safety and tolerability of microtesla transcranial...

Safety and Tolerability of Weak

Transcranial Stimulation with Pulsed

Electromagnetic Fields in Neuropathic Pain

Patients

Hidde Kleijer

S1717448

2013-05-22

Facultair begeleider:

Dr. R. Kortekaas

Mede-begeleider:

Dr. B. Ćurčić-Blake

Neuroimaging Center (NIC) UMCG

Afdeling Neurowetenschappen

Stage Wetenschap Geneeskunde

Periode

03-11-2012 t/m 27-04-2013

Hidde Kleijer Report research internship: final version Page 1 of 31

Contents

English abstract ................................................................................................................. 2

Nederlandse samenvatting ............................................................................................... 3

Introduction ....................................................................................................................... 4 Neuropathic pain ............................................................................................................. 4

Analgesic magnetic stimulation ...................................................................................... 6

Safety and tolerability ..................................................................................................... 8

This study ........................................................................................................................ 9

Methods ............................................................................................................................ 10

Participants .................................................................................................................... 10

Materials and setup ....................................................................................................... 12

Design and procedure ................................................................................................... 12

Statistical analysis ......................................................................................................... 14

Results .............................................................................................................................. 16 Raw data........................................................................................................................ 16

Pain Intensity, Pain Aversion, Finger taps, and Long number recollection ................. 17

DSST ............................................................................................................................. 17

POMS and PANAS ....................................................................................................... 18

Debriefing ..................................................................................................................... 19

Discussion......................................................................................................................... 20

Conclusion ....................................................................................................................... 21

References ........................................................................................................................ 22

Supplementary materials ............................................................................................... 27


English abstract

Safety and Tolerability of Weak Transcranial Stimulation with Pulsed Electromagnetic

Fields in Neuropathic Pain Patients

Neuropathic pain is notoriously hard to combat, leaving its sufferers often in daily pain.

Weak Transcranial Magnetic Stimulation (TMS) with Pulsed Electromagnetic Fields

(PEMF) could be a practical and effective new way to relieve neuropathic pain. Previous

research has shown analgesic effects of TMS in healthy volunteers and fibromyalgia

patients.

This study aimed to investigate whether the TMS device developed within our

research group can be safely and tolerably applied in a neuropathic pain patient population,

in order to know if we could safely proceed with testing for an analgesic effect in this

population with a longer stimulation period. In addition, we aimed to investigate whether

participants could discriminate between active and sham stimulation and to check for

preliminary analgesic effects.

To these ends cognitive function, motor function, and emotional state were tested

during TMS. Analgesic effects were preliminary investigated on a Verbal Analog Scale

(VAS), participants were asked repeatedly whether they thought stimulation was on or off,

and were debriefed after stimulation.

Results showed an effect on cognitive function: scores on the Digit-to-Symbol

Substitution Test (DSST) seemed to gradually increase during the TMS period regardless of

sham or active stimulation. Other results showed a possible decrease on the tension and

anxiety subscale of the Profile of Moods Scale (POMS) and a possible downward trend of

negative affect measured on the Positive and Negative Affect scale (PANAS). However, none

of these findings on emotional state survived correction for multiple comparisons. Results did

not show any decrease in neuropathic pain scores and participants could not discriminate

between active and sham stimulation.

Considering all results, we conclude there is no evidence of adverse effects of our

TMS device using PEMF in a neuropathic pain patient population and that it is suitable for

sham-controlled studies. To obtain an analgesic effect, stimulation may have to be applied

longer; a follow-up study has been started.


Nederlandse samenvatting

Veiligheid en Verdraagbaarheid van Zwakke Transcraniële Magnetische Stimulatie met

Pulserende Elektromagnetische Velden bij Neuropatische Pijnpatiënten

Neuropathische pijn is notoir lastig te behandelen, waardoor patiënten vaak dagelijks met

pijn moeten leven. Zwakke Transcraniële Stimulatie (TMS) met pulserende

elektromagnetische velden (Pulsed Electromagnetic Fields (PEMF)) zou een nieuwe

praktische en effectieve manier van pijnbestrijding kunnen zijn. Onderzoek hiernaar heeft

analgetische effecten aangetoond in gezonde vrijwilligers en fibromyalgiepatiënten.

Deze studie had als doel te onderzoeken of het TMSapparaat, dat binnen onze

onderzoeksgroep is ontwikkeld, veilig en verdraagbaar kan worden toegepast in een

populatie van neuropathische pijnpatiënten zodat we in een eventuele volgende studie veilig

langere stimulatie toe kunnen passen. Daarnaast was het doel te onderzoeken of de patiënten

actieve van neppe stimulatie kunnen onderscheiden en onderzoeken of er eventueel

preliminaire analgetische effecten aan zijn te tonen.

