Eva Maria Quinque: Brain, Mood and Cognition in Hypothyroidism.

Leipzig:
Max Planck Institute for Human Cognitive and Brain Sciences, 2015 (MPI
Series in Human Cognitive and Brain Sciences; 171)
Brain, mood and cognition in hypothyroidism
Impressum

Max Planck Institute for Human Cognitive and Brain Sciences, 2015

Diese Arbeit ist unter folgender Creative Commons-Lizenz lizenziert:

http://creativecommons.org/licenses/by-nc/3.0

Druck: Sächsisches Druck- und Verlagshaus Direct World, Dresden

Titelbild: © The Courtauld Gallery : „Un bar aux Folies-Bergère“ von Edouard Manet, Detail

ISBN 978-3-941504-56-1
 Brain, mood and cognition
in hypothyroidism

Dissertation
zur Erlangung des akademischen Grades
Dr. rer. med.
an der Medizinischen Fakultät
der Universität Leipzig

eingereicht von:
Diplompsychologin, Master of Philosophy (Cambridge, GB)
Eva Maria Quinque geb. Weig
geboren am 25.04.1985 in Pegnitz

angefertigt am:
Max-Planck-Institut für Kognitions- und Neurowissenschaften, Leipzig

Betreuer: Prof. Arno Villringer

Beschluss über die Verleihung des Doktorgrades vom: 17.11.2015

Table of Contents

I Introduction............................................................................................................. 1
II Theoretical Background........................................................................................ 5
1 The thyroid and its dysfunction ............................................................................ 5
1.1 The thyroid hormone system ........................................................................ 5
1.2 Hypothyroidism............................................................................................. 6
1.3 Autoimmune thyroiditis (Hashimoto’s disease) ............................................. 7
1.4 Mood in hypothyroidism................................................................................ 8
1.5 Cognition in hypothyroidism........................................................................ 10
2 Magnetic resonance imaging ............................................................................. 12
2.1 Physical basis............................................................................................. 12
2.2 Structural and functional MRI ..................................................................... 13
3 Hypothyroidism and the brain ............................................................................ 16
3.1 Animal studies ............................................................................................ 16
3.2 Human brain imaging studies ..................................................................... 19
4 Rational of the experimental work ...................................................................... 22
III Experimental Work ............................................................................................. 25
1 Publication 1: Quinque et al., 2013 .................................................................... 25
2 Publication 2: Quinque et al., 2014 .................................................................... 37
3 Treatment initiation effects ................................................................................. 48
IV Discussion and Outlook .................................................................................... 55
V Summary.............................................................................................................. 59
1 English Summary............................................................................................... 59
2 German Summary.............................................................................................. 63
VI References.......................................................................................................... 69
VII Appendix............................................................................................................ 87
1 Supplemental Material, Quinque et al., 2014 ..................................................... 87
2 Declaration of Authenticity ................................................................................. 92
3 Curriculum Vitae ................................................................................................ 93
4 List of publications ............................................................................................. 94
5 Acknowledgements............................................................................................ 96

i
Bibliographische Beschreibung

Quinque, Eva Maria

Brain, mood and cognition in hypothyroidism

Universität Leipzig, Dissertation

96 Seiten, 135 Referenzen, 9 Abbildungen, 2 Tabellen, 5 Anhänge

Referat:
Adult-onset hypothyroidism leads to mood and cognitive impairment (Canaris et al.,
1997; Joffe et al., 2012). Residual symptoms may even persist in patients with
biochemically adequate treatment (Saravanan et al., 2002). Reasons discussed for
residual symptoms include firstly independent effects of autoimmune processes on
the brain (Grabe et al., 2005), secondly brain hypothyroidism in spite of normal
serum hormone levels (Panicker et al., 2009a), thirdly comorbidities leading to a
selection bias in seeking health care (Kong et al., 2002) and fourthly reactive mental
processes to the awareness of having a chronic disease (Ladenson, 2002).
Disentangling these possible causes has important implications for treatment
strategies. The present study wants to contribute to the discussion by studying the
target organ of interest, the brain, and measuring levels of autoimmunity. Animal
studies have indicated that adult-onset hypothyroidism leads to impaired memory,
anxiety and depression associated with alterations in hippocampal and amygdalar
neuronal plasticity (Alzoubi et al., 2009; Montero-Pedrazuela et al., 2006, 2011).
Magnetic resonance imaging (MRI) is a powerful non-invasive tool to investigate the
effects of hormone action on structure and function of the brain in living patients
(Brabant et al., 2011; Pilhatsch et al., 2011) and will be used to study neural
correlates of hypothyroidism in the current research project. First data from invasive
human brain imaging studies have shown changes in brain glucose metabolism and
cerebral blood flow in hypothyroidism, but as of yet studies are inconsistent
concerning reversibility and localisation (Bauer et al., 2009; Constant et al., 2001;
Krausz et al., 2004).
As a prerequisite for the MRI study, we successfully translated and validated a set of
questionnaires (McMillan et al., 2006; 2008) to measure symptoms, quality of life and
treatment satisfaction in hypothyroidism (publication 1). In the main study, we found
subclinically reduced mood in long-term adequately treated patients, but the mood
alterations were not associated with alterations in depression-related brain networks.
We identified thyroid autoimmunity and treatment duration as factors of neural
alterations in long-term treated hypothyroidism. In the control group comparison we
did not find structural and functional brain alterations (publication 2). More evidence
is needed on neural alterations in hypothyroidism, ideally from larger population-
based samples. Nonetheless, in long-term treated patients presenting with residual
symptoms, alternative causes such as comorbidities and reactive mental processes
to the awareness of having a chronic disease should be considered.
iii
List of Abbreviations

BOLD Blood oxygen level dependent

CBF Cerebral blood flow
fMRI Functional magnetic resonance imaging
T3 Triiodothyronine
T4 Tetraiodothyronine
LTP Long-term potentiation
MR Magnetic resonance
MRI Magnetic resonance imaging
PET Positron emission tomography
PROMs Patient-reported outcome measures
ROI Region of interest
SPECT Single photon emission computed tomography
ThyDQoL Thyroid-dependent quality of life questionnaire
ThySRQ Underactive thyroid symptom rating questionnaire
ThyTSQ Thyroid treatment satisfaction questionnaire
TPO-ab Thyroid peroxidase antibodies
TSH Thyroid stimulating hormone
VBM Voxel-based morphometry

v
List of Figures

Figure 1: National iodine status in 2013 showing urinary iodine concentrations

(UIC) of school-aged children. Subnational data means that data does not
cover the whole country and iodine intake may vary across subregions.
Figure reprinted with permission from Pearce et al., 2013. ..................................1

Figure 2: The thyroid hormone cycle. Own figure inspired by figure 1.3 in Ehlert
and von Känel, 2011 and figure 1 in Dayan and Panicker, 2009..........................6

Figure 3: Own example dataset illustrating structural MRI preprocessing using

voxel-based morphometry, (a) structural T1 image, (b) mean image after
normalisation, (c) extracted grey matter tissue, (d) 8mm smoothed image.. ......13

Figure 4: Illustration of the contrast method used in task-based fMRI. Results of

a onesample t-test showing significantly higher BOLD responses to memory
encoding vs. rest in healthy participants overlayed on a structural MRI scan.
Modified from figures 1 and 3, Quinque et al., 2013……………………………. ..14

Figure 5: Hypothyroid rats show reversibly impaired learning and memory in a

radial arm water maze (a) and reversibly reduced excitatory postsynaptic
field potentials (fEPSP), a measure of long-term potentiation in the
hippocampus (b). Modified with permission from Alzoubi et al., 2009. ...............16

Figure 6: The expression of parvalbumin is increased in dentate gyrus and CA 1

regions of the hippocampus in thyroidectomised hypothyroid rats and
adequately treated rats. Parvalbumin is a protein involved in LTP induction.
Modified with permission from Fernández-Lamo et al., 2009.. ...........................17

Figure 7: Group differences in glucose metabolism before treatment (a) and

correlation of treatment-related changes in metabolism with changes in
clinical parameters (b). Figures modified with permission from Bauer et al.,
2009. ..................................................................................................................19

Figure 8: Schematic view of the study design.......................................................... 22

Figure 9: Comprehensive summary of brain imaging studies on hypothyroidism,

depicting sample sizes (green bars) and TSH levels (blue symbols) in the
hypothyroid and treated state (if available).........................................................52

vii
List of Tables

Table 1: Sample characteristics and results of group comparisons at both

sessions (pre/post treatment), changes between the sessions in the patient
group, and the interaction between session and group. .....................................49

Table 2: Mood parameters pre- and posttreatment initiation in hypothyroid

patients and healthy controls and results of group comparisons, changes
with treatment in the patient group and interaction between session and
group. .................................................................................................................50

ix
Chapter I Introduction

I Introduction

Hypothyroidism during foetal brain development leads to severe and irreversible

mental retardation (Führer et al., 2014), known as cretinism. It is mainly caused by

severe iodine deficiency. The prevalence for this condition has been reduced by a

highly successful public health program to eliminate iodine deficiency disorders by

introducing iodised salt to affected populations. It has been launched by the World

Health Organisation in 1990 and until 2000 the access of households to iodised salt

increased from 20-30% to 70% (Hetzel, 2005).

Figure 1: National iodine status in 2013 showing urinary iodine concentrations (UIC) of school-
aged children. Subnational data means that data does not cover the whole country and iodine
intake may vary across subregions. Figure reprinted with permission from Pearce et al., 2013.

However, inadequate levels of iodine intake, including iodine excess, are still present

in many countries (Pearce et al., 2013; see Fig. 1). Germany was still listed as a

iodine deficient country in 2004 (Delange et al., 2004), but recent studies report

adequate iodine levels (Meisinger et al. 2012; Pearce et al., 2013; Völzke et al.,
1
Chapter I Introduction

2012). Important to note, in contrast to the clear association between severe iodine

deficiency and cretinism, but also thyroid enlargement (goitre), there is a more

complex relationship between mild iodine deficiency or excess iodine intake and

prevalence rates for thyroid diseases with onset in adulthood (Laurberg et al., 2010).

Autoimmune thyroiditis, or Hashimoto’s disease, is the most common cause for adult-

onset hypothyroidism in Germany (Gärtner et al., 2002; see chapters II.1.2 and

II.1.3). It occurs more often in goitre patients and incidence rates are expected to

decrease with increasing iodine availability (Laurberg et al., 2010). However, it could

be shown that sudden rises in iodine uptake in previously iodine deficient

populations, as happens during the implementation phase of iodination programs,

increase the prevalence for autoimmune thyroiditis (Kahaly et al., 1998; Pedersen et

al., 2011) and associated hypothyroidism (Bjergved et al., 2012; Meisinger et al.,

2012). Therefore, we can currently even expect a transient increase in adult-onset

autoimmune hypothyroidism in Germany for those born before 1990 or even 2004,

and this patient group will be addressed in the current research project. Prevalence

estimates for hypothyroidism or subclinical hypothyroidism are 5% for the whole

population, with higher rates in women (8%) than men (3%) and an increase with age

up to 21% in females and 16% of males over the age of 74 (Roberts and Ladenson,

2004; Vanderpump, 2011).

Although the neurocognitive effects of adult-onset hypothyroidism are not as

deleterious as seen during foetal development, impairment of mood and cognition

has reliably been reported for severe, partly also for mild adult-onset hypothyroidism

(Allolio and Schulte, 1996; Hetzel, 2005; Roberts and Ladenson, 2004). Residual

symptoms may even persist in patients with biochemically adequate treatment

(Saravanan et al., 2002; Wekking et al., 2005; see chapters II.1.4 and II.1.5).

2
Chapter I Introduction

Reasons discussed for residual symptoms include firstly independent effects of

autoimmune processes on the brain (Grabe et al., 2005), secondly brain hypo-

thyroidism in spite of normal serum hormone levels (Panicker et al., 2009a), thirdly

comorbidities leading to a higher chance of having thyroid hormone values tested

(Kong et al., 2002) and fourthly reactive mental processes to the awareness of

having a chronic disease (Ladenson, 2002). Disentangling these possible causes has

important implications for treatment strategies. The present study wants to contribute

to the discussion by studying the target organ of interest, the brain, and individual

levels of autoimmunity. Studies of the brain in hypothyroid rodents have shown

impaired cell signalling in hippocampus and amygdala related to memory and

depression (Alzoubi et al., 2009; Montero-Pedrazuela et al., 2006, 2011; see chapter

II.3.1). However, little is known about neural correlates of hypothyroidism in humans.

Magnetic resonance imaging (MRI, see chapter II.2) is a powerful non-invasive tool

to investigate the effects of hormone action on structure and function of the brain in

living patients (Brabant et al., 2011; Pilhatsch et al., 2011) and will be used to study

neural correlates of hypothyroidism here. First invasive human brain imaging studies

have shown changes in brain glucose metabolism and cerebral blood flow in hypo-

thyroidism, but as of yet studies are inconsistent concerning reversibility and locali-

sation (Bauer et al., 2009; Constant et al., 2001; Krausz et al., 2004; see chapter

II.3.2).

We are interested both in initial treatment effects of levothyroxine to reestablish

euthyroidism as well as in long-term treatment effects to investigate possible causes

for residual symptoms. In order to study independent effects of the autoimmune

process, we measure thyroid peroxidase antibodies (TPO-ab) in addition to thyroid

hormone values.

3
Chapter I Introduction

In the following chapter I will summarise the current state of the literature in this

interdisciplinary research field. This will include sections on the thyroid hormone

system, (autoimmune) hypothyroidism, related mood and cognitive impairment, the

MRI methods used, and animal as well as human brain imaging studies. Con-

sequentially, I will derive the rational for the experimental work (chapter II). Our

experimental work resulted in two publications that form the present cumulative

dissertation (chapter III). I will close with a general discussion and some proposals

for future investigations (chapter IV).

4
Chapter II Theoretical Background

II Theoretical Background

1 The thyroid and its dysfunction

1.1 The thyroid hormone system

The thyroid is a butterfly-shaped endocrine gland situated below the larynx (Ehlert

and von Känel, 2011). It produces the hormone triiodothyronine (T3) and the pro-

hormone tetraiodothyronine (T4) and releases them into the blood stream, where

they are mainly bound to transport proteins. The small portion of unbound (pro-)

hormones are called free T3 (fT3) and free T4 (fT4), respectively. At target cells,

including neurons, fT3 binds to thyroid hormone receptors in the cell membrane and

thus influences gene transcription in the cell (Janssen et al., 2001). Furthermore, it

can lead to an increase in glucose uptake into the cells leading to general metabolic

enhancement (Roberts and Ladenson, 2004). fT4 itself is not active, it needs

deiodinisation by the enzymes deiodinase 1 or 2 (d1/d2) to fT3 at the target cell to

become effective. 80% of fT3 is produced by this production on demand (Dayan and

Panicker, 2009). The thyroid hormone system is feedback-regulated via the

hypothalamus and the pituitary gland that releases thyroid stimulating hormone

(TSH) to the thyroid gland in order to increase T3 and T4 release if hormone levels

are too low and vice versa (see Fig. 2 for a schematic view). TSH is the most

sensitive indicator for a dysfunction of the thyroid hormone system (Boelart and

Franklyn, 2005; Ehlert and von Känel, 2011). Functional disorders of the thyroid are

classified according to three serum parameters: TSH, fT4 and fT3. High TSH levels

(>4mU/l) indicate hypothyroidism, whereas low TSH levels (<0,4mU/l) are defined as

hyperthyroidism (Pfannenstiel et al., 1999). As long as TSH is altered in isolation, the

condition is called subclinical. If in addition fT4 or fT3 are outside reference levels,
5
Chapter II Theoretical Background

the conditions are called overt. In the present work I focus on the condition of hypo-

thyroidism and will now focus on this part of the thyroid hormone continuum.

Hypothalamus

Thyrotropin releasing hormone (TRH)

Feedback
Pituitary Gland
Target Cells
Thyrotropin stimulating hormone (TSH)
fT4 d1/d2 fT3
Stimulation of
Thyroid Gland T3 protein synthesis

Blood Circulation:
T3, T4 mainly bound to
transport proteins
T4

Figure 2: The thyroid hormone cycle. Own figure inspired by figure 1.3 in Ehlert and von Känel,
2011 and figure 1 in Dayan and Panicker, 2009.

1.2 Hypothyroidism

The main clinical symptoms of hypothyroidism are weight gain, cold intolerance,

tiredness, obstipation, bradycardia, hair loss, depression and cognitive deficits

(Allolio and Schulte, 1996; Roberts and Ladenson, 2004). Hypothyroidism is routinely

treated with synthetic thyroxine, called levothyroxine, restoring hormone levels to the

normal range. It is still under discussion whether some patients may benefit from

additional replacement with fT3, mimicking the exact output of the healthy thyroid that

produces small amounts of fT3 in addition to fT4 (Roberts and Ladenson, 2004).

The most frequent cause of adult-onset hypothyroidism is autoimmune thyroiditis due

to TPO-ab (Hashimoto’s thyroiditis), affecting 1-2% of the population (Gärtner et al.,

6
Chapter II Theoretical Background

2002). The second most common cause is medical intervention, including thyroi-

dectomy or radioiodine treatment for thyroid cancer or hyperthyroidism. This patient

group experiences abrupt hypothyroidism after the intervention and is then timely

treated with levothyroxine. Cancer patients receive supraphysiologically high doses

to suppress TSH for preventive reasons. Other rare causes are the so-called secon-

dary forms of hypothyroidism due to deficits within the thyroid feedback cycle, which

are TSH or thyrotropin releasing hormone (TRH) deficiency (Pfannenstiel et al.,

1999). For a control group study on hypothyroidism the first group of patients with

Hashimoto’s thyroiditis is best suited for several reasons. Firstly, prevalence is

highest, secondly treatment aims at a euthyroid status that is comparable to normal

thyroid function, thirdly no iatrogenic intervention has taken place that could possibly

influence results by the intervention itself or the initial disease. Finally, independent

effects of autoimmune thyroid activity on mood are discussed in the literature on

hypothyroidism and can be studied in this patient group (Gärtner et al., 2002; Grabe

et al., 2005; Ott et al., 2011).

1.3 Autoimmune thyroiditis (Hashimoto’s disease)

The cause of the most common autoimmune disease (Ehlert and von Känel, 2011)

was unclear until the concept of autoimmunity became known in the 1950’s and it

was not until the 1980’s that thyroid peroxidase was identified as the main target of

the immune system in patients with Hashimoto’s thyroiditis (Caturegli et al., 2013).

