Seizure: European Journal of Epilepsy 100 (2022) 44–50

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Seizure: European Journal of Epilepsy

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Safety and efficacy of cathodal transcranial direct current stimulation in

patients with Lennox Gastaut Syndrome: An open-label, prospective,
single-center, single-blinded, pilot study
Daniel San-Juan a, *, Axel Galindo Ruiz a, Armando Baigts Arriola a,
Gerardo Quiñones Pesqueira a, Giulio Ruffini b, Carlos Trenado c
a
Clinical Neurophysiology Department, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
b
Neuroelectrics Corporation, Cambridge, MA, USA
c
Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: Lennox-Gastaut Syndrome (SLG) is a severe form of childhood refractory epilepsy. Only one pilot study
tDCS has been conducted using cathodal transcranial direct current stimulation (c-tDCs; 2mAx30minx5days) in LGS
Lennox Gastaut syndrome with promising results (-99% seizure reduction at 5 days). Our aim was to explore and replicate the efficacy and
Seizure
safety of 10 daily sessions of c-tDCs in SLG.
Epilepsy
Methods: We conducted a one-blinded, single-center pilot clinical study of c-tDCs (2mAx 30 min x 10 days),
Transcranial direct current stimulation
Refractory seizure applied over the highest amplitude or frequent epileptiform interictal discharges areas using scalp EEG re­
cordings without changes in their treatments. The tDCS device used was Enobio EEG® (Neuroelectrics, Barce­
lona, Spain). The primary outcome was based on the seizure frequency using seizure diaries before, during 10
days of treatment, and then on a 4 and 8 weeks of follow-up. The rate of adverse events was recorded as a
secondary outcome. Descriptive statistics and Wilcoxon signed-rank test were used
Results: Twenty-four patients were enrolled. The mean age was 10.1 ± 5.8 years old and 75% male. All the
patients had severe mental retardation and abnormal neurological examinations. A significant median percentual
seizure frequency reduction was found: 68.12% (p = 0.05) at 1 week, 68.12% (p = 0.002) in the second week. We
found no significant reduction at 1 and 2 months; mainly tonic and atonic seizures were reduced significantly at
all times. Only mild self-limited side effects were recorded mainly itching and erythema in the application zone
Conclusion: Ten sessions of c-tDCs in combination with pharmacologic treatment in LGS is safe and appears to
reduce significatively tonic and atonic seizure frequency at 2 months of follow-up.

1. Introduction electroencephalographic (EEG) anomalies with a pattern of slow-spike

waves <3 Hz [16]. Almost all LGS patients have moderate to severe
Epilepsy is a non-commutable disease that affects around 50 million cognitive impairment [47]. Seizures usually begin to occur before the
people around the world, with an average of 4–10:1000 habitants. age of 8 years and persist into adulthood in more than 90% of patients.
Worldwide it is estimated that 5 million people are diagnosed each year Six antiseizure medications (ASM) are approved to treat seizures in
with epilepsy [61]. Lennox-Gastaut Syndrome (LGS) is one of the most patients with LGS with partial seizure control [19]. Other treatments
severe childhood developmental epileptic encephalopathies that typi­ such as ketogenic diet, resective surgery, corpus callosotomy, and vagus
cally arise by age 7 years, with peak onset between age 3 and 5 years nerve stimulation are used to treat SLG patients and the outcome often
[16,19,57]. This syndrome has multiple causes and an incidence of remains disappointing regarding seizure control or cognitive func­
approximately two cases per 100,000 population [19]. It is character­ tioning, and new treatments are needed [34].
ized by the presence of multiple, refractory seizure (SZs) types, pre­ Transcranial direct current stimulation (tDCS) is a re-emergent, safe,
dominantly tonic SZs, atypical absences and drop attacks, and and non-invasive method for focal brain stimulation. There is a long

* Corresponding author at: Av. Insurgentes Sur 3877, Col. La Fama, Tlalpan, México City México.
E-mail address: dsanjuan@[Link] (D. San-Juan).

