Pharmacodynamics

Localization of Scopolamine Induced

Electrocortical Brain Activity Changes,
in Healthy Humans at Rest

The Journal of Clinical Pharmacology

53(6) 619625
The Author(s) 2013
DOI: 10.1002/jcph.83

Pedro Miguel Ramos Reis, MSc1, Holger Eckhardt, MSc1, Pierre Denise, MD, PhD2,
Friedrich Bodem, PhD1, and Matthias Lochmann, MD, PhD1

Abstract
To prevent the participants of parabolic flights from nausea they are optionally treated with subcutaneously injected antiemetic scopolamine. The range
of side effects of this substance include reductions of the a2 frequency band. Previous studies, however, have given no information as to which generator
centers are responsible for this effect. The objective of this study therefore, is to identify the cortex area that may be responsible for this effect. Six
participants were subcutaneously administered 0.7 mg of scopolamine. EEG was recorded for 10 minutes before to 20 minutes after injection. Data
preprocessing followed including filtering and artifact minimization. A statistical analysis was performed with sLORETA/eLORETA software for each
subject over a time window from 3 minutes before to 1720 minutes after scopolamine injection. Results show, that in the BA7, the precuneus, on both
hemispheres suffered a a2 activity decrease in absolute power. The identified brain cortex center is an important hub with high connectivity and
centrality values within the neural network. It contributes to the control of movement and to space orientation. Therefore, an activity alteration in this
area can possibly explain the antiemetic effect of scopolamine and open a window to understand the origin of motion sickness.

Keywords
brain mapping, electroencephalography, motion sickness, parietal lobe, scopolamine hydrobromide

Since the very advent of aerospace medicine, scientists use

special aircrafts for various types of research during ight
maneuvers, increasing or reducing the normal gravitational acceleration. Pilots create inside the airplane cabin, a
zero gravity (0G) by ying the airplane along a parabolic
arc, corresponding exactly to the trajectory of a body
moving forward in free fall. It is common, for a mission to
have up to 50 consecutive parabolas.
The pleasant sensation of weightlessness can easily
turn into a problem if motion sickness occurs. Roughly
6080% of the astronauts exposed to microgravity,
experience motion sickness during the rst 3 days of
spaceight. Symptoms include: pallor, cold sweating,
increased body temperature, malaise, loss of appetite,
hypersalivation, nausea, vomiting, fatigue, headache,
dizziness, and blurred vision.1,2
The origin of motion sickness is unknown, but
scientists postulate that it is an effect of conicting
sensory perception3,4 and more specically in the case of
space motion sickness a conict when repetitive angular
and linear acceleration and deceleration create confusion
in the vestibular system.1,2
According to this hypothesis, motion sickness occurs
when there is a repeated conict between the information
generated by the proprioceptive and visual sensors and
what the person expects from its relative position to the
environment. In parabolic ights, motion sickness can

considerably disrupt ongoing experiments, thus being

unpleasant for the crew.
Motion sickness prevention and control frequently
resorts to pharmaceuticals such as scopolamine hydrobromide. This is an anticholinergic drug and commonly
used in this context. Only 0.3 mg to 1.2 mg have to be
administrated subcutaneously for an effective treatment.5
It acts by interfering with the vestibular input to the central
nervous system, thus preventing vomiting, which is the
most prominent symptom of motion sickness. Although
scopolamine is efcient in preventing vomiting,2 its use is
not without adverse effects. These include drowsiness,
dilated pupils, tachycardia, hallucinations, mood or mental
changes, dryness of the mouth, and the respiratory
airways.2,5 Scopolamine also causes attention and memory
decits,610 visual memory impairment10 and amnesia.11 It

1
FriedrichAlexanderUniversitt ErlangenNrnberg, Sport und
Bewegungsmedizin Institut fr Sportwissenschaft und Sport,
Erlangen, Germany
2
Normandie Univ, UNICAEN, Inserm, Caen, France

Submitted for publication 15 February 2013; accepted 11 March 2013.

