Brain Activation during Perception and Anticipation of Dyspnea in Chronic Obstructive Pulmonary Disease

Abstract

Background: Dyspnea is the impairing cardinal symptom in COPD, but the underlying brain mechanisms and their relationships to clinical patient characteristics are widely unknown. This study compared neural responses to the perception and anticipation of dyspnea between patients with stable moderate-to-severe COPD and healthy controls. Moreover, associations between COPD-specific brain activation and clinical patient characteristics were examined.
Methods: During functional magnetic resonance imaging, dyspnea was induced in patients with stable moderate-to-severe COPD (n = 17) and healthy control subjects (n = 21) by resistive-loaded breathing. Blocks of severe and mild dyspnea were alternating, with each block being preceded by visually cued anticipation phases.
Results: During the perception of increased dyspnea, both patients and controls showed comparable brain activation in common dyspnea-relevant sensorimotor and cortico-limbic brain regions. During the anticipation of increased dyspnea, patients showed higher activation in hippocampus and amygdala than controls which was significantly correlated with reduced exercise capacity, reduced health-related quality of life, and higher levels of dyspnea and anxiety.
Conclusions: This study suggests that patients with stable moderate-to-severe COPD show higher activation in emotion-related brain areas than healthy controls during the anticipation, but not during the actual perception of experimentally induced dyspnea. These brain activations were related to important clinical characteristics and might contribute to an unfavorable course of the disease via maladaptive psychological and behavioral mechanisms.

Full text

ORIGINAL RESEARCH
published: 23 August 2017
doi: 10.3389/fphys.2017.00617
Frontiers in Physiology | www.frontiersin.org 1August 2017 | Volume 8 | Article 617
Edited by:
Reinoud Gosens,
University of Groningen, Netherlands
Reviewed by:
Nicolle Jasmin Domnik,
Queen’s University, Canada
Iulia Ioan,
Hôpital d’Enfants, France
*Correspondence:
Andreas von Leupoldt
andreas.vonleupoldt@ppw.kuleuven.be
Specialty section:
This article was submitted to
Respiratory Physiology,
a section of the journal
Frontiers in Physiology
Received: 18 May 2017
Accepted: 09 August 2017
Published: 23 August 2017
Citation:
Esser RW, Stoeckel MC, Kirsten A,
Watz H, Taube K, Lehmann K,
Magnussen H, Büchel C and von
Leupoldt A (2017) Brain Activation
during Perception and Anticipation of
Dyspnea in Chronic Obstructive
Pulmonary Disease.
Front. Physiol. 8:617.
doi: 10.3389/fphys.2017.00617
Brain Activation during Perception
and Anticipation of Dyspnea in
Chronic Obstructive Pulmonary
Disease
Roland W. Esser 1, Maria C. Stoeckel 1, Anne Kirsten 2, Henrik Watz 2, Karin Taube 3,
Kirsten Lehmann 3, Helgo Magnussen 2, Christian Büchel 1and Andreas von Leupoldt 1, 4*
1Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2Pulmonary
Research Institute at LungClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research,
Grosshansdorf, Germany, 3Atem-Reha GmbH, Hamburg, Germany, 4Research Group Health Psychology, University of
Leuven, Leuven, Belgium
Background: Dyspnea is the impairing cardinal symptom in COPD, but the underlying
brain mechanisms and their relationships to clinical patient characteristics are widely
unknown. This study compared neural responses to the perception and anticipation of
dyspnea between patients with stable moderate-to-severe COPD and healthy controls.
Moreover, associations between COPD-specific brain activation and clinical patient
characteristics were examined.
Methods: During functional magnetic resonance imaging, dyspnea was induced in
patients with stable moderate-to-severe COPD (n=17) and healthy control subjects
(n=21) by resistive-loaded breathing. Blocks of severe and mild dyspnea were
alternating, with each block being preceded by visually cued anticipation phases.
Results: During the perception of increased dyspnea, both patients and controls
showed comparable brain activation in common dyspnea-relevant sensorimotor and
cortico-limbic brain regions. During the anticipation of increased dyspnea, patients
showed higher activation in hippocampus and amygdala than controls which was
significantly correlated with reduced exercise capacity, reduced health-related quality of
life, and higher levels of dyspnea and anxiety.
Conclusions: This study suggests that patients with stable moderate-to-severe COPD
show higher activation in emotion-related brain areas than healthy controls during the
anticipation, but not during the actual perception of experimentally induced dyspnea.
These brain activations were related to important clinical characteristics and might
contribute to an unfavorable course of the disease via maladaptive psychological and
behavioral mechanisms.