Om deze doelen te bewerkstelligen zijn er ten tijde van de stimulatie een

motorfunctietest en twee cognitieve testen afgenomen. Voor en na TMS zijn er

emotievragenlijsten afgenomen en na de stimulatie werden patiënten open bevraagd naar

hun ervaringen. Daarnaast is tijdens de stimulatie steeds naar de pijnscore op de Verbale

Analoge Schaal (VAS) en naar hun idee of ze neppe of echte stimulatie kregen gevraagd.

Resultaten lieten een effect op cognitieve functie zien: scores op de nummer-naar-

symbool substitutietest (Digit-to-Symbol Substitution Test (DSST)) leken gedurende de

stimulatie gradueel te stijgen, ongeacht actieve of neppe stimulatie. Daarnaast leek de score

op een sub-schaal van de Profiel van Stemmingen Schaal (Profile of Moods Scale (POMS)) te

verminderen na stimulatie en was er een dalende trend in het Negatieve Affect gemeten op de

Positief en Negatief Affect Schaal (Positive and Negative Affect Scale (PANAS)) te zien. Geen

van deze bevindingen doorstond echter correctie voor meerdere vergelijkingen. Pijnscores

waren niet lager tijdens stimulatie en patiënten konden geen onderscheid maken tussen

actieve en neppe stimulatie.

Wij concluderen dat er geen bewijs is gevonden voor bijwerkingen van ons TMS

apparaat dat transcranieel PEMF toepast in een populatie van neuropathische pijnpatiënten

en dat het apparaat geschikt is voor placebo-gecontroleerde studies. Om een analgetisch

effect te verkrijgen moet de stimulatie wellicht langer worden toegediend, iets wat we in een

volgende studie zijn gaan doen.


Introduction

Neuropathic pain

Neuropathic pain (NP) is ‘pain caused by a lesion or disease of the somatosensory nervous

system’ according to the International Association for the Study of Pain (IASP) taxonomy

(1). A division can be made between a lesion or disease in the central somatosensory nervous

system (central neuropathic pain) and a lesion or disease in the peripheral somatosensory

nervous system (peripheral neuropathic pain). The pain can be continuous, paroxysmal, or a

combination of both.

Other characteristics of neuropathic pain are a spontaneous and continuous burning or

throbbing sensation that can vary in intensity, and/or an intermittent shooting, stabbing

sensation with an electric-like quality (2). The pain itself is often accompanied by allodynia,

hyperalgesia, hyperesthesia, paresthesia, and dysesthesia (see table 1). The first two are

thought to be due to central and/or peripheral sensitization (2).

It should be noted that the term neuropathic pain is descriptive and not diagnostic.

Underlying causes should always be investigated. Based on criteria formulated by Treede et

al. (3) patients can be graded as having unlikely, possible, probable, or definite neuropathic

pain (see table 2).

Allodynia Pain due to a stimulus that does not normally

provoke pain

Hyperalgesia Increased pain from a stimulus that normally

provokes pain

Hyperesthesia Increased sensitivity to stimulation, excluding

the special senses

Paresthesia An abnormal sensation, whether spontaneous or

evoked

Dysesthesia An unpleasant abnormal sensation, whether

spontaneous or evoked

Sensitization Increased responsiveness of nociceptive neurons

to their normal input, and/or recruitment of a

response to normally subthreshold inputs. This

can be central (e.g. dysfunction of pain control

systems of the central nervous system) and/or

peripheral (e.g. nociceptor dysfunction)

Table 1. Explanation of characteristics associated with neuropathic

pain.

Information reproduced from the International Association for the Study

of Pain (IASP;(1,2)).


Any disease or treatment capable of causing nerve damage can in principle cause neuropathic

pain. Central neuropathic pain can for instance be caused by: a stroke, multiple sclerosis,

Parkinson’s disease, and spinal cord injury. Diseases causing peripheral neuropathic pain

include (but are not limited to): diabetic neuropathy, HIV, tumors, and a herpes infection

(post-herpetic neuralgia; (2)). The damage of the somatosensory system can be caused in

several ways that can each play a role in neuropathic pain. These include: infection, trauma

(including iatrogenic), inflammation, metabolic abnormalities, toxins (chemotherapy,

neurotoxins), radiation, compression, and infiltration (2).

Possible

NP

Probable

NP

Definite

NP

Criterion 1 Pain with a distinct neuroanatomically

plausible distribution

x x x

Criterion 2 A history suggestive of a relevant lesion or

disease affecting the peripheral or central

somatosensory system

x x x

Criterion 3 Demonstration of the distinct

neuroanatomically plausible distribution by at

least one confirmatory test

x x

Criterion 4 Demonstration of the relevant lesion or disease

by at least one confirmatory test

x

Unlikely NP Criteria 1 & 2 not (both) fulfilled

Type Symptoms Mechanisms

1 Prominent allodynia

Negligible sensory deficits

Abnormal activity in primary afferent

nociceptors leading to central sensitization

2 Spontaneous pain

Little or no allodynia

Marked sensory deficits

Apparently little contribution of primary

afferent nociceptors to the pain. Possibly

central sensitization due to deafferentation

3 Sensory deficits

Allodynia

Deafferentation leading to central

reorganization: sprouting of large

myelinated fibers into the substantia

gelatinosa making contact with neurons

formerly connected with nociceptors

Table 2. Grading system for neuropathic pain as proposed by Treede et al. (3).

