Transcranial direct current stimulation for hyperactivity and noncompliance in autistic disorder

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Transcranial Direct Current Stimulation for Hyperactivity

and Noncompliance in Autistic Disorder

Journal: The World Journal of Biological Psychiatry

Manuscript ID: SWBP-2014-0100

Manuscript Categories: Brief Report

Date Submitted by the Author: 10-Oct-2014

Complete List of Authors: D'Urso, Giordano; Seconda Università di Napoli, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva Bruzzese, Dario; Università di Napoli "Federico II", Dipartimento di Sanità Pubblica Ferrucci, Roberta; Department of Psychiatry, University of Milan; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Milano, IT, priori, alberto; Department of Psychiatry, University of Milan; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Milano, IT, Pascotto, Antonio; Seconda Università di Napoli, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva Galderisi, Silvana; Seconda Università di Napoli, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva Altamura, Carlo; University of Milan, Psychiatry Bravaccio, Carmela; Università di Napoli "Federico II", Dipartimento di Pediatria

Keywords: Autistic disorder, Behaviour, Biological treatment, Transcranial magnetic stimulation

URL: http:/mc.manuscriptcentral.com/swbp - e-mail: [email protected]

The World Journal of Biological Psychiatry

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Title of the article:

Transcranial Direct Current Stimulation for Hyperactivity and Noncompliance in Autistic Disorder

Short Title:

TDCS in Autistic Disorder

Authors:

Giordano D’Ursoa, MD, PhD; Dario Bruzzese

b, PhD; Roberta Ferrucci

c, PsyD, PhD; Alberto Priori

c,

MD, PhD; Antonio Pascottoa, MD; Silvana Galderisi

a, MD, PhD; Alfredo Carlo Altamura MD

d and

Carmela Bravaccioe MD, PhD

a Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Seconda Università di Napoli, Naples,

Italy

b Dipartimento di Sanità Pubblica, Università di Napoli "Federico II", Naples, Italy

c Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università di Milano, Centro di

Neurostimolazione e Disordini del Movimento, Fondazione IRCCS Ca' Granda Ospedale Maggiore

Policlinico di Milano, Milan, Italy

d Dipartimento di Psichiatria, Università di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore

Policlinico di Milano, Milan, Italy

e Dipartimento di Pediatria, Università di Napoli "Federico II", Naples, Italy

Corresponding Author:

Name: Giordano D’Urso

Address: via Pansini n.5 - Edificio 18, Piano Terra, 80131, Napoli, Italy

phone (office): +390817462652

cell phone: +393385714722

fax: +390817462378

e-mail address: [email protected]

Key Words: tDCS, autism, pervasive developmental disorders, intellectual disability, brain

stimulation, NIBS, non-invasive brain stimulation

Word count in abstract: 194

Word count in article body: 2575

Tables: 1

Figures: 1

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Abstract

Objectives: To evaluate the safety, efficacy, and feasibility of inhibitory transcranial direct current

stimulation (tDCS) for the treatment of behavioral abnormalities of autistic patients.

Methods: Twelve young adult patients with Autistic Disorder were enrolled. All subjects presented

Intellectual Disability and most of them had speech impairment. The Aberrant Behavior Checklist

(ABC) was administered as the primary outcome measure before and after a 2-week tDCS course. All

subjects received 10 daily applications of 20 minute/1.5mA/cathodal (inhibitory) tDCS over the left

dorso-lateral pre-frontal cortex.

Results: Eight out of ten study completers improved in their abnormal behaviors, reaching an average

reduction of 26.7% of the total ABC score. The remaining 2 patients showed no changes. In the whole

group of completers, among the 5 subscales contributing to the significant reduction of the total score,

the most remarkable and statistically significant change was seen in the subscale assessing

hyperactivity and non-compliance (- 35.9%, p=0.002). No adverse effects were reported.

Conclusions: Inhibitory tDCS improved the ABC rating scores for autistic behaviors. Owing to its ease

of use, cost-effectiveness and the limited availability of specific treatment strategies, tDCS might be a

valid therapeutic option to be tested in autistic patients.

