Academic Year 2015 - 2017

TRANSCRANIAL DIRECT CURRENT STIMULATION

(tDCS) AS A TREATMENT FOR DRUG-RESISTANT

EPILEPSY

Charlotte CORTVRINDT

Promotor: Prof. Dr. Kristl Vonck

Dissertation presented in the 2nd Master year in the programme of

MASTER OF MEDICINE IN MEDICINE

“The author and the promotor give the permission to use this thesis for consultation and to

copy parts of it for personal use. Every other use is subject to the copyright laws, more

specifically the source must be extensively specified when using results from this thesis.”

Date 9/12/2016

Charlotte Cortvrindt Prof. dr. Kristl Vonck

Preface Choosing between all the subjects was not that difficult to me, because this subject caught my eye and triggered me the most. Since we did not have the theory classes of Neurology yet at that time, my knowledge in this area was very low. I have always liked the mystery in this field and this subject in particular, raised many questions to me. First, I would like to thank my promotor, Prof. dr. Kristl Vonck. It is true that I did not feel confident at the start, that I would manage writing a thesis on something I did know so few about. My promotor reassured me from our first appointment, gave me a lot of tips and was always very fast in answering my emails and correcting my writings. At the same time, she gave me a lot of freedom and made writing this thesis a positive experience to me. I would like to thank her for giving me the opportunity to grow in an area I was still so small in, and to do things I did not thought I could. Secondly, I want to show gratitude to my parents and my sister, for always supporting me in this process, and helping me out wherever they could. And finally Nele Cuypers deserves a special thanks, for investing time in reading my thesis and sharing her objective insights with me.

Table of contents

Abstract (EN & NL) 1

Introduction 4

Research question 6

Methodology 7

Results 9

1.   Neurobiological mechanisms 9

1.1   Direct effects 9

1.2   Indirect effects 9

1.3   After-effects 10

1.4   Homeostatic plasticity 11

2.   Stimulation parameters 12

2.1   Electrode position & size 14

2.2   Current density & stimulation duration 16

2.3   Repetition rate & frequency 18

3.   Other factors that affect clinical efficacy 19

3.1 Patient characteristics 19

3.2 Condition and activity of the brain 20

3.3 Practical factors 22

4. Safety and side effects 22

5. Long-term outcomes 24

Discussion 25

1.   How to further investigate the neurobiological mechanisms 25

2.   Optimal management protocol 27

2.1   Electrode position & size 27

2.2 Current density & stimulation duration 31

2.3 Repetition rate & frequency 32

3. Other factors that affect clinical efficacy 33

4. Safety and side effects 35

5. Long-term evolution 37

Conclusion 39

References 40

1

Abstract (EN)

Introduction: For some patients with drug-resistant epilepsy, surgical resection of the

epileptogenic zone is a successful treatment option. When patients are unsuitable candidates or

unwilling to receive surgery, neurostimulation presents a valuable alternative. Two invasive

neurostimulation modalities – Vagal Nerve Stimulation (VNS) and Deep Brain Stimulation

(DBS) - are currently FDA-approved in drug-resistant epilepsy patients and are used in practice.

Non-invasive neurostimulation - e.g. tVNS, Transcranial Magnetic Stimulation (TMS) and

Transcranial Direct Current Stimulation (tDCS) - has gained more interest the last decades. In

tDCS, 2 sponge electrodes are placed on the scalp to deliver a weak constant current, which

induces an electrical field in the brain and alters excitability. Promising results have been

observed after cathodal tDCS application in epilepsy patients and with limited side effects,

however, many uncertainties remain.

Methodology: A literature study was performed and in Pubmed, the following terms were

used and this yielded the first relevant articles: ‘refractory epilepsy treatment’, ‘Vonck epilepsy’

and ‘F Fregni neurology’ with the filter ‘last 5 years’. Via the snowball-method, more studies

were included. Afterwards, the terms ‘tDCS mechanisms’, ‘tDCS epilepsy’, ‘sex differences

tDCS’, ‘age differences tDCS’ and ‘ethical tDCS’ delivered the final studies.

Results: There are several hypotheses on the involved neurobiological mechanisms of tDCS.

Direct effects are caused by membrane potential changes and after-effects by both synaptic and

non-synaptic mechanisms. However, indirect effects and antagonistic homeostatic effects are

seen as well. For tDCS almost no side effects are reported, but before utilisation in practice, the

correct stimulation parameters (electrode position, size, current density, stimulation duration,

repetition rate and frequency) should be determined and therefore, the most recent clinical trials

in epilepsy patients were collected and listed in a table. Furthermore, other factors seem to affect

tDCS efficacy as well and these are subdivided in patient characteristics (e.g. sex and age),

condition and activity of the brain and practical factors.

Discussion: The highly complex and entire tDCS mechanism is still far from revealed. Further

elucidation of the mechanism would provide important insights and possibilities for developing

the optimal treatment protocol. Today, insufficient data are available to design this treatment

protocol. There are insufficient clinical trials in epilepsy patients and a lack of subjects in the

trials. In the future, applications of tDCS may be developed, such as the use of tDCS as a

2

diagnostic tool to identify patients that are suited for implantation of an invasive

neurostimulation device.

Conclusion: Studies on tDCS as a treatment for drug-resistant epilepsy have shown promising

results, however 2 issues need to be resolved before application in practice: the long-term

outcomes are still unclear, and the optimal stimulation protocol is not yet designed.

Abstract (NL)

Inleiding: Sommige patiënten met medicatie-resistente epilepsie kunnen chirurgie ondergaan

waarbij de epileptische zone wordt gereseceerd, maar wanneer de patiënt niet geschikt is voor

chirurgie of geen chirurgie wil, zou neurostimulatie een alternatief kunnen bieden. Twee

invasieve types van neurostimulatie – Vagal Nerve Stimulation (VNS) en Deep Brain

Stimulation (DBS) - zijn reeds goedgekeurd door de FDA voor medicatie-resistente epilepsie

patiënten en worden al gebruikt in de praktijk. Niet-invasieve neurostimulatie - bv. tVNS,

Transcranial Magnetic Stimulation (TMS) en Transcranial Direct Current Stimulation (tDCS)

- heeft de laatste decaden aan belang gewonnen. tDCS wordt uitgevoerd door 2 electroden op

de schedel te plaatsen en deze brengen een zwakke constante stroom over, die geproduceerd

wordt door een batterij. Op deze manier wordt een elektrisch veld in de hersenen geproduceerd

en dit moduleert de exciteerbaarheid van de corticale neuronen. Het gebruik van tDCS voor

epilepsie patiënten heeft reeds veelbelovende resultaten opgeleverd met minimale rapportering

aan bijwerkingen, maar er zijn nog steeds veel onduidelijkheden.

Methodologie: Een literatuurstudie werd voltrokken en in Pubmed werden volgende termen

gebruikt en dit leverde de eerste relevante artikels op: ‘refractory epilepsy treatment’, ‘Vonck

epilepsy’ en ‘F Fregni neurology’ met de filter ‘last 5 years’. Via de sneeuwbal-methode werden

nog artikels geïncludeerd. Daarna werden de termen ‘tDCS mechanisms’, ‘tDCS epilepsy’, ‘sex

differences tDCS’, ‘age differences tDCS’ en ‘ethical tDCS’ gebruikt en zo werden de laatste

artikels gevonden.

Resultaten: Er zijn verschillende hypothesen omtrent de neurobiologische mechanismen van

tDCS. De directe effecten worden veroorzaakt door membraanpotentiaal veranderingen en de

langdurige effecten door synaptische en non-synaptische mechanismen. Echter, ook indirecte

en antagonistische homeostatische effecten werden waargenomen. tDCS vertoonde bijna geen

bijwerkingen, maar voordat de techniek in de praktijk kan gebruikt worden, moeten de correcte

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stimulatieparameters (positie en grootte van de electroden, stroomsterkte, stimulatieduur, aantal

sessies en frequentie) bepaald worden. Daarom werden de meest recente klinische studies met

epilepsie patiënten verzameld en opgelijst in een tabel. Bovendien lijken ook andere factoren

de efficiëntie van tDCS te beïnvloeden en deze worden onderverdeeld in: patiënt kenmerken

(bv. geslacht en leeftijd), toestand en activiteit van de hersenen en praktische factoren.

Discussie: Het enorm complexe tDCS mechanisme is nog lang niet volledig ontrafeld. Echter,

dit zou belangrijke inzichten opleveren en mogelijkheden voor het ontwikkelen van het

optimale behandelingsprotocol. Tot op heden zijn er onvoldoende gegevens beschikbaar om dit

protocol te ontwerpen, omwille van een tekort aan klinische studies met epilepsie patiënten en

een tekort aan patiënten in deze studies. In de toekomst zullen misschien andere toepassingen

van tDCS ontwikkeld worden, bv. het gebruik als een diagnostisch middel om de patiënten te

identificeren die geschikt zijn voor de implantatie van een invasief neurostimulatie toestel.

Conclusie: Studies over tDCS als een behandeling voor medicatie-resistente epilepsie hebben

al veelbelovende resultaten aangetoond, maar 2 problemen moeten nog opgelost worden

vooraleer het volwaardig gebruik van tDCS in de praktijk mogelijk is. De resultaten op langere

termijn moeten nog onderzocht worden en het optimale behandelingsprotocol is nog niet

ontworpen.

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Introduction

Epilepsy is a neurological disorder that is characterized by the occurrence of multiple seizures,

which can be explained by hyper-excitability of neurons and hyper-synchrony of neuronal

networks (1). It is treated with antiepileptic drugs (AED’s) such as lamotrigine, oxcarbazepine,

levetiracetam, topiramate, zonisamide etc. (2). When seizures cannot be controlled with the

combination of 2 or 3 AED’s, the condition is called ‘drug-resistant epilepsy’. About one in 3

patients develop this uncontrolled form of epilepsy (3). In some patients with partial epilepsy,

the epileptogenic zone can be resected surgically. A cohort study was performed and about half

of the patients were still seizure-free 5 years post-surgery (4). Even better results were seen

after specifically anterior temporal resections (4). Not all patients are suitable candidates for

epilepsy surgery due to the localisation of the epileptogenic zone in functional brain tissue or

the presence of multiple foci. Furthermore, disadvantageous consequences may occur, such as

postoperative decline in verbal function (4).

This is why neurologists have recently put focus on an alternative treatment: neurostimulation.

