Biomed Imaging Interv J 2007; 3(1):e25
© 2007 Biomedical Imaging and
Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient
NJ Ray1, PhD,
ML Kringelbach1, PhD,
N Jenkinson1, PhD,
SLF Owen1, BSc,
P Davies3, FRCP,
S Wang2, PhD,
N De Pennington2, MRCS,
PC Hansen1, PhD,
J Stein1, RCPS,
TZ Aziz2 DSc
1 Department of Physiology, Anatomy and
Genetics, University of Oxford, UK
2 Department of Neurosurgery, Radcliffe Infirmary, Oxford, UK
3 Department of Neurology, Radcliffe Infirmary, Oxford, UK.
Purpose: Treatment-resistant cluster headache can be
successfully alleviated with deep brain stimulation (DBS) of the posterior
hypothalamus . Magnetoencephalography (MEG) is a non-invasive functional
imaging technique with both high temporal and high spatial resolution. However,
it is not known whether the inherent electromagnetic (EM) noise produced by
high frequency DBS is compatible with MEG.
Materials and methods: We used MEG to record brain
activity in an asymptomatic cluster headache patient with a DBS implanted in
the right posterior hypothalamus while he made small movements during periods
of no stimulation, 7 Hz stimulation and 180 Hz stimulation.
Results: We were able to measure brain activity
successfully both during low and high frequency stimulation. Analysis of the
MEG recordings showed similar activation in motor areas in during the patient�s
movements as expected. We also observed similar activations in cortical and
subcortical areas that have previously been reported to be associated with pain
when the patient�s stimulator was turned on or off [2,3].
Conclusion: These results show that MEG can be used
to measure brain activity regardless of the presence of high frequency deep
brain stimulation. � 2007 Biomedical Imaging and Intervention Journal. All
Keywords: Magnetoencephalography, DBS, cluster headache, pain
Deep brain stimulation (DBS) offers a unique opportunity to
study the underlying pathophysiology of the human disorders that can be treated
using DBS. Unfortunately, functional magnetic resonance imaging (fMRI) is
inappropriate for mapping DBS-induced changes in brain activity, as the strong
magnetic fields involved in fMRI can cause overheating or movement of the
electrode or the associated implantable pulse generator that is situated under
the skin of the chest. Magnetoencephalography (MEG) records the magnetic
component of the electromagnetic signal generated by the brain. It can provide
a spatial resolution that rivals fMRI techniques (around 5 mm�), yet unlike
fMRI it has a temporal resolution in the order of milliseconds.
The choice of frequency is dependent on the site of
stimulation. We have previously shown that it is possible to use MEG to record
the brain activity of a patient with a DBS electrode implanted within the
periventricular grey/periaquaductal grey to control phantom limb pain  with
a therapeutic stimulation frequency of 7 Hz.
However, the majority of DBS patients receive high-frequency
stimulation (130-180 Hz). It is possible that the significant increase in EM
energy generated at high-frequency DBS will interfere with the MEG sensors.
Therefore, it is important to assess whether MEG is suitable for studying
patients using high frequency settings.
The patient, described previously by Owen , was a
56-year-old male with an 11-year history of cluster headache attacks. The
headaches had a seasonal pattern starting in September or October every year
and occurred three to four times a day, lasting for 45 minutes on average. The
pain originated over the right forehead and radiated to the ipsilateral vertex
and was associated with lacrimation and excess rhinorrhea.
He was previously given carbamazepine, methysergide (2 mg
three times daily), cafergot, co-proxamol, verapamil (240 mg twice daily),
lithium (800 mg twice daily), amitryptiline and at the time of referral was
partially controlled on injections of sumatriptan and high-dose prednisolone.
The patient�s stimulator was turned off for 30 minutes prior
to scanning. We attached electrodes to his forearm for an EMG measurement. He
was then scanned for 10 minutes. At 22-second intervals he was asked to rate
his pain by pressing a button to stop a line moving along a scale measuring
from �not painful� to �very painful�. The screen was blank between ratings.
The patient�s stimulator was then turned on and set to 7 Hz.
After another 5 minutes we began the second 10-minute scan along with the
rating task. The protocol was then repeated a final time with the stimulator
set at 180 Hz.
The recordings were collected using a 275-channel CTF Omega
system (CTF Systems Inc., Port Coquitlam, Canada) at Aston University. Data
were sampled at 1200 Hz with an anti-aliasing cut-off filter of 200 Hz.
The patient was scanned with MRI before and after surgery to
get a high-resolution T1 volume with 1x1x1 mm voxel dimensions. After
the MEG scan, we used a 3-D digitizer (Polhemus Fastrack) to digitize the shape
of the patient�s head relative to the position of the headcoils, with respect
to the nasion, and the left and right ear, which could be later
registered on the MRI scan. There were no significant head movements between
The EMG was recorded on one of the MEG system�s EEG channels
and was later used to identify the motor response to the pain-rating task.
In line with the previous experiment (Kringelbach, 2006),
the data were analysed using Synthetic Aperture Magnetometry (SAM). This is an
adaptive beam-forming technique used to analyse EEG and MEG data, which
provides continuous 3-D images of cortical power changes . SAM can highlight
changes in cortical synchronisation; some of which have been shown to be
related to the hemodynamic responses found with fMRI .
