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Electroconvulsive therapy increases temporal

gray matter volume and cortical thickness
Alexander Sartoriusa,b,n, Traute Demirakcac, Andreas Böhringerb,
Christian Clemm von Hohenberga,b, Suna Su Aksayb,
Jan Malte Bumbb, Laura Kranasterb, Gabriele Endec

a
Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health,
Medical Faculty Mannheim, University of Heidelberg, Germany
b
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty
Mannheim, University of Heidelberg, Germany
c
Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University
of Heidelberg, Germany

Received 3 June 2015; received in revised form 14 October 2015; accepted 20 December 2015

KEYWORDS Abstract
Depression; Electroconvulsive therapy (ECT) is a treatment of choice for severe and therapy resistant forms
Electroconvulsive of major depressive episodes (MDE). Temporal brain volume alterations in MDE have been
therapy; described for more than two decades.
VBM; In our prospective study we aimed to investigate individual pre–post ECT treatment whole brain
Cortical thickness;
gray matter (GM) volume changes (quantified with voxel-based morphometry) in a sample of 18
Hippocampus;
patients with MDE. In addition, we studied the effect of ECT on voxel-based cortical thickness in
Amygdala
cortical brain regions.
The most prominent longitudinal GM increases (significant at a whole brain corrected level)
occurred in temporal lobe regions. Within specific region of interest analyses we detected
highly significant increases of GM in the hippocampus and the amygdala and to a lesser extent in
the habenula (left p=0.003, right p =0.032). A voxel based cortical thickness analysis revealed
an increase in cortical temporal regions (basically temporal pole and insula) further
corroborating our cortical voxel-based morphometry results.
Neither GM decreases or white matter increases nor correlations of GM changes with basic
psychopathological parameters were detected.
We corroborate earlier findings of hippocampal and amygdala GM volume increase following an
acute ECT series in patients with MDE. Temporal GM volume increase was significant on a whole
brain level and further corroborated by a cortical thickness analysis. Our data widely exclude

n
Correspondence to: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim,
University of Heidelberg, J5, 68159 Mannheim, Germany. Tel.: +49 621 17032913.
E-mail address: alexander.sartorius@zi-mannheim.de (A. Sartorius).