Different methods of neurostimulation have been developed. There are invasive and non-

invasive devices, which can stimulate different sites of the nervous system: cranial nerves like

the vagus and trigeminal nerve, or the central nervous system, for example the cerebellum, the

nuclei of the thalamus, the hippocampus and many more (5). Two invasive modalities are

already used in practice; these are Vagus Nerve Stimulation and Deep Brain Stimulation. VNS

was the first neurostimulation method to be FDA-approved for the treatment of drug-resistant

epilepsy with partial onset seizures (5). Englot et al. investigated the outcome of VNS therapy

in 5554 patients and compared their results with other studies. Similar outcomes were seen:

around 40% of the patients showed 50% seizure reduction or more in the first 4 months of

therapy, while after 2-4 years of VNS therapy, 60% of the patients had a 50% seizure reduction

or more and 8% became seizure-free (6). These seizure reductions can be explained by the

inhibitory effect of the stimulation on the visceral afferents in the vagus nerve, which project to

the thalamus, cortex and subcortical regions (5). Therefore, no identification of the seizure focus

is needed (7). A second example of invasive neurostimulation is DBS. The results, application

and hypothetical mechanism of this therapy depend on the stimulation target (8). Various targets

can be stimulated, such as the anterior nucleus of the thalamus (ANT), the centromedian nucleus

of the thalamus (CMT), the hippocampus, the subthalamic nucleus (STN), the cerebellum and

so on (8). ANT DBS for example shows best results in complex partial seizures, located in the

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limbic system and is FDA-approved in Europe and Canada (9). Identification of the seizure

focus is again not necessary, as its mechanism of action is probably the activation of inhibitory

corticothalamic projections that widely and unspecifically spread in the brain (5,8).

Non-invasive neurostimulation is a technique that was already invented in times when the first

medical documents were written. Electrical torpedo fish were put on the regions of interest and

were supposed to make headache or other pain disappear (10). Afterwards it fell into oblivion,

but the last decades, neurologists gained interest again in this treatment. Study results showed

that it can be effective in Parkinson disease, chronic pain and recovery from stroke for instance

(10). Cranial nerves like the vagus nerve and the trigeminal nerve can be stimulated

transcutaneously. tVNS is performed by placing electrodes on the skin of the ear - on the

auricular branch of the vagus nerve - and has shown good results in patients with drug-resistant

epilepsy (11). Trigeminal Nerve Stimulation (TNS) follows the same principle as tVNS, except

for the fact that in TNS, the afferents of the trigeminal nerve are stimulated on the facial skin.

A reduction in seizure frequency has been proven and the device is FDA-approved in Europe

and Canada, but not yet in the USA (5). Finally, there is the possibility of stimulating the central

nervous system in a non-invasive way. In TMS, electromagnetic induction is utilized to direct

the induced currents to a specific focus in the brain. Repetitive TMS (rTMS) – which means

that trains of stimuli are fired consecutively – can induce plastic changes. It can modulate the

cortical excitability and depending on the stimulation frequency, this results in either long-term

potentiation (LTP) or long-term depression (LTD) (10,12). Beneficial effects are seen in several

neurological disorders and epilepsy is one of them (12). Overall, level C evidence for rTMS in

the treatment of epilepsy is confirmed, but more evidence is necessary for worldwide

application of this technique. In status epilepticus for example, only level D proof is established

and therefore, this therapy cannot be recommended to these patients at this time (12).

Transcranial Direct Current Stimulation is another form of non-invasive neuromodulation and

the focus in this study will be on this technique. Two sponge electrodes are placed on the scalp

at certain localisations, fixed with a plastic headband and connected to a current generator. The

electrodes are soaked in a saline solution or electrode cream is applied to improve conductivity

(13,14). One electrode is the negative electrode and is called the cathode, the other one is the

positive electrode and is called the anode. A weak constant current of maximum 1-2mA is then

produced by the generator connected to the electrodes, with the aim of passing current through

the brain between both electrodes (15). The induced electrical field modulates cortical

excitability. Cathodal stimulation implies that current flow is directed from cathode to anode

and this results in hyperpolarization of neurons in the stimulated brain area and excitability-

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reduction; anodal stimulation does the opposite (15). Evidently, excitability-reducing effects

are desired in an epilepsy treatment and therefore, cathodal stimulation is applied in these

patients (15).

A significant seizure reduction after tDCS has been shown in various studies. Nitsche and

Paulus for example performed a randomized double-blinded clinical trial, where drug-resistant

epilepsy patients with focal onset seizures were treated with cathodal tDCS. After 20 minutes

of stimulation at 1mA, seizure frequency tended to decrease and continued decreasing in the

month after therapy (16).

In most studies to date, tDCS has been reported to be safe and causing nearly no side effects, in

similarity to the other non-invasive neurostimulation techniques. An itching sensation

underneath the electrodes at the beginning of the stimulation session is commonly reported, but

this is not harmful (13,17,18). Other potential but infrequent side effects are: headache,

tiredness, nausea, insomnia and skin burns (17).

Research question

tDCS application in epilepsy patients has shown promising results in clinical trials, but little is

known about the utilisation of tDCS in practice. Several questions need to be answered before

tDCS can be used as a therapy for drug-resistant epilepsy patients. By performing a literature

search, this work tried to answer some of the unanswered issues. How can appropriate and

patient-specific values for stimulation parameters be determined? Is the therapy safe enough,

without too many side effects, using these parameters? What other factors could affect clinical

efficacy? What do we know about long-term outcomes and what could be further developments

with the technique? Before asking these questions, the neurobiological mechanisms of cathodal

tDCS were examined, in order to search for the answers in a more rational way.

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Methodology

To start with, 4 articles with information about the basic principles of epilepsy treatment were

found in Pubmed, using the following terms: ‘refractory epilepsy’, ‘epilepsy drug therapy’ and

‘epilepsy surgery’. Then focus was put on the neurostimulation modalities. The terms

‘refractory epilepsy treatment’ yielded 3 articles that provided an overview of the different

neurostimulation methods, whereas the following terms: ‘deep brain stimulation epilepsy’,

‘VNS seizure reduction’, ‘transcranial magnetic stimulation epilepsy’ and ‘Vonck epilepsy’,

delivered 7 articles with more specific information of separate modalities. To assure obtaining

most recent results, a filter was used: ‘last 5 years’ and all articles were screened and compared.

When the full text of an article was not available, Research Gate was employed or a request

was sent to the author by mail. Thereafter ‘F Fregni neurology’ was searched in google scholar,

which yielded 2 useful articles whom one was: ‘Transcranial Direct Current Stimulation in

Epilepsy’, from San-Juan et al. Its references were screened and 20 more interesting articles

were found. The selection of appropriate articles was conducted by filtering the titles and

abstracts on articles about the mechanisms of tDCS, tolerability and effects and improvements

of tDCS, and especially investigations in epilepsy patients. Several authors described their view

on current problems with tDCS and these critical notes were compared and put together.

Afterwards, 3 more specific articles were found in Pubmed by using the terms ‘tDCS

mechanism’ with a filter ‘last 5 years’. Via the references of one of these articles, 2 more articles

about interesting aspects of the neurobiological mechanisms were included.

Then, research was done on the optimal stimulation parameters. Two trials that were discussed

in the study from San-Juan et al. were included and in Pubmed, 7 more studies were found,

using the terms ‘tDCS epilepsy’, the filter ‘last 5 years’ and ‘sort by: most recent’. In this way,

all interesting trials of tDCS in epilepsy patients, since the first clinical trial of Fregni et al. in

2006, were included.

Afterwards, Pubmed was scanned for articles about other factors that affect clinical efficacy.

Utilisation of the terms ‘sex differences tDCS’ yielded 3 articles, and ‘age differences tDCS’

yielded one. The following terms were tried as well, but did not deliver relevant articles: ‘patient

characteristics tDCS’, ‘efficacy tDCS characteristics’, ‘tDCS outcome social’ and ‘social factor

tDCS’. Studies about the influence of activity and condition of the brain on tDCS effects were

searched in Pubmed, using the terms: ‘brain activity affecting cathodal tDCS’ and ‘brain

8

activity cathodal tDCS’, but likewise, no relevant studies were found. Finally, 2 articles about

the ethical concerns were selected, using the terms ‘ethical tDCS’ in Pubmed.

The methodology of all studies was verified for number of subjects, animal versus human

studies, representativeness of the results and so on. Trials with a small amount of subjects were

included sometimes, since few major studies on tDCS in epilepsy patients are conducted up till

now. Human studies were preferred, however, when useful information about the technique or

neurobiological mechanisms of the technique was provided in animal studies, these were

included as well.

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Results

1. Neurobiological mechanisms

1.1  Direct effects

tDCS induces an electrical field in the brain and this modifies cortical excitability (15). It is

considered a neuromodulatory technique in stead of neurostimulatory like TMS and others,

since – in case of anodal stimulation – it does not directly induce action potentials which

requires rapid depolarisation (14). Instead, the neuronal resting membrane potential is

modulated by a slight tonic hyperpolarisation after cathodal tDCS, or a slight tonic

depolarisation after anodal tDCS. This excitability shift leads to either less or more spontaneous

cell firing, depending on stimulation polarity (13,14). Nitsche et al. conducted investigations in

2005 on the human motor cortex to investigate the direct effects of tDCS on the cortex and its

temporal profile (19). Four measurements were made in healthy subjects to estimate changes in

various parameters of excitability: 1) recording of the motor thresholds (MT), which represents

neuronal membrane potential shifts; 2) recording of the input-output curve (I-O curve), which

reflects neuronal membrane potential shifts as well as synaptic mechanisms and the recruitment

of larger neuronal populations; 3) recording of motor cortex inhibition and facilitation

representing synaptic mechanisms, namely the activity of inhibitory (GABAergic) and

excitatory (glutamatergic) interneurons; and 4) recording of motor cortex indirect-waves (I-

waves) reflecting synaptic mechanisms (probably GABAergic and glutamatergic) in cortical

interactions between circuits (19). The main finding of this study is that the effects during tDCS

are dependent on membrane potential changes and not so much on synaptic changes (19). This

is demonstrated by the I-O curve decline during short-lasting cathodal tDCS: sodium and

calcium channel activity changes (non-synaptic) intracortically lead to hyperpolarization of the

postsynaptic membrane potential, whereas nearly no alterations in intracortical inhibition,

facilitation or I-wave facilitation were found during cathodal tDCS (19).