Keywords: COPD, pathophysiology, management, treatment, dyspnea, anxiety, quality of life

Esser et al. Dyspnea Perception and Anticipation in COPD
INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is a prevalent
and debilitating respiratory disease, characterized by persistent
and usually progressive airflow limitation (O’Donnell et al.,
2007; GOLD, 2017). Dyspnea is the cardinal respiratory
symptom of COPD, causing significant reductions in patients’
exercise capacity and quality of life, and is frequently linked
to comorbid anxiety and depression (Schlecht et al., 2005;
Martínez Francés et al., 2008; Maurer et al., 2008; Roche, 2009;
Yohannes and Alexopoulos, 2014; Waschki et al., 2015; GOLD,
2017). Dyspnea is usually experienced as highly aversive and
threatening (American Thoracic Society, 1999; Parshall et al.,
2012). Consequently, many patients avoid situations associated
with dyspnea, especially physical activity (O’Donnell, 2006).
This maladaptive avoidance behavior results in progressive
deconditioning, ultimately increasing dyspnea at lower activity
levels and contributing to disease progression (Reardon et al.,
2006; Troosters et al., 2013; Waschki et al., 2015). In particular,
the fearful anticipation of dyspnea is suggested to play a key role
within this spiral of decline (Hayen et al., 2013).
The brain mechanisms underlying the perception and
anticipation of dyspnea are still poorly understood. Previous
neuroimaging studies in healthy volunteers have identified
multiple dyspnea-related brain areas, presumably related to
different aspects of dyspnea. Somatosensory and motor aspects
are thought to be processed by sensorimotor areas (e.g.,
SM1, SII), while affective-motivational aspects are processed by
cortico-limbic areas including anterior insula, anterior cingulate
cortex (ACC), hippocampus, prefrontal cortex (PFC), and
amygdala (von Leupoldt and Dahme, 2005; Davenport and Vovk,
2009; Evans, 2010). Preliminary findings suggest an involvement
of several of these areas such as the insula, amygdala, ACC and
the periaqueductal gray (PAG) during the fearful anticipation
of impending dyspnea (Stoeckel et al., 2015, 2016; Faull et al.,
2016). This converges with studies on other aversive states,
e.g., fear, aversive learning, and pain, reporting activation in
similar cortico-limbic structures (Peyron et al., 2000; Apkarian
et al., 2005; Sehlmeyer et al., 2009; Wiech and Tracey, 2013).
Unfortunately, neuroimaging studies with high spatial resolution
(e.g., functional magnetic resonance imaging [fMRI]) on the
anticipation and perception of dyspnea in COPD patients are
widely absent, which greatly limits our understanding of the
potential contribution of disease-specific brain mechanisms to
the patients’ burden.
However, COPD-specific brain mechanisms due to chronic
dyspnea experiences seem highly plausible (Herigstad et al.,
2011). For example, contemporary models on the effects of
chronic pain suggest that brain activation in pain patients shifts
with chronicity from sensory to emotion-related areas, leading
to increased activation preferentially in cortico-limbic structures
(Apkarian et al., 2011; Mansour et al., 2014). Moreover, enhanced
activation was recently demonstrated in emotion-related brain
areas (i.e., PFC, ACC) of COPD patients while reading dyspnea-
related statements (Herigstad et al., 2015).
This fMRI-study aimed (1) to compare brain activation
during the perception and anticipation of resistive-load induced
increased dyspnea between patients with COPD and healthy
control subjects and (2) to evaluate potential associations with
patient characteristics. Analogous to findings on chronic pain
(Apkarian et al., 2005, 2011; Mansour et al., 2014; Baliki
and Apkarian, 2015), we hypothesized that during dyspnea
perception, both groups activate similar dyspnea-relevant brain
areas, with patients showing higher activation in cortico-limbic
structures. Based on findings on fear, aversive learning, and
dyspnea anticipation (Sehlmeyer et al., 2009; Wiech and Tracey,
2013; Stoeckel et al., 2015; Faull et al., 2016), we further
hypothesized that patients show enhanced activation in emotion-
related brain areas during dyspnea anticipation.
METHODS
Participants
Seventeen outpatients with stable (no exacerbation within the
last year) moderate-to-severe COPD (GOLD stage 2 and 3)
were recruited at a Pulmonary Research Institute at LungClinic
Grosshansdorf, Grosshansdorf, Germany (14 patients) and
an outpatient pulmonary rehabilitation center (three patients
before start of the rehabilitation program; Atem-Reha GmbH,
Hamburg, Germany). The control group consisted of 21
individuals, recruited from the database of the Pulmonary
Research Institute and was matched for age, sex, and body-mass-
index. All subjects participated in a previous study on structural
brain changes in COPD (Esser et al., 2016). This study was
approved by the ethics committees of the Medical Associations
Hamburg (PV3006) and Schleswig-Holstein (IV/EK/122/08),
and was conducted according to the Declaration of Helsinki.
Written informed consent was obtained from each participant
prior to testing.
