J Neurophysiol 115: 2214 –2223, 2016.

First published February 10, 2016; doi:10.1152/jn.01058.2015.

Electroencephalographic detection of respiratory-related cortical activity in

humans: from event-related approaches to continuous connectivity evaluation

Anna L. Hudson,1 Xavier Navarro-Sune,2 Jacques Martinerie,3 Pierre Pouget,3 Mathieu Raux,2,4
Mario Chavez,3 and X Thomas Similowski2,5
1
Neuroscience Research Australia and University of New South Wales, Sydney, Australia; 2Sorbonne Universités, Université
Pierre et Marie Curie, University of Paris 06, Institut National de la Santé et de la Recherche Médicale, UMRS1158
Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; 3Centre National de la Recherche Scientifique
UMR7225 at the Institut du Cerveau et de la Moelle Épinière, Paris, France; 4Assistance Publique-Hopitaux de Paris (AP-
HP), Groupe Hospitalier Pitie-Salpêtrière-Charles Foix, Département d’Anesthésie-Réanimation, Paris, France; and 5AP-HP,
Groupe Hospitalier Pitie-Salpêtrière-Charles Foix, Service de Pneumologie et Réanimation Medicale, Paris, France
Submitted 30 November 2015; accepted in final form 3 February 2016

Hudson AL, Navarro-Sune X, Martinerie J, Pouget P, Raux
M, Chavez M, Similowski T. Electroencephalographic detection
of respiratory-related cortical activity in humans: from event-
related approaches to continuous connectivity evaluation. J Neu-
rophysiol 115: 2214 –2223, 2016. First published February 10,
2016; doi:10.1152/jn.01058.2015.—The presence of a respiratory-
related cortical activity during tidal breathing is abnormal and a
hallmark of respiratory difficulties, but its detection requires su-
perior discrimination and temporal resolution. The aim of this
study was to validate a computational method using EEG covari-
ance (or connectivity) matrices to detect a change in brain activity
related to breathing. In 17 healthy subjects, EEG was recorded
during resting unloaded breathing (RB), voluntary sniffs, and
breathing against an inspiratory threshold load (ITL). EEG were
analyzed by the specially developed covariance-based classifier,
event-related potentials, and time-frequency (T-F) distributions.
Nine subjects repeated the protocol. The classifier could accurately
detect ITL and sniffs compared with the reference period of RB.
For ITL, EEG-based detection was superior to airflow-based de-
tection (P ⬍ 0.05). A coincident improvement in EEG-airflow
correlation in ITL compared with RB (P ⬍ 0.05) confirmed that
EEG detection relates to breathing. Premotor potential incidence
was significantly higher before inspiration in sniffs and ITL com-
pared with RB (P ⬍ 0.05), but T-F distributions revealed a
significant difference between sniffs and RB only (P ⬍ 0.05).
Intraclass correlation values ranged from poor (⫺0.2) to excellent
(1.0). Thus, as for conventional event-related potential analysis,
the covariance-based classifier can accurately predict a change in
brain state related to a change in respiratory state, and given its
capacity for near “real-time” detection, it is suitable to monitor the
respiratory state in respiratory and critically ill patients in the
development of a brain-ventilator interface.
BCI; voluntary movement; mechanical ventilation; dyspnea
BREATHING IS USUALLY UNDER automatic control via rhythmic
activity that originates in the medulla (e.g., Feldman and Del
Negro 2006), but respiratory motoneurones can also be acti-
vated by corticospinal projections (Gandevia and Rothwell
1987; Murphy et al. 1990; Sharshar et al. 2004; Similowski et
al. 1996). The cortical areas associated with contractions of the
respiratory muscles include the primary motor cortex, premo-
Address for reprint requests and other correspondence: A. L. Hudson,
Neuroscience Research Australia, Margarete Ainsworth Bldg., Barker St
Randwick, NSW 2031 Australia (e-mail: a.hudson@neura.edu.au).
2214 0022-3077/16 Copyright © 2016 the American Physiological Society
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tor cortex, and supplementary motor area (e.g., Colebatch et al.
1991; McKay et al. 2003). A cortical contribution to breathing
can be detected by electroencephalographic recordings (EEG)
in the form of premotor potentials (or Bereitschaftspotentials;
for review, see Colebatch 2007; Shibasaki and Hallett 2006)
and were first demonstrated for voluntary sniffs (Macefield and
Gandevia 1991). In awake healthy subjects, premotor poten-
tials also precede inspiration in acute and prolonged (1 h)
inspiratory loading (Raux et al. 2007b; Tremoureux et al. 2010)
and they precede expiration in expiratory loading (Morawiec et
al. 2015). EEG evidence of cortical activity during loaded
breathing is supported by positron emission tomography (Fink
et al. 1996; Isaev et al. 2002) and functional MRI (Raux et al.
2013) studies. Therefore, there is a cortical component to
respiratory load compensation. Of note, a reduced motor
threshold for diaphragmatic responses evoked by transcranial
motor stimulation over the motor cortex in patients with
chronic obstructive pulmonary disease is consistent with in-
creased cortical excitability due to chronically increased respi-
ratory load (Hopkinson et al. 2004).
In healthy subjects, the loads that induce cortical activity are
externally imposed. However, patients with respiratory disease
experience acute intermittent and chronic loading of their
respiratory muscles due to, for example, bronchoconstriction or
dynamic hyperinflation. In addition to an intrinsic load, criti-
cally ill patients requiring mechanical ventilation can experi-
ence patient-ventilator asynchrony. Respiratory loads that in-
duce cortical activity can be associated with dyspnea
(Morawiec et al. 2015), including during experimental patient-
ventilator asynchrony in healthy subjects (Raux et al. 2007a).
In mechanically ventilated patients who are able to communi-
cate, dyspnea can be improved with ventilator adjustment
(Schmidt et al. 2011), but many critically ill patients cannot
verbally report their dyspnea. In this setting, EEG provides a
method to detect respiratory-related cortical activity in criti-
cally ill patients, which could be used to improve mechanical
ventilator settings and to identify and correct dyspnea without
the need for direct communication with the patient (see Raux
et al. 2007a).
Using event-related approaches to study respiratory-related
cortical activity has the major advantage of respiratory speci-
ficity, insofar as the EEG signal is processed according to
respiratory events. This provides protection against EEG
www.jn.org
 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY
changes concomitant with respiratory changes but not actually
due to them. However, analysis of EEG signals by event-
related potential methodology has limitations including as-
sumptions of on-going brain activity and the temporal variabil-
ity of the evoked response as well as high susceptibility to
low-frequency movement-related artifacts. This is true for
premotor potentials and for alternative methods such as time-
frequency analysis (e.g., to reveal event-related desynchroni-
zation) that have been applied to EEG signals to demonstrate
cortical changes before limb movements (for review, see
Makeig et al. 2004; Mouraux and Iannetti 2008; Pfurtscheller