1.2 Indirect effects

The mechanisms stated above are ‘direct’ results of tDCS, but this stimulation technique also

causes ‘indirect’ effects. More distant cortical, subcortical and corticospinal neurons can be

affected through connections with directly stimulated neurons (20). Moreover, not only neurons

10

are involved in the process. Surrounding tissue like blood vessels, connective tissue etc. are

affected as well (20). Monai et al. demonstrated in mouse brain that glial cells contribute to the

tDCS-induced metaplasticity alterations, which refer to the plasticity alterations of synaptic

plasticity (cfr. Infra). Astrocytes all over the brain are activated by anodal stimulation to secrete

signalling molecules and this leads to changes in metaplasticity (21). The IP3-signaling pathway

and intracellular calcium elevation in the astrocytes are responsible for these changes, and they

are dependent on N-methyl-D-aspartate (NMDA)-receptor activity (21). The effect of cathodal

tDCS on glial cells and the effects in the human brain have not been investigated.

1.3 After-effects

When tDCS is applied for a certain duration and at a certain intensity (at least 8 minutes of

stimulation with a current of 1-2mA is necessary), long-lasting effects are seen (13). Nitsche et

al. have shown in 12 to 20 healthy humans, that by testing their 4 modulating parameters of

excitability, after-effects are dependent on synaptic mechanisms (19). This is demonstrated by

parameter 3 which represents synaptic mechanisms. Intracortical inhibition is increased and

facilitation is reduced after cathodal tDCS (19). The after-effects can be referred to as LTP in

case of anodal stimulation, and LTD when cathodal stimulation is used (14). They are protein

synthesis dependent and can be explained by modulation of the NMDA-receptor efficacy, but

also modifications of intracellular cyclic adenosine monophosphate (cAMP) and calcium levels

contribute to these effects (13,14). Ion channels or receptors that lead to membrane potential

shifts probably do not contribute to the after-effects, since these modifications are not stable

long enough (19).

Synaptic mechanisms can be subdivided in presynaptic and postsynaptic alterations, but their

relative importance in synaptic plasticity development is not clear yet. Postsynaptic alterations

can be unravelled by pharmacological studies, for example using NMDA-receptor antagonists

and gamma-aminobutyric acid-A (GABAA)-receptor agonists (22). Disadvantages of these

studies are that presynaptical mechanisms are unexplored, nor are the exact, local alterations

(22). Some pharmacological experiments were conducted in 7 to 11 healthy humans, and results

showed that in postsynaptic neurons, a significant decrease in glutamate concentration as well

as in GABA concentration was seen after cathodal stimulation (22). When neuronal firing rate

is reduced, enzymatic changes such as alterations in glucose oxidation occur, and this leads to

diminished glutamate synthesis (22). GABA concentration reduces along with glutamate,

because of their biochemical relationship, although a reduction in GABA concentration does

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not explain LTD-like effects of cathodal tDCS (22). Other neurotransmitters can influence

synaptic plasticity induced by tDCS and this is shown by several pharmacological studies in

humans, but the effects of other neurotransmitters are not linear. The dopamine precursor L-

dopa prolongs inhibitory plasticity, whereas D2-receptor antagonists abolish induced plasticity

and D2-receptor agonists in high or low dosage reduce plasticity (20). D2-receptor agonists in

medium dosage however, restore plasticity (20). Acetylcholine-reuptake inhibitors have

analogous effects as L-dopa, while serotonine-reuptake inhibitors abolish inhibition and turn it

into plasticity facilitation (20). It is logical that neurotransmitters and receptors in the central

nervous system are influenced in some way by the constant electrical field induced by tDCS,

since most neurotransmitters and receptors have electrical features (20).

Ardolino et al. examined axonal excitability changes in 17 healthy humans and concluded that

after-effects also depend on non-synaptic alterations (23). They attributed these effects to

migration and conformational changes of transmembrane proteins and channels, caused by the

constant electrical field in that brain area (23). The electrical field also affects the acid-base

balance, which causes water electrolysis and stimulates H+-dissociation, and this again

influences neuronal cell membranes and transmembrane proteins (23). Intracellular pH and

calcium concentration are closely related, but the effect of cathodal tDCS on these 2 factors is

not yet clear (23).

1.4 Homeostatic plasticity

When tDCS is applied repeatedly, another mechanism can be established, namely homeostatic

plasticity. It means that synaptic plasticity is dependent on previous network activity and is thus

regulated by the neurons themselves. The duration of previous activity and the time interval

between both stimulation sessions determine this phenomenon (24). In Fricke et al.’s study,

cathodal tDCS was applied in the motor cortex of 9 healthy humans for 5 minutes and this

caused a reduction in Motor Evoked Potentials (MEPs), lasting 5 minutes after stimulation (24).

When a second tDCS session was administered 30 minutes after the first one, the effects were

identical to the effects of the first session (24). A second tDCS application between 3 or 10

minutes after the first one in contrast, led to a reduction of the inhibitory effect or even a

reversion (24). One possible explanation given by the authors is that the activation of L-type

voltage-gated calcium channels (L-VGCCs) in postsynaptic neurons could be enhanced by the

2 consequent tDCS sessions leading to intracellular calcium-level rises and MEPs facilitation

in stead of reduction of MEPs (24). This manifestation is an example of homeostatic plasticity.

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However, when the second stimulation was applied immediately after the first one, this comes

down to a cathodal tDCS session of 10 minutes, prolongation of MEPs suppression was seen

up to 30 minutes (24). As a result of the longer stimulation duration, other processes might

originate, including the release of tumor necrosis factor (TNF)-α, brain-derived neurotrophic

factor (BDNF) and others, and these processes might overrule homeostatic plasticity effects

(24).

2. Stimulation parameters

Cathodal tDCS application in epilepsy patients is still in its experimental phase and the best

treatment protocol to obtain optimal results has not yet been defined. When stimulation

parameters such as current intensity or stimulation duration are modified, this could either lead

to more beneficial effects, or to more adverse effects. Therefore, it is important to sort out which

values are most appropriate for each parameter. In this section, the most recent trials (starting

from 2006) applying tDCS in epilepsy patients have been collected and listed in table 1, together

with their respective stimulation parameters and outcomes. Obviously, only human clinical

trials are assembled here and the studies are placed in chronological order. When the electrode

position is determined more precisely in some studies, codes are used according to the

International EEG 10-20 system.

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Table 1: overview of available clinical trials in epilepsy patients

Study Electrode Position & Size

Current Density & Strength

Stimulation Duration

Repetition Rate & Frequency

Population & Study design

Outcome

Fregni et al., 2006.25

Cat over epileptogenic focus An over silent area 35cm2

1mA 0,29A/m2

20 min 1 session 19 pts Drug-resistant epilepsy, malformations of cortical development Mean age 24 RCT

Sz frequency reduction of 44%

Nitsche and Paulus, 2009.16

Cat over epileptogenic focus

1mA

20 min 1 session Drug-resistant focal epilepsy, malformations of cortical development Case study

Sz frequency reduction Trend-wise during 1 month

Yook et al., 2011.26

Cat over epileptogenic focus: midpoint P4 and T4 * An over left SOR 25cm2

2mA 0,80A/m2

20 min per session 200 min in total

10 sessions in total 5 days per week

1 pt Drug-resistant epilepsy, focal cortical dysplasia Age 11 Case study

Sz frequency reduction of >50% Sz duration reduction 2 months after tDCS

Varga et al., 2011.27

Cat over area of peak negativity 25cm2 An over area of peak positivity 100cm2

1mA 0,40A/m2

20 min 1 session 5 pts Drug-resistant focal continuous spikes and waves during slow sleep Age 6-11 Sham-controlled cross-over study

No epileptic activity reduction Possibly epileptic propagation reduction

Faria et al., 2012.28

Cat over CP5 left 3 An’s over SOR: FP1, FPz, FP2 1,1cm2 **

1mA 9,09A/m2

10 min per session 30 min per week

3 sessions per week delivered on the same day

2 pts Epileptic encephalopathy Age 7 and 11 Case study

Epileptic activity reduction During tDCS

Auvichayapat et al., 2013.29

Cat over epileptogenic focus An over contralateral shoulder

1mA 20 min 1 session 36 pts Drug-resistant focal epilepsy Age 6-15 RCT

Sz frequency reduction 2 days after tDCS Small reduction 1 month after tDCS

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Assenza et al., 2014.1

Cat over T4 (pt 1) and T5 (pt 2) An over contralateral homologous region 12,25cm2

1mA 0,82A/m2

9 min 1 session 2 pts Drug-resistant focal epilepsy Age 17 and 24 Sham-controlled cross-over study

Sz frequency reduction of 70% in pt 1 50% in pt 2 1 month after tDCS

Zoghi et al., 2016.30

Cat over right temporal lobe 12cm2 An over left SOR 35cm2

1mA 0,83A/m2

9 min per session 18 min in total

2 sessions with 20 min interval***

1 pt Drug-resistant temporal lobe epilepsy Age 48 Case study

Sz frequency reduction of 75% 4 months after tDCS

Tekturk et al., 2016.31

Cat over T3 or T4 An over contralateral SOR 35cm2

2mA 0,57A/m2

30 min per session 90 min in total

3 sessions delivered on 3 consecutive days

12 pts Drug-resistant mesial temporal lobe epilepsy, hippocampal sclerosis Mean age 35 Sham-controlled cross-over study

Sz frequency reduction of 93,66% 1 month after tDCS

Legend: Cat = Cathodal electrode; An = Anodal electrode; RCT = Randomized Controlled Trial Pt = Patient; Sz = seizure; SOR = supraorbital region * This referred to the right temporoparietal area ** EEG electrodes were used for stimulation in this study *** This referred to the 9-20-9 protocol

2.1 Electrode position & size

When electrodes are moved slightly to a different place on the skull, the stimulation effect can

be different (16). One explanation for this phenomenon is that electrical field strength is high

and more or less homogeneous under the stimulation electrode, but a quick reduction is seen

when the distance to the stimulation electrode increases, until conversion of polarization of

neurons in deeper cortical sulci (14,32). That is why moving the electrode only a few

centimetres, can change cortical excitability of the area of interest and tDCS treatment efficacy

(32,33,34). Efficacy however, also depends on current flow direction and thus position of the

reference electrode is important too (16). Likewise, the specific tissue characteristics of the

brain area receiving the current, such as the morphology, layering, cellular composition,

conductivity and cerebrospinal fluid can alter the stimulation effect (14,17,35). And lastly, the

electrode position determines partly how much current is delivered to the skull and how much

15

to the brain tissue (14). A higher amount of current will be shunted through the scalp when the

distance between both electrodes is smaller (36). This might lead, in some circumstances, to a

lower efficacy of the reference electrode without changing efficacy of the stimulation electrode,

but this is not certain yet (36).