TPO-ab are found in 90-95% of patients (Janssen et al., 2001; Roberts and

Ladenson, 2004). The presence of TPO-ab highly increases the likelihood of

developing hypothyroidism (Vanderpump and Tunbridge, 2002), wherefore the

7
Chapter II Theoretical Background

presence of antibodies is used for initial treatment decisions (Allolio and Schulte,

1996; Prummel and Wiersinga, 2005). Hashimoto’s thyroiditis is equally treated by

levothyroxine, as causal cures targeting the autoimmune process are still scarce.

However, first attempts using selenium have been made (Ott et al., 2011). It has

been argued that independent of the symptoms caused by the hypothyroidism, the

autoimmune process may exhibit an independent effect on patients’ mood and

cognition (Gärtner et al., 2002; Grabe et al., 2005; Leyhe et al., 2008; Ott et al.,

2011). Examining the independent effect of TPO-ab on mood, cognition and brain is

therefore of special interest to the current study.

1.4 Mood in hypothyroidism

Reduced perceived health and more hypothyroidism-related symptoms were found in

overtly hypothyroid patients (Canaris et al., 1997; Schraml and Beason-Held, 2010).

Concerning subclinical hypothyroidism, the literature is less decided (Joffe et al.,

2012). On the one hand, no heightened depressivity or anxiety was found in some

studies (Bono et al., 2004). However, levothyroxine removal in long-term treated

patients leading to subclinical hypothyroidism revealed a reduction in perceived

health and well-being (Samuels et al., 2007).

Concerning the initial treatment effect of levothyroxine replacement therapy, some

studies found an improvement (Bono et al., 2004; Correia et al., 2009; Miller et al.,

2006), although not all report complete normalisation. Other placebo-controlled

treatment studies on mildly hypothyroid subjects found no changes beyond the

placebo effect (Jorde et al., 2006; Kong et al., 2002). Most studies on long-term

treated hypothyroidism found impaired perceived health status and increased mental

8
Chapter II Theoretical Background

strain (Samuels et al., 2007; Saravanan et al., 2002; Wekking et al., 2005) and an

increased prevalence of depression and anxiety (Panicker et al., 2009b).

Concerning autoimmune thyroid disease, reduced perceived health was found in

euthyroid Hashimoto’s disease (Bianchi et al., 2004; Ott et al., 2011). In the general

population, autoimmune thyroid disease was associated with increased anxiety,

physical symptoms and depression (Grabe et al., 2005; Pop et al., 1998). One study

showed that TPO-ab activity can be reduced by selenium supplementation alongside

subjective health improvement (Gärtner et al., 2002), suggesting an interesting new

treatment approach.

In conclusion, whereas mood alterations are robustly reported in overt untreated

hypothyroidism, the literature is less coherent concerning untreated subclinical

hypothyroidism and levothyroxine-treated conditions. It is still an open issue where

residual alterations despite adequate treatment result from. Explanations discussed

are insufficient normalisation of thyroid hormone levels at target tissues such as the

brain despite normal serum hormone levels (Panicker et al., 2009a), independent

effects of thyroid autoimmunity by TPO-ab (Ott et al., 2011), selection bias in seeking

health care (Kong et al., 2002) and reactive mental processes to the awareness of

having a chronic disease (Ladenson, 2002). The current study wants to add to the

discussion by investigating neural correlates of mood during treatment initiation and

in long-term treated hypothyroidism of autoimmune origin.

Patient-reported outcome measures (PROMs) used to study mood in hypothyroidism

so far have mainly been generic instruments that are applicable to several diseases

such as the Short-Form 36 (Bullinger and Kirchberger, 1998), a questionnaire on

self-reported mental and physical health, or questionnaires measuring depressive

symptoms (Hamilton depression scale, Baumann, 1976). They are therefore widely-

9
Chapter II Theoretical Background

used and well-suited for comparisons between studies, but instruments specific for a

certain disease have been shown to be more sensitive to change (Eurich et al., 2006;

de Vries et al., 2005). For the assessment of hypothyroidism-specific symptoms,

homemade symptom lists have been used so far (Jorde et al., 2006; Ott et al., 2011;

Saravanan et al., 2002), leading to little comparability across studies. Hence, we

wanted to include validated disease-specific instruments in addition to well-known

generic instruments and as none were available in German, we translated and

validated a set of English questionnaires in cooperation with the original author team

(McMillan et al., 2006; 2008). This important methodological prerequisite forms part

of the first publication of this dissertation.

1.5 Cognition in hypothyroidism

The cognitive domains most discussed in hypothyroidism are memory, working

memory, attention and psychomotor speed. Studies are highly heterogeneous as to

the severity, treatment status, cause of disease, age range and study population and

have produced equally heterogeneous results.

Verbal or spatial memory deficits (Baldini et al., 1997; Burmeister et al., 2001;

Correia et al., 2009; Miller et al., 2006), as well as working memory impairment

(Schraml et al., 2011) have been reported in untreated hypothyroidism. The same

studies found no attention deficit (Burmeister et al., 2001; Miller et al., 2006) and

other studies found neither memory nor attention to be impaired in untreated

hypothyroidism (Bono et al., 2004; Jorde et al., 2006; Schraml et al., 2011).

Interestingly, one study found significant subjective impairment in broad cognitive

domains despite objective impairment in verbal memory only (Burmeister et al.,

10
Chapter II Theoretical Background

2001). Small TSH changes within the normal range did not produce alterations in

attention or working memory (Walsh et al., 2006), whereas levothyroxine removal in

long-term treated patients leading to subclinical hypothyroidism led to a reduction in

working memory ability (Samuels et al., 2007). Two reviews on the topic conclude at

least for subclinical hypothyroidism that the inconsistent findings suggest at most

rather subtle cognitive deficits (Joffe et al., 2012; Samuels et al., 2010).

Treatment initiation with levothyroxine led to a significant improvement in most

studies (Baldini et al., 1997; Burmeister et al., 2001; Jaeschke et al., 1996; Miller et

al., 2006), but not always normalised to control group levels (Correia et al., 2009) and

was indistinguishable from placebo control groups in other studies (Jorde et al.,

2006; Parle et al., 2010).

Studies on long-term treated hypothyroidism found impaired memory and attention

(Wekking et al., 2005) and another study impaired working memory and motor

learning (Samuels et al., 2007), whereas no cognitive impairment was found in other

studies (Kramer et al., 2009). Studies on the role of autoimmunity on cognition in

hypothyroidism are scarce. One study on long-term treated patients with Hashimoto’s

thyroiditis showed a very specific attention deficit (Leyhe et al., 2008).

In conclusion, the behavioural literature on cognition in hypothyroidism is indecisive,

especially concerning subclinical and long-term treated hypothyroidism. A potentially

independent role of autoimmunity on cognition as suggested for mood impairment

(Gärtner et al., 2002; Grabe et al., 2005) has so far not been studied. We therefore

find it warranted to include high-load cognitive testing in the present work to investi-

gate potentially subtle cognitive impairment and to pay special attention to autoim-

mune involvement.

11
Chapter II Theoretical Background

2 Magnetic resonance imaging

2.1 Physical basis

The magnetic resonance (MR) technique is based on an intrinsic property of

(hydrogen) protons, namely their spin. It means that they contain a perpetual rotating

charge that produces a measurable stable magnetic axis. If many protons of e.g. a

human brain enter a strong magnetic field such as an MR scanner, the magnetic

axes of some of these protons align with the magnetic field, leading to a measurable

net magnetisation along the scanner magnet (Jäncke, 2005; Schneider and Fink,

2013). During MR measurement this magnetisation is excited by a high frequency

electromagnetic wave causing the protons to turn their magnetic axis by the angle

the wave is send out. This produces a measurable alternating voltage. After

switching off the electromagnetic wave the system regains the stable magnetic field.

Different processes reflect the decay of the induced transverse magnetisation, called

T1-, T2- and T2*-relaxation (Logothetis, 2008). The process of excitation and rela-

xation is repeated many times to gather robust data. The differentiation of tissue

types in the brain is possible because different characteristics of the tissues such as

proton density or magnetic properties influence the relaxation times. Acquisition para-

meters, e.g. the repetition time between the excitations, can be adapted to optimise

contrast between tissues of interest. In addition, the signal depends on the magnetic

field strength, allowing for detailed spatial coding. In order to reconstruct a 3-

dimensional image of the brain, a grid of unique magnetic field strengths is estab-

lished by adding three magnetic gradients along the three spatial axes to the main

magnetic field (Buxton, 2009; Weishaupt et al., 2009).

12
Chapter II Theoretical Background

2.2 Structural and functional MRI

For analysing brain structure, the properties of the three main tissue types of the

brain: grey matter, white matter and cerebrospinal fluid, and their influence on the

relaxation times, are crucial. T1-relaxation times differentiate best between grey and

white matter, wherefore T1-weighted contrast images are most often used for

structural analyses. The probability of each voxel belonging to one of the three tissue

types can be calculated by voxel-based morphometry (VBM, Ashburner and Friston,

2000).

Figure 3: Own example dataset illustrating structural MRI preprocessing using voxel-based
morphometry, (a) structural T1 image, (b) mean image after normalisation, (c) extracted grey
matter tissue, (d) 8mm smoothed image.

The magnetisation-prepared rapid gradient echo sequence (MP-RAGE) is optimised

to differentiate between grey matter (darker) and white matter (lighter), cerebrospinal

fluid appears black (Schneider and Fink, 2013; see Fig. 3 a) and has therefore been

used here. Raw structural images require preprocessing before use in group
13
Chapter II Theoretical Background

analyses in order to ensure comparability between subjects for later voxel-wise

comparison of grey matter probability values. Preprocessing includes normalisation

to a standard brain, here the Montreal Neurological Institute (MNI) space as well as

segmentation of the different tissue types and smoothing by a Gaussian Kernel

(Ashburner and Friston, 2000; see Fig. 3). Details of acquisition parameters, data

processing and group analyses are given in publication 2 (chapter III.1) and the

respective supplemental material (chapter VII.1).

Figure 4: Illustration of the contrast method used in task-based fMRI. Results of a onesample t-
test showing significantly higher BOLD responses to memory encoding vs. rest in healthy
participants overlayed on a structural MRI scan. Modified from figures 1 and 3, Quinque et al.,
2013.

Functional MRI (fMRI) exploits the so-called BOLD-effect, the blood oxygen level

dependent effect. Neurally active brain areas expend more oxygen leading to a local

increase in blood flow beyond actual oxygen requirement. As a result, there is a

transient increase in oxyhaemoglobin and a reduction in deoxyhaemoglobin. The

T2*-relaxation time is susceptible to magnetic properties of tissues and as

oxyhaemoglobin and deoxyhaemoglobin differ in this respect, T2*-weighted images

14
Chapter II Theoretical Background

reflect changes in blood-oxygen levels over time, providing an indirect measure of

neural activity (Buckner and Logan, 2001; Logothetis, 2008).

In resting-state fMRI spontaneous BOLD signal changes over time in a resting

participant are investigated allowing the analysis of neural connectivity between brain

regions. This neural connectivity represents an important feature of the brain, namely

its organisation in functional networks. It thus ideally supplements structural MRI

methods (e.g. VBM) that study brain regions in isolation or task-based fMRI studies

that are always confined to the specific domain studied (Biswal et al., 1995; Fox and

Raichle, 2007). A large array of processing options has been developed to address

several research questions (Margulies et al., 2010). In the case of a priori information

about regions of interest (ROI), seed-based analysis is suitable. Seed-based resting-

state fMRI looks into the correlation of the average BOLD time course of the ROI with

the BOLD time course of all other voxels in the brain. The physiological rational

behind this analysis is the idea that the amount of shared functionality is related to

the synchrony of time courses during rest (Fox and Raichle, 2007). Bauer et al.,

(2009) provide region-specific data about brain areas related to altered glucose

metabolism in hypothyroidism. Therefore, we were able to enter valid a priori seeds

to investigate functional connectivity in hypothyroidism and used this informed

approach in the current study, see publication 2 (chapter III.1) and the respective

supplemental material (chapter VII.1).

15
Chapter II Theoretical Background

3 Hypothyroidism and the brain

3.1 Animal studies

Animal studies on hypothyroidism suggest both behavioural deficits and correlated

physiological pathomechanisms. Several studies found that hypothyroid rats are

impaired in spatial learning, accompanied by a reduction in long-term potentiation

(LTP) in the hippocampus, a neurophysiological correlate of memory (Alzoubi et al.,

2009; Artis et al., 2011). Both memory impairment and LTP reduction were reversible

with levothyroxine treatment (Alzoubi et al., 2009; see Fig. 5).

Figure 5: Hypothyroid rats show reversibly impaired learning and memory in a radial arm water
maze (a) and reversibly reduced excitatory postsynaptic field potentials (fEPSP), a measure of
long-term potentiation in the hippocampus (b). Modified with permission from Alzoubi et al.,
2009.

In contrast, Fernández-Lamo et al., (2009) report impairment in associative learning

and altered protein expression involved in LTP induction despite adequate treatment

(see Fig. 6). Levothyroxine treatment prevented memory impairment and hippocam-

pal cell death in an Alzheimer’s disease mouse model (Fu et al., 2010). Further

hippocampal alterations as known from Alzheimer’s disease such as atrophy,

inflammation (Chaalal et al., 2014) or amyloid-β peptide formation (Ghenimi et al.,

16
Chapter II Theoretical Background

2010) have been found in hypothyroidism and linked to memory impairment.

Moreover, the formation of new hippocampal neurons was found to be impaired

because of reduced survival of neural cell progenitors (Ambrogini et al., 2005; Cortés

et al., 2012; Desouza et al., 2005; Montero-Pedrazuela et al., 2006).

dentate gyrus CA1

control

hypothyroid

treated

Figure 6: The expression of parvalbumin is increased in dentate gyrus and CA 1 regions of the
hippocampus in thyroidectomised hypothyroid rats and adequately treated rats. Parvalbumin
is a protein involved in LTP induction. Modified with permission from Fernández-Lamo et al.,
2009.

The reported studies induced severe hypothyroidism in order to achieve proof of

principle in experimental models either by thyroidectomy or by applying high doses of

an anti-thyroid agent. A single study explicitly elicited only subclinical hypothyroidism

by partial thyroidectomy and again showed memory impairment alongside alterations

in the hippocampal signalling cascade (Ge et al., 2012). Studies may thus be

generalised to subclinical hypothyroidism as often encountered in clinical practice,

but more animal studies in mild hypothyroidism are needed.

17
Chapter II Theoretical Background

In the affective domain, hypothyroidism led to enhanced fear conditioning coinciding

with increased corticosterone release and a heightened number of corticosteroid

receptors in the amygdala (Montero-Pedrazuela et al., 2011). A genetically caused

form of brain hypothyroidism produced depressive and anxious behaviour that was

successfully treatable with hormone replacement (Pilhatsch et al., 2010) and reduced

survival of neural cell progenitors in the hippocampus could be associated with

depressive behaviour (Montero-Pedrazuela et al., 2006).

Although research has focussed on the hippocampus and related memory impair-

ment, other brain regions have been shown to be altered by hypothyroidism as well,

e.g. the amygdala as described above (Montero-Pedrazuela et al., 2011). Moreover,

T3 and T4 levels were undetectable or significantly reduced not only in hippocampus

and amygdala, but also in parietooccipital cortex, limbic forebrain, hypothalamus,

midbrain, cerebellum, medulla and frontal cortex (Broedel et al., 2003). Finally, levels

of the neurotransmitters dopamine, norepinephrine and serotonin have recently been

shown to be reduced in cerebral cortex, thalamus, midbrain, cerebellum and pons-

medulla (Hassan et al., 2013).

We will include an associative memory fMRI task known to elicit hippocampal activity

(Henke et al., 1997) in order to investigate hippocampal alterations in hypothyroidism

as suggested by animal research. In addition, we will study structural and resting-

state functional MRI of the whole brain in order to observe effects of the

pathomechanisms reported for several brain regions.

18
Chapter II Theoretical Background

3.2 Human brain imaging studies

Brain glucose metabolism and cerebral blood flow (CBF), measured by positron

emission tomography (PET) and single photon emission computed tomography

(SPECT), invasive brain imaging methods requiring the injection of radioactive

tracers, have reliably shown changes in overt and subclinical hypothyroidism.

Alterations proved reversible shortly after reestablishment of euthyroidism in some

studies (Constant et al., 2001; Bauer et al., 2009; Schraml and Beason-Held, 2010),

while others showed persistent alterations (Krausz et al., 2004; Nagamachi et al.,

2004).

Figure 7: Group differences in glucose metabolism before treatment (a) and correlation of
treatment-related changes in metabolism with changes in clinical parameters (b). Figures
modified with permission from Bauer et al., 2009.

In terms of localisation, diffuse (Constant et al., 2001) or regionally specific alte-

rations have been reported, although reports include areas across all four brain

19
Chapter II Theoretical Background

lobules (Bauer et al., 2009; Krausz et al., 2004; Nagamachi et al., 2004; Schraml and

Beason-Held, 2010). Direct associations between neural alterations and clinical

parameters such as thyroid hormone status, mood and cognition are far less studied.

Schraml and Beason-Held (2010) showed an association between TSH and CBF in

occipital cortex, psychomotor speed and precentral gyrus as well as depressivity and

frontal and thalamic areas during overt hypothyroidism. Bauer et al. (2009) showed

that the restoration of glucose metabolism was correlated with the normalisation of

TSH, symptom load and mood in anterior cingulate cortex and amygdala (see Fig. 7).

In addition to invasive brain imaging methods, a series of working memory task-

based fMRI studies in adult-onset hypothyroidism has been performed before and

shortly after treatment initiation. Reversible alterations in attentional load effects in

frontoparietal areas have been found (He et al., 2011; Yin et al., 2013; Zhu et al.,

2006). Task-based studies on other cognitive functions discussed in hypothyroidism

such as memory are lacking. No brain imaging study is known to us on associative

memory in adult-onset hypothyroidism in spite of extensive animal literature on

hippocampal involvement in hypothyroidism (see section 3.1). However, there is

evidence from teenagers with congenital hypothyroidism that hippocampal activity is

altered during an associative memory task despite unimpaired behavioural perfor-

mance (Wheeler et al., 2011).

