A Novel Magnetic Stimulator Increases Experimental
Pain Tolerance in Healthy Volunteers
Sham-Controlled Crossover Study
Rudie Kortekaas1*, Lotte E. van Nierop1.¤, Veroni G. Baas1., Karl-Heinz Konopka2, Marten Harbers4,
Johannes H. van der Hoeven3, Marten van Wijhe2, Andre ´ Aleman1, Natasha M. Maurits3
1Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 2Department of Anesthesiology, University
Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 3Department of Neurology, University Medical Center Groningen, University of
Groningen, Groningen, The Netherlands, 4Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
The ‘complex neural pulse’TM(CNP) is a neuromodulation protocol employing weak pulsed electromagnetic fields (PEMF). A
pioneering paper reported an analgesic effect in healthy humans after 30 minutes of CNP-stimulation using three nested
whole head coils. We aimed to devise and validate a stimulator with a novel design entailing a multitude of small coils at
known anatomical positions on a head cap, to improve applicability. The main hypothesis was that CNP delivery with this
novel device would also increase heat pain thresholds. Twenty healthy volunteers were enrolled in this double-blind, sham-
controlled, crossover study. Thirty minutes of PEMF (CNP) or sham was applied to the head. After one week the other
treatment was given. Before and after each treatment, primary and secondary outcomes were measured. Primary outcome
was heat pain threshold (HPT) measured with thermal quantitative sensory testing. Other outcomes were warmth detection
threshold, and aspects of cognition, emotion and motor performance. As hypothesized heat pain threshold was significantly
increased after the PEMF stimulation. All other outcomes were unaltered by the PEMF but there was a trend level reduction
of cognitive performance after PEMF stimulation as measured by the digit-symbol substitution task. Results from this pilot
study suggest that our device is able to stimulate the brain and to modulate its function. This is in agreement with previous
studies that used similar magnetic field strengths to stimulate the brain. Specifically, pain control may be achieved with
PEMF and for this analgesic effect, coil design does not appear to play a dominant role. In addition, the flexible
configuration with small coils on a head cap improves clinical applicability.
Trial Registration: Dutch Cochrane Centre NTR1093
Citation: Kortekaas R, van Nierop LE, Baas VG, Konopka K-H, Harbers M, et al. (2013) A Novel Magnetic Stimulator Increases Experimental Pain Tolerance in
Healthy Volunteers - A Double-Blind Sham-Controlled Crossover Study. PLoS ONE 8(4): e61926. doi:10.1371/journal.pone.0061926
Editor: Sam Eldabe, The James Cook University Hospital, United Kingdom
Received September 5, 2012; Accepted March 17, 2013; Published April 1 , 2013
Copyright: ? 2013 Kortekaas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Source of funding: University Medical Center Groningen, The Netherlands. The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: Co-authors Andre ´ Aleman and Natasha Maurits are PLOS ONE Editorial Board members. This does not alter the authors’ adherence to all
the PLOS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
¤ Current address: Institute for Risk Assessment Science, University of Utrecht, Utrecht, The Netherlands
. These authors contributed equally to this work.
Magnetic stimulation of the brain is a safe and non-invasive way
to modulate brain function. The best known method is transcra-
nial magnetic stimulation (TMS) and uses strong (1–2 T) and short
(,1 ms) pulses. In 1985 Barker et al. described the induction of
involuntary movement by stimulation of the motor cortex which
indicates that TMS is able to induce action potentials in the brain
Weaker magnetic stimulation can be achieved with small or
large coils, either commercially available or custom built. This
technique often uses pulsed stimulation and is then referred to as
pulsed electromagnetic field (PEMF) stimulation. Recently, some
evidence has been found that exposure to MRI systems may
change mood , brain metabolism  and brain activation .
In humans PEMF appears to have both analgesic  and
antidepressant  effects.
Often commercial stimulation systems (e.g. NeoSync, Inc.,
PEMF Systems, Inc., CNP Therapeutics Inc.) use a limited
number of small coils while in research the use of one or more
Helmholz coils is often reported . Helmholz coils are large coils
that fit around the head and generate a relatively homogeneous
magnetic field. The disadvantage of few coils as well as of very
large coils is that it is difficult to investigate which stimulation sites
in the brain are most effective for inducing a specific effect. Large
coils are also impractical due to their size and weight which
impedes their wide spread therapeutic use in either a clinical or
even an extramural i.e. domestic setting. By far the most practical
stimulation system for wide spread clinical and extramural use
would be a small magnetic stimulator that is easy to use and able to
PLOS ONE | www.plosone.org1April 2013 | Volume 8 | Issue 4 | e61926
selectively stimulate specific brain areas. It should also be able to
generate any type of magnetic wave to maximize applicability.
