Fakultt fr Medizin

Abteilung fr Neuroradiologie

Klinik fr psychosomatische Medizin und Psychotherapie

On the neurobiology of somatoform pain:

A functional magnetic resonance imaging
investigation

Alexander Otti

Vollstndiger Abdruck der von der Fakultt fr Medizin der Technischen Universitt Mnchen zur
Erlangung des akademischen Grades eines

Doctor of Philosophy (Ph.D.)

genehmigten Dissertation.

Vorsitzender: Univ.-Prof. Dr. Arthur Konnerth

Betreuer: Univ.-Prof. Dr. Claus Zimmer

Prfer der Dissertation:

1. Univ.-Prof. Dr. Peter Henningsen

2. Univ.-Prof. Dr. Harald Gndel, Universitt Ulm

Die Dissertation wurde am 29.11.2013 bei der Fakultt fr Medizin der Technischen Universitt
Mnchen eingereicht und durch die Fakultt fr Medizin am 11.02.2014 angenommen.
 Abstract

Abstract

Somatoform pain disorder is characterised by chronic pain without significant peripheral organic

pathology. A central dysfunction that disrupts the brains capacity to process emotions is

claimed to be the neural correlate. However, there is little direct experimental evidence to

support this hypothesis. The studies presented in this thesis address this question using

functional magnetic resonance tomography, a modern non-invasive technique for brain imaging.

First, I examine alterations of the neural correlates of emotional processing. Specifically, I focus

on empathy for pain, a fundamental affective behavioural trait in everyday social life. Study I

demonstrates that patients show lower activation of the perigenual anterior cingulate cortex

during the sharing of other peoples pain. This area is involved in constructing affective

meaning. This finding suggests that patients with somatoform pain have a disturbed emotional

processing owing to decreased activation of empathetic-affective networks.

Second, I test whether alterations in neural circuits related to affective function only appear

during a specific emotional behaviour, such as empathy, or if they are more deeply ingrained in

the human brain. Study II and III demonstrate that patients suffering from somatoform pain show

a shift to higher frequencies of spontaneous oscillations of neural activity in the cingular-insular

(i.e. fronto-insular) network and the anterior default mode network even during a resting state

without external stimulation. No differences are observed in the functional connectivity, a

measure of the spatial extent of resting state networks, or in functional network connectivity, a

measure of their interplay. These data suggest that chronic medically unexplained pain is an

endogenous process that occurs within neural systems dedicated to emotional processing.

Taken together, these findings may lead to a more specific and detailed neurobiological

understanding of the clinical observation of disturbed affect in patients experiencing chronic pain

disorder.

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 Table of contents

Table of contents

1. Introduction ............................................................................................................................ 3
1.1 Functional somatic syndromes characteristics and clinical implications ......................... 3

1.2 Pain dimensions and neuroimaging ............................................................................... 4

1.3 Empathy for pain behavioural facets and neural basis ................................................... 7

1.4 The neurobiology of somatoform pain............................................................................... 9

1.5 The human brains resting state.......................................................................................10

1.6 Parameters for the description of brain function ...............................................................12

1.7 Functional magnetic resonance imaging and electrophysiology.......................................13

2. Aim .......................................................................................................................................17

3. Study I - Neural correlates of deficits in pain-related affective meaning construction in patients

with chronic pain disorder .........................................................................................................20

4. Study II - Frequency shifts in the anterior default mode network and the salience network in
chronic pain disorder .................................................................................................................21

5. Study III - Functional network connectivity of pain-related resting state networks in

somatoform pain disorder: an exploratory fMRI study ...............................................................22

6. Discussion ............................................................................................................................23

7. References ...........................................................................................................................28

8. List of publications.................................................................................................................37
8.1 Publications that are part of this thesis (see attachment) .................................................37

8.2 Other publications............................................................................................................38

9. Acknowledgements ...............................................................................................................39

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 1. Introduction

1. Introduction

What are the reasons for chronic pain when no significant organic pathology can be located? Is

it an emotional problem? Is it a home-made phenomenon intrinsically produced by the

human brain? The imaging studies presented in this thesis aim to elucidate the neurobiology of

somatoform pain disorder. Specifically, I address the following questions:

1. Is there neurobiological evidence that somatoform pain mirrors an impaired access to ones

own and others emotions?

2. Does the human cerebrum intrinsically i.e. without external stimulation - produce specific

patterns of endogenous activity that are related to chronic pain without sufficient peripheral

causes? Is somatoform pain disorder associated with alterations in the spatial and temporal

domains of neural networks dedicated to emotional processing during a resting state of the

organism?

1.1 Functional somatic syndromes characteristics and clinical implications

Functional somatic syndromes, symptoms without a significant organic correlate, present a

large challenge for modern medicine. These psychosomatic diseases are common throughout

the world and are costly for health care systems. Furthermore, these disorders are subject to

becoming chronic and leading to severe suffering. Their cause has eluded diagnostics, and

even the most advanced therapies cannot offer relief (Wessely et al., 1999, Grabe et al., 2003,

Barsky et al., 2005, Henningsen et al., 2007, Fink and Schroder, 2010). Somatoform pain

disorder plays an important role among functional syndromes. It is characterised by ongoing

pain suggestive of physical illness and injury symptoms that cannot be fully explained by a

general medical condition, the direct effect of a substance, or another mental disorder (Kroenke

et al., 1997, APA, 2000). Patients often persistently refuse to accept the conclusion that there is

no adequate physical cause for their bodily symptoms except for short periods during or

immediately after medical investigation (WHO, 2005). As in anxiety disorders and in depression,

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 1. Introduction

patients experience severe impairments in quality of life and have high numbers of sick days

and consultations (Kroenke et al., 1997, Jackson and Kroenke, 2008). Therefore, research on

the aetiology of somatoform pain is required. However, only a few studies have examined the

neurobiology of somatoform pain. These studies support the notion that somatoform pain

reflects dysfunction of pain processing in the central nervous system (Stoeter et al., 2007,

Gundel et al., 2008, Garcia-Campayo et al., 2009, Valet et al., 2009).

1.2 Pain dimensions and neuroimaging

As shown by modern imaging methods, such as functional magnetic resonance imaging and

positron emission tomography, pain is a multidimensional phenomenon that can be

experimentally related to distinct brain regions (Valet et al., 2010):

a) The sensory-discriminative component comprises the detection, localisation and

determination of the quality and quantity of a painful stimulus. The noxious information reaches

the thalamus via trigemino-thalamic and spino-thalamic fibres. Projections from the (ventro-)

lateral nuclei mainly extend to the primary and secondary somatosensory cortex. Therefore, this

system is called the lateral pain system.

b) The affective dimension of pain perception reflects anxiety, unpleasantness, emotional

awareness, and the monitoring of bodily states mediated by the anterior insula and the anterior

cingulate cortex (Craig, 2002, 2003, Seeley et al., 2007). The (ventro-) medial nuclei of the

thalamus project to these regions and represent the gate of the so-called medial pain system.

The insular cortex shows a functional organisation following an anterior-posterior axis. Its

posterior region mediates somatosensory processing, whereas the anterior insula is responsible

for emotional processing (Taylor et al., 2009, Kurth et al., 2010, Cauda et al., 2011). Activity

within the posterior insula is associated with pain intensity. Function of the anterior insular

cortex is related to anxiety (Lin et al., 2013). The anterior cingulate cortex also underpins

affective processing and is associated with the unpleasantness of pain (Peyron et al., 2000).

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 1. Introduction

Activity of the medial prefrontal cortex and the orbitofrontal cortex is associated with anxiety

(Ochsner et al., 2006). In addition, the amygdala is a contributor to the affective processing of

pain. This region is associated with emotional stimuli and emotional learning (Phelps and

LeDoux, 2005, Wiech and Tracey, 2009).

c) The medial pain system also subserves the cognitive dimension, which reflects the

evaluation of painful stimuli and its effects on the organism. Attention, appraisal and anticipation

are highly influential to the subjective experience of pain (Wiech et al., 2008). Anterior cingulate

cortex and insula activity are enhanced when high intensities of pain are expected (Koyama et

al., 2005). The medial prefrontal cortex shows higher activation during self-referential attention

and anticipation of pain (Straube et al., 2009). Moreover, this area is involved in endogenous

pain inhibition (Zubieta et al., 2001, Seifert et al., 2009).

d) Another facet of pain-processing is the motor-dimension, which is evident during shortening

reactions and relieving postures. Brain regions underlying motor-functions, such as the primary

motor cortex, the middle anterior cingulate cortex, the supplementary motor area, the basal

ganglia and the cerebellum, show (inconsistent) activation during pain perception (Valet et al.,

2010).

e) Autonomous reactions, such as increased pulse, perspiration and vaso-vagal syncopes,

represent the vegetative dimension of the experience of pain. Regions related to the processing

of stress and vegetative functions, such as the anterior cingulate cortex, the medial prefrontal

cortex, the hypothalamus and the amygdala, seem to play an important role (Valet et al., 2010).

Interestingly, some of these regions, especially those related to the affective dimension, are also

activated during the perception of pain in others.

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 1. Introduction

Figure 1: Central pain processing (modified Otti and Noll-Hussong, 2011)

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 1. Introduction

1.3 Empathy for pain behavioural facets and neural basis

Pain is critical for survival. It not only warns the organism of a physical threat value, but

additionally will automatically attract emotional attention leading to high affective contagion and

empathy in potential caregivers (Craig, 2004b). The construct of empathy is defined as

identifying with and sharing the feelings and thoughts of others. Recent functional imaging

studies show that empathy for pain and physical pain share the same neural circuits as

proposed by Preston and De Waal (2002) in a neuro-integrative model of human empathy (for

review see Fan et al., 2011, Lamm et al., 2011). The mere observation of actions activates the

same brain regions as the generation of the very same actions, known as perception-action

coupling (Prinz, 1997, Hommel et al., 2001, Decety and Jackson, 2004). The primary overlap

between the states of observing or experiencing pain occurs in the anterior insula, anterior

cingulate cortex and middle cingulate cortex. Activation of the anterior cingulate cortex is

correlated with the subjective intensity of empathically perceived pain (Jackson et al., 2005).

The response of the anterior insula is associated with attention to pain in self (Lovero et al.,

2009) and others (Craig, 2004a, Moriguchi et al., 2007, Silani et al., 2008, Bird et al., 2010).

Interestingly, as demonstrated by Singer et al. (2006), the observer exhibits less activation of

the cingulo-insular system if the person suffering from pain displayed unfair behaviour prior to

the painful experience. Additionally, social differences between the observer and the person in

pain can lead to similar effects (Hein et al., 2010, Azevedo et al., 2012, Bernhardt and Singer,

2012, Sheng and Han, 2012). Furthermore, activation is observed in the supplemental motor

area (Decety and Jackson, 2004). The role of the somatosensory cortex in empathy for pain is

still under debate (Singer et al., 2004, Cheng et al., 2008). This region seems to be activated if

visual stimuli are used (Lamm et al., 2011). Apart from these core regions (Decety and Jackson,

2004, Fan et al., 2011), other brain areas can contribute to empathy, including the medial

prefrontal cortex and lateral parietal regions. These regions are not directly involved in the

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 1. Introduction

affective response to anothers pain but underlie other functions, such as cognitive processes

and emotional regulation.

Empathy requires the ability to access ones own and others affective states. Recent functional

imaging research has demonstrated that less activation within affective-empathetic neural

networks while observing the pain of others is associated with impaired recognition of ones own

emotions and deficits in empathic abilities (Moriguchi et al., 2006, Moriguchi et al., 2007).

Figure 2: Core-regions of empathy for pain

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 1. Introduction

1.4 The neurobiology of somatoform pain

Patients suffering from somatoform pain show difficulties in realising and interpreting affective

signals. They perceive emotions as mere physical sensations (Duddu et al., 2006), a

phenomenon that has been conceptualised as alexithymia (Sifneos, 1996). Compared to other

psychiatric diseases, somatoform disorders (Wessely et al., 1999) are related to subjective

emotional awareness of feelings (Subic-Wrana et al., 2005, Subic-Wrana et al., 2010).

Therefore, patients with somatoform pain experience emotional distress more somatically

(Mabe et al., 1990, Subic-Wrana et al., 2005, Waller and Scheidt, 2006, Subic-Wrana et al.,

2010) in terms of a bodily distress syndrome (Silton et al., 2011). This leads to a higher

subjective pain perception and pain catastrophising (Petrak et al., 2003). In other words,

patients with somatoform pain often are not aware of their own or others affective states

(Moriguchi et al., 2006, Clore and Pappas, 2007, Pedrosa Gil et al., 2009, de Greck et al.,

2011). Thus, from an neurointegrative point of view, it has been suggested that clinical chronic

pain and other mental disorders (Apkarian et al., 2011) might be exacerbated by a reduced

capacity to appropriately assign affective meaning to sensory and internal cues (Roy et al.,

2012). Accordingly, there are hints that a lack of emotional awareness, as defined by "difficulty

identifying feelings of oneself and others, is associated with lower back pain (Mehling and

Krause, 2005). Biologically, this specific mind-body discrepancy reflects a neural imbalance of

sensory-discriminative, affective, cognitive, executive, vegetative and introspective functions

(Chaturvedi and Desai, 2006, Beauregard, 2007, Rief and Broadbent, 2007, Verkuil et al., 2007,

Browning et al., 2011). The question arises whether somatoform pain is associated with

impaired empathetic abilities and altered activity in affective-empathetic systems, such as the

anterior cingulate cortex, insula, supplemental motor area, and somatosensory cortex. However,

little is known about the neural mechanisms of somatoform pain. Patients show a significant

loss of grey matter in the cingular-insular system and in the medial prefrontal cortex (Valet et al.,

2009). Furthermore, altered brain function has been reported. Gndel et al. (2008)

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 1. Introduction

demonstrated that the experimental application of heat leads to enhanced activation of the

anterior cingulate cortex, insular cortex, amygdala and parahippocampal gyrus, but a reduced

response of the ventral medial prefrontal cortex. Stoeter et al. (2007) reported similar findings

but showed enhanced activation of the dorsal mPFC in the patient group.

1.5 The human brains resting state

The fact that the body is lying down is no reason

for supposing that the mind is at peace.
Rest is far from restful.
Seneca, ~ 60 A.D.

Our knowledge of the neurobiology of somatoform disorders is primarily based on a handful of

imaging studies measuring the neural response to a specific stimulus, such as heat. However,

the human brain also produces permanent and spontaneous fluctuations of neural activity even

during a resting state without external stimulation. The brains dark energy (Zhang and

Raichle, 2010) is approximately 30 times higher than its extrinsic activity. Alterations within this

stimulus-independent activity might be associated with chronic pain without sufficient peripheral

organic pathology.

The brains intrinsic energy is highly organised in several intrinsic connectivity networks (Fox et

al., 2005), which consist of regions characterised from experiments using external stimulation,

such as the direct application of pain or the presentation of visual stimuli depicting others in

pain. Even without tactile stimulation, spontaneous activity within the sensorimotor network can

be detected. The cingular-insular system, which overlaps with areas dedicated to the affective

processing of pain, also shows spontaneous neural oscillations without nociceptive input.

Among intrinsic connectivity networks, the so-called default mode network holds a special

position. In 1997, a meta-analysis by Shulman et al. demonstrated that not all networks increase

their activity during external stimulation. Some areas show an inverse activation pattern, with

increased activation during rest but relatively decreased activation during goal-directed

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 1. Introduction

behaviour and externally oriented attention (Shulman et al., 1997). Mazoyer et al. (2001)

provided further evidence for a task-negative system that was finally described as the default

mode network by Raichle et al. (2001). The main components of this circuit are shown

schematically in Figure 3. The circuit consists of strongly connected hubs (red) and more weakly

(blue) integrated associated areas. Both an anterior and a posterior subsystem can be detected

depending on the method of analysis and the structure of the data (Mantini et al., 2007, Calhoun

et al., 2008, Damoiseaux et al., 2008). The anterior default mode network is composed of the

ventromedial and dorsomedial prefrontal cortices (vMPFC, dMPFC), including the orbitofrontal

and anterior cingulate cortices, as well as the precuneus (Prec). The precuneus (Prec), the

posterior cingulate (PCC), the retrospenial cortex (rspC), the inferior parietal lobule (IPL), the

temporal cortex and the hippocampal formation, including the parahippocampus (HF+),

represent the posterior part of the default mode network. Whenever the organism focuses on its

own inner status, the default mode network shows enhanced activation (Gusnard et al., 2001,

D'Argembeau et al., 2005, Kong et al., 2006, Buckner and Carroll, 2007, Schneider et al., 2008,

Otti et al., 2010).

Figure 3: Default Mode Network (Otti et al., 2012).

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 1. Introduction

1.6 Parameters for the description of brain function

Taken together, the following termini are relevant to describe the brains functional architecture

during rest and stimulation by functional magnetic resonance imaging:

1. The terminus activation describes the extent of neural activity in brain regions during

specific conditions, i.e. the level of excitation and inhibition.

2. As described above, the brain shows endogenous low-frequency oscillations in neural activity

even during a resting state. However, different brain regions can have differences in the time-

courses of the fluctuations in neural activity. Significant functional connectivity between

different brain regions represents a significant correlation between the time-courses of the

fluctuations of neural activity, which establish a functional neural network (Calhoun et al., 2001).

3. The power spectra describe the spectrum of the frequencies of the aforementioned neural

oscillations within a network (Garrity et al., 2007, Salvador et al., 2008, Cauda et al., 2009,

Malinen et al., 2010). In the current study, six equally spaced frequency bins were used (0

0.04 Hz; 0.04 0.08 Hz; 0.08 0.12 Hz; 0.12 0.16 Hz; 0.16 0.20 Hz; 0.20 0.24 Hz). The

main advantage of 6 bins compared to larger numbers is that it reduces the number of multiple

comparisons (level of significance p < 0.0083 = 0.05/6; Bonferroni correction for 6 frequency

bins). A lower number of bins, however, might have led to false-negative results as the spectral

changes are rapid as a function of frequency.

4. Recently, functional network connectivity has gained attention. This parameter reflects the

functional interaction between networks (Jafri et al., 2008).

5. All the aforementioned termini can be summarised as

activity.

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 1. Introduction

1.7 Functional magnetic resonance imaging and electrophysiology

How does functional magnetic resonance imaging directly visualize neural activity? The succinct

answer is that it does not! It leads to images of physiological reactions of the brain that are

correlated with neuronal activation. The key-concept of functional magnetic resonance imaging

is: enhanced activity of neurons increases their metabolic requirements in form of a higher

oxygen-extraction which leads, in turn, to an increased blood flow. Oxygenated and

deoxygenated hemoglobin show different magnetic susceptibilities (Pauling and Coryell, 1936).

Functional magnetic resonance imaging measures changes of the concentration of

deoxgenated hemoglobin which indicates the oxygen consumption within a brain region.

Therefore, the signal from the scanner does not directly reflect neural activation but an

epiphenomenon the blood-oxygen-level dependent effect (Ogawa and Lee, 1990, Ogawa et

al., 1990, Heeger and Ress, 2002).

In a hallmark-report, Logothetis et al. (2001) simultaneously recorded functional magnetic

resonance imaging data and electrophysiological activity from the visual cortex of anesthetized

monkeys. Three types of electrophysiological data were obtained: single-unit activity (spiking

of a single neuron close to the electrode), multi-unit activity (firing rate of smalls groups of

neurons) and local field potentials (summations of excitatory/inhibitory postsynaptic potentials

as well as dendritic after-hyperpolarizations and intrinsic membrane oscillations). Especially the

local field potentials - and to a less extent also the single- and multi-unit recording - can predict

the signal change of the blood-oxygen-levels (Logothetis, 2003). The amplitude and timing of

the functional magnetic resonance imaging signal is related to the local field potential power

(Magri et al., 2012). As shown by Goense and Logothetis (2008) in awake monkeys, a

hemodynamic response can even be detected in cases when action potentials are completely

absent (for similiar effects see Viswanathan and Freeman, 2007, Rauch et al., 2008). There is a

strong correlation between the local field potential and the functional magnetic resonance

imaging signal also in human beings as shown by Huettel et al. (2004) in nine patients who had

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 1. Introduction

indwelling subdural electrodes as part of presurgical testing. These findings support the idea

that the functional magnetic resonance imaging signal correlates strongly, in many cases, with

the underlying local field potential (Huettel et al., 2004, Kayser et al., 2004, Ureshi et al., 2004,

Niessing et al., 2005, Shmuel et al., 2006, Devor et al., 2007, Masamoto et al., 2008). Some

studies note exceptions to the idea, that the functional magnetic resonance imaging signal

typically represents local field potentials, and report strong correlations between blood-oxygen-

levels and action potentials (Rees et al., 2000, Kim et al., 2004, Mukamel et al., 2005, Nir et al.,

2007, Burns et al., 2010, Bartolo et al., 2011). However, the association between action

potentials and local field potentials is dependent on the input into a region due to the

heterogeneous nature of the local field potential. Thus, hemodynamic responses and spike rate

correlations cannot typically be assumed (Ekstrom, 2010). Furthermore, it might be dependent

of the task if action potentials or local field potentials are stronger correlated with the functional

magnetic resonance imaging signal (Burns et al., 2010, Bartolo et al., 2011). Taken together,

these data suggest a significant link between the blood-oxygen-levels and neural activation.