http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
0924-977X/& 2016 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
2 A. Sartorius et al.
white matter loss as an indirect cause of GM growth. Our data add further evidence to the
hypothesis that ECT enables plasticity falsifying older ideas of ECT induced “brain damaging”.
& 2016 Elsevier B.V. and ECNP. All rights reserved.
1. Introduction
Depression remains a highly prevalent severe psychiatric
illness with limited therapeutic options and an enormous
individual and societal burden. The World Health Organization
(WHO) has ranked depression as the fourth leading cause of
disability worldwide (Murray and Lopez, 1996; Ustun et al.,
2004). Lifetime prevalence is estimated up to 15% (Kessler and
Bromet, 2013). The results of the largest outpatient trial on
major depressive disorder (STAR-D) illustrate the substantial
challenges in finding effective pharmacotherapeutic and psy-
chotherapeutic treatments for depression since one third of all
patients remained ill after level 4 treatment, the final
escalation of the treatment algorithm (Trivedi et al., 2006;
Rush et al., 2003, 2006a, 2006b).
Electroconvulsive therapy (ECT) is a treatment of choice
for severe and therapy resistant forms of depressive epi-
sodes (Fink and Taylor, 2007). ECT is performed under short
anesthesia and muscle relaxation, a safe routine treatment
even in very ill and highly comorbid patients (Sartorius and
Hewer, 2007). The antidepressive effect is definitely not
caused by the electrical current but by generalized seizure
activity (Sebag-Montefiore, 1974; Swartz and Larson, 1986;
Folkerts, 1996). It has been postulated that “therapeutic“
seizures have to affect deeper brain structures like the
diencephalon, basal ganglia or the hippocampal formation
in order to achieve clinical improvement (Abrams and
Taylor, 1976; Abrams, 2002; Sartorius et al., 2006). Whether
the affection itself or the ability of these structures to
terminate cortical seizure activity (anticonvulsive action)
might be reflecting or resulting in the antidepressive actions
of ECT remains unclear (Merkl et al., 2009; Bolwig, 2011).
Hippocampal volume alterations in major depression have
been described for more than two decades (Sheline et al.,
1996). First meta-analyses identified lower hippocampal
volumes in patients suffering from depression in 2004
(Videbech and Ravnkilde, 2004; Campbell et al., 2004).
Further meta-analyses provided evidence for both, hippo-
campal atrophy as a state maker, indicating the length of
current episode and the number of previous episodes
(McKinnon et al., 2009), as well as a putative trait marker
in first episode patients (Cole et al., 2011). Pharmacother-
apy could provide a protective effect (Frodl et al., 2008). In
cross-sectional studies age is an important confounder as
another meta-analysis (Arnone et al., 2012) and an own
study in depressed patients have indicated (Biedermann
et al., 2015). A recent longitudinal study provided not only
further evidence for an association of hippocampal volume
increase and remission, but also for cortical thickness
analysis as a predictive marker (Phillips et al., 2015).
It has been postulated that specifically ECT might exert
neurorestorative effects due to its known ability to increase
the levels of hippocampal neurotrophic factors (Sartorius
Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
et al., 2009), which might be necessary for a successful
therapy of treatment resistant depression (Taylor, 2008).
While (lower) pre-treatment hippocampal volume was
not able to predict the success of ECT in terms of improve-
ment of clinical symptoms (Ten Doesschate et al., 2014),
another study detected larger hippocampal volume as a
negative outcome predictor (Lekwauwa et al., 2005) in
geriatric depression. It seems also possible that a smaller
hippocampal volume is associated with acute memory
problems after ECT (Lekwauwa et al., 2005), a finding
which is corroborated by higher incidence of memory
problems after ECT in patients concomitantly suffering from
depression and Alzheimer’s disease (Hausner et al., 2011).
Changes in hippocampal volume during ECT have also
been investigated: Three studies found an increase in
hippocampal volume, with both manually outlined
(Nordanskog et al., 2010) and automatically reconstructed
and estimated (Tendolkar et al., 2013; Joshi et al., 2015)
hippocampal volume. A fourth study used voxel-based
morphometry and found volume increases in the hippocam-
pal complex and the subgenual cortex, as well as volume
decrease in the prefrontal cortex (Dukart et al., 2014).
These results may be partially affected by drug treatment.
Furthermore, the relation between clinical improvement
and volume increase is unclear with conflicting results: A
greater decrease in the clinical score was accompanied by
less increase in hippocampal volume in one study (Dukart
et al., 2014), but also an opposite finding (with low effect
size) (Joshi et al., 2015) or no obvious relation (Tendolkar
et al., 2013) between these parameters have been
reported. A follow-up study on the other hand showed that
the hippocampal volume increase vanishes after several
months (Nordanskog et al., 2014).
Recent studies give the impression that the brain region
mostly affected by ECT is the hippocampus but there are
some hints (Dukart et al., 2014; Joshi et al., 2015) that
more brain regions are involved, e.g. the amygdala, insula
and the cingulate gyrus.
Specific changes in clinical parameters have been related
to changes in hippocampal complex volume in a small
sample of patients (Dukart et al., 2014) and to hippocampal
volume increase (Joshi et al., 2015) in a larger sample. A
relation to other regions has not been reported yet.
In our prospective study we aimed to investigate indivi-
dual pre–post treatment changes in whole brain gray matter
volume in a sample of ECT treated patients with major
depression. In addition, we studied the effect of ECT on
voxel based cortical thickness in cortical brain regions. Due