and Lopes da Silva 1999). For clinical applications, a major
limitation of event-related approaches to detect respiratory-
related cortical activity is a large number of trials are required
to improve the signal to noise ratio.
The spatiotemporal dynamics of EEG, assessed by interac-
tions of large-scale cortical networks that consider dynamic
changes in the brain’s intrinsic activity, can be used to inves-
tigate brain function on a continuous basis, namely irrespective
of discrete events. However, it is not known if these methods
are suitable to detect and characterize respiratory-related cor-
tical activity. Recently, we have developed signal processing
techniques to discriminate between different breathing condi-
tions using a machine learning based on the EEG covariance
matrices (Navarro-Sune et al. 2016). Given its improved tem-
poral resolution, the aim of the present study was to validate
the novel covariance-based classifier as a method to identify
respiratory-related cortical activity in humans, in other words,
to discriminate between resting unloaded breathing and loaded
breathing using continuous and rapid EEG processing.
METHODS
The studies were carried out in 17 subjects (9 female) aged 21–29
yr. The subjects gave informed written consent to the procedures
which conformed with the Declaration of Helsinki and were approved
by the Comité de Protection des Personnes Ile-de-France VI, Pitie-
Salpetriere, Paris, France. EEG activity was recorded during three
respiratory conditions: resting unloaded breathing, voluntary brisk
inhalations (i.e., sniffs), and breathing against an inspiratory threshold
load (ITL). Nine subjects (5 female) repeated the protocol for reli-
ability testing. To determine the optimal technique to discriminate
between respiratory conditions, EEG were analyzed by premotor
potentials, time-frequency analysis of these potentials, and a covari-
ance-based classifier that detects changes in respiratory condition
using EEG covariance matrices. The degree of correlation between
EEG and airflow was also compared between respiratory conditions,
with the hypothesis that a change in correlation would help ascertain
the respiratory origin of putative changes in EEG patterns. Within this
framework, the degree of correlation between EEG and electrocardio-
gram was used as control. A subset of these data has been used for
statistical and methodological development of the classifier (Navarro-
Sune et al. 2016).
Experimental Setup
Subjects were seated in a comfortable chair with neck support and
watched a film on a large computer screen during EEG recordings to
distract their attention from their breathing and the experimental
environment in general. They wore a nose clip and breathed through
a mouthpiece connected to a pneumotachograph (Hans Ruldoph), and
airflow was measured with a ⫾2 cmH2O linear differential pressure
transducer (DP45-18; Validyne, Northridge, CA). The pneumotacho-
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2215
graph was connected to a two-way valve (2700 series; Hans Rul-
dolph). End-tidal CO2 was measured at the expiratory port by an
infrared CO2 gas analyzer (Servomex, Plaine Saint Denis, France),
and when required, an ITL (Respironics) was attached to the inspira-
tory port of the two-way valve. Opening airway pressure was mea-
sured close to the mouth with a ⫾225 cmH2O differential pressure
transducer (DP15-34; Validyne). An electrocardiogram (ECG) was
measured with two surface electrodes placed on the left side of the
chest, above and below the nipple. Respiratory and ECG signals were
sampled at 2 kHz.
An active electrode system (ActiCap; BrainProducts) was used to
record scalp EEG from 32 electrodes positioned according to the
international EEG 10 –20 system, including 2 electrodes on the ear
lobes. Electrooculographic activity (EOG) was monitored with an
electrode positioned under the right eye. The recordings were ampli-
fied and digitized at 2.5 kHz (BrainAmp; BrainProducts). Online,
recordings were referenced to FCz with a ground at FPz. EEG signals
were time locked to respiratory signals with simultaneous digital
trigger pulses that were automatically generated from a threshold
crossing of inspiratory airflow and manually verified offline by visual
inspection.
Experimental Protocol
Subjects performed three conditions (duration: 10 –20 min each): 1)
resting unloaded breathing, in which no instructions were given to the
subject in relation to their breathing; 2) self-paced brisk voluntary
inhalations, akin to “sniffs” but made through the mouth due to the
experimental apparatus (subjects were instructed to perform the
“sniffs” at the start of the usual inspiratory phase of the respiratory
cycle, but not every cycle); and 3) breathing with an ITL set to ⬃23
cmH2O (range: 18 –25 cmH2O), placed on the inspiratory port of the
two-way valve. Subjects always performed the resting breathing
condition first to minimize awareness that their breathing was being
manipulated. The sniff and ITL conditions were then performed in
random order. At the end of each condition, subjects rated their level
of respiratory discomfort during the condition using a visual-analog
scale that ranged from zero: “no breathlessness or discomfort” to 10:
“maximal breathlessness or discomfort.” There was a break of 5–10
min between conditions.
Reliability. Nine subjects repeated the same protocol of resting
unloaded breathing, voluntary sniffs, and ITL, quasirandomized as in
the first visit. The interval between visits averaged 18.1 [7.3; 95%
confidence interval (CI)] days with a range of 6 –38 days. The ITL was
set to the same pressure as the first visit.
Data Analysis
Respiratory variables. Tidal volume, inspiratory time, peak nega-
tive mouth pressure, end-tidal CO2, respiratory rate, and ventilation
were measured for resting breathing and ITL for recordings from nine
subjects on the 2 days of the protocol.
Premotor potential analysis. Offline, recordings were resampled at
250 Hz, referenced to linked-ear electrodes, and band-pass filtered
(0.05–10 Hz). Before ensemble averaging, the EEG was divided into
3.5-s epochs, 2.5 s before and 1 s after the onset of inspiration, based
on the onset of inspiratory flow (resting breathing and sniffs) or
negative mouth pressure (ITL). Individual segments were visually
inspected and rejected from the average if they exhibited artifact, e.g.,
large deviations from baseline or intense EOG activity. One subject
had such frequent and intense EOG activity such that after removal of
the artifact-affected segments, 25 or less segments remained for the
ensemble averages. Therefore, data from this subject were removed
from the premotor potential analysis. For the remaining 16 subjects,
72 ⫾ 12 segments (means ⫾ SD, range: 38 – 80) were averaged for
each condition.
2216 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY
Average EEG traces were examined for the presence of an inspira-
tory premotor potential as described previously (Raux et al. 2007b),
i.e., a slow increasingly negative shift in the EEG signal starting from
⬃1 s before inspiration. If present, the preinspiratory latency of each
premotor potential was measured as the duration (in ms) between the
onset of EEG negativity and the start of inspiration and the amplitude
was measured (in ␮V) at this “zero flow” point.