The use of multiple light coils on a head cap eliminates subject
motion relative to the coils and the coils may be positioned over
known anatomical sites. We selected the 10/20 system as used in
EEG for the positioning of the coils because this allows for easy
coupling of newly found knowledge to EEG findings and to
functional neuroanatomy because the brain structures under the
electromagnets are known . One of our aims was the
construction of such a stimulation system.
The complex neural pulse (CNPTM)  has been used as a
PEMF at low field strength and it was shown to have analgesic
efficacy in snails , rats  and humans . A recent study in
humans applied PEMF with the gradient coil of an MR scanner
and found a negative correlation between field strength and brain
activation in a network of brain areas that respond to pain . A
second aim of the present study was to investigate the analgesic
potency of the CNP when administered with our own device.
The underlying mechanism of PEMF induced analgesia is
poorly understood. There is some evidence for endogenous opioid
mediation of PEMF analgesia in animals[8,11], but in humans the
mechanism is largely unknown. It is known that mood has a strong
influence on pain experience  and improved mood is thus a
potential mediator of PEMF analgesia, especially because PEMF
was reported to improve mood in depressed patients .
Further, dopaminergic tone is correlated to mood and also
sensitive to PEMF and TMS [13,14]. In addition, dopamine has a
modulatory effect on pain (for review see ) making dopami-
nergic tone another, although related, possible mediator of PEMF
analgesia. Non-invasive assessment of dopaminergic tone in
humans requires PET or SPECT imaging. However, there are
behavioral markers that are safer, quicker, cheaper and more
practical: the speed of finger tapping and the size of handwriting
are both highly significantly correlated with central dopaminergic
tone as established by PET or SPECT[16,17]. Our final aim was
to find evidence for mediation of an analgesic effect by mood or
We applied the CNP  and studied its effects on the
experience of experimentally induced heat pain in healthy
volunteers. We also assessed emotional state as a potential
mediating factor of analgesia and aspects of motor and cognitive
Materials and Methods
This research has been approved by the Medical Ethical
Committee of the University Medical Center Groningen.
Informed consent was obtained from the subjects and the clinical
investigation was conducted according to the principles expressed
in the Declaration of Helsinki.
A personal computer (Pentium) and interface card (K8000,
Velleman, Gavere, Belgium) were used as Arbitrary Waveform
Generator (see figure 1). Digitization resolution was 3 ms, no extra
filtering was applied.
The computer ran a bash shell on Debian Linux (www.debian.
org). C++ programs were written that contained instructions for
wave generation using the libk8000 library (freshmeat.net/
projects/libk8000). Compilation with g++ resulted in one small
(,100 kB) executable for each wave.
To increase the low power output of the K8000 a DC coupled
amplifier was built (figure S1). The amplifier had a medical power
supply and an isolation unit as additional safety features.
Magnetic field generation and head cap
The electromagnets consisted of 25 mm long, 9 mm thick reed
relays (Reed Relay 275–232, Radio Shack, Fort Worth, TX, USA)
of which the reed switch was replaced  by an M2630 mm
grade 2 steel bolt, transforming them into iron core electromag-
nets. Measurements of electrical properties with an RLC bridge on
a single coil yielded the following values: resistance: 245 V,
inductance at 100 Hz: 122 mH, at 1 kHz: 89 mH (without iron
core: 13.5 mH).
Nineteen of these electromagnets were radially attached to a
regular EEG cap with a chin strap (SU-60 and KR, MedCaT,
Erica, The Netherlands) using non-metallic nuts on the inside of
the cap. Electromagnets were positioned according to the
international 10/20 system for EEG electrodes (figure 1).
All electrical equipment was powered through a
medical isolation transformer (H01.96.00, Jansen Medicars,
Maarssen, Netherlands) (see figure 1).
The entire setup was tested with an International Safety
Analyzer (601PRO, BIO-TEK Instruments Inc., Winooski, VT,
USA) as a class I, type B device according to norm 601 of the
International Electrotechnical Commission (IEC; 1988). Leak
currents to earth were below 20% of the norm, patient leak
currents were below 1.8% of the norm (always below 10 mA) at a
current consumption of 0.2 A. The device passed all tests for a
class I type B clinical device.
Characterization of the setup.
density was 1.45 mT at each electromagnet (see figure 2).