Brain imaging studies explicitly on patients with Hashimoto’s thyroiditis have so far

been confined to SPECT analyses and have reliably shown diffuse hypoperfusion in

different samples including unmedicated euthyroidism (Piga et al., 2004), untreated

hypothyroidism (Kaya et al., 2007) and euthyroidism under adequate treatment

(Zettinig et al., 2003). In the adequately treated patients hypoperfusion was not

correlated with current TSH, TPO-ab levels, anxiety or depression, but only to the

20
Chapter II Theoretical Background

duration of the disease (Zettinig et al., 2003). These SPECT data suggest brain

alterations specific to Hashimoto’s disease, but data on other brain imaging modali-

ties are lacking and will be investigated here.

Two recent structural MRI studies in severely hypothyroid patients, published

concurrently with our own, report either widespread alterations in grey and white

matter (Singh et al., 2013) or a decrease in right hippocampal volume (Cooke et al.,

2014). However, both studies neither report behavioural measures nor treatment

effects, so that we do not know whether the reported findings are reversible and

related to symptoms. We will try to answer these questions here.

Brain imaging data on long-term treated hypothyroidism are scarce, but may well

differ from short-term treatment effects as suggested by persistent hypoperfusion

shown in long-term adequately treated Hashimoto’s disease patients (Zettinig et al.,

2003). A recent VBM study included longer-term treated Hashimoto’s thyroiditis

patients, but reports only a very specific correlation between a small region of interest

(left inferior frontal gyrus) and performance in a single task (Leyhe et al., 2013). More

data is thus needed on brain structure and function in long-term treated patients with

Hashimoto’s thyroiditis. We will include a respective patient group here.

Resting-state fMRI allows the study of functional connectivity, extending the analysis

of neural activity in isolated regions to the physiologically more valid assessment of

neural networks spanning several brain regions (Fox and Raichle, 2007). Connec-

tivity networks have been shown to be altered in related diseases such as Alzhei-

mer’s disease (Greicius et al., 2004). Therefore, we want to introduce it to the study

of hypothyroidism here.

21
Chapter II Theoretical Background

4 Rational of the experimental work

From the current state of the literature as summarised above, we derived the need

for the following experimental work:

The lack of appropriate disease-specific PROMs was identified and overcome by

translating and validating a set of existing English questionnaires. Furthermore, we

identified both newly diagnosed patients as well as longer-term adequately treated

patients as study groups of interest for the main MRI study, because both initial and

residual cognitive and affective symptoms have been reported and their neural

correlates may help us to understand their cause. Moreover, we saw the need for

paying special attention to independent effects of autoimmunity and thus included

patients with autoimmune thyroiditis and measured TPO-ab levels in serum in

addition to thyroid hormone levels.

Session 1 Session 2
MRI scan MRI scan
• VBM, rs-fMRI, task fMRI • VBM, rs-fMRI, task fMRI
Neuropsychology Neuropsychology
• mood, cognition • mood, cognition
Blood sample Blood sample
• TSH, fT3, fT4, TPO-Ab • TSH, fT3, fT4, TPO-Ab

1st day 8th day 3rd month

Study groups
Newly diagnosed
patient group Diagnosis Medication
Longterm-treated
patient group Continued medication
Healthy control
group No medication

Figure 8: Schematic view of the study design.

22
Chapter II Theoretical Background

Finally, as to the level of analysis and hence the selection of the employed methods,

we wanted to bridge a gap between the mainly behavioural literature on human

patients and the invasive animal literature on pathomechanisms at a cellular level.

We therefore applied structural and functional MRI as well as thorough neuropsycho-

logical testing of mood and cognition within a single study. Fig. 8 provides a schema-

tic description of the study design.

We hypothesise that untreated and possibly also long-term treated patients show

mood and cognitive impairment that are associated with structural and functional

brain changes reflected by altered grey matter density, functional connectivity and

brain activity during an associative memory task in areas related to memory (hippo-

campus) and depression (amygdala) and respective brain networks. We hypothesise

that further brain areas are affected, especially those that showed altered glucose

metabolism during hypothyroidism (posterior cingulate cortex, subcallosal cortex) and

that brain changes are related to individual TPO-ab levels.

23
Chapter III Experimental Work

III Experimental Work

1 Publication 1: Quinque et al., 2013

25
Chapter III Experimental Work

26
Chapter III Experimental Work

27
Chapter III Experimental Work

28
Chapter III Experimental Work

29
Chapter III Experimental Work

30
Chapter III Experimental Work

31
Chapter III Experimental Work

32
Chapter III Experimental Work

33
Chapter III Experimental Work

34
Chapter III Experimental Work

35
Chapter III Experimental Work

36
Chapter III Experimental Work

2 Publication 2: Quinque et al., 2014

37
Chapter III Experimental Work

38
Chapter III Experimental Work

39
Chapter III Experimental Work

40
Chapter III Experimental Work

41
Chapter III Experimental Work

42
Chapter III Experimental Work

43
Chapter III Experimental Work

44
Chapter III Experimental Work

45
Chapter III Experimental Work

46
Chapter III Experimental Work

47
Chapter III Experimental Work

3 Treatment initiation effects

In addition to the long-term treated patient group described in publication 2, we have

also studied a newly-diagnosed patient group to investigate treatment initiation

effects. Acquisition and analysis procedures were almost identical to those reported

in publication 2. Therefore, I will here only report specifics of this study arm.

Sample

Eleven patients newly diagnosed with hypothyroidism due to autoimmune thyroiditis

were recruited via local endocrinologists, screening of blood donors and among

participants of an ongoing large population-based study (LIFE study). One patient

had to be excluded due to a benign brain anomaly, another because hypothyroidism

could not be confirmed at study entry. Nine healthy control subjects (as described in

detail in publication 2) were selected to match the patients in age, sex and

intelligence.

Data analysis

Data of the first session was compared between groups to establish alterations in

untreated hypothyroidism by means of t-tests for independent samples. Treatment

initiation effects were assessed by paired t-tests to measure changes in the patient

group between the sessions. Moreover, the interaction between session and group

was calculated from analyses of covariance in order to investigate whether changes

over the sessions were specific to the patient group. Lastly, the second session was

compared between groups in order to find out whether patients reverted to a control

48
Chapter III Experimental Work

group level with treatment, again by means of t-tests for independent samples. All

analyses were controlled for age and sex. Pearson correlations were used to corre-

late changes in mood and biochemical thyroid status with change in brain structure

and function.

Results

In the final sample, nine newly diagnosed patients and nine healthy control subjects

were included (see table 1 for an overview of sample characteristics). All participants

were free of lifetime psychiatric or neurological illnesses, one patient received

constant hypertensive medication. Data for one patient each were missing for the

memory fMRI task and the resting-state fMRI due to technical problems and

panicking, respectively. A corresponding control subject was excluded for the

respective analyses to maintain matching of the groups.

Table 1: Sample characteristics and results of group comparisons at both sessions (pre/post
treatment), changes between the sessions in the patient group, and the interaction between
session and group.
Patient group Control group *Group **Change ***Inter-
n=9 n=9 comparison action
Age (years) 42±5 38±8 n.s.
Sex 1 male 1 male n.a.
Intelligence (IQ) 104±10 107±8 n.s.

pre post pre post pre post patients

TSH (mU/l)
6.1±1 3.4±1 2.9±1 2.5±1 <.01 =.08 <.01 <.01
fT3 (pmol/l)
4.8±1 4.6±1 4.5±1 4.4±0.4 n.s. n.s. n.s. n.s.
fT4 (pmol/l)
12.6±2 15.7±2 14.9±1 14.5±1 <.05 n.s. <.01 <.01
TPO-ab (U/ml)
285±184 287±184 11±2 9±3 <.01 <.01 n.s. n.s.
*p-values of t-tests between the groups at both sessions, **p-values of a paired t-test within the patient
group on changes between the two sessions *** p-values of the interaction between session and
group calculated by analyses of covariance. Reference range was 0.4-4.0 for thyroid stimulating hor-
mone (TSH), 3.1-6.79 for free triiodothyronine (fT3), 12.8-20.4 for free thyroxine (fT4), < 34 for thyroid
peroxidase antibodies (TPO-ab), Kratzsch et al., 2008. Abbreviations: n.s. – not significant, n.a. – not
applicable.

49
Chapter III Experimental Work

Levels of TSH and fT4 were significantly altered in the hypothyroid state and reverted

to normal levels with treatment, although there was still a trend (p=0.08) for higher

TSH values in the patient group. fT3 was within the normal range throughout and

was not altered with treatment, whereas TPO-ab levels were constantly higher in the

patient group (see Tab. 1).

Table 2: Mood parameters pre- and posttreatment initiation in hypothyroid patients and healthy
controls and results of group comparisons, changes with treatment in the patient group and
interaction between session and group.
Patient group Control group *Group **Change ***Inter-
n=9 n=9 comparison action

pre post pre post pre post patients

Beck depression
6.0±5 3.0±2 2.8±3 2.6±2 =.10 n.s. =.08 n.s.
inventory

Hamilton
6.4±4 2.6±2 3.8±3 2.6±2 n.s. n.s. <.01 =.09
depression scale

WBQ-12 23±5 27±4 29±3 30±4 <.05 n.s. <.05 n.s.

SCL-90 1.3±0.2 1.1±0.1 1.2±0.2 1.1±0.1 =.09 n.s. <.05 =.06

Short Form 36 –
55±6 53±10 55±4 55±3 n.s. n.s. n.s. n.s.
physical health

Short Form36 –
45±8 52±5 52±5 51±5 <.05 n.s. <.05 <.05
mental health

ThySRQ 6.9±3 3.8±2 2.8±2 3.2±2 <.01 n.s. <.01 <.05

ThyDQoL 1.2±0.7 1.8±0.7 1.6±0.7 1.6±0.6 n.s. n.s. <.05 <.05

*p-values of t-tests between the groups at both sessions, **p-values of a paired t-test within the patient
group over the two sessions *** p-values of the interaction between session and group calculated by
analyses of covariance. Abbreviations: n.s. – not significant, WBQ – Well-Being Questionnaire, SCL –
Symptom Check List, ThySRQ –Underactive Thyroid Symptom Rating Questionnaire, ThyDQoL –
Thyroid-Dependent Quality of Life Questionnaire.

Patients showed reduced well-being (WBQ-12, Witthaus et al., 2001), perceived

mental health (Short Form 36-mental, Bullinger and Kirchberger, 1998) and more

hypothyroidism-related symptoms (ThySRQ, McMillan et al., 2008) compared to the

control group and a trend for higher depressivity (Beck depression inventory, Haut-

50
Chapter III Experimental Work

zinger et al., 1994) and more psychological strain (SCL-90, Franke, 2002) in the

hypothyroid state. After treatment initiation differences to the control group were no

longer detected. All but perceived physical health improved in the patient group and

the interaction between session and group was significant for a subset of measures

(see Tab. 2).

There were no significant group differences in performance in any of the cognitive

tasks at any session and no significant interaction, but an expected learning effect

over time for a subset of tasks in both groups (data not shown). We did not find any

differences in grey matter density even before treatment onset, unspecific changes

over time in both groups, but no interaction between session and group (data not

shown). We found no change with treatment in resting-state functional networks in

the patient group nor was there a significant interaction. Two connectivity differences

at session one turned out to be caused by unspecific changes in the control group

(data not shown). In the fMRI memory task, patients outperformed the healthy control

group behaviourally at session two (percent correct patient group: 73±8, control

group: 62±11; p<0.05), the same descriptive trend was there at session one (percent

correct patient group: 70±9, control group: 64±8, p>0.1). As interpretability of the

functional data would thus be very limited, we did not analyse the task-based fMRI

data further. Planned correlation analyses of the change in brain structure and

function with changes in thyroid hormone levels and mood showed no coherent

relationship (data not shown).

Discussion

We found subclinically reduced mood in mildly hypothyroid patients that recovered

with treatment. In contrast, we found no evidence for cognitive deficits, grey matter

51
Chapter III Experimental Work

alterations or functional connectivity changes and no systematic associations with

thyroid hormone levels or mood. The observed mood normalisation with treatment

possibly mirrors a placebo effect as a recent review (Dayan and Panicker, 2013) has

shown that the effect is only observed in studies employing healthy control groups as

used here, but not when compared to placebo control groups.

100
160
90

140
80

120 70
mean TSH (mU/l)

60

sample size
100

50
80

40
60
30
40
20

20
10

0 0
1 2 3 4 5 6 7 8 9 10 11 12
1 - Own study 7 - Bauer et al. 2009
2 - Constant et al. 2001 8 - Schraml & Beason-Held 2010 sample size
3 - Krausz et al. 2004 9 - He et al. 2011 hypothyroid state
4 - Nagamachi et al. 2004 10 - Yin et al. 2013 treated state
5 - Zhu et al. 2006 11 - Singh et al. 2013
6 - Kaya et al. 2007 12 - Cooke et al. 2014

Figure 9: Comprehensive summary of brain imaging studies on hypothyroidism, depicting

sample sizes (green bars) and TSH levels (blue symbols) in the hypothyroid and treated state
(if available).

Although sample size was small (n=9), it is comparable to other clinical brain imaging

studies in the field that were able to show differences in untreated hypothyroidism

and partly changes with treatment (see Fig. 9, green bars). However, our subjects

showed milder hypothyroidism at study entry and accordingly lower changes in

thyroid hormone levels with treatment (see Fig. 9, blue symbols). From an experi-

menttal perspective, our patient group is ill-suited to show proof of principle of

52
Chapter III Experimental Work

changes due to hormonal action, as the effect size of the independent variable is

small. From a clinical perspective however, this group is especially interesting as it is

still debated whether to treat or not to treat mild subclinical hypothyroidism (Owen

and Lazarus, 2003; Vanderpump, 2003).

In addition to altered thyroid hormone levels, the patient group showed significantly

heightened TPO-ab activity throughout the study. However, this did not lead to

significant group differences. This does not support the idea of an independent influ-

ence of thyroid autoimmunity on cognition, mood and brain (Gärtner et al., 2002;

Leyhe et al., 2008), but given the limited power of the study, may as well be a false

negative finding.

In summary, in this study on treatment initiation in mild autoimmune hypothyroidism

we cannot rule out the possibility of a false negative finding in cognition, brain struc-

ture and function nor a placebo effect concerning mood normalisation and hence

cannot draw any definite conclusions. In order to avoid publication bias in the field

commonly suffering from low power due to recruitment difficulties, we have made our

dataset publically available for sharing to improve meta-analyses (Poldrack and

Gorgolewski, 2014; http://neurovault.org/collections/169/).

53
Chapter IV Discussion and Outlook

IV Discussion and Outlook

The experimental findings have already been discussed in the respective sections.

Here, I will therefore concentrate on more general issues that have arisen during the

course of the research project.

Sample size in both study arms of the MRI study was small (n=18 treated patients,

n=9 newly diagnosed patients), but comparable to other MRI studies in the field. Low

power is thus an endemic problem of the research area, mainly performed in

developed countries where hypothyroidism is usually detected at an early stage, so

that severe cases are rare. Additional constraints due to either requirements of the

MR technique (no ferromagnetic implants, no tattoos) or experimental considerations

(age limit, exclusion of comorbidities) further limit the number of available subjects.

Therefore, options to increase subject numbers should be considered for future

studies in order to increase the robustness of findings. Firstly, data from large

population-based studies may be used (see also discussion below and outlook).

Secondly, multicentre studies may be initiated. Thirdly, data should be made

available at adequate levels of detail for later meta-analyses, including null findings to

avoid bias. The NeuroVault project allows the publishing of unthresholded statistical

maps of brain imaging data to share results at a whole-brain level rather than just

reporting peak activations (Poldrack and Gorgolewski, 2014). We have uploaded

results of both MRI study arms there (http://neurovault.org).

Interest in thyroid function has been high in large population-based samples that

have recently emerged thanks to computational advances in handling such large

datasets. Many were published concurrently with or after the current study, resulting

in substantial new evidence concerning hypothyroidism and both mood (7 studies

55
Chapter IV Discussion and Outlook

with 1000 to 33.000 participants) and cognition (11 studies with 81 to 2000 partici-

pants) that are relevant to our own findings and shall thus be discussed below. The

studies consistently report impairment of mood independent of biochemical thyroid

hormone levels in long-term treated patients (Jørgensen et al., 2014; Panicker et al.,

2009b; van de Ven et al., 2012a). In contrast, people with unknown incidental

hypothyroidism or high normal TSH values did not show reduced mood (de Jongh et

al., 2011; Jørgensen et al., 2014; Klaver et al., 2013; Kvetny et al., 2014; Medici et

al., 2014; Panicker et al., 2009b; van de Ven et al., 2012a, 2012b). The authors

consistently conclude that unspecific factors such as comorbidities leading to

selection bias in seeking health care or the awareness of having a chronic disease

cause the mood disturbance observed in clinical but not in population-based

samples. However, another possible cause was suggested by Panicker et al.

(2009a). In treated patients brain hypothyroidism may persist despite serum hormone

levels in the reference range, because of genetic differences in deiodinase enzymes

needed to transform the artificial fT4, standard treatment for hypothyroidism, into the

neurally active fT3 in the brain. We were, however, not able to find brain alterations in

treated patients that would support this hypothesis and several attempts to

administer T4/T3 combination therapy to eliminate possible brain hypothyroidism

have been unsuccessful (see Grozinsky-Glasberg et al., 2006 for a review). Effects

may be limited to carriers of specific polymorphisms though, hidden when

investigated in unselected samples (Panicker et al., 2009a; Wiersinga et al., 2009).

This line of research therefore warrants further study in larger samples (see outlook).

Concerning cognition, two comparably small studies (n<500) have found an

association between hypothyroidism and cognitive impairment (Johnson et al., 2011;

Resta et al., 2012), but most have not (Booth et al., 2012; Castellano et al., 2013;

56
Chapter IV Discussion and Outlook

Formiga et al., 2014; Forti et al., 2012; de Jongh et al., 2011; Moon et al., 2014;

Parsaik et al., 2014). Overall, effects were small or absent independent of treatment

status in line with our own findings in treated as well as newly diagnosed patients.

Although our own findings may be false negative due to the small sample size, the

overwhelming evidence from well-powered studies suggests that mild hypothyroidism

does indeed not cause clinically significant cognitive impairment as suggested by

early clinical studies (Baldini et al., 1997; Burmeister et al., 2001).