There is also accumulating experimental evidence for an electrophysiological equivalent of the

endogenous fluctuations of the functional magnetic resonance imaging signal during a resting

state. As shown recently by Thompson et al. (2013) and Pan et al. (2013), infra-slow local field

potentials (<0.5 Hz) have a high spatial and temporal coherence with the endogenous changes

of the blood-oxygen-levels. Furthermore, the delta- and gamma frequencies of the local field

potentials in the rat-brain seem to be related to spontaneous hemodynamic changes (Pan et al.,

2011, Magri et al., 2012). Functional connectivity between different brain regions during rest is

associated with the low-frequency oscillations of the local field potential (<20 Hz) (Wang et al.,

2012). Shmuel and Leopold (2008) found that fluctuations in the hemodynamic response in

widespread areas in visual cortex were significantly correlated with neuronal activity from a

single recording site in the visual area 1. They argue that functional connectivity in the resting

state can be linked to synchronization of slow oscillations in the underlying neuronal signals.

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 1. Introduction

(However, please note that Logothetis et al. (2009) reanalyzed the data of Shmuel and Leopold

(2008) and argue that their results are not due to functional connectivity but local differences in

vascularisation).

Resting state networks have a unique electrophysiological signature. Mantini et al. (2007)

combined functional magnetic resonance imaging with electroencephalography and

demonstrated that the default mode network is associated with a strong beta- and gamma-

activity, whereas the contribution of alpha-activity is low. The sensorimotor network shows a

high beta-activity but relatively low contribution of theta-activity. (For further studies see Cannon

and Baldwin, 2012, Yuan et al., 2012, Chang et al., 2013, Fahoum et al., 2013, Mayhew et al.,

2013, Nasrallah et al., 2013, Wong et al., 2013).

Another important aspect of the principle of functional magnetic resonance imaging is the

association between neural activity and changes in the vascular system. Neural activity changes

the diameter of arterioles significantly (Ngai et al., 1995, Iadecola, 1998, Attwell and Iadecola,

2002, Iadecola, 2002). However, the neurovascular coupling also puts limits on the spatial

specificity of the functional magnetic resonance signal because arteriolar dilatation and

increased blood flow can also be detected some millimetres distant to the peak of neuronal

activity. Here the question arises if there are others factors besides neural activity that influence

the functional magnetic resonance imaging signal. There are specific regions in the midbrain

that broadly project dopaminergic fibers to small arterioles that can modulate the local flow

pattern (Krimer et al., 1998). Furthermore, astrocytes seem to play an important role. Using tow-

photon imaging, Takano et al. (2006) showed that a release of calcium-ions from glial cells

leads to a significant vasodilatation which might influence functional magnetic resonance

imaging measurements (for review of glial effects on cerebral blood flow see Attwell et al.,

2010).

The aforementioned studies suggest that neural activity is correlated with the functional

magnetic resonance signal. Furthermore, there is electrophysiological evidence that functional

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 1. Introduction

magnetic resonance imaging measures slow-frequency fluctuations of neural activity and

functional connectivity between remote brain regions during a resting state. However, the exact

physiological source of the resting state signal is still unknown and it remains unclear to which

extent the hemodynamic response is influenced by other factors besides neural activity.

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 2. Aim

2. Aim

The studies presented here provide neurobiological evidence for the hypothesis that

somatoform pain reflects a central dysfunction in neural circuits dedicated to emotional

processing. Functional magnetic resonance imaging is chosen for these studies as this method

visualises brain networks in vivo with a high spatial resolution and does not require the

application of contrast agents. The patients and controls participating in the current studies are

clinically and psychometrically characterised by instruments such as the Structured Clinical

Interview for DSM Disorders (Wittchen et al., 1997, APA, 2000), SF-36 (McHorney et al., 1993,

Bullinger, 1995, Keller et al., 1998, Alonso et al., 2004), PHQ-15 (Kroenke et al., 2002, Kroenke

et al., 2010), the Wisconsin Brief Pain Questionnaire, (Cleeland and Ryan, 1994), the Beck

Depression Inventory I (Hautzinger, 1991, Heinz et al., 2007), and the Trait Anxiety Inventory

(Laux et al., 1981).

Study I tests whether somatoform pain is associated with altered neural activation during

empathy for pain, a specific and evolutionary fundamental emotional behavioural trait used in

everyday social interactions. Using an established picture paradigm (Jackson et al., 2006), I

hypothesise that somatoform pain is associated with diminished activation of the core regions of

empathic processing, such as the anterior cingulate cortex and the insula, while observing

another persons pain.

The objective of Study II is to test whether somatoform pain is associated with alterations in the

spatial and temporal domains of pain-related resting state networks. Intrinsic (resting state)

activity is approximately 30 times higher than the extrinsically motivated activity (Sokoloff et al.,

1955, Fox et al., 2005). Highly organised in resting state networks, the brains dark energy

(Zhang and Raichle, 2010) appears without external stimulation and may play an important role

for the development of chronic pain. Given the lack of a peripheral organic pathology, the

question arises whether the brain is producing patterns of neural activity that are associated

with somatoform pain. Specifically, I hypothesise that patients suffering from somatoform pain

17
 2. Aim

show altered frequencies of the spontaneous oscillations (power spectra) of neural activity

within pain-related networks, such as the anterior and posterior default mode network, the

cingular-insular (i.e. fronto-insular) network, and the sensorimotor network. Furthermore, I

postulate that somatoform pain is related to changes in the functional connectivity within these

networks. Herein, independent component analysis, a new data-driven approach, is used for the

analysis of brain networks (Calhoun et al., 2001, Calhoun et al., 2008). The main advantage of

this method is that it requires no a priori assumptions of the intrinsic structure of the data. Its

high reliability is remarkable as iterative techniques are based on multiple computational

processes that statistically lead to a high variance (Zuo et al., 2010). Moreover, the number of

independent components is based on a mere statistical estimation and not on

neurophysiological hypotheses (Cole et al., 2010).

Study III expands upon functional network connectivity, a new approach for testing one

important facet of the resting state network model to examine the intrinsic functional connectivity

between networks active during the resting state. As shown recently in individuals with

schizophrenia, differences in inter-network communication in regards to functional network

connectivity could be a valid measure reflecting cortical-processing deficits in patients with

chronic psychiatric symptoms. Therefore, I aim to test the practical relevance of functional

network connectivity for chronic, medically unexplained pain (Jafri et al., 2008). Specifically,

given a disconnection of pain-related neural systems, I hypothesise that alterations exist in the

functional network connectivity between the anterior and posterior default mode network, the

cingular-insular (i.e. fronto-insular) network and the default mode network in patients with

somatoform pain disorder.

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 2. Aim

All three of the studies were published in peer-reviewed journals:

Study I:

Noll-Hussong et al. Neural correlates of deficits in pain-related affective meaning construction in

patients with chronic pain disorder. Psychosomatic Medicine. 2013; 75(2):124-36.

Study II:

Otti et al. Frequency shifts in the anterior default mode network and the salience network in

chronic pain disorder. BMC Psychiatry. 2013; 13:84.

Study III:

Otti et al. Functional network connectivity of pain-related resting state networks in somatoform

pain disorder an exploratory fMRI study. Journal of Psychiatry and Neuroscience. 2013;

38(1):57-65.

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 3. Study I

3. Study I - Neural correlates of deficits in pain-related affective meaning construction in

patients with chronic pain disorder

Published in Psychosomatic Medicine. 2013; 75 (2):124-36.

The aim of this study is to investigate the effect of impaired affective regulation in somatoform

pain disorder. To test this, I focus on empathy for pain, a fundamental affective behavioural trait.

Twenty-one patients suffering from somatoform pain disorder and 19 healthy controls are

enrolled in the study. (These participants are also used in Study II and Study III). During

functional magnetic resonance imaging, participants are presented with pictures depicting

human hands and feet in different painful and nonpainful situations and asked to estimate the

perceived pain intensity. The healthy controls show significantly higher activation of the left

perigenual anterior cingulate cortex and a trend toward higher subjective pain ratings than the

patients. The neuroimaging results are not influenced by the scores on the self-assessment

instruments (Beck Depression Inventory I, Interpersonal Reactivity Index, and 20-item Toronto

Alexithymia Scale). These findings suggest that altered central pain perception is due to a

decreased neural response in affective cerebral systems, which I interpret as a deficit in pain-

related affective meaning construction. Furthermore, these results highlight the neurobiological

effect of chronic pain on every day social life.

For this study, I independently analysed both the behavioural data and the imaging data

Furthermore, I recruited the participants with Dr. med. M. Noll-Hussong, and scanned

participants with Dr. rer. nat. A. Wohlschlger and Dr. M. Noll-Hussong. Prof. Dr. C. Zimmer,

Prof. Dr. P. Henningsen, PD Dr. C. Lahmann, Dr. J. Ronel, Dr. C. Subic-Wrana, Prof. Dr. J.

Decety, Prof. Dr. R. Lane, Prof. Dr. H. Gndel, and Dr. M. Noll-Hussong were responsible for

the research design.

20
 4. Study II

4. Study II - Frequency shifts in the anterior default mode network and the salience

network in chronic pain disorder

Published in BMC Psychiatry. 2013; 13:84.

The aim of this study is to test whether somatoform pain is associated with changes in spatial

and temporal properties of endogenous patterns of activity in pain-related neural networks

during the resting state. Twenty-one clinically and psychometrically well-characterised patients

who suffered from chronic pain disorder and 19 age- and healthy controls undergo 3-Tesla-

functional magnetic resonance imaging. (These participants are also used in Study I and Study

III). All neuroimaging data are analysed using independent component analysis including power

spectra analysis. In patients suffering from chronic pain disorder, the fronto-insular salience

network (i.e. cingular-insular network) and the anterior default mode network, which comprises

the prefrontal cortex and precuneus, oscillate predominantly at higher frequencies (0.20 - 0.24

Hz). No significant differences in power spectra are observed in the posterior default mode

network, which consists of the precuneus as well as lateral parietal regions, and the

sensorimotor network. No significant changes are observed in the spatial functional connectivity

of the networks. These results indicate that chronic pain disorder may be a self-sustaining and

endogenous mental process that affects temporal organisation by causing a frequency shift in

the dynamic rhythm of cortical networks associated with emotional homeostasis.

For this study, I independently analysed both the behavioural data and the imaging data using

new data-driven techniques. Furthermore, together with Dr. M. Noll-Hussong, I recruited the

participants. Together with Dr. A. Wohlschlger and Dr. M. Noll-Hussong, I scanned

participants. Prof. Dr. C. Zimmer and Prof. Dr. H. Gndel were responsible for the research

design.

21
 5. Study III

5. Study III - Functional network connectivity of pain-related resting state networks in

somatoform pain disorder: an exploratory fMRI study

Published in Journal of Psychiatry and Neuroscience. 2013; 38 (1):57-65.

Whereas Study II is focused on intra-network activity, the purpose of Study III is to visualise the

interplay between functional networks in healthy individuals and patients with somatoform pain

disorder. I compare 21 patients suffering from somatoform pain and 19 healthy controls using 3-

Tesla-functional magnetic resonance imaging. (These participants are also used in Study I and

Study II). All neuroimaging data are analysed using independent component analysis.

Significant functional network connectivity is detected between the cingular-insular network (i.e.

fronto-insular network) and the sensorimotor/anterior default mode network, between the

anterior default mode network and the posterior default mode network/sensorimotor network,

and between the posterior default mode network and the sensorimotor network. Interestingly, no

group differences in functional network connectivity are seen. To my knowledge, these findings

are the first to demonstrate resting functional network connectivity among pain-related intrinsic

connectivity networks. However, these results suggest that functional network connectivity alone

is not sufficient to describe the putative central dysfunction underpinning somatoform pain

disorder.

For this study, I independently analysed both the behavioural data and the imaging data using

new data-driven techniques. Furthermore, together with Dr. M. Noll-Hussong, I recruited the

participants. Together with Dr. A. Wohlschlger and Dr. M. Noll-Hussong, I scanned

participants. Prof. Dr. C. Zimmer, Prof. Dr. P. Henningsen, Prof. Dr. H. Gndel, and Dr. M. Noll-

Hussong were responsible for the research design.

22
 6. Discussion

6. Discussion

Chronic somatoform pain is a severe psychosomatic disease currently diagnosed by exclusion.

My thesis addresses this issue and aims to visualise the neural substrates of somatoform pain

disorder. First, using the example of empathy for pain, I address the question of whether

neurobiological evidence exists for difficulties in accessing ones own or others emotions.

Second, I test whether chronic pain without a significant peripheral organic correlate reflects a

specific pattern of endogenous neural activity during a resting state without external stimulation.

A reasonably sized group of clinically well-classified patients and healthy controls undergo

functional magnetic resonance tomography. In contrast to other techniques, such as positron

emission tomography, functional magnetic resonance imaging is a non-invasive method that

visualises brain function with high spatial resolution and without the application of radioactive

tracers.

While empathizing with pain of another person, patients exhibit a significantly lower activation of

the left perigenual anterior cingulate cortex. Furthermore, they show a trend to perceive

anothers pain as less intense compared to healthy controls. Moreover, patients have less

empathy and more difficulties in describing their feelings. These findings suggest that

somatoform pain is associated with an impaired access to ones own and others emotions as

the perigenual anterior cingulate cortex plays a role in processing affective information. This role

includes assigning emotional valence to internal and external stimuli and conditioned emotional

learning, regulating autonomic and endocrine functions, and assessing motivation and empathy

for pain (Vogt et al., 1992, Devinsky et al., 1995, Whalen et al., 1998, Roy et al., 2012).

Furthermore, the perigenual anterior cingulate cortex was found to be involved in the processing

of both somatic (Derbyshire et al., 1997, Lorenz et al., 2003, Lui et al., 2008) and visceral pain

(Aziz et al., 2000, Fan et al., 2009). Vogt et al. suggested that the activation of the perigenual

anterior cingulate cortex may be involved in affective responses to noxious stimuli, such as the

suffering associated with pain (Vogt et al., 1996). Frewen and colleagues observed a correlation

23
 6. Discussion

between activation of the perigenual anterior cingulate cortex and emotional awareness in

healthy subjects during recall of traumatic experiences (Frewen et al., 2008). Interestingly, this

region is also functionally related to the onset of uncertainty of impending, externally applied

thermal stimuli at noxious and non-noxious temperatures (Mohr et al., 2005). In summary, the

perigenual anterior cingulate cortex is integral for the construction and deployment of affective

meaning (Roy et al., 2012), which may be disturbed in somatoform pain disorder.

In contrast to the control subjects, somatoform pain patients are subjectively accustomed to the

sensory experience of lasting pain, i.e., they are certain that they will feel persistent pain. Thus, I

suggest that in the healthy controls, the experience of pain induced by the visual pain paradigm

may be more surprising and, thus, a more intense and differentiable experience, resulting in a

higher activation of the perigenual anterior cingulate cortex and a trend corresponding with a

higher pain intensity rating. One may speculate that a type of habituation is present in chronic

pain patients in the affective dimension of the painful experience that is isolated in this study

using the visual pain paradigm. Against this background, the prolonged activation of pain-

processing areas could potentially diminish stimulus-evoked responses in those areas and thus

explain the finding that chronic pain patients exhibit a lower activation of the perigenual anterior

cingulate cortex than pain-free controls (Rennefeld et al., 2010).

Furthermore, the functional architecture of the resting state is investigated in this thesis. Neural

activity within the fronto-insular network (i. e. cingular-insular network) and the anterior default

mode network shows significantly shifted frequencies in patients suffering from somatoform pain

disorder compared with healthy controls. Specifically, there is a general trend towards higher

spectral power in the 0.20-0.24 kHz frequency bin in patients versus control subjects. However,

no significant group differences in spectral power are detected in the sensorimotor network and

the posterior default mode network. Although the current study cannot provide causation,

several aspects suggest there is a strong relationship between the pain condition and altered

patterns of endogenous neural activity during the resting state. The cingular-insular network (i.e.

24
 6. Discussion

fronto-insular network) and the anterior default mode network instantiate affective and

introspective neuroprocessing (Gusnard et al., 2001, D'Argembeau et al., 2005, Buckner and

Carroll, 2007, Mantini et al., 2007, Seeley et al., 2007, Otti et al., 2010). In addition to the

activation detected during empathy for pain, these findings could reflect a neurobiological

rationale for the strong impression of clinicians that patients who suffer from somatoform pain

often show disturbed affective processing in terms of reduced subjective emotional awareness

and impaired social understanding (Subic-Wrana et al., 2010). Furthermore, somatoform pain is

associated with higher autonomic arousal (Thieme et al., 2006, Stoeter et al., 2007), which, in

turn, has been associated with increased activation in the cingulate cortex, the insula, and

medial prefrontal regions (Querleux et al., 2008, Cauda et al., 2009). Moreover, the various

bodily complaints in patients with somatoform pain have consistently been associated with a

high affective component of individual pain, which indicates impaired emotional regulation

(Burba et al., 2006, Kirmayer and Looper, 2006, Waller and Scheidt, 2006, Verkuil et al., 2007).

The fact that no differences were previously observed in the sensorimotor network underlying

sensory-discriminative processing (Biswal et al., 1995) supports this idea that somatoform pain

is especially related to emotional processing. Furthermore, these results expand the findings of

Malinen et al. (2010) and Cauda et al. (2009), who found similar alterations of power spectra in

chronic pain associated with various organic diseases, such as diabetic neuropathic pain or

phantom limb pain. Interestingly, as shown by the current study, peripheral organic correlates

do not seem to be necessary for these changes in the neurobiology of the brain.

In contrast to Malinen et al. (2010), who reported weaker functional connectivity between the

insula and anterior cingulate cortex in predominantly nociceptive chronic pain, and Baliki et al.

(2008), who found diminished default mode network connectivity in chronic back pain patients, I

do not find changes in spatial functional connectivity. In contrast to chronic pain caused by

diverse peripheral causes, I presume that somatoform pain, which cannot be explained fully by

25
 6. Discussion

nociceptive input, is not associated with changes in the spatial domain of the functional

architecture of the brains resting state.

In contrast to our hypothesis, the current studies show that persistent non-nociceptive pain does

not lead to changes in functional network connectivity among pain-associated networks during a

resting state. In patients and healthy controls, significant functional network connectivity is

observed between the cingular-insular network (i.e. fronto-insular network) and sensorimotor

network/anterior default mode network, the anterior default mode network and the posterior

default mode network/sensorimotor network, and the posterior default mode network and the

sensorimotor network. The sensorimotor network strongly interacts with the cingular-insular (or

fronto-insular) network, the anterior default mode network, and the posterior default mode

network. These results suggest that functional network connectivity signatures alone are not

sufficient for characterisation of the putative central dysfunction underlying somatoform pain

disorder.

However, to my knowledge, this is the first demonstration of the intrinsic interconnection of pain-

related connectivity networks in healthy controls at resting state. These interactions again

suggest that sensory-discriminative processing is highly related to affective processing, self-

referential thoughts and memory functions. Furthermore, the timing of the sensorimotor network

is offset from the other intrinsic connectivity networks by some seconds. Emotional and

cognitive processing seems to precede the activity of the sensorimotor system during a resting

state. This result might explain the influence of the inner world with its various subjective states,

such as anxiety, sadness and individual predictions about the future, on the perception of the

outer world via sensory systems (Bar, 2009, Coen et al., 2011, Vancleef and Peters, 2011).