DC shifted sine waves (min 0 V, max
+3.47 V) of different frequencies were generated with a Function
Generator (Model 110, Wavetek, San Diego, CA, USA) and a DC
power supply and were then used as input to the amplifier.
The following were measured: voltage into the amplifier,
voltage out of the amplifier and magnetic flux density (Gauss-/
Teslameter, FH 54, with an axial Hall probe, HS-AGB5-4805,
Magnet-Physik, Cologne, Germany) at the scalp side of one of the
The coils acted as a low pass filter, limiting the frequency
response of the system: while the amplifier had its 50% frequency
around 90 kHz, the coils showed a 50% frequency at about
300 Hz (figure 3).
Legal and ethical.
Before clinical testing of the stimulator, a
description of the equipment and a copy of the Insurance
Certificate were filed with The Dutch Health Care Inspectorate
(Inspectie voor de Gezondheidszorg) to comply with legislation.
The study conformed to national legislation on medical research
and was approved by the Medical Ethical Committee of the
University Medical Center Groningen, the Netherlands. In
addition the study was registered in the Dutch Trial Register
(Dutch Cochrane Centre, NTR1093, http://www.trialregister.nl/
Also, we conformed to the Dutch Personal Data Protection Act
(‘‘Wet Bescherming Persoonsgegevens’’ of 2001). Subjects gave
written informed consent and received neither financial nor
curricular incentives for their participation.
Twenty healthy volunteers, all native Dutch speak-
ers, were recruited through advertisements on bulletin boards of
the University of Groningen. Inclusion criteria were: 18–80 years
old, subjectively healthy. Exclusion criteria were: neurological (e.g.
epilepsy) history, psychiatric history, recent use (within four weeks)
Maximum magnetic flux
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of prescription or non-prescription psychopharmaca, use of .10
units of coffee per day, use of .10 units of alcohol per day,
presence in the body of MRI incompatible implants.
This was a single center, double-blind, sham-
controlled crossover study conducted in the Netherlands. The
within-subjects design was balanced for treatment order. All
subjects received a sham and an active treatment at the same time
of the day with one week in between. By using a random number
generator on the stimulus PC, neither the subject nor the
experimenter was aware of the nature of the treatment. The code
was broken after all twenty subjects had been treated twice. Also,
two field strengths were tested in order to investigate dose (field
strength) effects on the outcome parameters: HIGH (amplitude
1.1 mT) and LOW (amplitude 0.4 mT). Half of the subjects
received HIGH and half received LOW as their active treatment.
During a session the volunteers were seated
behind a desk while wearing the treatment cap. Each session
consisted of four blocks of fifteen minutes each. The blocks were
identical in all aspects, except that during the first and last block
only zeroes were sent to the DAC. During the second and third
block either PEMF (LOW or HIGH field, one option per subject)
or sham (all subjects) was applied through all electromagnets so
that a total of 30 minutes of PEMF or sham stimulation was
applied in each session. For sham too, only zeroes were sent to the
The applied field was measured afterwards with a tesla meter
(FH 54, Magnet-Physik, Cologne, Germany) and a digital storage
oscilloscope (DSO-101, Syscomp Electronic Design Limited,
Toronto, Canada) and is presented in figure 2. The used PEMF
is based on a published pattern , but for simplicity we removed
all trailing zeroes except one and shifted it to positive only. This
does not have a direct influence on the first time derivative of the
field strength, which is proportional to the induced current
according to Faraday’s law. Every integer was converted to a
voltage and presented for approximately 3 ms, resulting in a wave
duration of just under 2.5 s. For the LOW treatment all numbers
in the digital wave were divided by two (the relationship between
this digit and the resulting field strength is not linear). The sham
Figure 1. Schematic overview of the hardware. The interface card translates digital values into voltages. The amplifier in turn increases power
to generate pulsed magnetic fields in nineteen small electromagnets radially attached to the head cap. Photo by S. Martens, consent to publication
was obtained from the subject.
Figure 2. Different stages of the CNP signal. The digital version of the CNP wave as published in the literature (A) and used here (B), was
converted by PC and interface card to the analogue version (C), which was amplified (D) and converted to a magnetic wave (E), all to the same time
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treatment had the same length and time resolution, but all points
on the digital wave had the value of 0.
Several tests were selected to sample
the emotional, sensory, motor and cognitive domain. Two
emotional inventories were administered before and after all other
tests. The other tests were performed in four consecutive identical
blocks of fifteen minutes each. For all parameters, the initial value
was subtracted from the other values on a per subject per session
basis. In case the measure was repeated within a block, the mean
value per block was calculated.
