical significance of α = 0.001. Due to multiple comparisons and
the concomitant high chance of false positives the obtained results were corrected with the
cluster-level false discovery rate (FDR) at a significance level of α = 0.05. Correlation
coefficients were calculated with cluster-wise means (in arbitrary units) in Matlab (v. r2010b,
The MathWorks, Inc., Natick, United States of America).
For the analysis of serotonergic projections from the DRN, we calculated a regression model
in SPM8 using 5-HT1A BPND values of the DRN ROI as independent variables and whole
brain GMV as dependent variable. Sex, age and total GMV were control variables for the
reasons mentioned above. Further, GMV of the DRN was added in the regression model to
eliminate potential confounding effects of DRN gray matter and whole brain gray matter
interactions. GMV values were obtained from the DRN ROI overlaid on the MRI images. We
excluded voxels exhibiting BPND or GMV voxel values below 0.1. The level of statistical
significance was set at α = 0.001 and only results with a cluster size over 100 voxels are
reported.
For the analysis of smoking status on BPND a regression analysis was set up in SPM8 using
5-HT1A BPND values as independent variables and smoking status or number of smoked
cigarettes as dependent variables, respectively, controlling for sex, age and GMV. Age effects
on GMV were calculated with a regression analysis using GMV as independent variable and
age as dependent variable controlling for sex and GMV. In both analyses an uncorrected α =
0.001 was accepted as level of significance.
RESULTS
5-HT1A receptor binding positively correlated with gray matter volumes within
distinctive brain regions
In this pooled study sample, male study subjects significantly differed from females in GMV,
weight and total injected radiotracer dose (Table 1). In line with previous results of our group,
5-HT1A BPND, an index for receptor density, peaked in the parahippocampal gyri, the temporal
poles and the insula (Figures 1A, Figure 3, Table S1 and [Stein et al., 2008]).
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Serotonin-1A BPND strongly correlated with GMV in the hippocampus (the cluster in the right
hippocampus spread from the posterior hippocampus to the parahippocampus), the posterior
medial temporal cortex, the posterior inferior temporal cortex, the medial occipital cortex and
the pericalcarine region in each hemisphere (R2 values ranged from 0.308 to 0.503, p < 0.05
cluster-level false discovery rate [FDR]) corrected, see Figures 1B, 1C and Table 2). In other
words, 5-HT1A heteroreceptor binding strongly correlated with relative volumes of gray matter
in these specific regions. Negative correlations between 5-HT1A BPND and GMV were
restricted to two regions in the cerebellum (Table 2).
Figure 1 Serotonin-1A (5-HT1A) receptor binding is positively associated with regional gray matter.
(A) 5-HT1A receptor distribution in vivo measured with positron emission tomography displayed with
the surface-rendering algorithm used by the visualization program MRIcro
(http://www.cabiatl.com/mricro/mricro/mricro.html) (B) T maps showing that 5-HT1A binding potential
(BPND) strongly correlates with gray matter volume (GMV). Significant positive correlations were
superimposed on MR images (p < 0.05, FDR cluster-level corrected, see Table 2), coordinates
correspond to the standard Montreal Neurological Institute (MNI) stereotactic system. (C) Regression
graphs between GMV and 5-HT1A BPND (multiple regression analysis controlled for sex, age and total
GMV, adjusted values in arbitrary units) correspond to cluster means of each subject (in red circles
(B), N = 35).
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5-HT1A receptor binding in the raphe region positively correlated with gray
matter volume in the anterior cingulate cortex
Previous data show that presynaptic 5-HT1A autoreceptors in the DRN regulate tonic
serotonergic firing, serotonin release and the postsynaptic density of 5-HT1A
heteroreceptors and 5-HT transporters (Bose et al., 2011). Hypothesizing that the
influence of the DRN autoregulation extends to gray matter, we investigated
associations between 5-HT1A autoreceptor binding in the DRN and whole brain GMV
at projection sites. We observed a positive correlation between the dorsal raphe 5-
HT1A BPND and GMV in the right perigenual anterior cingulate cortex (R2 = 0.656, p =
0.001, uncorrected, Figure 2A, 2B).
Post-hoc ROI analysis revealed regional differences in the relation between 5-HT1A
receptor binding and GMV
An intuitive caveat to the results might be that these associations could be merely
based on primary larger numbers of neuronal or glial cells expressing 5-HT1A
Figure 2 Network analysis. 5-HT1A receptor
binding of the dorsal raphe nucleus (DRN) is
positively associated with gray matter volume of
the anterior cingulate cortex (ACC). (A)
Significant cluster superimposed on a sagittal
MRI slice (regression analysis, R2 = 0.656, p <
0.001, uncorrected, cluster peak: t = 5, MNI: x =
6, y = 35, z = 3). (B) Data points represent cluster
means (adjusted values in arbitrary units) of each
subject (N = 35) as adjusted by regression
analysis controlled for sex, age total GMV and
GMV of the DRN.
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receptors and thus a priori higher GMV values. Therefore, we investigated if the
resulting clusters were exclusively situated in regions with high regional GMV and
quantified the BPND and GMV values of 48 ROIs covering the whole brain. We found
several regions, such as the cingulate cortex or the amygdala, which despite high
regional GMV and 5-HT1A BPND values did not exhibit significant positive associations
in the voxel-by-voxel analysis (Figure 3). Furthermore, we calculated ratios between
GMV and BPND values to assess regional proportions between 5-HT1A receptor
binding and gray matter in the whole brain. These GMV/BPND ratios ranged from 0.54
in the temporal pole to 4.8 in the caudate region, suggesting high regional variability
within the ratio of regional GMV and 5-HT1A BPND (Figure 3).
Following that, to confirm the associations between 5-HT1A BPND and GMV obtained
by voxel-by-voxel analysis, we repeated the regression analysis within two ROIs. The
ROIs should have similar GMV and 5-HT1A BPND values, one exhibiting and one
lacking the associations as obtained by voxel-by-voxel analysis. Out of the 48
quantified ROIs, the hippocampus and the insula were the only two regions meeting
the selection criteria (GMV/BPND: insula = 0.63, hippocampus = 0.64, GMV: insula
and hippocampus = 0.53, BPND: insula = 0.84, hippocampus = 0.83, see Figure 3
and Table S1). In the voxel-by-voxel analysis, the hippocampus exhibited significant
positive associations between 5-HT1A receptor BPND and GMV, but in the insula,
despite similar values, 5-HT1A BPND did not correlate with GMV. Congruent to the
voxel-by-voxel analysis, in the post-hoc ROI analysis a significant positive correlation
was observed in the hippocampus (r = 0.41, p = 0.02) but not in the insula (r = - 0.03,
p = 0.87).
No effects of age or smoking status
To rule out cortical atrophy due to aging was somehow related to the results, we analyzed
our dataset for age-related effects. Multiple regression analysis in SPM8 revealed a negative
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Figure 3 Area-specific differences in the relation between 5-HT1A receptor binding and gray matter
volume. Gray matter volume (GMV, red) and 5-HT1A binding potential (BPND, blue), in arbitrary units,
quantified in 48 brain regions of interest (ROI) covering the whole brain. This demonstrates high
variabilities between 5-HT1A receptor densities and regional volumes of gray matter (also see Table
S1).
correlation for GMV and age in the left medial occipital cortex (t = 4.24, p < 0.001,
uncorrected, x = -27, y = -81, z = 26) near the angular gyrus. BPND was negatively correlated
with age in a cluster around the left postcentral gyrus (t = 3.82, p < 0.001, uncorrected; x = -
22, y = -27, z = 62). These results indicate that an effect of aging in our data occurred in
different brain areas than the main results. Smoking status was available for 34 participants,
out of which 14 were smokers (6 female, mean cigarettes per day = 7.1 ± 4.8). Multiple
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regression analysis revealed that neither smoking status nor number of smoked cigarettes
was associated with 5-HT1A BPND (all p > 0.001).
DISCUSSION
Our results demonstrate positive associations between 5-HT1A receptor binding and gray
matter. In distinctive regions of both hemispheres, as in the hippocampi and in temporal
cortices, 5-HT1A receptor binding was strongly correlated with gray matter. These results
were not just based on a priori higher regional values of gray matter, because we
demonstrated that in regions such as the insula, in contrast to the hippocampus, there were
no significant positive associations, although having comparable gray matter and 5-HT1A
receptor binding. We observed a large variability between 5-HT1A binding and gray matter in
the whole brain. We also found that 5-HT1A autoreceptor binding in the DRN was positively
associated with gray matter in the anterior cingulate cortex. The results were not affected by
cortical atrophy due to aging or smoking status. A large number of previous findings in animal
models (Daubert and Condron, 2010; Gaspar et al., 2003) show direct links between
serotonergic receptors like the 5-HT1A receptor and neuroplasticity. Furthermore, there is
evidence that allows direct inference from MRI-based measurements to changes of the
underlying neuronal structures (la Fougère et al., 2010). Therefore, we propose that the
discovered associations provide valuable insights into the relationship between 5-HT1A
receptor binding and gray matter cytoarchitecture in adult human brains in vivo.
Serotonin is highly active in shaping neurons during embryonic development and early
postnatal neuronal maturation, and this neuroplastic role is partially conserved in specific
brain regions throughout adulthood (Gould, 1999). Downstream cytosolic signaling kinases
from membrane-bound small G proteins (Ye and Carew, 2010), that activate transcription
factors (McClung and Nestler, 2008) and epigenetic mechanisms (Borrelli et al., 2008) were
suggested to effect neuronal reconfigurations. Serotonergic-1A receptors are able to
modulate the activity of these pathways (Cowen, 2007; Polter and Li, 2010). Recently a study
using hippocampal cell cultures could show, that 5-HT1A receptors are essential for normal
synaptogenesis (Mogha et al., 2012). Blockade of astrocytic 5-HT1A receptors leads to a
reduction of synaptic connections between neurons (Wilson et al., 1998) and fits well to
findings demonstrating that the 5-HT1A receptor is required for behavioral and neurogenic
effects of the selective serotonin reuptake inhibitors (Santarelli et al., 2003). From a
neurobiological perspective, we suggest that neuroplastic effects of 5-HT1A receptors might
contribute to the observed association between 5-HT1A binding and alterations of regional
gray matter.
