Download Long Term Effects of Low Frequency (10 Hz)

914
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
References
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following low-frequency repetitive transcranial magnetic stimulation in a patient with Tourette syndrome and comorbid obsessive-compulsive disorder.
Brain Stimul 2014;7:341e3 [Letter].
Long Term Effects of Low
Frequency (10 Hz) Vagus
Nerve Stimulation on EEG
and Heart Rate Variability
in Crohn’s Disease: A Case
Report
Dear Editor,
We report the first clinical case of long-term low frequency vagus
nerve stimulation (VNS) in a patient with Crohn’s disease (CD), a
chronic inflammatory disorder characterized by relapsing and remitting periods of gastrointestinal inflammation [1]. There is no definitive
cure of CD and there is a strong need for an efficient treatment
inducing sustained remission. We have shown, in an experimental
model of CD, that chronic low frequency VNS activates the cholinergic
anti-inflammatory pathway through vagal efferents [2]. VNS is thus a
therapeutic option for CD though it has only been used at high frequency in epilepsy and depression [3]. Long-term low frequency
(10 Hz) VNS has never been tested in CD and its central effect remains
unknown. Here, we share our first evaluation of the effect of 10 Hz VNS
in CD on both brain and parasympathetic nervous system.
Methods
A 49 year old male adult with ileal CD since 28 years with ileocecal resection in 1986, under maintenance treatment with immunosuppressant (IMURELÒ: 200 mg/day) since 2005, was implanted
with VNS in April 2012 while he was in moderate to severe flare
of its CD [Crohn’s disease activity index (CDAI) of 330
(threshold ¼ 150) and ulcerated stenosis of the ileo-colonic anastomosis]. After a written informed consent, the medical team opted
for a VNS protocol (http://clinical trial.gov identifier NCT01569503).
Under general anesthesia, an electrode (Model 302, Cyberonics,
Houston, Texas) was positioned on the left cervical VN and linked to
a stimulator (Model 102). The device was switched on at 0.5 mA the
day of the surgery and increased by 0.25 mA each week until 1 mA.
Stimulation parameters were: 30 s ON e 5 min OFF, 500 ms, 10 Hz.
VNS was continuously performed over 12 months.
EEG and electrocardiographic (ECG) recordings were performed
one week before, at week 6 and months 6, 9 and 12 post VNS implantation. EEG was recorded from 96 active electrodes (Acticap,
Brain products, Germany). Signals were acquired at resting state,
eyes-closed, during a 20 min period and digitized at a sampling
rate of 500 Hz. Data were further processed off-line using EEG
Lab (sccn.ucsd.edu/eeglab) and SPM (www.fil.ion.ucl.ac.uk/spm)
toolboxes. Blinks, muscular activity and VNS artifacts were removed
using independent component analysis as proposed in EEG Lab.
Data were re-referenced to the common average and EEG power
was computed in the canonical frequency bands (delta 1e4 Hz;
theta 3.5e7 Hz; alpha 7.5e13 Hz; beta 14e29 Hz; gamma
30e45 Hz) using a sliding time window of 10 s duration shifted
every 5 s during the whole EEG session. For each frequency band,
a Student t-test was performed to test the difference of EEG power
between VNS treatment and pre-VNS period.
VN activity was explored using heart rate variability (HRV) analysis from ECG recorded signal (Kubios, Finland) as we previously
described [4]. A standard spectral analysis was applied on interbeat intervals using a Fast Fourier Transform. High Frequency power
spectrum (HF, from 0.15 to 0.40 Hz) component was chosen to characterize parasympathetic tone fluctuations associated to VNS.
Results
VNS induced significant (P < 0.05) changes in resting EEG in all
frequency bands with shared spatial pattern (Fig. 1). In particular,
activations were observed over the mediofrontal electrodes for
both low and high frequency bands with the most important activation for theta band. An additional activation was found in the occipital electrodes for the gamma band (Fig. 1A). Significant
correlations (P < 0.05) were detected between EEG and HF-HRV
for delta (T ¼ 3.32), theta (T ¼ 3.26), beta (T ¼ 2.75), and gamma
(T ¼ 3.26) frequency bands. Interestingly, a positive correlation
was observed between HF-HRV and beta-gamma bands in occipital
electrodes. The highest level of significance was in the gamma band
for the negative correlation between HF-HRV and EEG power on the
left and right temporo-parietal electrodes (Fig. 1B). Beside these effects, the patient presented a significant clinical improvement, with
a progressive decrease of the CDAI score and an endoscopic remission at month 12, associated to an increase of the parasympathetic
tone as marked by the elevation of HF-HRV (Supplemental Data).
Discussion
To our knowledge, this is the first time that a positive effect of
long-term low frequency VNS is described on EEG, HF-HRV and clinical level in a CD patient. Although we cannot completely rule out a
placebo effect or even an improvement unrelated to the treatment,
it is worth mentioning that the patient is still in remission after 27
months under VNS and stopping immunosuppressant at month 16.