Because the current analysis does not provide insight into causality, these results encourage

further research on putative effects of activity within the default mode network and cingular-

insular (or fronto-insular) network on the sensorimotor network.

26
 6. Discussion

There is no significant correlation between the imaging data and anxiety (Ochsner et al., 2006),

depression (Henningsen et al., 2003, Muller et al., 2008, Hanel et al., 2009) or pain intensity in

the patient group of the current studies. Importantly, a similar discrepancy between activation

detected by functional magnetic resonance imaging and behavioural measurements was also

described in a study investigating the altered cerebral response to noxious heat stimulation in

patients with somatoform pain disorder (Gundel et al., 2008). Thus, differences between

patients and controls may be more easily detected via neuroimaging methods than through

subjective behavioural ratings, in accordance with several other studies (Smolka et al., 2005,

Silani et al., 2008, Bird et al., 2010, Noll-Hussong et al., 2010). As a whole, the results of the

studies presented in this thesis seem to correspond with some of the clinically relevant

emotional challenges confronting patients and their social networks, such as their family and

physicians.

The present study is limited due to the lack of measurements of possible sources of

physiological artefacts such as respiration, cardiac function or blood pressure. However, in the

agreement with previous findings, the current results are unlikely to be confounded by these

factors (Cauda et al., 2009, Malinen et al., 2010). Furthermore, functional magnetic resonance

imaging relies on the measurement of signals dependent on blood oxygen levels, from which

conclusions about neural activity are drawn. However, it is still under debate whether this

epiphenomenon is also influenced by other cerebral processes, such as activity-independent

changes of the concentration of fast neurotransmitters (Attwell and Iadecola, 2002, Logothetis,

2008). One important limitation of the current studies is medication. More than half of the

patients are undergoing treatment with antidepressants and analgesics. The effect of

medication of the blood-oxygen-level-dependent effect is poorly understood. It is of note that

despite ethical reasons, it is nearly impossible to convince the somatoform pain patients to

interrupt their (psychotropic) medication in this intentionally naturalistic study.

27
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36
 8. List of publications

8. List of publications

8.1 Publications that are part of this thesis (see attachment)

Neural correlates of deficits in pain-related affective meaning construction in patients with

chronic pain disorder

Michael Noll-Hussong, Otti A, Wohlschlaeger A. M., Zimmer C, Henningsen P, Lahmann C,

Ronel J, Subic-Wrana C, Lane RD, Decety J, Guendel H.

Psychosomatic Medicine. 2013 Feb; 75 (2):124-36. Epub 2013 Jan 29.

Frequency shifts in the anterior default mode network and the salience network in chronic pain

disorder.

Alexander Otti, Harald Guendel, Afra M. Wohlschlaeger, Claus Zimmer, Micheal Noll-Hussong.

BMC Psychiatry. 2013 Mar 13;13:84.

Functional network connectivity of pain-related resting state networks in somatoform pain

disorder an exploratory fMRI study

Alexander Otti, Harald Guendel, Peter Henningsen, Claus Zimmer, Afra M. Wohlschlaeger,

Michael Noll-Hussong.

Journal of Psychiatry and Neuroscience. 2013 Jan; 38(1):57-65.

37
 8. List of publications

8.2 Other publications

Aftermath of sexual abuse history on adult patients suffering from chronic functional pain

syndromes: an fMRI pilot study.

Noll-Hussong M, Otti A, Laeer L, Wohlschlaeger A, Zimmer C, Lahmann C, Henningsen P,

Toelle T, Guendel H. Journal of Psychosomatic Research. 2010 May; 68(5):483-7. Epub 2010

Mar 16.

I know the pain you feel-how the human brain's default mode predicts our resonance to

another's suffering.

Otti A, Guendel H, Ler L, Wohlschlaeger AM, Lane RD, Decety J, Zimmer C, Henningsen P,

Noll-Hussong M. Neuroscience. 2010 Aug 11;169(1):143-8. Epub 2010 May 5.

Acupuncture-Induced Pain Relief and the Human Brains Default Mode Network - An Extended

View of Central Effects of Acupuncture Analgesia

Otti A and Noll-Hussong M. Research in Complementary Medicine (Forschende

Komplementrmedizin). 2012; 19(4):197-201. Epub 2012 Aug 3. Review.

Intrinsic brain activity with pain.

Otti A, Noll-Hussong M. Schmerz. 2011 Sep; 25(5):501-7. Review. German.

Default mode network of the brain. Neurobiology and clinical significance.

Otti A, Gndel H, Wohlschlger A, Zimmer C, Sorg C, Noll-Hussong M. Nervenarzt. 2012 Jan;

83(1):16, 18-24. Review. German.

38
 9. Acknowledgements

9. Acknowledgements

I would like to extend warm thanks to Prof. Dr. Claus Zimmer (Abteilung fr Neuroradiologie,

Klinikum rechts der Isar, Technische Universitt Mnchen), Prof. Dr. Peter Henningsen (Klinik

fr Psychosomatische Medizin und Psychotherapie, Klinikum rechts der Isar, Technische

Universitt Mnchen) and Prof. Dr. Harald Gndel (Universittsklinik fr Psychosomatische

Medizin und Psychotherapie, Universittsklinikum Ulm) for their scientific mentorship and the

opportunity to perform highly innovative research using the most advanced experimental

techniques.

I am especially grateful to Dr. M. Noll Hussong (Universittsklinik fr Psychosomatische Medizin

und Psychotherapie, Universittsklinikum Ulm) for the very good atmosphere of scientific

cooperation. I will never forget his kind and constructive academic support. I attribute this to why

we never lost our sense of humour even during challenging periods of our research.

I would like to thank Dr. A. Wohlschlger and Dr. L. Ler (Abteilung fr Neuroradiologie,

Klinikum rechts der Isar, Technische Universitt Mnchen) for their support, for teaching me the

background of functional magnetic resonance imaging and various modern data-analysis

techniques.

Personally, I would also express my gratitude to my friend and colleague M. Mailnder for our

thrilling and controversial academic discussions. Though sometimes intimidating, his keen

intellect helped me to never lose my faith in the supreme power of the human spirit.

The project was supported by the Komitee fr klinische Forschung (KKF).

39
 Study I

Neural correlates of deficits in

pain-related affective meaning construction

in patients with chronic pain disorder

Published in

Psychosomatic Medicine. 2013; 75 (2):124-36.

Promotional and commercial use of the material in print, digital or mobile- device format is
prohibited without the permission from the publisher Lippincott Williams & Wilkins.

Please contact [email protected] for further information.

Lippincott Williams & Wilkins, the editors and authors and their respective employees are not
responsible or liable for the use of any such inaccurate or misleading data, opinion or
information contained in the adapted version of figure.
SPECIAL SERIES ON NEUROSCIENCE
IN HEALTH AND DISEASE

Neural Correlates of Deficits in Pain-Related Affective Meaning Construction in

Patients With Chronic Pain Disorder
MICHAEL NOLL-HUSSONG, MD, ALEXANDER OTTI, AFRA M. WOHLSCHLAEGER, PHD, CLAUS ZIMMER, MD, PETER HENNINGSEN, MD,
CLAAS LAHMANN, MD, JORAM RONEL, MD, CLAUDIA SUBIC-WRANA, PHD, RICHARD D. LANE, MD, PHD, JEAN DECETY, PHD,
AND HARALD GUENDEL, MD

Objective: Psychological and neural mechanisms of the affective dimension of pain are known to be disturbed in patients with chronic
pain disorder. The aim of this functional magnetic resonance imaging study was to assess the neurofunctional and behavioral measures
underlying the ability to construct pain-related affective meaning in a painful situation by comparing 21 clinically and psychometrically
well-characterized patients with persistent non-nociceptive somatoform pain with 19 healthy controls. Methods: The functional
magnetic resonance imaging task involved viewing pictures depicting human hands and feet in different painful and nonpainful
situations. Participants were asked to estimate the perceived pain intensity. These data were correlated with behavioral measures of
depression, alexithymia, and general cognitive and emotional empathy. Results: In a hypothesis-driven region-of-interest analysis, the
healthy control group exhibited greater activation of the left perigenual anterior cingulate cortex than patients with pain (Montreal
Neurological Institute coordinates (x y z) = j8 38 0; cluster extent = 54 voxels; T = 4.28; p = .006 corrected for multiple comparisons at
cluster level). No group differences in the activation of the anterior insular cortex were found. Scores on self-assessment instruments
(Beck Depression Inventory I, Interpersonal Reactivity Index, and 20-item Toronto Alexithymia Scale) did not influence neuroimaging
results. Conclusions: Our results suggest that patients with chronic medically unexplained pain have an altered neural pain perception
process owing to decreased activation of empathetic-affective networks, which we interpret as a deficit in pain-related affective
meaning construction. These findings may lead to a more specific and detailed neurobiological understanding of the clinical impression
of disturbed affect in patients with chronic pain disorder. Key words: pain disorder, somatoform pain disorder, affective meaning,
empathy, affective neuroscience, functional magnetic resonance imaging.

ACC = anterior cingulate cortex; BDI-I = Beck Depression Inventory somatoform pain disorder often have difficulties realizing and
I; BOLD = blood oxygenation levelYdependent; BPI = Brief Pain interpreting emotional signals within themselves and perceive
Inventory; CIP = congenital insensitivity to pain; fMRI = functional these signals as mere physical sensations (8)Va phenomenon
magnetic resonance imaging; pACC = perigenual ACC; ROI = region that has been conceptualized as alexithymia (9). More specifi-
of interest; SCID-I = Structured Clinical Interview for DSM Disorders;
cally, patients with somatoform disorders (and/or functional so-
SD = standard deviation; SMA = supplementary motor area.
matic syndromes (10)) often show reduced subjective emotional
awareness of feelings compared with patients with other psy-
INTRODUCTION chiatric diagnoses (11,12), thus experiencing emotional distress

P ain perception involves psychological (1) and neural

mechanisms that represent the affective meaning (2) or di-
mension (3) of this homeostatic emotion (4). For sensory pain,
somatically (11Y14) as bodily distress syndrome (15). Patients
with somatoform disorders often are not aware of and do not
understand their own or others emotional states (16Y19); from a
heightened pain perception has been found in patients with neurointegrative point of view, it has been suggested that (among
somatoform pain disorder (5). These patients are characterized other mental disorders) clinical chronic pain (20) might be ex-
by ongoing pain suggesting physical illness and injury symptoms acerbated by a reduced capacity to appropriately assign affective
that cannot be fully explained by a general medical condition, the meaning to sensory and internal cues (21). Accordingly, there
direct effect of a substance, or another mental disorder (6). There are hints that a lack of emotional awareness (difficulty identi-
is often a persistent refusal to acceptVexcept for short periods fying feelings of oneself and others) is associated with low back
during or immediately after medical investigationVthe medical pain (22). Biologically, this specific mind-body discrepancy
conclusion that there is no adequate physical cause for the (23Y26) seems to reflect a neural imbalance between sensory-
physical symptoms of these patients (7). Individuals with discriminative, affective (27), cognitive, executive, vegetative,
and introspective functions, and emotional empathy (i.e., sharing
of others emotions in social contexts; for details, see de Greck
From the Klinik fuer Psychosomatische Medizin und Psychotherapie (M.N.- et al. (16) and Parr et al. (28)), andVat a higher levelVin the
H., H.G.), Universitaetsklinikum Ulm, University of Ulm, Ulm; Abteilung fuer
Neuroradiologie (A.O., A.M.W., C.Z.) and Klinik fuer Psychosomatische construction of conceptual information in the ventromedial pre-
Medizin und Psychotherapie (A.O., P.H., C.L., J.R.), Klinikum rechts der Isar, frontal cortex that drives affective, physiological, and behavioral
Technische Universitaet Muenchen, Muenchen; and Klinik fuer Psychosoma- responses (21) within this mental disorder (13,18,29,30).
tische Medizin und Psychotherapie (C.S.-W.), Johannes Gutenberg-Universitaet
Mainz, Mainz, Germany; and Department of Psychiatry (R.D.L.), The Uni- Remarkably, it has recently been demonstrated that the ob-
versity of Arizona, Tucson, Arizona; and Departments of Psychology (J.D.) and servation of body parts in painful situations even results in a
Psychiatry and Behavioral Neuroscience (J.D.), The University of Chicago, pain networkYassociated blood oxygenation levelYdependent
Chicago, Illinois.
Address correspondence and reprint requests to Michael Noll-Hussong, MD, (BOLD) activation pattern in patients with congenital insensi-
Clinic for Psychosomatic Medicine, University of Ulm, Albert Einstein Allee tivity to pain (CIP; i.e., patients who cannot refer to their own
23, D-89081 Ulm, Germany. E-mail: [email protected] nociceptive experience of pain to understand how the pain
Received for publication September 19, 2011; revision received October 4,
2012. of others feels) (31). Interestingly, the behaviors of patients with
DOI: 10.1097/PSY.0b013e31827e60f3 CIP did not differ significantly in self-rated empathy from the

124 Psychosomatic Medicine 75:124Y136 (2013)

0033-3174/13/7502Y0124
Copyright * 2013 by the American Psychosomatic Society

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AFFECTIVE MEANING IN CHRONIC PAIN DISORDER

behaviors of the control participants. With reference to patients orders is the repeated presentation of physical symptoms together with per-
with CIP who have never experienced nociceptive pain, one sistent requests for medical examinations despite repeated negative findings
and reassurances by doctors that the symptoms have no physical basis. If
could question whetherVand, if so, whichVneural circuits are any physical disorders are present, the disorders do not explain the nature
activated in patients on the other end of the non-nociceptive pain and extent of the symptoms or the distress and preoccupation of the patient
spectrum (i.e., those with persistent non-nociceptive somatoform (7). Multisomatoform disorder is defined as three or more medically unex-
pain). Thus, how do clinically well-classified patients who plained, currently bothersome physical symptoms plus a long (Q2 years)
history of somatization (32). It has been shown that, compared with mood
exclusively and subjectively perceive their continuing non-
and anxiety disorders, multisomatoform disorder is associated with compa-
nociceptive chronic pain to be a solely physical (sensory) phe- rable impairments in health-related quality of life, more self-reported dis-
nomenon in benign chronic pain disorder (32,33) differ, ability days and clinic visits, and the highest level of provider frustration
both neurobiologically and psychometrically, from healthy con- (32,43), thus covering the clinical reality of patients with complex overlapping
trols with regard to the relative contributions of automatic reso- diagnoses (44).
nance and perspective taking to understanding their own and In this context, as first precondition, the physical component summary
measure (45) in our patient group had to be at least 1 SD below the population
others pain? norm (i.e., e40), as measured with the 36-item Short-Form Health Survey
In this study, we adopted a functional magnetic resonance (SF-36), thus meeting the DSM-IV Criterion B for significant distress or
imaging (fMRI) paradigm that has been used in previous psychosocial impairment due to the somatoform pain in patients with pain
studies to evaluate empathy for pain in both healthy individuals disorder (6). As second precondition, the scores for the 15-item Patient Health
(34) and patients with CIP (31) but has not yet been applied to Questionnaire had to be higher than 10, representing medium somatic
symptom severity. The German version of the Brief Pain Inventory (BPI) (46)
patients with persistent pain that has no convincing organic was used to estimate the intensity of the participants pain. Patients with
etiology. Self-assessments were used to collect behavioral insufficient cognitive abilities and severe chronic somatic diseases, unambiguous
measures of depression, alexithymia, and both general cogni- nociceptive pain (e.g., postsurgery pain), hypochondria, posttraumatic stress dis-
tive and emotional empathy. We hypothesized that the ability to order, a severe comorbid mental disorder that causes a major impairment of
imagine how one would feel in a particular painful situation social functioning (e.g., schizophrenia or severe substance abuse), or insufficient
German-language skills were excluded. All participants were white, of white
(sometimes also referred to as pain empathy) is disturbed in origin, and right-handed, as assessed by the Edinburgh Handedness Inventory
patients with chronic pain disorder. Furthermore, we antici- (47). Data were collected from 2006 to 2010.
pated thatVin contrast to feeling the pain directly, such as with
thermal pain experimentsVpatients with ongoing somatoform
pain who are visually confronted with new painful situations Psychometric Instruments
and asked to perform self-perspective (35) are ultimately less The occurrence of somatoform disorders was assessed in a modified
structured psychiatric interview (SCID-I, German version) (48) in accordance
aware of their own emotions than the healthy control popula- with DSM-IV criteria (6). The SCID-I evaluates the patients current (the last
tion. Relatedly, we would suggest that our patients are more 4 weeks before the interview) and lifetime psychiatric status for major Axis I
physically somatosensory oriented than healthy controls, thus psychiatric disorders with criteria corresponding to the DSM-IV.
reflecting a lower differentiation in emotion and a lower The BPI was developed by the Pain Research Group of the World Health
awareness of emotional complexity (12,36). Thus, when com- Organization Collaborating Center for Symptom Evaluation in Cancer Care to
provide information on the intensity of pain (sensory dimension) and the
paring patients with chronic pain disorder with healthy con- degree to which pain interferes with function (reactive dimension). The BPI
trols, we would first expect a disturbance in neural response in a used in this study shows front and back body diagrams, four pain severity
core network consisting of the anterior cingulate cortex (ACC) items, and seven pain interference items rated on 0 to 10 scales, and a question
(37) and the insular cortex, which is associated with emotional on the percentage of pain relief by analgesics during a 24-hour recall period
awareness of and emotional empathy for pain (38,39). Second, (49). The validity of the BPI has been demonstrated in the German version
(46) and in the measure of pain in patients without cancer (50).
we would argue that this disturbance should consequently in- The SF-36 is a by multipurpose short-form health survey with 36 questions
fluence the generation of integrative conceptual information (51) that yields an eight-scale profile of functional health and well-being scores,
that contributes to the construction of affective meaning (21). psychometrically based physical and mental health summary measures, and a
preference-based health utility index. The SF-36 is a generic measure that
METHOD differs from questionnaires targeting a specific age, disease, or treatment group.
This study was approved by the local ethics committee (Klinikum rechts Accordingly, the SF-36 has proven useful in surveys of the general population
der Isar, Medical Faculty of Technische, Universitaet Muenchen, Muenchen, and specific groups when comparing the relative burden of diseases and when
Germany) and performed in accordance with the Declaration of Helsinki. differentiating the health benefits generated by a diverse range of diffe-
rent treatments (52). Its German translation has been validated in a variety of
German healthcare settings (53Y55).
Participants The 15-item Patient Health Questionnaire is a brief self-administered
Participants were 19 healthy controls (12 women) and 21 outpatients (17 questionnaire that has proven useful in screening for somatization and in
women) with German-language skills and chronic pain disorder (operationa- monitoring somatic symptom severity for clinical practice and research pur-
lized as pain-predominant mulisomatoform disorder) (33,40Y42). The mean poses. Scores of 5, 10, and 15 represent cutoff points for low, medium, and
(SD) age was 48.79 (12.25) for the control group and 46.62 (12.49) for the high somatic symptom severity, respectively (56,57).
patient group. All participants provided written informed consent. Pain dis- The intelligence level of participants was assessed with the Multiple Selection
order is a form of somatoform disorder (6). Pain-predominant multisomato- Vocabulary Test (MSVT-B). The MSVT-B, which is an accelerated, objective, and
form disorder, which is a moderately severe somatoform disorder, was primarily reliable test that measures the general level of intelligence, is only insignificantly
diagnosed by an experienced physician who performed a modified Structured influenced by mental disorders (58). The results of the test correlate with the
Clinical Interview for DSM Disorders (SCID-I) using the official criteria for global intelligence quotient in healthy adults and are less sensitive to current
somatoform and chronic pain disorder. The main feature of somatoform dis- disturbances than other tests, such as the Wechsler Adult Intelligence Scale (59).