NP = Neuropathic Pain.

Table 3. Subdivision of neuropathic pain based on underlying pain mechanisms.

By Rowbotham et al. and Fields et al. (4,5).


Clearly, this wide arrange of etiologies makes for a heterogeneous group of patients.

Therefore Rowbotham et al. and Fields et al. (4,5) provide a subdivision of neuropathic pain

based on probable underlying pain mechanisms (see table 3).

The prevalence of neuropathic pain ranges from 3% to 17.9% (6–11) depending on

survey method, country and definition of neuropathic pain. A higher prevalence is often

reported in women and middle age (50-64 years). In the Netherlands the incidence has been

reported to be about 1% (12). Patients suffering from this type of pain have a significantly

lower quality of life compared to healthy controls (13) and compared to other chronic pain

patients (14). These and other studies show that financial costs for both patients themselves

and the society are relatively high (15).

Combating neuropathic pain is notoriously difficult. Pharmacological strategies

include Tricyclic Antidepressants (TCAs), Selective Serotonin and Norepinephrine Reuptake

Inhibitors (SSNRIs), calcium channel α2-δ ligands, topical lidocain, opoid analgesics,

tramadol, anticonvulsants (e.g. carbamazepine), and topical capsaicin (16,17). However,

these drugs have a limited efficacy, providing partial pain relief in only 40-60% of patients

and causing a lot of side effects (16). So from both ethical and economical perspectives better

treatments for neuropathic pain are much needed. Approaches using magnetic stimulating

could be safe and effective options with little side effects (15,18).

Analgesic magnetic stimulation

The idea of using magnetism as treatment for several conditions dates back as far as the times

of the great Greek philosophers and ancient Chinese and Incan civilizations. In the late

twentieth century it was discovered that electromagnetic stimulation can non-invasively

speed up bone fracture repair (19–21) and since then many more uses have been discovered

and are still being discovered (19). Forms of Transcranial Magnetic Stimulation (TMS) have

for instance been found to be of use in the treatment of (antidepressant resistant) depression

(22–25) and several studies show it can have an analgesic effect as well (15,18,26–28).

TMS is a non-invasive technique in which magnetic stimulation of the cortex is

achieved by placing electromagnetic coils on the scalp. The mechanism of action is

presumably based on Faradays principle: When you let a changing primary current run in a

wire this will produce a changing magnetic field that is proportional to that current. This in

turn creates an electric field that produces a secondary (eddy) current in the opposite direction

in a nearby conductor (19,29). Because human tissue can act as a conductor, especially neural

tissue, changing magnetic fields can influence human tissue in this way, e.g. by depolarizing

the membrane potential.

The effectiveness of TMS has been found to be dependent on waveform and the

direction of the current produced in the anatomical space. For example, with other parameters

being equal stimulating the motor cortex until a Motor Evoked Potential (MEP) can be

measured in the contralateral abductor of the thumb (pollicis brevis), is easier when

stimulating with an eddy current flowing from posterior to anterior (29). The TMS waveform

can be either monophasic of biphasic (see figure 1; (30)), each capable of inducing different

effects in different ways, dependent on the setting.


These waveforms can be applied as a single pulse, but also repetitively (repetitive

(r)TMS), the latter seemingly having the best effectiveness for clinical application. For

repetitive TMS not only the waveform of the magnetic pulses, but also the frequency of the

pulses matters. The standard idea is that TMS can inhibit or excite brain regions by directly

influencing (possibly depolarizing) neural membrane potentials, but other mechanisms of

action are possible. An indicator of this is the fact that direct effects during TMS can be

different from those persisting after the stimulation (29). rTMS is increasingly used as

treatment for therapy resistant depression and has potential to be a viable alternative for

electroconvulsive therapy (22–25).

Research is also showing some promise for the use of rTMS in the treatment of

neuropathic pain, although the optimal stimulation parameters (i.e. stimulation site, waveform

and frequency) are unclear (15,18). Currently, most studies focus on the stimulation of the

motor cortex with sub-motor threshold pulses, using a high frequency of around 10 Hz (15).

Remarkably, in 2007 Thomas et al. (31) found analgesic effects of specific pulsed

electromagnetic fields (PEMF) applied transcranially.

PEMF are the type of magnetic stimulations used to speed bone fracture repair as

discussed above. In these instances and in other studies examining the pain modulating

effects of PEMF, these fields were applied peripherally instead of transcranially. The

magnetic fields used by Thomas et al. (31) were much weaker than in conventional TMS.

PEMF are measured in the mili/microtesla range (400 μT was used by Thomas et al.) whereas

conventional TMS is measured in teslas. Therefore we will call this type of magnetic

stimulation (PEMF applied transcranially) weak TMS (μTMS).