Warmth detection threshold (WDT) and heat
pain threshold (HPT) were taken as indicators of sensory and pain
perception, respectively. WDT and HPT were measured with
thermal quantitative sensory testing (tQST) with a computer
controlled thermode (Thermotest, Somedic, Ho ¨rby, Sweden). The
thermode was held in the non-dominant hand with the heatable
surface at a thenar palmar position.
The thermode temperature started at 32uC and started
warming up at 0.3uC/s at an unpredictable moment (figure 4).
Subjects were instructed to report the moment at which they
noticed that the thermode had started to warm up. The
temperature at which this happens is called the WDT.
When the temperature of the thermode induced a pain
sensation with an intensity of 7 on a scale from 0 (no pain) to 10
(severe pain) subjects pressed an ’escape button’ which resulted in
immediate and rapid cooling (3uC/sec) of the thermode to 32uC.
The temperature at which they pressed the button is called the
HPT and this variable was the primary outcome.
WDTs and HPTs were always measured in triplo and two of
these triplets were measured during each 15-minute time block.
For each triplet, the median was considered for analysis.
The speed of finger tapping was measured with a hand counter
(‘hand tally’). Subjects were instructed to hold the counter in the
dominant hand and to press the button with the thumb of the
same hand as often as possible in 20 s. During each 15-minute
block this was measured twice in duplo. For each doublet, the
average was considered for analysis.
The size of handwriting was assessed by the request to copy a
text (single sentence of 24 words, 132 characters) by hand onto a
blank piece of paper. This was done once in each 15-minute block,
resulting in four time points per subjects per session. The total
surface area of the written text (cm2) was determined and used for
Once in each 15-minute block Digit-Symbol
Substitution Test (DSST) of the Wechsler Adult Intelligence Scale
(WAIS) was applied. The DSTT provides a composite
measure of attention, working memory, psychomotor speed,
processing speed, high-speed visuomotor speed and visuospatial
speed. Subjects were instructed to correctly substitute as many
symbols by digits as possible in 90 seconds. The number of correct
substitutions was used for further analysis.
To assess emotional state during the experiment,
the Dutch versions of the Positive and Negative Affect Schedule
(PANAS) and the Profile Of Mood States (POMS) were
completed at the beginning and at the end of both experimental
sessions. An extra item ‘‘happy’’ was added to the PANAS,
Figure 3. Frequency characteristics of amplifier, coils and amplifier + + coils.
Figure 4. Schematic of thermal quantitative sensory testing
(tQST) method for assessing Warmth Detection Threshold
(WDT) and Heat Pain Threshold (HPT). See text for details.
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resulting in a total of 21 items; they were combined to result in a
score for positive associations and a score for negative associations.
The POMS resulted in scores on the subscales Depression and
dejection, Anger and hostility, Fatigue and inertia, Vigor and activity and
Tension and anxiety.
After all measurements subjects were de-
briefed and asked to report any unusual sensations, moods or
thoughts during the experiment. Also they were asked whether
they noticed the treatment with magnetic fields.
For all outcomes the pre-treatment value was
subtracted on an individual basis. The primary outcome was then
tested across treatments with a one-sided paired t test on the
difference scores. Significance was accepted at 0.05. For the
secondary outcomes an exploratory analysis was done on the
treatments using two-sided paired t tests on the difference scores.
In this case, a conservative multiple comparisons correction
(Bonferroni, 11 comparisons) led to significance being accepted at
Figures in the results section show the
change after treatment relative to the first measurement in the
same subject in the same session. Bars indicate means and
standard error of the mean.
Table 1 shows demographic and clinical characteristics for each
treatment group. The median (interquartile range-IQR) of weekly
coffee consumption was 3 (16.25) units. The median (IQR) of
weekly alcohol consumption was 3.5 (4.1) units.
Safety, exit interview and blindness
None of the volunteers reported adverse events or other
complaints. At the exit interview they were invited to guess which
treatment they had just received. There was no relationship
between the actual treatment and the subjects’ guess.
There were no statistical differences between data from the
LOW and the HIGH treatment, therefore the two treatment
groups were combined into one.
Treatment effects on tQST, motor function and emotion
Both WDT and HPT increased over the experiment. The
primary outcome parameter, HPT was increased more after
PEMFthan after sham (t(19)=1.98, p=0.0313, Cohen’s
d=0.613), but for WDT there was no significant treatment effect
(t(19)=0.114, p=0.455) (figure 5).