Key Words: tDCS, autism, pervasive developmental disorders, intellectual disability, TMS

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Introduction

Autistic Disorder (AD) is a complex neurodevelopmental disorder with an increasing prevalence

(Dawson 2013). One of the most recent theories on the etiopathogenesis of AD holds that

neurophysiological alterations, cognitive deficits, and behavior abnormalities are due to a

developmental disorder capable of affecting brain growth. In particular, the composition of the so

called “cell minicolumns” is affected. Minicolumns are cylindrical morphofunctional units

perpendicular to the cortical surface. Whereas their core comprises radially oriented arrays of

pyramidal projection neurons, their periphery comprises combinations of GABAergic interneurons that

provide for a diversity of signaling properties that dynamically modulate pyramidal cell inputs and

outputs. In the cerebral cortex of autistic patients, the peripheral compartment of the minicolumns is

narrower than that of the age-matched controls, especially in the prefrontal cortical areas (Casanova et

al. 2006). Such alteration entails a reduced inhibitory function by the GABAergic interneurons.

Consequently, because of the prevailing excitatory action stemming from the pyramidal cells, the

adjacent minicolumns tend to stimulate one another, thereby causing an abnormal activation across the

cerebral cortex even in response to low inputs. Furthermore, esearch on the motor cortex of autistic

patients has demonstrated a reduction in GABAA - mediated inhibition, as compared to that of healthy

subjects (Enticott et al. 2010). Thus, the alterations in the inhibitory cortical networks may indeed

underlie the impaired behavioral patterns displayed by autistic subjects, including a higher incidence of

seizures, increased neurophysiological stress, irritability, agitation, hyperactivity, stereotyped

behaviors, concretism, tactile and auditory hypersensitivity (Casanova et al. 2003).

So far, no specific treatment for AD exists, and individual goals for treatment vary among patients and

may include a combination of therapies (Myers et al. 2007).

Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS)

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and transcranial direct current stimulation (tDCS), have proven to be effective, and, not least, safe in

treating psychiatric and neurological disorders (Kuo et al. 2014; Lefaucheur et al. 2014).

RTMS has been also used in AD patients and was able to partially revert their neurocognitive deficits,

as well as neurophysiological and behavioral impairments. Indeed, neurophysiological studies have

mostly used rTMS in high-functioning autistic patients at low inhibitory frequencies to modulate the

dorsolateral prefrontal cortex (DLPFC), a high-order association area, which plays a major role in

minicolumnar pathology (Sokhadze et al. 2009, 2010, 2012). Furthermore, targeting the DLPFC area

also guarantees, as a trans-synaptic effect, a cascade of modulatory action on all the other intertwined

neuronal networks, thereby inducing a widespread reduction in cortical excitability (Walsh and

Pascual-Leone 2003). In high-functioning autistic patients, rTMS improves error monitoring,

correction function and the performance on attention tasks. Interestingly, besides the primary outcomes

represented by the neuropsychological and neurophysiological parameters, these studies also reported

reduced repetitive-ritualistic behaviors as secondary outcomes. One possible explanation for these

changes is that low-frequency rTMS is able to bolster the inhibitory function of interneurons, thus

restoring the cortical excitatory/inhibitory physiological balance, commonly altered in the minicolumns

of autistic patients. Consistently, two case reports demonstrated that the application of low-frequency

rTMS to the frontal cortex led to an improvement in some autism core features (Niederhofer 2012;

Cristancho et al. 2014).

In a recent report we outlined the rationale of using another technique, i.e. the tDCS, for the treatment

of autism-related behavioral disturbances and assessed for the first time the efficacy of cathodal

inhibitory tDCS over the left DLPFC in an autistic patient (D’Urso et al. 2014). Given that the

unbalanced excitatory-inhibitory cortical tone in the DLPFC may be responsible for abnormal autistic

behaviors, we had hypothesized that cathodal inhibitory tDCS over this area could benefit patients by

restoring inhibition. The treatment of the first patient confirmed this hypothesis. The main aim of the

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present study was thence to verify, in a bigger sample of very challenging and behaviorally

compromised autistic patients, whether cathodal tDCS applied over the left DLPFC can effectively

reduce the dysfunctional behaviors related to AD. We therefore designed an open label phase II study

to assess the feasibility, safety, and therapeutic efficacy of tDCS in this category of extremely severe

patients.