Corresponding Author:
Pedro Miguel Ramos Reis, MSc, Gebbertstr 132b, 91058 Erlangen,
Germany
Email: pedro.reis@sport.unierlangen.de

620
also causes an increase of reference and working memory
errors,12 detriments in reaction time, rapid information
processing13 and nally, learning impairments.14 Consequently, scientists use it to test the efcacy of memory
boosting drugs, serving as a memory impairment platform.
In a previous study10 researchers attempted to use
photic driving response (PDRs) EEG analysis to access
cerebral dysfunction caused by scopolamine. They
veried that a2 band power suffered a signicant
decrease at most of the recording sites. In another study15
the authors constructed a pharmacokineticpharmacodynamic model that relates the serum concentration of
scopolamine to changes in the total power in the aband.
The authors used the aband because it was the only
frequency band signicantly affected with a decrease in
absolute power, observed from 30 to 90 minutes after drug
administration.

Why It Is Important to do This Study

These and other studies do not give any information about
which cortex sources are responsible for the effects of
scopolamine. However, this is a prerequisite to understand
the wide range of effects produced by this drug, the origin
of motion sickness and its many different symptoms. New
knowledge thus elaborated, may facilitate the design of
new approaches for the treatment of ight crews
frequently administered with scopolamine.

What We Expect
Scopolamine and motion sickness affect a variety of brain
functions. For that reason, we anticipate that the affected
generator centers carry out connectivity functions between
specic parts of the brain.
We also expect that the aband is the most signicantly
affected brain frequency, in agreement with other
studies.10,15,16

Objectives of This Study

To nd which brain areas and frequencies waves
scopolamine inuences.

Methods
Subjects
We performed our study with six male volunteers. Their
age ranged from 23 to 34 years, with an average age of
29.2 years. Participants had a clean psychiatric history and
no known neurological decits. They participated in the
13th parabolic ight mission of the DRL (Deutsches
Zentrum fr Luft und Raumfahrt; German Space Agency)
and chose to receive preight scopolamine motion
sickness prevention treatment. All participants gave their

The Journal of Clinical Pharmacology / Vol 53 No 6 (2013)

permission for the experiment by a written informed

consent. The experimental protocol complied with the
declaration of Helsinki. Furthermore, the ethic commission of the FriedrichAlexanderUniversitt Erlangen
Nrnberg gave its approval for the experiment. Additionally the Comit de Protection des Personnes CPP Nord
Quest III and the Agence Franaise de Scurit Sanitaire
des Produits de Sant (AFSSAPS) also gave approval for
the experiment. Finally, we took an insurance contract for
every participant, against possible risks and liabilities.
Scopolamine Administration and Brain Activity
Recording
The ight surgeon gave the participants, subcutaneously,
0.7 mg of scopolamine. We asked the participants to, sit,
relax, shut their eyes and use earplugs, to minimize their
sensory stimuli input, and started data recording. This took
place approximately 2 hours before the parabolic ight in
a quiet room, at the laboratories of Novespace, Paris,
France.
Following guidelines from the Research and Technology Organization of NATO17 and our medical crew
clinical experience, rst time yers receive specic
dosages: 0.7 for adult male and 0.5 mg for adult female.
A subcutaneous injection is preferred to an intravenous
one, because it is done with a small, short needle with
minimal risk of nerve lesion, infection, hematoma, and
minor discomfort to the participants. Other groups prefer a
transdermal disk patch but to achieve the same therapeutic
efcacy it is necessary a dose, up to six times of an
intramuscular injection. Yet, this can bring the risk of toxic
side effects.18
EEG data were recorded with 64 equidistant active
electrodes (actiCap, Brain Products GmbH, Gilching,
Mnchen, Germany). Active electrodes strongly reduce
the bioelectrical source impedance and thus widely reduce
cable movement artifacts. The electrode cap we used in the
measurements has equal distances between electrodes,
reaching below the hat brim line. This facilitates the source
localization calculation. Thus, avoiding misleading results
commonly associated with methods requiring homogeneous EEG signal sampling over the full head surface, that
is, of the full bioelectric activity projected onto the scalp.19
Additionally, we used custom electrode positions. These
are required for reliable source localization results.20
Hence, we used an ultrasonic electrodes placement device
(Zebris Medical GmbH, Isny, Germany).
Before recording, we made sure that the impedance of
each electrode was below 20 kV, using an electrode gel.
After the recordings, we veried that the impedance was at
the same level as at the start of the experiment. Every
electrode cable used an individual electrical shield,
keeping electrical interference at a minimum. We recorded
the participants EEG activity from 10 minutes before until
20 minutes after scopolamine injection at a sampling rate