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Nevertheless, this interpretation must be considered with caution, because one voxel in high-
resolution structural MRI contains too many neuronal cells to reliably link our results with
mechanisms observed in cell cultures or animal models (for review see [(May, 2011)]). To
better pin down how 5-HT1A receptor-mediated neuroplasticity might affect gray matter in the
living brain, further longitudinal investigations are needed. A possible alternative explanation
to our results could simply be, that regional 5-HT1A binding was elevated through primary
higher regional amounts of gray matter. However, considering results from animal models,
we have several arguments against this.
Firstly, we predominately found positive associations. In a similar study using structural MRI,
PET and the D2/D3 receptor ligand [18F]fallypride, Woodward et al. (Woodward et al., 2009)
previously pointed out that negative associations are unexpected. Hypothetically, the density
of 5-HT1A receptors should vary with the amount of gray matter within a region, in other
words the more gray matter, the more receptors it can support and vice versa. A recent study,
however, nicely demonstrates divergent values between 5-HT1A binding and neuronal
densities in humans as measured by stereology and autoradiography (Underwood et al.,
2008). This result is congruent to the broad variability in the range between 5-HT1A binding
and GMV shown in our study. The predominantly positive associations in our study go well
along with the finding, that astrocytic 5-HT1A receptors (via S-100ß) are necessary for
maintaining the neuronal integrity (Whitaker-Azmitia, 2001). In the absence of S-100ß a
mature neuron can regress its major processes and even enter apoptosis (Whitaker-Azmitia,
2001). Secondly, the associations between 5-HT1A binding and gray matter were obtained
symmetrically in both hemispheres, which indicates validity. The distinctive regional pattern
could be explained by varying strengths of 5-HT1A mediated neuroplastic effects (Cowen,
2007). Thirdly, the insula, even with similar 5-HT1A and GMV values as the hippocampus, did
not exhibhit significant associations. This further suggests a region-specific mechanism and
might indicate that the observed associations were not based on higher numbers of regional
neuronal and glial cells, both associated with GMV. According to the current state of
knowledge 5-HT1A mediated neroplasticity is more active in the hippocampus than in the
insula (Santarelli et al., 2003). In the hippocampus 5-HT1A receptors were demonstrated to
stimulate neurogenesis and dendritic maturation (Yan et al., 1997). Finally, we demonstrated
an association between 5-HT1A receptors in one of the major serotonergic nuclei, the DRN,
and gray matter at serotonergic axon terminals in the anterior cingulate cortex.
Hypothetically, interregional correlation between 5-HT1A auto- and heteroreceptors (Hahn et
al., 2010) could foster the observed association between 5-HT1A receptors and GMV in this
study. The autoregulatory influence of the DRN on serotonergic heteroreceptors at axon
terminals in the forebrain, by neuroplastic properties of 5-HT1A receptors, might thus extend
to GMV. Patients suffering from mood disorders exhibit both significantly reduced GMV of the
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anterior cingulate cortex and altered 5-HT1A receptor density in the raphe nucleus (Salvadore
et al., 2011; Savitz and Drevets, 2009; van Tol et al., 2010). We could speculate here, that a
disturbance in this association might contribute to the reduction of GMV in the anterior
cingulate cortex.
In summary, the associations between 5-HT1A binding and GMV could theoretically result
from a priori higher regional amounts of gray matter or other unknown mechanisms. But
given the high amount of clear evidence, we suggest that neuroplastic actions of 5-HT1A
receptors should be taken into account as explanatory model for this dataset. The 5-HT1A
receptor, in addition, could prove to be an interesting target in clinical studies on altered
neuroplasticity in brain disorders, due to well known behavioral behavioral functions such as
mediating mood (Savitz et al., 2009), anxiety (Akimova et al., 2009) or cognition (Ogren et
al., 2008).
Limitations
This dataset does not imply that the observed associations can be causally attributed to
neuroplastic actions of 5-HT1A receptors. For such a deduction a longitudinal, interventional
and translational approach in a future study would be more favorable, for which this dataset
provides excellent justification.
Furthermore, as previously pointed out (Tost et al., 2010) the neurobiological correlates of
changes in brain morphology measured by structural neuroimaging are not sufficiently
resolved, for an excellent recent review see (Zatorre et al., 2012). Even at high-resolution
MRI, there are still ten thousands of interconnected neuronal and glial cells packed in one
single voxel. Thus, more translational cell studies on neuroplasticity are necessary to exactly
determine what cellular processes are mediated by serotonin and the 5-HT1A receptor that
could gain effects, large enough to be detectable by structural MRI (May, 2011).
Finally, we did not use correction for partial volume effects (PVC) of the PET data. Although
this may be an obvious issue, PVC is typically carried out by using the corresponding
segmented MRI, namely, the gray and white matter probability maps. More precisely, the GM
values represent the denominator of the PVC algorithm (Muller-Gartner et al., 1992). This
implies that the PET activity concentrations are adjusted for individual differences in the GM
volume. However, the current study particularly aims to investigate the association between
individual differences in 5-HT1A binding and GM volume. Hence, MRI-based PVC would
include the effect of interest as nuisance variable, which in turn cancels the association.
Accordingly, no PVC was carried out in the similar investigation of Woodward et al. (2009).
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Conclusions
Our results demonstrate that 5-HT1A receptor binding is positively associated with gray
matter in specific regions such as the hippocampus and the temporal cortices in both
hemispheres. Furthermore 5-HT1A autoreceptor binding in the midbrain is positively
associated gray matter in the anterior cingulate cortex. Currently, it is hard to pin down the
molecular mechanisms underlying our results, mostly because, there are no exact models
which cellular compounds correspond to the signal strength in a single voxel. To increase the
validity of neuroimaging studies, this issue must be an objective of further studies.
With regard to translational neuroscience, assessments of processes underlying networking
and reorganization of neurons as well as early surrogate markers to predict and monitor
treatment response were demanded (Cramer et al., 2011). With combinations of structural
and molecular neuroimaging, as performed in this multimodal study, dysfunctional
neuroregulatory processes leading to loss of gray matter might be investigated at early
stages in clinical populations. This could lead to a more comprehensive understanding of
neurodegenerative diseases as Alzheimer’s disease, schizophrenia and mood disorders and
ultimately to a better diagnostic assessment and therapeutic evaluation of patients with these
highly life impairing disorders.
ACKNOWLEDGEMENTS
This research was partly supported by grants from the Austrian Science Fund, and the
Austrian National Bank (P 11468) to R. L. A. Hahn is recipient of a DOC-fellowship of the
Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy. We are
grateful to the technical and medical teams of the PET and High-Field MRI Centre, Medical
University of Vienna, especially to K. Kletter, R. Dudczak, E. Moser, L.-K. Mien, and F. Gerstl.
Furthermore, we would like to thank U. Moser, M. Fink, and P. Stein for medical support and
A. Saulin for help with the manuscript.
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Table 1 Demographic and radiochemical variables of study subjects
all subjects
males
females
p
n 35
17
18
age 26.6 ± 6.8
29.6 ± 8.4
24.4 ± 2.5
0.026+
weight (kg) 71.3 ± 14.6
79.7 ± 11.7
62.5 ± 12.2
< 0.001
GMV (cm3) 731.5 ± 73.8
777.5 ± 53.9
682.8 ± 58.5
< 0.001
injected dose (MBq) 385 ± 36
396.9 ± 45.8
372.3 ± 14.4
0.002+
RCP (%) 97.7 ± 1.4
98 ± 1.4
97.4 ± 1.3
0,320
Data are given as means ± standard deviation. GMV = total grey matter volume, MBq =
Megabecquerel, RCP = radiochemical purity, p compares males and females with
independant sample t-test or Mann-Whitney U test (+) where normal distribution was not
obtained by Levene's test.
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Table 2
Statistical results as obtained by Statistical Parametric Mapping (SPM8).
region
peak
cluster
x y z t z R2 p−FWE p−FDR voxels
positive correlation
right posterior medial temporal
42 −32 0
6.7 5.2
0.487 < 0.001 < 0.001 952
right hippocampus/ parahippocampus
29 −39 0
6.2 4.9
0.503 < 0.001 < 0.001 850
right medial occipital
38 −92 −5
4.9 4.1
0.308 < 0.001 < 0.001 541
right inferior orbitofrontal
51 20 −8
4.9 4.2
0.403 0.002 0.001 434
right posterior inferior temporal
59 −32 −15
5.4 4.5
0.436 0.002 0.002 416
left posterior medial temporal
−44 −26 −6
6.7 5.2
0.386 0.003 0.002 400
right superior parietal
24 −53 48
6.0 4.8
0.449 0.004 0.002 381
left posterior inferior temporal
−53 −42 −14
5.1 4.3
0.302 0.004 0.002 374
left medial occipital
−21 −101 9
4.9 4.2
0.217 0.006 0.002 349
left pericalcarine
−27 −57 5
6.1 4.9
0.424 0.009 0.003 323
left precentral
−33 5 41
5.7 4.7
0.183 0.031 0.01 253
right pericalcarine
30 −57 8
7.2 5.4
0.489 0.043 0.013 234
right inferior occipital
38 −65 −11
5.5 4.5
0.308 0.089 0.026 195
left hippocampus
−24 −27 −14
5.3 4.4
0.428 0.127 0.035 176
negative correlation
left posterior lobe of cerebellum
−26 −57 −23
−6 −4.83
0.422 0.102 0.176 363
left cerebellar crus
−50 −69 −23
−5.4 −4.48
0.461 0.349 0.35 10
Voxel−wise regression analysis results between whole−brain 5−HT1A binding potential (BPND) and whole−brain grey
matter volume (GMV). Stereotactical coordinates (x. y. z) represent cluster peaks in standard Montreal Institute of
Neurology (MNI) space. FWE = family wise error. FDR = false discovery rate. Note that R2 values were calulated
cluster−wise between 5−HT1A BPND and GMV and therefore do not correspond to peak t − or z − values.