to previous findings we additionally investigated regional
gray matter volume changes and cortical thickness analyses
for hippocampus, amygdala (Joshi et al., 2015) and explora-
tory the habenula (Ranft et al., 2010) as regions of interest,
where a volume increase due to ECT treatment was
expected and therefore hypothesized.
Electroconvulsive therapy increases temporal gray matter volume and cortical thickness
2. Experimental procedures
2.1. Subjects
Twenty psychiatric inpatients fulfilling the pertinent diagnostic
criteria of a major depressive episode, as defined by the Diagnostic
and Statistical Manual, 4th edition (DSM-IV-TR) were enrolled into
this prospective study between April 2008 and July 2012. All
patients were treated as inpatients at the Department of Psychiatry
and Psychotherapy of the Central Institute of Mental Health,
Mannheim. It was possible to perform an individual pre- and post-
ECT MR imaging scan from 18 of these 20 patients. All subjects gave
written, informed consent before enrollment. The study was
approved by the ethics committee of the University of Mannheim/
Heidelberg and performed in accordance with the Declaration of
Helsinki. Nine of the eighteen patients were female, mean age was
52 yr714 yr. Patients were screened using the Hamilton Depression
Scale (HAMD, 21 item version) (pre-ECT 31.878.2; post-ECT
10.677.3) and the Mini-Mental-Status-Examination (MMSE) (pre-
ECT 27.971.8; post-ECT 26.974.75). 56% of the patients remitted
and 83% responded to the treatment. A mean number of 11.374.8
individual ECT sessions were administered. Patients were main-
tained on the same drug treatment throughout the study period
(besides lorazepam tapering). A clinical part of the study data has
been published which included all 20 patients (Bumb et al., 2015;
Sartorius et al., 2015).
2.2. ECT
ECT was performed right unilaterally or bilaterally with a Thyma-
trons IV device (Somatics, LLC. Lake Bluff, IL, USA). ECT anesthesia
was performed with thiopental or S-ketamine (Janke et al., 2015;
Hoyer et al., 2014) and succinylcholine for muscle relaxation in all
cases. Patients were treated using right unilateral electrode place-
ment and seizure threshold was titrated in all patients during the
first treatment and continued with 42.5 times seizure threshold.
Stimulation dose was subsequently increased if patients did not
respond clinically or if the seizures were insufficient during the ECT
course (i.e. usually motor response time o20 s and EEG seizure
activity o30 s).
2.3. MR image acquisition
Pre-ECT scans were acquired 1 or 2 days before the first ECT, post-
ECT scans were acquired at least two days and within two weeks
after the last ECT session. Imaging data were collected on a 3T MRI
scanner (TRIO, Siemens Medical Systems, Erlangen, Germany)
between 2008 and 2012 at the Central Institute of Mental Health
in Mannheim. The T1-weighted high-resolution structural scan was
acquired using 3-D magnetization-prepared-rapid-acquisition-gradi-
ent-echo (MPRAGE) with 192 sagittal slices, voxel size 1  1  1
mm3, 256 mm field of view, repetition time 1570 ms, echo time
2.75 ms, flip angle 151, echo spacing 8.2 ms, inversion time 800 ms.
2.4. MR image analysis
All preprocessing steps and statistical analysis of the MRI data were
carried out using the SPM12 software package (http://www.fil.ion.
ucl.ac.uk/spm/software/spm12/).
2.4.1. Longitudinal comparison
At first pre- and post-ECT T1-weighted anatomical images of the
patients were coregistered, without re-slicing, by aligning the later
acquired image to the earlier image via a rigid body transformation
Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
3
(SPM12 coregister) to minimize the differences between the images
caused by the positioning of the individuals within the head coil.
The next step was the registration of the later image to the
earlier image using the longitudinal registration toolbox of SPM12
including a bias correction. This longitudinal registration tool, a
substitute of the high dimensional warp tool of SPM8, constructs an
average or midpoint image and warps the individual images to this
average to maximize the spatial conformity. Each warp process
results in a deformation matrix, which reflects the change neces-
sary for fitting the individual image to the midpoint image, voxel by
voxel. The Jacobian determinant which maps these necessary
deformations is produced for each participant and represents the
degree of contraction or expansion that is required to transform a
given voxel from the respective scan to the same voxel space of the
midpoint image. The saved Jacobian rate is the difference between
the two Jacobian determinants.
Midpoint images were further processed using the segment
routine of SPM12 (new segment in SPM8, segment in SPM12) using
6 different tissue probability maps. The resulting native gray matter
images were multiplied with the Jacobian rate resulting in an image
reflecting the morphometric changes within the gray matter. To
minimize the possibility of including white matter and other areas
outside of gray matter and to avoid edge effects the value of the
minimal amount of gray matter was set at 20% (0.2 voxel value).
For normalization the DARTEL (Diffeomorphic Anatomical Regis-
tration Through Exponentiated Lie algebra) approach (Ashburner,
2007) was used to enable a more accurate spatial normalization.
Anatomical images of all patients’ pre-ECT and healthy control
subjects were used to create a customized template.
To avoid segmentation faults, the clean-up routine of the
segmentation tool that extracts brain from the segmented images
was set to “thorough clean” additionally the option for bias
correction was used to refer to field inhomogeneity. Segmented
gray matter images were DARTEL imported and used to construct a
customized GM template which was afterwards aligned to the
MNI space.
The Jacobian adjusted gray matter images were normalized to
this DARTEL-MNI template and smoothed with an 8 mm isotropic
Gaussian kernel.