[Link]
Received 17 January 2022; Received in revised form 14 June 2022; Accepted 16 June 2022
Available online 17 June 2022
1059-1311/© 2022 British Epilepsy Association. Published by Elsevier Ltd. This article is made available under the Elsevier license ([Link]
access/userlicense/1.0/).
D. San-Juan et al. Seizure: European Journal of Epilepsy 100 (2022) 44–50

history of the use of electricity in medicine and currently some neuro­ 2.3. Exclusion criteria
modulation devices FDA approved are based on this effect [20]. tDCS is a
non-invasive method for cortical excitability modulation by subthresh­ Patients were excluded from study participation in the presence of
old membrane depolarization or hyperpolarization (cathodal stimula­ one or more of the following: uncertainty regarding the diagnosis of
tion decreases the cortical excitability while anodal stimulation medically-refractory LGS; history of non-epileptic or psychogenic SZs;
increases it) which has been shown to be economical, and easy to use idiopathic generalized epilepsies; status epilepticus in 3 months prior to
[38,43]. The effects of one session (20 or 30 min) of tDCS in humans can the study enrollment; suspicion of, or history significant for syncope; any
last up to 90 min [42]. uncontrolled coexisting medical condition; neurodegenerative disease;
The complete mechanism of action of tDCS is only partially under­ symptomatic cerebrovascular disease; chronic skin disease or damage to
stood. Animal and clinical studies have provided insight into the the skin on the scalp that may interfere with tDCS treatment; dental
mechanisms underlying the acute and long-term effects of tDCS ([25, fillings or medical devices (i.e. cardiac pacemaker, deep brain stimu­
31]; Nitsche, [40,43]). Pioneering works showed that weak, direct lator, medication infusion pump, or cochlear implant); substance abuse
electric currents (1–2 mA) could be effectively delivered trans-cranially or dependence at the time of screening, or anytime within the 1-year
to induce bidirectional, polarity-dependent changes in cortical neurons. prior to enrollment, any condition that in the opinion of the
In particular, the capacity of tDCS to reduce cortical excitability beneath researcher makes the subject not appropriate for the study.
the cathode of the applied field (cathodal tDCS; ctDCS) has been tested
in several clinical trials aimed to reduce seizures in patients with epi­ 2.4. Protocol
lepsy with promising results [48,51]. A potential benefit of cathodal
tDCS regarding focal epilepsy is that the applied electrical fields affect a Patients underwent ten, 30-minute multichannel tDCS sessions (with
relatively large region of cortex and subcortical structures [14], and thus ~30 s ramp-up, 30-second ramp-down period) over two weeks (10
precise localization of the epileptic focus (i.e. beyond the resolution of consecutive weekdays with weekends off). Parents recorded daily SZs
scalp EEG) is not necessary. In 2016 Auvichayapat et al., conducted the frequency for two weeks prior to initiation of tDCS treatment (estab­
first pilot study (30 min x 2 mA x 5days) using c-tDCs in patients with lishing a baseline seizure count), during the 10-days of tDCS treatment,
LGS with promising results, however, this has not been replicated and and for at least 8-weeks after the stimulation course. An Epileptologist
neither evaluated more daily sessions to contribute to find the best (G.Q) assessed the frequency and type of SZs and, also adverse events.
protocol of c-tDCs. The objective of our single-blinded, single-center
pilot study is to replicate and explore the efficacy and safety of extended 2.5. Multichannel tDCS
10-daily sessions of c-tDCs in patients with LGS.
Multichannel tDCS and EEG recording were operated using the
2. Methods Enobio® (Neuroelectrics, Barcelona, Spain). Customized montages of up
to 8 electrodes were used, with locations and currents personalized for
