Transcranial Magnetic Stimulation in Autism Spectrum Disorder: Challenges, Promise, and Roadmap for Future Research Lindsay M

REVIEW ARTICLE Transcranial Magnetic Stimulation in Autism Spectrum Disorder: Challenges, Promise, and Roadmap for Future Research Lindsay M. Oberman, Peter G. Enticott, Manuel F. Casanova, Alexander Rotenberg, Alvaro Pascual-Leone, James T. McCracken, and the TMS in ASD Consensus Group†

Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive patho- physiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. Autism Res 2015, 00: 000–000. VC 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Keywords: autism spectrum disorder; transcranial magnetic stimulation; consensus; review; treatment

Introduction ASD symptoms include impairments in social communication, restricted and repetitive behaviors, interests Autism Spectrum Disorder (ASD) is a behaviorally and activities [American Psychiatric Association, 2013]. deﬁned complex neurodevelopmental syndrome. Core The diagnosis of ASD is based on observations and

†Stephanie Ameis, Department of Psychiatry, University of Toronto, Toronto, Canada; David Brock, Neuronetics, Inc., Malvern, Pennsylvania; Paul Croarkin, Department of Psychiatry, Mayo Clinic, Rochester, Minnesota; Geraldine Dawson, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina; Mark Demitrack, Neuronetics, Inc., Malvern, Pennsylvania; Donald Gilbert, Department of Pediatrics and Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Eric Hollander, Department of Psychiatry and Behavioral Sci- ences, Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York; Marco Iacoboni, Department of Psychiatry and Biobeha- vioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California; Kelvin Lim, Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota; Stewart Mostofsky, Department of Neurology and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Mary- land;Ernest Pedapati, Department of Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Susan Swedo, National Institute of Mental Health, Washington, DC,; Kim Hollingsworth Taylor, Clearly Present Foundation, Minneapolis, Mn USA Christopher Wall, PrairieCare, Rodches- ter, Minnesota; Paul Wang, Autism Speaks, New York, New York; Winifred Wu, Strategic Regulatory Partners, Minneapolis, Minnesota Conflict of interest: LMO has no biomedical financial interests or potential conflicts of interest to disclose. PGE has no biomedical financial interests or potential conflicts of interest to disclose. MFC has no biomedical financial interests or potential conflicts of interest to disclose. AR is listedasan inventor on a patent for apparatus and method of use of TMS in epilepsy. He is a co-founder of Neuro’motion Inc. and serves on the medical advisory board of NeuroRex Inc. APL serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Axilum Robotics, Magstim, Neuroelectrics, and Neosync; and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI). JTM reports receiving consultant income from Roche and Dart Neuroscience, and has received research contract support from Roche. The content of this article reflects discussion had at the “Transcranial Magnetic Stimulation (TMS) Therapy for Autism Consensus Conference” held in May of 2014 and supported by the Clearly Present Foundation, Autism Speaks, and Neuronetics, Inc. From the Neuroplasticity and Autism Spectrum Disorder Program and Department of Psychiatry and Human Behavior, E.P. Bradley Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode, Island (L.M.O.); Cognitive Neuroscience Unit, School of Psychology, Deakin University, Burwood, Victoria, Australia (P.G.E.); Department of Psychiatry and Behavioral Science, University of Louisville, Louisville, Kentucky (M.F.C.); Neuromodulation Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts (A.R.); Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Med- ical School, Boston, Massachusetts (A.R., A.P.-L.); Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California (J.T.M.) Received June 24, 2015; accepted for publication September 01, 2015 Address for correspondence and reprints: Lindsay Oberman, Neuroplasticity and Autism Spectrum Disorder Program, E.P. Bradley Hospital, 1011 Veterans Memorial Parkway, East Providence, RI 02915. E-mail: [email protected] Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/aur.1567 VC 2015 International Society for Autism Research, Wiley Periodicals, Inc.