As described in table 1, the cathode is usually placed over the epileptogenic focus and the anode

over a contralateral, non-epileptogenic area. Fregni et al. determined anode position as the area

with normal EEG activity or the smallest amount of epileptogenic activity (25). Assenza et al.

used the contralateral homologous region, and in the studies with a temporal epileptogenic

focus, contralateral supraorbital region is chosen to locate the reference electrode (1,26,30,31).

The conventional electrodes are large, rectangular, sponge electrodes of 5 x 7cm and thus a size

of 35cm2, although it can vary between 25 and 35cm2 in previously used protocols (14,37).

Assenza et al. used square electrodes of 3,5 x 3,5cm, but the rationale for deviating from the

standard electrode shape was not mentioned (1).

Spatial focality is low, using the large, conventional electrodes (35). There are 3 main reasons

for trying to improve spatial focality in tDCS: 1) it would enable more precise analysis and

interpretation of research results about the effects of tDCS, 2) applicability of tDCS in the

clinical setting could improve by offering a more selective stimulation, and 3) less undesirable

effects would occur if only the region of interest was stimulated (36). Removing the reference

electrode from the scalp and placing it somewhere else on the body, seems a smart solution to

rule out the unwanted anodal stimulation of the cortical area underneath the electrode (36).

Especially in epilepsy patients it is important to avoid any excitability enhancement.

Nevertheless, both the stimulation electrode and the reference electrode should be positioned

correctly to the scalp to provide the right current direction to obtain a certain effect.

Furthermore, brain stem activation could result from the extracephalic reference electrode

position when high current intensity is used and this could cause dangerous disturbances of the

autonomous central nervous system (36). However, Auvichayapat et al. tested cathodal tDCS

in 36 drug-resistant focal epilepsy children in a randomized controlled trial (RCT), placing the

anode on the shoulder (29). In this study, no adverse effects were seen using a current strength

of 1mA, moreover, an immediate and longer-lasting seizure reduction was seen in these

children (29). This montage was also investigated in 3 virtual models, developed from high-

resolution MR images of healthy children’s brain, and they concluded that moving the anode

from the scalp to the shoulder reduced the electrical field strength in the silent area about 100%

(38). This could extensively lower the risk of seizure induction in that area, where previously

the excitability-enhancing anode was placed (38). Furthermore, it significantly increases the

16

induced electrical field in the deeper brain regions, such as the hippocampus and thalamus,

which might improve tDCS potency (38). And lastly, no alterations in cardiac or brain stem

activities are seen up till now (38). However, as the electrical field is maximally spread under

the cathode in this montage, the whole field distribution in the brain is changed and this implies

alterations in tDCS efficacy as well, which needs further investigation (38).

Two other options to ameliorate spatial focality in tDCS are: reducing stimulation electrode

size while keeping current density constant in order to retain stimulation efficacy, or enlarging

reference electrode size under constant current strength, so that current density and thus

functional efficacy diminish (36). These 2 options were tested in 12 healthy subjects, with

respectively a stimulation electrode of 3,5cm2 in stead of 35cm2, and a reference electrode of

100cm2 in the other experiment. Results demonstrated that in both cases de stimulation efficacy

was unchanged, except for off course in the first experiment, the cortical areas that were situated

outside the stimulated zone, due to the smaller stimulation electrode size (36). Since a smaller

area was stimulated, effectivity in depth could be minor and a smaller number of afferents might

be affected (36). These possible issues need further investigation. On the other hand, stimulating

only the motor cortex for example, is not possible with the large conventional electrodes: part

of the somatosensory and premotor cortices will unavoidably be stimulated too. For this reason,

stimulation with smaller electrodes could be an advantage when more precise stimulation is

needed with the same efficacy (36). In the second experiment with the large reference electrode

as well, more selective stimulation is possible without reducing efficacy (36).

Likewise, Varga et al. tested stimulation with a cathode of 25cm2 and a reference electrode of

100cm2 to increase focality, but in 5 epilepsy patients in stead of in healthy humans. They,

however, did not obtain significant seizure reductions (27). Zoghi et al. treated a drug-resistant

temporal lobe epilepsy patient with tDCS using a cathode of 3 x 4cm, but retaining the

conventional anode size of 5 x 7cm. This patient in contrast, had a significant reduction of

seizure frequency (30). Faria et al. investigated simultaneous EEG recording while stimulating

with the same circular EEG electrodes with a diameter of 1,18cm, using one cathode and 3

anodes. They as well acquired significant beneficial results in both patients (28).

2.2 Current density & stimulation duration

Current strength or intensity (I) determines, among others, deepness of the stimulation effect

(1). An animal study showed that repetitive application of cathodal tDCS in a genetic absence

model improves the after-effects when higher current intensity is used compared to low

17

intensity, by significantly shortening the duration of the spike and slow-wave discharges on the

long term (39). However, the influence of current intensity on the duration of separate seizures

on the long term has not been proven in humans in a single session protocol yet.

Current density (J) is the quotient of current intensity and contact surface area of the stimulating

electrode (a): J= I/a, expressed in A/m2 (15). Current density determines the strength of the

electrical field and thus potency and efficacy of tDCS (14). However, if current density is raised,

the increase in effect is not always a linear phenomenon. A possible explanation is that the

population of targeted neurons is altered because the current flow reaches deeper neurons than

when a lower current density is used (14). Second issue with raising this parameter to obtain

more efficient stimulation effects, is the higher risk of side effects (14).

In the search to the optimal value for current density, this parameter has fluctuated between

0,29 and 0,80A/m2 in most experiments, as described in a manuscript by Nitsche et al., where

they illustrate the state of the art 2008 (14). However, they predicted that the limits would

continue to expand and this is demonstrated in table 1 (14). Faria et al. retained current intensity

at 1mA, but by using EEG electrodes as stimulation electrodes, current density rises to

9,09A/m2 (28). No side effects were reported and a significant epileptiform activity reduction

was seen, but the experiment was executed in only 2 epilepsy patients and without comparison

to sham stimulation (28). Assenza et al. and Zoghi et al. respectively used stimulation electrodes

of 12,25cm2 and 12cm2, and they acquired current densities of 0,82 and 0,83A/m2 (1,30).

Similarly to the investigation of Faria et al., these studies did not document any side effects, the

results were significant, and the studies only contained respectively 2 patients but with sham-

control, and one patient without sham-control (1,30).

Stimulation duration determines the duration of the after-effects (1,14). A short tDCS

application of a few seconds for example, does not elicit after-effects, whereas stimulating for

around 10 minutes, does (14). tDCS’s temporal characteristics are inherent to the technique,

and therefore, a certain stimulation duration is necessary to obtain satisfactory efficacy and

duration of the effects (36). The optimal stimulation duration depends on the targeted area,

because a difference in the duration of effects is seen when distinct areas are compared (14). In

the first studies using cathodal tDCS as a treatment for epilepsy patients, a standard stimulation

duration of 20 minutes was used and this provided significant beneficial effects

(16,25,26,27,29). Since 2012, different protocols were explored, decreasing duration by half or

increasing it to 30 minutes and combining multiple sessions (1,28,30,31).

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2.3 Repetition rate & frequency

Besides extending stimulation duration, there is the option of administering more than one tDCS

session, in order to prolong the after-effects (1,30). The interval between the sessions is

determinative in these protocols. Nitsche et al. described how long the interval should be to

avoid a prolongation of the after-effects and this depends on the stimulation duration of the first

session: tDCS application of 4 seconds only needs a break of 10 seconds between the

stimulation sessions; when short-lasting after-effects of around 10 minutes are induced, a one-

hour break is necessary; and when long-lasting after-effects of one hour or more are effectuated,

the break should last 48 hours to one week (14). When, in contrast, a prolongation and

stabilization of the after-effects is intended, they propose a daily stimulation (14). However,

homeostatic plasticity has been described in the motor cortex of healthy humans, which means

that inhibitory effects were reduced or even inverted in stead of prolonged when, in this case, a

second 5 minute stimulation was applied after a 3 to 10 minute break (24). But when the inter-

stimulus interval was shorter than 3 minutes, after-effects lasted up to 30 minutes in stead of 5

minutes and were thus clearly prolonged (24).

Zoghi et al. implemented the 9-20-9 protocol, where 2 stimulations of 9 minutes are separated

by a 20 minute break, in a drug-resistant temporal lobe epilepsy patient. Here as well, elongation

of the after-effects was described, namely a significant reduction in seizure frequency, lasting

up to 4 months (30). Originally, Monte-Silva et al. explored the optimal inter-stimulus interval

for cathodal tDCS in the motor cortex of 12 healthy humans, and developed 5 treatment

protocols, including the one that Zoghi et al. applied (40). The 9-0-9 protocol elongated after-

effects from 60 minutes (after one 9 minute session) to 90 minutes (40). In both the 9-3-9 and

9-20-9 protocols, the second session is delivered during the after-effects of the first stimulation

and this might cause antagonistic homeostatic plasticity effects as stated above, but in this trial,

it led to prolongation of the after-effects from 60 to 120 minutes (40). Moreover, the amplitude

of excitability-reduction was about 15-20% higher in the 9-20-9 protocol than after a single 9

minute stimulation (40). When the second session was administered after the after-effects of the

first session, that is, in the 9-3h-9 and the 9-24h-9 protocol, excitability-reduction was first

attenuated or abolished, but finally re-established (40). Conclusion of this study was that the

optimal inter-stimulus interval to prolong and magnify the after-effects, would be to deliver the

second stimulation session during the after-effects of the first session (40).

Studies investigating the options of varying the number of stimulation sessions in order to

improve efficacy of cathodal tDCS were not found. Yook et al. applied 10 sessions of 20

19

minutes with an interval of at least one day, using a current of 2mA, to a drug-resistant epilepsy

patient. They showed significant diminution in seizure frequency and duration, lasting at least

2 months (26). Faria et al. used EEG electrodes to deliver 3 sessions of 10 minutes on one day,

but with an unknown interval, and demonstrated significant epileptiform activity reduction only

during tDCS (28). Both studies however, were not sham-controlled.

3. Other factors that affect clinical efficacy

3.1 Patient characteristics

Interindividual differences in effect are seen while using the same stimulation parameters. Sex

differences are described in cathodal tDCS: in some studies the treatment seems more effective

in men, while in other, efficacy is higher in women (14,31). Excitability-diminishing after-

effects of cathodal motor cortex stimulation significantly lasted longer in women than in men

and likewise, excitability decrease during short-lasting cathodal tDCS was stronger in women

than in men (41). An explanation for the observed sex differences in this study could be that sex

hormones interact with cortical plasticity modulation (41). In women with normal menstrual

cycles, progesterone rises in the luteal phase and in this period, stronger cortical excitability-

reducing effects were seen in a TMS study, whereas in the mid-phollicular phase (when

estradiol rises) there was less inhibition and more facilitation (41). Furthermore, in female

epilepsy patients, seizures can exacerbate in the premenstrual phase and this could be explained

by the temporal decrease in progesterone level (41). Another study, on utilitarian behaviour,

states that the male-female difference in anatomical, functional and neurochemical (e.g. the

dopaminergic system in the frontal cortex) brain organisation might lead to distinct effects of

tDCS in men compared to women (42).