2.1. Participants each patient as has been previously published [30]. Briefly, the cathodes
were placed over the most active interictal epileptiform discharge (IEDs)
Twenty-four participants aged 4 to 31 were included in a single- area (defined as the zone [electrodes] with the highest discharge
center, single-blind pilot clinical trial performed over a total of 12 amplitude and/or frequency, according to the 10/20 system) as
weeks consisting of a) a 2-week of baseline seizure frequency evaluation, observed on the scalp EEG immediately before applying the c-tDCs. The
b) 2 weeks of active intervention, and c) 8 weeks of follow-up. This study anode electrodes were arranged over a contralateral area to obtain a
was conducted at the National Institute of Neurology and Neurosurgery focal effect, especially when generalized epileptiform activity was
(INNN, Mexico City) under the approbation of Bioethics and Research observed with the highest amplitude in bi-frontal regions (4–8 elec­
committee and all aspects of the study were in line with the declaration trodes) or in case of multifocal epileptiform activity always 8 electrodes
of Helsinki. All participants provided verbal and written informed con­ of stimulation were used.
sent, and verbal and written assent was obtained for the pediatric pa­ During each session for 30 min, a maximum total injected current
tients enrolled in the study, along with parental/guardian informed (across all cathodes) of 2 mA of current was applied, with a maximum at
consent, as appropriate. any one electrode of 600 µA/cm2. The current intensity was ramped up
over 5 s, then sustained at the stimulation intensity for 30 min, then
2.2. Inclusion criteria ramped down over 5 s.
Awake 30-minute EEGs were performed prior to and immediately
Inclusion criteria necessary for study enrollment were as follows: after treatment (at the end of 10 sessions), and at follow-up (after one
ages 6 to 35 years old, with an established diagnosis of LGS according to and two months). These were conducted and analyzed according to the
the criteria established by an international consensus [3] recognized by American Clinical Neurophysiology Society recommendations using the
epileptic semiology and a compatible EEG for LGS, continued SZs 10/20 international system [53]. All IEDs were analyzed visually by a
despite adequate dosage in trials of at least 2 or more ASMs within the board-certified clinical neurophysiologist (D.S.).
last year, no changes in any ASM or its doses in the 3 weeks prior to
enrollment, with no planned dose and/or medication changes during, 2.6. Personalization of treatment
and at least 8 weeks post-tDCS, a reported SZs frequency of ≥3 SZs per
month (focal, generalized or bilateral tonic-clonic seizures) over the Stimulation was applied with customized montages (determined by
three months prior to enrollment, and a minimum of 4 SZs during the 8 G.R) designed to simultaneously apply maximal cathodal stimulation
weeks initial period, verbal and written informed consent obtained from over the seizure focus, while minimizing currents in adjacent regions
the study participant prior to enrollment, and/or the subject’s legal and in other regions with epileptogenic potential. First, a computational
guardian when applicable; and capacity to maintain compliance with all model of brain anatomy was developed using mathematical finite ele­
study requirements. Patients with SLG implanted with vagal nerve ments modeling (Fischer et al. 2017). The location of seizure focus was
stimulator devices in off state and previously callosomized were determined by the lead investigator (DS). Next, a computer algorithm
included as well. (Stimweaver©, Neuroelectrics, Barcelona, Spain) was used to determine
the placement of up to eight independent electrodes on the scalp (usu­
ally 4 to 8 electrodes), to optimize the intensity and polarity of the
currents (Miranda et al. 2013; Ruffini et al. 2014; Miranda et al. 2018).