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To measure the level of alexithymia, which is a state of deficiency in un- was presented for 2 seconds (as in the scanner experiment), followed by a blank
derstanding, processing, or describing emotions (9), each participant completed screen. After 4 seconds, a sound reminded the participants to rate the pain in-
the validated German version (60) of the 20-item Toronto Alexithymia Scale tensity of the picture by pressing the corresponding target button, as rehearsed in
(TAS-20), which uses a five-point Likert response scale (61) and cutoff scoring the training phase. The next picture was shown immediately after a numeric
(e51 = nonalexithymia; 52Y60 = possible alexithymia; Q61 = alexithymia). button had been pressed. The ratings for each stimulus were recorded. If a par-
The German version of the Interpersonal Reactivity Index (IRI) was also used ticipants response time exceeded 4 seconds, an omission error was recorded.
(62). This 28-item self-report questionnaire consists of four scales, each of which The stimuli were presented inside and outside the scanner with the use of a
measures a distinct component of empathy. The four scales include empathic computer running the Presentation software (Neurobehavioral Systems Inc.,
concern (feeling emotional concern for others), perspective taking (ability to Albany, CA; http://www.neurobs.com).
cognitively take the perspective of others), fantasy (emotional identification with
characters in films, books, and so on), and personal distress (tendency to become Data Acquisition and Analysis
anxious when witnessing suffering peoples need for others help). Images were acquired using a 3-T Philips Achieva Scanner (Philips Medical
Beck Depression Inventory I (BDI-I) is a 21-item self-reporting instrument Systems, Best, the Netherlands) with a standard eight-channel SENSE head
that measures cognitive and endogenous aspects of depression on a four-point coil. Thirty-two contiguous slices (no gap) with steep angulation (to exclude the
scale ranging from 0 to 3 (standard cutoffs are as follows: 0Y9 = no depression; eyes) were acquired using a gradient-echo echo-planar sequence with the fol-
10Y18 = mild depression; 19Y29 = moderate depression; 930 = severe de- lowing parameters: repetition time = 2000 milliseconds; echo time = 35 mil-
pression). This questionnaire has undergone extensive reliability and validation liseconds; flip angle = 82-; field of view = 220 mm; slice thickness = 4 mm;
studies (63,64). matrix = 80  80; voxel size = 2.75  2.75 mm; SENSE factor = 2. Anatomical
The German version of the State-Trait Anxiety Inventory (STAI-T) is a valid images were obtained using a T1-weighted turbo gradient-echo sequence with
and reliable 20-item questionnaire that measures the general level of anxiety on the following specifications: repetition time = 9 milliseconds; echo time = 4
four-point scales ranging from 1 to 4 (65). Spielberger states that trait anxiety milliseconds; flip angle = 8-; field of view = 240 mm; matrix = 240  240;
implies differences between people in the disposition to respond to stressful voxel size = 1 mm isotropic; slice = 170; gap = 0.
situations with varying amounts of State-Anxiety. But whether or not people Data analysis was performed using SPM5 (Statistical Parametric Mapping
who differ in Trait-Anxiety will show corresponding differences in State- software; Wellcome Department of Imaging Neuroscience, London, UK; http://
Anxiety depends on the extent to which each of them perceives a specific www.fil.ion.ucl.ac.uk). The first three images of each run were discarded to
situation as psychologically dangerous or threatening, and this is greatly allow longitudinal magnetization to equilibrate. The preprocessing steps in-
influenced by each individuals past experience (66). cluded the following: a) realignment and unwarping of images to correct for
movement artifacts and related susceptibility artifacts; b) coregistration of an-
Visual Stimuli atomical images to functional images; c) segmentation and normalization of
anatomical images to standard stereotactic space (Montreal Neurological In-
The stimuli were previously developed and validated by Jackson et al. (34)
stitute); d) application of normalization transformation to functional images;
through fMRI experiments evaluating empathy, impact of self, and other per-
and e) smoothing with an 8-mm Gaussian kernel for group analysis.
spectives in healthy individuals. The stimuli consisted of a series of photos that
We modeled the conditions as blocks to capture task-related effects. The
show white (67) human feet and hands in various painful and nonpainful
blocks were then convolved with the canonical hemodynamic response func-
situations that occur in everyday life. Pictures were taken from positions im-
tion. For each participant, the images were subjected to fixed-effects analysis.
plying a first-person perspective (i.e., a mental rotation of the limbs by the
Random-effects analysis was performed at the group level.
observer was not required). The 120 stimuli used in this study were selected
For single-group analyses, we applied an a priori threshold of p G .001
from a larger sample and grouped into four levels of pain (no, low, medium, and
uncorrected at the voxel level and p G .05 corrected for multiple comparisons at
high pain, with 30 pictures for each level) based on the pain intensity ratings of
the cluster level. We used a cluster extent threshold of 10 voxels. For group
20 healthy participants (34). Photographs of limbs were smoothed using a
comparison, analysis of variance was performed to test for main effects and
Gaussian filter to avoid any influence related to age and sex.
Group  Stimulus interaction (F tests) using an a priori threshold of p G .001
uncorrected at the voxel level, with a cluster extent threshold of 10 voxels. For
Scanning Method and Procedure post hoc t tests, we again applied an a priori threshold of p G .001 uncorrected at
To become familiar with the stimuli and postscan rating procedure, the par- the voxel level and p G .05 corrected for multiple comparisons at the cluster
ticipants underwent training outside the scanner immediately before the fMRI level, with a cluster extent threshold of 10 voxels. To compare our results with
experiment. Twelve stimuli that were not used in the fMRI paradigm were pre- those of previous studies and to prevent any relevant activation from being
sented in random order (three from each of the four aforementioned pain intensity overlooked, we performed region-of-interest (ROI) analyses (Wake Forest
conditions). Participants were instructed to adopt self-perspective when rating the University Pickatlas; http://fmri.wfubmc.edu/cms/software). ROI were derived
subjective intensity of pain for each stimulus on a scale from 0 (no pain) to from the Automated Anatomic Labeling software, which is implemented in the
9 (strongest pain imaginable) by pressing the corresponding key on a numeric Wake Forest University Pickatlas. In accordance with previous studies, the ROI
keypad as quickly and accurately as possible. The presentation of the stimuli was analyzed included the following: right and left ACC, right and left middle
cycled until the participant became acclimated to the rating procedure. cingulate cortices (MCC), right and left postcentral gyri, right and left sup-
For the fMRI task, the stimuli were projected into the scanner tube by a plementary motor areas (SMAs), and right and left insulae (34,38,68,69).
projector, and the stimuli were grouped into 12 blocks, each of which consisted To determine significant group differences in the psychometric data set, we
of nine stimuli from the same pain condition chosen in random order. Each applied t tests and defined p G .05 as the threshold for significance.
stimulus appeared only once throughout the entire experiment. The presentation
of each picture lasted 2 seconds, followed by a 1-second blank screen; thus, the
duration of each block was 27 seconds. Four additional blocks of the same
RESULTS
length constituted a baseline condition that consisted of a blank screen with a
green fixation cross at the center. This resulted in a total set of 16 blocks (three Pain Ratings
blocks per pain condition plus four baseline blocks). The task consisted of Among participants with chronic pain disorder who rated
presenting the blocks from this set in random order, resulting in a total task time their own pain intensity on the average (Item 5) using the
of 432 seconds. BPI before scanning, the M (SD) value was 7 of 10 (2.24). For
Immediately after the fMRI procedure, the participants were interviewed
outside the scanner. The stimuli were presented to them in the same order as comparison, in cancer-induced bone pain, which is the most
previously shown in the fMRI task. All participants were reminded to adopt self- common cause of pain in patients with cancer, the median
perspective and to respond as quickly and accurately as possible. Each stimulus average pain as rated with the BPI was found to be 4 of 10 (70).

126 Psychosomatic Medicine 75:124Y136 (2013)

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TABLE 1. Results of the Postscan Psychometrics of the Participants

Patients Controls p

Pain rating
No pain 0.65 (1.28) 0.54 (0.88) .36
Pain (all conditions) 4.31 (1.73) 5.05 (1.12) .06
Beck Depression Inventory I
Total score 17.84 (9.03) 4.43 (4.70) G.001
Somatization 8.33 (3.43) 2.26 (2.49) G.001
Interpersonal Reactivity Index
Perspective taking 14.83 (3.98) 16.24 (3.96) .06
Empathic concern 13.92 (3.99) 16.53 (4.82) .04
Fantasy 16.88 (2.93) 19.96 (5.52) .02
Personal distress 15.20 (2.74) 14.53 (5.02) .30
20-Item Toronto Alexithymia Scale 53.19 (9.18) 44.37 (8.56) .003

Data are expressed as mean (standard deviation).

P values G .05 are presented in boldface.

All patients with chronic pain experienced pain throughout the Compared with the control group, the patients reported
scanning, whereas none of the control participants reported significantly higher levels of depression in the total score of
experiencing any pain during the scanning. the BDI-I, indicating mild depression, on average, (Table 1)
and higher trait anxiety (STAI-T) scores. Furthermore, the
patients suffered more from the somatic symptoms of de-
Behavioral Measures pression and showed significantly higher levels of alexithymia
The control group attributed a marginally higher pain intensity in TAS-20 compared with the controls (Table 1). The patients
to all pain pictures than to the patients (p = .057) (Table 1). showed significantly lower levels on the empathic concern

TABLE 2. Main Effects and Interactions in BOLD Signaling Using Analysis of Variance

Region of Interest Montreal Neurological Institute Coordinates (x y z) k F p

Main effects: Group

Left anterior cingulate cortex j4 40 j6 11 15.08 .03
Left middle cingulate cortex j10 2 42 76 20.28 .005
Right middle cingulate cortex 18 j26 42 96 20.21 .006
10 j6 44 44 17.14 .02
Left insula j40 14 6 49 20.69 .004
Right supplemental motor area 10 j6 46 34 17.78 .02
Left postcentral gyrus j30 j40 72 26 19.52 .01
j52 j4 40 11 15.69 .06
Right postcentral gyrus 56 j4 32 13 15.43 .06
Main effects: Stimulus
Left anterior cingulate cortex j2 32 j4 44 9.70 .03
Right anterior cingulate cortex 0 32 j2 21 8.82 .04
Right middle cingulate cortex 6 18 44 49 17.73 G.001
Left supplemental motor area j2 16 50 21.81 454 G.001
Right supplemental motor area 4 18 48 21.66 356 G.001
Left postcentral gyrus j42 j44 60 18.90 109 G.001
j56 j24 30 16.66 85 G.001
Right postcentral gyrus 60 j22 44 11.76 13 .02
Group  Stimulus interaction
No suprathreshold voxels

BOLD = blood oxygenation levelYdependent.

The table presents Montreal Neurological Institute coordinates, F-scores, and cluster sizes in voxels for pain-related brain areas (region of interestYbased analysis;
height threshold p G .001 uncorrected at the voxel level; extent threshold k 9 10 voxels; p value in the table corrected for familywise error at the voxel level).

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M. NOLL-HUSSONG et al.

and fantasy scales of IRI (Table 1). However, the group dif- gyri. Main effects of the factor Stimulus were seen in the left and
ferences found in IRI and TAS-20 are confounded by the level right pACC, right MCC, left insula, left and right SMA, and both
postcentral gyri. No significant group-stimulus interaction was
of depression in the BDI-I, and the differences did not remain detected (even when at a more lenient threshold of p G .05
significant after the removal of the BDI-I score as an inter- uncorrected at the voxel level) (Table 2).
fering variable. & Single-group analyses: Pain 9 Baseline. In the control and patient
The pain ratings and the empathic concern subscale of groups, the perception of painful stimuli was associated with increased
IRI (r = 0.6; p = .01) were positively correlated for patients with activation of the ACC, postcentral gyrus, insula, and SMA (Table 3,
Fig. 1).
chronic pain disorder. Furthermore, TAS-20 score and its three & Single-group analyses: No Pain 9 Baseline. In the patient group,
subscores (difficulty identifying feelings, difficulty de- nonpainful visual stimuli led to increased activation of the left
scribing feelings, and externally oriented thinking) were ACC, left MCC, both insulae, both SMAs, and both postcentral
positively correlated with the BDI-I score (r = 0.524; p = .015) gyri. In the control group, the perception of nonpainful stimuli was
in the patient group. In contrast, TAS-20 scores were posi- associated with increased activation of the right and left SMAs,
right and left insulae, and left postcentral gyrus (Table 4).
tively correlated with the personal distress subscale of IRI
& Single-group analyses: Pain 9 No Pain. In the control group, the
(r = 0.535; p = .018) in the control group. perception of painful stimuli was associated with increased acti-
No significant intelligence level differences were detected vation of the postcentral gyrus, left dorsal ACC, and both insulae
in our participants using the MSVT-B (patients, M (SD) = (Table 3, Fig. 2). No such signal change was observed in patients
27.47 (5.51); controls, M (SD) = 26.37 (7.85); p = .612) when comparing Pain 9 No Pain (Table 5, Fig. 2).
(71,72). & Group comparison: Pain 9 Baseline. No significant group
differences were found. After the influence of depression was
controlled for, introduction of the BDI-I, TAS-20, IRI scores
fMRI Measurements as confounding variables did not change the comparison results
& Analysis of variance: main effects and interactions. Main effects of (Table 3, Fig. 1).
the factor Group were seen in the left perigenual ACC (pACC), & Group comparison: No Pain 9 Baseline. No significant group
left and right MCC, left insula, right SMA, and both postcentral differences were found. After the influence of depression was

TABLE 3. BOLD Signal Differences Between Patients and Controls in the Pain 9 Baseline Contrast

Pain 9 Baseline
Region of Interest
Montreal Neurological Institute Coordinates (x y z) k T p

Controls
Left anterior cingulate cortex 0 4 30 13 4.51 .047
Right middle cingulate cortex 2 4 30 11 4.24 .8
Left insula j28 24 2 355 7.6 G.001
Left supplemental motor area j8 22 50 1016 8.46 G.001
Right supplemental motor area 2 8 60 472 6.65 G.001
Left postcentral gyrus j60 j22 30 160 6.85 G.001
j40 j36 42 65 6.66 .01
Right postcentral gyrus 56 j24 44 46 4.54 .03
Patients
Left anterior cingulate cortex 0 8 23 21 5.12 .030
Right middle cingulate cortex 2 6 30 17 5.19 .05
4 18 44 60 4.60 .08
Left insula j28 22 4 461 5.75 G.001
Right insula 42 16 2 42 5.08 .01
Left supplemental motor area j2 16 50 658 6.43 G.001
Right supplemental motor area 4 10 58 518 7.74 G.001
Left postcentral gyrus j20 j74 56 1293 6.70 G.001
Right postcentral gyrus 34 j36 44 274 5.59 G.001
Controls 9 Patients
No suprathreshold voxels
Patients 9 Controls
No suprathreshold voxels

BOLD = blood oxygenation levelYdependent.

The table presents Montreal Neurological Institute coordinates, T-scores, and cluster sizes in voxels for pain-related brain areas that were activated in response to
painful picture stimuli (region of interestYbased analysis; height threshold p G .001 uncorrected at the voxel level; p G .05 corrected for multiple comparisons at the
cluster level [the actual value of the latter is given in the table]; extent threshold k 9 10 voxels; nonsignificant activations are presented in italics).

128 Psychosomatic Medicine 75:124Y136 (2013)

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Figure 1. Activation of pain-related brain areas in response to painful picture stimuli computing Pain 9 Baseline. Controls showed significant activation of the left
insula, both supplementary motor areas, and both postcentral gyri (data not shown). Patients showed significant activation of the left anterior cingulate cortex, both
insulae, both supplementary motor areas, and both postcentral gyri (data not shown). No significant group differences were detected (region of interestYbased
analysis; height threshold p G .001 uncorrected at the voxel level and p G .05 corrected for multiple comparisons at the cluster level; extent threshold k 9 10 voxels).

controlled for, introduction of the BDI-I, TAS-20, and IRI scores Negative Results
as confounding variables did not change the comparison results No significant group differences in the activation of the anterior
(Table 4).
& Group comparison: Pain 9 No Pain. In the post hoc t test, the insular cortex could be found in any of the analyses mentioned
control group exhibited a higher activation of the left pACC herein. Even at a more lenient threshold (p G .01 uncorrected at the
compared with the patients when comparing Pain 9 No Pain voxel and cluster levels), no significant differences were detected in
(Table 5, Fig. 2). the insula. None of our behavioral measures, especially TAS-20,
Controlling for the influence of the BDI-I, TAS-20, and IRI correlated with insular activation, even when the participants of
scores as confounding variables did not change the results both groups were pooled. No sex differences in pain perception
(Table 5, Fig. 2). (74) could be determined in our sample.

Additional Findings and Methodological Remarks DISCUSSION

This study used thresholds of p G .001 uncorrected at the In this study, we aimed to show that the ability to imagine how
voxel level and p G .05 corrected for multiple comparisons at one would feel in a particular painful situation is disturbed in
the cluster level (extent threshold of 10 voxels). Interestingly, a patients with chronic pain disorder. Our results demonstrate that,
statistically stronger correction at the voxel level (p G .05 compared with healthy controls, the patients exhibited a signifi-
corrected for false discovery rate) led to an additional sig- cantly lower activation of the left pACC, indicating an altered
nificant activation found in the left dorsal ACC in the control neuroprocessing of both inner-oriented and outer-oriented emo-
group. Controlling for the influence of the BDI-I, TAS-20, and tional awareness in patients with chronic pain disorder (75). Self-
IRI scores as confounding variables did not change the results. rating measures of depression, alexithymia, and general cognitive
This finding clearly provides further evidence for the risk of and emotional empathy did not influence the neuroimaging results.
false-positive results with the use of the false discovery rate Accordingly, our study expands the findings of Valeriani et al.
correction in fMRI imaging analysis, as recently stated by (76), who showed that explicitly healthy individuals who re-
Chumbley and Friston (73), and will not be further discussed. ceived painful laser stimulations map the observed pain of others

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TABLE 4. BOLD Signal Differences Between Patients and Controls in the No Pain 9 Baseline Contrast

No Pain 9 Baseline
Region of Interest
Montreal Neurological Institute Coordinates (x y z) k T p

Controls
Left insula j36 22 j2 156 6.27 G.001
Left supplemental motor area j4 16 50 421 5.66 G.001
Right supplemental motor area 4 18 66 209 5.09 G.001
Left postcentral gyrus j40 j36 42 33 4.95 .04
j60 j22 30 23 4.68 .06
Patients
Left anterior cingulate cortex j2 4 30 25 5.11 .03
Left middle cingulate cortex j2 2 32 12 4.25 .06
Left insula j30 22 4 133 5.14 G.001
Right insula 34 22 j2 124 5.42 G.001
Left supplemental motor area 0 12 54 327 5.84 G.001
Right supplemental motor area 4 16 52 292 6.04 G.001
Left postcentral gyrus j42 j34 44 74 6.12 .009
j46 j8 50 46 5.20 .02
j42 j42 58 40 4.44 .03
Right postcentral gyrus 48 j28 40 100 5.28 .004
Controls 9 Patients
No suprathreshold voxels
Patients 9 Controls
No suprathreshold voxels

BOLD = blood oxygenation levelYdependent.