Chaieb et al. however, demonstrate that cathodal stimulation of the primary visual cortex does

not lead to sex differential outcomes, in contrast to anodal stimulation, which causes

significantly stronger excitability-enhancement in females 10 minutes after application (43).

They declare that the dissimilarity with the effects in the motor cortex might come from the

different functioning of both structures. The primary motor cortex sends signals to the

periphery, while the primary visual cortex receives information from the periphery, linking it

to other information from distinct cortical areas and thus multiple neurotransmitter receptors

are involved in these projections, which can modulate stimulation effects in a different way

20

than in the primary motor cortex (43). A more detailed explanation of sex hormone’s roles in

cortical excitability modulation is provided in this study: estradiol elevations lead to more

activation of neuronal sodium channels and consequently a higher recruitment of excitatory

interneurons, whereas progesterone increases inhibition through modulation of GABAA-

receptors (41,43). In animal studies, morphological changes of pyramidal cells in the

hippocampus are seen during menstrual cycles, suggesting an influence of steroid hormones at

synaptic level and not only on interneurons (43).

Age differences have not yet been significantly reported and proved, but cannot be ruled out

(14). Interindividual variations in general could among others result from patient-specific

differences in the electrical field that has been produced in the brain, because of personal

anatomical characteristics (44). The most important element determining electrical field

strength is the thickness of cerebrospinal fluid layers: the more voluminous the fluid, the lower

the electrical field (44). Older patients tend to have more extensive amounts of cerebrospinal

fluid and this might influence the effect of tDCS (35,44). In paediatric patients in contrast,

vascularisation of the fontanels is higher than in adults and the extent and age of suture closure

can differ between patients as well. These could have an impact on tDCS effect too (35).

In 2011, the first sham-controlled trial of cathodal tDCS in children (6-11 years of age) with

epilepsy was conducted, but it did not show any epileptiform activity reduction (27). The

investigators clarify that this could be explained by the possibility that tDCS’ mechanism lays

in reducing propagation of epileptiform activity, and that this effect was missed due to the

smaller stimulation electrode that was used (27). In 2013, Auvichayapat et al. executed a RCT

in 36 children (6-15 years of age) with drug-resistant focal epilepsy and proved efficacy of

tDCS using similar parameters as in an adult population (one session of 20 minutes with 1mA)

(29).

3.2 Condition and activity of the brain

Analysis of multiple studies has shown that the previous, actual and future activity of the

targeted brain area or another area can interfere with the stimulation effect (14). For example,

when the motor cortex is stimulated, the effect could be abolished by a substantial activation of

that area or another (14). tDCS is a neuromodulatory technique, this means that in anodal

stimulation, it makes neurons reach their threshold more easily when the membrane potential

is close to the threshold, that is, when the neurons are already activated to some extent because

the patient is using that brain area (45). No specific experiments have been performed applying

21

cathodal tDCS in epilepsy patients, while executing a certain cognitive task. Fertonani and

Miniussi show that a neuronal network as a whole is more easily affected by tDCS than one

single neuron (45). Thus the activation grade of a network influences stimulation effects and

could even revert them (45). Likewise, when 2 neuronal networks are stimulated by tDCS

because they overlap neuroanatomically, the network with most ongoing activity will be

activated (45). In that way, brain activity could cause spatial differences in effect as well (45).

The investigators state that the ongoing network status and its topology are of such importance,

that they have a greater influence on the stimulation effect than the stimulation polarity used

(45).

Varga et al. investigated the effect of tDCS in electrical status epilepticus during slow sleep,

with the aim of testing whether tDCS could interrupt ongoing epileptiform activity, for example

in patients with status epilepticus (27). The results however were disappointing, since no

epileptiform activity reduction was seen (27). An animal trial in contrast, did prove tDCS’

ability to suppress acute seizures in rats (46). Yet, no proof of efficacy of tDCS in status

epilepticus human patients has been provided up to date (27).

The condition of the brain might have an influence as well: various types of lesions imply

distinct anatomical and/or functional alterations (20). Skull deformities will alter current flow

in a different way than stroke or traumatic brain injuries for instance. The latter are 2 examples

of injuries causing local accumulation of cerebrospinal fluid, which will shunt current flow and

thus change stimulation effect (20). Malformations of cortical development are a common cause

of drug-resistant epilepsy and since these patients frequently are not suited for surgical

treatment, tDCS might be an interesting alternative (25). Fregni et al. proved in their RCT that

the technique was well-tolerated in the 19 subjects, and a significant seizure frequency

reduction was shown (25). Yook et al. investigated the effect of tDCS in an 11 years old epilepsy

patient with focal cortical dysplasia, mental retardation and microcephaly. Here as well, a

significant reduction of seizure frequency was demonstrated up to 2 months after tDCS (26).

However, in both studies no comparison between patients with cortical malformations and

epilepsy patients with normal cortical development was made, and in the latter, stimulation

effects were not compared to sham stimulation effects to rule out placebo effect (25,26).

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3.3 Practical factors

The conductive solution used on the electrodes may have an influence on stimulation efficacy.

When EEG electrodes are used for tDCS, an EEG gel is applied in stead of the conventional

saline solution. A lower electrode-skin impedance is seen in this model, as well as a more stable

electrical connection to the scalp (28). Decreasing salinity of the electrodes indeed leads to more

homogeneous distribution of the current and diminishes peak current concentration at the edges

of the pads (20). Designing electrodes with more appropriate shape and material could

contribute to increased stimulation strength and focality (20). Likewise, preparation of the skin

before stimulation lowers resistance and causes a more homogeneous electrical field under the

electrode (14). The impact of these practical factors on the outcomes of tDCS in epilepsy

patients has not been described yet.

4. Safety and side effects

Nitsche et al. investigated in 2008 the safety of using tDCS in healthy individuals. They

concluded that the most frequently used stimulation parameters at that time, which were a

maximum current density of 0,029mA/cm2 and maximum stimulation duration of 13 minutes,

did not cause significant side effects like skin burn, tissue damage or cognitive distortion (14).

Only minor side effects such as local itching, fatigue, headache and nausea had incidentally

been reported (14). More frequently, a slight itching sensation was noted at the beginning of

stimulation, but this faded in most cases (14). Although an electrical field could actually cause

tissue damage due to electrolysis, pH disturbance and protein modification, the brain can avert

this because of its high perfusion level and buffering capacity (14).

However, these safety results are not assured in all situations. Tissue damage can for example

be caused by tDCS application on foramina, open fontanels or skull defects, because current

flow is focused on a smaller area with thus a higher impact when current density is large enough

(14). Prolonged stimulation duration could compromise safety, but in this study, no cognitive

or emotional distortion was reported after a 50 minutes lasting stimulation (14). Correct

electrode positioning is also important in preserving safety. When for example the brain stem

is affected, this could have dangerous consequences (14). Current strength should be maintained

to provide a constant electrical field. This means that the device needs to be able to notice when

tissue resistance decreases and to adapt current strength, so the tissue does not receive

23

dangerous and possibly painful peak levels (14). Stimulation frequency and interval as well

have to be well controlled to maintain safety. And finally, the patient’s condition and the person

executing tDCS can influence safety: a licensed and well-trained doctor should perform the

stimulation (14). One example of a patient in non-optimal condition described in this review is

a patient with skin disease, which could cause significantly more skin irritation under the

electrode and therefore skin control before stimulation is necessary (14). The slightly red skin

that sometimes appears afterwards, is not always a sign of skin irritation. If only redness is seen,

this points more towards simple vasodilatation (14).

In 2009, Nitsche et al. published a study about the effect of tDCS in epilepsy patients. Here as

well, only mild side effects such as headache and tiredness were seen (16). Seizures could be

induced through cathodal stimulation, because locally under the anode, excitability is

augmented and these patients are possibly more vulnerable. Nevertheless, no evidence of this

adverse effect was found not in animals, nor in humans (16). The conclusion of Fregni et al.’s

RCT was that cathodal tDCS did not cause seizures in patients with drug-resistant epilepsy and

that it was well-tolerated in these patients (15). In their review, they determined that the

technique is also safe in paediatric patients (15). Even in a case report of a drug-resistant

epilepsy patient with focal cortical dysplasia, mental retardation and microcephaly, it was

shown that no seizure induction or other side effects occurred (26).

However, seizure induction through cathodal tDCS cannot be ruled out completely. Yet the risk

can be reduced by using a large or extracephalic reference electrode (16). In 2011, a systematic

review on safety and side effects of tDCS was conducted and the conclusion was that only

minor and few side effects were found in healthy humans after one or 2 stimulation sessions,

but almost half of the trials did not describe presence nor absence of side effects, and this points

towards a selective reporting bias (47). Of all studies that wrote about side effects, 37% declared

that there were none (47). The side effects that were found are, in order of frequency: itching

in 39,3%, tingling in 22,2% (this was seen more when small electrodes were used), headache

in 14,8%, burning sensation in 8,7% and discomfort in 10,4% (47). Most serious side effect

identified in healthy humans was skin lesion at the site of the electrode, when a current strength

of 2mA was used (47). More severe effects such as brain damage were only seen in rats, when

stimulated with a 100 times higher stimulation strength than applied in humans (47). Diffusion-

weighted magnetic resonance imaging (DWI) can show limitation in water diffusivity and this

would indicate deficient ion homeostasis and evolution of brain oedema (48). No evidence of

brain oedema, neither structural alterations of brain tissue or blood-brain barrier was seen in

this study (48).

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5. Long-term outcomes

San-Juan et al. state that a single cathodal tDCS session, using standard stimulation parameters,

induces effects that last for one to 48 hours (15). In the attempt of using tDCS as a treatment

for drug-resistant epilepsy, longer-lasting effects are off course required. In table 1 however,

seizure frequency reductions persisting up to one month have been reported after a single

session and even longer lasting reductions are seen after multiple sessions (1,16,26,29,30,31).