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Methods

Study design, recruitment, and setting

All participants underwent active treatment. They were enrolled at the Child and Adolescent

Neuropsychiatric Clinic of the Second University of Naples, where they were first diagnosed with

Autistic Disorder and where they still undergo periodic follow-up visits. TDCS treatments, instead,

were carried out at two centers for neuropsychiatric rehabilitation. In these centers, at the time of

enrollment, patients were already attending an outpatient daily occupational rehabilitation program,

which remained the same throughout the study.

Subjects

The study sample is outlined in Table 1. Patients undergoing psychopharmacological treatments were

included, provided that the dosages had remained the same for one month before the trial and remained

the same throughout the study. Moreover, at the time of enrollment, our recruited subjects had not

manifested any significant behavioral improvements in a long time, despite receiving continuous

pharmacological treatments and being involved in psychiatric rehabilitation programs.

During tDCS sessions, they were under the supervision of their reference operators and were free to

move around and carry out their routine activities.

Treatment

Neuromodulation was carried out by an HDC stimulator (Newronika) connected to two spongy

electrodes, soaked on each side in a saline solution and covered with conductive gel. A negative

electrode, viz, a cathode (5 x 5 cm), was placed over the scalp overlying the left dorsolateral prefrontal

cortex (F3 according to the EEG 10/20 system). The circuit was then closed by virtue of a positive

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electrode, viz, an anode (5 x 8 cm), also connected to the stimulator but placed in an extra-cephalic

position on the lateral aspect of the patient’s right arm. Patients received daily applications of 20

minute/1.5mA tDCS for ten consecutive weekdays (1,8 C and 0.045 C/cm2 per session, 18 C per

treatment).

Assessment

Patients’ behavioral symptoms were evaluated according to the Aberrant Behavior Checklist (ABC)

(Aman and Singh 1994). In this study, a trained psychologist completed the ABC for each patient just

before and 1 week after the tDCS course. Behavioral ratings were based on direct observation, as

reported by the caregivers (mostly parents) and professionals of the rehabilitation center.

Statistics

Data were summarized as means ± standard deviation for continuous variables and as frequencies (%)

for categorical variables. Changes in ABC total and subscale scores were defined by subtracting the

baseline scores from those reported after tDCS treatment. Negative values therefore indicate a decline

in ABC scores. For the assessment of the significance of within-subject changes, the paired t test and

the corresponding 95% CIs were computed. All significance tests were two-sided with the significance

level set at 0.05. Statistical analyses were carried out using R vers. 2.15 (R Development Core Team

2012).

Ethical factors

This study enrolled the most severe and behaviorally challenging patients attending our rehabilitation

program. Considering the severity of their symptoms, we decided not to include a placebo control arm

in the study design, similarly to what is generally acknowledged for suicidal depression (Thase 1996).

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The experimental protocol was approved by the Ethics Committee of “Federico II” University Hospital

(Naples, Italy). All the legal attorneys representing the study participants, and when possible, the

participants themselves, signed the informed consent form approved by the Ethics Committee.

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Results

Ten out of the 12 study subjects completed the study. Two (No. 6 and No. 8 of Table 1) interrupted the

treatment because unable to tolerate the treatment procedures. More specifically, although these two

patients had clinical and demographic characteristics similar to the rest of the sample, they displayed a

greater degree of discomfort in having to keep the spongy electrodes fixed in place, as they

continuously tried to remove them.

Eight out of ten study completers showed a substantial improvement in their abnormal behaviors, with

an average reduction of 26.7% (±7.5) of the total ABC score compared with the basal scores. The two

remaining patients showed no clinically significant changes after the treatment (No. 7 and No.12 of

Table 1).

For the group of completers as a whole, ABC total scores ranged from 47-133 (mean 91.6 ± 28.2) at

baseline, whereas after tDCS treatment scores ranged from 42-95 (mean 69.9 ± 16.9). The mean

difference was -21.7 (95% C.I. -33.3 ; -10.1, p=0.002). Among the 5 ABC subscales, subscale 1

(irritability, agitation, and crying [mean difference -5.5, 95% C.I. -8.6 ; -2.4, p=0.003]), subscale 2

(social withdrawal and lethargy [mean difference -4.3, 95% C.I. -8.1 ; -0-5, p=0.03]), and subscale 4

(hyperactivity and non-compliance [mean difference -9.0, 95% C.I. -13.8 ; -4.2, p=0.002]) significantly

decreased after treatment. By contrast, the decline in the scores of subscale 3 (stereotypic behavior),

and subscale 5 (inappropriate speech) reached no statistical significance (Figure 1).