INSAR Autism Research 00: 00–00, 2015 1 assessments of behavior using Diagnostic and Statistical of the stimulation itself. The aftereffects of rTMS are Manual of Mental Disorders (DSM) ) or International thought to relate to activity-dependent changes in the Classification of Diseases (ICD) criteria, however, post- effectiveness of synaptic connections between cortical mortem, genetic and neuroimaging data indicate that neurons, reflecting cortical plasticity mechanisms [Fitz- the behavioral ASD phenotype is the product of atypi- gerald, Fountain, & Daskalakis, 2006; Hoogendam, cal brain development [Ameis & Catani, 2015]. Despite Ramakers, & Di Lazzaro 2010; Thickbroom, 2007; Zie- many years of research, our understanding of this atypi- mann, et al., 2008]. Single and paired pulse TMS proto- cal neurodevelopment is limited. The brain networks cols are exclusively used for investigational purposes, responsible for the high-level skills that are impaired as while rTMS protocols can be used both in investiga- part of the core ASD features are complex and require tional and therapeutic applications. efficient integration of multiple, distributed brain Given the current data emphasizing circuit-level dys- regions. Thus, ASD pathophysiology likely is not lim- function as well as aberrant synaptic plasticity and exci- ited to dysfunction of a single brain region, but rather a tation/inhibition ratio in ASD (see [Ameis & Catani, breakdown in the functioning and integration of long- 2015; Casanova, Buxhoeveden, & Gomez, 2003; Ober- range neural circuits. man, Rotenberg, & Pascual-Leone, 2014; Rubenstein & Over the past quarter century, neuroscience techni- Merzenich, 2003] for reviews) and the capacity of TMS ques have been developed and applied to ASD to study to both investigate and modulate cortical excitability brain structure and function. Additionally, clinical trials and plasticity [see Huang, Edwards, Rounis, Bhatia, & of therapeutic inteventions aimed at modulating brain Rothwell, 2005; Huerta & Volpe, 2009; Thickbroom, functioning have also been evaluated. In this article, we 2007; Ziemann, 2004], the potential for TMS in the will discuss one neuroscientific technique, namely trans- field of autism research is beginning to be explored in a cranial magnetic stimulation (TMS) that has been used number of laboratories world-wide. both to study the neural mechanisms of ASD as well as The inaugural “Transcranial Magnetic Stimulation to therapeutically target the predicted dysfunction. (TMS) Therapy for Autism Consensus Conference” was TMS is a method for noninvasive focal brain stimula- held in May of 2014 with a second conference held in tion, where localized intracranial electrical currents, large May of 2015. The purpose of these conferences was to enough to depolarize a small population of neurons, are gather TMS and autism researchers and clinicians to generated by rapidly changing extracranial magnetic share recent progress in the field, promote collaboration fields [Wagner, Valero-Cabre, & Pascual-Leone, 2007]. across laboratories and disciplines, and establish con- TMS can be applied in single pulses, pairs of pulses, or sensus on TMS parameters that may be useful for the repeated trains of pulses (rTMS). Following standardized study of pathophysiology and the potential treatment guidelines and procedures, human studies with adults of ASD. This article benefitted from the combined and children have demonstrated TMS procedures to be expertise and discussions of those present at these con- safe and well tolerated[Croarkin, Wall, & Lee, 2011; Gar- ferences. This is an evolving area of research with great vey & Gilbert, 2004; Hong et al., 2015; Rajapakse & Kir- promise, but also many open questions that have yet to ton, 2013; Rossi, Hallett, Rossini, Pascual-Leone, & Safety be explored. In this article, we review the current data of T.M.S. Consensus Group, 2009]. related to the use of TMS both as an investigational and When single pulse TMS is applied in primary motor a therapeutic tool, discuss the challenges inherent in cortex (M1) at suprathreshold intensities, it activates this type of research, and propose a roadmap for future corticospinal outputs, producing a twitch in a periph- research in this area. eral muscle (a motor evoked potential (MEP)), which can be used as an index of corticospinal excitability [Barker, Jalinous, & Freeston, 1985]. Early TMS studies Published Reports of TMS in ASD discovered that the evoked responses are primarily TMS as an Investigative Tool reflective of functioning of intracortical circuits (rather Different TMS paradigms have been developed to probe than the corticospinal projection neurons themselves) cortical excitability, inhibitory control, and plasticity [Day et al., 1989]. Thus, protocols to probe intracortical respectively, and have been used to explore the neuro- inhibitory and facilitatory processes using paired pulse physiology of ASD, generally among individuals with- stimulation protocols have also been developed [Claus, out intellectual disability (findings summarized in Weis, Jahnke, Plewe, & Brunholzl, 1992; Kujirai et al., Table 1). 1993; Valls-Sole, Pascual-Leone, Wassermann, & Hallett, 1992; Ziemann, 1999]. Finally, trains of repeated TMS pulses (rTMS) at various stimulation frequencies and Single pulse TMS. In ASD, single pulse TMS has been patterns can induce a lasting modification of activity in used to probe baseline levels of corticospinal excitabil- the targeted brain region, which can outlast the effects ity and modulation of corticospinal excitability in