Whole brain GM volume changes represented by the Jacobian
rate images were entered in several multiple regression analyses
with age and sex as covariates of no interest.
To verify the whole brain result and confirm that it is not caused
by a bias due to white matter reduction, we extracted the mean
voxel values of the hippocampus for gray and white matter voxel
values for both time-points, as well as of the peak values of other
regions that were affected by the volume change.
2.4.2. Voxel-based cortical thickness (VBCT)
VBCT was calculated as suggested by Hutton et al. (2008) using an
SPM toolbox provided by the authors. Below, we describe some
specific details about this method and how it was employed in the
present study. A full description of the method has been given
elsewhere (Hutton et al., 2008).
First, individual pre and post-ECT T1-weighted anatomical
images were segmented into gray matter (GM), white matter
(WM), and cerebro-spinal fluid (CSF) using the segmentation algo-
rithm implemented in SPM12. Next, these tissue segments were
sub-sampled to 0.5 mm using trilinear interpolation and an initial
estimate of the GM/WM and GM/CSF boundaries was calculated
from the tissue segments. To identify sulcal voxels, in which
thickness may be overestimated, layers of one voxel thickness were
successively added to surround the WM starting from the initial WM
map. The thickness of each layer was then computed and compared
to the expected thickness of this layer. Voxels in which the
calculated thickness of a single layer exceeded the expected
thickness were labeled as sulcal voxels. Subsequently, cortical
4 A. Sartorius et al.
thickness was calculated for the GM maps using the non-straight
line distance proposed by Jones et al. (2000). This method solves
Laplace’s equation to construct trajectories passing through the
cortical sheet connecting one surface to the other. For sulcal
voxels, the length of the trajectory was set to be half of the total
possible trajectory through the voxel. The resulting VBCT maps
were sampled to 1 mm3 isotropic resolution and co-registered to the
individual average image derived from the longitudinal registration
procedure described above for each participant. VBCT maps were
then normalized to MNI space using the transformation parameters
calculated during the DARTEL based normalization procedure also
used for longitudinal voxel based morphometric analyses (see
above). Finally, the normalized VBCT maps were smoothed with
an 8 mm isotropic Gaussian kernel.
2.4.3. Cross-sectional analysis
To evaluate possible local brain volume reductions in MDD patients
we selected 36 anatomical images from our database of healthy
control subjects, which were acquired with the same sequence and
head coil within the same time period. These 36 healthy controls
were of comparable age and matched for sex (Table 1).
Anatomical images of 36 healthy controls (HC) of comparable age
and sex were used to scan for local reductions due to the illness
condition for the whole brain (Table 1). A DARTEL template of all
subjects was constructed and aligned to the MNI space for the
comparison to an age-matched sample of healthy controls. White
and gray matter images of all subjects were registered to this
template and modulated. To evaluate volume differences, gray and
white matter images were modulated by multiplication with the
determinant of the Jacobian of the spatial normalization function
(Good et al., 2001) to correct for volume changes by normalization.
The obtained modulated GM and WM images with a voxel size of
1  1  1 mm3 were smoothed with an 8 mm3 isotropic Gaussian
kernel and were used for statistical analysis. Sample homogeneity
was checked using the VBM8 toolbox (http://dbm.neuro.uni-jena.
de/). An integration of all voxels of the native tissue class images in
spatial correspondence to the original data was used to estimate
the whole brain volume (Klauschen et al., 2009; Whitford et al.,
2005). This revealed measures of global GM, WM and CSF compart
ment volumes for each participant, the sum of all three compart
ments served as an estimate of total intracranial volume (TIV).
Masks for regions of interest (ROI), hippocampus, amygdala and
thalamus, were created using the WFU PickAtlas (http://fmri.
wfubmc.edu/software/PickAtlas). To extract the voxel values of
the habenula, we created a 2 mm sphere around the coordinates
reported by Ullsperger (Ullsperger and von Cramon, 2003) (L/R
Habenular complex (bilateral) x=3/ 5 y= 25 z =8 (Talairach)
transferred into MNI space (5, 24,6; 5, 26,8)).
2.4.4. Statistical analysis
A general linear model approach was used to determine the voxel
wise relative difference in GM tissue partition maps revealed from
the VBM image processing by analysis of covariance (ANCOVA) and a
regression analysis. In order to avoid possible edge effects between
different tissue types, all voxels with GM or WM values of less than
0.1 (absolute threshold masking) were excluded. Age, sex and total
Table 1 Cross-sectional group demographics.
Sex Group Mean age (yr) N sd (yr)
Male HC 47.94 18 713.7
PAT 48.22 9 714.2
Female HC 55.17 18 713.0
PAT 55.22 9 713.7
Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
intracranial volume (TIV) were used as nuisance variables, in order
to remove all the effects that can be explained by these variables
from the data. Results concerning the GM volume change are
reported with a threshold of p =0.05 family wise error (FWE) whole
brain corrected on voxel level. For the comparison to healthy
controls we used a threshold of p=0.05 FWE corrected on cluster
level with a cluster building threshold of p=0.001 uncorrected.
Correlations to changes of clinical parameters as well as meta-
bolic changes were performed on the Jacobian rate image.
Mean voxel values were extracted from the brain regions with
the most prominent volume changes and the hypothesized ROIs.
The analyses of all other variables were accomplished with IBM
SPSS statistics 20. The threshold for significance in these analyses