621

Ramos Reis et al.

of 2000 Hz, with a resolution of 22 bits, and referenced to

the common average value.
Data Analysis
Data PreProcessing. Data preprocessing was executed
using the Vision Analyzer 2 software package (Brain
Products GmbH, Gilching, Mnchen, Germany). After
loading the EEG data into the programs, we applied the
following procedures: (1) Band pass ltering (low cutoff
f 0.5 Hz, slope 12 dB/oct, c 0.3, high cutoff f 70
Hz, slope 12 dB/oct, c 0.3) with a notch lter of 50 Hz
for mains hum suppression. (2) Visual artifact correction.21 (3) Load the electrodes positions data. (4) Virtual
electrode calculation by topographical interpolation, for
replacement of electrodes affected with substantial noise
and electrical interference. (5) Selection of data segments
affected with myoelectric or other severe artifacts, by
means of an automatic method. Checking the signal for a
maximal allowed voltage gradient of 50 V/ms and a
maximal allowed absolute amplitude difference of
200 V, maximum allowed amplitude of 200 V. Further
checking for a minimal allowed amplitude of 200 V
over an interval of 200 ms and a lowest allowed amplitude
of 0.5 V over an interval of 100 ms. (6) Another visual
inspection of the EEG signals for further selection of bad
data intervals. (7) Data segmentation with a time window
from 3 minutes before until scopolamine injection and
another time window, from 17 to 20 minutes after
scopolamine injection, when the scopolamine serum level
is reaching peek value.15 (8) Further segmentation of the
data in intervals of 4 seconds each with a 10% overlap.
Removing previously selected bad intervals. (9) Export of
the processed EEG and electrode position data, into
LORETA format.
EEG Source Localization. We determined signal source
locations with the sLORETA/eLORETAKEY software
package2224 using the exact low resolution brain
electromagnetic tomography (eLORETA) method.25
eLORETA, does not require standardization for correct
localization.24,25 It computes the threedimensional distribution of intracerebral bioelectrical sources from their
potential eld recorded on the scalp.26
The author demonstrates that eLORETA is a genuine
inverse solution approach to the source localization
problem. More than a merely a linear imaging method
and that it yields an exact zero error localization, even in
the presence of measurement and structured biological
noise. The current versions of sLORETA and eLORETA
use a realistic head model, calculated by Fuchs et al22
and an electrode coordinate system, proposed by Jurcak
et al23
The procedure for eLORETA analysis included: (1)
Loading of the exported EEG data from the Analyser2. (2)
Registration of real electrodes. (3) Creation of an
eLORETA transformation matrix from the electrode

coordinates. (4) Creation of a cross spectrum of the

EEG. (5) Calculation of eLORETA les from the cross
spectra, (6) Statistical analysis.
Statistical Analysis. For statistical analysis, we used the
sLORETA/eLORETAKEY statistical nonparametric
permutation (SnPM) software package, based on the
Fishers permutation test27 which has been applied, for
example, by Nichols and Holmes28 to neuroscientic data
analysis.
We opted for SnPM since this method is most adequate
for single subject or small sample studies.28,29 In contrast,
statistical parametric mapping (SPM) requires larger
population samples,30 for instance, 10 subjects to reach
80% of statistical power with a 0.05.
To visualize the EEG activity differences under the
given different experimental conditions, we carried out,
for all time frames and frequencies, a paired samples ttest
(A B) for the log of the ratio of the averages (similar to
log of the Fratio) yielded by the eLORETA Electrode/
Voxelwise (relative power type) normalization.
For evaluating statistical signicance, we used a non
parametric randomization test, performing 5000 randomizations and computing bullet proof corrected critical
thresholds and P values. According to several studies10,15,16 it is expected that a2 band activity is reduced
after scopolamine administration. Thus, for the statistical
testing, we used the onetailed hypothesis. Voxelby
voxel t values in Talairach space are displayed as statistical
nonparametric maps (SnPMs) output. The program
indicates the Brodmann areas31 (BA), identied with
signicant activation levels.