Assenza et al. explain that their one month lasting clinical results are substantially longer than

the proven excitability-diminishing effects of cathodal tDCS in the cortex and that this might

come about through other local anti-epileptic mechanisms, for example inhibitory gene

expression and long-term modulations (1). Yook et al. applied cathodal tDCS with a 2mA

current, stimulating 10 sessions spread over 2 weeks, 20 minutes per session, in a drug-resistant

epilepsy patient with focal cortical dysplasia (26). Two months post-therapy the patient only

had 6 seizures, whereas before treatment, she would have had about 16 seizures in 2 months

(26). After those 2 months, again the same stimulation protocol of 2 weeks was performed and

the outcomes had even more improved: only one seizure was reported in the following 2 months

(26). Another treatment protocol, where 2 sessions of 9 minutes, separated by a 20 minute break,

were delivered to a drug-resistant temporal lobe epilepsy patient, even resulted in seizure

frequency reduction that persisted for 4 months (30). However, both studies were not sham-

controlled. The latest evolutions in stimulation parameters tend towards stronger protocols, and

this is demonstrated in the most recent study in table 1: tDCS was performed for 30 minutes,

repeatedly in 3 sessions, with a current of 2mA, and the authors refer to this protocol as

‘modulated tDCS’ (31). No side effects were reported and a highly significant seizure reduction

was seen, but these effects did not last longer than one month and thus no profit on the long-

term outcomes was caused by this modulated tDCS protocol (31).

25

Discussion

The perfect treatment for drug-resistant epilepsy, would be one that is adapted to each specific

patient, based on knowledge of the disease mechanism, precisely proceeds against the affected

brain area so no adverse effects occur, and would be acceptable in all ways, highly effective

and financially feasible (10). Off course the perfect therapy does not exist, but the goal should

be to get as close as possible. Therefore, the currently known factors influencing tDCS efficacy

are assembled in figure 1, and several aspects of the tDCS treatment will be discussed in this

section.

Figure 1: Schematic overview of factors related to the efficacy of tDCS

1. How to further investigate the neurobiological mechanisms After interpretation and integration of multiple studies, the conclusion is that the complete

picture of the neurobiological mechanisms of cathodal tDCS is still far from revealed. We know

that through sodium and calcium channel blocking, neuronal cell membrane potential is

hyperpolarized and excitation threshold elevated (19). Longer-lasting cathodal stimulation

induces after-effects that come about through synaptic plasticity changes in particular, and these

consist among other things of postsynaptic glutamate concentration and NMDA-receptor

activation reduction, which leads to a decrease in calcium influx and thus excitability

diminution (13,14,19). These 2 mechanisms explain how cathodal tDCS can lower neuronal

26

firing rate and thus seizure induction, but there are different sublevels of explanation which

interact with one another and there are still many unknown interactions. Step by step researchers

discover more parts of the process, but the complexity is enormous and much more research is

needed to fully understand the whole. That is why resulting stimulation effects are often

unpredictable and not just the sum of their parts (45).

There are still important gaps in the understanding of the mechanisms. Many studies are

executed in the motor cortex, such as the study about mechanisms of excitability changes from

Nitsche et al. and the study about homeostatic plasticity from Fricke et al. These results may

differ from experiments in other cortical areas, due to anatomical and functional diversity.

Specific research on the mechanism of action in the different cortical areas would be interesting.

Postsynaptic plasticity changes can be investigated through pharmacological studies, but

presynaptic mechanisms might play an important role too and these are not unravelled yet. The

same applies to the effects of tDCS on glial cells: anodal stimulation activates astrocytes all

over the brain, which causes intracellular calcium elevation and contributes to metaplasticity

changes, but the effect of cathodal tDCS on glial cells has not been investigated so far (21). It

might cause opposite effects on astrocytes than anodal tDCS, meaning an intracellular calcium

reduction and thus plasticity inhibition, but this is only hypothetical. Therefore, more broadly

oriented research is required, with focus on other components than only the neuronal cells.

The role of exctitatory (glutamate) and inhibitory (GABA) neurotransmitters in the induction

of inhibitory plasticity through cathodal tDCS has been revealed, but other neurotransmitters in

the brain seem to interact in this process too. Their exact effects are not sufficiently studied yet,

although they could become important when tDCS is used in practice as an epilepsy therapy.

Serotonine for example, appears to convert the inhibition into facilitatory plasticity (20).

Consequently, when an epilepsy patient simultaneously suffers from depression and takes

antidepressant medication such as serotonine-reuptake inhibitors (e.g. citalopram), these could

counteract the tDCS treatment (15). Serotonine-reuptake inhibitors are only one example of

medications influencing the effects of tDCS. Hence more research is needed to confirm these

results and to explore the mechanism of interaction of different neurotransmitters in inhibitory

plasticity induction and perhaps on membrane hyperpolarization through cathodal tDCS.

Potential medication interactions can then be understood and predicted.

Some factors that interfere with clinical efficacy of tDCS are described in this study, but more

could be discovered. More detailed knowledge about the correlation between the

neurophysiologic mechanism and its effect on neuronal functions, to be able to optimize tDCS

application in practice, could be acquired by combining tDCS with neurophysiologic mapping

27

methods and brain imaging, for example electroencephalography (EEG), functional magnetic

resonance tomography (fMRI), anatomically accurate high resolution MRI and positron

emission tomography (PET), and this will be discussed later (14,35,37). Magnetic resonance

spectroscopy (MRS) is a non-invasive imaging tool that can detect alterations in cortical

neurotransmitter concentrations in a specific region of interest (22). Plausibly, this technique is

sensitive to functionally relevant changes in concentration, which would be around 10% of the

total neurotransmitter concentration, as it has already shown that cathodal tDCS causes

reduction in glutamate- and GABA-levels (22). MRS could therefore be interesting for example

in research on the influence of other neurotransmitters on tDCS effects and the interactions with

pharmacological treatment.

2. Optimal management protocol

In the 1960s, when the first studies about cortical direct current stimulation were performed in

animals, researchers already discovered that anodal currents enhance neuronal excitability and

cathodal stimulation reduces neuronal activity (16,49). Bindman et al. used a glass micro-

electrode to deliver currents of 0-1µA to rat’s brain during 5-10 minutes and concluded that

after-effects could last for 1-5 hours (49). These were interesting results, but still far from the

ideal, patient-specific epilepsy treatment. In the last decades however, research has been done

to develop optimal treatment protocols with the right parameters for humans. Present findings,

as listed in table 1, will be discussed here.

2.1 Electrode position & size

Varga et al. described the electrode positions by using EEG findings: the area of peak negativity

is the area with the highest grade of excitability, which corresponds to the epileptogenic focus.

Hence, this is the correct site for cathode placement and vice versa. Auvichayapat et al. and

Assenza et al. tested tDCS with anode position respectively on the contralateral shoulder and

on the contralateral homologous region in patients with drug-resistant focal epilepsy. The

sample size of the latter was too small to provide high evidence on the accuracy of the

extracephalic reference electrode position, but both studies were compared to sham stimulation

28

(Auvichayapat et al. conducted a RCT) and showed a significant reduction in seizure frequency

(1,29). This suggests efficacy of this montage, but needs further exploration. In most studies in

patients with temporal lobe epilepsy thus far, the anode is placed on the contralateral

supraorbital region. Beneficial results are seen in these studies, but as temporal lobe epilepsy is

one of the most common types of epilepsy, the correct electrode placement needs to be defined

more in detail.

tDCS with the conventional electrodes implies low spatial resolution and therefore, a

stimulation model has been designed to increase focality, by ameliorating both electrode

position and size (35). A ring electrode configuration was developed, with one central

stimulation electrode and 4 surrounding reference electrodes, each at 3cm distance from the

central electrode and all electrodes were circular and had a size of 0,5cm2, as shown in figure 2

(35). This montage can improve focality because of the smaller electrode size, better positioning

Figure 2: conventional tDCS versus HD-tDCS, from Datta et al.35

29

and the ring configuration (35). Peak induced electrical field is located between the electrodes

at an intermediate lobe when stimulated with the conventional electrodes, while with this ring

electrode configuration, it is concentrated at the sulcus and gyri directly underneath the

stimulation electrode (35,37). In this study, the design was tested on human brain models and

results were interesting, demonstrating an equivalent induced electrical field magnitude by

conventional stimulation with 1mA and stimulation with this montage using a current of 2mA.

This might indicate that this model could be safe and more focal at the same time (35). In

another study it is called high definition tDCS (HD-tDCS) and it is applied in 24 healthy humans

to investigate its influence on pain perception (37). Just like in the previous study, a 2mA

current was delivered to the motor cortex, only here the distance between stimulating and

reference electrodes was enlarged to 7cm and the electrode size was 1,13cm2. Again promising

results were seen, without concomitant side effects (37). It should be noted however, that in

both studies anodal tDCS was applied in stead of cathodal, and not in epilepsy patients. This

may alter the results; thus more specific research is necessary to elaborate this stimulation

method with improved focality. Faria et al. used one stimulating EEG electrode and 3 reference

EEG electrodes (all had a size of 1,1cm2) to deliver a 1mA current at 2 epilepsy patients and

they obtained beneficial results, but another configuration than the ring montage was used,

which naturally influences results (28).

It is important to realise that at this point, complexity is too high to create ideal patient-specific

electrode montages. There is evidence that current could concentrate at the edge of gyri, causing

inhomogeneous distribution of the electrical field; more distant neurons can be affected through

connections with stimulated neurons; tissue characteristics and neuronal orientation specific to

the stimulated brain area could alter outcomes; depending on electrode position, current is

shunted to some extent through skin and skull; and finally even inexplicable factors contribute

all together to unpredictable stimulation outcomes, using a certain montage in a certain patient

(20). Therefore, as long as not all interacting factors are completely revealed and understood, it

seems a better option to focus on development of computational models. These can serve as

tools for research on this topic, but could also provide the possibility to adapt electrode montage

to each specific patient, before the onset of treatment (20).

Faria et al. came up with the idea of using EEG electrodes for stimulation and recording at the

same time (28). The combined EEG-tDCS application could enable quantification of interictal

events, but especially the continuous recording of epileptiform activity during stimulation could

provide the opportunity to control safety and efficacy during treatment and adjust the electrode

placements if necessary (28). Since it is not possible with current technologies to calculate

30

distribution of the electrical field in a patient’s brain and this varies between patients and is thus

unpredictable, this might be an interesting option for determining electrode position in each

patient individually. Current density under the electrode in this montage however, is more than

10 times higher than in previously used stimulation protocols. In these 2 patients it did not cause

any adverse effects, although it should be noticed that therapy was performed while the patients

were asleep (28). In this experiment, 3 electrodes were placed close to each other above the

contralateral eye brow, because this is the common anodal site for stimulating central areas and

no epileptiform activity was seen in this region. The cathodal electrode was placed at site CP5

on the left hemisphere, which corresponded to the area with epileptogenic foci (28). The

purpose of utilising one cathode and 3 anodes is to reduce the intensity of anodal stimulation,

since current density is higher under the single cathode than under the ‘large’ anode, and this

enables more focal stimulation (28). The smaller electrode size per se, contributes to the more

focally delivered treatment, but the main advantage of this method is that all electrodes can be

placed close to the scalp projection of the epileptogenic focus and also close to each other,

which increases efficacy of stimulation and sensitivity of recording (28). Nonetheless,

disadvantageous effects of the higher current density and electrical field cannot be excluded

based on this study.