Premotor potential analysis was performed on Cz and FCz deriva-
tions. Although inspiratory premotor potentials have previously been
reported for Cz only (e.g., Macefield and Gandevia 1991; Raux et al.
2007b; Tremoureux et al. 2010), the observed potentials were more
frequent and were larger in amplitude at FCz. Therefore, FCz was
used as the most likely to reflect activity in the premotor and
supplementary motor areas.
Time-frequency analysis. Time-frequency analysis was performed
for FCz on same EEG epochs as premotor potential analysis (n ⫽ 16
subjects), but signals were resampled at 1,000 Hz. Wavelet time-
frequency distributions were obtained using the wavelet transform
(Tallon-Baudry et al. 1997). The EEG signal x(t) at FCz was con-
volved with a complex Morlet’s wavelet function defined as:
w(t, f 0) ⫽ A exp 冉 冊
⫺t2
2␴t2
⫻ exp (i2␲ f 0t)
Wavelets were normalized and thus:
A ⫽ (␴t兹␲)⫺1⁄2
The width of each wavelet function m ⫽ f0/␴f was chosen to be 7,
where ␴f ⫽ 1/2␲ ␴t. The parameter m corresponds to the number of
significant cycles of the wavelet function and defines the trade-off
between temporal and frequency resolution (i.e., for larger values of
m, the frequency resolution increases but the temporal resolution
decreases). A m value larger than 5 ensures the necessary admissibil-
ity condition for the wavelet function (an oscillating function is
admissible if it has finite energy and zero mean value). Time-
frequency contents were represented as the energy of the convolved
signal:
ⱍ
E(t, f 0) ⫽ w(t, f 0) 丢 x(t) ⱍ 2
To detect preinspiratory changes in temporal and spectral power of
the EEG, a “baseline” period of a 300-ms duration was defined. For
resting breathing and ITL, the baseline period commenced at peak
expiratory flow of the preceding breaths, based on the average airflow
signal of the analyzed segments. For the sniff condition, as the
maneuvers were self-paced and interspersed with spontaneous
breaths, the expiratory time was shortened and likely more variable.
For the sniff condition, baseline was considered to be ⫺1,900 to
⫺1,600 ms before the onset of inspiratory flow, estimated from the
average latency ⫹99% CI of sniff premotor potentials (Macefield and
Gandevia 1991).
Following preprocessing (each trial was assigned zero mean, uni-
tary variance, and corrected by the baseline), single-trial time-fre-
quency maps were computed. For each frequency, single-trial time-
frequency maps were corrected by the mean and standard deviation
power during the baseline period. P(t,f) was then averaged across all
trials for each condition.
To quantify the time-frequency maps in the different conditions, a
region of interest (ROI) between 0 and 2 Hz and ⫺1,000 and 0 ms was
selected. Visually, this low-frequency band showed the greatest dif-
ferentiation between conditions and the time period was common to
all conditions as the mean preinspiratory latency of the premotor
potentials was ⬃1,000 ms or less (see Fig. 3). The mean value of the
top 20% of time-frequency values in this ROI was determined for
each subject and condition (Mouraux and Iannetti 2008). The same
ROI was used for reliability measures.
Covariance-based classifier. EEG data were also analyzed using an
algorithm that classifies brain activity in different conditions using a
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semisupervised approach (Navarro-Sune et al. 2016). We tested for
altered brain activity in “modified” breathing conditions (i.e., ITL and
sniffs), compared with reference activity (e.g., resting breathing) and
detection was performed using covariance matrices, a very appropri-
ate feature to capture the spatiotemporal structure of the EEG
(Barachant et al. 2012; Varela et al. 2001).
EEG signals from frontal and central channels (F3, F4, C3, C4,
FCz, Fz, Cz, FC2, and FC6) were downsampled to 250 Hz and
band-pass filtered (8 –24 Hz) to enhance motor cortical activity (or mu
rhythm) found in this frequency band (Pfurtscheller and Lopes da
Silva 1999). During the learning process, the reference period (20% of
resting breathing) was divided into a series of signals Xm (m ⫽
1, ь ь ь, M number of segments). Let X ⫽ Xm 僆 RP ⫻ N a reference
period of EEG signals recorded during N temporal samples of a
time window equal to 5 s with 50% overlap and P EEG channels
(see Fig. 1). Each X matrix was centered and normalized. Then,
spatial covariance matrices C were estimated for each X by: C ⫽
(X XT)/trace (X XT).
Since C are symmetric positive definite matrices that lie in a
Riemannian manifold, the distance between two matrices C1 and C2
can be defined as:
distR(C1, C2) ⫽ 关 兺k⫽1
p
log2 ⬀k兴1⁄2
␣k the k-th eigenvalue of [(C1)⫺1 (C2)] k ⫽ 1:p.
To represent the reference period, prototypes Sj, j ⫽ 1, ь ь ь, L,
were determined from the distribution of the covariance matrices Ci,
i ⫽ 1: M. Each prototype represented a subclass of covariance
matrices and was estimated by the Karcher average of covariance
matrices. The calculation procedure of prototypes was based on a
modified K means clustering algorithm, where the geometric mean of
M matrices was obtained by the following formula for calculating the
average Karcher MR (Moakher 2005):
MR (C1, C2, ь ь ь , CM) ⫽ arg min 兺m⫽1
M
distR (Cm, C)
Calculating MR may be performed using a gradient descent procedure
that converges rapidly (Pennec et al. 2006).
During the testing process, the classifier compares the covariance
matrices from both resting and altered breathing with the prototypes
learned from the reference period.
First, the distribution of the distance from all the covariance
matrices C i, i ⫽ 1: M, to the closest prototype S was calculated, and
then the absolute values of deviations from the median of the distri-
bution were determined. The average deviation was used to estimate
the rejection threshold beyond which the covariance matrices no
longer belonged to the reference situation, i.e., dispersion from pro-
totypes or altered brain activity.
The application of a threshold, based on the dispersion of the
matrices corresponding to the reference period, allowed detection of a
characteristic change in EEG activity in a situation of modified
breathing.
For comparison to detection by EEG, a similar procedure was
performed using the airflow signal only. Here, an amplitude feature of
the airflow signal for 5-s windows with 50% overlap was calculated.
The distance between the time-windows in the reference period and
modified breathing was used to classify breathing states (for details,
see Navarro-Sune et al. 2016).
We tested the sensitivity of the different detection methods by a
10-fold cross validation. The reference period of resting breathing was
divided into 10 equal parts. Comparison between nine of these parts
from the reference period and the test set from the modified situations
of ITL and sniffs was then performed. This procedure was repeated
nine times to take account all combinations of nine parts from the
reference period. This allowed us to create receiver operating char-
acteristic curves (ROCs) and a complete sensitivity/specificity report.
The ROC curve is a fundamental tool for diagnostic test evaluation
and the area under the curve (AUC) quantifies the sensitivity/speci-
 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY 2217