No adverse effects were reported, except for some patients displaying a slight, temporary skin irritation

at the site of stimulation.

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Discussion

This open label pilot study, involving a young adult sample of low-functioning autistic patients with

highly challenging behaviors, suggests that tDCS applied to the left DLPFC is feasible, safe, and

effective in the treatment of autism-related behavioral disorders. In fact, cathodal tDCS applied to the

left DLPFC was able to partially revert our patients’ maladaptive behaviors. In our opinion, this

therapeutic effect was most likely induced by a reduction in cortical excitability in the DLPFC and by

the ensuing cascade of inhibitory effects on all the neuronal networks intertwined with this region.

The contralateral extra-cephalic positioning of the anode was adopted to allow the current flow to

penetrate more deeply into the brain (Parazzini et al. 2013a). We purposely chose to administer tDCS

to the left and not to the right DLPFC to maximize the safety of the procedure. More specifically, had

we placed the cathode electrode over the right DLPFC and the anode electrode over the left arm, the

current flow could have compromised the cardiac region (Parazzini et al. 2013b). Accordingly, whether

a similar or different clinical outcome could have been achieved, had tDCS been administered to the

right DLPFC, remains to be clarified.

Previous studies reported promising results with rTMS in AD. RTMS does however have some

limitations as its application requires costly equipment, highly specialized centers and, not least,

immobilization of patients for several minutes. This last condition is very hard to achieve in low-

functioning autistic patients, who constitute the most conspicuous and clinically challenging sub-

population of autistic patients. Contrariwise, tDCS is not only inexpensive but also easy to use.

In the present article we report the experience of treating 12 low-functioning autistic patients with

highly challenging behaviors in a naturalistic setting. Carrying out the treatment at the Rehabilitation

Center—which served as a perfect naturalistic setting where our young patients were accustomed to

going regularly for their daily rehabilitation activities—was of fundamental importance. It was this

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familiar setting that rendered the evaluation of the therapeutic effect of tDCS more reliable and

generalizable. Indeed, since autistic patients are hypersensitive to their environmental contexts,

everyday life experiences, and routines, any changes to their everyday lives and practices would have

determined, per se, an evaluation bias. The possibility of administering tDCS in a familiar context was

made feasible by the fact that the device is easy to use and does not create space issues.

Therefore, 10 out of 12 low functioning patients were able to complete the tDCS cycle, regardless of

their severe behavioral symptoms—a result that confirms, at least for the time being, the feasibility of

tDCS for treating these patients.

Another important advantage of tDCS in autism is that it can also treat epileptic patients. In fact, given

that cathodal tDCS reduces cortical excitability, it does not cause seizures. Indeed, it has even been

proposed for the treatment of drug refractory focal epilepsy (Fregni et al. 2006). By contrast, in rTMS

protocols, history of epilepsy is generally considered as an exclusion criterion. Thus, because of the

high comorbidity rates of autism and epilepsy, the risk of inducing seizures has to be carefully

considered when choosing a treatment for behavioral abnormalities of autistic patients. Remarkably, in

our study we were able to enroll an epileptic patient who would have most likely been excluded from

an rTMS protocol.

Only 2 out of 10 study completers were unresponsive to the treatment (subjects No. 7 and No.12 of

Table 1). Interestingly, these were the least severely ill patients at baseline, as compared to the rest of

the sample. Briefly, they obtained the lowest pre-treatment ABC scores, suffered from moderate

Intellectual Disability (whereas most study subjects were severely disabled), and one of them had no

speech impairment at all. Moreover, they both scored the lowest ratio between the hyperactivity/non-

compliance subscale and the total score at the baseline (data not shown). Taken together, these

observations may suggest a positive correlation between the effect size of tDCS on autistic patients and

the clinical severity at baseline, both in global terms and in terms of the relative burden of hyperactivity

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and non-compliant behavior.