52
Table S1
Binding potential and gray matter volume values for 48 regions of interest as quantified with an AAL based atlas (data sorted by GMV/nBPND)
was reported between the amygdala and the anterior insula after duloxetine intake (van
Marle et al., 2011), here 19 healthy subjects were analyzed. VBM-based seed regions were
not considered in either of these studies. Noteably, rFC and rFCD changes after SSRI intake
were regionally restricted to intrinsic areas around increased gray matter in the PCC.
Cognitive load adherent in blocked design task activation was previously located at the PCC
(Newton et al., 2011). Furthermore, transient BOLD responses at block transitions occur at
the PCC and many other regions (Fox et al., 2005), yet inserted intervals accounting for
delay in the hemodynamic response function limit these transitions. Variance from cognitive
load and transitions might theoretically spill into the analyzed baseline blocks, which should
be taken into account upon comparison of our data with traditionally obtained resting-state
data. Hence, it remains intriguing that whole-brain connectivity density analysis, which is not
related to seed-based connectivity, identifies the same region as connectivity from increased
gray matter signal. The mechanisms that SSRIs interfere with in this region are therefore
likely to be associated with several factors altering substrates detectable both in T1-weighted
as well as EPI MRI sequences. The existing gap between underlying molecular mechanisms
and alterations of voxel-intensity values are vigorously debated (for critical review and
comments see (Draganski and Kherif, 2013; Erickson, 2013; Fields, 2013; Thomas and
Baker, 2013), so that strong gray matter changes as shown in this study emphasize the need
for more translational work on molecular players mediating in vivo structural and functional
changes of neuronal networks as measured by MRI.
The following study limitations must be reported. Though we analyzed a rather low subject
number, sample sizes of active groups within previous studies have been even lower than in
73
our study (Anand et al., 2005; McCabe and Mishor, 2011). Therefore, this factor, though
indeed a limitation, remains a common feature in many pharmacologic neuroimaging studies.
In addition, subjects were not balanced according to sex, this issue was however addressed
by including sex as nuisance variable.
In summary, we found that study subjects after SSRI intake exhibited significant gray matter
changes. Moreover, almost identical locations of increased resting functional connectivity and
connectivity density associated with gray matter increases in the PCC provide evidence for
the involvement of SSRIs in multiple mechanisms changing brain structure and functionality.
When taken together, these results point towards plastic changes of brain structure and
function as neuronal substrate of effects associated with SSRI intake and offer a paradigm
for further exploration of these mechanisms in psychiatric patients.
5. ACKNOWLEDGEMENTS
Data have been measured within a project funded by an investigator-initiated and
unrestricted research grant from H. Lundbeck A/S, Denmark to S. Kasper. The sponsors and
funders did not participate in the design and conduct of the study and were not involved in
the preparation, review, or approval of the manuscript. The study protocol has been planned
by the authors who retained full academic control. In the study presented here we applied
new data analysis approaches in structural and functional magnetic resonance imaging
recently available beyond the scope of a study already published (Windischberger et al.,
2010). The work of C. Kraus has been funded by an intramural grant of the research cluster
between the Medical University of Vienna and the University of Vienna (FA103FC001) to R.
Lanzenberger and C. Lamm. A. Hahn was funded by a DOC fellowship of the Austrian
Academy of Sciences at the Department of Psychiatry and Psychotherapy. The authors are
grateful to C. Spindelegger, U. Moser, P. Stein, M. Fink, L. Pezawas, A. Erfurth, and M. Willeit
for their medical support, and to A. Holik, S. Friedreich, F. Gerstl, and E. Moser for technical
74
support. We thank M. Spies for native English editing. The study is part of C. Kraus’ thesis
“Serotonin and Neuroplasticity” supervised by R. Lanzenberger in the Clinical Neurosciences
PhD program at the Medical University of Vienna, Austria. Parts of this study have been or
will be presented by P. Baldinger at the 19th European Congress of Psychiatry (EPA), March
12-15, 2011, Vienna, Austria, by M. Savli at the 24thEuropean College of
Neuropsychopharmacology (ECNP) Congress, September 3-7, 2011, Paris, France, and by
C. Kraus at the 11th World Congress of Biological Psychiatry (WFSBP), June 23-27, 2013,
Kyoto, Japan.
6. CONFLICT OF INTEREST
Without any relevance to this work, S. Kasper declares that he has received grant/research
support from Eli Lilly, Lundbeck A/S, Bristol-Myers Squibb, Servier, Sepracor,
GlaxoSmithKline, Organon, and has served as a consultant or on advisory boards for
AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lily, Lundbeck
A/S, Pfizer, Organon, Sepracor, Janssen, and Novartis, and has served on speakers’
bureaus for AstraZeneca, Eli Lilly, Lundbeck A/S, Servier, Sepracor and Janssen. R.
Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca
and Lundbeck A/S.
75
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79
TABLES
all subjects
males
females
P
N 17
11
6
Age (years) 26.5 ± 6.1
28 ± 7.1
23.8 ± 2.1
0.185
BMI (kg2/m) 22.3 ± 2.3
22 ± 2.7
23 ± 1.3
0.382
Cigarettes/day 1.8 ± 4
0.8 ± 2.2
3.6 ± 5.7
0.533+
Alcohol/week 5.7 ± 6.5
3.9 ± 4.9
9 ± 8.2
0.128
tGMD 919.3
918.6 ± 19.9
920.6 ± 14.8
0.746
Table 1: Demographic data of the study sample. Data are given as means ± SD. Alcohol units per
week = alcohol consumption (liter) × alcohol by volume ratio. BMI = body mass index. tGMD = total
gray matter density (placebo condition). P compares males and females with independent sample t-
test or Mann-Whitney U test (+) where normal distribution was not obtained by Levene's test.
80
Table 2: Regions exhibiting increases of gray matter density (GMD) after SSRI intake vs. placebo
intake. Voxel−wise whole brain repeated measurements ANOVA using GMD MRIs with treatment
modality (SSRIs or placebo) as factors controlling for whole brain GMD and sex. Stereotactical
coordinates (x, y, z) represent cluster peaks in standard Montreal Institute of Neurology (MNI) space.
There was no interaction between MDD diagnosis or sex and 5-HTT BPND. In the midbrain,
weak increases of 5-HTT-BPND in healthy subjects between val-homozygotes and met-
carriers were found. Furthermore, weak increases of 5-HTT BPND were observed in the
midbrain in val-homozygote healthy subjects compared to val-homozygote MDD patients.
There was no association between allelic distribution and major depression. To sum up, all
voxel-wise and ROI-based testing yielded negative results and none of the post-hoc tests
survived correction.
Our results are in concordance with a previous PET study applying [11C]DASB in 49 healthy
subjects, where the authors neither detected differences in 5-HTT binding in relation to
BDNF genotype nor a correlation between blood BDNF levels and central 5-HTT binding
[11]. Additionally, no effect on 5-HT2A binding was shown in this work. Here, the authors
calculated the radiotracer BPND similar to our study by applying a fully automated reference
region model (MRTM2) [22] and an automated ROI-delineation. The only other currently
published human PET-study investigating the impact of BDNF polymorphisms on 5-HTT
binding reports differences in men and shows no effect of genotype status on 5-HT1A binding
[10]. Men homozygous for the val-allele exhibited significantly higher 5-HTT binding in
regions such as the hippocampus, insula or dorsal raphe compared to met-carrier, while this
effect was absent in women. Furthermore, reductions of 5-HTT binding in met-carrier (n=3)
compared to val-homozygotes (n=6) in an independent [123I]-ß-CIT-study with male suicide
attempters were demonstrated, but this reduction was absent when pooled with healthy
controls. The authors also used a reference region model with [11C]-MADAM, a tracer
exhibiting a comparable 5-HTT affinity to [11C]DASB [27], the ROIs were manually delineated
on individual magnetic resonance images (MRI). Notably, our group previously reported
strong correlations of BPND values between automatically and manually delineated ROIs
[23]. The radioligand and the method of ROI generation are on these grounds an unlikely
source of variance leading to alternative results. Importantly, in search of arguments for this
difference, one must mention that the number of male met-carriers in that collective was low
94
(n=4), which makes the analysis vulnerable to outliers and hence may increase type-I errors.
Likewise, our study exhibits a subgroup with a low subject number and indeed we saw an
outlier in the MDD met-carrier group (n=3) when we plotted the individual BPND values (data
not shown). Hence, our results in depressed patients have to be interpreted with caution. But
the fact that both the study by Klein et al., which exhibits a large sample size of healthy
volunteers, as well as our study did not reproduce higher 5-HTT binding in val-homozygote
healthy subjects, rather speaks for an absent effect of BDNF Val66Met on 5-HTT binding.
Apart from this, our study agrees with the data by Henningsson et al., on an absent effect of
Val66Met on 5-HT1A receptor binding in healthy subjects [10]. Both studies apply the same
radioligand, i.e. [carbonyl-11C]WAY-100635, exhibit an almost identical number of subjects
(n=53 in Henningsson et al.), and modeled 5-HT1A binding by a reference region model
(BPND). These results are in contradiction to a recent finding reporting 5-HT1A reductions in
healthy met-allele carriers [12], which is not present in MDD patients. In this study 50 healthy
subjects and 50 MDD patients were measured with the radioligand [carbonyl-11C]WAY-
100635, yet 5-HT1A binding was calculated by an arterial input function (BPF). Most
interestingly, when the authors repeated their analysis with BPND values, the reduction of 5-
HT1A binding in healthy met-carriers was not detectable, suggesting that this finding was
associated with the method of radioligand modeling. Following the discussion of the authors,
one cannot rule out that Val66Met causes differences of radioligand binding in the blood
leading to a bias in the arterial input function. Although, our results are in agreement with all
previous studies on 5-HT1A binding using reference tissue models [10, 12], validation by a
different tracer not susceptible to modeling methodology is further needed. Taken together,
while there are currently contradicting findings on the in vivo effect of BDNF Val66Met
genotypes on 5-HTT binding [10, 11], this study adds data emphasizing the absence of such
an effect. Moreover, this work corroborates previous results by reference tissue models
demonstrating no association between BDNF Val66Met genotype status and 5-HT1A
95
receptor binding [10, 12] and is in contradiction with a study reporting binding values
modeled with arterial blood sampling [12].