In SAM, the brain is divided into many target locations
(typically into voxels with dimensions of 5x5x5 mm3). An optimal spatial
filter was computed for each voxel, linking the signal at the target location
to the signals recorded at the MEG sensor locations. The filter leaves signals
from the location of interest unperturbed whilst signals from other locations
are attenuated. This focusing is achieved by selectively weighing the
contribution that each sensor makes to the overall output of the spatial
filter. The jack-knife statistical method was used to calculate the total
amount of power in the specified frequency band within each of the active
(during button press) and passive (2 seconds before button press) states to
produce a t-map. A 3-D image of the brain was then produced by repeating this
procedure for each voxel (5x5x5 mm3). Power changes in the 10-20 Hz,
20-30 Hz and 30-60 Hz frequency bands were then calculated between the active
and passive states, and the threshold was set at t>2.3.
We were able to record the patient�s brain activity with MEG
in all conditions regardless of stimulator activity (Table 1). In all
conditions, somatosensory and motor cortex were activated in the active
(button-press) compared with passive (100 ms before the button-press) states.
We also found activation in the 10-20 Hz frequency band in the periaquaductal
grey (PAG) only when the patient�s stimulator was turned off (Figure 1).
We did not design our tasks to look for specific activations
in any particular region. So we cannot say whether these activations fit with
expectations or not. We report them here as they may serve as guidelines for
directing future investigations. The activations in PAG in particular must be
considered with caution, given the unreliability with which our analysis can
localise sources far below the cortex. When we threshold the activations at a t
value of 2 (corresponding to a confidence interval of 95%), we found that the
activation could be located at around 15 m left and right of the PAG but the
peak is at the location we have listed in Table 1.
When the stimulator was turned on, the fMRI showed
activations in frontal brain regions previously associated with the pain relief
network (Figure 2).
Figure 3 shows 10 seconds of raw data traces in all three
We have shown that it is possible to use MEG to study
changes in brain activity even during high-frequency DBS. In all conditions, we
found activity in brain regions serving motor control when the patient was
pressing a button to rate his pain. While this is not a new finding in itself,
it does show that it is feasible to use MEG and synthetic aperture magnetometry
(SAM) techniques to image the brain during high-frequency DBS. However, we do
not know yet if the stimulator has produced artefacts that are not detectable
with the analysis we have carried out. It is possible that the sensor data is
compromised by the presence of the battery, electrode and the stimulation
itself, but it is undetectable after the filtering is done in SAM. Further work
is needed to ascertain whether different types of analysis will still yield
data resistant to artefacts from DBS.� This work must also use multiple subject
numbers to ensure that the findings presented here are reliable.
This study was intended to investigate the effects of
high-frequency stimulation on MEG recordings. During analysis, however, we
found patterns of activation that could be explained by the current opinion on
pain and pain-relief. The posterior hypothalamus contains several
neurochemically distinct cell groups. One of these is the Hypocr/Orx neurons
that are activated by nociceptive stimuli and reach structures involved in
nociceptive relay and modulation, including the PAG . We found PAG
activation only when the patient�s stimulator was turned off, which may be
related to these connections. In a fMRI study, it was found that PAG was
activated if subjects were anticipating a painful stimulus, even before they
were subjected to pain . The patient in the present study was aware that his
stimulator had been turned off. The activations in PAG may have been related to
the patient anticipating his pain to return.
We also found activations that have been associated with the
pain relief functions of the mid-anterior orbitofrontal cortex , which were
most effective in the 180 Hz stimulation condition. This result is similar to
that reported in a previous paper studying the effects of low-frequency DBS
As well as treating the motor and pain conditions previously
mentioned, DBS is� being applied to an extending number of disorders; OCD ,
depression , epilepsy . However, the mechanisms by which DBS is
effective in any of these situations is unclear. Although we must proceed with
caution when considering our activations, particularly in PAG given that it is
sub-cortical, this study suggests that MEG will be a useful tool for understanding
the neural changes induced by DBS.
Charles Wolfson Charitable Trust, Norman Collisson
Foundation, Templeton Foundation and MRC.
Figure 1 Brainstem activation (PAG) in the 10-20 Hz frequency band when the patient�s stimulator was turned off.
Figure 2 Orbitofrontal activations in the 10-20 Hz frequency band during 180 Hz stimulation (top image), but not during no stimulation (bottom image).
Figure 3 Raw data from a central channel during no stimulation, and with stimulation at 7 Hz and 180 Hz.
Table 1 Active brain regions.
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|Received 14 December 2006; received in revised format 19 February 2007; accepted 4 March 2007
Correspondence: Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, United Kingdom. Tel.: +44 1865 272498; Fax: +44 1865 272469; E-mail: firstname.lastname@example.org (Nicola Ray).
Please cite as: Ray NJ, Kringelbach ML, Jenkinson N, Owen SLF, Davies P, Wang S, De Pennington N, Hansen PC, Stein J, Aziz TZ,
Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient, Biomed Imaging Interv J 2007; 3(1):e25
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