Regarding the eight patients who clinically responded to tDCS, it is worth specifying that behavioral

improvement was more noticeable when patients were not engaged in structured activities, an

encouraging result when considering that it is under these circumstances that the dysfunctional

behavior of these patients is more manifest. Reduction in dysphoria, anxiety, and tantrums, consistently

described both by our professionals and patients’ caregivers, well correlates with the quantitative data

of the ABC subscale for irritability-agitation-crying (subscale No.1). Indeed, in accordance with

previous evidence on the modulatory effects of tDCS on mood, a statistically significant improvement

was seen in these behavioral symptoms (p=0.012) after tDCS course.

Of great importance and of potential impact on treatment programs for patients with autism spectrum

disorders was also the statistically significant reduction of the ABC subscale scores for No.2, which

relates to “lethargy and social withdrawal” and for No.4, which relates to “hyperactivity and lack of

compliance”. In particular, this latter subscale displayed the most numerically relevant change detected

in our study, with a mean reduction in responders of 35.9% (±14.7). The importance of these results is

linked to the very psychopathological dimensions considered in these two subscales, in that they are

mostly accountable for the poor adherence shown by autistic patients to rehabilitation programs.

Consequently, tDCS could provide a crucial support to the rehabilitation programs, rendering them far

more efficacious.

Despite such interesting findings and the possible implications on the clinical treatment of autistic

patients, our results did present one limitation, i.e. the adoption of the open label design. Indeed, the

severity of behavioral disturbances, the magnitude of improvement, the resistance to previous standard

treatment and the lack of awareness and judgment correlated to the Intellectual Disability make a

placebo effect highly unlikely in our sample. Nonetheless, we cannot rule out the possibility that the

raters’ expectation bias might have influenced the trial outcomes. Thus, to fully substantiate our results,

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sham-controlled clinical studies on larger samples and of longer duration are warranted. Lastly, given

the tolerability of tDCS treatment and its potential to induce neuroplastic changes, it would be of

pivotal importance to carry out phase II trials involving autistic subjects in the developmental age

(Brunoni et al. 2012). In the early stage of AD, in fact, there would be a better chance of preventing the

stabilization and chronicization of neurophysiological and behavioral disturbances, thereby improving

the prognosis for such lifelong disabling condition.

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Conclusion

This open label clinical study, conducted on a small sample of young adult autistic patients with highly

challenging behaviors, demonstrated that tDCS can benefit patients with low-functioning autistic

disorder. Indeed, it was able to reduce, in a clinically and statistically significant way, core autistic

behaviors, i.e., irritability, agitation, crying, as well as social withdrawal, lethargy, hyperactivity, and

non-compliance, without causing any adverse events. Being safe, easy to apply, and economical, tDCS

could have a significant role in the management of autistic symptoms for which no specific treatments

currently exist.

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Acknowledgements

We wish to thank Prof. Giovanni Salvati, Dr. Maria Iaderosa, and Dr. Dario Frascadore of the Serapide

Center of Villaricca (Naples, Italy), as well as Prof. Giuseppe Miranda, Dr. Gianfranca Auricchio, Dr.

Felice Del Genio, Dr. Giuseppina Nappi, Dr. Paola Di Franco, and Mr. Carmelo Fabrizio of the AIAS

of Nola (Naples, Italy) for their collaboration. In particular, we thank them for providing their support

in raising parents’ awareness on the potential effectiveness of tDCS in autism. Indeed, thanks to their

time and dedication, we were able to recruit the subjects for our pilot study. Furthermore, we thank

them for providing us with professional operators, as well as facilities and stimulation devices for the

treatments.

Finally, we truly thank Dr Paola Merolla for her precious help in editing the manuscript.