was set to 0.05.
3. Results
We found a mean increase of 3.7% in the relative whole
brain GM volume in MDD patients after ECT (before ECT:
41.9%, post-ECT: 43.4%). This increase, which was also
indicated by a significant paired t-test (t= 3.6, df = 17,
p =0.002), was observed on an individual level in the
majority of the patients (only two showed a decrease).
Estimated WM volume did not change significantly.
3.1. Longitudinal changes – volume
The GM adjusted and normalized images of the Jacobian
rate represent the voxelwise volume changes over time. A
one sample t-test was conducted to test for significant local
changes (mean value greater than zero representing an
increase in volume, mean value lower than zero represents
a decrease in volume).
There was no volume decrease in any region for the
whole sample. Concerning a volume increase, the most
prominent changes occurred in the right temporal lobe,
including the hippocampus and parahippocampal area as
well as the insula, fusiform gyrus and the amydgala (see
Figure 1, po0.05 FWE corrected on voxel level). Twelve
percent of the voxels within this cluster were located in the
right insula, 10% each in the parahippocampal gyrus and the
superior temporal pole. Additional regions with bilateral
changes were the supramarginal gyrus, extending to the
postcentral gyrus. The left insula and bilaterally the middle
part of the cingulate gyrus were also affected (Table 2).
3.1.1. Hippocampus ROI analysis
A ROI analysis of the hippocampal area showed that the
whole length of the hippocampus was affected (Figure 2A,
po0.05 FWE small volume corrected) and the increase was
highly localized (Figure 2B, blue hippocampal mask, red/
lilac hippocampal volume increase).
Extracted GM values (eigenvalues of hippocampus) ver-
ified that the volume increase within the hippocampus was
not caused by WM decrease or a difference in the signal
intensity. GM values increased significantly, whereas WM
values did not change (see Table 3).
3.1.2. Amygdala ROI analysis
GM amygdala volume also increased as shown by the ROI
analysis (po0.001 FWE small volume corrected, see
Figure 2C, and Table 2 (bottom)).
Electroconvulsive therapy increases temporal gray matter volume and cortical thickness
Figure 1 Rendered whole brain GM changes: post-ECT4pre-ECT (whole brain FWE corrected, p= 0.05, min. cluster size 100 voxel).
3.1.3. Habenula ROI analysis
The mean voxel values of the left habenula sphere
increased more from t1 (0.425 (70.085) to t2 (0.439
(70.093); t= 4.413, po0.001) than the values in the
right habenula (t1: 0.319 (70.048) t2: 0.331 (70.0499),
t = 2.74, p =0.014), see also Figure 2D.
3.2. Cross-sectional analysis
The whole brain comparison to healthy controls revealed no
brain region with greater GM volume in MDD patients. Only
one significant cluster, located in the thalamus (3, 18, 0;
1152 voxel; t = 4.42, p= 0.026 (FWE corrected on cluster
level) showed greater GM volume in controls than in MDD
patients (Figure 3).
ROI analysis of the hippocampus and the amygdala
showed only marginal greater GM volume in HC for the
hippocampus (n.s., see Figure 3) and no differences for the
amygdala.
Mean GM values of the habenula – which is located within
the thalamus cluster – showed significant greater values in
HCs compared to patients (po0.017, see Table 4).
3.3. Clinical correlations
None of the clinical variables and their changes showed a
significant influence on GM volume changes.
3.4. VBCT analysis results
Results for the cortical thickness analysis are reported in
Table 5 and Figure 4. Basically, after FWE correction, only in
the region of the temporal pole and the insula changes due
to ECT were detectable. Additionally, these findings corro-
borate the cortical VBM results. This is demonstrated in
Figure 4 by using an overlay image.
Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
5
4. Discussion
Our study results strongly indicate for the first time that ECT
induced cortical temporal growth is due to an increase in
gray matter (GM) as well as cortical thickness. Our data
exclude white matter loss as an indirect cause of GM
growth, in other words GM growth is absolute and not
relative. Our results corroborate earlier findings of ECT
induced hippocampal volume increase, which have been
quantified manually (Nordanskog et al., 2010) or automati-
cally (Dukart et al., 2014; Joshi et al., 2015; Tendolkar
et al., 2013). Again, our finding is the first demonstrating a
hippocampal GM increase at a FWE corrected level of
significance. A hippocampal GM growth could be a result
of an ECT induced neurotrophin rise, which was reported in
animal models in numerous studies (Sartorius et al., 2009;
Angelucci et al., 2002; O'Donovan et al., 2014; Gersner
et al., 2014; Nordgren et al., 2013).
The neurotrophin hypothesis of depression generally
states that repetitive neuronal activity enhances the
expression of neurotrophins (like e.g. brain-derived neuro-
trophic factor (BDNF)) to modify synaptic transmission and
connectivity thereby providing a connection between neu-
ronal activity and synaptic plasticity (Lang et al., 2004).
Following this idea increased synapse formation might play
a role in antidepressant treatment action (Henn et al.,
2004). While the number of new functional neurons within
the hippocampus can be increased by ECT (Weber et al.,
2013) and neurogenesis might explain most of the variance
in exercise induced hippocampal growth (Biedermann et al.,
2014), it still remains unclear to which extend neurogenesis,
synaptogenesis and other factors like e.g. glial cells,
microglia, proliferating and pyknotic cells, neuronal activa-
tion, as well as blood vessel density and arborization could
contribute to ECT induced GM increase. However, our
findings of temporal GM growth corroborate the neurotro-
phin hypothesis of depression.
It is another very important finding of our study that no
longitudinal GM decreases due to an ECT treatment were
detected in our whole brain analysis. This adds further
6 A. Sartorius et al.