Post-bronchodilator lung function (forced expiratory volume
in 1 s, FEV1; forced vital capacity, FVC) was measured using
standard spirometry (Miller et al., 2005), based on established
reference values (Quanjer et al., 1993). All control subjects
had normal lung function (FEV1%pred >80%; FEV1/FVC
>0.7) and no history of respiratory disease. All participants
were screened using a standardized diagnostic interview to
exclude psychiatric or neurological disorders (First et al.,
1996). Furthermore, participants completed the Hospital Anxiety
and Depression Scale (HADS) to assess individual levels of
anxiety and depression (Herrmann et al., 1995). In patients,
further clinical characteristics were collected including exercise
capacity (6-min-walk distance, 6MWD) (ATS Committee
on Proficiency Standards for Clinical Pulmonary Function
Laboratories, 2002), disease-specific quality of life (St. George’s
Respiratory Questionnaire, SGRQ) (Jones et al., 1992), and
degree of dyspnea during daily activities (modified Medical
Research Council Dyspnea Scale, mMRC) (Bestall et al., 1999).
Apparatus and Respiratory Parameters
Participants breathed through a face mask, connected to
an MR-compatible pneumotachograph (ZAN 600 unit, ZAN
Messgeräte GmbH, Oberhulba, Germany) ending in a two-way
non-rebreathing valve. A 2.6 m tube (diameter: 3.5 cm) was
permanently connected to the inspiratory port of the valve,
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Esser et al. Dyspnea Perception and Anticipation in COPD
while the expiratory port was left free. This enabled the easy
introduction and removal of MR-compatible, flow-resistive loads
of variable magnitudes at the distal end of the tube. These
loads (in-house manufactured) consisted of MR-compatible
resistive screens of different porosity, which are permanently
mounted in hard plastic casings. Each of these loads provides a
known, calibrated resistance to the inspiratory air flow during
loaded conditions, which is depending on the porosity of the
screens (i.e., the lower the porosity, the higher the resistance).
Respiratory parameters including partial pressure of end-tidal
CO2(PETCO2), peak inspiratory pressure (PI), tidal volume (VT),
breathing frequency (f), minute ventilation (VE), and inspiratory
time (TI) were measured continuously.
Experimental Protocol
One day prior to MRI testing, each subject was placed in
a supine position (outside the scanner) and presented with
different inspiratory loads of increasing magnitude. Each load
was presented for 24 s and subsequently rated with regard to
dyspnea intensity using a Borg Scale (0 =“not noticeable”
to 10 =“maximally imaginable”). The sensation of dyspnea
was explained as “uncomfortable or difficult breathing” to our
participants. Load magnitude was increased until subjects reliably
reported a sensation of “severe” dyspnea (Borg Score ≥5). That
load was then used to induce severe dyspnea during scanning. For
the mild dyspnea condition, the smallest load that was reliably
rated as different from unloaded breathing was used.
On the day of MRI scanning and after completing the
questionnaires, participants were familiarized with the
experimental design and set-up to avoid unintended learning
processes during MRI data acquisition. Therefore, each
subject underwent a computer-based standardized instruction,
including explicit details on the associations between visual cues
and experimental conditions, outside the scanner. Participants
learned the association between different colors of the fixation
cross indicating “mild” and “severe” load condition and changes
in the thickness of fixation crosses used to differentiate between
unloaded anticipation (thin cross) and loaded breathing (thick
cross) periods. Furthermore, subjects were acquainted with
the button response system used for Borg Scale ratings. Then,
participants were connected to the breathing circuit and entered
the scanner. Visual cues and Borg Scales were projected into the
scanner bore via a mirror system, using Presentation software
(Neurobehavioral Systems, Inc., Albany, CA). A test run allowed
subjects to familiarize themselves with the button-box response
system and all cues and scales.
During MRI scanning, 10 blocks of mild dyspnea and 10
blocks of severe dyspnea were presented, each lasting 24 s. In a
fixed order, each mild dyspnea condition was followed by a severe
dyspnea condition. Each loaded dyspnea condition was preceded
by a 6 s visually cued, unloaded anticipation period signaling with
100% contingency the upcoming load condition. Each loaded
condition was followed by Borg Scale ratings of dyspnea intensity
and unpleasantness, presented in randomized order. Borg Scale
ratings lasted approximately 20 s and served to recover from
loaded breathing as well as to re-establish baseline breathing
before the next load condition. All experimental events and Borg
Scale ratings were recorded via the Presentation software (for a
diagram of scanning protocol, see Figure 1).
Data Analysis
Respiratory parameters and Borg Scale ratings were averaged
across respective experimental conditions and analyzed with
SPSS Statistics 22 software (SPSS Inc., Chicago, IL), using a
significance level of p<0.05. We employed two-sample t-tests,
Mann-Whitney-U-tests (non-normal distributions), and χ2-tests
(frequency data).
MRI data were obtained on a 3T Magnetom-TRIO System
(Siemens, Erlangen, Germany) using a 32-channel head coil.