Lastly, it should be noted that other factors than cognitive and affective symptoms as

studied here are important for clinical treatment decisions. Most importantly, over-

treatment resulting in hyperthyroidism has been associated with increased cardio-

vascular mortality and reduced bone mineral density. In contrast, hypothyroidism has

been associated with an increased risk for atherosclerosis and diabetes. Comprehen-

sive assessment of comorbidities and side effects of treatment thus need thorough

monitoring (Duntas et al., 2012; Owen and Lazarus, 2003; Vanderpump, 2003).

Outlook
Only one of the population-based studies looking at thyroid function has included

brain imaging data (Rotterdam Scan Study, de Jong et al., 2006, 2007). The authors

however report only on the volumes of two brain areas of interest, hippocampus and

amygdala. Given that additional brain areas may be affected by hypothyroidism (e.g.

Bauer et al., 2009) and not only structural, but also functional alterations may occur

(e.g. Zhu et al., 2006), large population-based studies including whole-brain

structural and functional MRI are needed to validate hypotheses generated by small

clinical samples with sufficient statistical power. Fortunately, such a dataset has

recently been acquired (LIFE study, Leipzig) and we have already obtained permis-

57
Chapter IV Discussion and Outlook

sion to analyse the data. Ideally, we will additionally obtain genetic data on poly-

morphisms in the genes coding for deiodinases. Should polymorphisms indeed

influence the availability of thyroid hormones at the brain level (Panicker et al.,

2009a; Dayan and Panicker, 2013), this should result in differences in brain structure

and function as measurable with MRI in thyroid healthy people, but even more so in

levothyroxine-treated patients and may possibly explain residual mood alterations.

In addition, we found autoimmunity and disease duration to be associated with neural

structure and function in long-term adequately treated patients. An obvious future line

of research would therefore be to follow up on studies using selenium supplemen-

tation to reduce TPO-ab in autoimmune thyroiditis and investigate possible neural

underpinnings of the observed mood improvement (Gärtner et al., 2002). In order to

further study effects of disease duration, a longitudinal study over a longer time scale

in adequately treated patients would be required.

Finally, I would like to mention an anecdotal observation made during the study with

implications for current recommendations for levothyroxine administration. Many

participating patients reported that the recommended intake time half an hour before

breakfast is the most bothering consequence of the disease, reducing quality of life.

However, a recent randomised double-blind crossover study (Bolk et al., 2010)

showed that levothyroxine uptake was even slightly better when taken before

bedtime, possibly due to eating habits such as coffee consumption at breakfast.

Interestingly, patients were allowed to choose their preferred intake time after the

study ended. After one year, the majority preferred intake at bedtime. The study was

performed in the Netherlands and described eating habits are similar in Germany.

The promising pioneer study should thus be replicated in an independent sample and

recommendations for levothyroxine intake time may then require reconsideration.

58
Chapter V Summary

V Summary

Zusammenfassung der Arbeit

Dissertation zur Erlangung des akademischen Grades Dr. rer. med.

Brain, mood and cognition in hypothyroidism

eingereicht von: Eva Maria Quinque geb. Weig

angefertigt am: Max-Planck-Institut für Kognitions- und Neurowissenschaften, Leipzig
betreut von: Prof. Arno Villringer

März 2015

1 English Summary

Hypothyroidism during foetal brain development leads to severe and irreversible

mental retardation. Large-scale public health efforts to reduce iodine deficiency have,

however, largely eliminated the condition (Führer et al., 2014; Pearce et al., 2013).

Adult-onset hypothyroidism has received comparably much less attention, despite

consistent reports about mood and cognitive impairment (Canaris et al., 1997; Joffe

et al., 2012). Prevalence is about 5%, with higher rates in women than men (Roberts

and Ladenson, 2004). Residual symptoms have been reported in patients with

biochemically adequate treatment (Samuels et al., 2007; Saravanan et al., 2002).

Reasons discussed for residual symptoms include firstly independent effects of

autoimmune processes on the brain, the most common cause of adult-onset

hypothyroidism (Grabe et al., 2005), secondly brain hypothyroidism in spite of normal

serum hormone levels (Panicker et al., 2009a), thirdly comorbidities leading to a

59
Chapter V Summary

higher chance of having thyroid hormone values tested (Kong et al., 2002) and

fourthly reactive mental processes to the awareness of having a chronic disease

(Ladenson, 2002). Disentangling these possible causes has important implications

for treatment strategies. The present study wants to contribute to the discussion by

studying the target organ of interest, the brain, and individual levels of autoimmunity.

Studies of the brain in hypothyroid rodents have shown impaired synaptic plasticity in

the hippocampus associated with impaired spatial learning (Alzoubi et al., 2009) and

neurophysiological changes in the amygdala and hippocampus related to increased

anxiety and depression (Montero-Pedrazuela et al., 2006, 2011). However, little is

known about neural correlates of hypothyroidism-related symptoms in humans. First

studies using PET and SPECT have shown changes in brain glucose metabolism

and cerebral blood flow in hypothyroidism, but as of yet studies are inconsistent

concerning reversibility and localisation (Bauer et al., 2009; Constant et al., 2001;

Krausz et al., 2004). Magnetic resonance imaging (MRI) is a powerful non-invasive

tool to investigate the effects of hormone action on structure and function of the brain

in living patients (Brabant et al., 2011; Pilhatsch et al., 2011) and has been used to

study neural correlates of hypothyroidism here. We were interested both in initial

treatment effects of levothyroxine to reestablish euthyroidism as well as in long-term

treatment effects to investigate possible causes for residual symptoms. In order to

study independent effects of the autoimmune process, we have included patients

with hypothyroidism of autoimmune genesis and have measured thyroid peroxidase

antibodies (TPO-ab) in addition to thyroid hormone values.

As a methodological prerequisite for the main MRI study, we firstly translated a set of

questionnaires on symptoms, quality of life and treatment satisfaction in hypo-

thyroidism (McMillan et al., 2006; 2008) and validated them in an independent

60
Chapter V Summary

sample (n=101). Reliability and structural validity was satisfactory for all three

questionnaires (Quinque et al., 2013, publication 1).

In the first arm of our MRI study, we investigated 18 long-term adequately treated

patients with autoimmune hypothyroidism and 18 matched healthy control subjects.

We applied structural and functional MRI as well as neuropsychological testing to

assess mood and cognition. For the analysis of brain structure, we used voxel-based

morphometry (Ashburner and Friston, 2000), that allows voxel-wise comparison of

grey matter density values between groups. In addition we performed an associative

memory task using functional MRI (fMRI) in order to investigate hippocampus-

dependent brain activity. Finally, we applied seed-based resting-state fMRI (Fox and

Raichle, 2007) to study neural connectivity of brain regions that are known to be

altered in hypothyroidism (Bauer et al., 2009).

Results showed that adequately treated patients report more symptoms, higher

depressivity and reduced well-being as compared to healthy control subjects

(Quinque et al., 2013, publication 1). However, these mood alterations were not

related to brain structure and function in depression-specific brain regions. Further-

more, we did not find differences between patient and control group in cognitive

performance, brain structure, functional connectivity or brain activity during associa-

tive memory encoding. We did however find higher TPO-ab levels to be associated

with higher grey matter density in the right amygdala and increased connectivity

between subcallosal cortex and left parahippocampal gyrus, all part of a depression

and fear network (Quidé et al., 2012). Moreover, treatment duration was related to

structural and functional changes in areas associated with depression and untreated

hypothyroidism. Therefore, we identified autoimmunity and treatment duration as

61
Chapter V Summary

possible factors to explain neural sources of residual symptoms in long-term treated

hypothyroidism (Quinque et al., 2014, publication 2).

In the second study arm we investigated 9 newly diagnosed patients before and 3

months after treatment initiation and 9 healthy matched control subjects. Patients

showed mild hypothyroidism that reverted to normal levels with treatment. The

groups did not differ significantly in cognitive performance or brain structure and

function, even before treatment. However, patients reported reduced mood that

reverted to control group levels with treatment. This may be due to a placebo effect

described in the literature (Dayan and Panicker, 2013). Compared to studies that

showed brain alterations in the untreated state (Bauer et al., 2009; Singh et al.,

2013), the current sample showed milder hypothyroidism (TSH (mU/l) 6 vs. 17 and

124, respectively), but was of a similar size (n=9 vs. 13 and 10, respectively).

Therefore, we can currently neither rule out a false negative finding nor a true lack of

alterations in mild hypothyroidism as suggested by recent large population-based

studies (Jørgensen et al., 2014; Kvetny et al., 2014; Moon et al., 2014). We have

made our dataset publically available (http://neurovault.org) in order to contribute

data to the field commonly relying on small patient samples.

Future studies on the neural correlates of hypothyroidism should use larger samples

from population-based studies or by pooling data across studies to avoid power

problems endemic to the resource-intensive MRI method. Effects of autoimmunity

and disease duration should be followed up. In mildly hypothyroid or long-term

adequately treated patients presenting with residual symptoms, alternative causes

such as reactive mental processes to the awareness of having a chronic disease

should be considered.

62
Chapter V Summary

2 German Summary

Eine Hypothyreose während der fötalen Hirnentwicklung, meist bedingt durch starken

Iodmangel, führt zu schwerer und irreversibler geistiger Behinderung, bekannt als

Kretinismus. Kretinismus ist dank weltweiter Programme zur Iodierung von Speise-

salz inzwischen sehr selten (Führer et al., 2014; Pearce et al., 2013). Der Hypo-

thyreose mit Beginn im Erwachsenenalter wurde vergleichsweise weniger Aufmerk-

samkeit zuteil, obwohl auch für diese affektive und kognitive Beeinträchtigungen

berichtet werden (Canaris et al., 1997; Joffe et al., 2012). Die Prävalenz für klinische

oder subklinische Hypothyreose beträgt etwa 5%. Frauen sind etwa doppelt so

häufig betroffen wie Männer (Roberts and Ladenson, 2004). Symptome wurden auch

in adäquat hormonsubstituierten Patienten berichtet (Samuels et al., 2007;

Saravanan et al., 2002). Mögliche Gründe hierfür sind erstens unabhängige Effekte

von Autoimmunprozessen auf das Gehirn, der häufigsten Ursache für eine Hypo-

thyreose im Erwachsenenalter (Grabe et al., 2005), zweitens Schilddrüsenhormon-

mangel im Gehirn trotz normaler peripherer Schilddrüsenhormonwerte (Panicker et

al., 2009a), drittens Komorbiditäten, die zu einer höheren Wahrscheinlichkeit führen,

dass als Nebenbefund eine Hypothyreose diagnostiziert wird (Kong et al., 2002),

oder viertens reaktive psychische Prozesse auf die Diagnose einer chronischen

Erkrankung (Ladenson, 2002). Die Analyse dieser möglichen Ursachen hat wichtige

Implikationen für Behandlungsstrategien. Die vorliegende Studie möchte einen

Beitrag zu dieser Diskussion leisten, indem das interessierende Zielorgan, das

Gehirn, sowie die Stärke der Autoimmunaktivität untersucht werden. Studien an den

Gehirnen hypothyreoter Nagetiere zeigten Beeinträchtigungen in der synaptischen

Plastizität im Hippocampus, assoziiert mit Defiziten im räumlichen Lernen (Alzoubi et

al., 2009), sowie neurophysiologische Veränderungen in Amygdala und Hippocam-

63
Chapter V Summary

pus in Verbindung mit erhöhter Angst und Depression (Montero-Pedrazuela et al.,

2006, 2011). Zu neuronalen Korrelaten der Hypothyreose bei Menschen ist weniger

bekannt. Erste Studien mit PET und SPECT zeigten Veränderung im zerebralen

Glukosestoffwechsel sowie im Blutfluss, waren jedoch inkonsistent in Bezug auf

Reversibilität und Lokalisation der Veränderungen (Bauer et al., 2009; Constant et

al., 2001; Krausz et al., 2004).

Im vorliegenden Projekt haben wir die nicht-invasive Magnetresonanztomographie

(MRT) genutzt, um neuronale Korrelate der Hypothyreose beim Menschen zu unter-

suchen. Wir interessierten uns dabei für Korrelate der akuten Hypothyreose, für

initiale Behandlungseffekte mit Levothyroxin zur Wiederherstellung der Euthyreose

und für Effekte einer adäquaten Langzeitbehandlung, um Gründe für mögliche

persistierende Symptome zu untersuchen. Um unabhängige Effekte des Autoimmun-

prozesses zu analysieren, untersuchten wir Patienten mit einer Hypothyreose auto-

immuner Genese und erhoben Thyreoperoxidase- (TPO) Antikörper-Titer neben den

Schilddrüsenhormonwerten.

Als methodische Vorarbeit für die MRT-Studie haben wir Fragebögen zu den

Themen Symptome, Lebensqualität sowie Behandlungszufriedenheit bei Hypo-

thyreose übersetzt (McMillan et al., 2006; 2008) und an einer unabhängigen Stich-

probe (n=101) validiert. Reliabilität und Konstruktvalidität waren zufriedenstellend

(Quinque et al., 2013, Publikation 1).

Im ersten Teil der MRT-Studie untersuchten wir 18 aktuell euthyreote Patienten mit

autoimmuner Hypothyreose unter langjähriger Hormonsubstitution sowie 18 gesunde

Kontrollprobanden. Erhoben wurden strukturelle und funktionelle MRT Daten, neuro-

psychologische Testverfahren zur Messung von kognitiver Performanz, sowie

Fragebögen zur Erfassung von selbstberichteter Stimmung. Für die Analyse von

64
Chapter V Summary

Hirnstrukturen haben wir die Methode der voxel-basierten Morphometrie verwendet

(Ashburner and Friston, 2001). Die Methode erlaubt den voxelweisen Vergleich der

Dichte der grauen Substanz. Zusätzlich haben wir mittels funktionellem MRT (fMRT)

die Gehirnaktivität, besonders die im Hippocampus, während eines assoziativen

Gedächtnistests untersucht. Zudem haben wir die sogenannte „seed-based resting

state“ fMRT Methode genutzt (Fox and Raichle, 2007), um die neuronale Konnektivi-

tät der Hirnareale zu untersuchen, die veränderten Metabolismus bei Hypothyreose

gezeigt haben (Bauer et al., 2009).

Im Vergleich zur Kontrollgruppe berichteten adäquat behandelte Patienten mehr

Symptome, höhere Depressivität und reduziertes Wohlbefinden (Quinque et al.,

2013, Publikation 1). Diese Stimmungsveränderungen waren jedoch nicht mit

Hirnstruktur oder -funktion in depressionsspezifischen Arealen assoziiert. Die Patien-

ten unterschieden sich nicht von der Kontrollgruppe in der kognitiven Performanz,

Hirnstruktur, neuronalen Konnektivität oder Hirnaktivität während eines Gedächtnis-

tests. Die Höhe der TPO-Antikörper-Titer war jedoch mit erhöhter Dichte der grauen

Substanz in der rechten Amygdala sowie mit einer erhöhten neuronalen Konnektivität

zwischen dem Cortex Subcallosus und dem linken parahippocampalen Gyrus

korreliert. Alle genannten Regionen gehören einem Depressions- und Angstnetzwerk

an (Quidé et al., 2012). Zudem war die Erkrankungsdauer mit strukturellen und funk-

tionellen Veränderungen in Arealen korreliert, die mit Depression und unbehandelter

Hypothyreose in Verbindung gebracht werden. Daher haben wir Autoimmunität und

Erkrankungsdauer als mögliche Faktoren zur Erklärung neuronaler Ursachen für

residuale Symptome bei chronischer behandelter Autoimmunthyreoiditis identifiziert

(Quinque et al., 2014, Publikation 2).

65
Chapter V Summary

Am zweiten Teil der MRT-Studie nahmen 9 neu diagnostizierte Patienten mit auto-

immuner Hypothyreose vor und 3 Monate nach Beginn der Hormonsubstitution mit

Levothyroxin teil, sowie 9 gesunde Kontrollprobanden. Die Patienten waren zu

Studienbeginn leicht hypothyreot, bei der Wiederholungsmessung waren alle

Serumhormonwerte im Normbereich. Die Gruppen unterschieden sich bei keinem

Messzeitpunkt signifikant in der kognitiven Performanz, Hirnstruktur oder -funktion.

Die Patienten berichteten jedoch reduzierte Stimmung, die sich mit der Medikation

normalisierte. Dabei könnte es sich jedoch um einen in der Literatur beschriebenen

Placebo-Effekt handeln (Dayan and Panicker, 2013). Im Vergleich zu hirnbildgeben-

den Studien, die signifikante Gruppenunterschiede im Zustand vor der Behandlung

gezeigt haben (Bauer et al., 2009; Singh et al., 2013), wies unsere Patientengruppe

eine mildere Form der Hypothyreose auf (TSH (mU/l) 6 versus 17 bzw. 124), die

Stichprobengröße war jedoch vergleichbar (n=9 versus 13 bzw. 10). Wir können

daher derzeit weder ein falsch negatives Ergebnis noch die Abwesenheit von

neuronalen Veränderungen bei milder Hypothyreose ausschließen, wie es aktuelle

populationsbasierte Studien nahelegen (Jørgensen et al., 2014; Kvetny et al., 2014;

Moon et al., 2014). Wir haben die Daten öffentlich zugänglich gemacht

(http://neurovault.org), um den Publikationsbias in dem Forschungsgebiet, das häufig

mit kleinen Patientenkohorten arbeitet, zu vermindern.

Zukünftige Studien zu neuronalen Korrelaten der Hypothyrose sollten möglichst

größere Stichproben aus populationsbasierten Studien oder gepoolte Daten aus

mehreren Studien nutzen, um das endemische Problem geringer statistischer Power

der ressourcenintensiven MRT-Methode zu verringern. Autoimmunität und Er-

krankungsdauer sollten dabei weiter untersucht werden. Bei Patienten mit

subklinischer Hypothyreose sowie bei adäquat eingestellten Patienten, die über

66
Chapter V Summary

residuale Stimmungsveränderungen klagen, sollten aber auch andere mögliche

Ursachen wie beispielsweise Komorbiditäten oder reaktive psychische Prozesse auf

die Diagnose einer chronischen Erkrankung in der Behandlungsstrategie mit

berücksichtigt werden.