A B
Computation of covariance matrices Matrices in the Riemannian manifold
Resting Breathing ITL C1,... CM
Airflow insp.
EEG signals
1

2
RB
T
3

... P
ITL
1,...N 5s windows 5s

distR
threshold Riemannian
distance

Euclidean
distance

Fig. 1. Schema to demonstrate detection of an altered “brain state” with the covariance-based classifier. A: covariance matrices are computed from 1, ь ь ь P EEG
signals and 1, ь ь ь N 5-s sliding windows to capture the spatiotemporal dynamics of the EEG. This is first done for a reference period of resting breathing to
generate prototypes of this “brain state.” Covariance matrices are then computed from recordings during different breathing conditions: unloaded resting
breathing (RB), breathing with an inspiratory threshold load (ITL), or voluntary sniffs. The Riemannian distance (distR) to the prototype for RB and ITL is
depicted in A, bottom (see also histogram in Fig. 4A). B: a 3-dimensional visualization of covariance matrices (C1, ь ь ь CM) as points on an imaginary manifold.
The distance between matrices, for example, for RB (shown in red) and ITL (shown in blue), are then compared with a prototype (S). If the distance is greater
than a threshold (T ⫽ MAD dist 共S, C1, ь ь ь CM兲; where MAD is the median absolute deviation; see METHODS) then there is an altered brain state. The ability
of the covariance-based classifier to detect a change in brain state is tested using the receiver operator characteristic curve (ROC; see METHODS for details). The
inset highlights the difference between Riemannian (used in the classifier) and Euclidean geometry to compute the distance between 2 points.

ficity ratio. A test with perfect discrimination has an AUC equal to 1
and a random discrimination has a value equal to 0.5.
EEG correlations. We tested for correlation between the power of
EEG signals at FCz, Cz, Fz, C3, and C4 with airflow. As for the
covariance-based classifier, 5-s windows with 50% overlap were used.
Autocorrelation and time trends were present in our time series,
indicating that low-frequency variability was important and would
increase the chance that spurious correlations would occur in standard
inference tests. Therefore, after de-trending, we used a procedure to
examine correlations using the method recommended by Pyper and
Peterman (1998), which adjusts degrees of freedom to account for
autocorrelation and computes the Fisher-transformed correlation (cor-
rected for autocorrelation) that has a Gaussian distribution with mean
0 and unitary variance. As a control, correlations between EEG and
ECG were computed in the same way.
Statistics
Group data are presented as mean (95% CI) or median interquartile
range ([IQR]) for parametric and nonparametric data, respectively.
The H statistic [degrees of freedom (df)] is shown for unpaired data
and the F statistic or ␹2-value (df) is shown for parametric and
nonparametric repeated measures tests, respectively. The criterion for
statistical significance was taken as P ⬍ 0.05.
A Kruskal-Wallis one-way ANOVA on ranks with pairwise post
hoc testing using the Tukey’s test was performed to compare the
incidence, amplitude, and latency of inspiratory premotor potentials
between conditions.
All other data were repeated measures. Therefore, for the group of
17 subjects, conditions (3 levels) were compared one-way repeated
measures (RM) ANOVA for parametric data or with Friedman RM
ANOVA on ranks for nonparametric data and pairwise post hoc
testing with Tukey’s test. For the nine subjects who repeated the
protocol, two-way RM ANOVAs were used to compare between
condition (2 or 3 levels) and day (2 levels) with Tukey’s test for post
hoc pairwise comparisons. Latency, amplitude, and top 20% data
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failed normality testing (Shapiro-Wilk, P ⬍ 0.05) and thus data were
transformed with the rank procedure before statistical testing by
two-way RM ANOVA. Two-way RM ANOVA was also used to
compare between EEG- or airflow-based detection of brain state with
condition (ITL and sniff) and type (flow or EEG) as factors.
The correlation between EEG and airflow during resting breathing
and ITL are nonoverlapping correlations from the same sample
population. Therefore, they were compared using the Pearson-Filon
test for Fisher-transformed correlations (Raghunathan et al. 1996).
The same procedure was used for EEG-ECG correlation.
For the nine subjects who repeated the protocol, the reliability of
respiratory variables and EEG analyses was assessed using intraclass
correlation (ICC) analysis (mixed model, single measures). The reli-
ability was assessed independently for each condition. t-Tests were
used to compare inspiratory time and tidal volume when an inspira-
tory premotor potential did or did not occur during resting breathing
in these nine subjects.
RESULTS
Premotor Potentials
Figure 2A shows typical examples of the averaged prein-
spiratory FCz EEG signal in the different respiratory condi-
tions. As expected, inspiratory premotor potentials were pres-
ent in the sniff and ITL conditions, but ensemble averaged
EEG was unchanged during resting unloaded breathing. For
the group of 16 subjects, all had an inspiratory premotor
potential during sniffs, 13 during ITL, and 3 subjects during
resting breathing such that premotor potential incidence sig-
nificantly varied with condition [H(2) ⫽ 25.5, P ⬍ 0.05; Fig. 3].
Premotor potentials were more common in sniff and ITL
conditions compared with resting breathing (P ⬍ 0.05), but
there was no difference between sniffs and ITL (P ⬎ 0.05).
The latency [F(2,29) ⫽ 2.3, P ⫽ 0.1] and amplitude [F(2,29) ⫽
2218 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY

Fig. 2. Representative EEG data during RB, voluntary sniffs, and breathing with an ITL. A: epochs of EEG at FCz (linked earlobe reference; A1A2),
time locked to the onset of inspiratory airflow or negative airway pressure, were averaged to investigate the presence of inspiratory premotor potentials.
For this typical subject, the potential was absent in RB, but present in the sniff and ITL condition as evidenced by the increasing negativity of the EEG
signal ⬃1,000 ms before the onset of inspiration. B: for the same subject and same epochs of EEG as the average data in A (numbers for both analysis
types given above each map), time-frequency maps were computed. There were differences in the power of the low-frequency components. To quantify
these differences, the average value of the top 20% of pixels from a region of interest (see METHODS) was calculated. The color scale is ⫺5 to 20 for all
panels.

1.8, P ⫽ 0.2] of premotor potentials did not differ with
condition (Fig. 3).
Time-Frequency Maps
Computation of the premotor-related temporal and fre-
quency changes in EEG revealed differences between respira-
tory conditions. Differences were evident in a ROI of low
frequencies (0 –2 Hz) at a similar latency to premotor poten-
tials, i.e., from ⬃1 s before the onset of inspiration. Typical
data from one subject are shown in Fig. 2 and quantification of
group data in Fig. 3. Consistent with the premotor potential
incidence, there were significant differences between respira-
tory conditions, quantified as the mean top 20% pixel value in
the ROI [␹2(2) ⫽ 11.4, P ⬍ 0.01; see METHODS]. Compared with

A B
Pre-motor potentials Time-frequency maps
Incidence (%) Pre-inspiratory latency (ms) Amplitude (µV) Top 20% pixel value
100 * 2000 8 80
*
80 *
1500 6 60
60
1000 4 40
40
500 2 20
20
3/16 16/16 13/16 3/16 16/16 13/16
0 0 0 0
RB Sniffs ITL RB Sniffs ITL RB Sniffs ITL RB Sniffs ITL

Fig. 3. Group data for premotor potential and time-frequency analyses. A: the incidence and mean [95% confidence interval (CI)] latency, amplitude of
inspiratory premotor potentials at FCz in RB, voluntary sniffs, and breathing with an ITL for the group of subjects (n ⫽ 16). For mean preinspiratory
latency and amplitude, the number of subjects for mean data in each condition is indicated in the bars. B: for all 16 subjects and the same epochs of EEG,
the average top 20% pixel values from time-frequency maps are shown at right. Median interquartile range ([IQR]) is shown for pixel value. *Statistically
different to RB.

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 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY
resting breathing, the average pixel value was significantly
greater in voluntary sniff (P ⬍ 0.05) but not in ITL. Thus the
power of the EEG in a low-frequency ROI was greatest in the
voluntary sniff condition and smallest in resting breathing.
Covariance-Based Classifier
Detection of altered breathing condition by the classifier was
assessed by the area under the ROC curve. With resting
unloaded breathing as the reference period, the AUC averaged
0.85 (0.05) for ITL and 0.83 (0.07) for the sniff detection,
respectively. Classification based on the airflow signal only
averaged 0.57 (0.15) for ITL but was 0.83 (0.09) for the sniffs.
There was a significant effect of detection type [i.e., EEG or
airflow based; F(1,16) ⫽ 9.1; P ⬍ 0.05], condition [ITL or sniff;
F(1,16) ⫽ 6.4; P ⬍ 0.05], and an interaction [F(1,16) ⫽ 9.5; P ⬍
0.05]. Post hoc testing revealed that flow-based detection was
better in the sniff condition than ITL (P ⬍ 0.05) and that
EEG-based detection was superior to airflow-based detection
for ITL only (P ⬍ 0.05; Fig. 4).
EEG Correlations
To confirm that changes in brain activity during ITL de-
tected by the EEG-based classifier was related to breathing,
correlations between EEG and airflow were assessed. All five
central EEG channels had high EEG-airflow correlations, rang-
ing between 0.61 and 1.0 in resting breathing and 0.73 and 1.19
in ITL. Maximal mean correlations in both conditions were for
FCz and thus statistical testing was performed on this channel
only. For the group of 17 subjects, mean EEG-airflow corre-
lation was 0.99 (0.07) in ITL, significantly higher than 0.83
(0.07) in resting breathing (z value: ⫺8.44, P ⬍ 0.05). As a
control, we tested the correlation between EEG and ECG at
FCz and it did not differ between breathing conditions (z value:
0.34, P ⫽ 0.7). Mean EEG-ECG correlation was 0.89 (0.13)
during resting breathing and 0.87 (0.10) in ITL.
Respiratory Discomfort
On a 10-cm scale with 10.0 cm as maximal, ratings of
respiratory discomfort differed with condition [F(2,32) ⫽ 59.0;
P ⬍ 0.05]. Respiratory discomfort was greatest during ITL and
averaged 4.7 (0.9) cm. This was significantly higher than 0.6
A B
Separation distances Mean area under ROC curve
1800 RB 1.0
ITL
1600
1400 0.8
1200
Frequency
1000 0.6
800
600
0.4
400
0.2
200
0 cantly different to airflow-based detection.
0 10 20 30 40 0
Distance of prototypes
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2219
(0.4) cm during resting breathing and 1.5 (0.8) cm for sniffs
(P ⬍ 0.05 for both).
Reliability
Data for the subgroup of subjects who repeated the same
protocol of resting breathing, sniffs, and ITL on 2 days are
shown in Tables 1 and 2. The same between-condition differ-
ences were observed for premotor potential and time-frequency
analyses, and there was no difference in any measure between
days. The interclass correlation values for the reliability of
these measures (where applicable, i.e., adequate data) ranged
from poor (⫺0.14) to excellent (1.0).
Changes in brain activity by covariance-based classifier
averaged 0.90 (0.05) and 0.85 (0.09) for ITL and sniff condi-
tions, respectively, on day 1 and 0.80 (0.07) and 0.84 (0.12),
respectively, on day 2. There was no main effect of condition
[F(1,8) ⬍ 0.001, P ⫽ 1.0] or day [F(1,8) ⫽ 1.7, P ⫽ 0.2]. A
statistically significant interaction between condition and day
[F(1,8) ⫽ 11.6, P ⫽ 0.009] revealed superior detection of ITL
on day 1 compared with day 2 (P ⫽ 0.05). This may be due to
subjects not being naïve to manipulation of their breathing
during the resting breathing condition (that is used as a refer-
ence) on day 2. Despite good detection, as indicated by the
high ROC values, reliability assessment showed poor ICC
values of ⫺0.2 and 0.5 for ITL and sniff detection, respec-
tively.
Mean and ICC values for EEG-airflow and EEG-ECG cor-
relations for resting breathing and ITL and respiratory vari-
ables from the corresponding recording sessions are shown in
Table 2. As expected, ITL changed respiratory variables,
except for ventilation, which was similar to that in resting
breathing. There was no effect of day on any variable and the
ICC values ranged from 0.34 to 0.90. For the occurrences when
an inspiratory premotor potential was observed during resting
breathing, inspiratory time was ⬃40% longer and tidal volume
⬃40% larger compared with these parameters when a premotor
potential was not observed (P ⬍ 0.05 for both).
DISCUSSION
The most significant outcome from this study is that a
change in breathing condition can be detected accurately from
the spatiotemporal dynamics of EEG signals. Compared with
Fig. 4. Detection of altered breathing condition by
covariance-based classifier on EEG and airflow. A:
Airflow
representative histogram of the Riemannian dis-
* EEG
tance between EEG covariance matrices in RB and
ITL. As assessed by the area under the ROC (see
METHODS), this subject had the best detection
(0.99). Not all subjects had perfect discrimination
as shown by the mean data in B. However, for
individual subjects, the poorest detection was 0.65
using EEG compared with 0.18 when detection was
based on airflow. B: mean (95% CI) area under the
ROC for detection between a reference period of
RB and ITL (left) or RB and sniffs (right). Airflow-
and EEG- based detection are shown in white and
black bars, respectively. The EEG method had
superior detection between RB and ITL. *Signifi-
RB/ITL RB/sniff
2220 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY

Table 1. Reliability of premotor potential and time-frequency analysis of respiratory-related cortical activity
Resting Breathing Sniffs ITL F Statistic and P Value
Day 1 Day 2 ICC Day 1 Day 2 ICC Day 1 Day 2 ICC Condition Day

Incidence 3/9 3/9 — 9/9* 9/9* 1.0 7/9 * 9/9 * — F(2,48) ⫽ 19.8; P ⬍ 0.05 F(1,48) ⫽ 0.6; P ⫽ 0.4
Amplitude, ␮V 3.8 (3.0) 4.3 (3.5) — 5.3 (2.1) 7.9 (3.2) 0.65 4.8 (2.9) 6.5 (5.3) 0.56 F(2,34) ⫽ 2.5; P ⫽ 0.1 F(1,35) ⫽ 1.0; P ⫽ 0.3
Latency, ms 1083.3 (851.3) 825.0 (887.1) — 878.8 (439.5) 836.7 (357.3) 0.28 602.9 (277.2) 898.9 (411.7) 0.52 F(2,35) ⫽ 0.6; P ⫽ 0.6 F(1,35) ⫽ 0.07; P ⫽ 0.8
Top 20% pixel 10.9 (4.3) 9.5 [8.5–14.0] 0.27 32.8* (17.3) 42.7* [26.0–128.2] ⫺0.14 21.9 (13.3) 24.1 [7.2–42.5] 0.40 F(2,16) ⫽ 10.8; P ⬍ 0.05 F(1,8) ⫽ 1.9; P ⫽ 0.2

Incidence and mean [95% confidence interval (CI)] or median (interquartile range [IQR]) data for the subgroup of subjects who repeated the protocol of resting
breathing, voluntary sniffs, and breathing with an inspiratory threshold load (ITL) on 2 days. Averaged EEG activity was compared by premotor potential
incidence, latency and amplitude or quantified by the mean top 20% pixel value in a common region of interest (see METHODS) in time-frequency maps. Intraclass
correlation (ICC) values as well as the F statistic and P values from two-way repeated measures (RM) ANOVA are shown. *Statistically different from resting
breathing in post hoc tests (P ⬍ 0.05).

event-based approaches, this method considerably reduces the
number of ventilatory cycles needed to detect a change and
therefore improves processing speed. In healthy subjects, de-
tection of loaded breathing was superior using EEG signals
rather than airflow. A higher EEG-airflow correlation in loaded
compared with resting breathing confirms the change in brain
state detected by the covariance-based classifier is related to
respiration. Although premotor potential incidence could also
discriminate between breathing conditions for the group of
subjects, discrimination was not possible in subjects who
exhibited a premotor potential during resting breathing. The
long preprocessing time of this averaging technique is a limi-
tation for clinical applications. Accurate and rapid detection of
loaded breathing in healthy subjects, a model of lung disease,
respiratory failure, and ventilator fighting are important steps
towards the development of a brain-ventilator interface.
Loaded Breathing, Altered Brain State, and
Neurophysiological Substrates
The Bereitschaftspotential (or premotor potential) is a slow
negativity that reflects synchronized changes in the postsynap-
tic potentials of cortical neurones (Colebatch 2007; Shibasaki
and Hallett 2006). Respiratory-related cortical activity has
been demonstrated previously using this time-locked EEG
averaging technique (see Introduction). As for limb move-
ments (for review, see Shibasaki and Hallett 2006) premotor
potentials are observed during sniffs and inspiratory loaded
breathing in EEG deviations considered to reflect activity in the
Table 2. Reliability of EEG correlations and respiratory variables in resting breathing and ITL
Day 1 Day 2
supplementary motor area and premotor and primary motor
cortices. A recent study has demonstrated similar current
sources (or dipoles) for premotor potentials during voluntary
sniffs and finger flexions using principal component analysis
(Jeran et al. 2013). Cortical activity during loaded breathing is
proposed to reflect cortical automatization rather than breath-
to-breath modulated “voluntary” inspirations as would occur in
the sniff condition. This notion derives from the comparison of
functional MRI patterns observed during single-breath inspira-
tory loading and continuous inspiratory loading, which showed
a reduction in overall brain activity but reinforcement of
supplementary motor area activity during continuous loading
(Raux et al. 2013). This is similar to what is observed during
“overlearning” or cortical automatization (Lehericy et al. 2005;
Wu et al. 2004, 2008).
We had anticipated that time-frequency decomposition
would reveal differences in alpha and beta activity between
respiratory conditions, consistent with event-related desyn-
chronization as described for voluntary limb movements (for
review, see Pfurtscheller and Lopes da Silva 1999). Breathing
is rhythmic and the period between trials is relatively fixed.
Therefore, unlike limb movement studies, we were unable to
have a baseline that was removed in time from our stimulus or
a long interevent interval of at least 10 s as recommended
(Mouraux and Iannetti 2008; Pfurtscheller and Lopes da Silva
1999). Rather, we observed and quantified differences in low-
frequency EEG power (see Figs. 1 and 2) that likely reflects
premotor potentials in the different conditions. As time-fre-
ICC Day 1 Day 2 ICC Day 1 Day 2