Results
Pre versus post scopolamine injection comparison showed
a a2 band decrease in absolute power with a signicant
above the t critical value (P < .05; .533) for the one tailed
Pre > Post test (Table 1). This change, in brain activity,
occurred in the precuneus, BA 7 (Figure 1). All other
observations were nonsignicant (Table 1).

Discussion
In this study, we aim at nding which brain areas and
frequency bands scopolamine affects. Surely, we have
effectively found an interesting affected area. For our
investigation, we used EEG recordings of six subjects,
before and after intramuscular injection of 0.70 mg of
scopolamine.
Research15 found that intramuscular injection of
scopolamine has low stability and interindividual values
of blood serum concentration. This did not allow for
PharmacokineticsPharmacodynamics (PKPD) modeling of scopolamineinduced changes in EEG, using the
sigmoidal Emax model. However, in our study, this seems

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The Journal of Clinical Pharmacology / Vol 53 No 6 (2013)

Table 1. eLORETA Critical and
Statistical Thresholds (n 6)
t critical P < .10a
t critical P < .05b
t critical P < .01b
d
u
a1
a2
b1
b2
b3
V
Twotailed (Pre < > Post).
Onetailed (Pre > Post).
P < .05.

P < .10.
a

b


0.533
0.533
0.567
0.3499
0.2415
0.2752

0.5558 ,
0.1325
0.1466
0.1201
0.0068

sufcient for determining a brain center, which research

shows to be key for several brain functions that motion
sickness and scopolamine affect. The special location and
functions of this particular area, which we expose below,
further conrm the high robustness of our methods and
that even though we were unable to measure PKPD for
each individual; these differences are insignicant for this
purpose.
To nd the EEG signal changes and the brain cortex
area responsible for these, we used the eLORETA method.
Results show that after the drug administration a decrease
of the a2 frequency band activity occurred as expected.10,15,16 The software presented the cortex area
responsible for this decrease as the BA 7, that is, the
precuneus, in the parietal lobe. These ndings are more
specic than in earlier studies, which could only nd

Figure 1. Displayed are six orthogonal views of the cortex (top), five orthogonal views (middle), and a slice view of significant areas with a density
coding color scale (right). Structural anatomy is shown in a gray scale (L, left; R, right; A, anterior; P, posterior). Images show statistical nonparametric
maps (SnPM) of eLORETA differences in the a2 frequency band. These compare the conditions preinjection (condition A) and postinjection
(condition B) (n 6). The images are based on Log of Fratios, not standardized current density. The difference is significant for the onetailed test
Pre > Pos. Red colors indicate increased activity in the preinjection condition. This means that the precuneus (BA7) was more active before
scopolamine injection.

Ramos Reis et al.

the affected frequency wave and a partial scalp projection.

Because previous research32 has associated a waves
desynchronization and suppression with inhibition or
disengagement of cortical areas, these results indicate an
inhibition of the precuneus and related functions by
scopolamine.
Similarly to what occurs due to the aging process,
scopolamine also induces a hypocholinergic state, that is,
it reduces the number of muscarinic receptors. This can
explain why this drug affects EEG activity and the
precuneus. As a result, memory and learning, as we
describe next, are usually impaired. Therefore, scopolamine, is often used as a drug in model studies of central
nervous system ageing.15
The precuneus carries out several highly integrated
functions. Cavanna and Trimble33 describe the precuneus
functional anatomy and its behavioral correlates. The
authors state that the precuneus has central functions in
visomotor tasks, such as tracking and visual learning; is
fundamental to rene information about egocentric and
allocentric spatial relations for body movement control,
and for higher order processes such as voluntary attention
shift. This also includes more abstract mental imagery tasks
and the control of visually guided reaching in humans. The
precuneus is active during movement preparation and
execution, particularly when a person tries to coordinate
two limbs according to a complex spatiotemporal pattern.
Further, the precuneus is active during tasks requiring
spatial information about the direction of movements in an
imaginary eld, motor imagery, visual rotation, deductive
reasoning, music processing, and mental navigation. In
addition to a central role in these functions, its location in
the cortex is rather important. It is located in a central area,
in the posterior region of the medial parietal cortex,
strategically favorable, provided of a major association
area, with widespread connections. The precuneus, thus, is
a key part of the neural substrate of visual imagery
occurring in episodic memory recall, consciousness, self
processing, and episodic memory.
The reader can wonder if all the above functions and
activities are associated with considerable energy consumption. Indeed, this structure exhibits one of the highest
metabolic activity patterns of all brain regions. During the
conscious resting state, it consumes 35% more glucose
than in any other area of the cerebral cortex.34 Furthermore, this area is somewhat hypoactive in mental states of
decreased or abolished consciousness like sleep, hypnotic
state, pharmacological sedation, and in the vegetative
state.33 Clinicians and researchers often observe this state
of decreased consciousness and certain drowsiness in
subjects after the drug administration. Subjects go trough a
change in behavior, self and general awareness. Their
performance and rapid information processing are also
often impaired. This results in undesired conditions for a
next ight.13,35