Statement of Interest

Giordano D’Urso, Dario Bruzzese, Antonio Pascotto, and Carmela Bravaccio report no financial

interests or potential conflicts of interest relevant to the subject matter of the manuscript over the last

two years, at present, and in the foreseeable future. Roberta Ferrucci and Alberto Priori are

stakeholders of Newronika s.r.l., a spin-off company of the Fondazione IRCCS Ca’ Granda Ospedale

Maggiore Policlinico and of the Università degli Studi di Milano. Alfredo Carlo Altamura has served as

a consultant for Roche, Lundbeck, Merck, Astra Zeneca, Bristol-Myers Squibb, Janssen-Cilag, Otsuka

and received fees from the speaker Bureau of Sanofi, Eli Lilly, and Pfizer. Silvana Galderisi received

fees for educational programs or advisory boards from Amgen Dompé, AstraZeneca, Bristol-Myers

Squibb, Eli-Lilly, Otsuka, Innova-Pharma, and Janssen-Cilag.

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References

Aman MG, Singh NN. 1994. Aberrant Behavior Checklist - Community. Supplementary Manual. East

Aurora (NY): Slosson Educational Publications.

Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, Edwards DJ, Valero-Cabre

A, Rotenberg A, Pascual-Leone A, and others. 2012. Clinical research with transcranial direct current

stimulation (tDCS): challenges and future directions. Brain Stimul. 5(3):175-195.

Casanova MF, Buxhoeveden D, Gomez J. 2003. Disruption in the inhibitory architecture of the cell

minicolumn: Implications for autism. Neuroscientist. 9(6):496–507.

Casanova MF, van Kooten IA, Switala AE, van Engeland H, Heinsen H, Steinbusch HW, Hof PR,

Trippe J, Stone J, Schmitz C. 2006. Minicolumnar abnormalities in autism. Acta Neuropathol.

112(3):287-303.

Cristancho P, Akkineni K, Constantino JN, Carter AR, O'Reardon JP. 2014. Transcranial Magnetic

Stimulation in a 15-Year-Old: Patient With Autism and Comorbid Depression. J ECT. Jun 24. [Epub

ahead of print] PubMed PMID: 24979652.

Dawson G. 2013. Dramatic Increase in Autism Prevalence Parallels Explosion of Research Into Its

Biology and Causes. JAMA Psychiatry. 70(1):9-10.

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https://www.researchgate.net/publication/233774102_Dramatic_Increase_in_Autism_Prevalence_Parallels_Explosion_of_Research_Into_Its_Biology_and_Causes?el=1_x_8&enrichId=rgreq-1344d72f9adcf0142058b72fb1cac5ac&enrichSource=Y292ZXJQYWdlOzI3NDA4NjE3OTtBUzoyMTQyMTQ5NzIwNTU1NTJAMTQyODA4NDIzNzM3Ng==

https://www.researchgate.net/publication/263516526_Transcranial_Magnetic_Stimulation_in_a_15-Year-Old_Patient_With_Autism_and_Comorbid_Depression?el=1_x_8&enrichId=rgreq-1344d72f9adcf0142058b72fb1cac5ac&enrichSource=Y292ZXJQYWdlOzI3NDA4NjE3OTtBUzoyMTQyMTQ5NzIwNTU1NTJAMTQyODA4NDIzNzM3Ng==






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D'Urso G, Ferrucci R, Bruzzese D, Pascotto A, Priori A, Altamura AC, Galderisi S, Bravaccio C.

2014.Transcranial direct current stimulation for autistic disorder. Biol Psychiatry 2014;76(5):e5-6.

Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB. 2010. A preliminary transcranial

magnetic stimulation study of cortical inhibition and excitability in high-functioning autism and

Asperger disorder. Dev Med Child Neurol. 52(8):179-183.

Fregni F, Thome-Souza S, Nitsche MA, Freedman SD, Valente KD, Pascual-Leone A. 2006. A

controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia.

47(2):335–342.

Kuo MF, Paulus W, Nitsche MA. 2014. Therapeutic effects of non-invasive brain stimulation with

direct currents (tDCS) in neuropsychiatric diseases. Neuroimage. 15;85 Pt 3:948-60.

Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM,

Cincotta M, de Carvalho M, De Ridder D, and others. 2014. Evidence-based guidelines on the

therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Jun 5.

pii: S1388-2457(14)00296-X. doi: 10.1016/j.clinph.2014.05.021. [Epub ahead of print].

Myers SM, Johnson CP, American Academy of Pediatrics Council on Children With Disabilities. 2007.