Table 2 GM volume changes.

x y z Cluster size P (FWE- T Z

(voxel) corrected)

Whole brain analysis

Inferior and middle temporal gyrus Right 60 38 16 14,604 0.000 15.06 6.65
Temporal pole 32 16 33 0.000 12.7 6.25
Insula and putamen 39 9 6 0.000 12.61 6.23
Supra-marginal and post-central gyrus Left 56 26 27 510 0.000 13.82 6.45
Postcentral gyrus Right 51 20 39 998 0.000 13.81 6.45
Supra-marginal gyrus 52 33 36 0.002 9.62 5.56
Supplement motor area and middle cingu- Left 6 2 46 754 0.000 11.25 5.95
late gyrus
Middle cingulate gyrus 9 12 33 0.010 8.37 5.2
Middle cingulate gyrus 4 12 40 0.017 7.99 5.08

Pre and postcentral gyrus Right 52 0 34 363 0.000 11.07 5.91

Inferior and middle temporal gyrus Left 54 64 6 420 0.002 9.81 5.61
Middle and inferior temporal gyrus 57 57 4 0.005 9.02 5.39
Middle temporal gyrus 45 54 8 0.011 8.35 5.2

Anterior cingulate gyrus 9 16 27 317 0.005 8.9 5.36

Middle cingulate gyrus 12 26 32 0.021 7.84 5.04

Frontal inferior gyrus Left 44 6 15 866 0.006 8.87 5.35

Rolandic operuclum 44 3 14 0.008 8.6 5.27
Insula and putamen 33 14 15 0.009 8.52 5.25

Region of interest analysis

Hippokampus Right 22 6 22 826 0.000* 11.95 6.10
Hippokampus Left 27 14 24 583 0.001* 6.54 4.56
Amygdala Right 26 3 27 555 0.000* 12.21 6.15
Amygdala Left 24 2 28 433 0.002* 5.68 4.20
Habenula Right 6 26 8 8 0.032* 2.51 2.28
Habenula Left 8 26 8 16 0.003* 3.66 3.10

Bold rows: cluster maxima, italic: other local maxima within the same cluster, minimal distance 4 mm – respective extension to other
brain areas; * small volume FWE corrected. Whole brain analysis: peak voxel and maximal 3 adjacent local maxima, minimal cluster
size 100, po0.05 FWE whole brain corrected, ROI analysis: peak voxel, po0.05 small volume FWE corrected.