For the WAIS symbol to digit substitution task there was a non-
significant effect of treatment (t(19)=2.82, p=0.0110, alpha
crit=0.0045) with lower performance after PEMF.
The two motor variables, used as indices of dopaminergic
function, were both unaltered by the PEMF: finger tapping
(t(19)=0.920, p=0.369) and handwriting (t(19)=1.20, p=0.245).
From the emotional variables the PANAS showed that the
change in positive associations was negative i.e. subjects were less
positive after the treatment. Likewise, the change in negative
associations was positive indicating that subjects were more
negative after the experiment. Despite these changes there was
no evidence of a significant treatment effect: positive associations
p=0.938). Also for the POMS there was no evidence of a
significant treatment effect on any of the emotional subscales (all
t(19),=0.157, all p.=0.358).
We aimed to construct a novel device for cerebral PEMF
stimulation and tested the hypothesis that the stimulation exerted
an analgesic effect when applying a wave pattern known as CNP
As hypothesized the weak field PEMF treatment for 30 minutes
increased HPT compared to sham stimulation. The effect size as
indicated by Cohen’s d is ’medium’ to ’large’. During sham
exposure HPT increased by approximately 1uC. In addition, the
PEMF effect added approximately 0.7uC to the HPT. Thus the
HPT increasing effects of PEMF were similar in magnitude to the
habituation effect that developed over the course of the
experiment. Taking into consideration that the thermode temper-
ature increased by 0.3uC/s, treated subjects allowed the already
hot thermode to warm up for an additional 2 to 3 seconds on
Our PEMF effects on tQST results are in agreement with a
previous study  which used a very similar time varying magnetic
pulse. Despite a significant number of methodological differences
(within-subjects vs. between-subjects, nineteen radial electromag-
nets vs. three orthogonal Helmholz coils) they found a similar
result to ours, being an increased HPT due to PEMF treatment
and no treatment effect on WDT. They also observed that PEMF
Table 1. Demographic characteristics for each treatment
(%)mean age (min, max, stdev)
5 8060 29.4 (24, 44, 8.35)
5 80 8025.8 (20, 40, 8.07)
5 100 80 24.6 (23, 29, 2.51)
5 100 100 24.4 (22, 28, 2.61)
Figure 5. Effects of PEMF treatment on changes in skin
sensitivity. Warmth detection threshold (WDT) was unaltered by
PEMF (p=0.455) but heat pain threshold (HPT) increased more after
PEMF than after sham stimulation. * significantly different at p,0.05.
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effects were more pronounced in women which is compatible with
the fact that our effect was robust and that our population was
mainly (90%) female. The increased HPT also confirms that the
current arrangement of coils, using the international coordinate
system derived from EEG, is effective for the induction of
experimental analgesia. The trailing zeros in the CNP as described
in the patent  do not seem to be necessary for its analgesic
effect because we omitted them in this study.
This study shows that the PEMF effect appeared to be quite
specific for HPT. PEMF treatment had no effect on WDT,
indicating that the ability to detect warmth, a non-noxious thermal
stimulus, remained unaltered by the pulsating magnetic field. This
is in agreement with the literature  and it is a very advantageous
property for an analgesic treatment: to only reduce pain without
reducing a person’s sensitivity. Finger tapping speed, handwriting,
PANAS and POMS results were all unaffected by the PEMF
The digit to symbol substitution task showed a non-significant
treatment effect with worse performance after PEMF than after
sham. The fact that this did not reach significance was because we
did not have a hypothesis about cognition so this is a result from an
explorative analysis with a conservative multiple comparisons
correction. However, there is some biological plausibility because
it was recently shown that cognitive control and sensory processing
can both be influenced simultaneously by one intervention or
manipulation . These considerations combined with the need
for analgesic treatments without cognitive side effects, motivate the
future study of cognitive performance after PEMF treatment.
In order to gather information concerning the working
mechanism of the induced analgesia, we also measured two
emotional parameters and two motor parameters that are sensitive
to dopaminergic tone. No treatment effects on the emotional state
were found so we have no evidence that emotional changes were
mediating the PEMF effects on HPT. We also found no treatment
effects on the two behavioral indices of dopaminergic tone. Taken
together these findings suggest that PEMF analgesia is not
mediated by changes in emotion or in central dopaminergic tone.