623
The central role of the precuneus is further demonstrated trough application of graph theory methods.36,37
Several studies38,39 include the precuneus, along with
the insula, the superior parietal cortex and the superior
frontal cortex, in the group of brain areas with high
betweenness centrality and thus constituting hubs. In
graph theory betweenness centrality is a quantity used to
describe the centrality of a network node. It is equal to the
number of shortest paths connecting all vertices that pass
through that node. Beyond connectivity, it is used to
measure the load placed on the node and the importance of
the node to the network. Investigators can identify a hub
based on its degree, participation in modular connectivity,
or centrality. The degree is often used as a simple indicator
of the nodes importance in the network.36 In another
study40 the authors report that, when considering multiple
network measures (including node degree, connection
strength and centrality), a particular set of brain regions
located predominantly in the posterior medial cortex, were
highly and densely interconnected. These included
portions of the posterior cingulate and the precuneus.
They form a structural core, which implies that this cortex
center is essential to regulation and communication
distribution, between multiple other functional cortex
areas. This explains why administration of scopolamine
engenders all kinds of effects ranging from impaired
learning to memory loss, rats taking longer to nd the way
out of the maze, impairments of the visual memory, and
some effects in attention and motor tasks.
Study Limitations
Small sample size limits our study, even though, the
statistical methods used (SnPM) allow for low sample size
or even single subject studies. A larger population sample
would allow more statistical power and higher statistical
signicant differences.
The utilized electrodes positions measurement system
also limits this study. We used a Zebris electrodes
placement ultrasound device (Zebris Medical GmbH). A
more recent study (nonpublished) showed that this
system reliability could still improve.
Another limitation of this study was the choice of a 17
20 minutes post injection time window. A 3090 minutes
window might be of interest too, as it can be expected that
the EEG activity is stronger inuenced by scopolamine
then due to a lag time between serum concentration and the
resulting inuence on the bioelectrical brain cell
functions.15
Lastly, due to technical and budget limitations, we
could not collect PKPD data and account for inter
individual variability which, is larger in intramuscular
administration of scopolamine.15 Even though this
study results are quite plausible it would be good to
repeat this study and collect PKPD data to conrm the
results.

624

Conclusion
The interesting results of this study show that scopolamine
administration causes a signicant effect on the precuneus
activity.
Because the precuneus is a highly integrated cortex
structure with an important role as a main network hub, a
variety of effects may be stimulated by this drug,
consequently, impairing various cerebral functions. This
is additional evidence to support the hypothesis that this
neural structure is primarily involved in the development
of motion sickness and additionally, that scopolamine
owes its antiemetic potency to its ability to change this
structure activity.
If motion sickness depends in part, on how the
precuneus can cope with a changing information ow
and its distribution, countermeasures, developed in the
future, should target this structure and its functions, by
changing its regulatory activity in a way, avoiding the
conict between information input and output.
Acknowledgment
This study was supported by the DLR (Deutsches Zentrum fr
Luft und Raumfahrt; German Space Agency; project number
50WB0832).

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