67
Chapter VI References

VI References

Allolio B. & Schulte H.M. (Eds.). (1996). Praktische Endokrinologie. Urban &
Schwarzenberg: München, Wien, Baltimore.

Alzoubi, K.H., Gerges, N.Z., Aleisa, A.M. & Alkadhi, K.A. (2009). Levothyroxin re-
stores hypothyroidism-induced impairment of hippocampus-dependent learning
and memory: behavioral, electrophysiological, and molecular studies. Hippo-
campus, 19, 66-78.

Ambrogini, P., Cuppini, R., Ferri, P., Mancini, C., Ciaroni, S., Voci, A., Gerdoni, E. &
Gallo, G. (2005). Thyroid hormones affect neurogenesis in the dentate gyrus of
adult rat. Neuroendocrinology, 81, 244-253.

Artis, A.S., Bitiktas, S., Taşkin, E., Dolu, N., Liman, N. & Suer, C. (2011). Experimen-
tal hypothyroidism delays field excitatory post-synaptic potentials and disrupts
hippocampal long-term potentiation in the dentate gyrus of hippocampal forma-
tion and Y-maze performance in adult rats. J Neuroendocrinol, 24, 422-433.

Ashburner, J. & Friston, K.J. (2000). Voxel-based morphometry – the methods.

NeuroImage, 11; 805-821.

Baldini, M., Vita, A., Mauri, M.C., Amodei, V., Carrisi, M., Bravin, S. & Cantalamesse,
L. (1997). Psychopathological and cognitive features in subclinical hypothyroi-
dism. Prog Neuropsychopharmacol Biol Psychiatry, 21, 925-935.

Bauer, M., Silverman, H.S., Schlagenhauf, F., London, E.D., Geist, C.L., van Herle,
K., Rasgon, N., Martinez, D., Miller, K., van Herle, A., Berman, S.M., Phelps,
M.E, & Whybrow, P.C. (2009). Brain glucose metabolism in hypothyroidism: a
positron emission tomography study before and after thyroid hormone replace-
ment therapy. J Clin Endocrinol Metab, 94, 2922-2929.

69
Chapter VI References

Baumann, U. (1976). Methodische Untersuchungen zur Hamilton-Depressionsskala.

Arch Psychiatr Nervenkr, 222, 359-375.

Beydoun, M.A., Beydoun, H.A., Shroff, M. R., Kitner-Triolo, M.H., & Zonderman, A.B.
(2012). Serum leptin, thyroxine and thyroid-stimulating hormone levels interact to
affect cognitive function among US adults: evidence from a large representative
survey. Neurobiol Aging, 33(8), 1730-1743 .

Bianchi, G.P., Zaccheroni, V., Solaroli, E., Vescini, F., Cerutti, R., Zoli, M. & Marche-
sini, G. (2004). Health-related quality of life in patients with thyroid disorders.
Qual Life Res, 13; 45-54.

Biswal, B., Yetkin, F.Z., Haughton, V.M. & Hyde, J.S. (1995). Functional connectivity
in the motor cortex of resting human brain using echo-planar MRI. Magn Res
Med, 34, 537-541.

Bjergved, L., Jørgensen, T., Perrild, H., Carlé, A., Cerqueira, C., Krejbjerg, A.,
Laurberg, P., Ovesen, L, Bülow Pedersen, I., Banke Rasmussen, L. & Knudsen,
N. (2012). Predictors of change in serum TSH after iodine fortification: an 11-year
follow-up to the DanThyr study. J Clin Endocrinol Metab, 97(11), 4022-4029.

Boelart, K. & Franklyn, J.A. (2005). Thyroid hormone in health and disease. J Endo-
crinol, 187, 1-15.

Bolk, N., Visser, T.J., Nijman, J., Jongste, I.J., Tijssen, J.G.P. & Berghout, A. (2010).
Effects of evening vs morning levothyroxine intake. Arch Intern Med, 170(22),
1996-2003.

Bono, G., Fancellu, R., Blandini, F., Santoro, G. & Mauri, M. (2004). Cognitive and
affective status in mild hypothyroidism and interactions with l-thyroxine treatment.
Acta Neurol Scand, 110; 59-66.

70
Chapter VI References

Booth, T., Deary, I.J. & Starr, J.M. (2012). Thyroid stimulating hormone, free thyro-
xine and cognitive ability in old age: the Lothian birth cohort study 1936. Psycho-
neuroendocrinology, 38(4), 597-601.

Brabant, G., Cain, J., Jackson, A. & Kreitschmann-Andermahr, I. (2011). Visualizing

hormones actions in the brain. Trends Endocrinol Metab, 22(5), 153-163.

Broedel, O., Eravci, M., Fuxius, S., Smolarz, T., Jeitner, A., Grau, H., Stoltenburg-
Didinger, G., Plueckhan, H., Meinhold, H. & Baumgartner, A. (2003). Effects of
hyper- and hypothyroidism on thyroid hormone concentrations in regions of the
rat brain. Am J Physiol Endocrinol Metab, 285, E470-E480.

Buckner, R.L. & Logan, J.M. (2001). Chapter 2, Functional Neuroimaging Methods:
PET and fMRI. In R. Cabeza & A. Kingstone (Eds.). Handbook of Functional
Neuroimaging of Cognition. Cambridge, MA: MIT Press.

Bullinger, M. & Kirchberger, I. (1998). SF-36. Fragebogen zum Gesundheitszustand

Handanweisung. Göttingen: Hogrefe.

Burmeister, L.A., Ganguli, M., Dodge, H.H., Toczek, T., DeKosky, S.T. & Nebes, R.D.
(2001). Hypothyroidism and cognition: preliminary evidence for a specific defect
in memory. Thyroid, 11 (12), 1177-1185.

Buxton, R.B. (2009). Introduction to functional magnetic resonance imaging (2nd ed.).
Cambridge: Cambridge University Press.

Canaris, G.J., Steiner, J.F. & Ridgway, E.C. (1997). Do traditional symptoms of hypo-
thyroidism correlate with biochemical disease? J Gen Intern Med, 12; 544-550.

Castellano, C.A., Laurin, D., Langlois, M.F., Fortier, M., Tessier, D., Gaudreau, P.,
Ferland, G., Payette, H., Lorrain, D. & Cunnane, S.C. (2013). Thyroid function
and cognition in the euthyroid elderly: a case-control study embedded in Quebec
longitudinal study – NuAge. Psychoneuroendocrinology, 38(9),1772-1776.

71
Chapter VI References

Caturegli, P., De Remigis, A., Chuang, K., Dembele, M., Iwama, A. & Iwama, S.
(2013). Hashimoto Thyroiditis: celebrating the centennial through the lens oft he
John Hopkins Hospital surgical pathology records. Thyroid, 23(2), 142-150.

Chaalal, A., Poirier, R., Blum, D., Gillet, B., Le Blanc, P., Basquin, M., Buée, M.,
Laroche, S. & Enderlin, V. (2014). PTU-induced hypothyroidism in rats leads to
several early neuropathological signs of Alzheimer’s disease in the hippocampus
and spatial memory impairments. Hippocampus, 24, 1381-1393.

Constant, E.L., de Volder, A.G., Ivanoiu, A., Bol, A., Labar, D., Seghers, A., Cosnard,
G., Melin, J. & Daumerie, C. (2001). Cerebral blood flow and glucose metabolism
in hypothyroidism: a positron emission tomography study. J Clin Endocrino.
Metab, 86, 3864-3870.

Cooke, G.E., Mullally, S., Correia, N., O’Mara, S.M. & Gibney, J. (2014). Hippocam-
pal volume is decreased in adults with hypothyroidism. Thyroid, 24(3), 433-440.

Correia, N., Mullally, S., Cooke, G., Tun, T. K., Phelan, N., Feeney, J., Fitzgibbon, M.,
Boran, G., O'Mara, S. & Gibney, J. (2009). Evidence for a specific defect in hip-
pocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol
Metab, 94(10), 3789-3797.

Cortés, C., Eugenin, E., Aliaga, E., Carreňo, L.J., Bueno, S.M., Gonzalez, P.A.,
Gayol, S., Naranjo, D., Noches, V., Marassi, M.P., Rosenthal, D., Jadue, C.,
Ibarra, P., Keitel, C., Wohllk, N., Court, F., Kalergis, A.M. & Riedel, C.A. (2012).
Hypothyroidism in the adult rat causes incremental changes in brain-derived
neurotrophic factor (BDNF), neuronal and astrocyte apoptosis, gliosis and
deterioration of postsynaptic density. Thyroid, 22(9), 951-963.

Dayan, C.M. & Panicker, V. (2009). Novel insights into thyroid hormones from the
study of common genetic variation. Nat Rev Endocrinol, 5, 211-218.

72
Chapter VI References

Dayan, C.M. & Panicker, V. (2013). Hypothyroidism and depression. Eur Thyroid J,
2, 168-179.

Delange, F., Bürgi, H. & Moinier, B. (2004). Chapter 8, Iodine deficiency disorders
(IDD) in western and central Europe. In B.S. Hetzel, F. Delange, J.T. Dunn, J.
Ling, V. Mannar & C. Pandav (Eds.). Towards the global elimination of brain
damage due to iodine deficiency. Delhi: Oxford University Press.

Desouza, L.A., Ladiwala, U., Daniel, S.M., Agashe, S., Vaidya, R.A. & Vaidya, V.A.
(2005). Thyroid hormone regulates hippocampal neurogenesis in the adult rat
brain. Mol Cell Neurosci, 29, 414-426.

Duntas, L.H., Amino, N., Hay, I., McDermott, M., Peeters, R., Vaismann, M., Ward,
L., Williams, G., San Luis Jr., T.O.L. & Yen, P. (2012). Thyroid disorders, non-
communicable diseases that gravely impact public health: a commentary and
statement by the advisory board of the world thyroid federation. Thyroid, 22(6),
566-567.

Ehlert, U. & von Känel, R. (Hrsg.) (2011). Psychoendokrinologie und Psychoimmuno-

logie. Berlin: Springer.

Engum, A., Bjøro, T., Mykletun, A. & Dahl, A.A. (2002). An association between
depression, anxiety and thyroid function - a clinical fact or an artefact? Acta
Psychiatr Scand, 106, 27-34.

Eurich, D.T., Johnson, J.E., Reid, K.J. & Spertus, J.A. (2006). Assessing responsive-
ness of generic and specific health related quality of life measures in heart
failure. Health Qual Life Outcomes, 4 (89).

Fernández-Lamo, I., Montero-Pedrazuela, A., Delgado-García, J.M. & Guadaño-

Ferraz, A. (2009). Effects of thyroid hormone replacement on associative
learning and hippocampal synaptic plasticity in adult hypothyroid rats. Eur J
Neurosci, 30, 679-692.

73
Chapter VI References

Formiga, F., Ferrer, A., Padros, G., Contra, A., Corbella, X. & Pujol, R. (2014).
Thyroid status and functional and cognitive status at baseline and survival after 3
years of follow-up: the OCTABAIX study. Eur J Endocrinol, 170, 69-75.

Forti, P., Olivelli, V., Rietti, E., Maltoni, B., Pirazzoli, G., Gatti, R., Gioia, M.G. &
Ravaglia, G. (2012). Serum thyroid-stimulating hormone as a predictor of cogni-
tive impairment in an elderly cohort. Gerontology, 58, 41-49.

Fox, M.D. & Raichle, M.E. (2007). Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nat Rev Neurosci, 8, 700-711.

Franke, G.H. (2002). SCL-90-R Symptomcheckliste von L.R. Derogatis – Deutsche

Version, 2.Aufl. Göttingen: Beltz Test GmbH.

Friston, K., Ashburner, J.T., Kiebel, S.J., Nichols, T.E. & Penny, W.D. (Eds.). (2007).
Statistical Parametric Mapping. London: Academic Press.

Friston, K.J., Jezzard, P. & Turner, R. (1994). Analysis of functional MRI time-series.
Hum Brain Mapp, 1, 153-171.

Fu, A. L., Zhou, C.Y. & Chen, X. (2010). Thyroid hormone prevents cognitive deficit
in mouse model of Alzheimer’s disease. Neuropharmacology, 58, 722-729.

Führer, D., Mann, K., Feldkamp, J., Krude, H., Spitzweg, C., Kratzsch, J. & Schott, M.
(2014). Schilddrüsenfunktionsstörungen in der Schwangerschaft. Dtsch Med
Wochenschr, 139(42), 2148-2152.

Gärtner, R., Gasnier, B.C.H., Dietrich, J.W., Krebs, B. & Angstwurm, W.A. (2002).
Selenium supplementation in patients with autoimmune thyroiditis decreases
thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab, 87, 1687-
1691.

74
Chapter VI References

Ge, J.-F., Peng, L., Hu, C.-M. & Wu, T.-N. (2012). Impaired learning and memory
performance in subclinical hypothyroidism rat model induced by hemi-thyroid
electrocauterization. J Neuroendocrinol, 24(6), 953-961.

Ghenimi, N., Alfos, S., Redonnet, A., Higueret, P, Pallet, V. & Enderlin, V. (2010).
Adult-onset hypothyroidism induces amyoidogenic pathway of amyoid precursor
protein processing in the rat hippocampus. J Neuroendocrinol, 22, 951-959.

Grabe, H.J., Völzke, H., Lüdemann, J., Wolff, B., Schwahn, C., John, U., Meng, W. &
Freyberger, H.J. (2005). Mental and physical complaints in thyroid disorders in
the general population. Acta Psychiatr Scand, 112; 286-293.

Greicius, M.D., Srivastava, G., Reiss, A.L. & Menon, V. (2004). Default-mode net-
work activity distinguishes Alzheimer’s disease from healthy aging: evidence from
functional MRI. PNAS, 101(13), 4637-4642.

Grozinsky-Glasberg, S., Fraser, A., Nahshoni, E., Weizman, A. & Leibovici, L. (2006).
Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for
clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin
Endocrinol Metab, 91(7), 2592-2599.

Hassan, W.A., Aly, M.S., Abdel Rahman, T. & Shahat, A.S. (2013). Impact of experi-
mental hypothyroidism on monoamines level in discrete brain regions and other
peripheral tissues of young and adult male rats. Int J Devl Neurosci, 31, 225-233.

Hautzinger, M., Bailer, M., Worall, H. & Keller, F. (1994). Beck-Depressions-Inventar

(BDI). Bern: Hans Huber Verlag.

He, X.S., Ma, N., Pan, Z.L., Wang, Z.X., Li, N., Zhang, X.C., Zhou, J.N., Zhu, D.F. &
Zhang, D.R. (2011). Functional magnetic resource imaging assessment of
altered brain function in hypothyroidism during working memory processing. Eur
J Endocrinol, 164, 951-959.

75
Chapter VI References

Henke, K., Buck, A., Weber, B. & Wieser, H.G. (1997). Human hippocampus establi-
shes associations in memory. Hippocampus, 7, 249-256.

Hetzel, B.S. (2005). Towards the global elimination of brain damage due to iodine
deficiency – the role of the international council for control of iodine deficiency
disorders. Int J Epidemiol, 34(4), 762-764.

Jäncke, L. (2005). Methoden der Bildgebung in der Psychologie und den kognitiven
Neurowissenschaften. Stuttgart: Kohlhammer.

Jaeschke, R., Guyatt, G., Gerstein, H., Patterson, C., Molloy, W., Cook, D., Harper,
S., Griffith, L. & Carbotte R. (1996). Does treatment with l-thyroxine influence
health status in middle-aged and older adults with subclinical hypothyroidism? J
Gen Intern Med, 11; 744-749.

Janssen, O.E., Heufelder, A.E. & Mann, K. (2001). Kapitel 3, Schilddrüsener-

krankungen. In: D. Ganten & K. Ruckpaul (Eds.). Endokrinopathien. Heidelberg:
Springer.

Joffe, R.T., Pearce, E.N., Hennessey, J.V., Ryan, J.J. & Stern, R.A. (2012). Subclini-
cal hypothyroidism, mood, and cognition in older adults: a review. Int J Geriatr
Psychiatry, 28(2), 111-118.

Johnson, L.Q., Hobson, V., Jenkins, M., Dentino, A., Ragain, R.M. & O’Bryant, S.
(2011). The influence of thyroid function on cognition in a sample of ethnically
diverse, rural-dwelling women: a project FRONTIER study. J Neuropsychiatry
Clin Neurosci, 23(2), 219-222.

De Jong, F.J., den Heijer, T., Visser, T.J., de Rijke, Y.B., Drexhage, H.A., Hofman, A.
& Breteler, M.M.B. (2006). Thyroid hormones, dementia, and atrophy of the
medial temporal lobe. J Clin Endocrinol Metab, 91(7), 2569-2573.

76
Chapter VI References

De Jong, F.J., Peeters, R.P., den Heijer, T., van der Deure, W.M., Hofman, A.,
Uitterlinden, A.G., Visser, T.J. & Breteler, M.M.B. (2007). The association of poly-
morphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone
parameters and atrophy of the medial temporal lobe. J Clin Endocrinol Metab,
92, 636-640.

De Jongh, R.T., Lips, P., van Schoor, N.M., Rijs, K.S., Deeg, D.J., Comijs, H.C.,
Kramer, M.H., Vandenbroucke, J.P. & Dekkers, O.M. (2011). Endogenous sub-
clinical thyroid disorders, physical and cognitive function, depression, and
mortality in older individuals. Eur J Endocrinol, 165(4), 545-554.

Jorde, R., Waterloo, K., Storhaug, H., Nyrnes, A., Sundsfjord, J. & Jenssen, T.G.
(2006). Neuropsychological function and symptoms in subjects with subclinical
hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab,
91(1), 145-153.

Jørgensen, P., Langhammer, A., Krokstad, S. & Forsmo, S. (2014). Is there an

association between disease ignorance and self-rated health? The HUNT study,
a cross-sectional survey. BMJ Open, 4, e004962.

Kahaly, G.J., Dienes, H.P., Beyer, J. & Hommel, G. (1998). Iodide induces thyroid
autoimmunity in patients with endemic goiter: a randomized, double-blind,
placebo-controlled trial. European Journal of Endocrinology, 139, 290-297.

Kaya, M., Cermik, T.F., Bedel, D., Kutucu, Y., Tuglu, C. & Yigitbasi, Ö.N. (2007).
Assessment of alterations in regional cerebral blood flow in patients with hypo-
thyroidism due to Hashimoto’s thyroiditis. J Endocrinol Invest, 30, 491-496.