The fact that pain tolerance was increased does not identify a
single neuroanatomical structure as the mediating location
because the level of pain tolerance is the end result of the total
function of the anterolateral somatosensory system: nociceptors,
thin fibers, dorsal horn, ventral commissure, spinothalamic tract,
periaqueductal grey and reticular formation, ventromedial,
mediodorsal and intrathalamic thalamus, insula and anterior
cingulate cortex. The latter two are involved in the emotional
aspects of pain such as tolerability and suffering. Therefore, these
are plausible areas for mediation of increased pain tolerance and
in fact a relatively recent study found support for the notion that
brain activation in insula and anterior cingulate cortex as
measured with fMRI was decreased by PEMF stimulation with
The mechanisms by which electromagnetic fields can influence
biological systems are not yet fully understood. An abundance of
mechanisms have been proposed and a large number of them have
been confirmed experimentally (for review see e.g.  or ).
The most established mechanism is induction of an electrical
potential due to changing magnetic flux density (Faraday’s law). As
a result ion motion (current) is altered, which in turn induces
changes in synaptic potentials. Because synaptic potentials
determine the likelihood of an action potential, this is a plausible
mechanism for PEMF effects on neuronal activity: PEMF per se
may not induce action potentials like TMS does, but it can change
the temporal probability of action potentials. A recent paper found
evidence for magnetic sensitivity in the low mT range of
cryptochrome, a protein that is expressed throughout the tree of
life including humans . Human cryptochrome has indeed been
shown to be sensitive to magnetic fields . Cryptochrome is thus
a candidate mediator of the analgesic  and antidepressant 
effects of PEMF on humans. Mediation of PEMF effects by
cryptochrome, being a protein sensitive to both light and magnetic
fields, could also explain why PEMF effects were reported to be
highly dependent on lighting conditions .
We found no differences between the effects induced by the two
field strengths: apparently the intensities were equipotent. Dose-
dependency of PEMF effects is generally very steep and has been
described for different systems to occur below 1 mT , below
500 nT  and even below 50 nT . It appears that the two
field strengths used in our study (0.4 and 1.1 mT) both induced the
Concerning the penetration depth of our stimulation, it is often
heard that TMS penetrates 1–2 cm, although H-coils can reach
up to 6 cm . Such statements are incomplete and inaccurate
because what is implied is that TMS can induce action potentials
at these depths. It is unknown whether magnetic fields have to
induce action potentials in order to be effective at modulating
biological functions. On the contrary, weak pulsed fields (PEMF)
are effective in humans [5,6] and it is highly unlikely that the direct
induction of action potentials in the brain plays a role here. The
magnetic permeability of biological tissues is very similar to that of
air or vacuum meaning that the main factor determining the field
strength of low frequency PEMF in the brain, apart from the
current and the coil design, is the distance to the coil.
Thresholds for PEMF effects on living systems have been
estimated at 500 nT  and even 50 nT . Flux density was
measured in our study at five distances from the coils with flux
density values between 1 mT and 0.1 mT. These values fit very
closely to an exponential dependence of flux density on distance.
Extrapolating using this exponential dependence predicted flux
densities of 500 and 50 nT to be reached at 2.2 and 2.9 cm from
the coil respectively. This strengthens the notion that our
stimulator induces biologically relevant magnetic fields in the
In terms of safety, our newly designed magnetic stimulator
conformed to the assessment criteria of the Dutch Work Group for
the Classification of Instruments in University Hospitals (Wibaz)
and is a class I, type B device according to the IEC 601-1988
norm. This indicates that the device is electrically safe to be used
on humans. With regard to neurological safety, epileptic seizures
are the main serious adverse event that can potentially be induced
by magnetic stimulation. However, the risk of inducing seizures is
controllable because it is a function of frequency and field
strength. Importantly, the stimulator described here falls well
below the field strength described in the above paper: our field
strength was not 100–220%  of the motor evoked potential
threshold, but in the order of 0.05%. Therefore it seems highly
unlikely that induction of epileptic seizures is a risk with the
current setup. None of the volunteers could detect the stimulation
or had adverse effects or other complaints so that the PEMF
procedure appears to be completely safe.
A strength of this study is that we provide data from an actual
measurement of the magnetic field whereas this is frequently
omitted in PEMF reports. Additionally, we confirmed our
prediction that HPT would increase after PEMF treatment and
we measured many additional parameters. This study was sham-
controlled and volunteers detected no difference so it was truly
double-blind for the whole duration of the experiment. Although
the treatment groups (PEMF-sham and sham-PEMF) were not
fully balanced with respect to age, gender and handedness, the use
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PLOS ONE | www.plosone.org6 April 2013 | Volume 8 | Issue 4 | e61926
of a crossover design precluded confusing group effects for Download full-text
treatment effects. In the paired design every subject served as
their own control thus reducing the obscuring effects of
As a limitation, the generalizability of this trial is limited because
it was performed in a relatively small group (n=20) consisting
mostly of young women. Another limitation is that although the
device permits considerable anatomical specificity of the PEMF
stimulation, for this pilot we stimulated all locations simultaneous-
ly. Future studies should aim to elucidate the relative contribution
of the individual electromagnets.