Preclinical data report that BDNF promotes development and function of serotonergic
neurons by enhancing survival and differentiation [28], increasing local 5-HT [29] modifying
the firing pattern of serotonergic raphe neurons [28, 30] and altering the function of
serotonergic receptors such as the 5-HT1A and 5-HT2A receptors and the 5-HTT [2, 29, 31].
Vice-versa, raised extracellular 5-HT levels occurring upon administration of SSRIs are
thought to increase local BDNF levels by enhanced phosphorylation of serotonergic receptor
coupled cAMP response element-binding (CREB) protein [32-34], a common target of BDNF
and G protein-coupled serotonergic receptors [2]. Confronted with this evidence, one is
puzzled upon the lack of strong evidence for an association between BDNF and
serotonergic structures in humans in vivo. However, preclinical studies are not consistent
and negative results regarding the expression of 5-HT receptors and transporter are
reported [31, 35]. Although the interaction between the BNDF and 5-HT provides a
promising bridge between structural and functional neuronal activity, and serves as
explanatory hypothesis for neuronal plasticity deficits in neuropsychiatric disorders, exact
mechanisms underlying the regulation of the cross connection between BDNF and 5-HT in
humans remain unresolved [36]. Our data in concert with above referred work speak for a
similar expression of 5-HTT and 5-HT1A receptors upon life-time BDNF reduction, but
unfortunately do not illuminate the mechanisms leading to this observation. Theoretically,
counter-regulatory or compensatory effects may have altered 5-HTT and 5-HT1A expression.
Furthermore, it is possible that not absolute numbers but functional activity of serotonergic
structures is altered by BDNF.
The evidence on connections between depression and BNDF genotype status is
inconsistent as well. Meta-analytical research suggested an association of Val66Met with
major depressive disorder antidepressant treatment response or hippocampal volume and a
role of gender and ethnicity [37-39]. However, recent meta-analyses refuted these
96
associations and detected power deficits in many trials [40-42]. Low serum levels of BDNF
were suggested as potential peripheral marker of depression and increase of serum BDNF
as response to the appropriate first-line treatment with selective 5-HT reuptake inhibitors
(SSRIs). Likewise, this association is weaker than initially thought and there is no
relationship between symptom severity and BDNF serum concentration [43]. Our results
suggest no association between allelic distribution and diagnosis. Our small number of MDD
subjects remain a limiting factor in that regard.
LIMITATIONS
Unfortunately a common problem of human PET studies is weak power resulting from low
subject numbers, owed to the large effort of conducting PET-imaging. This is even more
intrinsic to genetic PET studies reporting results based on genotype subgroups [44] and in
SNP neuroimaging studies where pooling of rare genotype groups is common practice. The
low subject number in the MDD met-carrier group could therefore be a limitation of our study.
One elegant way to circumvent this issue in future studies would be pooling data between
PET centers, which is already common in MRI studies. Second, mean age of genotype
groups is heterogeneous, yet controlled for in all statistical analyses. Finally, we did not
model PET data with an arterial input function [45], because arterial blood data were not
collected. This would have been useful to confirm reported differences according to the
methodology for calculating 5-HT1A binding with [carbonyl-11C]WAY-100635, an issue we are
trying to resolve in future studies [46].
CONCLUSION
Although others have investigated the effects of the BDNF gene on 5-HTT and 5-HT1A
binding with PET, this study adds data to the ongoing discussion about the cross connection
97
between 5-HT and BDNF. While previous work in humans demonstrated contradicting
results, due to this work the conclusion of an absent influence of Val66Met on 5-HTT and 5-
HT1A has gained substantial support.
ACKNOWLEDGEMENTS
The authors are grateful to U. Moser, E. Akimova, P. Stein, M. Fink, C. Spindelegger, A.
Höflich, I. Hofer-Irmler, S. Zgud, S. Pichler, A. Kautzky and D. Winkler for medical and
administrative support, and M. Savli for technical support. We thank the PET team,
especially G. Karanikas, T. Traub-Weidinger, L.-K. Mien, J. Ungersboeck, K. Kletter, L. Nics,
and C. Philippe for technical support. Further, we thank the genetics team of D. Rujescu,
especially M. Friedl, A. Hartmann, I. Giegling.
The study is part of C. Kraus’ thesis “Serotonin and Neuroplasticity” supervised by R.
Lanzenberger in the Clinical Neurosciences PhD program at the Medical University of
Vienna, Austria. Parts of this study have been presented by P. Baldinger at the 19th at the
11th World Congress of Biological Psychiatry (WFSBP), June 23rd – 27th, 2013, Kyoto, Japan.
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101
Table 1. Demographic variables of the entire study sample.
val/val
met-carrier
p
healthy subjects
[carbonyl-11C]WAY-100635
N (=51) 30
21
Age (years) 43.8 ± 13.1
45.1 ± 12.36
0.737
Sex (f/m) 21/9
16/5
0.626*
weight 72.9 ± 17.1
67.1 ± 10.5
0.169
SA 296.9 ± 269.1
285.7 ± 197.3
0.702
[11
C]DASB
N (=25) 19
6
Age (years) 31.0 ± 8.8
33.0 ± 13.2
0.672
Sex (f/m) 8/11
1/5
0.258*
weight 76.7 ± 12.1
80.2 ± 10.8
0.537
SA 44.1 ± 47.7
25.6 ± 25.4
0.378
MDD patients
[11
C]DASB N (=16) 13
3
HAMD 19.4 ± 3.6
21± 3.5
0.495
Age (years) 41.1 ± 8.9
46.7 ± 7.5
0.34
Sex (f/m) 9/4
3/0
0.267*
weight 77.7 ± 21.3
61.3 ± 2.5
0.251
+
SA 63.9 ± 22.6
62.5 ± 16.7
0.925
Data are given as means ± standard deviations (SD). P-values compare pooled
BNDF Val66Met genotype groups with independent sample t-test, chi-square(*) or
(BPND) according to BDNF Val66Met genotype status in 25 healthy subjects and 16
depressed patients.
region
healthy subjects
MDD patients
val/val (n=19)
met-carrier (n=6)
p
val/val (n=13)
met-carrier (n=3)
p
Anterior cingulate 0.42 ± 0.08 0.40 ± 0.06 0.759
0.38 ± 0.14 0.32 ± 0.15 0.517
Amygdala 1.24 ± 0.13 1.14 ± 0.17 0.167
1.06 ± 0.24 1.14 ± 0.46 0.685
Medial cingulate 0.40 ± 0.07 0.37 ± 0.08 0.431
0.37 ± 0.13 0.30 ± 0.12 0.395
Hippocampus 0.46 ± 0.08 0.41 ± 0.08 0.206
0.40 ± 0.10 0.44 ± 0.11 0.525
N. caudatus 1.84 ± 0.21 1.73 ± 0.22 0.305
1.72 ± 0.32 1.50 ± 0.35 0.309
Putamen 1.88 ± 0.18 1.85 ± 0.27 0.756
1.75 ± 0.28 1.50 ± 0.30 0.248
Thalamus 2.07 ± 0.23 1.88 ± 0.11 0.071
1.88 ± 0.37 1.72 ± 0.45 0.527
Striatum 1.70 ± 0.16 1.66 ± 0.22 0.624
1.58 ± 0.25 1.37 ± 0.28 0.231
Midbrain 2.91 ± 0.33 2.58 ± 0.31 0.040
2.62 ± 0.41 3.20 ± 1.80 0.382*
N. accumbens 1.95 ± 0.3 1.82 ± 0.26 0.327
1.82 ± 0.30 1.67 ± 0.46 0.572
Regions of interest (ROIs) in standardized MNI space (Montreal Neurological Institute) were
calculated by automatic anatomical labeling in both hemispheres and averaged. Data are given as 5-
HTT BPND means ± standard deviations (SD). T-tests or U-test (*) compare differences between
val/val and met-carrier for each ROI.
104
IV. GENERAL DISCUSSION and RAISED QUESTIONS
With this work we investigated a series of issues on the association of neuroplasticity with
serotonin in the living human brain. To this goal, neuroimaging methods such as structural
and functional MRI and PET with the radioligands [11C]DASB and [carbonyl-11C]WAY-100635
were used for the to probe relationships between elevated 5-HT levels, gray matter,
important serotonergic proteins and the neurotrophine brain derived neurotrophic factor. The
here presented results underline that some of the known functions of 5-HT shaping the
neuronal architecture of the brain in embryonic and early post-natal periods are very likely, at
least partly, conserved throughout adulthood.