The table presents Montreal Neurological Institute coordinates, T-scores, and cluster sizes in voxels for pain-related brain areas that were activated in response to
nonpainful picture stimuli (region of interestYbased analysis; height threshold p G .001 uncorrected at the voxel level; p G .05 corrected for multiple comparisons at the
cluster level [the actual value of the latter is given in the table]; extent threshold k 9 10 voxels; nonsignificant activations are presented in italics).

according to their own feelings rather than the feelings attributed In general, the pain matrix is best evaluated by activating
to a stranger. These results suggest that the subjective experience acute pain experience (83), and one may speculate whether the
of pain influences social interactions by inducing the sufferer to differences in neural activations found in this study are another
evaluate others according to an egocentric stance. Thus, the example of the different activation patterns attributable to the
regulation of ones egocentric perspective is important for un- long-lasting experience of nonacute chronic pain. Thus, the
derstanding others (77). In our study, we report on the psycho- pain matrix may not be viewed as a stand-alone entity but rather
metric and neural BOLD characteristics of patients with chronic as a substrate modulated by a variety of brain regions, and this
pain disorder mapping the introjective (78Y80) pain of others, a interaction largely determines the pain experience (84). Thus,
topic previously unaddressed in the literature. Individuals with the cerebral signature for the pain perception of subjective
this disorder are often psychologically characterized as having spontaneous pain versus acute experimentally induced pain in
difficulty realizing and interpreting emotional signals within chronic pain conditions may not necessarily be represented by
themselves, thus perceiving the signals as mere sensory sensa- the conventional pain matrix concept (84Y86).
tions (8). We found functional neural disturbances that seem
to correspond to some of the clinically relevant emotional chal- Mental Comorbidity Pattern in Patients With
lenges faced by patients and their social networks, such as their Chronic Pain Disorder
family and physicians. Chronic pain disorder is a somatoform disorder that has a
high comorbidity with major depression and anxiety disorders
Activation of Pain Matrix in Patients With Chronic Pain (87,88). This comorbidity pattern (89Y91) is also present in
Disorder Compared With Healthy Participants our patients with respect to ratings for depression (92), anxi-
In the control group, Pain pictures elicited activation of the ety (93), and alexithymia (94). However, because most psy-
core regions of the pain matrix (81,82), such as the left somato- chotherapy studies for somatic conditions improved patients
sensory cortex, both insulae, and left dorsal ACC, compared with physical symptom severity but not their psychological distress
the No Pain condition (Table 5, Fig. 2). In contrast to the (e.g., for depression) (95,96), there seems to be an independent
control group, the patients showed no significant activation of relationship between medically unexplained somatic complaints
these regions when comparing Pain 9 No Pain (Table 5, Fig. 2). and depression (97). In this study, the self-report measures for

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Figure 2. (Montreal Neurological Institute coordinates (x y z) = j8 38 0; cluster extent k = 54 voxels; T = 4.28; p = .006) (region of interestYbased analysis; height
threshold p G .001 uncorrected at the voxel level and p G .05 corrected for multiple comparisons at the cluster level; extent threshold k 9 10 voxels; for illustration
purposes, a more lenient height threshold of p G .005, uncorrected, was used).

TABLE 5. BOLD Signal Differences Between Patients and Controls in the Pain 9 No Pain Contrast

Pain 9 No Pain
Region of Interest
Montreal Neurological Institute Coordinates (x y z) k T p

Controls
Left anterior cingulate cortex j4 24 24 90 4.92 .002
Left middle cingulate cortex j2 22 32 16 4.44 .05
Left insula j44 6 8 39 6.11 .02
Right insula 38 6 6 19 4.18 .02
Left postcentral gyrus j58 j22 26 144 6.00 G.001
Patients
No suprathreshold voxels
Controls 9 Patients
Left anterior cingulate cortex j8 38 0 54 4.28 .006
Left supplemental motor area j10 8 58 16 3.82 .05
Patients 9 Controls
No suprathreshold voxels

BOLD = blood oxygenation levelYdependent.

The table presents Montreal Neurological Institute coordinates, T-scores, and cluster sizes in voxels for pain-related brain areas that were activated in response to
painful picture stimuli (region of interestYbased analysis; height threshold p G .001 uncorrected at the voxel level; p G .05 corrected for multiple comparisons at the
cluster level [the actual value of the latter is given in the table]; extent threshold k 9 10 voxels; nonsignificant activations are presented in italics).

Psychosomatic Medicine 75:124Y136 (2013) 131

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SPECIAL SERIES ON NEUROSCIENCE
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M. NOLL-HUSSONG et al.

depression, alexithymia, and interpersonal reactivity did not ex- In a study of patients who never felt nociceptive pain due to
plain our neuroimaging results upon the introduction of the ap- CIP, conducted by Danziger et al. (116), the functional activity
propriate behavioral measures (BDI-I, TAS-20, and IRI) as of pACC in the healthy control group was positively correlated
confounding variables. As a first approximation, this incongruity with emotional empathy, especially the empathic concern
between behavioral and biological measures is consistent with the score of IRI (31). Our results might reflect an antipodal minus
general fallibility of self-assessments (97). Furthermore, it is activation of the same region in patients who always feel non-
noteworthy that brain activity during experimental pressure pain nociceptive somatoform pain. Hence, one could speculate that
in patients with fibromyalgia (chronic widespread pain) was re- pACC plays a pivotal role in the processing of pain as an af-
cently shown to not be modulated by depressive symptoms and fective regulator (i.e., pACC could be an affective-motivational
anxiety, using the BDI-I and STAI-T, respectively (98). Further- pain core region or hub) (21,117). Thus, pACC could be a brain
more, a similar discrepancy between BOLD activations and be- area with a high degree of connectivity, equalizing both self-
havioral measurements was described in a study investigating centered and other-centered emotional awareness (in a broader
altered cerebral response to noxious heat stimulation in patients sense, the bidirectional empathetic feelings) of pain. Current
with somatoform pain disorder (5), among other studies. Thus, social psychology interpretations of the different subscales of
the differences between our two groups may be more easily IRI posit that the empathic concern subscale refers to the
detected via neuroimaging methods than via self-assessed be- affective component of empathy (76). This idea is consistent
havioral ratings (33,99Y102). with patients with chronic pain disorder showing a positive
correlation between the pain ratings after scanning and the
pACC and the Affective Dimension of Chronic Pain empathic concern subscore of IRI. Thus, the idea that this
Disorders part of the ventromedial prefrontal cortex for self-evaluation
Compared with patients with chronic pain disorder, the and other evaluations of emotion (118) is integral in shaping
control group demonstrated a higher activation of the left pACC subcortical responses and may participate in the construc-
when comparing Pain 9 No Pain. This activation was not tion and deployment of (affective) meaning is particularly
attributable to greater activity in this region during the No tempting (21) as it could, for example, provide a neural basis for
Pain condition, relative to the baseline condition in patients the characteristic problems of pain reappraisal and distraction
compared with that in the control participants. In general, pACC found in patients with chronic pain disorder (119).
plays a role in processing affective information (which includes
assigning emotional valence to internal and external stimuli and Leftward Appearance of the Neural and the
conditioned emotional learning), regulating autonomic and en- Nonvariation of Insular Activations
docrine functions, and assessing motivation (103Y105), empathy The leftward location of our BOLD signaling in the insula
for pain (106), and, eventually, generation of affective meaning may be attributable to several factors in our right-handed par-
(21). Furthermore, pACC was found to be involved in the pro- ticipants. There is evidence of left hemisphere dominance for
cessing of both somatic (107Y109) and visceral (110,111) pain. local, narrowly focused attention, and right hemisphere domi-
Vogt et al. (112) suggested that activation of pACC may be in- nance for broad, sustained, global, and flexible attention
volved in affective responses to noxious stimuli, such as the (120Y123). Altogether, the self-centered mental simulation of
suffering associated with pain, and Frewen et al. (113) observed a the sensory qualities of others pain may be lateralized to the
correlation between activation of pACC and emotional awareness left hemisphere (124). Another factor to consider is that the right
in healthy participants as they recalled traumatic experiences. anterior insula is more typically associated with remapping to
Interestingly, pACC is also functionally related to the onset of the the conscious experience of bodily sensations (125,126). Thus,
uncertainty of impending, externally applied thermal stimuli at the left insula may reflect registration of pain that is accessible
noxious and non-noxious temperatures (114). In contrast to the to consciousness but may not necessarily be conscious (127).
control participants, our patients with chronic pain were subjec- As the insula is associated with the subjective evaluation of
tively accustomed to the sensory experience of lasting pain (i.e., bodily states and is involved in human feelings, this study has
they are certain that they will feel persistent pain). Thus, we shown that the individual affective-cognitive style is associated
suggest that, in our healthy controls, the experience of pain in- with insular activity in pain empathy processing (128). The
duced by the visual pain paradigm may be more surprising and potential contribution of insular dysfunction to the develop-
thus more intensive and differentiable, resulting in higher pACC ment of hyperalgesia has been demonstrated in rat models via
activation and a trend corresponding with a higher pain intensity local manipulations of dopaminergic, GABAergic, and opioi-
rating. One may speculate about a type of habituation among dergic neurotransmissions within this region, and insular
patients with chronic pain in the affective dimension of the hypometabolism in a patient with fibromyalgia was recently
painful experience that was isolated in this study using the visual demonstrated (55). In contrast, similar to Abbass et al. (100),
pain paradigm. Against this background, prolonged activation of who could not find initial differences in the insula between
pain processing areas could potentially diminish stimulus-evoked patients with autism spectrum conditions and controls, we did
BOLD responses in those areas and thus explain the finding that not find differences between patients with chronic pain disorder
patients with chronic pain exhibited lower pACC activation than and our healthy participants. However, we could not confirm
pain-free controls (115). one of the subsequent results of both Abbass et al. (100) and

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 Study II

Frequency shifts in

the anterior default mode network and

the salience network in chronic pain disorder

Published in

BMC Psychiatry. 2013; 13:84.

Otti et al. BMC Psychiatry 2013, 13:84
http://www.biomedcentral.com/1471-244X/13/84

RESEARCH ARTICLE Open Access

Frequency shifts in the anterior default mode

network and the salience network in chronic pain
disorder
Alexander Otti1,2, Harald Guendel3, Afra Wohlschlger2, Claus Zimmer2 and Michael Noll-Hussong3*

Abstract
Background: Recent functional imaging studies on chronic pain of various organic etiologies have shown
significant alterations in both the spatial and the temporal dimensions of the functional connectivity of the human
brain in its resting state. However, it remains unclear whether similar changes in intrinsic connectivity networks
(ICNs) also occur in patients with chronic pain disorder, defined as persistent, medically unexplained pain.
Methods: We compared 21 patients who suffered from chronic pain disorder with 19 age- and gender-matched
controls using 3T-fMRI. All neuroimaging data were analyzed using both independent component analysis (ICA)
and power spectra analysis.
Results: In patients suffering from chronic pain disorder, the fronto-insular salience network (FIN) and the anterior
default mode network (aDMN) predominantly oscillated at higher frequencies (0.20 - 0.24 Hz), whereas no
significant differences were observed in the posterior DMN (pDMN) and the sensorimotor network (SMN).
Conclusions: Our results indicate that chronic pain disorder may be a self-sustaining and endogenous mental
process that affects temporal organization in terms of a frequency shift in the rhythmical dynamics of cortical
networks associated with emotional homeostasis and introspection.
Keywords: Chronic pain disorder, Somatoform pain disorder, Resting state networks, Intrinsic connectivity networks,
Functional brain imaging, fMRI

Background monitoring [5], such as the medial prefrontal cortex, the

Chronic pain disorder, as defined in the DSM-IV [1], is a anterior cingulate cortex, and the insula [6].
somatoform disorder lasting longer than 6 months in In addition to studies concerning morphology and
which the predominant symptoms are bodily complaints paradigm-based activations, the temporal dimension of
of pain. Psychological factors are thought to be central neural processing has recently gained attention [7-9].
to the onset, severity, exacerbation and maintenance of This dynamic view of brain functioning emphasizes the
the complaint. Characteristically, patients with this clin- importance of the functional interplay between different
ically prevalent disorder have difficulties recognizing and brain regions, with a particular focus placed on altered
interpreting emotional signals within themselves; they resting state connectivity in mental disorders [10]. One
perceive these signals as physical symptoms [2]. More- of the strongest disruptors of this complex equilibrium
over, the disorder itself leads to significant neural alter- seems to be pain [11-14]. In a recent study of 10 patients
ations in regions associated with emotional awareness suffering from nociceptive chronic pain, the spatial co-
[3], affective meaning construction [4], and bodily state herence of the fronto-insular salience network (FIN)
was altered in the resting state [15]. Chronic pain
influenced the temporal aspects of functional connectiv-
ity by changing the frequency of the rhythmic oscilla-
* Correspondence: [email protected]
3
Klinik und Poliklinik fuer Psychosomatische Medizin und Psychotherapie,
tions in the BOLD-signal within the FIN from lower
University of Ulm, Albert-Einstein-Allee 23, Ulm D-89081, Germany levels (below 0.12 Hz) to a higher range (between 0.12
Full list of author information is available at the end of the article

2013 Otti et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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and 0.24 Hz) [15]. Moreover, chronic back pain seems to currently bothersome, physical symptoms in addition to a
disrupt the integrity of the so-called default mode net- long ( 2 years) history of somatization [19]. Because of the
work (DMN) [11], whereas diabetic neuropathic pain striking comorbidity of multisomatoform disorder with
changes the temporal coherence of the DMN [16]. major depression and anxiety disorders, it has been sug-
Interestingly, chronic pain not only influences neural gested that overlapping psychobiological mechanisms medi-
circuits but also tends to operate in a domain-general ate depression, anxiety, and somatization symptoms [20].
manner. Neuropathic diabetic pain, for example, also Compared with mood and anxiety disorders alone, mul-
changes the spatial functional anatomy of the sensori- tisomatoform disorder is associated with comparable im-
motor network (SMN) [16]. However, the aforemen- pairments in health-related quality of life, a greater number
tioned studies [15,16] have focused on chronic pain of self-reported disability days and clinic visits, and the
conditions without distinguishing between pain that can highest levels of provider frustration [21,22].
be clearly associated with a convincing organic correlate The Physical Component Summary (PCS) measure [23]
and somatoform pain (e.g., in chronic lower back pain in our patient group had to be 1 standard deviation or
[17]) or generalized pain. more below the population norm ( 40), as measured with
Thus, the present study aims to fill this gap, examining the SF-36 (see below). A score less than 40 also meets the
whether chronic pain disorder patients show similar al- DSM-IV criterion B for significant distress or psycho-
terations in frequency and functional connectivity within social impairment due to the somatoform pain in patients
the brains functional architecture. We define chronic with pain disorder [1]. As a second precondition, sum
pain disorder as pain that is not the result of a clear scores on the 15-item Patient Health-Questionnaire
organic etiology or that is out of proportion to the inten- (PHQ-15) had to be above 10, representing at least
sity of physical findings and that is caused by a well- medium somatic symptom severity (see below). The
classified mental disorder (ICD-10: F45.4x, DSM-IVR: German version of the Brief Pain Inventory (BPI) [24] was
307.80), characterized predominantly by chronic ongoing used to estimate the intensity of each participants pain.
pain [1,18]. Given that there is an endogenous central We reviewed patients medical charts and contacted the
process that is observed in chronic pain disorder, we treating physicians to rule out possible or unclear organic
hypothesize that pain-related resting state networks such explanations for the symptoms of our chronic pain pa-
as the DMN, FIN, and SMN will fluctuate at even higher tients. Patients with insufficient cognitive abilities, severe
frequencies in patients than in healthy controls. We also and chronic somatic or nervous diseases, unambiguous
hypothesize that these networks will show evidence of nociceptive pain, hypochondriasis, a severe comorbid
disturbed spatial functional connectivity. mental disorder causing major impairment in social func-
tioning (e.g., schizophrenia or severe substance abuse) or
Methods insufficient German language skills were excluded. All
This study was approved by an institutional ethics com- participants were white, of Caucasian origin, and right
mittee (Klinikum rechts der Isar, Medical Faculty of handed, as assessed by the Edinburgh handedness inven-
Technische Universitaet Muenchen, Germany) and tory [25]. Additional file 1: Table S6 lists all medications
was performed in accordance with the Declaration of that patients were currently taking.
Helsinki.
Nineteen healthy controls (mean age: 48.79 years, SD Psychometric measurement
12.25, 12 females) and 21 German-speaking patients Somatoform disorders were diagnosed using a modified
(mean age: 46.62 years, SD 12.49, 17 females) with semi-structured psychiatric interview, the German ver-
chronic pain disorder, defined as a pain-predominant sion of the SCID-I (Structured Clinical Interview for
multisomatoform disorder diagnosed by an experienced DSM Disorders) [26]. The SCID-I is the diagnostic cri-
physician using a modified SCID-I interview, provided terion standard and evaluates current (i.e., the 4 weeks
informed written consent and participated in the experi- preceding the interview) and lifetime psychiatric status
ment. The main feature of somatoform disorders is the for major Axis I mental disorders using criteria that cor-
repeated presentation of physical symptoms together respond to the DSM-IV [1].
with persistent requests for medical investigations, des- The SF-36 is a multipurpose, short form health survey
pite repeated negative findings and reassurances by phy- consisting of 36 questions [27]. It yields an 8-scale pro-
sicians that the symptoms have no physical basis. If any file of functional health and well-being scores, psycho-
physical disorders are present, they do not explain the metrically based physical and mental health summary
nature and extent of the symptoms or the distress and measures, and a preference-based health utility index. It
preoccupation that the patient has with them [18]. is a generic measure, as opposed to one that targets a
Multisomatoform disorder, a medium-to-severe somatoform specific age, disease, or treatment group. Accordingly,
disorder, is defined as three or more medically unexplained, the SF-36 has proved useful in surveys of both general
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and specific population groups. It compares the relative parameters: 9 ms TR; 4 ms TE; 8 degree flip angle; 240
burden of disease and differentiates the health benefits mm field of view (FOV); 240_240 matrix; voxel size 1
generated by a wide range of different treatments [28]. mm isotrop; 170 slices; no gap.
Its German translation has been validated in a variety of
German health care settings [29,30]. Data analysis and image processing
The PHQ-15 is a brief, self-administered questionnaire Data analysis was performed using SPM5 (Statistical
that has proved useful in screening for somatization and Parametric Mapping software, Wellcome Department of
in monitoring somatic symptom severity in clinical prac- Imaging Neuroscience, London, UK; http://www.fil.ion.ucl.
tice and in research. Scores of 5, 10, and 15 represent ac.uk). The first three images for each run were discarded to
the cutoff points for low, medium, and high somatic allow for equilibration of longitudinal magnetization. The
symptom severity, respectively [31,32]. preprocessing steps included (1) realignment and unwarping
The BPI, based on the Wisconsin Brief Pain Question- of the images to correct for movement artifacts and related
naire, was developed by the Pain Research Group of the susceptibility artifacts, (2) coregistration of the anatomical
WHO Collaborating Centre for Symptom Evaluation in images to the functional images, (3) segmentation and
Cancer Care to provide information on the intensity of normalization of the anatomical images to a standard
pain (the sensory dimension) and the degree to which stereotactic space (Montreal Neurological Institute, MNI;
pain interferes with function (the reactive dimension) Quebec, Canada), (4) application of a normalization trans-
[33]. The validity of the German version [24] and the formation to the functional images, and (5) smoothing with
ability of the BPI to measure pain in patients without a Gaussian kernel of 8 mm for group analysis.
cancer [34] have been demonstrated.
The applied Beck Depression Inventory I (BDI-I) is a Connectivity analysis
21-item self-reported instrument that measures cogni- We performed an independent component analysis (ICA)
tive and endogenous aspects of depression on a four- by using the group ICA function included in the fMRI
point scale ranging from 0 to 3. The standard cut-offs toolbox (GIFT version 1.3h; http://icatb.sourceforge.net)
are as follows: 09 indicates no depression, 1018 developed for the analysis of fMRI data [38-40]. First, the
indicates mild depression, 1929 indicates moderate individual data were concatenated across time, followed
depression, and >30 indicates severe depression. This by the computation of subject-specific components and
questionnaire has undergone extensive reliability and time courses. The analysis proceeded in three stages: (1)
validation studies [35,36]. data reduction, (2) application of the ICA algorithm, and
The German version of the Trait Anxiety Inventory (3) back reconstruction for each individual subject [38]. In
(STAI-T) is a valid and reliable 20-item questionnaire the first step (1), data from each subject underwent princi-
that measures the general level of anxiety on four-point pal component analysis to reduce the computational com-
scales ranging from 1 to 4 [37]. plexity of the analysis. In so doing, most of the content of
the data was preserved. After concatenating the resulting
Functional MRI resting state paradigm volumes, the number of independent sources was esti-
Participants were asked to close their eyes and relax but mated using the GIFT dimensionality estimation tool
to remain awake. This portion of the experiment lasted based on the aggregated data and using the minimum-
370 seconds. Following the scanning session, partici- description-length criteria [41]. The final reduction step,
pants were asked whether they had fallen asleep during according to the selected number of components, was
the scan; those who provided a positive or ambiguous achieved again using principal component analysis. In the
answer were excluded from the study. second stage of the analysis (2), we used the Infomax algo-
rithm to run the appropriate ICA and a mask based on all
Data acquisition and fMRI procedures subjects. In the final stage of back reconstruction (3), time
Images were acquired with a 3T Philips Achieva Scanner courses and spatial maps were computed for each subject.
(Philips Medical Systems, Best, The Netherlands) using a The resulting mean spatial maps of each group were
standard 8-channel SENSE head coil. Thirty-two con- transformed to z scores for display [38].
tiguous slices (no gap), with a steep angulation to Individual subject maps of the ICNs were entered into
exclude the eyes, were acquired using a gradient echo- random effects analyses in SPM5. The results were
planar (EPI) sequence with the following parameters: thresholded at p = 0.05 and corrected for family wise
2000 ms repetition time (TR); 35 ms echo time (TE); 82 error (FWE) with a cluster extent threshold of 50 voxels.
degree flip angle; 220 mm FOV; 4 mm slice thickness; To enhance both the reliability and validity of this
80_80 matrix; voxel size 2.75_2.75 mm; SENSE factor 2. study, the ICNs were compared with networks that were
Anatomical images were obtained using a T1-weighted calculated from a sample of approximately 600 healthy
turbo gradient echo sequence with the following people in a study previously published by Allen et al.
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[42] that used spatial correlation (multiple regression) in group (Table 1). The level of depression was significantly cor-
the GIFT program [38] (see below for details). related with the level of anxiety (R = 0.593, p = 0.005). No
For comparison between groups, we used two-sample t- relevant correlation was observed between the level of
tests with the available psychometric depression and anx- clinical pain (BPI, item 5) and the level of depression (R =
iety scores as covariates of no interest. To detect even weak 0.01, p = 0.996) or the level of anxiety (R = 0.083, p = 0.736).
effects, a more lenient threshold was used for the group
comparison (p = 0.005, uncorrected on the voxel level (z > Functional MRI data spatial connectivity analysis
2.58), and p = 0.05, corrected for multiple comparisons on (Figures 1 and 2)
the cluster level, extent threshold k > 10 voxels). Correl- The ICA estimation resulted in 29 independent com-
ation analysis was performed at the same threshold. The ponents. In accord with published data from other
connectivity maps from GIFT were entered into SPM5. groups, we identified the following pain-related networks
We performed a partial correlation analysis (Pearson cor- (Figures 1 and 2, Additional file 2: Table S1, Additional
relation) between functional connectivity and the level of file 3: Table S2):
depression on the BDI-I, controlling for the level of anxiety
on the STAI-T. We also performed a partial correlation 1. The anterior default mode network (aDMN), which
analysis between functional connectivity and the level of comprises cortical midline structures such as the
anxiety on the STAI-T, controlling for the level of depres- medial prefrontal cortex and the precuneus
sion on the BDI-I. Finally, we correlated the average sub- [11,12,16,46]. The aDMN showed the strongest
jective pain during the last week (item 5 on the BPI) with overlap with component 25 from Allen et al. [42],
the functional connectivity using a bivariate correlation. which represents the anterior part of the default
mode network (multiple regression value: 0.22).
Power spectra analysis 2. The posterior default mode network (pDMN) of the
The GIFT toolbox spectral group compare function precuneus [11,12,16,46]. The pDMN showed the
was used to calculate power density frequency spectra strongest overlap with component 50 from Allen
for each subject at six equally spaced frequency bins et al. [42], which represents the posterior part of the
between 0 and 0.24 Hz at 0.04 Hz intervals (2-sample default mode network (multiple regression value:
t-test, p < 0.0083 0.05/6; Bonferroni-correction for 6 0.14).
frequency bins). Several previous studies have also used 3. The fronto-insular network (FIN), which comprises
power-spectra analysis (see [15,16,43,44]; please note that both the insula and the cingulate cortex [15,47].
the number of bins and the intervals are different in each Component 55 from Allen et al. [42], which
study). The level of depression (BDI-I) and the level of represents the fronto-insular salience network,
anxiety (STAI-T) were introduced as nuisance covariates. showed the strongest overlap with this network
Correlation analyses with all psychometric data were (multiple regression value: 0.22).
performed at the same threshold. 4. The sensorimotor network (SMN), which comprises
the pre- and post-central gyrus [48]. The SMN
Results showed the strongest overlap with component 29
Pain ratings from Allen et al. [42], which represents a
Prior to scanning, the German version of the Brief Pain sensorimotor network (multiple regression
Inventory (BPI) was used to estimate the intensity of the value: 0.14).
patients chronic pain during the previous week. On aver-
age, subjects rated their pain as a 7 (SD 2.24) using a Nu- No significant differences in spatial functional connect-
merical Rating Scale (NRS), which ranged from 0 (no ivity between the patient and control groups were
pain) to 10 (pain as bad as you can imagine) on item 5 detected (Additional file 4: Table S3). Moreover, no signifi-
of the BPI. For comparison, in cancer-induced bone pain, cant correlation was observed between the psychometric-
the most common cause of pain in patients with cancer, ally measured level of pain (BPI), anxiety (STAI-T),
the median average pain using the BPI was found to be 4 depression (BDI-I) and spatial functional connectivity [42]
[45]. All patients suffering from chronic pain disorder ex- in the patient group (Additional file 5: Table S4).
perienced pain throughout the fMRI scan.
Functional MRI data power spectra analysis (Table 2,
Psychometric measurement Figure 3)
Patients with chronic pain disorder showed significantly Compared to the control group, patients showed
higher BDI-I levels in the form of mild depression, higher power spectra in the aDMN and the FIN, ranging
higher trait-anxiety (STAI-T) scores and higher pain between 0.20 and 0.24 Hz. No significant correlation
levels on the BPI (item 5) compared with the control was observed among the level of pain, depression, trait-
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Table 1 Averages and comparisons of group scores