In summary, we built a magnetic stimulator capable of
producing fluctuating magnetic fields with arbitrary temporal
patterns within the 0–300 Hz frequency range. The use of an
established coordinate system allows studies with anatomical
specificity and integration with existing (EEG) literature. The use
of nineteen small electromagnets makes it possible to stimulate
specific neuroanatomical targets with the aim of modulating their
function. This setup allows double-blind, sham-controlled exper-
iments with arbitrary wave shape magnetic stimulation. These
advantages, in addition to low cost and high safety, make this
technology widely applicable for functional and clinical studies of
the brain. As expected PEMF stimulation of the brain with this
device caused increased pain tolerance in healthy subjects. At the
same time, sensitivity to non-noxious thermal stimuli remained
unchanged. We found no evidence for changes in emotional state
and motor parameters that correlate with dopaminergic tone, thus
it is unlikely that these would have mediated the changes in pain
amplifier with power supply (top) and amplifier (bot-
Electrical wiring diagram for the DC coupled
We are grateful to K. Vaartjes for design and construction of the amplifier,
to Y. Bloemhof for advice on construction and safety testing, and to L.
Nanetti for programming support, as well as to the subjects, who all
participated pro bono in this research, and to T. Nijboer for comments on
Conceived and designed the experiments: RK JHvdH MvW NMM.
Performed the experiments: RK LEvN VGB. Analyzed the data: RK
LEvN VGB. Contributed reagents/materials/analysis tools: JHvdH.
Wrote the paper: RK LEvN VGB KHK MH JHvdH MvW AA NMM.
1. Barker A, Jalinous R, Freeston I (1985) Non-invasive magnetic stimulation of
human motor cortex. Lancet 1: 1106–1107.
2. Rohan M, Parow A, Stoll A, Demopulos C, Friedman S, et al. (2004) Low-field
magnetic stimulation in bipolar depression using an MRI-based stimulator.
Am J Psychiatry 161: 93–98.
3. Volkow ND, Tomasi D, Wang G, Fowler JS, Telang F, et al. (2010) Effects of
low-field magnetic stimulation on brain glucose metabolism. Neuroimage 51:
4. Robertson J, Theberge J, Weller J, Drost D, Prato F, et al. (2010) Low-frequency
pulsed electromagnetic field exposure can alter neuroprocessing in humans.
J R Soc Interface 7: 467–473.
5. Shupak NM, Prato FS, Thomas AW (2004) Human exposure to a specific pulsed
magnetic field: effects on thermal sensory and pain thresholds. Neurosci Lett
6. Martiny K, Lunde M, Bech P (2010) Transcranial low voltage pulsed
electromagnetic fields in patients with treatment-resistant depression. Biol
Psychiatry 68: 163–169.
7. Okamoto M, Dan H, Sakamoto K, Takeo K, Shimizu K, et al. (2004) Three-
dimensional probabilistic anatomical cranio-cerebral correlation via the
international 10–20 system oriented for transcranial functional brain mapping.
Neuroimage 21: 99–111.
8. Thomas A, Kavaliers M, Prato F, Ossenkopp K (1997) Antinociceptive effects of
a pulsed magnetic field in the land snail, Cepaea nemoralis. Neurosci Lett 222:
9. Martin LJ, Koren SA, Persinger MA (2004) Influence of a complex magnetic
field application in rats upon thermal nociceptive thresholds: the importance of
polarity and timing. Int J Neurosci 114: 1259–1276.
10. Robertson J, Juen N, Theberge J, Weller J, Drost D, et al. (2010) Evidence for a
dose-dependent effect of pulsed magnetic fields on pain processing. Neurosci
Lett 482: 160–162.
11. Prato F, Robertson J, Desjardins D, Hensel J, Thomas A (2005) Daily repeated
magnetic field shielding induces analgesia in CD-1 mice. Bioelectromagnetics
12. Schmidt NB, Cook JH (1999) Effects of anxiety sensitivity on anxiety and pain
during a cold pressor challenge in patients with panic disorder. Behav Res Ther
13. Pogarell O, Koch W, Popperl G, Tatsch K, Jakob F, et al. (2006) Striatal
dopamine release after prefrontal repetitive transcranial magnetic stimulation in
major depression: preliminary results of a dynamic [123I]-IBZM SPECT study.