Tekturk et al. applied conventional tDCS in 12 temporal lobe epilepsy patients, but they

determined seizure focus more precisely, by combining EEG findings with cranial MRI (31).

Varga et al. visualised the focal epileptiform discharge on a 3D voltage-map, to exactly locate

the electrodes (27). The concordant use of EEG and specialised imaging techniques to define

optimal electrode positions, might be an even more detailed localisation method. Cancellli et

al. conducted an experiment using MRI human head models of epilepsy patients, in order to

increase efficacy of HD-tDCS by testing distinct electrode montages and thus personalizing

stimulation parameters (50). Guided by a real EEG session, the electrodes were placed at the

correct site and a 2mA current was delivered to the epileptogenic focus, and this yielded the

desired results (50). However, according to Brunoni et al., employing the EEG 10-20 system to

determine electrode position is appropriate when the conventional electrodes are used, but when

focality is increased (e.g. HD-tDCS), this might not be sufficiently precise and new techniques

could be interesting (20). Datta et al. therefore developed a gyri-precise MRI derived finite

element human head model with high spatial resolution of 1mm3 to calculate the induced

electrical field and/or current density and to further optimize tDCS (35).

Finally, a remark about the anode position should be made. The excitation-enhancement under

the anode can be partially obviated, but maybe it is possible to derive benefit from the anodal

31

effects (20). Epilepsy patients run higher risks in developing cognitive deficits, due to multiple

seizures and concomitant brain damage (51). Ongoing research in VNS and DBS now focusses

on treating the cognitive deficits as well as the epilepsy. Perhaps this is possible with tDCS too

and maybe it can be accomplished simultaneously, by positioning the cathode over the

epileptogenic focus and the anode over the damaged brain area causing cognitive dysfunction.

This would theoretically be the best electrode placement, but researchers are currently

investigating whether VNS stimulation of the same neuronal network could improve epilepsy

and cognitive dysfunction at the same time. These experiments could be extrapolated to tDCS

research and the correct electrode placement is off course essential.

2.2 Current density & stimulation duration

Both current strength and stimulation duration can be adapted to improve tDCS efficacy, but

Nitsche et al. suggest that the best option is to adjust duration, because of the non-linear effects

and potential side effects caused by increased density (14). However, according to Datta et al.,

a current density up to 39,8A/m2 may be applied without pain, and no side effects have been

reported when current density was raised to 9,09A/m2 for example in Faria et al.’s study,

although not enough subjects were included to draw conclusions about safety (28,35). After

Nitsche et al.’s suggestion, not many attempts have been made to elaborate stimulation duration

as the variable parameter to determine efficacy: in most studies, patients were treated for 20

minutes. Tekturk et al. delivered tDCS for 30 minutes and acquired significant long-lasting

beneficial results compared to sham stimulation and no side effects, yet it should be noticed

that current strength was also increased to 2mA and 3 sessions were provided in this protocol

(31). The studies that stimulated for 9 or 10 minutes also obtained significant beneficial

outcomes, but again comparison is not possible because current density and the number of

sessions varied between these and other studies (1,28,30). Moreover, the minor number of

subjects in each study, the lack of multiple RCT’s and the fact that outcomes of one stimulated

brain area cannot be extrapolated to another brain area, further impede comparison of currently

conducted studies and making deductions about utility and possibilities of stimulation duration

as the parameter to define efficacy.

On the other hand, if it would be possible to verify the appropriate values for current density

that provide optimal treatment efficacy along with safety assurance, this may be more

convenient for patients, because longer stimulation sessions might make the therapy less

feasible. tDCS application e.g. for one hour in stead of a few minutes would be less comfortable

32

for patients and would have a greater impact on their daily life and quality of life. Furthermore,

longer stimulation duration can prolong after-effects, but a saturation effect has been shown as

well (40).

.

2.3 Repetition rate & frequency

An animal study in a genetic absence rat model mentioned the importance of the interval

between 2 consecutive stimulation sessions in the induction of after-effects, but no concrete

values had been defined (39). Monte-Silva et al. stated that most maximization of after-effects

can be obtained when a second session is applied during the after-effects of the first session, so

when stimulation is performed during around 10 minutes, the inter-session interval should

amount 3 to 20 minutes (40). Analysis of table 1 confirms this theory, since Zoghi et al.

implemented the 9-20-9 protocol and obtained the longest-lasting results of all listed studies,

that is a 75% seizure reduction, lasting for 4 months (30). Faria et al. applied 3 sessions of 10

minutes on one day and they only acquired significant epileptiform activity reduction during

treatment (28). Since the inter-session interval is unknown, this might amount more than the

duration of the after-effects of the previous session (that is one or several hours) and this could

perhaps explain the short-lasting effects of the therapy, although this cannot be proved. Yook

et al. implemented a stimulation protocol with inter-session intervals of at least one day, but

they used a 2mA current in 10 sessions of 20 minutes and this combination led to after-effects

of at least 2 months (26). Moreover, after these 2 months, a second treatment of exact the same

protocol was performed and results hereafter were even better (cfr. Supra) (26). This suggests

that more permanent alterations in the brain, persisting at least 2 months, can be inflicted by

tDCS. It should be noted however, that both trials were not sham-controlled and consequently,

the significant effects might imply placebo effects as well.

Investigation on this topic would be interesting because it could clarify another issue as well:

when a second tDCS session is delivered during the after-effects of the first one, either

antagonistic homeostatic effects that decrease or invert excitability-reduction, or a prolongation

and intensification of the excitability-reducing after-effects might occur (24,40). This obviously

modifies treatment efficacy to a great extent and it is not clear yet how these completely

different outcomes can develop when similar inter-session intervals are used.

The optimal number of stimulation sessions in an intended patient treatment protocol remains

unclear. Most trials in epilepsy patients up till now aimed to investigate the effect of tDCS per

se by executing one stimulation session, but they did not yet try to develop a protocol for chronic

33

treatment of epilepsy patients. Further elaboration of this parameter is thus necessary before

tDCS can be applied in practice. Increasing the number of treatment sessions might as well

ameliorate efficacy and duration of the after-effects, since Yook et al. obtain 2 months lasting

after-effects after 10 stimulation sessions (26).

In the exploration of the ideal treatment protocol, the most advantageous combination of these

2 parameters should be investigated: how many sessions should be delivered on one day, while

every next session is delivered during the after-effects of the previous one, and how many days

should this be repeated? Perhaps patients will be able in the future to choose whether they rather

receive several sessions on one day, or rather one session a day, spread over several days, in

order to make the therapy as feasible and patient-adapted as possible. Perhaps however, adverse

effects will emerge when too many stimulation sessions are delivered in total? Or in constrast,

maybe the brain will adapt after receiving a certain amount of current and alterations could

cause even more efficient stimulation on the long term? These are important questions to be

resolved.

3. Other factors that affect clinical efficacy

Nitsche et al. propose to control the state and activity of the patient’s brain before, whilst and

after the therapy, and to avoid incidental interference (14). However, it could be seen from a

different point of view: maybe tDCS can be used as a therapy in combination with patient’s

brain activity. It is to say, the patient could be given a certain cognitive task to execute and

tDCS is then used as a co-stimulation technique. For other neurological disorders needing

anodal tDCS, this seems a feasible treatment option: the neuronal network of interest is partly

activated by the patient executing a certain task, and since tDCS affects neurons that are close

to their threshold, it could provide the final needs to fire the right neurons. For drug-resistant

epilepsy however, when cathodal tDCS is needed, it is not as simple. Hyperpolarization of a

certain neuronal network is the desired effect and it is not sure yet whether and how patients

could contribute to this. Researchers are investigating if maybe the excitability-enhancement in

a certain brain area, caused by the epilepsy, could be used and converted into activation of

another area, for instance to trigger speech. Another path of investigation is that perhaps

stimulation should be performed inter-ictally, to reward and promote the excitability-reduction.

These are only hypothetical theories, but they should be considered valuable paths to explore,

for several reasons. If it would be possible to let the patient contribute in the intended neuronal

34

modulation, perhaps a lower current intensity of tDCS will be necessary, which would make

therapy safer. Possibly, the patient could help to affect the correct burden of neurons by

executing a certain cognitive task and thus help in the determination of spatial focality, although

this is only a hypothesis. But the most important reason is, that this sort of patient co-operation

is not harmful in any way. Pharmacological help can cause side effects, more invasive methods

bring along disadvantages of the surgery, but this approach has none of all.

Kuo et al. described the effects of progesterone and estradiol on cortical excitability and thus

tDCS efficacy (41). More evidence is needed to prove that these hormones significantly

influence tDCS effects, but suppose they do, this should be considered when applying therapy

in female patients. Maybe, women using hormonal contraception should be treated differently

and therefore, it could be useful to verify this before treatment. Or maybe it could be profitable

to apply tDCS in female patients at a certain stage in their menstrual cycle. These hypotheses

need further investigation.

Cathodal tDCS in the human motor cortex has shown higher efficacy in women, in multiple

studies (41). Cathodal tDCS in the human visual cortex however, did not show any sex

differences in effects (43). And lastly, cathodal tDCS in the temporal lobe of patients with

temporal lobe epilepsy indicated higher efficacy in male patients, although only 10 subjects

were included in this experiment and this might imply a minor grade of evidence compared to

the other 2 studies (31). In any case, it is clear that the impact of gender on tDCS efficacy is not

clarified yet. Research on stimulation of the visual cortex might be less interesting for epilepsy

treatment development, thus specific RCT’s in epilepsy patients are needed. Kuo et al. analysed

multiple tDCS trials, but only trials where tDCS was conducted in the motor cortex of healthy

humans and not of epilepsy patients (41). Chaieb et al. as well, explored tDCS’ effectual

differences between male and female healthy subjects (43). Fumagalli et al. delivered tDCS in

the ventral prefrontal cortex and occipital cortex of healthy humans, to study the effect on

utilitarian behaviour and the difference in effect between men and women, so the outcomes

were expressed in changes in utilitarian behaviour and this obviously cannot be extrapolated to

outcomes in epilepsy patients expressed in seizure reductions. Nonetheless, the general idea of

variations between men and women in functional brain organisation that might cause

differences in tDCS efficacy, is still a plausible theory (42).