While neuroplastic effects of the 5-HT1A receptor function were previously discovered in
animals, we here translated this feature into in vivo human research by demonstrating strong
associations between the distribution of the 5-HT1A receptor and regional gray matter
volume. This result was mainly observed in brain regions with high 5HT1A receptor density,
yet restricted to certain regions and not present in others with equaly high 5-HT1A densitiy,
suggesting regional differences in neuroplastic functions. Furthermore, a correlation of 5-
HT1A autoreceptors in the dorsal raphe nuclei, one of the midbrain’s major serotonergic
nucleus, and cortical gray matter in the anterior cingulate cortex undermined the regulatory
function of the raphe nuclei. With the limitation of beeing correlational, these results in any
case justify further longitudinal investigations e.g. into how pharmacological manipulations of
5-HT1A receptor function would be able to effect changes of gray matter. Secondly, we found
that elevated 5-HT levels after selective serotonin reuptake inhibitor administration leads to
strong enhancements of cortical gray matter in the posterior cingulate cortex, which are in
turn associated with altered functional neuronal activity in this region. While this finding goes
along with previous work showing gray matter inceases after selective serotonin reuptake
inhibitor intake in psychiatric patients (Hoexter et al, 2012; Smith et al, 2012; Vermetten et al,
2003), gray matter increases in healthy subjects constitute a novel finding, as well as
adjacent functional alterations as consequence of enhanced gray matter. These results raise
105
many questions. Given that healthy subjects do not exhibit major neuropsychological
changes after 10 days of SSRI intake, one might ask what are the phenotypical correlates of
such strong signal increases. Consequently, this work demands closer investigations of the
biological correlate of VBM results. Several authors question the sensitivity regarding
neuronal changes in VBM studies (Bookstein, 2001; Franklin et al, 2013) and suspect
changes of perfusion and difusion of cerebral blood flow to underlie VBM findings. Indeed,
the huge gap between biological mechanisms and findings of MRI-based structural
neuroimaigng techniques are currently discussed controversially (Draganski & Kherif, 2013;
Erickson, 2013; Fields, 2013; Thomas & Baker, 2013). This work adds to the ongoing
discussion that neuroplastic serotonergic receptors might contribute to structural MRI signal
changes. This supposition provides new testable hypoptheses, that could combine
neurobiological data on neuroplasticity with neuroimaging-based in vivo information.
Finally, we found no evidence for an association between SERT or 5-HT1A availability upon
lifetime alterations of BDNF as produced by a common single nucleotid polymorphism
(Val66Met). This finding is controversial, because two previous studies demonstrated an
effect of this polymorphism on the expression of SERT and 5-HT1A receptors (Henningsson
et al, 2009). The dicrepancy might arise from methodological differences in quantification
using the radiligand [carbonyl-11C]WAY-100635, especially due to reference region data from
an aterial input function by other groups. Given the reported evidence in the introduction
section, BDNF and 5-HT posess many molecular crossconections, but previous studies
failed to report strong effects in one system upon deficites of the other. Reciprocal
compensatory mechanisms might be able to counter-regulate single weak points, and this
fits well to clinical studies generally reporting no clearcut evidence of “single-deficite”-
proteins in psychiatric conditions such as depression, in which BDNF and 5-HT are
considered relevant pathogenetic factors. In these disorders, pathophysiological concepts
comprise entaglements between biological vulnerability by genetical predisposition, multi-hit
neuropathological defictes and environmental adversities (Krishnan & Nestler, 2010;
106
Pittenger & Duman, 2008; Schmidt et al, 2011). Both 5-HT and BDNF would provide ample
neurobiological targets connecting these three concepts, yet until now only a very limited
number of studies encompass this phenomenologically heterogenous spectrum. Especially
studies applying imaging genetics and information on environmental adversities could better
unrevel the impact of these two neurophysiologic systems to pathomechanisms of
depression (Agren et al, 2012; Rabl et al, 2014; Witte et al, 2012). With this latter study we
have provided a groundwork and justification of such studies.
A limitation of this project constitutes the still insufficient resolution of neuroimaging
techniques and the lack of knowledge about exact neurobiological correlates of structural
MRI-based methods. Therefore, due to methodological constraints, it is currently not
possible to detect in vivo in humans how exactly 5-HT exerts it’s neuroplastic functions.
Nevertheless, a combination of MRI and PET in multimodal neuroimaging, as applied in the
first study, is elegantly capable of adding molecular information to the same voxel and thus
bringing neuroimaging closer to neurobiology. The next step, would be study human brain
function with combinations of structural, functional and molecular neuroimaging and in
translational animal models with additional post-mortem data, for examples see (Sagi et al,
2012; Vernon et al, 2011). Additional factors might have influenced our results, including low
power in the molecular imaging genetics study, where statistical power is a trade-off to high
efforts in conducting PET studies and subsequent splitting of study subjects into genotype
groups. Finally, we have to state in this section that binding potential results of [carbonyl-
11C]WAY-100635 vary according to the chosen reference region expecially under
consideration of the arterial input function, and that discrepent results between groups are
thought to be susceptible to heterogenous methodological aproaches, for review see
(Shrestha et al, 2012).
107
V. CONCLUSION and FUTURE PERSPECTIVES
This doctoral thesis was conducted to investigate neuroplastic functions of 5-HT in vivo in
healthy humans. By a combination of structural and functional MRI with molecular imaging of
the serotonergic system including imaging genetics, this work assess the links between 5-
HT and neuroplasticity with multiple methodological approaches. The central statements of
this thesis lies in demonstrating the relationship between structural, molecular, functional
and genetic properties of the human serotonergic system as measured with neuroimaging.
While this improved our knowledge on structural and functional properties of this
neurotransmitter system, future work on pathological alterations of serotonin’s neuroplastic
capabilites is needed. While previous knowledge revealed that 5-HT is implicated in the
pathogenesis of psychiatric diseases such as depression, and serotonergic receptors and
the 5-HT transporter are important targets in psychopharmacology, little is known about the
exact pathomechanisms of depression and the mechanisms of action of antidepressants.
Investigations of deficites in 5-HT mediated neuroplasticity in depression could hence
provide a unification of two previously competing major pathogenetic hypotheses, the
“neuroplasticity hypothesis” and the “monoamine hypothesis”.
Additionally, this work gives rise to still unresolved problems regarding the neurobiology
behind MRI-based neuroimaging methods. Bringing neuroimaging closer to neurobiology
could thereby reduce the gap between sophisticated neuroscientific “bench” aproaches in
animals such as optogenetics or stem cell research and low resolution human “bed side” in
vivo methods. Certainly, a better understanding of neurobiological alterations in vivo would
generate big leaps foreward in the understanding and treatment of psychiatric diseases such
as depression.
108
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APPENDIX – CURRICULUM VITAE
Dr. med. univ. Christoph Kraus
Schilfgasse 2, 2452 Mannersdorf Weinbergstraße 6, 7100 Neusiedl am See mobile: +43 664 4147931 Email: [email protected] Department of Psychiatry and Psychotherapy Medical University of Vienna Waehringer Guertel 18-20 A – 1090 Vienna, Austria
Personal Details: 1.7.1983 born in Eisenstadt
unmarried
Austrian
Primary Education:
1989-1993 Primary School
1993-2001 Gymnasium Neusiedl am See, Matura, 7.6.2001
Higher Education:
2002-2009 Medical Studies at the Medical University of Vienna
2007-2009 Diploma thesis at the Department of Psychoanalysis and
Psychotherapy under supervison from Ao. Univ. Prof. Mag. Dr. Jandl-
Jager Elisabeth entitled “Violence in childhood and recognition in the
medical system of Austria”.
17.9.2009 M.D. degree of the Medical University of Vienna
2012 – present PhD Thesis in Clinical Neurosciences (N790). Title: Serotonin and
Neuroplasticity – Investigated in vivo by Positron Emission
Tomography and structural Magnetic Resonance Imaging. Supervisor:
A/Prof. Rupert Lanzenberger, Mentors: Prof. Siegfried Kasper, A/Prof.
1.9.2011–present Clinical Training, Medical University of Vienna, Department of
Psychiatry and Psychotherapy
1.10.2012–1.10.2013 Clinical Training, Medical University of Vienna with emphasis on
treatment of forensic psychiatric Patients in the Prison “Justizanstalt
Josefstadt”
1.3.2014–30.9.2014 Psychiatric consultant service at the Vienna General Hospital (AKH)
1.10.2014-present Training in Neurology, Department of Neurology, Medical University of
Vienna, as required for specialist training
Scientific Collaborations:
2009 – present staff member in the „NEUROIMAGING LABs (NIL)“ (head Assoc.-Prof. PD Dr. Rupert Lanzenberger), Department of Psychiatry and Psychotherapy, MUW. Collaboration and Coinvestigator in clinical projects focused on neuroimaging and genetics:
2009 – 2011 Coinvestigator: Networks of Anxiety: Connectivity Analysis in Social Phobia using Functional Magnetic Resonance Imaging, OeNB procet number 12982, EK 619/2007, Principal Investigator: Assoc.-Prof. Priv.-Doz. Dipl.-Ing. Dr. Christian Windischberger, MUW Austria.
2009 – 2011 Coinvestigator: The influence of hormone replacement therapy on the cerebral serotonin-1A receptor distribution and mood in postmenopausal women. A longitudinal study using Positron Emission Tomography (PET) and the radioligand [carbonyl-11C]WAY-100635. Principal Investigator: O. Univ. Prof. Dr. h.c. mult Dr. med. S. Kasper, MUW Austria.
2010 – 2011 Coinvestigator: Effects of electroconvulsive therapy on serotonin-1A receptor binding in major depression. A longitudinal study using Positron Emission Tomography (PET) and the radioligand [carbonyl-11C]WAY-100635. Principal Investigator: Ao. Univ. Prof. Dr. Richard Frey, MUW Austria.
2010 – 2014 Coinvestigator: The influence of sex steroid hormones onserotonin transporter bindingin the human brain investigated by PET. OeNB project number 13214, EK 620/2008. Principal Investigator: Assoc.-Prof. Priv.-Doz. Dr. Rupert Lanzenberger, MUW Austria.
2011 – 2014 Coinvestigator: The Serotonin Transporter in Attention Deficit Hyperactivity Disorder Investigated with Positron Emission Tomography. OeNB project number AP13675ONB, EK 784/2009, Principal Investigator: Priv. Doz. Mag. Dr. Markus Mitterhauser, Austria.