Kong, W.M., Sheikh, M.H., Lumb, P.J., Freedman, D.B., Crook, M., Doré, C.J. &
Finer, N. (2002). A 6-month randomized trial of thyroxine treatment in women
with mild subclinical hypothyroidism. Am J Med, 112; 348-354.

77
Chapter VI References

Klaver, E.I., van Loon, H.C.M., Stienstra, R., Links, T.P., Keers, J.C., Kema, I.P.,
Muller Kobold, A.C., van der Klauw, M.M. & Wolffenbuttel, B.H.R. (2013). Thyroid
hormone status and health-related quality of life in the LifeLines cohort study.
Thyroid, 23(9), 1066-1073.

Kramer, C.K., von Mühlen, D., Kritz-Silversetin, D. & Barrett-Connor, E. (2009). Trea-
ted hypothyroidism, cognitive function, and depressed mood in old age: the
Rancho Bernardo Study. Eur J Endocrinol, 161, 917-921.

Kratzsch, J., Schubert, G., Pulzer, F., Pfaeffle, F., Pfaeffle, R., Koerner, A., Dietz, A.,
Rauh, M., Kiess, W. & Thiery, J. (2008). Reference intervals for TSH and thyroid
hormones are mainly affected by age, body mass index and number of blood
leucocytes, but hardly by gender and thyroid autoantibodies during the first
decade of life. Clin Biochem, 41, 1091-1098.

Krausz, Y., Freedman, N., Lester, H., Newman, J.P., Barkai, G., Bocher, M., Chisin,
R. & Bonne, O. (2004). Regional cerebral blood flow in patients with mild
hypothyroidism. J Nucl Med, 45(10), 1712-1715.

Kvetny, J., Ellervi, C. & Bech, P. (2014). Is suppressed thyroid-stimulating hormone

(TSH) associated with subclinical depression in the Danish General Suburban
Population Study? Nord J Psychiatry, epub ahead of print: doi: 10.3109/
08039488.2014.972454.

Ladenson, P.W. (2002). Psychological wellbeing in patients. Clin Endocrinol, 57, 575-
576.

Laurberg, P., Cerqueira, C., Ovesen, L., Rasmussen, L.B., Perrild, H., Andersen, S.,
Bülow Pedersen, I. & Carlé, A. (2010). Iodine intake as a determinant of thyroid
disorders in populations. Best Pract Res Clin Endocrinol Metab, 24, 13-27.

78
Chapter VI References

Leyhe, T., Ethofer, T., Bretscher, J., Künle, A., Säuberlich, A.-L., Klein, R., Gallwitz,
B., Häring, H.-U., Fallgatter, A., Klingberg, S., Sauer, R. & Müssig, K. (2013).
Low performance in attention testing is associated with reduced grey matter
density of the left inferior frontal gyrus in euthyroid patients with Hashimoto’s
thyroiditis. Brain Behav Immun, 27(1), 33-37.

Leyhe, T., Müssig, K., Weinert, C., Laske, C., Häring, H.-U., Saur, R., Klingberg, S. &
Gallwitz, B. (2008). Increased occurence of weaknesses in attention testing in
patients with Hashimoto’s thyroiditis compared to patients with other thyroid
illnesses. Psychoneuroendocrinology, 33, 1432-1436.

Logothetis, N.K. (2008). What we can do and what we cannot do with fMRI. Nature,
453, 869-878.

Margulies, D.S., Böttger, J., Long, X., Lv, Y., Kelly, C., Schäfer, A., Goldhahn, D.,
Abbushi, A., Milham, M.P., Lohmann, G. & Villringer, A. (2010). Resting develop-
ments: a review of fMRI post-processing methodologies for spontaneous brain
activity. Magn Reson Mater Phy, 23, 289-307.

McMillan, C., Bradley, C., Razvi, S. & Weaver, J. (2006). Psychometric evaluation of
a new questionnaire measuring treatment satisfaction in hypothyroidism: the
ThyTSQ. Value Health, 9(2), 132-139.

McMillan, C., Bradley, C., Razvi, S. & Weaver, J. (2008). Evaluation of new mea-
sures of the impact of hypothyroidism on quality of life and symptoms: the
ThyDQoL and ThySRQ. Value Health, 11(2), 285-294.

Medici, M., Direk, N., Visser, W.E., Korevaar, T.I.M., Hofman, A., Visser, T.J.,
Tiemeier, H. & Peeters, R.P. (2014). Thyroid function within the normal range
and the risk of depression: a population-based cohort study. J Clin Endocrinol
Metab, 99(4), 1213-1219.

79
Chapter VI References

Meisinger, C., Ittermann, T., Wallaschofski, H., Meier, M., Below, H., Kramer, A.,
Döring, A., Nauck, M. & Völzke, H. (2012). Geographic variations in the frequen-
cy of thyroid disorders and thyroid peroxidase antibodies in persons without
former thyroid disease within Germany. Eur J Endocrinol, 167, 363-371.

Miller, K.J., Parsons, T.D., Whybrow, P.C., van Herle, K., Rasgon, N., van Herle, A.,
Martinez, D., Silverman, D.H. & Bauer, M. (2006). Memory improvement with
treatment of hypothyroidism. Int J Neurosci, 116, 895-906.

Montero-Pedrazueala, A., Fernández-Lamo, I., Alieva, M., Pereda-Pérez, I., Venero,

C. & Guadaño-Ferraz, A. (2011).Adult-onset hypothyroidism enhances fear
memory and upregulates mineralcorticoid and glucocorticoid receptors in the
amygdala. PlosOne, 6(10), e26582.

Montero-Pedrazuela, A., Venero, C., Lavado-Autric, R., Fernández-Lamo, I., García-

Verdugo, J., Bernal, J. & Guadaño-Ferraz, A. (2006). Modulation of adult hippo-
campal neurogenesis by thyroid hormones: implications in depressive-like beha-
vior. Mol Psychiatry, 11; 361-371.

Moon, J.H., Park, Y.J., Kim, T.H., Han, J.W., Choi, S.H., Lim, S., Park, D.J., Kim,
K.W. & Jang, H.C. (2014). Lower-but-normal serum TSH level is associated with
the development or progression of cognitive impairment in elderly: Korean
Longitudinal Study on Health and Aging (KLoSHA). J Clin Endocrinol Metab, 99,
424-432.

Nagamachi, S., Jinnouchi, S., Nishii, R., Ishida, Y., Fujita, S., Futami, S., Kodama, T.,
Tamura, S. & Kawai, K. (2004). Cerebral blood flow abnormalities induced by
transient hypothyroidism after thyroidectomy. Ann Nucl Med, 18(6), 469-477.

Ott, J., Promberger, R., Kober, F., Neuhold, N., Tea, M., Huber, J.C. & Hermann, M.
(2011). Hashimoto’s thyroiditis affects symptom load and quality of life unrelated
to hypothyroidism: a prospective case-control study in women undergoing
thyroidectomy for benign goiter. Thyroid, 21(2), 161-167.

80
Chapter VI References

Owen, P.J.D. & Lazarus, J.H. (2003). Subclinical hypothyroidism: the case for treat-
ment. Trends Endocrinol Metab, 14(6), 257-261.

Panicker, V., Evans, J., Bjøro, T., Ǻsvold, B.O., Dayan, C.M. & Bjerkese, O. (2009b).
A paradoxical difference in relationship between anxiety, depression and thyroid
function in subjects on and not on T4: findings from the HUNT study. Clinical
Endocrinology, 71, 574-580.

Panicker, V., Saravanan, P., Vaidya, B., Evans, J., Hattersley, A.T., Frayling, T.M. &
Dayan, C.M. (2009a). Common variation in the DIO2 gene predicts baseline psy-
chological well-being and response to combination of thyroxine plus triiodthyro-
nine therapy in hypothyroid patients. J Clin Endocrinol Metab, 94, 1623-1629.

Parle, J., Roberts, L., Wilson, S., Pattison, H., Roalfe, A., Haque, M.S., Heath, C.,
Sheppard, M., Franklyn, J. & Hobbs, F.D. (2010). A randomized controlled trial
of the effect of thyroxine replacement on cognitive function in community-living
elderly subjects with subclinical hypothyroidism: the Birmingham elderly thyroid
study. J Clin Endocrinol Metab, 95, 3623-3632.

Parsaik, A.K., Singh, B., Roberts, R.O., Pankratz, S., Edwards, K.K., Geda, Y.E.,
Gharib, H., Boeve, B.F., Knopman, D.S. & Petersen, R.C. (2014). Hypo-
thyroidism and risk of mild cognitive impairment in elderly persons. JAMA Neurol,
71(2), 201-207.

Pedersen, I.B., Knudsen, N., Carlé, A., Vejbjerg, P., Jørgensen, T., Perrild, H.,
Ovesen, L., Rasmussen, L.B. & Laurberg, P. (2011). A cautious iodization pro-
gramme bringing iodine intake to a low recommended level is associated with an
increase in the prevalence of thyroid autoantibodies in the population. Clin Endo-
crinol, 75, 120-126.

Pearce, E.N., Andersson, M. & Zimmermann, M.B. (2013). Global iodine nutrition:
where do we stand in 2013? Thyroid, 23(5), 523-528.

81
Chapter VI References

Pfannenstiel, P., Hotze, L.A. & Saller, B. (1999). Schilddrüsenkrankheiten - Diagnose

und Therapie (4th ed.). Berlin: Berliner Medizinische Verlagsanstalt.

Piga, M., Serra, A., Deiana, L, Loi, G.L., Satta, L., Di Liberto, M. & Mariotti, S. (2004).
Brain perfusion abnormalities in patients with euthyroid autoimmune thyroiditis.
Eur J Nucl Med Mol Imaging, 31(12), 1639-1644.

Pilhatsch, M., Marxen, M., Winter, C., Smolka, M.N. & Bauer, M. (2011). Hypothyroi-
dism and mood disorders: integrating novel insights from brain imaging tech-
niques. Thyroid Research, 4 (suppl 1): S3.

Pilhatsch, M., Winter, C., Nordström, K., Vennström, B., Bauer, M. & Juckel, G.
(2010). Increased depressive behaviour in mice harboring the mutant thyroid
hormone receptor alpha 1. Behav Brain Res, 214; 187-192.

Poldrack, R.A. & Gorgolewski, K.J. (2014). Making big data open: data sharing in
neuroimaging. Nat Neurosci, 17(11), 1510-1517.

Pop, C.J., Maartens, LH., Leusink, G., van Son, M.J., Knottnerus, A.A., Ward, A.M.,
Metcalfe, R. & Weetman, A.P. (1998). Are autoimmune thyroid dysfunction and
depression related? J Clin Endocrinol Metab, 83(9), 3194-3197.

Prummel, M.F. & Wiersinga, W.M. (2005). Thyroid peroxidase autoantibodies in eu-
thyroid subjects. Best Pract Res Clin Endocrinol Metab, 19(1), 1-15.

Quidé, Y., Witteveen, A.B., El-Hage, W., Veltman, D.J. & Olff, M.(2012). Differences
between effects of psychological versus pharmacologicaltreatments on functional
and morphological brainalterations in anxiety disorders and major depressive
disorder: asystematic review. Neurosci Biobehav Rev, 36, 626-644.

82
Chapter VI References

Quinque, E.M., Karger, S., Arélin, K., Schroeter, M.L., Kratzsch, J. & Villringer, A.
(2014). Structural and functional MRI study of the brain, cognition and mood in
long-term adequately treated Hashimoto's thyroiditis. Psychoneuroendocrinology,
42, 188-198.

Quinque, E.M., Villringer, A., Kratzsch, J. & Karger, S. (2013). Patient- reported out-
comes in adequately treated hypothyroidism – insights from the German versions
of ThyDQoL, ThySRQ and ThyTSQ. Health Qual Life Outcomes 11; 68.

Resta, F., Triggiani, V., Barile, G., Benigno, M., Suppressa, P., Giagulli, V.A., Guas-
tamacchia, E. & Sabbà, C. (2012). Subclinical hypothyroidism and cognitive dys-
function in the elderly. Endocr Metab Immune Disord Drug Targets, 12, 260-267.

Roberts, C.G.P. & Ladenson, P.W. (2004). Hypothyroidism. The Lancet, 363, 793-
803.

Samuels, M.H. (2010). Cognitive function in subclinical hypothyroidism. J Clin Endo-

crinol Metab, 95(8), 3611-3613.

Samuels, M.H., Schuff, K.G., Carlson, N.E., Carello, P. & Janowsky, J.S. (2007).
Health status, mood, and cognition in experimentally induced subclinical hypo-
thyroidism. J Clin Endocrinol Metab, 92(7), 2545-2551.

Saravanan, P., Chau, W.-F., Roberts, N., Vedhara, K., Greenwood, R. & Dayan,
C.M. (2002). Psychological well-being in patients on ‘adequate’ doses of l-thyro-
xine: results of a large, controlled community-bases questionnaire study. Clin
Endocrinol, 57, 577-585.

Schneider, F. & Fink, G.R. (Eds.). (2013). Funktionelle MRT in Psychiatrie und
Neurologie (2nd ed.). Heidelberg: Springer Verlag.

83
Chapter VI References

Schraml, F.V. & Beason-Held, L.L. (2010). Technetium-99m ethyl cysteinate dimer
(ECD) cerebral accumulation and symptom and sign severity during hypo-
thyroidism. Neuro Endocrinol Lett, 31(1), 161-167.

Schraml, F.V., Goslar, P.W., Baxter, L. & Beason-Held, LL. (2011). Thyroid stimu-
lating hormone and cognition during severe, transient hypothyroidism. Neuro
Endocrinol Lett, 32(3), 279-285.

Singh, S., Modi, S., Bagga, D., Kaur, P. Shankar, L.R. & Khushu, S. (2013). Voxel-
based morphometry analysis in hypothyroidism using diffeomorphic anatomic
registration via an exponentiated lie algebra algorithm approach. J Neuroendo-
crinol, 25, 229-234.

Sperling, R.A., Chua, E., Cocchiarella, A., Rand-Giovannetti, E., Poldrack, R.,
Schacter, D.L. & Albert, M. (2003). Putting names to faces: successful encoding
of associative memories activates the anterior hippocampal formation. Neuro-
Image, 20, 1400-1410.

Vanderpump, M. (2003). Subclinical hypothyroidism: the case against treatment.

Trends Endocrinol Metab, 14(6), 262-266.

Vanderpump, M. (2011). The epidemiology of thyroid disease. Br Med Bull, 99, 39-
51.

Vanderpump, M. & Tunbridge, W. M. G. (2002). Epidemiology and prevention of

clinical and subclinical hypothyroidism. Thyroid, 12(10), 839-847.

Van de Ven, A., Muntjewerff, J.W., Netea-Meier, J., de Vegt, F., Ross, H.A., Sweep,
F.C., Kiemeney, L.A., Vos, P.E., Buitelaar, J.K., Hermus, A.R., den Heijer, M. &
Janzing, J.G. (2012a). Association between thyroid function, thyroid autoim-
munity, and state and trait factors of depression. Acta Psychiatr Scand, 126(5),
377-384.

84
Chapter VI References

Van de Ven, A., Netea-Maier, J., de Vegt, F., Ross, H.A., Sweep, F.C., Kiemeney,
L.A., Hermus, A.R. & den Heijer, M. (2012b). Is there a relationship between
fatigue perception and the serum levels of thyrotropin and free thyroxine in eu-
thyroid subjects? Thyroid, 22(12), 1236-1243.

Völzke, H., Ittermann, T., Albers, M., Friedrich, N., Nauck, M., Below, H. & Kramer, A.
(2012). Five-year change in morphological and functional alterations of the
thyroid gland: the study of health in Pomerania. Thyroid, 22(7), 737-746.

De Vries, M., Ouwendijk, R., Kessels, A., de Haan, M.W., Flobbe, K., Hunink,
M.R.M., van Engelshoven, J.M.A. & Nelemans, P.J. (2005). Comparison of
generic and disease-specific questionnaires for the assessment of quality of life
in patient with peripheral arterial disease. J Vasc Surg, 41, 261-268.

Walsh, J.P., Ward, L.C., Burke, V., Bhagat, C.I., Shiels, L., Henley, D., Gillett, M.J.,
Gilbert, R., Tanner, M. & Stuckey, B.G. (2006). Small changes in thyroxine do-
sage do not produce measurable changes in hypothyroid symptoms, well-being,
or quality of life: results of a double-blind, randomized clinical trial. J Endocrinol
Metab, 91, 2624-2630.

Weishaupt, D., Köchli, V.D. & Marincek, B. (2009). Wie funktioniert MRI? (6. Ed.)
Heidelberg: Springer Medizin Verlag.

Wekking, E.M., Appelhof, B.C., Fliers, E., Schene, A.H., Huyser, J., Tijssen, J.G.P. &
Wiersinga, W.M. (2005). Cognitive functioning and well-being in euthyroid
patients on thyroxine replacement therapy for primary hypothyroidism. Eur J
Endocrinol, 153, 747-753.

Wheeler, S.M., McAndrews, M.P., Sheard, E.D. & Rovet, J. (2011). Visuospatial
associative memory and hippocampal functioning in congenital hypothyroidism. J
Int Neuropsychol Soc, 18, 1-8.

85
Chapter VI References

Wiersinga, W.M. (2009). Do we need still more trials on T4 and T3 combination

therapy in hypothyroidism? Eur J Endocrinol, 161, 955-959.

Witthaus, E., Stewart, J. & Bradley, C. (2001). Treatment satisfaction and psycho-
logical well-being with insulin glargine compared with NPH in patients with Type
1 diabetes. Diabet Med, 18(8), 619–625.

Yin, J.J., Liao, L.M., Luo, D.X., Xu, K., Ma, S.H., Wang, Z.X., Le, H.B., Huang, R.R.,
Cai, Z.L. & Zhang, J. (2013). Spatial working memory impairment in subclinical
hypothyroidism: an fMRI study. Neuroendocrinology, 97, 260-270.

Zettinig, G., Asenbaum, S., Fueger, B.J., Hofmann, A., Diemling, M., Mittlboeck, M. &
Dudczak, R. (2003). Increased prevalence of subclinical brain perfusion
abnormalities in patients with autoimmune thyroiditis: evidence of Hashimoto’s
encephalitis. Clin Endocrinol, 59, 637-643.