Further, we show that low frequency VNS, supposed to activate
efferent fibers, also has an effect on the central nervous system as
we have previously shown in rats [5]. We observed significant
changes on EEG in both anterior and posterior electrodes. On anterior
electrodes, the most important increase was observed in the theta
band in fronto-medial electrodes. Kubota et al. [6] reported that frontal midline theta rhythm reflected high level of attentional load and
was associated with an increase in both sympathetic and parasympathetic indices. Asada et al. [7] have shown that the anterior cingulate
cortex (ACC) is the source of this frontal midline theta rhythm.
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
915
Figure 1. Part A of the figure shows the effects of 12 months of vagus nerve stimulation (VNS) on EEG for the delta, theta, alpha, beta and gamma frequency bands. Part B shows the
correlations between EEG frequency bands and HF-HRV during the 12 months of VNS.
Considering that ACC is also part of the central autonomic network
modulating the parasympathetic nervous system, we can hypothesize
that the increase in mediofrontal theta could reflect an activation of
the ACC. This is in line with the positive correlation outlined between
the theta band and HF-HRV. This is moreover corroborated by the
study of Sakai et al. [8] revealing that EEG theta power correlates positively with HF-HRV in healthy subjects. We also reported a positive
correlation between gamma band and HF-HRV, localized in the occipital cortex where the activity of gamma band is also increased by VNS.
Moreover, both fronto-medial theta and occipital gamma rhythms
correlate with HF-HRV. Mindfulness, known to increase HF-HRV,
has also been shown to increase the posterior gamma band [9]. These
data suggest that VNS would facilitate the interplay between the occipital cortex and anterior structures for the functional integration of
neuronal processes since occipital and frontal lobes are anatomically
and functionally connected [10]. In conclusion, the changes in theta
and gamma bands provide evidence that forebrain areas could be
involved in the mediation of VNS effect on HRV.
Acknowledgments
We would like to thank Françoise Bardin and David Tartry for
their helpful involvement in the schedule of the patient visits and
Nicolas Mathieu for the achievement of endoscopies.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.brs.2014.08.001.
Funding: This work was financially supported by the Appel à projet (AAP) translationnel INSERM-DGOS 2011.Conflict of interest statement: None of the authors has
any conflict of interest to disclose.
Didier Clarençon
Institut de Recherche Biomédicale des Armées (IRBA), BP 73,
Brétigny-sur-Orge Cedex, Paris F-91223, France
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Sonia Pellissier
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Département de Psychologie, Université de Savoie,
BP 1104, Chambéry F-73011, France
Valérie Sinniger
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Clinique Universitaire d’Hépato-Gastroentérologie,
CHU de Grenoble, F-38043, France
Astrid Kibleur
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Dominique Hoffman
Service de Neurochirurgie, CHU Grenoble - CHU de Grenoble,
F-38043, France
Laurent Vercueil
Service d’Epilepsie, CHU Grenoble - CHU de Grenoble,
F-38043, France
Olivier David
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Bruno Bonaz*
Grenoble Institut des Neurosciences (GIN), Centre de Recherche
INSERM 836 UJF-CEA-CHU, F-38043, France
Clinique Universitaire d’Hépato-Gastroentérologie,
CHU de Grenoble, F-38043, France
* Corresponding author. Clinique Universitaire
d’Hépato-Gastroentérologie, CHU de Grenoble, F-38043, France.
916
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
Tel.: þ33 (0) 6 80 01 38 78, þ33 (0) 4 76 76 55 97;
fax: þ33 (0) 4 76 76 52 97.
E-mail address: [email protected]
Received 17 July 2014
Available online 26 September 2014
http://dx.doi.org/10.1016/j.brs.2014.08.001
References
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nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci 2011;160(1e2):82e9.
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stimulation. J Clin Neurophysiol 2010;27(2):130e8.
[4] Pellissier S, Dantzer C, Canini F, Mathieu N, Bonaz B. Psychological adjustment
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[5] Reyt S, Picq C, Sinniger V, Clarencon D, Bonaz B, David O. Dynamic Causal
Modelling and physiological confounds: a functional MRI study of vagus nerve
stimulation. Neuroimage 2010;52(4):1456e64.
[6] Kubota Y, Sato W, Toichi M, et al. Frontal midline theta rhythm is correlated
with cardiac autonomic activities during the performance of an attention
demanding meditation procedure. Brain Res Cogn Brain Res 2001;11(2):
281e7.
[7] Asada H, Fukuda Y, Tsunoda S, Yamaguchi M, Tonoike M. Frontal midline theta
rhythms reflect alternative activation of prefrontal cortex and anterior cingulate cortex in humans. Neurosci Lett 1999;274(1):29e32.
[8] Sakai S, Hori E, Umeno K, Kitabayashi N, Ono T, Nishijo H. Specific acupuncture
sensation correlates with EEGs and autonomic changes in human subjects.
Auton Neurosci 2007;133(2):158e69.