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D. San-Juan et al. Seizure: European Journal of Epilepsy 100 (2022) 44–50

The algorithm employed in this pilot study facilitates scalp electrode patient’s characteristics are summarized in Table 1. All the patients
positioning to enable optimized delivery of pre-selected current to completed the clinical trial and were analyzed. All patients had mod­
clinically defined cerebral targets using first-generation personalized erate to severe mental retardation and abnormal focal neurological
electrical conduction head models. findings. SLG etiology was mainly unknown, followed by structural
secondary to perinatal hypoxic events, brain malformations, and neuro-
2.7. Stimulation in patients with skull defects infections. All subjects were on 3 or more ASMs. Five patients had un­
dergone previous neurosurgical interventions; 4 surgical callosotomies
A modeling pipeline to handle participants with skull defects and (plus two right frontal lobectomy, and one anterior cingulotomy), one
epicranial titanium (Ti) plates were developed as follows: First, in the patient had a VNS device implanted in the off state. Additionally, one
electrical head model participant used in the optimization, a manually patient underwent radiosurgical callosotomy. Table 2
segmented mask representative of the skull defect was included. The
conductivity of the lesion was set to that of CSF, which is an appropriate 4. Efficacy
value for acute lesions [17]. With this in place, the optimization algo­
rithm automatically scales the currents to achieve an E-field comparable 4.1. Seizure frequency of all types of seizures
to the target E-field in the participants with an intact skull, ensuring
safety and efficacy. The median baseline SZs frequency per week was 80 SZs considered
100% baseline SZs frequency, at 1st week a median of 25.5 SZs was
2.8. Adverse event monitoring observed which corresponds to a percentage decrease of 68.12%, at the
2nd week a median of 25.5 SZs was observed which corresponds to a
Tutors were asked about any perceived side effects from c-tDCs percentage decrease of 68.12%. At 1 month we found a median of 130
during and at the end of the session, and in the later 2-month monitoring SZs which corresponds to a 62.5% increase with respect to baseline,
interviews. Any potential adverse events were recorded. Additionally, while at 2 months a median of 167.5 SZs which corresponds to a
each patient’s tutors were given a seizure calendar for the 8 weeks 109.375% increase with respect to baseline.
follow-up period and asked to record the daily seizures they presented, The SZs frequency reduction (≥50%) with respect to the baseline was
and any adverse effects observed by the caregivers. held in 15/28 patients (53.57%) at 1 week, 18/28 patients (64.28%) at 2
weeks, 10/28 patients (35.71%) at 1 month, and 10/28 patients
2.9. Seizure frequency measures (35.71%) at 2 months.
Fig. 1 displays box plots corresponding to the mean SZs frequency
Per subject, seizure data were assessed by SZs diaries designed by the per week compared with the baseline using c-tDCs. Using the Wilcoxon
investigators. The parents or tutors were trained to identify and count sign test we found that the median number of SZs reduced significantly
the SZs types in the patients. For each subject, the SZs rate (expressed as from baseline to the first week (p=˂0.05) and second week (p=˂0.002)
SZs / week) during the 2 weeks prior to stimulation denoted the base­ of follow-up. We found no significant differences between baseline and 1
line. We determined the mean SZs and median SZs and percentage month and baseline and 2 months.
changes across subjects. A secondary outcome in SZs frequency was the
reduction of ≥50% of SZs compared with the baseline. All SZs were 4.2. Seizure frequency by type of seizures
classified according to the International League Against Epilepsy
Revised Classification of seizures(R. S. [22]). According to the type of SZs using Wilcoxon test for all the com­
parisons we found a significant reduction in any time for tonic
2.10. Sample size consideration (p=˂0.001) and atonic SZs (p = 0.05), however, the absence SZs only
was significantly reduced since baseline at 2 months of follow-up the (p
In this pilot study, we applied coarse estimates: based on published = 0.006) and didn’t find any significant effect in any time for partial SZs.
pivotal studies of neurostimulation devices in epilepsy (R. [23,37]) in
which 100–200 participants will be required to identify a meaningful 4.3. Adverse effects
seizure reduction. According to Thabane [56], the sample size of a pilot
study should be at least 10% of the sample size representative of the All the patients underwent an initial tingling sensation at the site of
target study population for the larger study. Hence, a sample size of 20 electrodes at the start of the active intervention. Minor side effects were
patients was chosen for the present open-label pilot study. observed in only 4 (16%) patients; characterized by localized erythema
under the cathodal electrodes immediately post-treatment during the
2.11. Statistical analysis first week only, it was self-limited and vanished without other

Descriptive statistics (mean, median, standard deviation, percent­ Table 1

ages, and ranges) were used for socio-demographic variables depending Clinical characteristics of 24 patients with Lennox-Gastaut syndrome.
on the type of variable. As seizure counts and type of seizures were non-
Cathodal tDCS n = 24
normal in distribution, we assessed for changes in median seizure fre­
quency relative to baseline and type of seizures using the non- Age (years), mean and SD 10 (±5.8)
range 4–31
parametric Wilcoxon signed-rank test. Statistical analysis was per­ Age at onset of seizures (years-old), mean and SD 4±3
formed with SPSS v.23 software and MATLAB R2021a (Mathworks Inc, Sex (male/female) 18/6
Natick Massachusetts). The statistical significance level was defined Etiology (n,%)
with a two-tailed p<0.05. Unknown 10(41.6%)
Structural
Perinatal hypoxia 8(33.3%)
3. Results Brain malformations 5(20.8%)
Neuro-infections 1(4.1%)
3.1. Participants Baseline Seizure frequency per week (mean, median,± SD) 698.3, 80, ± 2542.5
Number of ASMs 3.7 ± 1.1

Twenty-four subjects (age range: 3–31; 18 [75%] men) with diag­ SD: standard deviation. ASMs: Antiseizure medications.
nosed LGS were enrolled between February 2019 to May 2020. The Abbreviation: M: Male and F: Female.