Functional MRI scans were acquired with an echo planar
imaging T∗
2-sensitive sequence (48 contiguous axial slices in
descending order, 2 mm slice thickness with 1 mm gap,
TR =2870 ms, TE =25 ms, flip angle =80◦, field of
view =208 ×208 mm). After the fMRI-measurement, we
collected a high-resolution T1-weighted structural brain image
(MP-RAGE sequence, 1 mm isotropic voxel size, 240 slices).
fMRI data preprocessing and statistical analysis was carried
out using SPM8 (Statistical Parametric Mapping, http://www.fil.
ion.ucl.ac.uk/spm) within Matlab2013a (The MathWorks, Inc.,
Natick, Massachusetts, United States). The first two blocks of
each condition were excluded from the analysis to guarantee
full adaptation to scanner environment and experimental
conditions. All images were unwarped and realigned to the
first image, coregistered to the individual high resolution T1
structural image, normalized to the standard template, and
finally smoothed with an isotropic full-width at half-maximum
Gaussian kernel of 8 mm. Severe dyspnea conditions were
contrasted with mild dyspnea conditions rather than resting
baseline conditions in order to guarantee that attention is
similarly focused to the respiratory sensations in both contrasted
conditions and not free-floating as in rest conditions, which
could have biased brain activation patterns. Additionally, some
individuals might have experienced rest conditions as relieving
compared to the more aversive character of the other conditions,
which could have resulted in confounding relief-related brain
activations instead of non-stimulus resting state activation
patterns.
On single-subject level, the statistical model included
regressors for cue mild dyspnea, mild dyspnea, cue severe
dyspnea, severe dyspnea, and ratings. Mean global signal
intensity of each volume and PETCO2 time-logged to the
beginning of each scan were included as covariates-of-no-
interest, to correct for a potential effect of respiratory fluctuations
on brain response. To compare individual results on group-level,
contrasts for the perception of increased dyspnea [severe vs.
mild dyspnea] and for the anticipation of increased dyspnea [cue
mild vs. cue severe dyspnea] were created for each participant
to calculate separate one-sample t-tests for the patient and
control group. A conjunction null analysis tested for brain
areas showing shared significant activation between both groups.
Group differences in neural activation for the perception and
anticipation of increased dyspnea were tested with two-sample
t-tests. Here, smoking status (i.e., current, former, and never
smoker) was included as covariate-of-no-interest.
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Esser et al. Dyspnea Perception and Anticipation in COPD
FIGURE 1 | Diagram of scanning protocol for one trial (out of ten). The entire scan duration was about 13–17 min and differed between participants due to differences
in individual rating speed.
Differences in neural activation were accepted as significant
if exceeding a threshold of p<0.05 after whole-brain
family-wise error correction (FWE) or family-wise error
correction within predefined regions-of-interest (ROI). ROIs
were based on previous results on the neural processing of
dyspnea (Davenport and Vovk, 2009; Evans, 2010; Herigstad
et al., 2011), pain (Peyron et al., 2000; Apkarian et al.,
2005), fear and aversive learning (Sehlmeyer et al., 2009;
Wiech and Tracey, 2013), and included primary sensorimotor
cortex (SM1), secondary somatosensory cortex (SII)/operculum,
supplementary motor area (SMA), insula, ACC, thalamus,
PFC, hippocampus, amygdala, and midbrain/PAG. Bilateral
masks were generated from the automated anatomical labeling
(AAL) template (Tzourio-Mazoyer et al., 2002). For display
purposes, we used a threshold of p uncorrected <0.001 for all
figures.
Associations of brain activation with patient characteristics
(disease duration; exercise capacity, 6MWD; quality of life,
SGRQ; level of dyspnea, mMRC; and HADS anxiety and
depression scores) were examined by off-line partial correlation
analyses (controlled for smoking status).
RESULTS
Participants
As expected, patients showed significantly lower lung function
and a greater proportion of current and former smokers
compared to controls. There were no significant group
differences regarding sex, age, height, weight, body-mass-index,
and HADS scores. Furthermore, none of the participants showed
clinically relevant HADS depression or anxiety scores. Patients
with COPD had a relatively preserved 6MWD and minor
exertional dyspnea according to the mMRC grades (Table 1).
TABLE 1 | Baseline characteristics.
COPD Controls
Subjects, n 17 21
Females/males, n 8/9 11/10
Age, yr. 65.6 (9.3) 63.4 (8.8)
Height, cm 171.0 (8.2) 173.4 (9.4)
Weight, kg 75.1 (10.7) 77.5 (13.0)
Body mass index, kg/m225.8 (3.9) 25.7 (3.3)
FEV1, % predicted 47.2 (10.9) 122.9 (10.3)***
FVC, % predicted 93.1 (12.4) 126.2 (13.0)***
FEV1/FVC, % 41.0 (9.0) 79.8 (4.7)***
SMOKING STATUS, %
- Current smoker 53% 10%***
- Former smoker 47% 19%***
- Never smoker – 71%
Depression (HADS) 3.2 (2.0) 2.0 (2.2)
Anxiety (HADS) 3.1 (2.2) 2.1 (2.2)
DISEASE SEVERITY, n
- Moderate (GOLD stage II) 4 –
- Severe (GOLD stage III) 13 –
Disease duration, years 11.0 (6.2) –
Exercise capacity (6MWD), m 490 (70) –
Quality of life (SGRQ) 37.6 (13.5) –
Level of dyspnea (mMRC) 1.06 (0.8) –
Abbreviations: FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; HADS,
Hospital Anxiety and Depression Scale; 6MWD, 6-min-walk distance; SGRQ, St. George’s
Respiratory Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale.