That this type of stimulation seems to work is remarkable because one would expect

the fields to be much too low to have an effect. That is, if the effects should arise from the

direct influence on the membrane potential as is the theory for conventional TMS. Although

weak magnetic fields might only be able to slightly influence the membrane potential of one

cell, in a networks of neurons slight alterations could have large effects (32). However, it is

probable that other mechanisms are involved. Several theories have been proposed, but none

has yet been tested thoroughly enough to be objectively favored.

Figure 1. Biphasic and monophasic TMS waveforms

Reproduction of figure of Arai et al. (30).


Robertson et al. (33) state three mechanisms for magnetoception: ‘1) detection by

magnetic dipoles within cells; 2) detection of induced current; and 3) detection via the

different chemical reaction rates when the electron spins of free radicals are affected by a

magnetic field.’ It has been shown that PEMF can (either directly or indirectly) influence a

variety of molecules involved in the cell’s messenger systems (34), thereby possibly

influencing the opioid system (35). Tyrosine kinases appear to be sensitive to PEMF, most

notably the proteins of the src-family and the lyn-kinases (19). These are all key enzymes in

the signal transduction within cells, so influencing these can potentially have a wide variety

of effects.

How PEMF influences these molecules is unclear. Possibly it alters their energy

landscape, thereby activating or deactivating the enzyme. However, this could also be

achieved by resonating or counter phasing with the molecule’s own frequency (19). Of course

it is also possible that effects are mediated through other enzymes. Interestingly, it has

recently been found that cryptochrome could be a magnetoreceptor in animals that use

magnetoception to navigate (36). Humans also have small amounts of cryptochrome, so

effects of magnetic stimulation might be mediated through the stimulation of cryptochrome.

Regardless, PEMF has been shown to have clinical effects and to influence

electroencephalography (EEG) measurements. It has been reported to decrease alfa activity

(37) and the pain-related Somatosensory Evoked Potential (SEP; (38)), although on the whole

results are mixed (39). Apart from the renowned effect on bone fracture repair (19–21),

PEMF has been shown to stimulate growth and regeneration of nerve cells (40–42). Pain

modulating effects of PEMF have been found as well. In animals it has been reported to have

analgesic effects in snails (35) and rats (34,43), but also hyperalgesic effects in mice (44) and

snails (45). Whether the effect is analgesic or hyperalgesic seems to depend on research

design (e.g. interactions with other analgesics) and magnetic waveforms that were used.

In humans benefits of PEMF, applied peripherally or to the whole body, have been

found in: arthritis (46,47), diabetic neuropathy (48,49), carpal tunnel syndrome (50),

headaches (51), lumbar radiculopathy (52), fibromyalgia (53), and post-surgery (54). As

stated above, analgesic effects have been found by applying PEMF transcranially (μTMS) as

well. This has been found in fibromyalgia patients (31,55) and healthy volunteers’ heat pain

threshold (56,57) using the Complex Neural Pulse (CNP; or as we call it: the “Thomas

waveform”). μTMS has also been shown to have an antidepressant effect by Martiny et al.

(58) using a specific waveform we call the “Martiny waveform”. For a visual representation

of these waveforms, see figures 4 and 5 in the methods section.

Safety and tolerability

When guidelines are followed, TMS seems to be relatively safe (59). However it has been

reported to be able to cause seizures in some cases and it is often considered to be unpleasant,

i.e. causing: scalp pain, headaches and abnormal sensations (22,25,59). There is still some

debate about potential effects of TMS on emotional state, and cognitive and motor functions.

Because the severity of these side effects seem to be related to the intensity (strength,

duration, and frequency) of the magnetic stimulation, it is unlikely they are as much of a

problem for TMS.

Neuropathic pain and epilepsy appear to be comorbid (60). Seeing as though TMS can

cause epileptic seizures, especially in sensitive subjects, this could be a major problem for the

application of conventional TMS in a population of neuropathic pain patients. If TMS does

not cause seizures, as we expect, this would be an advantage over conventional TMS as a

possible treatment for neuropathic pain.

Other, more practical advantages of TMS over conventional TMS are a larger

flexibility of the emitted waveforms and a smaller size of the magnetic coils. The latter could


provide a more precise targeting of brain regions and makes TMS more practical in its use,

possibly allowing for treatments at the patient’s home. Furthermore, TMS seems suitable

for sham-controlled studies, since participants were not able to discriminate sham from active

stimulation (61). For conventional TMS it has always been a problem for sham-controlled

research that patients were able to discern sham from active stimulation because of the loud

sound and induced sensations of active stimulation.

This study

Using a TMS device designed within our research group we found that heat pain thresholds

in healthy volunteers could be increased, without increasing the warmth detection thresholds

(56). No adverse effects of our TMS device have been found in that and a follow-up study,

also in healthy volunteers (61).