Management of children with autism spectrum disorders. Pediatrics. 120(5):1162-1182.

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Niederhofer H. 2012. Effectiveness of repetitive Transcranial Magnetic Stimulation of 1 HZ for

Autism. Clinical Neuropsychiatry. 9(2):107.

Parazzini M, Rossi E, Rossi L, Priori A, Ravazzani P. 2013a. Evaluation of the current density in the

brainstem during transcranial direct current stimulation with extra-cephalic reference electrode. Clin

Neurophysiol. 124(5):1039-1040.

Parazzini M, Rossi E, Rossi L, Priori A, Ravazzani P. 2013b. Numerical estimation of the current

density in the heart during transcranial direct current stimulation. Brain Stimul. 6(3):457-459

Sokhadze EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova MF. 2009. Effects of low frequency

repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related

potentials during processing of illusory figures in autism. J Autism Dev Disord. 39(4):619-34.

R Development Core Team. 2012. R: A language and environment for statistical computing. Vienna,

Austria: R Foundation for Statistical Computing. Available from: http://www.R-project.org/.

Sokhadze EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova MF. 2009. Effects of low frequency

repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related

potentials during processing of illusory figures in autism. J Autism Dev Disord. 39(4):619-34.

Sokhadze E, Baruth J, Tasman A, Mansoor M, Ramaswamy R, Sears L, Mathai G, El-Baz A, Casanova

MF. 2010. Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Affects Event-

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Related Potential Measures of Novelty Processing in Autism. Appl Psychophysiol Biofeedback.

35(2):147–161.

Sokhadze E, Baruth J, Sears L, Sokhadze G, El-Baz A, Casanova M. 2012. Prefrontal

Neuromodulation Using rTMS Improves Error Monitoring and Correction Function in Autism. Appl

Psychophysiol Biofeedback. 37(2):91–102.

Thase, ME. 1996. How should efficacy be evaluated in randomized clinical trials of treatments for

depression? J. Clin. Psychiatry. 60 (Suppl 4), 23–31(discussion 32).

Walsh V and Pascual-Leone A. 2003. Transcranial magnetic stimulation: A neurochronometrics of

mind. Cambridge (MA): MIT Press. 319 p.

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Subject Study

Center

Age Sex Intellectual

Disability

Language

Disorder*

Medical

Comorbidities

Drug Treatment

during tDCS**

1 A 18 M severe - - - Paliperidone 12 mg

- Lithium 900 mg

2 A 26 M severe + - - Valproate 1000 mg

- Levomepromazine 50 mg

3 A 25 M severe - - - Olanzapine 7.5 mg

4 B 19 F severe + Epilepsy - Valproate 600 mg

- Oxcarbazepine 1500 mg

- Lacosamide 400 mg

- Levetiracetam 4000 mg

5 B 19 M severe + - - Risperidone 3 mg

- Carbamazepine 800 mg

- Delorazepam 1.5 mg

6 B 20 F severe + - - Valproate 450 mg

- Periciazine 8 mg

- Melatonine 3 mg

7 B 18 M moderate - - - Valproate 450 mg

8 B 18 M severe + - - Valproate 1000 mg

- Periciazine 130 mg

- Melatonine 3 mg

9 B 22 F severe + - - Risperidone 1,5 mg

- Lorazepam 2 mg

- Melatonine 3 mg

10 B 18 M severe + Down

Syndrome

- Risperidone 3 mg

11 B 21 M mild - - - Periciazine 90 mg

- Delorazepam 0.75mg

- Lormetazepam 1mg

12 B 18 M moderate + - - Risperidone 1.25 mg

Table 1. Demographic and clinical characteristics of participants. Study Centers: A=AIAS, Nola

(Naples, Italy); B=Serapide, Villaricca (Naples, Italy). *Less than four words appropriately used;

**daily dosage

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Figure 1. Aberrant Behavior Checklist scores before (T0) and after (T1) transcranial Direct Current

Stimulation course.

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Figure 1. Aberrant Behavior Checklist scores before (T0) and after (T1) transcranial Direct Current Stimulation course.

416x286mm (72 x 72 DPI)

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Transcranial direct current stimulation for hyperactivity and noncompliance in autistic disorder

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