Resting breathing Inspiratory threshold load Z value and P value

EEG correlations
FCz-airflow 0.79 (0.11) 0.79 (0.09) 0.79 0.98 (0.09)* 0.95 (0.11)* 0.45 ⫺5.13; P ⬍ 0.05 ⫺2.18; P ⬍ 0.05
FCz-ECG 0.91 (0.16) 0.91 (0.08) 0.44 0.88 (0.11) 0.95 (0.12) 0.21 0.86; P ⫽ 0.4 ⫺0.48; P ⫽ 0.6
Resting breathing Inspiratory threshold load F statistic and P value: F statistic and P value:
condition day
Respiratory variables
Inspiratory time, s 1.84 (0.28) 1.74 (0.38) 0.89 4.66 (1.46) 4.41 (2.47) 0.53 F(1,7) ⫽ 15.2; P ⬍ 0.05 F(1,7) ⫽ 0.7; P ⫽ 0.4
Tidal volume, liter 0.53 (0.10) 0.53 (0.16) 0.89 1.04 (0.36) 0.93 (0.27) 0.59 F(1,7) ⫽ 18.4; P ⬍ 0.05 F(1,7) ⫽ 0.9; P ⫽ 0.4
Pressure, cmH2O ⫺1.44 (0.24) ⫺1.43 (0.27) 0.34 ⫺22.36 (4.12) ⫺23.37 (4.66) 0.87 F(1,7) ⫽ 131.8; P ⬍ 0.05 F(1,7) ⫽ 1.0; P ⫽ 0.3
End-tidal CO2† 5.52 (0.70) 5.41 (0.25) 0.82 4.33 (0.53) 4.55 (0.63) 0.78 F(1,7) ⫽ 22.1; P ⬍ 0.05 F(1,7) ⫽ 0.6; P ⫽ 0.5
Respiratory rate, cycles/min 14.49 (2.43) 15.43 (3.33) 0.90 9.10 (2.67) 9.35 (4.32) 0.59 F(1,7) ⫽ 15.8; P ⬍ 0.05 F(1,7) ⫽ 1.4; P ⫽ 0.3
Ventilation, l/min 7.20 (0.78) 7.68 (1.36) 0.76 8.80 (3.62) 7.99 (3.06) 0.61 F(1,7) ⫽ 0.6; P ⫽ 0.5 F(1,7) ⫽ 0.02; P ⫽ 0.9

Mean (95% CI) correlation between FCz and airflow was significantly greater during ITL than resting breathing whereas the correlation between FCz and ECG
was similar. Respiratory variables are shown for 8 of the 9 subjects who repeated the protocol. One subject had missing data on day 2 due to a technical error.
ICC values and statistics are shown. *Statistical different to resting breathing in post hoc tests (P ⬍ 0.05); †statistical interaction between condition and day
[F(1,7) ⫽ 6.0; P ⬍ 0.05].