Patients Controls t-Test -p-
value;
Mean Median SD Range Mean SD Median Range
BPI (Item 5) 7 6 2.24 2-9 0 0 0 - 0.000
BDI-I: 17.84 20 9.03 3 - 37 4.43 4.70 2 0 -16 0.000
STAI-T 47.10 49 12.4 20 -70 35.94 8.56 34 23 - 50 0.002
Two-sample t-tests of average pain intensity (BPI), depression (BDI-I) and trait-anxiety (STAI-T) in patients with chronic pain disorder and healthy controls.
The threshold of significance is p < 0.05.

anxiety and spectral power (Additional file 6: Table S5). Our results support the study hypothesis that there is
These group differences were not influenced by levels of a shift of the endogenous oscillations of the brains rest-
depression and trait-anxiety as measured by the BDI-I ing state to higher frequencies in patients suffering from
and STAI-T, respectively. chronic ongoing pain, even when a physical examination
cannot (fully) explain the subjective symptoms and the
patients fulfill the official criteria for chronic pain
Discussion disorder.
This study reveals that neural activity within the FIN Furthermore, by demonstrating higher BOLD fluctua-
and the aDMN in patients with chronic pain disorder tions in the FIN and DMN in chronic pain disorder, our
shows significantly shifted frequencies in comparison findings expand the results of both Malinen et al. [15]
with healthy controls. Moreover, a general trend toward and Cauda et al. [16]. Other authors have discovered
higher power in the 0.20 - 0.24 Hz frequency bin was similar alterations in temporal coherence among patients
evident in patients compared with control subjects. suffering from chronic neuropathic pain associated with
However, significant changes in the spatial dimensions obvious organic diseases [49,50]. Compared to previous
of functional connectivity were not detected. studies on the brains temporal dynamics in chronic

Figure 1 ICNs of the control group. For illustration purposes, Figure 2 ICNs of the patient group. For illustration purposes,
spatial maps were thresholded at P = 0.05, corrected for family wise spatial maps were thresholded at P = 0.05, corrected for family wise
error (FWE) with a cluster extent threshold of 50 voxels; aDMN = error (FWE) with a cluster extent threshold of 50 voxels; aDMN =
anterior default mode network, pDMN = posterior default mode anterior default mode network, pDMN = posterior default mode
network, FIN = fronto-insular network, SMN = sensorimotor network. network, FIN = fronto-insular network, SMN = sensorimotor network.
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Table 2 Comparison of power spectra for all ICNs between patients and healthy controls
ICN Group Spectral power at different frequency-bins in percent of the whole power
0.0 0.04 Hz 0.04 0.08 Hz 0.08 0.12 Hz 0.12 0.16 Hz 0.16 0.20 Hz 0.20 0.24 Hz
aDMN Controls 31.732 20.831 12.677 15.703 12.415 9.881
Patients 29.507 19.989 12.833 12.960 11.932 15.351
p-value (t-test) 0.338 0.510 0.856 0.015 0.693 0.001
pDMN Controls 29.651 22.137 13.550 16.374 12.520 9.312
Patients 29.637 21.374 14.290 14.306 11.008 12.377
p-value (t-test) 0.993 0.580 0.373 0.118 0.175 0.019
FIN Controls 33.751 22.393 12.880 14.318 10.797 9.067
Patients 31.438 22.477 13.702 12.661 9.854 12.728
p-value (t-test) 0.262 0.933 0.260 0.179 0.378 0.005
SMN Controls 36.671 19.570 14.069 13.729 10.771 7.827
Patients 31.919 21.600 14.297 14.030 9.650 11.512
p-value (t-test) 0.117 0.153 0.852 0.839 0.343 0.016
Two-tailed t-test, p < 0.05/6, significant differences are included in bold.

pain, we used a different binning strategy for spectral Hz; 0.1 - 0.25 Hz). In our study, six equally spaced fre-
analyses. Malinen et al. [15] calculated spectral power at quency bins were used (00.04 Hz; 0.04 - 0.08 Hz; 0.08 -
three frequency bins (00.05 Hz; 0.05 - 0.12 Hz; 0.12 - 0.12 Hz; 0.12 - 0.16 Hz; 0.16 - 0.20 Hz; 0.20 - 0.24 Hz).
0.25 Hz), whereas Cauda et al. [16] defined four intervals The main advantage of using 6 bins compared to a
of interest (0.008 - 0.02 Hz; 0.02 - 0.05 Hz; 0.05 - 0.1 greater number of bins is that it reduces the number of
multiple comparisons (level of significance p < 0.0083
0.05/6; Bonferroni-correction for 6 frequency bins). A
lower number of bins, however, might have led to false-
negative results because the spectral changes are rapid,
increasing as a function of frequency. Furthermore,
whereas Malinen et al. [15] used a relatively broad inter-
val for the higher frequencies (0.12 0.25 Hz), we were
able to show that the upper end of the high-frequency
interval (between 0.20 and 0.24 Hz), in particular, might
be relevant in chronic pain disorder.
There was no significant correlation between shifts in
frequency of the BOLD-signal and the psychometric
level of anxiety [51], depression [20,52,53] or pain inten-
sity in the patient group of our study. Nevertheless, we
cannot definitely exclude the possibility that changes
were not due to persistent somatoform pain but were
due to other unknown variables. Furthermore, there was
no significant correlation between spectral power and
anxiety [51] or depression [20,52,53] Importantly, a simi-
lar discrepancy between BOLD activations and behav-
ioral measurements was also described in a study
investigating an altered cerebral response to noxious
heat stimulation in patients with somatoform pain dis-
order [6]. Thus, differences between our two groups
Figure 3 Power spectra of patients (red) and healthy controls may be more easily detected via neuroimaging methods
(green). Intrinsic neural activity within the aDMN and the FIN show than through subjective behavioral ratings, in accord
faster spontaneous fluctuations in patients with chronic pain with several other studies [54-57].
disorder. Error bars represent the standard error of the mean. Although our study does not demonstrate causal rela-
[1 00.04 Hz, 2 0.04 - 0.08 Hz, 3 0.08 - 0.12 Hz, 4 0.12 - 0.16
tionships, several findings suggest a strong relationship
Hz, 5 0.16 - 0.20 Hz, 6 0.20 - 0.24 Hz].
between pain-condition and altered spectral power.
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Somatoform pain is associated with higher autonomic provide a useful neurobiological framework that underlies
arousal [58,59], which, in turn, has been associated with one facet of the behavioral changes that impair the daily
increased activation in the fronto-insular regions [16,60]. lives of patients with chronic pain disorder.
Although autonomic activation was not measured dir-
ectly in our study, an altered psycho-vegetative state [57] Conclusions
might be the behavioral equivalent of increased FIN os- Though our study does not ascribe causation, our results
cillations in chronic pain disorder, as proposed by indicate that patients suffering from chronic pain disorder
Malinen et al. [15]. Remarkably, the FIN and DMN net- show distinct alterations in the temporal organization of
works seem to be involved in affective neuroprocessing: their brains. A persistent peripheral algetic input does not
Whereas the DMN subserves introspection, autobio- seem to be pivotal for changes in the functional architec-
graphic memory, self-referential processing, and social ture of the human brain associated with persistent
understanding [61-64], the FIN has been linked with somatoform pain in patients with chronic pain disorder.
personal salience, emotional awareness, and bodily state
monitoring [5,47,65]. Moreover, the various bodily com- Limitations
plaints in patients with somatoform pain have consist- The present study is limited because of the lack of mea-
ently been associated with a high affective component of surements of possible sources of physiological artifacts
individual pain, which indicates impaired emotional (e.g., respiration, cardiac function and blood pressure).
regulation [66-69]. Given these data, one might synop- However, high agreement with previous findings of alter-
tically speculate that our findings reflect one neurobio- ations in temporal activity in the FIN and the DMN sug-
logical facet of the strong clinical impression that gests that our results were most likely not confounded
patients who suffer from chronic pain disorder often by these factors [15,16]. The analgesic and antidepres-
show impaired subjective emotional awareness, affective sant medication administered to most of our outpatients
meaning construction [4] and social understanding [3]. (Additional file 1: Table S6) could have influenced the
No significant group differences were detected in the reported frequency shift [77,78]; the enduring influence
SMN, although previous studies have shown that of such drugs on BOLD oscillations is currently still un-
chronic pain leads to functional reorganization, de- known. It is noteworthy that, despite ethical reasons, it
creased gray matter density, and increased metabolism was nearly impossible to convince our patients with
within the somatosensory cortex [70-74]. One might chronic pain disorder to interrupt their psychotropic
speculate that chronic pain disorder relies more on dis- medication in this intentionally naturalistic study.
turbed affective and introspective processing than on the
disturbed somatosensory circuits that occur in patients
Additional files
who suffer from pain dependent on nociceptive input,
for example, in a patient with posttraumatic osteoarth- Additional file 1: Table S6. Medication of all 21 patients with chronic
ritis in the sample in Malinen et al. [15]. pain disorder.
We did not find changes in spatial functional connect- Additional file 2: Table S1. MNI-coordinates of the ICNs in the control
ivity, in contrast to Malinen et al. [15], who reported group. Results were thresholded at p = 0.05 and corrected for family wise
error (FWE) on the voxel level with a cluster extent threshold of k = 50
weaker functional connectivity between the insula and voxels.
anterior cingulate cortex in predominantly nociceptive Additional file 3: Table S2. MNI-coordinates of the ICNs in the patient
chronic pain, and Baliki et al. [11], who found dimin- group. Results were thresholded at p = 0.05 and corrected for family wise
ished DMN-connectivity in chronic back pain patients. error (FWE) on the voxel level with a cluster extent threshold of k= 50
voxels.
In contrast to pain caused by diverse peripheral causes,
Additional file 4: Table S3. MNI-coordinates of the group comparisons.
we presume that chronic somatoform pain, which at Results were thresholded at p = 0.005, uncorrected at the voxel-level, and
least cannot be fully explained by possible nociceptive p < 0.05, corrected for multiple comparisons on the cluster level, with a
input, is not associated with alterations in the spatial cluster extent threshold of k = 50 voxels; p represents p on the voxel-
level.
and functional architecture of the brains resting state.
Additional file 5: Table S4. Correlation between functional
Altogether, chronic pain disorder seems to be associated connectivity and psychometric measurement. Results were thresholded
with a frequency shift in the anterior default mode net- at p < 0.005, uncorrected on the voxel-level, and p < 0.05, corrected on
work and the salience network to higher (eigen)frequen- the cluster level, with a cluster extent threshold of k > 10 voxels; p
represents p on the cluster level; R represents Pearsons correlation-
cies. The resting state of the human brain is thought to coefficient. No significant correlation was detected.
serve as a memory of the future [63,75], which stores be- Additional file 6: Table S5. Pearsons correlation between spectral
havioral algorithms to allow a person to adequately cope power and psychometric measurements *The correlation with depression
with upcoming environmental events. Therefore, our re- (BDI-I) is controlled for anxiety (STAI-T) and vice versa; the level of
significance is p < 0.05; R represents the correlation-coefficient. No
search on resting state connectivity as a special form of significant correlation was detected.
neuronal oscillations in cortical networks [76] might
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Competing interests 14. Baliki MN, Baria AT, Apkarian AV: The cortical rhythms of chronic back
The authors declare that they have no competing interests. pain. J Neurosci 2011, 31:1398113990.
15. Malinen S, Vartiainen N, Hlushchuk Y, Koskinen M, Ramkumar P, Forss N,
Kalso E, Hari R: Aberrant temporal and spatial brain activity during rest in
Authors contributions
patients with chronic pain. Proc Natl Acad Sci U S A 2010, 107:64936497.
MN-H designed and conducted the research, analyzed the data, and
16. Cauda F, Sacco K, Duca S, Cocito D, D'Agata F, Geminiani GC, Canavero S:
contributed to the writing of the paper. AO conducted the research,
Altered resting state in diabetic neuropathic pain. PLoS One 2009, 4:e4542.
analyzed the data, and contributed to the writing of the paper. AMW
17. Jain R: Pain and the brain: lower back pain. J Clin Psychiatry 2009, 70:e41.
designed and performed the research. CZ and HG designed the research. All
18. WHO: ICD 10 International Statistical Classification of Diseases And Related
authors discussed the results and commented on the manuscript. All authors
Health Problems: Tenth Revision. Geneva: WHO; 2005.
read and approved the final manuscript.
19. Kroenke K, Spitzer RL, de Gruy FV 3rd, Hahn SR, Linzer M, Williams JB, Brody
D, Davies M: Multisomatoform disorder. An alternative to
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(Klinikum rechts der Isar, Technische Universitaet Muenchen, Germany) for 20. Stein DJ, Muller J: Cognitive-affective neuroscience of somatization
their helpful input concerning our analysis, as well as all the subjects who disorder and functional somatic syndromes: reconceptualizing the triad
participated in this study. This work was supported by a KKF fund (Klinikum of depression-anxiety-somatic symptoms. CNS Spectr 2008, 13:379384.
rechts der Isar, Technische Universitaet Muenchen, Germany) to Michael 21. Jackson JL, Kroenke K: Prevalence, impact, and prognosis of
Noll-Hussong and Afra Wohlschlaeger and a grant to Michael Noll-Hussong multisomatoform disorder in primary care: a 5-year follow-up study.
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Table S6 Medication of all 21 patients with chronic pain disorder

Patient Drug(s)

p01 Oxycodone, Citalopram, Valsartan/Hydrochlorothiazide

p02 Amitriptyline, Paroxetine

p03 Ibuprofen, Hypericin

p04 Oxycodone/Naloxone, Pregabalin, Amitriptyline, Tramadol, Tetrazepam,

Omeprazole, Lynestrenol

p05

p06

p07 Oxcarbazepine

p08 Hypericin; Cimicifuga racemosa

p09 Tramadol, Amitriptyline

p10

p11 Pregabalin, Citalopram, L-Thyroxine

p12

p13 Metformin, Simvastatin, Pioglitazone

p14 Diclofenac, Mirtazapine

p15

p16 Irbesartan

p17 Tilidine/Naloxone, Pregabalin, Doxepin, Esomeprazole

p18 Oxazepam

p19 Pregabalin, Hypericin

p20 Amitriptyline, Atenolol, Chlorthalidone

p21 Amitriptylin, Novaminsulfone, Hydromorphone, L-Thyroxine, Lercanidipine,

Atenolol, Rampril/Hydrochlorothiazide, Acetylsalicylic acid, Allopurinol, Simvastatin

1
 Table S1 MNI-coordinates of the ICNs in the control group Results were
thresholded at p = 0.05 and corrected for family wise error (FWE) on the voxel level
with a cluster extent threshold of k = 50 voxels.