Data are presented as mean (SD). ***p<0.001 for the comparison between COPD and
control group.
Dyspnea Ratings
Borg Scale ratings confirmed successful induction of mild and
severe dyspnea. Ratings for dyspnea intensity and unpleasantness
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Esser et al. Dyspnea Perception and Anticipation in COPD
were significantly higher for the severe compared to the
mild dyspnea condition without significant differences between
groups. Although patients reported slightly higher intensity
and unpleasantness of mild dyspnea (most likely reflecting the
chronic respiratory impairments in these patients), the increases
from mild to severe dyspnea conditions (i.e., 1intensity and 1
unpleasantness) were comparable between groups (Table 2).
Respiratory Parameters
Both groups showed comparable, mildly hypocapnic breathing
patterns during the perception (severe vs. mild dyspnea) and
anticipation (cue severe vs. cue mild dyspnea) of dyspnea
(Supplementary Data Sheet: Table S1). Although patients
compared to controls demonstrated different absolute values
of breathing frequency, minute ventilation, and inspiratory
time throughout experimental conditions, the differences
in respiratory parameters (i.e., 1values; Table 3) were
comparable between groups, suggesting comparable respiratory
changes in both patients and controls (see Supplementary
Data Sheet, for more detailed information on respiratory
parameters).
TABLE 2 | Resistive load magnitudes and Borg Scale dyspnea ratings.
COPD Controls
MILD DYSPNEA
- Load magnitudes, kPa/l/s 0.2 (0.2) 0.3 (0.2)
- Intensity ratings 1.7 (1.1) 0.9 (0.9)*
- Unpleasantness ratings 1.9 (1.4) 0.9 (0.8)**
SEVERE DYSPNEA
- Load magnitudes, kPa/l/s 2.0 (1.0) 3.3 (1.6)**
- Intensity ratings 5.1 (1.8) 4.5 (2.4)
- Unpleasantness ratings 4.9 (2.1) 4.3 (2.5)
1Intensity 3.4 (1.7) 3.6 (1.8)
1Unpleasantness 3.0 (1.6) 3.4 (2.0)
Data are presented as mean (SD). ∆intensity and ∆unpleasantness ratings represent the
difference of ratings for the severe dyspnea condition minus the mild dyspnea condition.
*p<0.05, **p<0.01 for the comparison between COPD and control group.
TABLE 3 | Group means (SD) for 1respiratory parameters of dyspnea anticipation
(cue severe dyspnea minus cue mild dyspnea) and dyspnea perception (severe
dyspnea minus mild dyspnea) for patients with COPD and control subjects.
1anticipation of dyspnea 1perception of dyspnea
COPD Controls COPD Controls
PETCO2, mmHg −0.19 (0.92) −0.45 (0.95) −0.27 (0.7) 0.07 (0.56)
PI, mbar −0.29 (0.92) 0.18 (1.51) 7.48 (4.39) 6.09 (3.37)
VT, L −0.03 (0.15) −0.03 (0.21) −0.1 (0.13) −0.13 (0.26)
f, breaths/min −0.37 (2.07) 0.23 (1.95) 0.13 (1.49) −0.59 (1.46)
VE, L/min −1.1 (0.99) −0.66 (2.56) −1.71 (1.1) −2.55 (2.55)
TI, s 0.02 (0.26) −0.13 (0.58) 0.19 (0.21) 0.27 (0.48)
Abbreviations: PETCO2, partial pressure of end-tidal CO2; PI, Peak inspiratory pressure;
VT, Tidal volume; f, Breathing frequency; VE, Minute ventilation; TI, Inspiratory time.
Functional Imaging Data
Perception of Dyspnea
One-sample within group t-tests for [severe vs. mild dyspnea]
showed a widely comparable pattern of brain activation in
both groups during the perception of increased dyspnea
(Figures 2A,B). This included areas related to sensorimotor
processes (i.e., SM1, SII/operculum, SMA, and thalamus)
and related to emotional/cognitive processing, such as insula,
ACC, and PFC (Table 4 for patient group; see Supplementary
Data Sheet for control group: Table S2). The conjunction
analysis confirmed these findings by demonstrating a massive
overlap of neural activation patterns between the patient
and control group (Figure 2C, and Supplementary Data
Sheet: Table S3). Notably, two-sample t-tests revealed no
group differences in brain activation during increased
dyspnea perception, i.e., neither enhanced nor reduced
activation was observed in patients as compared to control
subjects.