The aim of this current study was to investigate whether our TMS device could

safely be used on patients suffering from neuropathic pain and whether they could tolerate the

stimulation well, in order to check if we could safely investigate analgesic effects with a

longer stimulation period in a follow-up study. Therefore motor function tests, cognitive

function tests, and emotional state questionnaires were taken. Additionally, a debriefing took

place after the stimulation period asking the participants about any unusual feelings and

thoughts at that time and during the stimulation period. Other aims were to investigate

whether participants could distinguish sham from active stimulation and to preliminarily

investigate whether the intensity of and the aversion to their neuropathic pain would decrease.

We hypothesized there would be no significant changes in any of these tests, with the

exception of the pain intensity and pain aversion scores. We hypothesized that these would

decrease and additionally that participants would not be able to distinguish active from sham

stimulation.


Methods

Participants

Eleven patients, diagnosed with neuropathic pain by their physician, participated in this study

(see table 4). They were contacted through the Pain Centre at the University Medical Centre

Groningen (UMCG). They were 18-80 year old, subjectively healthy (disregarding the

neuropathic pain and its cause). Exclusion criteria included: manifest neurological illness

apart from their neuropathic pain, manifest psychiatric illness, recent (<4 weeks) use of:

antidepressants, antiepileptic drugs, or prescription psychopharmaca for other complaints

than their neuropathic pain, excessive (>10 units per day) use of coffee or alcohol, recent (< 4

weeks) use of any non-prescription psychopharmaca, first degree relative with epilepsy, and

MRI incompatibility.

NP

Patient

Gender Age Smoking

(cigarettes

per week)

Alcohol

(glasses

per week)

Coffee

(cups

per

week)

Weight

(kg)

Diagnosis Treede

Grade

Known medication

P1 f 58 30 1.5 25 53 Lower backpain Unlikely Tramadol, Paracetamol,

Propanolol

P2 f 68 0 0 3 75 Unknown Unlikely

Amlodipin,

hydrochlorothiazide,

Gemfibrozil,

Hydroxyzine

P3 f 60 140 0 21 67 Unknown Possible Imatinib,Levothyroxine

P4 f 71 20 0 30 85 Carpal tunnel syndrome Unlikely Prednisolone,

Azathioprin

P5 f 47 120 40 30 90 Neuropathic and

myofascial pain Unlikely Pregabalin, Amitriptylin

P6 f 46 0 3 21 55 NP C8 dermatome Unlikely Tramadol

P7*

Unlikely

P8 m 59 0 3.5 30 80 Peripheral nerve injury Possible Paracetamol, Tramadol,

Capsaicin

P9 m 54 50 2 35 85 Peripheral nerve injury Unlikely Diclofenac, Furosemide,

P10 m 58 0 25 1 105 Possible small fibre

polyneuropathy Unlikely

Tamsulosine, Atenolol,

Lisinopril, Gemfibrozil

P11 m 73 0 21 35 92 Axonal polyneuropathy Probable Flecainide

Average 60 %

female 59.4 36 9.6 23.1 78.7

Figure 2 provides an overview of the inclusion and exclusion of patients, starting from the list

of possibly suitable patients of the Pain Centre at the UMCG. This figure also shows this

process for the follow-up study to investigate the analgesic effects of our treatment for

Table 4. Participant’s information.

* Never showed up for the appointment. f=female; m=male. NP=Neuropathic Pain.


neuropathic pain. For that study only patients with a probable or definite Treede Grade (3)

were included.

Of the eleven participants, one never showed up, and two were not able to perform all

tests during the stimulation period, but did perform the ones before and after (see ‘design and

procedure’). Therefore the number of participants per data point during the stimulation period

is either eight or nine. Participants did not receive financial compensation and signed written

informed consent. This study was approved of by the local Medical Ethical Committee

(METc) of the University Medical Center Groningen.

Figure 2. Inclusion and exclusion overview. Inclusion was, among other things based on Treede

(3) classification and clinical diagnosis. A priori

exclusion was based on the information we had

before we contacted the patients, a posteriori

exclusion was based on information provided by the

patients that was until then unbeknownst to us.

NP=Neuropathic Pain.


Materials and setup

The set-up presented in figure 3 was similar to the one used in previous studies of our group

(56,61). It allowed for the use of different types of PEMF in nineteen small electromagnets

on the scalp. A computer running on Debian Linux (ww.debian.org) was given instructions

for wave generation. The output digital values of the computer were translated to voltages by

the interface card (K8000, Velleman, Gavere, Belgium) and amplified by a bipolar DC

coupled amplifier.

Finally the PEMF were generated by nineteen electromagnets consisting of reed

relays (Reed Relay 275-232, Radio Shack, Fort Worth, TX, USA) of which the reed switch

was replaced by an M2x30 mm steel bolt transforming them into iron core electromagnets

(measured resistance: 245 Ω, inductance at 100 Hz: 122 mH, at 1 kHz: 89 mH). These

electromagnets were radially attached, according to the international 10/20 system, to a non-

magnetic EEG cap (SU-60 and KR, MedCaT, Erica, The Netherlands). The electromagnets’

maximum magnetic flux density was 1.45 mT.