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Table 2 tDCS over M1 for 20 min or pharmacologic treatment plus placebo tDCS
Details of the adverse events using transcranial direct current stimulation in 24 1 session (1mAx20min). His-results showed a significant reduction in
patients with Lennox Gastaut Syndrome. seizure frequency during the active treatment (− 99.8% on 5th day) and
Subject Age Sex Adverse Events 4-weeks of follow-up (− 55.9%) in tonic, atonic, and absence seizures.
1 5 M Post-stimulation erythema (transitory) below the electrode
Also, the epileptiform discharges were significantly decreased in the
area tDCS group compared to the placebo during the treatment and one-
2 8 M Post-stimulation erythema (transitory) below the electrode month follow-up without serious adverse events [8]. Our study with
area more sessions (2mAx30minx10days) showed similar significative
3 14 F Post-stimulation erythema (transitory) below the electrode
seizure frequency reduction, mainly in tonic/atonic SZs during the
area and mild abrasions due to scratching.
4 10 M Post-stimulation erythema (transitory) below the electrode active treatment and follow-up of 2 months. Previous studies using
area c-tDCs in patients with refractory focal epilepsy showed an effect
depending on the doses and number of sessions [26] and open the op­
portunity to test the effect in future clinical trials using long-term c-tDCs
complications after 20 min of surveillance. treatment, as has been anecdotally published previously ([52], p.).
In four patients with previous surgical callosotomies individual head The complete mechanism of action of tDCS is only partially under­
modeling with customization of the stimulation montage ensured that stood. tDCS does not produce action potentials, but most likely affects
all currents remained within safe limits and were appropriately targeted the spike timing of individual neurons receiving suprathreshold inputs.
to the seizure focus. Two of these four participants were c-tDCs re­ However, it is well known that tDCS has a partially non-linear effect
sponders with >50% reduction in seizures in the 1st month and only one depending on the intensity and duration of the stimulation [10]. The
of the two remained with a similar response at 2 months of follow-up. acute effects are due to the main polarization mechanism that induces
changes in ionic concentrations (Na+, Ca+, K+, Cl–), alteration of the
5. Discussion acid-base balance, and transmembrane protein changes by synaptic [46]
and non-synaptic mechanisms [2]. Pharmacological studies have shown
Our results showed that ten consecutive days (with 2-day rest during that the long-lasting after-effects involve mainly N-methyl-d-aspartate
the weekend) of c-tDCs as adjunctive treatment in patients with LGS is (NMDA) receptors and the GABAergic system [33,39,40]. Repetitive
safe and appear to reduce significatively tonic/atonic seizure frequency tDCS induces cell migration, as well as cell orientation (growth cone
mainly at 2 months of follow-up direction), differentiation, and metabolism; the responses of which vary
Cathodal tDCS has been used in heterogeneous clinical trials with depending on the cell type sustainable responses in the form of
pediatric and adult patients with refractory epilepsy and multiple eti­ long-term potentiation (LTP)- or long-term depression (LTD)-like plas­
ologies ([4,5], 2016a; [21,24,49,50], 2018; [55,58,62,63]), including ticity [36]. Our finding supports the previous concept that a greater
small case series of epileptic syndromes such as Rasmussen syndrome number of c-tDCs sessions induce a sustained effect for at least 2 months
with promising results [8,49] or refractory continuous spike and wave of follow-up. However, additional clinical trials are needed.
during slow sleep [58] with negative results [29,58]. In a previous study Several factors of electrode montage and waveform (including shape,
that included children with pharmacoresistant focal epilepsy, one tDCS pulse width, polarity, frequency, duration, and amplitude of current as
session led to a minor but significant drop in clinical seizure frequency, well as number and frequency of sessions) influence the direct and
and a significant decrease of IEDs up to 57.6% by 48 h later [6]. On the remote effects of tDCS [11,44]. Deep recordings in humans during tDCS
other hand, other pediatric series in patients with epileptic spams and have been measured at between 0.05–0.5 V/m for 1 mA and 0.8 V/m for
Lennox Gastaut syndrome showed a significant reduction in seizure 2 mA tDCS [27,44,59]. Recently, voltage changes have been recorded at
frequency [7,62]. the subthalamic level in humans; the crude estimate of the generated
Auvichayapat et al. (2016) conducted the first randomized placebo- electric field with 2 mA bitemporal tDCS was 0.12 to 0.13 mV/mm [14].
controlled study of the effects of tDCS in 22 patients with LGS. The These direct and remote effects of tDCS are relevant in the SLG treatment
patients under c-tDCs received five consecutive days of 2 mA cathodal because the latest studies using concurrent scalp EEG-fMRI showed

Fig. 1. Box plots corresponding to the median seizure frequency per week compared with the baseline using c-tDCs in 24 patients with Lennox-Gastaut Syndrome.
Wilcoxon sign test showed that the median number of all types of seizures reduced (*) significantly from baseline to the first week (p=˂0.0465) and second week
(p=˂0.0018) of follow-up.