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2012 – present Coinvestigator: Multimodal Assessment of Neurobiological Markers for Psychiatric Disorders (MAN-BIOPSY). Research cluster “Multimodal Neuroimaging in clinical neurosciences (MMI-CNS), Medical University Vienna, University of Vienna. Principal Investigators: Assoc.-Prof. Priv.-Doz. Dr. Rupert Lanzenberger, Univ. Prof. Mag. Dr. Claus LammPhD
Other Universitary Acitvities:
2008 Initiation of the course: „Medizinsoziologie mit wechselndem Schwerpunkten: Balint-Gruppe, wissenschaftliche Methoden, Traumforschung“, together with Ao. Univ. Prof. Mag. Dr. Jandl-Jager in winterterm 08.
2009 Initiation of the course “Talks about death and dying“, starting in winterterm 09/10, togehter with Univ. Prof. Dr. Pötter, Univ. Prof. Dr. Watzke, Mag. Dr. Hladschik-Kermer, Mag. Kirchheiner
2012 – present Representative of resident psychiatrists at the Department of Psychiatry and Psychotherapy
Further Education:
2009 – 2012 Psychotherapeutic propaedeutics – H.O.P.P. Vienna 2012 Statistical Parametric Mapping Course, Center for Experimental
Medicine, Department of System Neuroscience UKE Eppendorf, Hamburg.
2012 PMOD basic Application and Small Animal Imaging Processing
Courses, Zürich 2013 – present Training in Cognitive Behavioural Therapy
1. FELLOWSHIPS
Young Scientist Association (YSA) of the Medical University of Vienna
Austrian Medical Chamber
Austrian Psychiatric and Psychotherapeutic Association
European College of Neuropsychopharmacology (ECNP)
2. TEACHING
2013 – now Student courses in clinical psychiatry and psychopharmacology at the Medical University of Vienna
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2014 – now Nurse Training in clinical psychiatry at the School of Nursery of the Viennese Hospital Association
2015 Thesis Completion of Dr. Patrick Köck, Thesis supervision cand. med. Clauddia Winkler
3. REVIEWER FOR MANUSCRIPTS:
Molecules [IF 2014: 2.42]
World Journal of Biological Psychiatry [IF 2014: 4.23]
International Journal of Neuropsychopharmacology [IF 2014: 4.0]
Journal of Psychiatry and Neuroscience [IF 2014: 7.49]
Rafaelsen Young Investigator’s award by the International College of
Neuropsychopharmacology (CINP) 2014
WFSBP Educational Grant, 2015
ECNP Travel Award, 2015
5. CHAIRS Co-Chair, Serotonin and Neuroplasticity at the WFSBP Conference 2015
Young Programme Sub-committee for the Seoul Congress
6. SCIENTIFIC FIELD OF WORK
Serotonin and Neuroplasticity, Neuroimaging of Neuropsychiatric disorders: ADHD,
Depression, Anxiety Disorders, Genetics in Neuroimaing
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7. PUBLICATION LIST
7.1 Articles
7.1.1 1ST Authorships:
1. Baldinger P, Kraus C, Rami-Mark C, Gryglewsky G, Kranz GS, Haeusler D, Hahn A, Wadsak W, Mitterhauser M, Rujescu D, Kasper S, Lanzenberger R. Interaction between 5-HTTLPR and 5-HT1B genotype status enhances serotonin-1A receptor binding. NeuroImage 2015 May 15;111:505-512. Epub 2015, [2014, IF: 6.36]
2. Kraus C, Baldinger P, Rami-Mark C, Gryglewsky G, Kranz GS, Haeusler D, Hahn A, Wadsak W, Mitterhauser M, Rujescu D, Kasper S, Lanzenberger R. Exploring the impact of BDNF Val66Met genotype on serotonin transporter and serotonin-1A receptor binding, PLOS-One, 2014 Sep 4;9(9) [2014: 3.23]
3. Kraus C, Ganger S, Losak J, Hahn A, Savli M, Kranz GS, Baldinger P, Windischberger C, Kasper S, Lanzenberger R, Gray matter and intrinsic network changes in the posterior cingulate cortex after selective serotonin reuptake inhibitor intake. NeuroImage 2014; 84:236-244. Epub 2013 Aug 26 [2014, IF: 6.36]
4. Kraus C, Hahn A, Savli M, Kranz GS, Baldinger P, Höflich A, Spindelegger C, Ungersböck J, Häusler D, Mitterhauser M, Windischberger C, Wadsak W, Kasper S, Lanzenberger R. Serotonin-1A receptor binding is positively associated gray matter volume – A multimodal neuroimaging study combining PET and structural MRI. NeuroImage 2012 Nov 15;63(3):1091-1098. Epub 2012 Jul 23 [2014, IF: 6.36]
5. Kraus C, Jandl-Jager E. Awareness and knowledge of child abuse amongst physicians - a descriptive study by a sample of rural Austria. Wien Klin Wochenschr. 2011 Jun;123(11-12):340-9. Epub 2011 May 4. [2014, IF: 0.84]
7.1.2 Co-authorships:
6. Seidel EM, Pfabigan D, Hahn A, Sladky R, Grahl A, Paul K, Kraus C, Küblböck M, Kranz G, Hummer A, Lanzenberger R, Windischberger C, Lamm C. Uncertainty during pain anticipation: The adaptive value of preparatory processes. Human Brain Mapping,. 2014 Oct 16. [Epub ahead of print], [2014, IF: 5.97]
7. Pfabigan D, Seidel EM, Sladky R, Hahn A, Paul K, Grahl A, Küblböck M, Kraus C, Hummer A, Kranz G, Windischberger C, Lanzenberger R, Lamm C, P300 amplitude variation is related to ventral striatum BOLD response during gain and loss anticipation: An EEG and fMRI experiment. NeuroImage 2014 Aug 1;96:12-21, Epub 2014 Apr 6 [2014, IF: 6.36].
8. Hahn A, Haeusler D, Kraus C, Höflich A, Kranz GS, Baldinger P, Savli M, Mitterhauser M, Wadsak W, Karanikas G, Kasper S, Lanzenberger R. Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression. Human Brain Mapping Hum Brain Mapp. 2014 Aug;35(8):3857-66. Epub 2014 Jan 17. [2014, IF: 5.97]
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9. Sladky R, Höflich A, Küblböck M, Kraus C, Baldinger P, Moser E, Lanzenberger R, Windischberger C. Disrupted efective connectivity between the amygdala and orbitofrontal cortex in social anxiety disorder during emotion discrimination revealed by dynamic causal modeling for fMRI, Cerebral Cortex, Epub 2013 Oct 9 [2014, IF: 8.66]
10. Baldinger P, Hahn A, Mitterhauser M, Kranz G, Friedl M, Wadsak W, Kraus C, Ungersböck J, Hartmann A, Giegling I, Rujescu D, Kasper S, Lanzenberger R. Impact of COMT genotype on serotonin-1A receptor binding investigated with PET. Brain Structure and Function 2014 Nov;219(6):2017-28. Epub 2013 Aug 9. [2014, IF: 5.62]
11. Hahn A, Kranz GS, Seidel EM, Sladky R, Kraus C, Küblböck M, Pfabigan DM, Hummer A, Grahl A, Ganger S, Windischberger C, Lamm C, Lanzenberger R. Comparing neural response to painful electrical stimulation with functional MRI at 3 and 7 Tesla. NeuroImage 2013 Nov 15;82:336-343. Epub 2013 Jun 12 [2014, IF: 6.36]
12. Kranz GS, Hahn A, Baldinger P, Häusler D, Philippe C, Kaufmann U, Wadsak W, Savli M, Höflich A, Kraus C, Vanicek T, Mitterhauser M, Kasper S, Lanzenberger R. Cerebral serotonin transporter asymmetry in males and male-to-female transsexuals: a PET study with [11C]DASB. Brain Structure and Function. 2014 Jan;219(1):171-83. Epub 2012 Dec 9 [2014, IF: 5.62]
13. Hahn A, Nics L, Baldinger P, Wadsak W, Savli M, Kraus C, Birkfellner W, Ungersboeck J, Haeusler D, Mitterhauser M, Karanikas G, Kasper S, Frey R, Lanzenberger R. Application of image-derived and venous input functions in major depression using [carbonyl-11C]WAY-100635. Nuclear Medicine and Biology 2013 Apr;40(3):371-7 [2014, IF: 2.41].