Design and procedure

A single-blind sham-controlled crossover interventional design was used in this study.

Participants underwent one period of stimulation with a duration of 60 minutes in which they

were sequentially exposed to different types and strengths of TMS waveforms (shown in

figures 4 and 5) or sham stimulation for periods of 5 minutes per type of stimulation. The

whole procedure is visually represented in figure 6.

Figure 3. Schematic overview of the hardware set-up.

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 placed according to the 10/20 system (56).


During the 5-minute periods several tests were taken. Participants performed a motor test and

two cognitive (working memory) tests. As motor test the finger tapping test was used, this

test consisted of participants pressing on a hand tally counter as many times as they could

within 20 seconds. The number of taps was used for analysis. The first cognitive test was the

Digit-to-Symbol Substitution Test (DSST) of the Wechsler Adult Intelligence Scale (62). In

this test participants are given nine symbols corresponding to the numbers one to nine and

they have to substitute these symbols with their corresponding numbers. We scored the

number of correct substitutions made in 90 seconds on four different cycling versions of the

test. The second cognitive test was a long number recollection test in which the longest span

of digits remembered by the participants was measured.

Figure 4. Waveforms as described in

the literature.

A: Thomas waveform (35). B: Martiny

waveform (58). Pictures are reproduced

from their respective papers.

Figure 5. The three different PEMF waveforms used in this study: Martiny, Thomas and an EEG

excerpt.

These are the waveforms as they were sent from the pc to the interface card, where 128 is translated to 0

V, 255 to +2 V, and 0 to -2 V. On the left the waveform similar to the one used by Martiny et al. to treat

depression (58). In the middle the waveform with which Thomas found analgesis effects (31). On the

right a random EEG excerpt.


To check for emotional changes, the Dutch version of the Profile of Mood States (POMS;

(63)) and the Positive Affect Negative Affect Schedule (PANAS; (64)) were taken before and

after the stimulation period. These validated questionnaires ask the participant about their

feelings at that time in a standardized way. In addition, after the stimulation period

participants were debriefed by asking them about any unusual feelings and thoughts at that

time and during the stimulation period.

As a preliminary investigation pain intensity scores and pain aversion scores were

measured. Participants were first asked to score the intensity of their neuropathic pain

according to the Verbal Analogue Scale (VAS; 0 = no pain at all, 10 = strongest pain

imaginable) and were asked directly after this to also score the aversion to the pain in the

same manner (0 = pain (if any) is not bothering at all, 10 = worst pain imaginable). This was

done twice for each 5-minute period during the whole stimulation period. Additionally, in

each period the participants were asked twice whether they thought the TMS was on or off.

Statistical analysis

All statistics were performed in Statistical Package for Social Sciences (SPSS) for Windows,

(SPSS Inc., Chicago, IL, USA). Paired t-tests were used to compare the POMS and PANAS

scores before and after the stimulation period. Paired t-tests were used as well to compare the

first measurements during the stimulation period (during S1) with the last measurements

(during the EEG excerpt waveform). A False Discovery Rate (FDR) correction was

performed to control for multiple comparisons on analyses we did not have a hypothesis

about ((p * n) / k; n=10; p=significance value, n=total number of tests performed, k=rank

number when all p-values are arranged from lowest (k=1) to highest (k=n)).

Repeated measures Analyses of Variance (rm ANOVAs) were used for each outcome

measured during the stimulation period. The within subject factors for these rm ANOVAs

Figure 6. Overview of a the whole procedure.

S = Sham; M = Martiny waveform; T = Thomas waveform; EEG = EEG waveform. M3 was as shown in

figure 5, M1 was a quarter of that intensity, and M2 a half. T2 is as shown in figure 5, T1 was half of that

intensity. Other abbreviations: POMS: Profile of Mood States; PANAS: Positive Affect Negative Affect

Schedule; VAS= Verbal Analogue Scale; DSST: Digit-to-Symbol Substitution Testp.


were: treatment (sham, active) and waveform (Martiny, Thomas, EEG). For this model the

results of all active Martiny, Thomas, and EEG waveforms stimulation periods were taken

together as one variable (i.e. ActiveMartiny, ActiveThomas, ActiveEEG). For the sham

stimulation the sham periods proceeding those active periods were taken together as the

corresponding type of sham variable (i.e. ShamMartiny, ShamThomas, ShamEEG).

When sphericity could not be assumed (Mauchly’s test p<.05), Greenhouse-Geisser

statistics were reported. For all statistical analyses α=.05. Paired t-tests were used to explore

any significant effects found with the rm ANOVAs. Paired t-test’s p-values were reported

two-tailed unless stated otherwise. When the differences between the compared variables

were not normally distributed, non-parametric equivalents of the paired t-test (Wilcoxon

signed rank test) and de repeated measures ANOVA (Friedman’s ANOVA) were used.