evidence to hypothesis that ECT enables and/or restores
plasticity (Bouckaert et al., 2014; Nordgren et al., 2013)
falsifying older ideas of ECT induced “brain damaging”.
4.1. Region of interest (ROI) analyses
4.1.1. Hippocampus
While only right hippocampal GM showed an ECT induced
growth on an FWE corrected level of significance, the ROI
analysis was significant for both sides accentuated on the right
side. While the study of Nordanskog et al. (2010) (manual
quantification) found a left sided accentuation, Dukart et al.
(2014) did not present data on sidedness. In the recent (and
largest) study of Joshi et al. (2015) only a trend towards a
greater effect on the left side was observed, while Tendolkar
et al. (2013) did not find evidence for a lateralization. Since
methodological differences between voxel-based morphome-
try and manual segmentation demonstrated a comparable
sensitivity in detecting volume differences (Bergouignan
et al., 2009), it seems plausible that a side specific effect of
ECT induced hippocampal GM increase is not very likely.
A large body of evidence justifies the idea of smaller
hippocampi in patients with major depressive disorder
(Videbech and Ravnkilde, 2004; Campbell et al., 2004),
but it remains unclear so far to what extent state (McKinnon
et al., 2009) and trait (Cole et al., 2011) factors can explain
the variance of hippocampal decline. Stress and depression
can induce hippocampal atrophy (Frodl and O'Keane, 2013),
which in turn can be “restored” by either direct brain
derived nerve growth factor injections (Hoshaw et al., 2005)
or by ECT (Gersner et al., 2014; Sartorius et al., 2009). Both
treatments are accompanied by antidepressive effects in
animal models (Hoshaw et al., 2005; Sartorius et al., 2003).
Of course other underlying causes for hippocampal growth
during an ECT series are possible, like improvements of
mobilization or drive during the treatment, since DSM IV
criteria of a major depressive episode like diminished
activities, loss of energy and psychomotor retardation easily

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European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
Electroconvulsive therapy increases temporal gray matter volume and cortical thickness 7

Figure 2 Region of interest (ROI) analysis, p= 0.05 small volume FWE corrected; (A) hippocampus bilateral, (B) blue hippocampus
mask, red/lila volume change, (C) ROI analysis amygdala, (D) ROI analysis habenula. (For interpretation of the references to color in
this figure legend, the reader is referred to the web version of this article.)

Table 3 Mean values of hippocampal ROI, extracted from the gray and white matter within the hippocampus mask.

Modulated voxel value Mean (std) pre-ECT Mean (std) post-ECT t-Value p

Right Gray matter 0.47 (0.079) 0.49 (0.080) 6.14 0.000

White matter 0.30 (0.051) 0.30 (0.053) 0.883 0.389

Left Gray matter 0.49 (0.086) 0.50 (0.085) 2.25 0.038

White matter 0.27 (0.044) 0.27 (0.045) 0.599 0.557

lead to a lack of mobilization. On the other hand, hippo- (Pajonk et al., 2010) and animal models (Biedermann et al.,
campal growth of comparable degree due to exercise is well 2012). From a clinical point of view, such a mechanism in
described in healthy controls (Maass et al., 2014; Pajonk severe major depression is rather unlikely since Joshi et al.
et al., 2010), patients suffering from psychiatric disorders (2015) reported a hippocampal growth within one week,

Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
8 A. Sartorius et al.

Figure 3 Significant higher GM volume in HCs compared to MDD, p =0.001 uncorrected voxel level, p = 0.026 FWE corrected
cluster level.

Table 4 Mean voxel values of the habenula ROI: MDD patients compared to HC.

Modulated mean GM voxel value MDD HC t-value p

Mean (sd) Mean (sd)

Left 0.425 (0.084) 0.483 (0.080) 2.42 0.019

Right 0.319 (0.045) 0.356 (0.053) 2.46 0.017

which is not a typical time span for observing first significant induces an unspecific volume increase of the bilateral
clinical improvement of drive or mobilization. amygdala complex independent of an enlargement of this
structure prior to ECT. Our bilateral volume increase data
certainly corroborate this view.
4.1.2. Amygdala