14. Hahn A, Wadsak W, Windischberger C, Baldinger P, Höflich A, Losak J, Nics L, Philippe C, Kranz GS, Kraus C, Mitterhauser M, Karanikas G, Kasper S, Lanzenberger R. Differential modulation of self-referential processing in the default mode network via serotonin-1A receptors. Proceedings of the National Academy of Sciences (PNAS) 2012 Feb 14;109(7):2619-24. Epub 2012 Jan 30. [2014, IF: 9.67]
15. Sladky R, Höflich A, Atanelov J, Kraus C, Baldinger P, Moser E, Lanzenberger R, Windischberger C. Increased neural habituation in the amygdala and orbitofrontal cortex in social anxiety disorder revealed by FMRI. PLOS One. 2012;7(11):e50050. Epub 2012 Nov 29. [2014, IF: 3.23]
7.2 Abstracts
7.2.1 1ST Authorships:
1. Kraus C, Savli M, Hahn A, Baldinger P, Höflich A, Mitterhauser M, Wadsak W, Windischberger C, Kasper S, Lanzenberger R. Serotonin-1A binding in the subgenual anterior cingulate cortex is associated with regional grey matter volume in striatum and temporal areas. 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria, European Psychiatry 2011, 26(1): P02-338
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2. Kraus C, Hahn A, Savli M, Mitterhauser M, Wadsak W, Windischberger C, Kasper S, Lanzenberger R. A positive Correlation Between Inhibitory Serotonergic Neurotransmission and Grey Matter Volume. 7th PhD Symposium, 15-16th June 2011, Vienna Austria
3. Kraus C, Savli M, Hahn A, Höflich A, Baldinger P, Mitterhauser M, Wadsak W, Kasper S, Lanzenberger R. Molecular imaging of the serotonergic system – Serotonin, an important effector in modulating emotions. 12th International Neuropsychoanalysis Congress, June 24 – 26, 2011, Berlin, Germany
4. Kraus C, Hahn A, Savli M, Höflich A, Baldinger P, Kranz GS, Mitterhauser M, Wadsak W, Kasper S, Lanzenberger R. Serotonin-A receptor binding in the dorsal raphe nucleus is associated with hippocampal grey matter volume. 24th European College of Neuropsychopharmacology (ECNP) Congress, 3-7 September 2011, Paris, France European Neuropsychopharmacology,Vol 21, Suppl. 3, S318-319
5. Kraus C, Hahn A, Savli M, Baldinger P, Höflich A, Kranz GS, Losak J, Mitterhauser M, Wadsak W, Windischberger C, Kasper S, Lanzenberger R. Multimodal neuroimaging detects serotonin-1A receptor mediated neuroplasticity in humans. 24th IGB Workshop, Regulation of Neural Gene Expression from Development to Disease, 16-19 October 2011 Capri, Italy
6. Kraus C, Savli M, Hahn A, Baldinger P, Höflich A, Ungersboeck J, Mitterhauser M, Windischberger C, Wadsak W, Kasper S, Lanzenberger R. Serotonin-1A receptor related morphogenic signaling is associated with regional brain volumes and network neuroplasticity 20th EPA European Congress of Psychiatry, Prague, 3-6 March 2012
7. Kraus C, Vanicek T, Baldinger P, Hartmann A, Wadsak W, Lanzenberger R. Relationship between 5-HT1B receptor SNPs and 5-HT1A receptor BPND in healthy subjects measured by PET. 8th International Imaging Genetics Conference, Irvine, California, USA, January 16th–17th, 2012
8. Kraus C, Savli M, Hahn A, Höflich A, Baldinger P, Wadsak W, Windischberger C, Mitterhauser M, Kasper S, Lanzenberger R. Multimodal neuroimaging with PET and MRI to investigate the relation between serotonergic neurotransmission and regional brain volumes. ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe, 15-18 March 2012, Nice, France European Neuropsychopharmacology, Vol xx, Suppl. x, March 2012, Sxx(P.x.xxx)
9. Kraus C, Mitterhauser M, Bauer A, Ding Y-S, Henry S, Rattay F, Savli M, Lanzenberger R. A Normative database of the serotonergic system in healthy subjects using multi-tracer PET 10th PhD Symposium, June 13-14, 2012, Vienna, Austria
10. Kraus C, Vanicek T, Wadsak W, Baldinger P, Hartmann A, Mitterhauser M, Ungersboeck J, Rujescu D, Kasper S, Lanzenberger R. 5-HT1B receptor gene status alters 5-HT1A binding as investigated in vivo by PET and [carbonyl-11C]WAY-100635 25th European College of Neuropsychopharmacology (ECNP) Congress, 13-17 October 2012, Vienna, Austria European Neuropsychopharmacology,Vol 2x, Suppl. x, Sxxx-xxx
11. Kraus C, Ganger S, Losak J, Hahn A, Savli M, Spies M, Baldinger P, Windischberger C, Kassper S, Lanzenberger R. Rapid gray matter increases and resting state network changes after selective serotonin reuptake inhibitor administration. 11th World Congress of Biological Psychiatry (WFSBP), June 23rd- 27th, 2013, Kyoto, Japan
12. Kraus C, Kranz GS, Küblböck M, Pfabigan D, Hahn A, Sladky R, Seidel EM, Hummer A, Paul K, Ganger S, Windischberger C, Lamm C, Lanzenberger R. Reward anticipation maps comparing high and ultrahigh field functional MRI. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
13. Kraus C, Baldinger P, Hahn A, Rami-Mark C, Wadsak W, Mitterhauser M, Kasper S, Lanzenberger R. Brain derived neurotrophic factor genotype status impacts on hippocampal serotonin-1A receptor binding. 13th Meeting of the Austrian Neuroscience Association (ANA) Vienna, 16–19 September 2013
14. Kraus C, Kranz GS, Pfabigan DM, Hoffmann A, Hahn A, Seidel EM, Küblböck M, Spies M, Paul K, Sladky R, Kasper S, Windischberger C, Lamm C, Lanzenberger R. Parahippocampal and insular gray matter volume correlates with empathy. 29th
CINP–World Congress of Neuropsychopharmacology, 22-26 June 2014, Vancouver, Canada
15. Kraus C, Stürkat IL, Sladky R, Hahn A, Pfabigan D, Tik M, Köck P, Windischberger C, Lamm C, Lanzenberger R. Altered structural plasticity in acute and remitted depressive patients investigated with ultra-high field magnetic resonance imaging. 28th ECNP Congress 29.8. – 1.9. 2015, Amsterdam.
7.2.2 Co-authorships:
1. Baldinger P, Savli M, Kranz GS, Höflich A, Kraus C, Windischberger C, Kasper S, Lanzenberger R. Are there structural brain changes following 10 days of SSRI administration investigated by voxel-based morphometry? 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria European Psychiatry 2011, 26(1): P02-317
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2. Höflich A, Philippe C, Savli M, Baldinger P, Kranz GS, Müller S, Häusler D, Zgud S, Kraus C, Wadsak W, Mitterhauser M, Lanzenberger R, Kasper S. Prediction of steady-state occupancy of the serotonin transporter based on single-dose occupancy: A [11C]DASB PET study. 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria European Psychiatry 2011, 26(1): P02-333
3. Sladky R, Kraus C, Tröstl J, Kasper S, Lanzenberger R, Moser E, Windischberger C. Orbitofrontal hyperactivity in social anxiety disorder patients: An fMRI study. 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria European Psychiatry 2011, 26(1): P01-179
4. Tröstl J, Sladky R, Hummer A, Kraus C, Moser E, Kasper S, Lanzenber R, Windischberger C. Reduced connectivity in the uncinate fiber tract between the frontal cortex and limbic subcortical areas in social phobia. 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria European Psychiatry 2011, 26(1): P01-182
5. Savli M, Hahn A, Häusler D, Baldinger P, Höflich A, Kraus C, Wadsak W, Mitterhauser M, Lanzenberger R, Dudczak R, Kasper S. Can the Median Raphe Nucleus predict Clinical Outcome in Patients with Major Depression? A [11C]DASB PET study Talk (Young Scientists award session) and Abstract (CD) YS-02-001 10th World Congress of Biolog. Psychiatry (WFSBP), 29.6.– 2.7.2011, Prague, Czech Republic
6. Hahn A, Lanzenberger R, Häusler D, Philippe C, Savli M, Baldinger P, Höflich A, Kraus C, Akimova E, Mitterhauser M, Wadsak W, Kasper S. Reduced Serotonin Transporter Association between Raphe Region and Ventral Striatum in Major Depressive Disorder. Talk (Free Communication) and Abstract (CD) FC-06-002 10th World Congress of Biolog. Psychiatry (WFSBP), 29.6.– 2.7.2011, Prague, Czech Republic
7. Savli M, Hahn A, Häusler D, Philippe C, Baldinger P, Höflich A, Kraus C, Kranz GS, Zgud S, Akimova E, Wadsak W, Mitterhauser M, Lanzenberger R, Dudczak R, Kasper S. The Impact of Software Motion Correction on PET Drug Occupancy Studies. 10th International Conference on Quantification of Brain Function with PET, May 24-28, 2011, Barcelona, Spain
8. Kranz GS, Kaufmann U, Ungersböck J, Hahn A, Stein P, Baldinger P, Höflich A, Zgud S, Kraus C, Losak J, Mitterhauser M, Wadsak W, Kasper S, Lanzenberger R. Estrogen and progesterone treatment affects serotoninergic neurotransmission in postmenopausal women. 17th Annual Meeting of the Organization for Human Brain Mapping, June 26-30, 2011, Quebec City, Canada
9. Sladky R, Kraus C, Tröstl J, Kasper S, Lanzenberger R, Moser E, Windischberger C. Orbitofrontal hyperactivity and habituation in social anxiety disorder patients: an
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fMRI study. 17th Annual Meeting of the Organization for Human Brain Mapping, June 26-30, 2011, Quebec City, Canada
10. Tröstl J, Sladky R, Hummer A, Kraus C, Moser E, Kasper S, Lanzenberger R, Windischberger C. White Matter Alterations in Social Anxiety Disorder: a DTI study. 17th Annual Meeting of the Organization for Human Brain Mapping, June 26-30, 2011, Quebec City, Canada
11. Höflich A, Hahn A, Kraus C, Baldinger P, Kranz GS, Windischberger C, Kasper S, Lanzenberger R. Resting-state functional connectivity of the raphe nuclei. 24th European College of Neuropsychopharmacology (ECNP) Congress, 3-7 September 2011, Paris, France European Neuropsychopharmacology,Vol 21, Suppl. 3, S319-320
12. Savli M, Baldinger P, Kranz GS, Höflich A, Kraus C, Losak J, Windischberger C, Kasper S, Lanzenberger R. Rapid gray matter density changes after selective serotonin reuptake inhibitor administration revealed by voxel-based-morphometry. 24th European College of Neuropsychopharmacology (ECNP) Congress, 3-7 September 2011, Paris, France European Neuropsychopharmacology,Vol 21, Suppl. 3, S312
13. Savli M, Hahn A, Häusler D, Baldinger P, Höflich A, Kraus C, Wadsak W, Mitterhauser M, Lanzenberger R, Dudczak R, Kasper S. The Impact of Median Raphe Nucleus Serotonin Transporter Binding on Depression: A [11C]DASB PET study. (Abstract and Talk). Annual Meeting of the International Society of NeuroImaging in Psychiatry (ISNIP), 07-10.09.2011, Heidelberg, Germany.
14. Tröstl J, Sladky R, Hummer A, Kraus C, Moser E, Kasper S, Lanzenberger R, Windischberger C. DTI of White Matter Alterations in the Uncinate Fasciculus of Social Phobia Patients. (Talk) 28th Annual Scientific Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRM), October 6-8, 2011, Leipzig, Germany.