Zhu, D.F., Wang, Z.X., Zhang, D.R., Pan, Z.L., He, S., Hu, X.P., Chen, X.C., Zhou,
J.N. (2006). fMRI revealed neural substrate for reversible working memory dys-
function in subclinical hypothyroidism. Brain, 129, 2923-2930.

86
Chapter VII Appendix

VII Appendix

1 Supplemental Material, Quinque et al., 2014

Structural and functional MRI study of the brain, cognition and mood in long-
term adequately treated Hashimoto’s thyroiditis

Eva M. Quinque, Stefan Karger, Katrin Arélin, Matthias L. Schroeter, Jürgen Kratzsch
and Arno Villringer

Supplemental Material

This material supplements but does not replace the content of the peer-reviewed

paper published in Psychoneuroendocrinology

Methods

MRI acquisition parameters

T1-weighted images were acquired using a three-dimensional magnetisation-

prepared rapid gradient echo sequence (sagittal orientation) with selective water

excitation and linear phase encoding. The following imaging parameters were used:

Inversion time (TI) 650 ms, repetition time (TR) 1.3 sec., repetition time of the

gradient-echo kernel 9.1 ms, echo time (TE) 3.46 ms, flip angle 10°, field of view

256x240 mm², 2 averages. To avoid aliasing, oversampling was performed in read

direction (head to foot). Reconstructed images were calculated using zero filling with

1x1x1 mm³ voxel size.

The resting-state and event-related fMRI data were acquired using T2*-weighted

gradient echo-planar image (EPI) pulse sequences with the following parameters:
87
Chapter VII Appendix

300 volumes, TR 2.0 sec., TE 30 ms, flip angle 90°, 30 slices, voxel resolution 3 mm

* 3 mm * 4 mm. During the event-related fMRI session, participants performed an

associative memory encoding task adapted from Sperling et al., (2003) presented

with Presentation software (Neurobehavioral Systems, Inc., version 12.7) on a back-

projection screen viewed via a mirror. Participants viewed black-and-white

photographs of faces (Jäger et al., 2005; http://psydok.sulb.uni-

saarland.de/volltexte/2005/505/) with a first name written underneath and were asked

to remember each person’s name. They had to decide whether they felt the name

fitted the face or not by a button press. Participants viewed a fixation cross between

trials. Participants viewed 90 encoding trials randomly interleaved with 30 nullevents

where they were shown a fixation cross for the trial duration of eight seconds. After

five minutes rest, participants performed the retrieval task in the scanner while

structural scans were acquired. During retrieval they viewed all faces again, this time

paired with the learned name and a distractor name paired with another face during

encoding. Participants had to choose the correct name by a button press and

reported whether they were sure or unsure about their response. There was no time

limit to ensure that all trials were responded to. Face-name pairings were randomised

for each participant and different sets were used at the two sessions.

Grey matter data analysis

Images were bias-field corrected, segmented and registered to standard Montreal

Neurological Institute (MNI) space using rigid-body transformation and the unified

segmentation approach (Ashburner and Friston 2005). Subsequently, images were

smoothed with a Gaussian kernel of 8 mm³ full width at half maximum (FWHM).

Resulting grey matter images were averaged across the two time points and entered

into group level analyses. All voxels with a minimum grey matter density probability of

88
Chapter VII Appendix

0.2 were included in the analyses. The exact coordinates of the regions reported in

Bauer et al., (2009) did not lie within grey matter for all subjects and 9 mm spheres

(27 voxels) were thus created around the described areas instead. Coordinates for

the areas were taken from the Harvard-Oxford Structural Atlas provided by

Functional magnetic resonance imaging of the brain Software Library (FSL), the

resulting regions of interest (ROIs) lying within grey matter for all subjects. The six

ROIs are the right hippocampus (MNI coordinates x=30, y=-24 z=-12), left

hippocampus (-30 -27 -12), right amygdala (27 0 -21), left amygdala (-24 -3 -18),

posterior cingulate cortex (0 -27 36) and subcallosal cortex (0 24 -12).

Resting-state fMRI data analysis

The preprocessing steps comprised three-dimensional motion correction, time series

despiking, 6 mm FWHM spatial smoothing, four-dimensional mean-based intensity

normalisation, band-pass temporal filtering (0.01-0.1 Hz), removing linear and

quadratic trends and regressing out eight nuisance signals (white matter,

cerebrospinal fluid and six motion parameters). No global signal regression was

performed to avoid spurious negative correlations driving group comparisons. The

output of these preprocessing steps was one 4-dimensional residual functional

volume for each participant. The normalisation of the functional volume was

performed via linear normalisation to MNI space using the FSL Linear Image

Registration Tool and the individual T1-weighted image as a prior.

Seed-based resting-state functional connectivity analysis calculates the correlation

between the seed regions and each other voxel in the brain. The resulting

connectivity maps per subject were subsequently averaged across the two time

points and entered into separate group comparisons to identify regions of altered

connectivity to the six seed regions. Significance level was set to p<0.0083 on the

89
Chapter VII Appendix

family-wise error corrected cluster size level to account for the use of six seed

regions for group and correlation analyses.

An explorative functional connectivity analysis was performed with those areas as

seeds that revealed a significant correlation between grey matter density and mood

in the patient group. This was done in order to gain information about involved

networks in addition to the result on isolated structures available with the VBM

analysis. Seeds were extracted using Marsbar, a toolbox for SPM8

(http://marsbar.sourceforge.net). Connectivity maps of the patient group were

entered into a onesample t-test controlled for age and sex. An FWE-corrected voxel-

level threshold of p<0.005 was chosen for illustration purposes and functional

networks were descriptively compared with networks reported in the literature

(Beckmann et al., 2005; Fox and Raichle 2007; Wang et al., 2012).

Event-related fMRI data analysis

Task-based fMRI data was preprocessed using SPM8 running on Matlab. Data were

slice-time corrected, realigned, corrected for field inhomogeneities (unwarping) and

normalised to MNI space using the unified segmentation approach (Ashburner and

Friston, 2005). EPI deformations were corrected using a fieldmap scan acquired

separately during the scanning session. An 8 mm Gaussian kernel was used for

smoothing and a high-pass filter of 128 Hz was used to account for slow signal drifts.

Results

The right postcentral gyrus was associated with a network resembling a sensory-

motor network (Beckmann et al., 2005; Figure 6d) comprising pre- and postcentral

gyrus and midcingulate areas. The left superior frontal gyrus revealed an executive

control network including mainly frontal areas (Beckmann et al., 2005; Figure 6f). The
90
Chapter VII Appendix

left cuneus was associated with a visual network consisting of mainly occipital areas

(Beckmann et al., 2005; Figure 6a) and the middle temporal gyrus belonged to the

default mode network including posterior and anterior cingulate cortices, medial

prefrontal cortex and inferior parietal cortex (Wang et al., 2012, see Figure S1). The

left temporal pole did not reveal a meaningful network as it only correlated with

regions directly adjacent to the seed region and its contralateral equivalent.

Figure S1: Resting-state networks of areas showing an association between grey matter
density and mood in the patient group. Connectivity maps are shown on coronal, sagittal and
axial slices oriented according to neurological convention. Labels of resembling networks as
described by Beckmann et al., 2005 or Wang et al., 2012 are shown next to the connectivity
maps.

91
Chapter VII Appendix

2 Declaration of Authenticity

Eigenständigkeitserklärung

Erklärung über die eigenständige Abfassung der Arbeit

Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig und ohne unzulässige
Hilfe oder Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe. Ich
versichere, dass Dritte von mir weder unmittelbar noch mittelbar geldwerte
Leistungen für Arbeiten erhalten haben, die im Zusammenhang mit dem Inhalt der
vorgelegten Dissertation stehen, und dass die vorgelegte Arbeit weder im Inland
noch im Ausland in gleicher oder ähnlicher Form einer anderen Prüfungsbehörde
zum Zweck einer Promotion oder eines anderen Prüfungsverfahrens vorgelegt
wurde. Alles aus anderen Quellen und von anderen Personen übernommene
Material, das in der Arbeit verwendet wurde oder auf das direkt Bezug genommen
wird, wurde als solches kenntlich gemacht. Insbesondere wurden alle Personen
genannt, die direkt an der Entstehung der vorliegenden Arbeit beteiligt waren.

Leipzig, März 2015 Eva Quinque

92
Chapter VII Appendix

3 Curriculum Vitae

Personal Data
Name Eva Maria Quinque née Weig
Date & place of birth 25.04.1985 in Pegnitz, Bavaria
Address Heinrich-Budde-Str. 16, 04157 Leipzig
Email evamaria_quinque@gmx.de

Education
since 10/2010 Department of Neurology, Max-Planck-Institute for Human Cognitive and
Brain Sciences (MPI), Leipzig
PhD: Brain, mood and cognition in hypothyroidism (A. Villringer)

10/2007 – 09/2008 Department of Experimental Psychology, University of Cambridge, GB

Master of Philosophy in the Biological Sciences:
Individual differences in iconic memory (J.D. Mollon)

10/2004 – 09/2007 & Department of Psychology, University of Leipzig

10/2008 – 09/2010 Diplom (1.0): Social cognition and executive functions in vascular cognitive
disorder (S. Frisch, M.L. Schroeter)

06/2003 Abitur Ratsgymnasium Osnabrück (1.2)

Work experience
since 12/2014 Scientific staff member at the Department of Neurology (A.Villringer), MPI
04/2009 – 09/2010 Student assistant at the Department of Neurology (A. Villringer), MPI
10/2009 – 12/2009 Intern at the Day Clinic for Cognitive Neurology, University Clinic Leipzig
01/2009 – 09/2009 Intern at the Memory Consultation Unit, University Clinic Leipzig
05/2005 – 09/2007 Student assistant at the Department of Cognitive Neurology (D.Y. von
Cramon), MPI

Scholarships
10/2010 – 11/2014 Max Planck Society
10/2007 – 07/2008 DAAD and Kurt Hahn Trust
04/2005 – 09/2010 Studienstiftung des deutschen Volkes

93
Chapter VII Appendix

4 List of publications

2014
*Quinque, E.M., Karger, S., Arélin, K., Schroeter, M.L., Kratzsch, J. & Villringer, A.
(2014). Structural and functional MRI study of the brain, cognition and mood in long-
term adequately treated Hashimoto's thyroiditis. Psychoneuroendocrinology, 42, 188-
198.

Frisch, S., Quinque, E.M. & Schroeter, M.L. (2014). Kognitive Funktionsstörungen
bei früher zerebraler Mikroangiopathie (Cognitive deficits in early small vessel
disease). Neuro aktuell: Informationsdienst für Neurologen & Psychiater, 27(8), 17.

Schäfer, A., Quinque, E.M., Kipping, J., Arélin, K., Roggenhofer, E., Frisch, S.,
Villringer, A., Mueller, K. & Schroeter, M.L. (2014). Early small vessel disease affects
frontoparietal and cerebellar hubs in close correlation with clinical symptoms: A
resting-state fMRI study. Journal of Cerebral Blood Flow and Metabolism 34(7),
1091-1095.

2013
*Quinque, E.M., Villringer, A., Kratzsch, J. & Karger, S. (2013). Patient- reported
outcomes in adequately treated hypothyroidism–— insights from the German
versions of ThyDQoL, ThySRQ and ThyTSQ. Health Qual Life Outcomes 11; 68.

2012
Quinque, E.M., Arélin, K., Dukart, J., Roggenhofer, E., Streitbürger, D.P., Villringer,
A., Frisch, S., Mueller, K. & Schroeter, M.L. (2012). Identifying the neural correlates
of executive functions in early cerebral microangiopathy: A combined VBM and DTI
study. Journal of Cerebral Blood Flow and Metabolism 32(10), 1869-1878.

* the two publications marked with an asterix form the present cumulative dissertation

94
Chapter VII Appendix

Conference contributions

2015
Quinque, E.M., Karger, S., Arélin, K., Schroeter, M.L., Kratzsch, J. & Villringer, A.
(2015). Brain, mood and cognition during treatment initiation in mild hypothyroidism.
Poster accepted for presentation at 17th European Congress of Endocrinology (ECE),
Dublin, Ireland.

2013
Schäfer, A., Quinque, E.M., Kipping, J., Arélin, K., Roggenhofer, E., Frisch, S.,
Villringer, A., Müller, K. & Schroeter, M.L. (2013). Central hubs affected by early
small vessel disease. Poster presented at 19th Annual Meeting of the Organization
for Human Brain Mapping (OHBM), Seattle, WA, USA.

2010
Weig, E.M., Arélin, K., Semler, V., Spengler, S., Villringer, A. & Schroeter, M.L.
(2010). Social cognition is impaired besides executive functions in cerebral
microangiopathy. Poster presented at Annual Meeting of German Society for
Psychiatry, Psychotherapy and Neurology (DGPPN), Berlin, Germany.

95
Chapter VII Appendix

5 Acknowledgements

Diese wissenschaftliche Arbeit wäre nicht möglich gewesen ohne die hervorragende
Zuarbeit vieler Kollegen. An erster Stelle bedanken möchte ich mich bei den
endokrinologischen Fachkollegen, allen voran Dr. Stefan Karger von der
Schilddrüsenambulanz der Universitätsklinik Leipzig, der die Patientenrekrutierung
durch seine Kontakte initiiert hat und alle Phasen des Projekts aus
endokrinologischer Sicht betreut hat. Den rekrutierenden Praxen Dr. Drynda, Dr.
Gerlach-Eniyew, Dr. Herrmann und Dr. Wiesner und deren Teams gilt mein
herzlicher Dank. Des Weiteren danke ich Annett Wiedemann für die Durchführung
der Blutentnahmen und MRT-Messungen (letzteres gemeinsam mit Christiane
Hummitzsch). Den MRT-aufklärenden Ärzten (Dr. Roggenhofer, Dr. Arélin, Dr.
Schroeter, Dr. Sehm) gilt besonderer dank für den unvermeidlich kurzfristigen
Einsatz bei den neu diagnostizierten Patienten. Vielen Dank allen, die meine vielen
Fragen zu den MRT-Analysetechniken geduldig beantwortet haben: Jöran Lepsien,
Karsten Müller, André Pampel, Judy Kipping, Alexander Schäfer und Yating Lv.
Vielen Dank an die Arbeitsgedächtnisgruppe um Angelika Thöne-Otto für ein offenes
und immer inspirierendes Diskussionsforum. Ganz lieben Dank an Ramona Menger,
Birgit Mittag, Cornelia Ketscher, Bettina Johst, Anne-Kathrin Franz, Sylvia Stasch
und die Grafikabteilung für Eure Unterstützung und Ermutigung. Danke an Anna
Hempel für die Unterstützung der Datenerhebung und an Sabrina Trapp und
Shahrzad Kharabian fürs Korrekturlesen. Ein ganz besonderer Dank gilt meinem
Betreuer Arno Villringer für die Freiheit, wirklich selbstständig forschen zu können
und für die Vision, die letztlich zu dieser Arbeit geführt hat, nämlich die neuro-
(psycho)logischen Auswirkungen internistischer Erkrankungen zu untersuchen.
Zuletzt gilt mein Dank den Teilnehmern der Studie, die mit großem zeitlichem Einsatz
die aufwendige Erhebung möglich gemacht haben.
Diese Arbeit wäre auch nicht möglich gewesen ohne die Unterstützung durch meine
Familie und Freunde, vielen Dank Euch allen.

96
MPI Series in Human Cognitive and Brain Sciences:
1 Anja Hahne 19 Silke Urban
Charakteristika syntaktischer und semantischer Prozesse bei der auditi- Verbinformationen im Satzverstehen
ven Sprachverarbeitung: Evidenz aus ereigniskorrelierten Potentialstudien
20 Katja Werheid
2 Ricarda Schubotz Implizites Sequenzlernen bei Morbus Parkinson
Erinnern kurzer Zeitdauern: Behaviorale und neurophysiologische
Korrelate einer Arbeitsgedächtnisfunktion 21 Doreen Nessler
Is it Memory or Illusion? Electrophysiological Characteristics of True and
3 Volker Bosch False Recognition
Das Halten von Information im Arbeitsgedächtnis: Dissoziationen
langsamer corticaler Potentiale 22 Christoph Herrmann
Die Bedeutung von 40-Hz-Oszillationen für kognitive Prozesse
4 Jorge Jovicich
An investigation of the use of Gradient- and Spin-Echo (GRASE) imaging 23 Christian Fiebach
for functional MRI of the human brain Working Memory and Syntax during Sentence Processing.
A neurocognitive investigation with event-related brain potentials and
5 Rosemary C. Dymond functional magnetic resonance imaging
Spatial Specificity and Temporal Accuracy in Functional Magnetic
Resonance Investigations 24 Grit Hein
Lokalisation von Doppelaufgabendefiziten bei gesunden älteren
6 Stefan Zysset Personen und neurologischen Patienten
Eine experimentalpsychologische Studie zu Gedächtnisabrufprozessen
unter Verwendung der funktionellen Magnetresonanztomographie 25 Monica de Filippis
Die visuelle Verarbeitung unbeachteter Wörter. Ein elektrophysiologischer
7 Ulrich Hartmann Ansatz
Ein mechanisches Finite-Elemente-Modell des menschlichen Kopfes
26 Ulrich Müller
8 Bertram Opitz Die katecholaminerge Modulation präfrontaler kognitiver Funktionen
Funktionelle Neuroanatomie der Verarbeitung einfacher und komplexer beim Menschen
akustischer Reize: Integration haemodynamischer und elektrophysiolo-
gischer Maße 27 Kristina Uhl
Kontrollfunktion des Arbeitsgedächtnisses über interferierende Information
9 Gisela Müller-Plath
Formale Modellierung visueller Suchstrategien mit Anwendungen bei der 28 Ina Bornkessel
Lokalisation von Hirnfunktionen und in der Diagnostik von Aufmerksam- The Argument Dependency Model: A Neurocognitive Approach to
keitsstörungen Incremental Interpretation

10 Thomas Jacobsen 29 Sonja Lattner

Characteristics of processing morphological structural and inherent case Neurophysiologische Untersuchungen zur auditorischen Verarbeitung
in language comprehension von Stimminformationen