Anticipation of Dyspnea
One-sample t-tests for [cue severe vs. cue mild dyspnea]
showed no statistically significant brain activation in any
of the two groups, neither in the whole-brain nor in the
ROI-based approach. However, two-sample t-tests revealed
significantly higher neural activation in the right amygdala
(peak: x, y, z =36, 2, −24, Z =3.33, ROI-corrected p
=0.025) and bilateral hippocampus (left peak: x, y, z =
−24, −14, −14, Z =4.38, ROI-corrected p=0.002; right
peak: x, y, z =20, −16, −16, Z =3.82, ROI-corrected p
=0.019; Figure 3) in the patient group compared to control
subjects. There were no differences between groups at a
whole-brain level and no significantly reduced activation in
patients as compared to control subjects for the anticipation of
dyspnea.
Associations between Brain Activation and Patient
Characteristics
Correlation analyses in the patient group revealed that neural
activation during dyspnea anticipation [cue severe vs. cue mild
dyspnea] in the left hippocampus was negatively correlated with
6MWD and positively correlated with mMRC and HADS anxiety
scores. Moreover, peak activations within the right amygdala
and right hippocampus were positively correlated with reduced
quality of life (i.e., higher SGRQ scores, Figure 3).
The lack of differences in brain activation between patient
and control group during the perception of increased dyspnea
allowed no offline partial correlation analyses for this contrast.
Instead, explorative post-hoc analyses included the respective
patient characteristics (e.g., disease duration, 6MWD, and scores
for SGRQ, mMRC, and HADS anxiety and depression) as
covariates-of-interest within a one-sample model for the patient
group. These analyses revealed a significant positive correlation
of disease duration with neural activation during increased
dyspnea [severe vs. mild dyspnea] in the left amygdala (peak:
x, y, z = −24, 2, −24, Z =3.44, ROI-corrected p=0.026,
Figure 4).
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Esser et al. Dyspnea Perception and Anticipation in COPD
FIGURE 2 | Brain activation during the perception of increased dyspnea. (A)
Patients with COPD showed significant activation in the supplementary-motor
area (SMA), sensorimotor cortices (SMC: primary sensorimotor cortex and
secondary somatosensory cortex/operculum), thalamus (Th), anterior cingulate
cortex (ACC), dorso-medial prefrontal cortex (dmPFC), and insula. (B) The
control group showed significant activation in comparable brain areas. (C) The
conjunction analysis (patients ∩control subjects) revealed shared brain
activation during increased dyspnea perception between the patient and
control group. For visual purposes, activation is thresholded at puncorrected <
0.001 with colorbars indicating T-values.
TABLE 4 | MNI-space peak coordinates, z-values, and p-values for regions
showing significant brain activation during increased dyspnea perception in
patients with COPD.
Brain Region x y z Z P
L SM1 −54 −18 34 5.58 0.003†
R 66 −2 14 4.70 0.008*
L SII/operculum −58 2 12 5.14 0.019†
R 64 6 12 4.89 0.001*
R SMA 10 6 46 4.78 0.002*
L Thalamus −14 −22 −6 3.84 0.025*
L INSULAR CORTEX
- Posterior −40 −4−2 4.64 0.003*
- Anterior −38 20 2 3.99 0.030*
R 50 10 −6 4.97 0.038†
L ACC −6 14 28 3.74 0.045*
R PFC
- Dorso-medial 4 20 42 4.40 0.009*
- Lateral 24 48 28 4.98 0.036†
L Cerebellum −14 −62 −22 4.95 0.040†
Abbreviations: L, left hemisphere; R, right hemisphere; SM1, primary sensorimotor cortex;
SII, secondary somatosensory cortex; SMA, supplementary-motor area; ACC, anterior
cingulate cortex; PFC, prefrontal cortex.
†whole-brain family-wise error corrected,*corrected for multiple comparisons within
respective bilateral ROIs.
DISCUSSION
The present fMRI study compared brain activation during the
perception and anticipation of resistive-load induced dyspnea
between patients with COPD and matched healthy controls.
Furthermore, we investigated the relationship between COPD-
specific brain activation and patient characteristics.
During the perception of increased dyspnea, patients and
control subjects showed widely comparable neural activation
patterns in commonly observed dyspnea-relevant sensorimotor
and cortico-limbic brain regions without significant differences
between groups. In contrast, while anticipating increased
dyspnea, enhanced neural activation was observed in patients
relative to control subjects in the bilateral hippocampus
and right amygdala. Notably, neural responses in these
emotion-related limbic brain regions were correlated with
clinical patient characteristics. Specifically, patients with
higher levels of anxiety and dyspnea as well as lower exercise
capacity showed higher anticipatory neural activation in
the left hippocampus, whereas patients with lower health-
related quality of life showed higher anticipatory neural
activity in the right hippocampus and amygdala. Additional
explorative findings indicated that patients with longer disease
duration showed higher amygdala activation during the
perception of increasing dyspnea. Taken together, these
results suggest that patients with stable moderate-to-severe
COPD show enhanced activation in emotion-related brain
areas than healthy control subjects during the anticipation,
but not during the perception of experimentally induced
increased dyspnea, which further relates to important clinical
characteristics.