Results

Raw data

Graphs of the data from all measurements are plotted for each patient and are shown in the

supplementary materials to provide an overview of the raw data. An overview of the results

of all statistical analyses is provided here in tables 5 and 6. On all five subscales of the

POMS, the scores of patient six are consistently lower after than before the stimulation

period.

DfM DfR F p

Pain intensity

Main effect treatment

1 8 1.37 .275

Main effect type

2 16 2.319 .131

Interaction effect treatment*type 2 16 .468 .635

Pain aversion


1 8 .473 .511

Main effect type

2 16 1.206 .325


Finger taps


1 8 .364 .563

Main effect type

2 16 1.384 .279


Long number recollection


1 8 3.449 .100

Main effect type*

2 9.336 1.235 .304


Main effect type**

DSST 5 X2=19.7 .001

Table 5. Rm ANOVAs outcomes.

*= Greenhouse-Geisser; **=Friedman’s ANOVA , which does not provide interaction effects.


Pain Intensity, Pain Aversion, Finger taps, and Long number recollection

No significant effects on the VAS scores, number of finger taps, and span of long numbers

recollections were found. Nor were any differences between the first and the last

measurement of these variables found (see tables 5 and 6).

DSST

Friedman’s ANOVA showed a significant main effect for waveform [X2(5)=19.7, p=.001],

but no other significant main or interaction effects. Post-hoc Wilcoxon signed rank tests

showed significant differences between all waveforms (see figure 7). DSST scores were

higher during the Thomas waveform periods [Mean(SD)=48.7(8.5)] than during the Martiny

waveform periods [Mean(SD)=43.9(9.5); T=2.4, p=.015]. DSST scores were higher during

the EEG periods [Mean(SD)=50.8(10)] than during the Thomas periods

[Mean(SD)=48.7(8.5); T=2.0, p=.044)].

Measurement Contrast t df p k P(corrected)

Pain intensity S1 vs EEG -0.83 8 .215**

Pain aversion -1.51 8 .085**

Finger taps -1.35 8 .214 7 .306

Long number recollection -1.35 8 .214 7 .306

DSST

-1.98

9

.079

3 .263

POMS depression and dejection scale* Before vs after T=9.5 9 .588 9 .653

POMS anger and hostility scale* T=1.8 9 .102 4 .255

POMS fatigue and inertia scale 1.7 9 .129 6 .215

POMS vigor and activity scale .4 9 .701 10 .701

POMS tension and anxiety scale -2.6 9 .029 1 .290

PANAS positive affect Before vs after 1.7 9 .123 5 .246

PANAS negative affect* T=-1.8 9 .068 2 .340

Table 6. Paired tests outcomes.

Paired t-tests, unless: *= Wilcoxon signed rank test; **=one tailed p-value, because there was a directional

hypothesis about these outcomes.


A trend that the first measurement was lower [Mean(SD)=42.3(3.4)] than the last

measurement of the stimulation period [Mean(SD)=49.0(3.7)] was found [t(8)=-2.0, p(two-

tailed)=.079]. This trend did not survive FDR correction [p(corrected): .290].

POMS and PANAS

No significant difference between active and sham stimulation were found on any scale,

except the tension and anxiety scale [t(9)=-2.6, p=.029]. The score on the tension and anxiety

scale was lower after the procedure [Mean(SD)=5.8(3.6)] than before the procedure

[Mean(SD)=7.5(4.3); see figure 8]. This difference however, did not survive FDR correction

[p(corrected)=.263].

A trend between the negative affect scores before [Mean (SD)=13.2(4.7)] and after

treatment [Mean after(SD)=12.1(3.2)] was found with a Wilcoxon signed rank test [T=-1.8,

p=.068]. This trend did not survive FDR correction [p(corrected)=.375].

Figure 7. Average DSST scores during stimulation

period.

Martiny periods: S1 until M3; Thomas periods: S4

until T2; EEG periods: S6 and EEG. Scores during the

Thomas periods were higher than during Martiny

periods [p=.015] and lower than EEG periods

[p=.044], showing an overall upward trend during

stimulation. Error bars: +/- 2 SE.


Debriefing

Participants guessed right about the TMS being active in 46% of cases (data from 9

participants, asked 24 times per patient). When debriefed, none of the participants reported

any unusual sensations or other striking effects during the stimulation periods, other than that

two patients reported a slight headache.

Figure 8. Tension and anxiety scores before and after

the stimulation period.

Tension and anxiety scores were on average lower after

the stimulation session [p(uncorrected)=.029,

p(corrected)=.375)]. Error bars: +/- 2 SE.


Discussion

In this study we tested the safety and tolerability of our TMS device in a population of

participants diagnosed with neuropathic pain, in order to see if we could safely proceed with

investigating an analgesic effect in a follow-up study. Results showed that participants scored

significantly higher on the DSST as the stimulation period progressed, regardless of active or

sham stimulation. This could suggest our TMS session slightly enhanced cognitive function.

However, this effect was probably due to a learning effect because four different (although

randomly cycling) versions of the test were used for a total of twelve times. One would

expect people to perform better when asked to do the exact same test again. Additionally,

there was no difference between active and sham stimulation.