Effectual differences caused by age cannot incontestably be proved, but perhaps the few

indications in that direction can be explained as follows. The effect of tDCS is dependent on

the condition of the brain before stimulation: When the brain is damaged somehow, it will not

optimally function again after tDCS, exactly alike a healthy brain. When people grow older,

35

their brain will degenerate to some extent and maybe this could underlie the difference in effect

between older and younger patients.

Varga et al. executed an experiment with tDCS in 5 children with drug-resistant continuous

spikes and waves during sleep, to investigate whether tDCS can interrupt ongoing epileptiform

activity and they used a smaller stimulation electrode (27). Since these 3 aspects all deviate

from the usual tDCS trials in epilepsy patients, no conclusions can be drawn about which aspect

that influences the effects to the greatest extent. A RCT in children with drug-resistant focal

epilepsy, stimulated with conventional electrodes, would provide more conclusive information.

Knowledge about patient characteristics that might influence the effect of cathodal tDCS is very

limited, especially when specifically applied in drug-resistant epilepsy patients. Age and gender

impact should further be explored and other factors should be considered as well. Perhaps socio-

economical status has a predictive value concerning tDCS outcome, or the time span that the

patient lives with the epilepsy, or smoking, or other habits. Detailed investigation on this topic

could be useful to develop patient-specific treatment protocols.

4. Safety and side effects

According to animal and human study results available so far, the current management

protocols are safe in healthy humans (14). In drug-resistant epilepsy patients however, not

enough experiments are effectuated to provide evidence of safety, and especially not in patients

with other neurophsychiatric comorbidities. More studies with non-healthy patients reported

side effects than studies with healthy patients, which also suggests that more research in non-

healthy patients is needed (47).

Reporting bias could be explained by the general thought that tDCS is a safe technique without

many side effects and therefore, researchers do not think it is necessary to thoroughly

investigate this in all populations (47). Nonetheless, safety of this therapy in different drug-

resistant epilepsy patients using distinct management protocols with for example daily sessions,

is not yet clearly defined. Brunoni et al. state that this topic should be interrogated actively and

they propose utilisation of a questionnaire that contains specific questions about side effects

that the patient did or did not experience (47). An issue in these experiments is the objectivity

of reporting: what does a patient understand by ‘tingling’ for instance. Description and severity

of the side effects will be reported differently in various patients. For that reason, objective

parameters are required as well. Tissue damage can be suggested by alterations in microglial

36

ED1 marker (anti-CD68 antibody) in the brain - through immunohistochemical assays thus not

in vivo - and alterations in serum neurone-specific enolase level (14,15). The latter only

indicates neuronal damage and this is off course not the only potential harmful consequence of

tDCS. Apparent diffusion coefficient (ADC) maps can be calculated from a MRI image of the

brain, pixel-by-pixel with a software program, and it is an indicator of tissue damage as well.

However, ADC is dependent on water diffusivity and tissue damage can be independent of this

(48). MRI provides several applications to test brain integrity after tDCS and can be useful in

further experiments on safety and side effects of the therapy: contrast-enhanced MRI, T1-, T2-

and diffusion-weighted MRI (DWI) are some possibilities (48).

Faria et al. were the first to conduct a trial combining tDCS with simultaneous EEG recording

(28). This method could be helpful in the future, because important information about the effect

of tDCS during stimulation can be gathered. Consequently, conclusions about safety can be

drawn more precisely and stimulation parameters can be adapted during tDCS application, at

that moment when the physician notices that safety is about to be compromised or the effects

are not what they should be. Study results were promising, but only 2 epilepsy patients were

tested and that is not sufficient to be certain about the quality and utility of this technique. Also,

an almost 6 times higher electrical field was produced when using the EEG electrodes for

stimulation and although it did not cause any problem in these 2 patients, it still needs

consideration before widespread use of this method (28).

Besides questionnaires, markers of tissue damage, MRI and EEG, safety and side effects can

further be estimated by performing cognitive tests and observing clinical symptoms after

therapy (14). Utilisation of all these techniques should provide more conclusive information

about tDCS safety with current management protocols, as well as with other potential protocols

and in distinct patient populations.

When safety and side effects of tDCS are compared with pharmacological treatment and

surgery, the conclusion can be as follows. The essential difference between drugs’ and tDCS’

mechanism of action, is that the latter operates locally, whereas anti-epileptic pharmaca affect

and supress the whole brain and could cause impairment of functioning, such as cognitive

impairment (16). In surgery as well this could be caused, if a healthy part of the brain is damaged

during the operation, and this among others, makes tDCS a safer therapy than brain surgery

(16). Both focality and non-invasiveness are advantageous aspects of tDCS concerning safety

and side effects.

37

5. Long-term evolution

As described above, after-effects of maximum 4 months have been reported after tDCS

treatment of drug-resistant epilepsy patients (30). To date, it is not clear yet how clinical after-

effects, meaning the seizure frequency reduction or epileptiform activity reduction, can last that

much longer than the proved after-effects on the cortex. Neither is it clear why in some epilepsy

patients when a certain stimulation protocol is used, improvement is only seen during therapy,

while in others, after-effects last for 4 months. Comparison of the results of currently published

clinical trials in epilepsy patients (listed in table 1) is not accurate for several reasons. First,

both studies that reported after-effects of more than one month, were case studies. The other

trials describing long-lasting after-effects, did not contain many study subjects either, except

for the trial of Auvichayapat et al., which was sham-controlled on top.

The second reason is that the investigations were executed in dissimilar patient populations:

different types of epilepsy, comorbidities and age could influence the outcomes. By extension,

stimulation parameters used in the studies differ as well. Therefore, specific trials should be

conducted in sufficient study subjects with comparable characteristics, testing distinct

stimulation protocols, with the aim of identifying the treatment protocol that causes most

beneficial and longest-lasting after-effects, without significant side effects. Investigation of the

mechanisms of these long-lasting clinical effects would be interesting too, because it could

provide the opportunity to manipulate them. Utilisation of tDCS in practice in epilepsy patients

would become more plausible when more knowledge about the long-term effects will be

gathered. Results on the longer-term of years are even more uncertain and this is logical,

because only a few studies have been conducted up till now and this happened in the last past

years. Possibly, the therapy will be more efficient when it is applied regularly in the same

patient, for several years. Or in contrast, perhaps it causes side effects or disadvantageous

effects on the long-term.

tDCS could be a good treatment option for epilepsy patients for multiple reasons, among which:

the technique is considered safe with almost no serious side effects reported yet. It is

inexpensive and easy to apply, with limited equipment and producing a low current. It is non-

invasive and might also be an alternative for patients with poor drug tolerability, adverse

pharmacological interactions, non-operable patients or specific patient populations, such as

pregnant women (15,20). On the other hand, invasive stimulation methods might have

advantages over tDCS, for instance because in tDCS more than half of the delivered current is

lost in the surrounding tissues without function (7). Therefore, invasive techniques might be

38

more efficient, because the skull does not need to be passed. However, no significant difference

in effect between the various methods of neurostimulation has been described and they all

appear to be safe and have few side effects (5,7,52). Furthermore, implantation of a device

might be more desirable for patients than non-invasive tDCS, because it is not visible nor

disturbing.

Another opportunity for using tDCS is now being explored and elaborated. It could potentially

serve as a diagnostic tool, to identify patients that are suitable for implantation with an invasive

device. In Germany, a minimal-invasive device is being developed, called ‘EASEE’

(Epikraniale Anbringung von Stimulations-Elektroden zur Epilepsiebehandlung). Stimulation

electrodes are implanted between the skull and the skin, connected to a battery on the right

shoulder (subscapular) and connected to a program to set the correct, individual stimulation

parameters. This minimal-invasive procedure is simple and causes few complications (53). The

device is invisible and maybe more feasible for patients than tDCS, especially for long-term

treatment. Nevertheless, cooperation between both devices might provide optimal treatment

opportunities: before implanting EASEE, tDCS could be applied as a predictor, to examine

whether it can cause seizure reductions or EEG epileptiform activity diminution, to verify

whether implantation of EASEE could be an appropriate treatment option for the patient.

tDCS appears a safe therapy, but ethical concerns have arised since this technique is being used

in healthy people for self-improvement. The current source could for example be a simple 9V

battery, so people could easily make the construction themselves by connecting the battery to a

pair of electrodes. This fairly safe, easy, cheap and effective technique could theoretically

enhance cognition, working memory, numerical competence and so on (54). That is why public

interest raises and a ‘do-it-yourself community’ (DIY) has grown (54). Obviously, some side

notes need to be made. This development is not without risk and people without any experience

in tDCS utilisation could for instance place the electrodes in the wrong position, which could

result in unintended effects. It is possible that these undesirable effects last for months, while

the users are not able to reverse them (54). Non-experts are not familiar with the technique, they

cannot adapt the standard protocols to small variants (e.g. left-handed people, individual

variabilities) and cannot always react correctly when something goes wrong. Moreover, they

do not know all possible interactions with other treatments and are not aware of the risks

(54,55). Journalists and scientists promoting tDCS, play a role in the growing DIY-community

process. Only facts and research results should be published, potential risks should be stressed,

and tDCS should not be called a miracle device (54). Researchers state that there is an urgent

need for policy development, to regulate the broad home-use of the device, but on the other

39

hand they suggest that prohibition should not be too strict, so that the DIY-community will not

be driven underground (54). Long-term studies should be performed to obtain more evidence,

and communication between scientists and bioethicists must ameliorate. Finally, the debate

about the acceptance of cognitive enhancement should be conducted. Various ideas for solving

these ethical issues have been proposed, but implementation gives still cause for concern

(54,55).

Conclusion

Transcranial direct current stimulation has come forward as an interesting treatment option for

patients with drug-resistant epilepsy. Promising results have been shown, but no evidence about

the long-term outcomes has been provided yet. The optimal management protocol with

appropriate parameters to deliver patient-specific treatment is a second issue that needs further

investigation, since interindividual variability is seen. Deeper exploration of the

neurobiological mechanisms might be an essential step in this research. Perhaps however, tDCS

could evolve and be developed to apply in other strategies, for example to serve as a diagnostic

tool. It might be useful for screening which patients are in the running for the implantation of

an invasive neurostimulation device. In any case, more research on several aspects is needed

before utilisation of tDCS in practice.

40

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