The observed brain activation in sensorimotor (SM1,
SII/operculum, SMA, and thalamus) and cortico-limbic (ACC,
insula, and PFC) areas during the perception of increased
dyspnea is in line with previous neuroimaging studies in healthy
volunteers (Peiffer et al., 2001; Evans et al., 2002; McKay
et al., 2003; von Leupoldt et al., 2008; Pattinson et al., 2009;
Binks et al., 2014). Our findings extend the notion of a dual
cortical pathway model of dyspnea perception with pathways
subserving either sensorimotor or affective aspects of dyspnea
to patients suffering from COPD (von Leupoldt and Dahme,
2005; Davenport and Vovk, 2009). Moreover, the present finding
that patients and control subjects demonstrated activation in
comparable dyspnea-relevant brain regions corresponds with
a recent study by Higashimoto et al. using near-infrared
spectroscopy (Higashimoto et al., 2015). Although limited in
spatial resolution, this study also demonstrated comparable
activations in pre-motoric areas between COPD patients and
healthy controls. In addition, several studies on chronic pain
syndromes similarly observed substantial overlap of brain
activation during the perception of acute pain in healthy
subjects and patients with several pain conditions (Derbyshire
et al., 2002; Apkarian et al., 2005, 2011; Baliki et al., 2006).
However, the absence of enhanced responses in emotion-
related areas during perceived dyspnea in COPD-patients is
contrasting with previous studies on chronic pain conditions
such as fibromyalgia, irritable bowel syndrome, and back pain
(Baliki et al., 2006; Jensen et al., 2009; Hashmi et al., 2013).
For example, Hashmi and colleagues (Hashmi et al., 2013)
demonstrated a shift toward more activation in emotion related
areas in those patients suffering from lower back pain, who
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Esser et al. Dyspnea Perception and Anticipation in COPD
FIGURE 3 | Brain areas with significantly higher neural activation in patients with COPD compared to the control group during the anticipation of increased dyspnea.
(A) Bilateral hippocampus, (B) right amygdala, and (C) right hippocampus and amygdala. Enhanced neural activation in these brain regions was correlated with
patient characteristics such as reduced exercise capacity, higher level of dyspnea, and anxiety in the left hippocampus (A), and reduced quality of life in right
hippocampus (B) and right amygdala (C). For visual purposes, activation is thresholded at puncorrected <0.001 with colorbars indicating T-values. Significant
correlations are presented as *p<0.05, **p<0.01, ***p<0.001.
FIGURE 4 | Positive correlation between left amygdala activation during the
perception of increased dyspnea and disease duration in patients with COPD.
For visual purposes, activation is thresholded at puncorrected <0.001 with
colorbars indicating T-values. Beta weights (y-axis) of individual subjects’ peak
voxel used in the scatter plot indicate neural activation using arbitrary units.
developed chronicity. The lack of comparable changes in our
study might be related to differences between studies regarding
sensory modalities (e.g., thermal pain vs. load induced dyspnea),
experimental designs (with vs. without anticipation conditions;
different control conditions), disease duration, or patient
characteristics (see below) including different exacerbations
phenotypes of COPD (Scioscia et al., 2017), which deserves
further investigation.
Importantly, during the anticipation of increased dyspnea,
patients with COPD compared to healthy control subjects
showed enhanced neural activation in hippocampus and
amygdala, both key areas in the processing of fear, aversive
learning, and pain (LeDoux, 2003; Sehlmeyer et al., 2009;
Wiech and Tracey, 2013). Recent findings in healthy individuals
demonstrated activation of the amygdala during the fearful
anticipation of resistive load induced dyspnea (Stoeckel et al.,
2015). Similarly, Apkarian et al. (2011) reported increased
amygdala activation prior to a pain stimulus peak in healthy
subjects, indicating a role of the amygdala in the anticipation of
impending pain. The importance of amygdala and hippocampus
in pain-related fear acquisition and memory processes was
furthermore confirmed for patients with chronic irritable
bowel syndrome (Icenhour et al., 2015). According to the
aforementioned model regarding brain circuitry involved
in the transition from acute to chronic pain (Apkarian
et al., 2011; Mansour et al., 2014), the hippocampus and the
amygdala are key regions of the limbic circuitry crucially
involved in emotional enhancement processes. This limbic
circuitry is presumed to “translate” sensory signals into more
emotional, cognitive suffering states, e.g., by modulating and
amplifying the emotional character of aversive nociceptive
input signals over time (Mansour et al., 2014). Our finding
of prominent recruitment of hippocampus and amygdala
in COPD patients during the anticipation of increased
dyspnea most likely reflects such an amplified emotional,
in particular more fearful, evaluation of upcoming dyspnea.
This might provide, at least partly, the neural basis for
subsequent fearful avoidance behavior in patients with COPD
and contribute to a spiral of decline in form of activity avoidance,
deconditioning, increased dyspnea and anxiety, and further
reductions in quality of life (Reardon et al., 2006; Troosters
et al., 2013). Support for this assumption comes from the
present observation that increased activation of hippocampus
and amygdala during increased dyspnea anticipation was
closely related to important clinical characteristics such as
reduced exercise capacity and quality of life as well as higher
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Esser et al. Dyspnea Perception and Anticipation in COPD
levels of dyspnea and anxiety. Notably, using structural MRI,
morphological changes of reduced gray matter volume in
hippocampus and amygdala were recently observed in patients
with COPD relative to control subjects (Esser et al., 2016),
which further supports the important role of these areas in
COPD.