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D. San-Juan et al. Seizure: European Journal of Epilepsy 100 (2022) 44–50

evidence of a cortically driven process within the epileptic network of complications in children [15,35].
LGS. This network is present in children and in older patients in the Other limitations of our study include: a small sample size; a short-
course of the syndrome and across diverse etiologies of epilepsy, sug­ term follow-up (two months); and no assessment of lifestyle or cogni­
gesting that LGS reflects shared "secondary network" involvement, tive effects potentially related to the application of c-tDCs. Analysis of
whereby interictal generalized paroxysmal fast activity rapidly propa­ the interaction between AEDs and tDCS was not performed due to the
gates from prefrontal cortex to the brainstem via extrapyramidal corti­ numerous amounts of combinations of AEDs. Although, pharmacolog­
coreticular pathways, whereas the thalamus is engaged secondarily ical studies using cathodal tDCS have shown that excitability reduction
[60]. In patients with failed corpus callosotomies there is an increased is not affected by carbamazepine or lorazepam [39,40]. Another limi­
local clustering coefficient and decreased small worldness of brain net­ tation is the lack of evaluation of the IEDs in the clinical study, never­
works compared with opposite effects in patients with good outcomes theless, the present and frequency of generalized SSW discharges < 2.5
[32]. A previous study found that epileptic seizure reduction in patients Hz in SLG poorly correlates with seizures control and prognosis [45].
with drug-resistant temporal lobe epilepsy correlated with the increase In conclusion, ten sessions of cathodal tDCS as adjunctive treatment
of the epileptic focus functional connectivity, in the whole frequency in patients with LGS is safe and appear to reduce significatively seizure
band and in the theta band [54]. frequency at 2 months of follow-up.
Another relevant issue is the placebo effect in epilepsy clinical trials
using devices. Several clinical trial in patients with epilepsy using Declaration of Competing Interest
transcranial magnetic stimulation [9], trigeminal nerve stimulation [18]
and responsive neuro-stimulation [37] found a 16–27% of responder All authors certify that this paper or any of its contents has not been
rates (for 50% responders). In fact, in the blinding phase of the deep published or submitted for publication elsewhere. All authors have full
brain stimulation randomized clinical trial of 109 patients (54 stimu­ access to the data and the right to publish all the data. Each of the au­
lated, 55 placeboes), the authors found no “statistically significant thors contributed to the work and have seen and agreed with the con­
treatment group difference” for 50% of responders during this phase (R. tents of the manuscript. No ghost writing by anyone not named on the
[23]). In the Auvichayapat et al. (2016) randomized placebo- controlled author list has occurred. All authors have agreed to submit the manu­
study of c-tDCs in SLG, the reduction of the seizure frequency by day was script to Seizure - European Journal of Epilepsy. The submitted study
decreased until 50% in the placebo arm mainly during the active phase was approved by the Institutional Review and Research Ethics Com­
of the treatment [8]. The lack of a control group is a limitation of our mittee. Declaration of Helsinki was followed. The authors declare no
study. conflicts of interest in this submission.

5.1. Safety of c-tDCs in epilepsy Disclosure

Evidence-based reviews related to the safe use of conventional tDCS Giulio Ruffini is a shareholder of Neuroelectrics
in human trials have not yet produced any reports of serious adverse
effects or irreversible injuries following over 33,200 sessions and 1000 Acknowledgments
subjects with repeated sessions [12,39]. Animal studies and modeling
evidence indicate that brain injury could occur at predicted current None.
densities in the brain of 6.3–13 A/m2 that are over an order of magni­
tude above those produced by tDCS in humans [6,24]. Submission statements
Mild skin erythema is common during tDCS and is not inherently
hazardous, also it’s self-limited [12]. Our patients also experience this All authors have seen and agree with the contents of the manuscript.
minor side effect self-limited. Other mild adverse events reported are Daniel San Juan, MD, principal author, takes full responsibility for the
itching (39.3%), tingling (22.2%), headache (14.8%), and burning data, analyses, interpretation, and the conduct of the review research;
sensation (8.7%) [13,51]. tDCS was not found to produce edema or Daniel San Juan, MD also has full access to all data; he has the right to
injurious alterations of the blood-brain barrier or cerebral tissue publish any all data separately and distinctly from any sponsor. We
detectable by MRI [41]. However, it is unknown if chronic c-tDCs can certify that the submission (aside from an abstract) is not under review
induce epilepsy through a kindling effect [28] or worsening of some type at any other publication. All authors participated in a meaningful way in
of epilepsy due to inaccurate localization of the electrodes over the the preparation of the manuscript.
epileptogenic areas. Children suffering from various neuropsychiatric
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