There is quite a discrepancy of data regarding whether 4.1.3. Habenula

amygdala is smaller or larger in depressed patients.
Burke et al. (2012) found smaller bilateral amygdalae in
depressed patients by manual segmentation. Kronenberg
et al. (2009) found even smaller amygdala volumes with an
inverse correlation to the number of individual depressive
episodes.
Contrasting these findings, Lange and Irle (2004) found
enlarged amygdala in young depressed women (), as well as
Frodl et al. (2002) in first episode depressed patients. A
meta-analysis in 2009 claimed to explain the differences in
morphometric imaging studies with medication effects:
Unmedicated depressed patient seemed to present with
smaller, and medicated patients with larger amygdala
volumes (Hamilton et al., 2009). A recent finding by
Romanczuk-Seiferth described larger amygdala (and hippo-
campi) GM volumes even in first-degree relatives of patients
with major depression, which argues for a trait marker
(Romanczuk-Seiferth et al., 2014). Interestingly, Ten
Doesschate recently described that larger amygdala volumes
predicted a positive ECT response (Ten Doesschate et al.,
2014). Combining the later findings, it seems that ECT
Post mortem studies (Ranft et al., 2010) and a recent high-
resolution magnetic resonance imaging study (Savitz et al.,
2011) described smaller habenula volumes in patients with
affective disorders. The later study reported the most pro-
nounced finding in bipolar patients: Especially unmedicated
patients presented with the smallest volumes and with no
differences compared to healthy controls when medicated. In
our cross-sectional results, a large thalamic cluster is found to
be smaller in the patient group when compared with matched
healthy controls. This large cluster includes the region of the
habenula, and specifically shows a smaller GM volume of the
habenula in our patient group. Thus, our data support earlier
findings. Furthermore, the lateral habenula is functionally
affected in an animal model of treatment resistant depression
(Gass et al., 2014; Winter et al., 2011). If the lateral habenula
indeed plays an important role in the pathophysiology of
depression (Sartorius et al., 2010, 2013; Kiening and Sartorius,
2013; Hoyer et al., 2012; Sartorius and Henn, 2007), the
volume increase of the lateral habenula observed in patients
treated with ECT corroborates this hypothesis.

Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
Electroconvulsive therapy increases temporal gray matter volume and cortical thickness 9

Table 5 Cortical thickness (VBCT) analysis.

x y z Cluster size (voxel) P (FWE-corrected) T Z

Temporal pole Right 36 15 26 345 0.333 6.50 4.55

Insula 40 12 7 344 0.506 6.13 4.39
Insula Left 44 1 6 159 0.765 5.64 4.18

4.2. Correlations of hippocampal volume changes

with clinical parameters

We did not identify any significant correlations of volume

changes with clinical parameters, such as initial depression
score or changes of depressive symptomatology with GM
volume changes of the hippocampus. Such correlations
between changes of GM and clinical symptom severeness have
been described positively (Dukart et al., 2014) and negatively
(Joshi et al., 2015). Other studies also failed to report any
correlation (Tendolkar et al., 2013; Nordanskog et al., 2014).
Due to the overwhelming evidence of smaller hippocampi
in patients suffering from depression it has been claimed that
ECT could exert neurorestorative effects on this structure
(Taylor, 2008). Since ECT effects on GM increase could be
brain region dependent and still absolutely unspecific this
might serve as an explanation for effects and side effects.
An ECT induced neurotrophin rise leads to an unspecific
increase of synaptogenesis and neurogenesis. Only a small
part of the induced neuronal growth becomes functionally
relevant (i.e. will be embedded into a functional neurocir-
cuit) (Weber et al., 2013), but it can be speculated that
those new neurons which decay can contribute to the
reversible cognitive side effects. The same argument holds
true for synaptogenesis and has already been formulated for
ECT induced mossy fiber sprouting within the dentate gyrus
(Moscrip et al., 2006).
Additionally, an unspecific increase of neuronal plasticity
could partially explain (besides medication, diagnosis, gender,
illness duration, number of episodes, etc.) why correlations to
changes of clinical syndrome severity remain hard to detect.

5. Conclusion

We were able to corroborate earlier findings of hippocampal

Figure 4 Regions with significant increase in cortical thickness
(blue), overlaid to regions with significant increase in GM volume
(red). (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
and amygdala GM volume increase following an acute ECT
series in patients with major depression. Temporal GM
volume increase was significant on a whole brain level and
further corroborated by a cortical thickness analysis. We did
not detect significant correlations with changes in psycho-
pathology, which could be either due to other covariates or
to the primary non-specificity of ECT-induced increases in
neuroplasticity.
Financial disclosures

Of course, results from such a small ROI adjacent to the None.

third ventricle have to be critically discussed: Higher field
strength would have been more appropriate to access such a Role of the funding source
small region and additional artifacts due to high suscept-
ibility gradients are possible. None.

Please cite this article as: Sartorius, A., et al., Electroconvulsive therapy increases temporal gray matter volume and cortical thickness.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2015.12.036
10
Contributors
Author AS designed the study and wrote the protocol. Authors TD,
AS, GE and AB managed the literature searches and analyses and
authors TD and AB the statistical analysis, and author AS wrote the
first draft of the manuscript. All authors contributed to and have
approved the final manuscript.
Conflict of interest
All authors declare no conflicts of interest.
Acknowledgment
None.
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