Network Region MNI k T p

aDMN R gyrus frontalis medius, pars orbitalis 2 50 -6 2650 26,12 0.000.

pDMN L middle cingulate cortex -6 -34 34 2805 17.64 0.000.

FIN L insula -38 20 -4 1455 20.06 0.000.

R insula 38 22 -16 1112 18,73 0.000.

L supplementary motor area 0 10 64 878 15.14 0.000.

L gyrus frontalis medius -40 46 20 339 12.94 0.000.

L middle cingulate gyrus 0 -16 42 62 9.94 0.000.

R supramarginal gyrus 56 -42 30 52 9,38 0.000.

SMN L postcentral gyrus -20 -32 70 6896 23.17 0.000.

R precentral 52 -12 48 55 8.86 0.000.

 Table S2 MNI-coordinates of the ICNs in the patient group Results were
thresholded at p = 0.05 and corrected for family wise error (FWE) on the voxel level
with a cluster extent threshold of k= 50 voxels.
Network Region MNI k T p

aDMN R gyrus frontalis medius, pars orbitalis 10 46 -4 3425 26.55 0.000

L precuneus -6 -56 22 277 10.29 0.000

pDMN R posterior cingulate cortex 4 -42 24 3692 26.71 0.000

FIN L insula -36 8 -2 1966 19.11 0.000

L supplementary motor area 0 8 44 1730 17.27 0.000

R insula 38 20 0 1064 16.64 0.000

L gyrus frontalis medius -34 44 30 435 11.54 0.000

L supramarginal gyrus -62 -44 28 125 10.59 0.000

R gyrus frontalis medius 36 48 30 123 8.76 0.000

SMN R gyrus parietalis superior 22 -48 70 7101 26.42 0.000

Table S3 MNI-coordinates of the group comparisons Results were thresholded at
p = 0.005, uncorrected at the voxel-level, and p < 0.05, corrected for multiple
comparisons on the cluster level, with a cluster extent threshold of k = 50 voxels; p
represents p on the voxel-level.

Network Region MNI k T p

aDMN: controls > patients L gyrus frontalis superior -24 38 36 24 3.40 0.538

aDMN: patients > controls - - - - -

pDMN: controls > patients - - - - -

pDMN: patients > controls L cuneus -10 -76 38 10 2.95 0.734

SMN: controls > patients R gyrus praecentralis 52 -14 46 212 4.11 0.103

L paracentral lobule -14 -32 54 73 3.81 0.285

R gyrus postcentralis 18 -38 60 44 3.74 0.527

L supplemental motor area -10 2 70 10 3.21 0.928

SMN: patients > controls - - - - -

FIN: controls > patients R gyrus frontalis inferior, 58 16 20 13 4.03 0.900

pars opercularis

FIN: patients > controls L gyrus frontalis inferior, -44 10 10 69 3.82 0.308

pars opercularis

L middle cingulated cortex -6 -22 42 11 3.47 0.921

 Table S4 Correlation between functional connectivity and psychometric
measurement Results were thresholded at p < 0.005, uncorrected on the voxel-
level, and p < 0.05, corrected on the cluster level, with a cluster extent threshold of k
> 10 voxels; p represents p on the cluster level; R represents Pearsons correlation-
coefficient. No significant correlation was detected.

BDI positive
Network Region MNI k T p R
aDMN L gyrus frontalis, pars orbitalis -2 58 -6 15 3.26 0,396 0.5993
L anterior cingulate cortex -2 40 4 10 3.18 0.585 0.5894
pDMN - - - - - -
SMN R gyrus praecentralis 24 -26 70 31 4.31 0.400 0.5737
R middle cingulate cortex 2 -16 50 50 3.82 0.6384 0.412
L gyrus postcentralis -22 -30 60 22 3.40 0.526 0.5035
L paracentrale lobule -6 -34 72 12 3.16 0.704 0.4809
FIN L gyrus frontalis medius -26 48 26 21 3.79 0.455 0.5364
R gyrus frontalis medius 30 48 26 10 3.58 0.665 0.5151
BDI negative
Network Region MNI k T p R
aDMN L gyrus frontalis medialis 0 54 16 93 3.86 0.32 -0.7432
pDMN - - - - - -
SMN - - - - - -
FIN - - - - - -

STAI-T positive
Network Region MNI k T p R
aDMN - - - - - -
pDMN - - - - - -
SMN L precuneus -14 -42 70 12 3.56 0.704 0.390
FIN - - - - - -

STAI-T negative
Network Region MNI k T p R
aDMN - - - - - -
pDMN - - - - - -
SMN - - - - - -
FIN L gyrus frontalis medialis -6 16 42 22 3.85 0.439 -0.5413
L insula -36 8 -6 22 3.70 0.439 -0.5357
L middle cingulate cortex 0 8 40 13 3.45 0.600 -0.5083
BPI item5
positive
Network Region MNI k T p R
aDMN - - - - - -
pDMN - - - - - -
SMN - - - - - -
CIN L gyrus frontalis medius -34 44 22 41 3.95 0.221 0.6916

BPI item5
negative
Network Region MNI k T p R
aDMN R gyrus rectus 4 52 -16 26 3.84 0.256 -0.6812
pDMN L precuneus -6 -64 36 16 3.59 0.376 -0.6567
SMN - - - - - -
CIN - - - - - -
Table S5 Pearsons correlation between spectral power and psychometric measurements *The correlation with depression
(BDI-I) is controlled for anxiety (STAI-T) and vice versa; the level of significance is p < 0.05; R represents the correlation-coefficient.
No significant correlation was detected.

ICN Psychometrics Spectral power at different frequency-bins in percent of the whole power
0.0 0.04 Hz 0.04 0.08 Hz 0.08 0.12 Hz 0.12 0.16 Hz 0.16 0.20 Hz 0.20 0.24 Hz
R 0.077 -0.300 -0.400 -0.056 0.315 0.116
aDMN BPI p 0.755 0.212 0.090 0.820 0.188 0.636
R 0.188 0.040 -0.232 -0.268 -0.436 0.186
BDI-I* p 0.427 0.866 0.325 0.252 0.055 0.433
R 0.168 0.000 0.224 0.016 0.136 -0.342
STAI-T* p 0.479 0.998 0.342 0.945 0.569 0.140
R -0.445 -0.150 0.284 0.415 0.381 -0.044
pDMN BPI p 0.056 0.540 0.238 0.077 0.108 0.859
R -0.041 0.269 -0.201 -0.140 -0.167 0.106
BDI-I* p 0.865 0.252 0.397 0.555 0.481 0.655
R 0.105 -0.258 -0.004 -0.90 0.087 0.090
STAI-T* p 0.661 0.272 0.987 0.706 0.717 0.706
R -0.105 -0.090 -0.293 0.188 0.227 0.103
FIN BPI p 0.669 0.714 0.224 0.441 0.350 0.674
R 0.424 -0.426 -0.137 -0.157 -0.379 0.145
BDI-I* p 0.063 0.061 0.564 0.508 0.099 0.542
R -0.020 0.208 0.078 0.014 0.338 0.325
STAI-T* p 0.932 0.379 0.745 0.954 0.145 0.162
R -0.301 0.272 0.267 0.445 0.044 -0.197
SMN BPI p 0.210 0.261 0.269 0.056 0.858 0.419
R 0.366 0.297 -0.437 -0.290 -0.378 -0.136
BDI-I* p 0.112 0.203 0.054 0.215 0.100 0.567
R 0.031 0.007 0.076 0.002 0.075 -0.134
STAI-T* p 0.898 0.976 0.749 0.992 0.753 0.572
 Study III

Functional network connectivity of pain-related

resting state networks in somatoform pain disorder:

an exploratory fMRI study

Published in

Journal of Psychiatry and Neuroscience.

2013; 38(1):57-65.
 Research Paper

Functional network connectivity of pain-related

resting state networks in somatoform pain disorder:
an exploratory fMRI study
Alexander Otti, MD (candidate); Harald Guendel, MD; Peter Henningsen, MD;
Claus Zimmer, MD; Afra M. Wohlschlaeger, PhD; Michael Noll-Hussong, MD
Otti, Zimmer, Wohlschlaeger Abteilung fuer Neuroradiologie, Klinikum rechts der Isar, Technische Universitaet Muenchen;
Otti, Henningsen Klinik und Poliklinik fuer Psychosomatische Medizin und Psychotherapie, Klinikum rechts der Isar, Tech-
nische Universitaet Muenchen, Muenchen; Guendel, Noll-Hussong Klinik und Poliklinik fuer Psychosomatische Medizin und
Psychotherapie, Universitaetsklinikum Ulm, Ulm, Germany

Early-released on Aug. 14, 2012; subject to revision.

Background: Without stimulation, the human brain spontaneously produces highly organized, low-frequency fluctuations of neural activ-
ity in intrinsic connectivity networks (ICNs). Furthermore, without adequate explanatory nociceptive input, patients with somatoform pain
disorder experience pain symptoms, thus implicating a central dysregulation of pain homeostasis. The present study aimed to test
whether interactions among pain-related ICNs, such as the default mode network (DMN), cingularinsular network (CIN) and sensorimo-
tor network (SMN), are altered in somatoform pain during resting conditions. Methods: Patients with somatoform pain disorder and
healthy controls underwent resting functional magnetic resonance imaging that lasted 370 seconds. Using a data-driven approach, the
ICNs were isolated, and the functional network connectivity (FNC) was computed. Results: Twenty-one patients and 19 controls en-
rolled in the study. Significant FNC (p < 0.05, corrected for false discovery rate) was detected between the CIN and SMN/anterior DMN,
the anterior DMN and posterior DMN/SMN, and the posterior DMN and SMN. Interestingly, no group differences in FNC were detected.
Limitations: The most important limitation of this study was the relatively short resting state paradigm. Conclusion: To our knowledge,
our results demonstrated for the first time the resting FNC among pain-related ICNs. However, our results suggest that FNC signatures
alone are not able to characterize the putative central dysfunction underpinning somatoform pain disorder.

Introduction The human brains resting state is characterized by low-

frequency fluctuations of spontaneous neural activity.8 With-
Somatoform pain disorder is a mental disorder characterized out stimulation, this activity is highly organized in several in-
by chronic bodily complaints without sufficient explanatory trinsic connectivity networks (ICNs).9 Some of the ICNs appear
peripheral pathology.1 Although the causes and mechanisms to be pain-related, such as the default mode network (DMN),
behind this mental disorder remain unclear, both functional which comprises cortical midline structures and lateral parietal
and structural alterations in the limbic structures seem to cor- regions,1012 the cingular-insular network (CIN), and the senso-
relate with this non-nociceptive chronic pain condition. 24 rimotor network (SMN).8,1319 There is interplay among the
Moreover, human brain imaging studies have revealed new regions within an ICN and among the ICNs themselves. As
roles that cortical neuronal networks play in chronic pain,5 in- shown recently in individuals with schizophrenia, differences
cluding the unpleasant quality of pain.6 The current study ex- in internetwork communication regarding FNC could be a
panded upon a new approach for testing one important facet valid measure that reflects the deficiencies in cortical process-
of the network model to examine the intrinsic functional con- ing in patients with chronic psychiatric symptoms.20 Therefore,
nectivity between networks active during resting state: the we aimed to test the practical relevance of FNC for chronic,
functional network connectivity (FNC).7 medically unexplained pain. Specifically, given a central

Correspondence to: M. Noll-Hussong, Clinic for Psychosomatic Medicine, University of Ulm, Am Hochstraess 8, D 89081 Ulm, Germany;
[email protected]
J Psychiatry Neurosci 2012.
Submitted Dec. 4, 2011; Revised Mar. 31, 2012; Accepted May 10, 2012.
DOI: 10.1503/jpn.110187

2012 Canadian Medical Association

J Psychiatry Neurosci 1
Otti et al.

disconnection of pain-related neural systems, we hypothesized ing to a modified structured psychiatric interview based on
that alterations exist in the FNC between the DMN, CIN and the German version of the SCID-I.28 The SCID-I evaluates the
SMN in patients with somatoform pain disorder. present (i.e., the 4 weeks preceding the interview) and life-
time psychiatric status for major Axis I psychiatric disorders
Methods using criteria that correspond with the DSM-IV.1
The SF-36 is a multipurpose, short-form health survey
This study was approved by the local ethics committee comprising 36 questions.29 It yields an 8-scale profile of func-
(Ethikkommission der Fakultaet fuer Medizin der Technischen Uni- tional health and well-being scores, psychometrically based
versitaet Muenchen) and conducted in accordance with the Dec- physical and mental health summary measures, and a
laration of Helsinki. We obtained written informed consent preference-based health utility index. This questionnaire is a
from all participants. Healthy controls were recruited from the generic measure instead of one that targets a specific age, dis-
general community. All patients had pain-predominant multi- ease or treatment group. Accordingly, the SF-36 has been
somatoform disorder12,21 and were recruited from outpatient de- proven useful in surveys of general and specific population
partments of neurology, internal medicine and pain treatment groups because it compares the relative burden of disease
centres. Pain-predominant multisomatoform disorder, a and differentiates the health benefits of a wide range of treat-
mediumsevere somatoform disorder, was primarily diag- ments.30 Its German translation has been validated in a var-
nosed by an experienced physician (M.N.-H.), who performed iety of German health care settings.31,32 The PCS subscore of
a modified Structured Clinical Interview for DSM-IV Axis I the SF-36 has been shown to be a valid and change-sensitive
Disorders (SCID-I), verifying the official criteria for somatoform indicator of bodily function and quality of life;33 moreover, it
and chronic pain disorder. We modified the interview to check addresses the major concerns of our patients more directly
for the presence of multisomatoform disorder according to the than the mental component summary.34
published criteria.22 The main feature of somatoform disorders The PHQ-1535,36 is a brief, self-administered questionnaire
is the repeated presentation of physical symptoms with persis- that is useful in screening for somatization and monitoring the
tent requests for medical examinations, despite repeated nega- severity of somatic symptoms in clinical practice and research.
tive findings and reassurances by doctors that the symptoms Scores of 5, 10 and 15 represent the cutoff values for low,
have no physical basis. If any physical disorders are present, medium and high somatic symptom severity, respectively.
the disorders do not explain the nature and extent of the symp- The Brief Pain Inventory (BPI)37 was developed by the
toms or the distress and preoccupation of the patient.23 Multiso- Pain Research Group of the World Health Organization Col-
matoform disorder is defined as 3 or more medically unex- laborating Centre for Symptom Evaluation in Cancer Care to
plained, currently bothersome physical symptoms plus a long provide information on the intensity of pain (the sensory di-
( 2 years) history of somatization.22 It has been shown that, mension) and degree to which pain interferes with function
compared with mood and anxiety disorders, multisomatoform (the reactive dimension). The validity of the BPI has been
disorder is associated with comparable impairments in health- demonstrated in both the German version26 and for measur-
related quality of life, more self-reported disability days and ing pain in patients without cancer.38 The BPI item scores for
clinic visits, and the highest level of provider frustration.22,24 each patient are provided in Appendix, Table S1, available at
In this context, as a precondition, the physical component cma.ca/jpn.
summary (PCS) measure25 in our patient group was required The Beck Depression Inventory (BDI-I)39,40 is a 21-item self-
to be 1 standard deviation [SD] or more below the population report instrument that measures cognitive and endogenous
norm (i.e., 40, as measured by the SF-36), thus meeting the aspects of depression on a 4-point scale ranging from 0 to 3.
DSM-IV criterion B for significant distress or psychosocial The standard cutoffs are as follows: a total score of 09 indi-
impairment due to the somatoform pain in patients with pain cates no depression, 1018 indicates mild depression, 1929
disorder.1 The second precondition was that the score on the indicates moderate depression and a score of 30 or greater in-
15-item Patient Health Questionnaire (PHQ-15) had to be dicates severe depression. This questionnaire has undergone
greater than 10, which represents medium somatic symptom extensive reliability and validation studies.
severity. We used the German version of the Brief Pain In- According to the homepage of the publishing house Pear-
ventory26 to estimate the intensity of the participants pain. son Assessments,41 the Symptom Checklist-90-R (SCL-90-
We excluded patients with insufficient cognitive abilities, R) instrument helps evaluate a broad range of psychological
severe chronic somatic diseases, unambiguous nociceptive problems and symptoms of psychopathology. The instru-
pain (postsurgical or phantom limb pain), hypochondria, ment is also useful in measuring patient progress or treat-
posttraumatic stress disorder (PTSD), a severe comorbid ment outcomes. The 90 items of the German version of this
mental disorder that caused major social functioning impair- checklist are scaled from 0 to 4 and are associated with
ment (e.g., schizophrenia or severe substance abuse), or in- problems that the patient has been experiencing during the
sufficient German language skills. We assessed handedness last 7 days.42 The summarizing global severity index is a
using the Edinburgh Handedness Inventory.27 de facto standard for psychotherapy clinical practice and
research, and it serves as a symptom severity thermom-
Psychometric measurement eter. The 9 specific subscales of the SCL-90 (e.g., SOM:
somatization) provide an overview of the spectrum of pa-
The occurrence of somatoform disorder was assessed accord- tient complaints.43

2 J Psychiatry Neurosci
 Functional network connectivity of pain-related resting state networks

Functional MRI resting state paradigm components and time courses. The toolbox performed the
analysis in 3 stages: data reduction, application of the ICA al-
Participants were asked to stay awake but close their eyes gorithm and back reconstruction for each participant.44 In the
and relax for 370 seconds. After the scanning session, partici- initial step, the data from each participant underwent princi-
pants were asked whether they had fallen asleep during the pal component analysis to reduce the computational com-
scan. Patients who responded positively or ambiguously plexity. Thus, most of the informational data content was
were excluded from the study. preserved. After concatenating the resulting volumes, 29 in-
dependent sources were estimated using the GIFT dimen-
Data acquisition and fMRI procedures sionality estimation tool based on the aggregated data. The
final reduction was again achieved using principal compon-
Images were acquired using a 3 T Philips Achieva scanner ent analysis according to the selected number of components.
with a standard 8-channel SENSE head coil. Thirty-two con- In the second stage of the analysis, we used the Infomax algo-
tiguous slices (no gap) were acquired with a steep angula- rithm to run the ICA and a mask based on all participants. In
tion, such that the eyes were excluded, using a gradient echo- the final stage of back reconstruction, the time courses and
planar sequence with the following parameters: repetition spatial maps were computed for each participant. The result-
time (TR) 2000 ms, echo time (TE) 35 ms, 82 flip angle, field ing mean spatial maps for each participant were transformed
of view (FOV) 220 mm, slice thickness 4 mm, 80 80 matrix, to z scores for display.44
2.75 2.75 mm voxel size, and SENSE factor 2. Anatomic im- Individual participant maps of the ICNs were entered into
ages were obtained using a T1-weighted turbo gradient echo 1-sample t tests for 1-group analyses and 2-sample t tests for
sequence with the following parameters: TR 9 ms, TE 4 ms, 8 group comparison in SPM5. Results were thresholded at
flip angle, FOV 240 mm, 240 240 matrix, 1 mm isotropic p = 0.05 and corrected for family-wise error with a cluster ex-
voxel size, 170 slices and no gap. tent threshold of 50 voxels.