11 Stefan Kölsch 30 Christin Grünewald

Brain and Music Die Rolle motorischer Schemata bei der Objektrepräsentation: Untersu-
A contribution to the investigation of central auditory processing with a chungen mit funktioneller Magnetresonanztomographie
new electrophysiological approach 31 Annett Schirmer
12 Stefan Frisch Emotional Speech Perception: Electrophysiological Insights into the
Verb-Argument-Struktur, Kasus und thematische Interpretation beim Processing of Emotional Prosody and Word Valence in Men and Women
Sprachverstehen 32 André J. Szameitat
13 Markus Ullsperger Die Funktionalität des lateral-präfrontalen Cortex für die Verarbeitung
The role of retrieval inhibition in directed forgetting – an event-related von Doppelaufgaben
brain potential analysis 33 Susanne Wagner
14 Martin Koch Verbales Arbeitsgedächtnis und die Verarbeitung ambiger Wörter in
Measurement of the Self-Diffusion Tensor of Water in the Human Brain Wort- und Satzkontexten

15 Axel Hutt 34 Sophie Manthey

Methoden zur Untersuchung der Dynamik raumzeitlicher Signale Hirn und Handlung: Untersuchung der Handlungsrepräsentation im
ventralen prämotorischen Cortex mit Hilfe der funktionellen Magnet-
16 Frithjof Kruggel Resonanz-Tomographie
Detektion und Quantifizierung von Hirnaktivität mit der funktionellen
Magnetresonanztomographie 35 Stefan Heim
Towards a Common Neural Network Model of Language Production and
17 Anja Dove Comprehension: fMRI Evidence for the Processing of Phonological and
Lokalisierung an internen Kontrollprozessen beteiligter Hirngebiete Syntactic Information in Single Words
mithilfe des Aufgabenwechselparadigmas und der ereigniskorrelierten
funktionellen Magnetresonanztomographie 36 Claudia Friedrich
Prosody and spoken word recognition: Behavioral and ERP correlates
18 Karsten Steinhauer
Hirnphysiologische Korrelate prosodischer Satzverarbeitung bei gespro- 37 Ulrike Lex
chener und geschriebener Sprache Sprachlateralisierung bei Rechts- und Linkshändern mit funktioneller
Magnetresonanztomographie
38 Thomas Arnold 57 Margret Hund-Georgiadis
Computergestützte Befundung klinischer Elektroenzephalogramme Die Organisation von Sprache und ihre Reorganisation bei ausgewählten,
neurologischen Erkrankungen gemessen mit funktioneller Magnetreso-
39 Carsten H. Wolters nanztomographie – Einflüsse von Händigkeit, Läsion, Performanz und
Influence of Tissue Conductivity Inhomogeneity and Anisotropy on EEG/ Perfusion
MEG based Source Localization in the Human Brain
58 Jutta L. Mueller
40 Ansgar Hantsch Mechanisms of auditory sentence comprehension in first and second
Fisch oder Karpfen? Lexikale Aktivierung von Benennungsalternative bei language: An electrophysiological miniature grammar study
der Objektbenennung
59 Franziska Biedermann
41 Peggy Bungert Auditorische Diskriminationsleistungen nach unilateralen Läsionen im
Zentralnervöse Verarbeitung akustischer Informationen Di- und Telenzephalon
Signalidentifikation, Signallateralisation und zeitgebundene Informati-
onsverarbeitung bei Patienten mit erworbenen Hirnschädigungen 60 Shirley-Ann Rüschemeyer
The Processing of Lexical Semantic and Syntactic Information in Spoken
42 Daniel Senkowski Sentences: Neuroimaging and Behavioral Studies of Native and Non-
Neuronal correlates of selective attention: An investigation of electro- Native Speakers
physiological brain responses in the EEG and MEG
61 Kerstin Leuckefeld
43 Gert Wollny The Development of Argument Processing Mechanisms in German.
Analysis of Changes in Temporal Series of Medical Images An Electrophysiological Investigation with School-Aged Children and
S 1 Markus Ullsperger & Michael Falkenstein Adults
Errors, Conflicts, and the Brain Current Opinions on Performance 62 Axel Christian Kühn
Monitoring Bestimmung der Lateralisierung von Sprachprozessen unter besondere
44 Angelika Wolf Berücksichtigung des temporalen Cortex, gemessen mit fMRT
Sprachverstehen mit Cochlea-Implantat: EKP-Studien mit postlingual 63 Ann Pannekamp
ertaubten erwachsenen CI-Trägern Prosodische Informationsverarbeitung bei normalsprachlichem und
45 Kirsten G. Volz deviantem Satzmaterial: Untersuchungen mit ereigniskorrelierten
Brain correlates of uncertain decisions: Types and degrees of uncertainty Hirnpotentialen
46 Hagen Huttner 64 Jan Derrfuß
Magnetresonanztomographische Untersuchungen über die anatomische Functional specialization in the lateral frontal cortex: The role of the
Variabilität des Frontallappens des menschlichen Großhirns inferior frontal junction in cognitive control
47 Dirk Köster 65 Andrea Mona Philipp
Morphology and Spoken Word Comprehension: Electrophysiological The cognitive representation of tasks – Exploring the role of response
Investigations of Internal Compound Structure modalities using the task-switching paradigm
48 Claudia A. Hruska 66 Ulrike Toepel
Einflüsse kontextueller und prosodischer Informationen in der audito- Contrastive Topic and Focus Information in Discourse – Prosodic
rischen Satzverarbeitung: Untersuchungen mit ereigniskorrelierten Realisation and Electrophysiological Brain Correlates
Hirnpotentialen 67 Karsten Müller
49 Hannes Ruge Die Anwendung von Spektral- und Waveletanalyse zur Untersuchung
Eine Analyse des raum-zeitlichen Musters neuronaler Aktivierung im der Dynamik von BOLD-Zeitreihen verschiedener Hirnareale
Aufgabenwechselparadigma zur Untersuchung handlungssteuernder 68 Sonja A.Kotz
Prozesse The role of the basal ganglia in auditory language processing: Evidence

50 Ricarda I. Schubotz from ERP lesion studies and functional neuroimaging
Human premotor cortex: Beyond motor performance 69 Sonja Rossi
51 Clemens von Zerssen The role of proficiency in syntactic second language processing: Evidence
Bewusstes Erinnern und falsches Wiedererkennen: Eine funktionelle MRT from event-related brain potentials in German and Italian
Studie neuroanatomischer Gedächtniskorrelate 70 Birte U. Forstmann
52 Christiane Weber Behavioral and neural correlates of endogenous control processes in task
Rhythm is gonna get you. switching
Electrophysiological markers of rhythmic processing in infants with and 71 Silke Paulmann
without risk for Specific Language Impairment (SLI) Electrophysiological Evidence on the Processing of Emotional Prosody:
53 Marc Schönwiesner Insights from Healthy and Patient Populations
Functional Mapping of Basic Acoustic Parameters in the Human Central 72 Matthias L. Schroeter
Auditory System Enlightening the Brain – Optical Imaging in Cognitive Neuroscience
54 Katja Fiehler 73 Julia Reinholz
Temporospatial characteristics of error correction Interhemispheric interaction in object- and word-related visual areas
55 Britta Stolterfoht 74 Evelyn C. Ferstl
Processing Word Order Variations and Ellipses: The Interplay of Syntax The Functional Neuroanatomy of Text Comprehension
and Information Structure during Sentence Comprehension
75 Miriam Gade
56 Claudia Danielmeier Aufgabeninhibition als Mechanismus der Konfliktreduktion zwischen
Neuronale Grundlagen der Interferenz zwischen Handlung und visueller Aufgabenrepräsentationen
Wahrnehmung
76 Juliane Hofmann 95 Henning Holle
Phonological, Morphological, and Semantic Aspects of Grammatical The Comprehension of Co-Speech Iconic Gestures: Behavioral, Electrophy-
Gender Processing in German siological and Neuroimaging Studies
77 Petra Augurzky 96 Marcel Braß
Attaching Relative Clauses in German – The Role of Implicit and Explicit Das inferior frontale Kreuzungsareal und seine Rolle bei der kognitiven
Prosody in Sentence Processing Kontrolle unseres Verhaltens
78 Uta Wolfensteller 97 Anna S. Hasting
Habituelle und arbiträre sensomotorische Verknüpfungen im lateralen Syntax in a blink: Early and automatic processing of syntactic rules as
prämotorischen Kortex des Menschen revealed by event-related brain potentials
79 Päivi Sivonen 98 Sebastian Jentschke
Event-related brain activation in speech perception: From sensory to Neural Correlates of Processing Syntax in Music and Language – Influ-
cognitive processes ences of Development, Musical Training and Language Impairment
80 Yun Nan 99 Amelie Mahlstedt
Music phrase structure perception: the neural basis, the effects of The Acquisition of Case marking Information as a Cue to Argument
acculturation and musical training Interpretation in German
An Electrophysiological Investigation with Pre-school Children
81 Katrin Schulze
Neural Correlates of Working Memory for Verbal and Tonal Stimuli in 100 Nikolaus Steinbeis
Nonmusicians and Musicians With and Without Absolute Pitch Investigating the meaning of music using EEG and fMRI
82 Korinna Eckstein 101 Tilmann A. Klein
Interaktion von Syntax und Prosodie beim Sprachverstehen: Untersu- Learning from errors: Genetic evidence for a central role of dopamine in
chungen anhand ereigniskorrelierter Hirnpotentiale human performance monitoring
83 Florian Th. Siebörger 102 Franziska Maria Korb
Funktionelle Neuroanatomie des Textverstehens: Kohärenzbildung bei Die funktionelle Spezialisierung des lateralen präfrontalen Cortex:
Witzen und anderen ungewöhnlichen Texten Untersuchungen mittels funktioneller Magnetresonanztomographie
84 Diana Böttger 103 Sonja Fleischhauer
Aktivität im Gamma-Frequenzbereich des EEG: Einfluss demographischer Neuronale Verarbeitung emotionaler Prosodie und Syntax: die Rolle des
Faktoren und kognitiver Korrelate verbalen Arbeitsgedächtnisses
85 Jörg Bahlmann 104 Friederike Sophie Haupt
Neural correlates of the processing of linear and hierarchical artificial The component mapping problem: An investigation of grammatical
grammar rules: Electrophysiological and neuroimaging studies function reanalysis in differing experimental contexts using eventrelated
brain potentials
86 Jan Zwickel
Specific Interference Effects Between Temporally Overlapping Action and 105 Jens Brauer
Perception Functional development and structural maturation in the brain‘s neural
network underlying language comprehension
87 Markus Ullsperger
Functional Neuroanatomy of Performance Monitoring: fMRI, ERP, and 106 Philipp Kanske
Patient Studies Exploring executive attention in emotion: ERP and fMRI evidence
88 Susanne Dietrich 107 Julia Grieser Painter
Vom Brüllen zum Wort – MRT-Studien zur kognitiven Verarbeitung Music, meaning, and a semantic space for musical sounds
emotionaler Vokalisationen
108 Daniela Sammler
89 Maren Schmidt-Kassow The Neuroanatomical Overlap of Syntax Processing in Music and
What‘s Beat got to do with ist? The Influence of Meter on Syntactic Language - Evidence from Lesion and Intracranial ERP Studies
Processing: ERP Evidence from Healthy and Patient populations
109 Norbert Zmyj
90 Monika Lück Selective Imitation in One-Year-Olds: How a Model‘s Characteristics
Die Verarbeitung morphologisch komplexer Wörter bei Kindern im Influence Imitation
Schulalter: Neurophysiologische Korrelate der Entwicklung
110 Thomas Fritz
91 Diana P. Szameitat Emotion investigated with music of variable valence – neurophysiology
Perzeption und akustische Eigenschaften von Emotionen in mensch- and cultural influence
lichem Lachen
111 Stefanie Regel
92 Beate Sabisch The comprehension of figurative language: Electrophysiological evidence
Mechanisms of auditory sentence comprehension in children with on the processing of irony
specific language impairment and children with developmental dyslexia:
A neurophysiological investigation 112 Miriam Beisert
Transformation Rules in Tool Use
93 Regine Oberecker
Grammatikverarbeitung im Kindesalter: EKP-Studien zum auditorischen 113 Veronika Krieghoff
Satzverstehen Neural correlates of Intentional Actions
94 Şükrü Barış Demiral 114 Andreja Bubić
Incremental Argument Interpretation in Turkish Sentence Comprehension Violation of expectations in sequence processing
115 Claudia Männel 135 Eugenia Solano-Castiella
Prosodic processing during language acquisition: Electrophysiological In vivo anatomical segmentation of the human amygdala and parcellati-
studies on intonational phrase processing on of emotional processing
116 Konstanze Albrecht 136 Marco Taubert
Brain correlates of cognitive processes underlying intertemporal choice for Plastizität im sensomotorischen System – Lerninduzierte Veränderungen
self and other in der Struktur und Funktion des menschlichen Gehirns
117 Katrin Sakreida 137 Patricia Garrido Vásquez
Nicht-motorische Funktionen des prämotorischen Kortex: Emotion Processing in Parkinson’s Disease:
Patientenstudien und funktionelle Bildgebung The Role of Motor Symptom Asymmetry
118 Susann Wolff 138 Michael Schwartze
The interplay of free word order and pro-drop in incremental sentence Adaptation to temporal structure
processing: Neurophysiological evidence from Japanese
139 Christine S. Schipke
119 Tim Raettig Processing Mechanisms of Argument Structure and Case-marking in
The Cortical Infrastructure of Language Processing: Evidence from Child Development: Neural Correlates and Behavioral Evidence
Functional and Anatomical Neuroimaging
140 Sarah Jessen
120 Maria Golde Emotion Perception in the Multisensory Brain
Premotor cortex contributions to abstract and action-related relational
processing 141 Jane Neumann
Beyond activation detection: Advancing computational techniques for
121 Daniel S. Margulies the analysis of functional MRI data
Resting-State Functional Connectivity fMRI: A new approach for asses-
sing functional neuroanatomy in humans with applications to neuroa- 142 Franziska Knolle
natomical, developmental and clinical questions Knowing what’s next: The role of the cerebellum in generating
predictions
122 Franziska Süß
The interplay between attention and syntactic processes in the adult and 143 Michael Skeide
developing brain: ERP evidences Syntax and semantics networks in the developing brain

123 Stefan Bode 144 Sarah M. E. Gierhan

From stimuli to motor responses: Decoding rules and decision mecha- Brain networks for language
nisms in the human brain Anatomy and functional roles of neural pathways supporting language
comprehension and repetition
124 Christiane Diefenbach
Interactions between sentence comprehension and concurrent action: 145 Lars Meyer
The role of movement effects and timing The Working Memory of Argument-Verb Dependencies
Spatiotemporal Brain Dynamics during Sentence Processing
125 Moritz M. Daum
Mechanismen der frühkindlichen Entwicklung des Handlungsverständ- 146 Benjamin Stahl
nisses Treatment of Non-Fluent Aphasia through
Melody, Rhythm and Formulaic Language
126 Jürgen Dukart
Contribution of FDG-PET and MRI to improve Understanding, Detection 147 Kathrin Rothermich
and Differentiation of Dementia The rhythm’s gonna get you: ERP and fMRI evidence on the interaction
of metric and semantic processing
127 Kamal Kumar Choudhary
Incremental Argument Interpretation in a Split Ergative Language: 148 Julia Merrill
Neurophysiological Evidence from Hindi Song and Speech Perception – Evidence from fMRI, Lesion Studies and
Musical Disorder
128 Peggy Sparenberg
Filling the Gap: Temporal and Motor Aspects of the Mental Simulation of 149 Klaus-Martin Krönke
Occluded Actions Learning by Doing?
Gesture-Based Word-Learning and its Neural Correlates in Healthy
129 Luming Wang Volunteers and Patients with Residual Aphasia
The Influence of Animacy and Context on Word Order Processing: Neuro-
physiological Evidence from Mandarin Chinese 150 Lisa Joana Knoll
When the hedgehog kisses the frog
130 Barbara Ettrich A functional and structural investigation of syntactic processing in the
Beeinträchtigung frontomedianer Funktionen bei Schädel-Hirn-Trauma developing brain
131 Sandra Dietrich 151 Nadine Diersch
Coordination of Unimanual Continuous Movements with External Events
Action prediction in the aging mind
132 R. Muralikrishnan
An Electrophysiological Investigation Of Tamil Dative-Subject Construc- 152 Thomas Dolk
tions A Referential Coding Account for the Social Simon Effect
133 Christian Obermeier 153 Mareike Bacha-Trams
Exploring the significance of task, timing and background noise on Neurotransmitter receptor distribution in Broca’s area and the posterior
gesture-speech integration superior temporal gyrus
134 Björn Herrmann 154 Andrea Michaela Walter
Grammar and perception: Dissociation of early auditory processes in the The role of goal representations in action control
brain
155 Anne Keitel
Action perception in development: The role of experience
156 Iris Nikola Knierim
Rules don’t come easy: Investigating feedback-based learning of
phonotactic rules in language.
157 Jan Schreiber
Plausibility Tracking: A method to evaluate anatomical connectivity
and microstructural properties along fiber pathways
158 Katja Macher
Die Beteiligung des Cerebellums am verbalen Arbeitsgedächtnis
159 Julia Erb
The neural dynamics of perceptual adaptation to degraded speech
160 Philipp Kanske
Neural bases of emotional processing in affective disorders
161 David Moreno-Dominguez
Whole-brain cortical parcellation: A hierarchical method based on
dMRI tractography
162 Maria Christine van der Steen
Temporal adaptation and anticipation mechanisms in sensorimotor
synchronization
163 Antje Strauß
Neural oscillatory dynamics of spoken word recognition
164 Jonas Obleser
The brain dynamics of comprehending degraded speech
165 Corinna E. Bonhage
Memory and Prediction in Sentence Processing
S 2 Tania Singer, Bethany E. Kok, Boris Bornemann, Matthias Bolz, and
Christina A. Bochow
The Resource Project
Background, Design, Samples, and Measurements
166 Anna Wilsch
Neural oscillations in auditory working memory
167 Dominique Goltz
Sustained Spatial Attention in Touch: Underlying Brain Areas and
Their Interaction
168 Juliane Dinse
A Model-Based Cortical Parcellation Scheme for High-Resolution
7 Tesla MRI Data
169 Gesa Schaadt
Visual, Auditory, and Visual-Auditory Speech Processing in School
Children with Writing Difficulties
170 Laura Verga
Learning together or learning alone: Investigating the role of social
interaction in second language word learning
171 Eva Maria Quinque
Brain, mood and cognition in hypothyroidism