An upward trend on the DSST is opposite to previous findings with the same device

using the Thomas waveform in which a downward trend was suggested but did not reach

significance (56). It should be noted that enhancement of cognitive capacity was not found in

the results from the long number recollection test.

Results showed a downward trend on the negative affect schedule of the PANAS and

a significant decrease on the tension and anxiety subscale of the POMS, but these differences

were not significant after FDR correction. Still, these possible trends are interesting

considering a new research project on antidepressant effects of TMS in our research group

using the Martiny waveform.

In the supplementary materials it can be seen that patient six responded with a

downward trend on all subscales of the POMS. Normally the response of one subject would

not be interesting, but in the case of magnetic stimulation some may be more sensitive to it

than others (65–67). Nothing can be concluded from the results of this one patient, but future

research should address the possibility that some subjects show a stronger response to the

stimulation and try to elucidate what might cause this.

Participants were not able to guess whether they were receiving active stimulation

better than chance (46%). This strongly indicates our TMS device is suitable for sham-

controlled research. Furthermore, participants did not report any unusual sensations or other

striking effects during the sessions, other than a slight headache after wearing the cap for

some time. The latter might be solved in the future by using a more comfortable cap. These

findings support the hypothesis that our TMS device is safe an tolerable, not only for

healthy volunteers (56,61), but in a neuropathic pain patient population as well.

Limitations of this study are the low number of participants (ten) and that the sham-

control was not optimal. Some measures of the ten participants were missing due to the

intensiveness of the session. The total number of participants for the measurements taken

during the stimulation period was nine and for some only eight. This limited the power of this

study, though strong adverse effects should still show.

The sham-control was not optimal because of the temporal uncertainty of the effects

of active stimulation. Any effects of stimulation might not be immediate and could carry over

to subsequent measures during sham-stimulation. Therefore only the effects of the session as

a whole could be studied. Because of these problems and the fact that there was no control

with only sham-stimulation, our findings are not in every way sham-controlled. This lack of a

sham-control however, is not necessarily a problem, because we were interested in whether

we would see any possible adverse effects of our TMS treatments. Any effects we did find

though, could be due to a placebo effect.

Opposed to our hypothesis no analgesic effects were found during the TMS

stimulation period. Because this was not the main aim of this study and therefore the design

was not optimized to find these results, this did not surprise us. In another study that is almost


finished, the analgesic effects of TMS on neuropathic pain are being studied with a more

appropriate (double blind) design. In that study, participants visited for two session (one

sham, one active) with one week apart to prevent a carry-over effect and stimulation was

given for a full half an hour in the active session.

Another reason why we might not have found an analgesic effect could be the

heterogeneity of the (small) group of patients we tested. Additionally, most of them had

unlikely neuropathic pain according to the Treede criteria (see table 4). For future studies

investigating analgesic effects in a neuropathic pain patient population it seems advisable to

select a more homogeneous group of patients. For instance on the basis of underlying illness,

type of neuropathic pain according to Rowbotham et al. (4) and Fields et al. (5), or other

measurable pain characteristics like allodynia. The latter could also be used to investigate the

pain itself more objectively, in addition to the VAS.

The follow-up study a similar thing was done by only including neuropathic pain

patients with probable and definite neuropathic pain. Still, this provides a very heterogeneous

group and the advice given above for selection could be used in the analysis of the data.

Conclusion

In conclusion, there is no evidence to suggest that our TMS device is not safe and tolerable

in a neuropathic pain patient population. Other than a questionable slight increase in

cognitive capability (which can hardly be considered to be a bad thing) no effects were found.

Unconfirmed trends we found point towards positive effects as well, i.e. reducing tension and

anxiety scores, and negative affect scores. Our hypothesis that participants would not be able

to distinguish between sham and active stimulation has been confirmed, showing that our

TMS device is suitable for sham-controlled research. No preliminary analgesic effects of

our TMS treatment were found in this study. Longer and continuous stimulation may be

needed to obtain this analgesic effect.


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Supplementary materials

POMS

Figure S1. POMS subscale scores before

and after for each subject.

Note that subject 6 responds with a downward

trend on each subscale.


PANAS

Figure S2. Positive and Negative Affect scores before and after for each subject. Only subject 8 showed a consistent (yet small) trend in improvement of affect.

Tests during session

Missing data point means no measurement could be done, mostly due to tiredness of the

patient.

Figure S3. VAS scores for pain intensity for each subject throughout the stimulation

session.


Figure S4. VAS scores of aversion to pain for each subject throughout the stimulation

session.

Subject 5 seemed to show an upward trend.

Figure S5. Span of numbers recollected in long number recollection test for each subject

throughout the stimulation session.


Figure S6. Amount of finger taps for each subject throughout the stimulation session.

Figure S7. Score on the DSST for each subject throughout the stimulation session.

Most subjects showed an upward trend.

safety and tolerability of microtesla transcranial...

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