15. Baldinger P, Kraus C, Friedl M, Haeusler D, Hartmann A, Mitterhauser M, Kranz G, Rujescu D, Kasper S, Lanzenberger R. 5-HT1A receptor genotype is associated with 5-HT1A receptor binding in the healthy human brain measured by PET. ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe, 15-18 March 2012, Nice, France European Neuropsychopharmacology, Vol xx, Suppl. x, March 2012, Sxx(P.x.xxx)
16. Hahn A, Wadsak W, Windischberger C, Baldinger P, Höflich A, Losak J, Nics L, Ungersböck J, Kranz GS, Kraus C, Mitterhauser M, Karanikas G, Kasper S, Lanzenberger R. Default mode network is modulated by serotonin-1A receptors. 18th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 10-14, 2012, Beijing, China NeuroImage Volume xx, Supplement x, August 2012, Pages Sxxx-Sxxx
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17. Sladky R, Höfich A, Tröstl J, Kraus C, Baldinger P, Moser E, Lanzenberger R, Windischberger C. Increased neural habituation in the amygdala and orbitofrontal cortex in social anxiety disorder revealed by fMRI. 18th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 10-14 2012, Beijing, China NeuroImage Volume xx, Supplement x, August 2012, Pages Sxx-Sx
18. Lanzenberger R, Hahn A, Ungersböck J, Friedl M, Baldinger P, Philippe C, Nics L, Kranz GS, Kraus C, Häusler D, Hartmann A, Savli M, Vanicek T, Mitterhauser M, Wadsak W, Rujescu D. Kasper S. A genetic variation of the serotonin-1B receptor affects serotonin-1A receptor in vivo binding. 18th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 10-14 2012, Beijing, China NeuroImage Volume xx, Supplement x, August 2012, Pages Sxx-Sx
19. Lanzenberger R. Mitterhauser M, Hahn A, Baldinger P, Friedl M, Kraus C, Pichler S, Rujescu D, Wadsak W, Kasper S. Molecular imaging genetics of the serotonin-1A receptor investigating the common rs6295 single nucleotide polymorphism. The 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain, August 9-11, 2012, Baltimore, Maryland, USA Journal of Cerebral Blood Flow and Metabolism 2012, Suppl. Xx
20. Baldinger P, Hahn A, Wadsak W, Friedl M, Kraus C, Mitterhauser M, Ungersböck J, Rujescu D, Kasper S, Lanzenberger R. Association between Catechol-O-methyltransferase Genotyp and Serotonin-1A Receptor Binding measured via Positron Emission Tomography 25th European College of Neuropsychopharmacology (ECNP) Congress, 13-17 October 2012, Vienna, Austria European Neuropsychopharmacology,Vol 2x, Suppl. x, Sxxx-xxx
21. Baldinger P, Hahn A, Mitterhauser M, Kraus C, Wadsak W, Rujescu D, Kasper S, Lanzenberger R. Genotyp of serotonin-1B receptor affects serotonin-1A receptor
binding in vivo 10th PhD Symposium, June 13-14, 2012, Vienna, Austria
22. Höflich A, Hahn A, Atanelov J, Baldinger P, Kraus C, Windischberger C, Kasper S, Lanzenberger R. Influence of ketamine on resting-state functional connectivity in healthy volunteers - A fMRI study. 10th PhD Symposium, June 13-14, 2012, Vienna, Austria
23. Seidel EM, Pfabigan D, Hahn A, Sladky R, Grahl A, Kraus C, Kueblboeck M, Kranz G, Hummer A, Lanzenberger R, Windischberger C, Lamm C. Uncertainty during pain anticipation – An fMRI and EEG experiment. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
24. Hahn A, Kranz G, Seidel EM, Sladky R, Kraus C, Kueblboeck M, Pfabigan D, Hummer A, Grahl A, Ganger S, Windischberger C, Lamm C, Lanzenberger R.
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Imaging the periaqueductal gray during pain processing at 3 and 7 Tesla functional MRI. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
25. Pfabigan D, Seidel EM, Sladky R., Hahn A, Paul K, Kueblboeck M, Kraus C, Hummer A, Kranz G, Windischberger C, Lanzenberger R, Lamm C. A multimodal study on gain and loss anticipation combining fMRI and EEG. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
26. Sladky R, Höflich A., Kuebelboeck M, Kraus C, Baldinger P, Moser E, Lanzenberger R, Windischberger C. Disrupted effective connectivity between amygdala and OFC in social anxiety disorder revealed by DCM. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
27. Ganger S, Hahn A, Sladky R, Kueblboeck M, Kranz G, Höflich A, Kraus C, Losak J, Spies M, Windischberger C, Lanzenberger R. Comparing techniques for resting state extraction from task data. 19th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 16-20, 2012, Seattle, USA
28. Küblböck M, Hummer A, Hahn A, Hoffmann A, Kraus C, Woletz M, Komorowski A, Lanzenberger R, Lamm C, Windischberger C. Reduction in vascular confounds of 3T and 7T fMRI group analysis results using the RESCALE method. 20th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 8-12, 2014, Hamburg, Germany.
29. Hoffmann A, Sladky R, Spies M, Küblböck M, Höflich A, Hummer A, Kranz GS, Woletz M, Lamm C, Lanzenberger R, Windischberger C. The Default Mode Network’s Frequency-dependency. 20th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 8-12, 2014, Hamburg, Germany.
30. Woletz M, Hoffmann A, Ganger S, Seiger R, Hahn A, Lamm C, Lanzenberger R, Windischberger C. Slice-timing correction for multi-band images in SPM. 20th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 8-12, 2014, Hamburg, Germany.
31. Sladky R, Minkova L, Höflich A, Kraus C, Baldinger P, Moser M, Lanzenberger R., Windischberger C. Task-dependent modulation of amygdalar connectivity in social anxiety disorder patients and healthy subjects. 20th Annual Meeting of the Organization for Human Brain Mapping (HBM), June 8-12, 2014, Hamburg, Germany.
32. Sladky R , Kraus C, Stürkat IL, Hoffmann A, Lamplmair D, Tik M, Spies M, Pfabigan D, Lamm C, Lanzenberger R, Windischberger C. Effective connectivity of amygdalar sub regions and OFC in acute and remitted MDD patients at 7T. 21st Annual Meeting of the Organization for Human Brain Mapping (HBM), June 14-18 2015, Honolulu, Hawaii, USA
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33. The influence of high‐ dose estradiol administration on limbic brain structures and
the ventricular system Seiger R, Hahn A, Hummer A, Kranz GS, Ganger S, Woletz M, Kraus C, Sladky R, Kasper S, Windischberger C, Lanzenberger R. DGPPN Kongress – Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde, November 25‐ 28 2015, Berlin
7.3 Lectures
1. Transkranielle Magnetstimulation als neue Behandlungsmethode bei Sozial Phobie. Fortbildungsveranstaltung der Klinischen Abteilung für Allgemeine Psychiatrie in Wien (Scientific seminar at the Department for Psychiatry and Pschotherapy, 21.10.10).
2. Einfluss der serotonergen Transmission auf die Struktur der Grauen Substanz. Winterseminar “Biologische Psychiatrie”, Oberlech 21.3.11 (Scientific seminar at the at the Wintersymposium “Biological Psychiatry, Oberlech, 21.03.11).
3. Serotonin-1A receptor distribution in the subgenual anterior cingulate cortex is associated with regional grey matter volume in the striatum and temporal areas. 19th European Congress of Psychiatry (EPA), March 12-15, 2011, Vienna, Austria, e-Poster presentation.
4. Inhibitory serotonergic neurotransmission correlates positively with cortical grey matter volume as revealed by PET and MRI. World Congress of Biological Psychiatry (WFSBP), May 31st, 2011, Prague, Czech Republic, free communication.
5. Serotonin-1a receptor related morphogenic signaling is associated with regional brain volumes and network neuroplasticity. 20th European Congress of Psychiatry, March 3-6, 2012, Prague, oral presentation.
6. Gen–Umwelt Interaktionen – Erfahrungsbedingte Plastizität in Gesundheit und psychiatrischen Erkrankungen, Winterseminar “Biologische Psychiatrie”, Oberlech 11.3.2013 (Scientific seminar at the at the Wintersymposium “Biological Psychiatry, Oberlech).
7. Rapid gray matter increases and resting state network changes after selective serotonin reuptake inhibitor administration, 11th World Congress of Biological Psychiatry (WFSBP), 26.6.2013, Kyoto, Japan, free communication.
8. Brain derived neurotrophic factor genotype status impacts on hippocampal serotonin-1A receptor binding, 13th Meeting of the Austrian Neuroscience Association (ANA),Vienna, 16.9.2013, oral presentation
9. Die Bedeutung des glutamatergen Systems bei psychiatrischern Erkrankungen, ÖGBP, 15.11.2013, Official Meeting of the Austrian Society for Neuropsychopharmacologgy and Biological Psychiatry.
10. Interaktionen zwischen Serotonintransporter und Serotonin-1B Rezeptor-Genotypen auf die Expression des Serotonin-1A Rezeptors, Winterseminar “Biologische Psychiatrie”, Oberlech (Scientific seminar at the at the Wintersymposium “Biological Psychiatry, Oberlech, 23.03.2014
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11. Interaction between serotonin transporter and 1B receptor genotype status impacts on serotonin 1A receptor binding, Oral Presentation, 22.5.2014, The 10th International Symposium on Functional NeuroReceptor Mapping of the Living Brain, Egmond aan Zee, The Netherlands
12. Serotonin and Neuroplasticity, Young Scientists Section at DEVELAGE-Symposium, Medical University of Vienna, 27.11.2014
13. Prädiktion des Behandlungserfolges bei Depression mit funktioneller MRT, (Scientific seminar at the at the Wintersymposium “Biological Psychiatry, Oberlech, 17.3.2015
14. Serotonin and Neuroplasticity, Interdisciplinary Meeting at the Center of Brain Science, 27.3.2015