Finally, post-hoc analyses revealed a positive correlation
between disease duration and amygdala activation during
the perception of increased dyspnea. Although explorative
in nature, this finding suggests that the chronic course of
COPD results in a functional modulation of a brain region
strongly related to fear and anxiety (LeDoux, 2003; Sehlmeyer
et al., 2009; Wiech and Tracey, 2013). Interestingly, a recent
study showed that longer COPD disease duration was also
related to reduced gray matter volume in the ACC (Esser
et al., 2016), a key structure for antinociception and the
regulation of emotional states that is tightly interconnected
with the amygdala (Tracey and Mantyh, 2007). Given the fact
that many patients with COPD develop comorbid anxiety
over time (Maurer et al., 2008; Yohannes and Alexopoulos,
2014), it might be speculated that this is related to increased
amygdala activation during dyspnea anticipation and perception,
paralleled by reduced antinociceptive ACC capabilities.
However, future studies are required directly addressing this
assumption.
When interpreting the present results, several limitations
need to be taken into account. We exclusively studied a
small group of highly motivated patients with stable health
status and relatively good physical condition without clinical
levels of comorbid anxiety and depression and no exacerbation
history within the last year. This limits the generalizability
of our findings and motivates future studies in other patient
populations with larger sample sizes, different and/or more
severe forms of COPD and related comorbidities. Moreover, the
use of resistive-load breathing for the experimental induction
of short-lasting dyspnea only mirrors some aspects of dyspnea,
i.e., the sense of increased work and effort of breathing, and
might not be comparable to sustained dyspnea experiences
outside the lab. Therefore, future studies are necessary to
extend the present findings to other qualities of dyspnea,
for example air hunger, which might be perceived and/or
anticipated differently (Banzett et al., 2008). Finally, future
longitudinal studies are needed to directly address how changes
in the neural processing of perceived and anticipated dyspnea
relate to the subsequent development of activity avoidance,
deconditioning, increased dyspnea and anxiety, and reduced
quality of life.
This study suggests that patients with stable moderate-to-
severe COPD show enhanced activation in emotion-related
brain areas compared with healthy control subjects during
the anticipation, but not during the perception, of increased
resistive-load induced dyspnea. Brain activation in these
areas was related to important clinical characteristics and
might contribute to the development of a downward spiral
including fearful activity avoidance, deconditioning, increased
dyspnea and anxiety, and reduced quality of life. Taken
together, our findings contribute to our understanding of
brain processes in COPD and their relation with clinical
outcomes and might provide potential targets for future
psychological interventions aimed at improving the burden for
patients.
AUTHOR CONTRIBUTIONS
RE, MS, HM, and AV contributed to the conception and
study design; RE, MS, AK, HW, KT, and KL contributed to
the data acquisition; RE, MS, CB, and AV contributed to the
data analysis; RE, MS, and AV drafted the paper; all authors
contributed to the interpretation of data, the editing of the paper,
provided critical revisions and approved the final version of the
manuscript.
FUNDING
This study was supported by grants from the German
Research Foundation (Deutsche Forschungsgemeinschaft, DFG;
Heisenberg-Stipendium, LE 1843/9-2, LE 1843/10-1; LE 1843/10-
3) to AV. AV is supported by a research grant from the Research
Fund KU Leuven, Belgium (STRT/13/002), by an infrastructure
grant from the Herculesstichting, Belgium (AKUL/13/07), and by
the “Asthenes” long-term structural funding Methusalem grant
(# METH/15/011) by the Flemish Government, Belgium.
ACKNOWLEDGMENTS
The authors wish to thank all volunteers for their participation in
this study and the members of the Pulmonary Research Institute
at LungClinic Grosshansdorf and the Atem-Reha GmbH for their
support during recruitment and pre-examination of patients.
Furthermore, we wish to thank Timo Kraemer, Katrin Bergholz,
Kathrin Wendt, Friederike Behmer, and Nergiz Turgut for
technical assistance during data acquisition.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: http://journal.frontiersin.org/article/10.3389/fphys.
2017.00617/full#supplementary-material
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Conflict of Interest Statement: KT and KL were employed by company Atem-
Reha GmbH. The authors declare that research was conducted in the absence of
any commercial or financial relationship that could be construed as a potential
conflict of interest.
The other authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2017 Esser, Stoeckel, Kirsten, Watz, Taube, Lehmann, Magnussen,
Büchel and von Leupoldt. This is an open-access article distributed under the terms
of the Creative Commons Attribution License (CC BY). The use, distribution or
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are credited and that the original publication in this journal is cited, in accordance
with accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms.
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