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 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY
quency analysis also requires multiple trials to be averaged and
the temporal resolution of low frequencies can be uncertain
(Mouraux and Iannetti 2008), it provides no greater advantage
than premotor potentials to discriminate between loaded and
unloaded breaths in a clinical setting.
Rather than test for time-locked responses at individual EEG
electrodes, the covariance-based classifier tests for changes in
brain activity as a result of altered interactions in large-scale
cortical networks. Functional interactions between brain re-
gions are tested by comparing local neural synchronization or
variance (i.e., within an EEG derivation) in the diagonal terms
(or power) of spatial covariance matrices and longer distance
characteristics of the synchronization of the neural network
(i.e., between EEG derivations) by the off-diagonal terms (see
Supplementary Video; Supplemental Material for this article is
available online at the Journal website). Here, matrices were
computed from central and frontal EEG channels with similar
detection accuracy for both sniffs and loaded breathing sug-
gesting the networks activated in these “brain states” are
similar and include the supplementary, prefrontal, and primary
somatosensory motor areas. With the use of the covariance-
based classifier, differences in the electrodes that give the best
detection of loaded breathing or sniffs suggest the exact pattern
of cortical activity also differs slightly between these respira-
tory tasks (Navarro-Sune et al. 2016; see also Isaev et al.
2002). There may be distinct, but overlapping, networks for
these breathing conditions as described for breathing and
speech (Loucks et al. 2007).
As the covariance-based classifier used segments of EEG
that were not synchronized with respiration, the altered brain
state may not necessarily reflect central network activity cor-
responding to a change in breathing condition. Respiratory
muscles are activated in voluntary and loaded breaths, (see
Hudson et al. 2011; Raux et al. 2007b) and the final motor
output is manifested as a change in airflow. A coincident
increase in the correlation between EEG and airflow in loaded
breathing compared with resting breathing suggests the altered
brain state as detected by the covariance-based classifier was
due to breathing-related activity.
Methodological Considerations (Including Reliability)
Premotor potentials were observed during resting breathing
in 3 of 17 subjects, at a similar incidence as described previ-
ously for healthy subjects (see Tremoureux et al. 2014) and
most likely due to an awareness or volitional control of
breathing due to the respiratory apparatus despite modest
efforts to prevent this. An increase in inspiratory time and tidal
volume during recordings when a premotor potential was
observed during resting breathing is consistent with previous
reports of cortical activation during augmented breaths (Jutand
et al. 2012). Although task-related differences in the properties
of premotor potentials have been reported in limb movements,
comparable amplitudes and latencies of premotor potentials in
different respiratory conditions are consistent with previous
studies of respiratory-related cortical activity (Launois et al.
2015; Morawiec et al. 2015; Raux et al. 2007b; Tremoureux et
al. 2010).
For premotor potentials and time-frequency analysis, only
EEG epochs free of intense EOG activity and large deviations
due to movement were included. For the covariance-based
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2221
classifier, a band-pass filter of 8 –24 Hz would have removed
major components of ocular and movement artifact. Further-
more, frontal polar electrodes were excluded and any vertical
ocular artifact is likely to have been reduced by 80% at the
frontal electrodes used in the covariance-based classifier (Croft
and Barry 2000).
For nine subjects, reliability was poor for premotor potential
and time-frequency analysis measures, except for premotor
potential incidence during the sniff condition. These data are
consistent with reproducibility of preinspiratory potentials
from three subjects during voluntary sniffs (Raux et al. 2007b)
and poor reliability for premotor potential latency in six sub-
jects who repeated a protocol of finger extension (Matsuhashi
and Hallett 2008). A limitation of premotor potentials is that
cortical activity cannot be quantified in all subjects and all
conditions if the potential is absent. However, quantification of
premotor potentials via low-frequency power in time-fre-
quency maps did not provide a more reliable method to detect
changes in different respiratory conditions. The covariance-
based classifier directly compares and tests for differences
between conditions with good accuracy (AUC ⬎0.8). Further-
more, it can detect a change in all subjects, in contrast to
event-related potentials that cannot discriminate between un-
loaded and loaded breathing when subjects evidence a premo-
tor potential in resting breathing.
Development of a Brain-Ventilator Interface
Premotor potential and time-frequency analyses used in this
study require a large number of trials to enhance the signal-
to-noise ratio. This is adequate for physiological explorations
in the laboratory when data can be analyzed offline. However,
for clinical applications such as a brain-ventilator interface that
uses EEG to detect a change in breathing, an improved detec-
tion method is required. Here, in healthy subjects, we could
accurately detect a change between resting and loaded breath-
ing using a semisupervised algorithm with short preprocessing
time (see also Navarro-Sune et al. 2016). Although the current
analysis was performed offline, pilot testing in our laboratory
has confirmed online detection is possible within a quasi-real-
time domain (⬎0.01 s for 5-s windows) following classifier
set-up (i.e., learning the reference period) of ⬃1 min (Navarro-
Sune et al. 2016). Thus, compared with premotor potential
analysis, detection of cortical activity is close to “real-time,”
which makes the covariance-based classifier suitable for mon-
itoring of respiratory state. Rapid detection is particularly
important in critically ill patients in whom respiratory state can
be labile due to changes in respiratory mechanics or neural
activity (e.g., due to changes in sedation or pain) that alter the
brain-lung interface.
Nine frontal and central EEG channels were used to detect a
change in breathing condition. Future studies should investi-
gate how to optimize intersubject detection with a minimal
number of electrodes, for example, by controlling for potential
nonrespiratory variations in the EEG such as head movement
artifact (see O’Regan and Marnane 2013). The proposal of a
brain ventilator interface that uses EEG to monitor medullary
respiratory activity to trigger a mechanical ventilation (Grave
de Peralta et al. 2013) requires further technical development.
The central neural drive can already be used to drive mechan-
ical ventilation via diaphragm EMG in neurally adjusted ven-
2222 EEG DETECTION OF RESPIRATORY-RELATED CORTICAL ACTIVITY
tilator assistance (e.g., Schmidt et al. 2015) and furthermore,
EEG monitoring of medullary activity does not consider neural
drive to the respiratory muscles that originates in cortical
circuits. Respiratory-related cortical activity has been shown to
be associated with respiratory discomfort in cases of extrinsic
respiratory loading (Morawiec et al. 2015; Raux et al. 2007a),
and this association is to be confirmed for intrinsic loads
experienced by respiratory and critically ill patients. Recently,
we proposed a brain-ventilator interface that uses EEG to
detect loaded breathing and respiratory discomfort (Navarro-
Sune et al. 2016). Here, we demonstrate for the first time that
respiratory-related cortical activity associated with loaded
breathing in healthy subjects can be detected accurately and
with improved time resolution.
GRANTS
This work was supported by the program Investissement d’Avenir EMMA-
0030 and ANR-10-AIHU 06 of the French Government and by the grant Legs
Poix from the Chancellerie de l’Universite de Paris, France. X. Navarro-Sune’s
postdoctoral position within UMRS1158 is funded by Air Liquide Medical
Systems. A. L. Hudson was supported by an National Health and Medical
Research Council of Australia (Australia) Early Career Fellowship.
DISCLOSURES
X. Navarro-Sune is employed by Air Liquide Medical Systems S.A.,
France. T. Similowski, M. Raux, M. Chavez, J. Martinerie, and P. Pouget are
listed as inventors for patents using EEG to adjust mechanical ventilation.
UMRS1158 and ALMS have a contract to develop a brain ventilator interface.
AUTHOR CONTRIBUTIONS
Author contributions: A.L.H., P.P., M.R., M.C., and T.S. conception and
design of research; A.L.H. performed experiments; A.L.H., J.M., and M.C.
analyzed data; A.L.H., X.N.-S., J.M., P.P., M.R., M.C., and T.S. interpreted
results of experiments; A.L.H. and X.N.-S. prepared figures; A.L.H. drafted
manuscript; A.L.H., X.N.-S., J.M., P.P., M.R., M.C., and T.S. edited and
revised manuscript; A.L.H., X.N.-S., J.M., P.P., M.R., M.C., and T.S. ap-
proved final version of manuscript.
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