Image processing and data analysis: preprocessing Functional network connectivity

The data analysis was performed using the SPM5 (Statistical The functional networks isolated by ICA are both spatially
Parametric Mapping software, Wellcome Trust Centre for and temporally independent.44 However, temporal correla-
Neuroimaging, www.fil.ion.ucl.ac.uk). We discarded the first tions can exist between the networks. To measure this func-
3 images of each run to allow for equilibration of the longitu- tional network connectivity (FNC), we computed a con-
dinal magnetization. The preprocessing steps included strained maximal lagged correlation using the FNC toolbox
1. the realignment and unwarping of the images to correct for (http://mialab.mrn.org/software/#fnc).20 Next, the maximal
movement artifacts and related susceptibility artifacts, lagged correlation was assessed between all pair-wise com-
2. a coregistration of the anatomic to the functional images, binations of the 4 ICNs selected for the analysis, which led to
3. the segmentation and normalization of the anatomic image 6 possible combinations.
to the standard stereotactic space (Montreal Neurological We calculated the correlation between the 2 time courses
Institute [MNI]),4 using the following formula, where is the correlation be-
4. the application of a normalization transformation to the tween 2 time courses, X is time course 1 (dimension T
functional images, and 1 unit), Y is time course 2 (dimension T 1 unit), T is the
5. the smoothing with a 8 mm Gaussian kernel for the group number of time points in the time course, io is the starting ref-
analysis. erence of the 2 original time courses, i is the noninteger
change in time in seconds, Xio is X at the initial reference
Connectivity analysis point io, Yio+i is Y shifted from the reference point io, i is the
maximal lagged correlation and i is the lag between the
We performed an independent component analysis (ICA) on time courses in seconds:20
all participants (patients and controls) using the group ICA
from the fMRI toolbox (GIFT version 1.3h; http://icatb
.sourceforge.net) developed for fMRI data analysis.44 Follow-
ing the method of Jafri and colleagues,20 we additionally per-
formed 2 separate group ICAs on patients and controls to
ensure that the resulting components had similar resting
state fluctuations in the 2 groups, as in the resulting com- The correlation and lag values were computed for all par-
ponents attained from all [...] participants combined.20 For ticipants and then averaged for the controls and patients. The
group comparisons, however, a separate group ICA may not correlation value reflects the dependency between 2 resting
be optimal because it biases toward false-positive results of state networks. Significant correlation combinations from the
group differences.45 Therefore, we reported and used the data 6 possible combinations were separately extracted for both
of the combined ICA for group comparisons. groups, which led to FNC maps for each group (t test,
First, the individual data sets were concatenated across p < 0.05). In addition, corresponding to the significant correl-
time. This was followed by computing the subject-specific ation combinations, the averaged lag values, which represent

J Psychiatry Neurosci 3
Otti et al.

the amount of delay between 2 correlated component time among participants with somatoform pain disorder (item 5)
courses, were calculated for each group.20 using the BPI was 7 of 10 (SD 2.24). All of the patients with
chronic pain but none of the controls experienced persistent
Group difference somatoform pain throughout the scan (Table 1 and Appendix 1,
Table S1).
Significant differences in the FNC between patients and con- In accordance with published results, we identified the fol-
trols were calculated using a 2-sample t test (p < 0.05, cor- lowing pain-related networks by visual inspection (Fig. 1 and
rected for false discovery rate).46 The lag values were com- Table 2):
pared between both groups (2-sample t test, p < 0.05, the anterior default mode network (aDMN), which consists
corrected for false discovery rate). of the cortical midline structures, such as the medial pre-
frontal cortex and precuneus;1517,47
Correlation analysis the posterior default mode network (pDMN), which con-
sists of the lateral parietal regions and precuneus;1517,47
The FNC was correlated with the BDI and BPI scores the CIN, which consists of both the insular and cingular
(p < 0.05, corrected for multiple comparisons). cortex;13,19 and
the SMN, which consists of the pre- and postcentral
Results gyrus.14
The FNCs of the patients with chronic pain and the con-
In all, 19 healthy controls (mean age 48.79 [SD 12.25] yr; trol group are shown in Figure 2. Both groups showed a
12 women) and 21 outpatients (mean age 46.62 [SD 12.49] yr; significant FNC between the CIN and SMN, the aDMN
17 women) were involved in this study. All participants were and pDMN/SMN, and the pDMN and SMN. No sig -
native speakers of German and were of Caucasian origin. All nificant differences in FNCs were found between groups
participants were right-handed. Participant demographic (Fig. 3). No significant correlation was found between the
and clinical characteristics are summarized in Table 1. FNC and BDI or BPI scores (p < 0.05, corrected for multiple
Before the fMRI scan, the mean value of pain intensity comparisons).

Table 1: Demographic and clinical characteristics of healthy controls and patients with somatoform pain

Group; mean (SD) [range]*

Characteristic Controls Patients

Age, yr 48.79 (12.25) [2464] 46.62 (12.49) [2268]

Sex, no. male:female 7:12 4:17
Medication, no.
Antidepressants 10
Analgesics/relaxants/NSAIDs 10
Anxiolytics 1
BDI score 4.43 (4.70) [016] 17.84 (9.03) [337]
BPI item (scale)
1: Pain within the last week (yes/no) 19 no 21 yes
2: Pain today (yes/no) 19 no 21 yes
3: Pain at its worst during the last week (010) 7 (2.25)
4: Pain at its least during the last week (010) 4.21 (2.5)
5: Pain on the average (010) 5.63 (2.1)
6: Pain right now (010) 5.53 (2.9)
8: Pain relief by therapy (010) 5.50 (2.8)
9: Impairment (010)
9A: General activity 5.74 (2.6)
9B: Mood 4.84 (2.9)
9C: Walking ability 4.32 (3.1)
9D: Normal work 5.37 (2.5)
9E: Relation with other people 4 (2.6)
9F: Sleep 4.89 (3.0)
9G: Enjoyment of life 4.86 (2.8)
SCL-90-R
Global severity index 0.28 (0.28) 0.96 (0.56)
Somatization 0.34 (0.31) 1.4 (0.64)
39 26
BDI = Beck Depression Inventory; BPI = Brief Pain Inventory; NSAID = nonsteroidal anti-inflammatory drug; SCL-90-R = Symptom
42
Checklist 90 R; SD = standard deviation.
*Unless otherwise indicated.
Significant group differences, p < 0.05.

4 J Psychiatry Neurosci
 Functional network connectivity of pain-related resting state networks

Discussion sis does not provide insight into causality, our results encour-
age further research on the putative effects of DMN and CIN
The present study shows how pain-related ICNs are inter- activity on the SMN.
connected during the resting state using a reasonably sized Contrary to our hypothesis, the present study shows that
group of clinically well-classified participants. Using a data- somatoform pain does not lead to significantly disturbed
driven approach, we isolated the CIN, SMN and DMN. Ac- FNC among pain-associated networks during the resting
cording to previous studies, an anterior and posterior sub- state. This finding is remarkable because chronic pain has
system of the DMN could be identified.47,48 The aDMN is been shown to be a strong disruptor of intranetwork func-
associated with cognitive control of emotions and self- tional connectivity within the somatosensory, affective and
referential processing, whereas the pDMN is related to cognitive neural systems.1315,17 Notably, our patients subject-
mnestic functions.4953 The CIN subserves affective reactions, ively experienced severe ongoing pain, as their pain intensity
and the SMN underpins sensory-discriminative pro - rating using the BPI was 7 of 10. In comparison, in cancer-
cessing.18,19 The SMN strongly interacts with the CIN, aDMN induced bone pain, for example, which is the most common
and pDMN. These interactions suggest that sensory- cause of pain in cancer patients, the median average pain
discriminative processing is highly related to affective pro- rating based on the BPI has been reported to be 4 of 10.57 One
cessing, self-referential thoughts and memory functions. Fur- may speculate several explanations for this finding. Evidence
thermore, the SMN lags the time course of the other ICNs by for an important role of resting FNC in central nervous sys-
seconds. Emotional and cognitive processing appear to pre- tem disorders stems from research on schizophrenia, which
cede the activity of the sensorimotor system during the rest- is widely known to be characterized by bizarre inner
ing state. This may explain the influence of the inner world, processes, such as hallucinations, delusions and disorganized
with its various subjective states, such as anxiety, sadness thoughts.20 One important characteristic of schizophrenia is
and individual predictions about the future on the perception the patients disability to distinguish between inner experi-
of the outer world via sensory systems.5456 Because our analy- ences caused by psychotic states and outer reality. Somato-
form pain, however, is not associated with a disturbed sense
of reality or personality. Thus, disturbed FNC may reflect
aDMN 24.3
highly disorganized states of consciousness rather than
symptoms, such as ongoing non-nociceptive pain.
Furthermore, as external triggers, such as aversive emo-
tional experiences, are considered to be relevant in the etiol-
0.0 ogy of somatoform pain disorder, one may speculate that sig-
pDMN nificant differences in FNC are not elicited during rest but in
29.9
response to stimulation. For example, noxious heat led to
higher blood oxygenlevel dependent signalling in the insula
and parahippocampal gyrus, while medial prefrontal cortex
activity was reduced.58 Reduced insula and amygdala activity
0.0
was observed during emotional empathy, indicating dis-
turbed emotional processing.59
CIN However, fibromyalgia, which most closely resembles so-
22.1
matoform pain disorders in many aspects, displays a charac-
teristic connectivity pattern during rest, as recently shown
by Cifre and colleagues.60 They found that functional connec-
0.0 tivity of the anterior cingulate, insula and somatosensory
regions with amygdala and basal ganglia was enhanced,
SMN whereas the interplay between somatosensory and default
18.2
mode regions was reduced. In our study, however, a non-
significantly higher FNC between the CIN and SMN was ob-
served in controls, whereas the FNC of the aDMN/pDMN,
aDMN/SMN, and pDMN/SMN was nonsignificantly
0.0 higher in patients with somatoform pain. For this reason, the
lack of differences between controls and patients in terms of
FNC may mirror methodological issues rather than etio-
Fig. 1: Intrinsic connectivity networks (ICNs) of the entire partici-
logical characteristics of different psychiatric and psychoso-
pant group (19 healthy controls and 21 patients with somatoform
matic entities.
pain): anterior default mode network (aDMN), posterior default
mode network (pDMN), cingular-insular network (CIN) and sensori-
motor network (SMN). For illustration purposes, the spatial maps of Limitations
the patients and controls were concatenated into SPM5 and thresh-
olded at p < 0.05, corrected for family-wise error; the colour bars An important limitation of the current study was medication.
represent t values. Antidepressants and analgesics were being taken by more

J Psychiatry Neurosci 5
Otti et al.

Table 2: Intrinsic connectivity networks*

MNI coordinate
Cluster size,
Network Region x y z voxels t value

Anterior default mode network Left anterior cingular cortex 2 46 6 7559 24.33
Left gyrus frontalis inferior, pars orbitalis 34 18 20 328 10.34
Left precuneus 6 54 24 180 10.26
Right gyrus frontalis inferior, pars orbitalis 38 24 16 379 10.20
Left middle cingular cortex 0 14 36 115 9.89
Right precuneus 6 52 24 30 7.52
Right thalamus 4 16 6 49 7.03
Left gyrus parahippocampalis 22 28 14 8 6.38
Posterior default mode network Right posterior cingular cortex 6 42 26 7846 29.88
Left gyrus angularis 42 62 40 686 10.17
Right gyrus angularis 38 58 38 423 7.69
Left gyrus temporalis medius 54 10 18 3 6.20
Cingularinsular network Left insula 40 16 6 2940 22.08
Right supplementary motor area 2 12 64 2642 17.01
Right gyrus frontalis inferior, pars orbitalis 40 24 12 2046 16.39
Left gyrus frontalis medius 36 52 18 765 10.63
2 16 44 211 10.56
Left gyrus supramarginalis 60 42 24 295 8.97
Left precentral gyrus 40 2 54 242 8.93
Right gyrus supramarginalis 62 40 26 150 8.06
Left gyrus frontals inferior, pars opercularis 52 14 32 41 7.37
Right gyrus frontalis medius 30 50 22 72 7.03
Right precentral gyrus 46 6 48 19 6.89
Right gyrus temporalis medius 52 22 12 12 6.21
Sensorimotor network Right precentral gyrus 24 16 70 16580 18.19
Right insula 34 24 14 48 8.19
2 10 4 16 6.82
Right gyrus temporalis inferior 52 66 6 3 5.96
MNI = Montreal Neurological Institute.
*p < 0.05, corrected for family wise error.
Determined using the Wake Forest University Pickatlas (http://fmri.wfubmc.edu/software/PickAtlas).

3.0 3.0
7 7
SMN SMN
Controls Patients
2.5 2.5

2.0 2.0

27 12 1.5 12 1.5
27

pDMN aDMN pDMN aDMN

1.0 1.0

0.5 0.5

CIN
L R L R
14 14
0.0 0.0
Lag time, s Lag time, s

Fig. 2: Functional network connectivity (FNC) between the anterior default mode network (aDMN), posterior default mode network (pDMN),
sensorimotor network (SMN) and cingularinsular network (CIN) in the control group (left) and patient group (right). Arrows represent a signifi-
cant correlation between components (p < 0.05, corrected for false discovery rate). The lag time between the connected networks is shown by
the direction of each arrow. An arrow that connects the CIN and SMN (pointing toward the latter) signifies that the time course of the SMN is
delayed with respect to the CIN. However, no significant group differences were detected (p < 0.05, corrected for false discovery rate).

6 J Psychiatry Neurosci
 Functional network connectivity of pain-related resting state networks

than half of our patients. It is of note that despite ethical rea- Conclusion
sons, it was nearly impossible to convince patients with so-
matoform pain to interrupt their (psychotropic) medication To our knowledge, our results demonstrate for the first time
in this intentionally naturalistic study. As the patients of resting FNC between pain-related ICNs and its association
Cifre and colleagues60 did not undergo a drug washout, we with somatoform pain disorder. In contrast to our hypothe-
cannot exclude the possibility that medication influenced our sis, the resting FNC approach may not sufficiently explain
results. Moreover, regarding the poor health status of our pa- the putative central dysfunction of pain homeostasis in
tients, our resting paradigm lasting 370 seconds was rela- chronic non-nociceptive pain. Our negative results encourage
tively short. Other studies used rest sessions of about 10 min- further research on the effect of chronic pain and affective
utes.13,60 However, given that patients with somatoform pain disorders on the FNC of the human brain.
normally complain about long recumbency in the scanner,
one may argue that a longer paradigm may have enhanced Acknowledgements: This work was supported by a KKF fund
(Klinikum rechts der Isar, Technische Universitaet Muenchen, Ger-
patient pain and led to false-positive results.
many) awarded to M. Noll-Hussong and A.M. Wohlschlaeger and a
Given the high comorbidity of somatoform pain with affect- grant awarded to M. Noll-Hussong from the Dr. Ing. Leonhard-
ive disorders61 and their influence on brain function,58,62 de- Lorenz Foundation (Technische Universitaet Muenchen, Germany).
pressive symptoms may have influenced our results. Several
Competing interests: None declared for A. Otti and C. Zimmer.
studies have indicated an important role of functional con- H. Guendel declares receiving consultancy fees, payment for expert tes-
nectivity in depressive symptoms. For example, functional timony and payment for lectures from MAN, Oc and AUDI, and a
connectivity within the DMN was enhanced in our study, grant from the German Federal Ministry of Education and Research
which has been correlated with stronger self-referential (grant 01EL0815). P. Henningsen declares having received lecture spon-
sorship from Lilly and book royalties from Cambridge University
processes in depressed patients.6365 Northoff and colleagues66 Press. A.M. Wohlschlaeger declares having received support through
found meta-analytic evidence that not only intranetwork con- her institution from German Federal Ministry of Education and Re-
nectivity, but also disturbed interplay between several brain search grant 01EV0710. As above for M. Noll-Hussong; he also declares
systems, may be the neural underpinning of this disease. In having received travel support from the German Academic Exchange
Service DAAD).
our study, however, no significant effect of depression on
FNC was observed. Contributors: A. Otti conducted the research, analyzed data, and

0.7 3.0
0.7
1.0
Controls Patients Controls v. patients 2.4
0.6
0.6
1.8
0.8
0.5
0.5
1.2

0.4 0.6
0.4 0.6
Correlation,
Correlation

0.3 0.0
0.3 0.4
0.6
0.2 0.2
0.2 1.2
0.1 0.1
1.8
0.0
0.0 0.0 2.4

0.1 0.1 3.0

Lag time, s
SMN/pDMN

SMN/pDMN

SMN/pDMN

aDMN/pDMN

aDMN/CIN
aDMN/pDMN

aDMN/CIN

aDMN/pDMN

aDMN/CIN

pDMN/CIN

pDMN/CIN
SMN/CIN

pDMN/CIN

SMN/CIN

SMN/CIN
SMN/aDMN

SMN/aDMN

SMN/aDMN

Intrinsic connectivity network

Fig. 3: Correlation and lag values between intrinsic connectivity networks (ICNs) of the controls (left) and patients (middle) and a group com-
parison (right). The numbers on the abscissa represent the 6 possible combinations between the ICNs. The ordinates show the correlation co-
efficient describing the functional network connectivity (FNC) of each combination for the controls and patients and the difference in the correl-
ation coefficient (correlation ) between the controls and patients. The red-dotted horizontal line shows the user p value threshold (p < 0.05,
corrected for false discovery rate). Blue horizontal lines show correlation p values of each test. The colour of the bars represents the lag time
in seconds. In controls and patients, significant FNC was detected between the SMN/aDMN, SMN/CIN, SMN/pDMN and aDMN/pDMN but not
the aDMN/CIN or pDMN/CIN. Compared with the control group, the FNC of patients was nonsignificantly lower between the SMN/CIN and
nonsignificantly higher between all the other ICNs. aDMN = anterior default mode network; CIN = cingularinsular network; pDMN = posterior
default mode network; SMN = sensorimotor network.

J Psychiatry Neurosci 7
Otti et al.

wrote the paper. H. Guendel designed the research and wrote the pa- in the motor cortex of resting human brain using echo-planar MRI.
per. P. Henningsen and C. Zimmer designed the research. Magn Reson Med 1995;34:537-41.
A.M. Wohlschlaeger designed and performed the research. M. Noll-
Hussong designed and conducted the research, analyzed the data, 19. Seeley WW, Menon V, Schatzberg AF, et al. Dissociable intrinsic
and wrote the paper. All authors have approved the final article. connectivity networks for salience processing and executive con-
trol. J Neurosci 2007;27:2349-56.

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J Psychiatry Neurosci 9
Appendix 1 to Otti A, Guendel H, Henningsen P, et al. Functional network connectivity of pain-related resting state
networks in somatoform pain disorder: an exploratory fMRI study. J Psychiatry Neurosci 2012.

DOI: 10.1503/jpn.110187

Copyright 2012, Canadian Medical Association or its licensors.

Table S1: Brief Pain Inventory item scores for each patient*

BPI item

Patient 1 2 3 4 5 6 8 9A 9B 9C 9D 9E 9F 9G

1 Yes Yes 5 5 5 2 3 4 5 4 3 7 6 8
2 Yes Yes 8 3 6 5 8 8 7 7 7 4 4 7
3 Yes Yes 8 7 7 8 7 8 9 6 7 7 10 9
4 Yes Yes 10 9 9 10 9 10 4 9 10 9 9 3
5 Yes Yes 9 4 5 6 5 7 7 0 7 3 1 4
6 Yes Yes 2 1 2 1 2 1 3 3 1 0 1
7 Yes Yes 4 0 2 1 3 1 2 3 1 2 1
8 Yes Yes
9 Yes Yes 6 3 5 4 3 5 6 1 8 5 5 7
10 Yes Yes 10 7 9 9 0 9 9 10 1 5 9 7
11 Yes Yes 10 7 8 10 0 9 0 4 2 0 2 0
12 Yes Yes 7 5 6 8 5 4 2 1 4 0 6 1
13 Yes Yes 5 4 4 5 5 4 3 5 7 4 5 3
14 Yes Yes 8 6 8 8 7 8 9 8 8 6 8 8
15 Yes Yes
16 Yes Yes 8 6 7 7 4 2 3 4 2 5 3
17 Yes Yes 5 1 3 3 9 3 5 3 6 5 5 6
18 Yes Yes 7 4 6 5 3 6 5 7 3 4 7 5
19 Yes Yes 5 0 4 3 5 2 3 2 4 1 0 3
20 Yes Yes 7 3 4 3 5 5 7 0 7 5 3 6
21 Yes Yes 9 5 7 7 2 8 7 7 8 7 6 7
BPI = Brief Pain Inventory (Radbruch L, Loick G, Kiencke P, et al. Validation of the German version of the Brief Pain Inventory. J Pain Symptom Manage
1999;18:180-7.)
*Missing data are indicated with an em-dash. BPI items are as follows: 1 = pain within the last week, 2 = pain today, 3 = pain at its worst during the last
week, 4 = pain at its least during the last week, 5 = pain on the average, 6 = pain right now, 8 = pain relief by therapy, 9A = impairment of general activity,
9B = impairment of mood, 9C = impairment of walking ability, 9D = impairment of normal work, 9E = impairment of relations with other people, 9F =
impairment of sleep, 9G = impairment of enjoyment of life.