J Psychiatr Res 40: 307–314.
14. Strafella AP, Paus T, Barrett J, Dagher A (2001) Repetitive transcranial
magnetic stimulation of the human prefrontal cortex induces dopamine release
in the caudate nucleus. J Neurosci 21: RC157.
15. Potvin S, Grignon S, Marchand S (2009) Human evidence of a supra-spinal
modulating role of dopamine on pain perception. Synapse 63: 390–402.
16. Volkow ND, Gur RC, Wang GJ, Fowler JS, Moberg PJ, et al. (1998) Association
between decline in brain dopamine activity with age and cognitive and motor
impairment in healthy individuals. Am J Psychiatry 155: 344–349.
17. Ku ¨nstler U, Juhnhold U, Knapp W, Gertz H (1999) Positive correlation between
reduction of handwriting area and D2 dopamine receptor occupancy during
treatment with neuroleptic drugs. Psychiatry Res 90: 31–39.
18. Richards P, Persinger M, Koren S (1993) Modification of activation and
evaluation properties of narratives by weak complex magnetic field patterns that
simulate limbic burst firing. Int J Neurosci 71: 71–85.
19. Thomas A, Kavaliers M, Prato F, Ossenkopp K (1997) Pulsed magnetic field
induced "analgesia" in the land snail, Cepaea nemoralis, and the effects of mu,
delta, and kappa opioid receptor agonists/antagonists. Peptides 18: 703–709.
20. Wais D (1944) The measurement of adult intelligence. Williams & Wilkins,
Baltimore (MD): 272.
21. Watson D, Clark LA, Tellegen A (1988) Development and validation of brief
measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol
22. Thomas A, Prato F, Kavaliers M, Persinger M (2001) Electrotherapy device
using low frequency magnetic pulses. US Patent 6,234,953, 09/194,930: 1–33.
23. Gard T, Ho ¨lzel BK, Sack AT, Hempel H, Lazar SW, et al. (2012) Pain
attenuation through mindfulness is associated with decreased cognitive control
and increased sensory processing in the brain. Cereb Cortex 22(11):2692–702..
24. Challis L (2005) Mechanisms for interaction between RF fields and biological
tissue. Bioelectromagnetics Suppl 7: S98–S106.
25. Goodman R, Blank M (2002) Insights into electromagnetic interaction
mechanisms. J Cell Physiol 192: 16–22.
26. Maeda K, Robinson AJ, Henbest KB, Hogben HJ, Biskup T, et al. (2012)
Magnetically sensitive light-induced reactions in cryptochrome are consistent
with its proposed role as a magnetoreceptor. Proc Natl Acad Sci U S A 109:
27. Foley LE, Gegear RJ, Reppert SM (2011) Human cryptochrome exhibits light-
dependent magnetosensitivity. Nat Commun 2: 356.
28. Prato F, Kavaliers M, Cullen A, Thomas A (1997) Light-dependent and-
independent behavioral effects of extremely low frequency magnetic fields in a
land snail are consistent with a parametric resonance mechanism. Bioelectro-
magnetics 18: 284–291.
29. Prato F, Desjardins-Holmes D, Keenliside L, Demoor J, Robertson J, et al.
(2011) The detection threshold for extremely low frequency magnetic fields may
be below 1000 nT-Hz in mice. Bioelectromagnetics 32(7): 561–569.
30. Cuppen J, Wiegertjes G, Lobee H, Savelkoul H, Elmusharaf M, et al. (2007)
Immune stimulation in fish and chicken through weak low frequency
electromagnetic fields. Environmentalist 27: 577–583.
31. Roth Y, Amir A, Levkovitz Y, Zangen A (2007) Three-dimensional distribution
of the electric field induced in the brain by transcranial magnetic stimulation
using figure-8 and deep H-coils. J Clin Neurophysiol 24: 31–38.
32. Wassermann E (1998) Risk and safety of repetitive transcranial magnetic
stimulation: report and suggested guidelines from the international workshop on
the safety of repetitive transcranial magnetic stimulation, June 5–7, 1996.
Electroencephalogr Clin Neurophysiol 108: 1–16.
Magnetic Stimulation Increases Pain Tolerance
PLOS ONE | www.plosone.org7 April 2013 | Volume 8 | Issue 4 | e61926