[9] Berkovich-Ohana A, Glicksohn J, Goldstein A. Mindfulness-induced changes in
gamma band activity - implications for the default mode network, selfreference and attention. Clin Neurophysiol 2012;123(4):700e10.
[10] Forkel SJ, Thiebaut de Schotten M, Kawadler JM, Dell’Acqua F, Danek A,
Catani M. The anatomy of fronto-occipital connections from early blunt dissections to contemporary tractography. Cortex 2014;56(7):73e84.
Reduction of TMS
Strength Near MRI
Scanner Could be
Explained by
Electromagnetic Coupling
to MRI Magnet
In a recent paper, Yau and colleagues made the very interesting
observation that the amplitude of the magnetic field pulses induced
by a TMS coil was reduced up to 5% when the coil was placed in
certain orientations near or in the bore of an MRI scanner [1]. The
authors showed that the reduction of the TMS magnetic pulse
amplitude appears related to the spatial gradient of the magnetic
field. Yau et al. speculated that the TMS field reduction is due to
an interaction between the static magnetic field of the scanner
and the TMS coil.
While I agree that this effect is likely due to an interaction of
the TMS coil with the MRI superconducting coils generating the
static magnetic field, I would argue that it is a dynamic electromagnetic interaction based on Lenz’s law rather than an effect
of the static magnetic field. First, we have to consider what the
MRI static magnetic field could and could not do to the TMS
coil field. The MRI static magnetic field results in increased forces
in the TMS coil [2]. These forces can temporarily deform the coil
during the TMS pulse, potentially altering the TMS pulse shape. As
well, the work done by these forces can effectively increase the
internal electrical losses in the coil, decreasing the TMS field
strength. However, for the well-designed, rigid, MRI-compatible
TMS coil used by Yau and colleagues, it is unlikely that these factors are large enough to account for the TMS coil field reduction.
This hypothesis is supported by the fact that the TMS field reduction was stronger for coil positions outside the scanner bore
where the static magnetic field and hence the forces acting on
the coil are much weaker than inside the bore. Besides these
potentially weak effects, the static magnetic field should not affect
the pulsed magnetic field of the TMS coil. By linear superposition,
the pulsed TMS field simply adds to the static field of the scanner.
Indeed, the search coil used for the measurements of Yau et al.
cannot detect the static magnetic field, since it relies on electromagnetic induction associated with dynamically changing magnetic fields.
Therefore, an alternative, more plausible explanation of the TMS
field reduction is the dynamic reaction of coils in the MRI scanner,
most likely the superconducting coil that generates the static magnetic field. Generally, between any two coils there is electromagnetic coupling that is determined by the amount of magnetic flux
from one coil that is linked to the other coil. When a TMS coil is
placed near or inside an MRI scanner bore, the TMS coil can couple
to the coils in the MRI scanner. The latter include the coils producing, respectively, the static magnetic field, gradient magnetic fields,
and radio-frequency field. When the TMS coil is pulsed, the generated magnetic flux that is coupled to a given MRI coil will induce a
voltage in it. The induced voltage will result in current flow that is
inversely proportional to the electrical impedance terminating the
MRI coil. This current will, in turn, generate a magnetic field that
opposes the magnetic field of the TMS coil, following Lenz’s law.
Thus, for sufficiently strong coupling between the TMS coil and
one or more of the MRI coils, and sufficiently low impedance in series with these coils, the scanner would generate a magnetic field in
response to the TMS pulse that partially cancels the TMS magnetic
field.
The electromagnetic coupling between the TMS and MRI coils
depends on their geometry and relative position. For TMS coil
placements outside the MRI bore, the coupling may be strongest
with the superconducting solenoid coil that generates the static
magnetic field in the scanner, since the latter has the largest diameter and a field that extends outside the bore [3]. In contrast, the
gradient and RF coils are smaller in size and consequently have
field patterns that are more spatially confined within the bore.
Furthermore, the static MRI magnet is superconducting and its terminals are shorted together. Hence the coil is terminated with
zero resistance, although the inductance can be significant,
limiting the magnitude of the induced pulsed current. On the
other hand, the gradient and radio-frequency coils are connected
to driving electronics that would present a high impedance in
off state. This may further reduce the ability of these coils to
generate a significant field in response to the TMS pulse (The electromagnetic interaction between the gradient and radio-frequency
coils and the TMS coil may nevertheless be significant during
scanning.).
To try to understand why the TMS field reduction effect is
dependent on the coil location and orientation, we have to consider
how they affect the coupling between the TMS coil and the MRI
static magnet coil. The latter consists of several circular loops in a
solenoid-like configuration [3]. On the other hand, the figure-8
TMS coil consists of two co-planar circular windings connected
electrically in series so that the electrical current in the two loops
circulates in opposite directions. Therefore the magnetic fields
generated by the loops have opposite polarity. The effect of the
flux generated by one of the TMS coil loops that penetrates the
MRI solenoid is mostly canceled out by the effect of the flux of