2 Oberman et al./TMS in ASD INSAR INSAR Table 1. Published Reports of Investigational Use of TMS in ASD Intellectual Mean age Paper Diagnosis Disability n (ASD) (years) Gender Medication Site Frequency Intensity

Theoret et al. [2005], Current ASD None 10 Age Range: M/F – L M1 Single Pulse and Paired Single Pulse590%, 100%, Biology 23–58 Pulse (1, 2, 3, 6, 9, 105%, 110%, 115%, 120%, 12, 15 msec ISI) 130%, 140%, 150%, 160% RMT; Paired Pulse 5 80% and 120% RMT Minio-Paluello et al. [2009], Bio- AS None 16 28 M – L M1 Single Pulse 120% RMT logical Psychiatry Oberman et al. [2010], Frontiers AS None 5 41 M/F – L M1 TBS 80% AMT in Synaptic Neuroscience Enticott et al. [2010], Develop- ASD (11 HFA, None 25 16.67 M/F clomipramine, risperidone, que- L and R M1 Single Pulse and Paired Single Pulse5115% RMT; Paired mental Medicine and Child 14 AS) tiapine, venlafaxine, ﬂouxe- Pulse (2 and 15 msec Pulse590% and 115% RMT Neurology tine, valproate ISI) Jung et al. [2012], Developmen- ASD (7 HFA, 6 None 15 18 M/F None R M1 (PAS) PAS, Single Pulse and Lowest intensity producing aver- tal Medicine and Child AS, 2 PDD- NOS) Paired Pulse (2 and 3 age 1 mV motor-evoked Neurology msec ISI) potential Oberman et al. [2012], European AS None 35 (cTBS), 36 M/F – L M1 TBS 80% AMT Journal of Neuroscience

bra ta.TSi S 3 ASD in al./TMS et Oberman of which 9 also iTBS Enticott et al. [2012], Biological ASD None 34 26 M/F SSRI, atypical antipsychotic, L M1 Single Pulse 120% RMT Psychiatry benzodiazapine, antidepressant Enticott et al. [2013], Frontiers ASD None 32 25 M/F SSRI, atypical antipsychotic, L M1 Single Pulse 120% RMT in Human Neuroscience benzodiazapine, antidepressant Enticott et al. [2013], ASD None 36 26 M/F ﬂuoxetine, citalopram, sertraline, L and R M1 Single Pulse and Paired Single Pulse5115% and Neuropharmacology lorazepam, olanzapine, Pulse (2, 15 and 100 130% RMT; 115% and venlafaxine, risperidone, msec ISI) mirtazapine, quetiapine 130% AMT; Paired Pulse590% RMT and 120% RMT Oberman et al. [2014], Frontiers ASD None 19 12 M citalopram, atomoxetine, L M1 TBS 80% AMT in Human Neuroscience buspirone, sertraline, methylphenidate, risperidone, guanfacine Oberman et al., [2014], Medical ASD None 35 36 M/F – L M1 TBS 80% AMT Hypotheses

Pulses Assessment Side Paper Duration Trains Delivered Sessions Blinding Times Reported Effects Effects

Theoret et al. [2005], Current n/a n/a 264 1 None Online No group difference in RMT or response Not Indicated Biology to ppTMS. Impaired corticospinal facilitation in response to ﬁnger movements viewed from the egocetnric point of view in the ASD group. Minio-Paluello et al. [2009], Bio- n/a n/a 72 1 None Online No modulation of corticospinal excitabil- Not Indicated logical Psychiatry ity in response to the observation of painful stimuli affecting another individual in the Asperger’s Group. bra ta.TSi ASD in al./TMS et Oberman 4 Table 1. Continued Pulses Assessment Side Paper Duration Trains Delivered Sessions Blinding Times Reported Effects Effects

Oberman et al. [2010], Frontiers 190 s (iTBS), iTBS: 20 3 2s, 600 2 (1 cTBS, None Before, 5, 10, 20, 30, Longer lasting facilitation None in Synaptic Neuroscience 47 s (cTBS) 10 s ISI; cTBS 1 iTBS) 40, 50, 60, 75, 90, (enhanced MEP) following iTBS in 1 train of 47 s 105, 120min after ASD Longer lasting inhibition cTBS (suppressed MEP) following cTBS in ASD No effect the following day using opposite protocol for ASD (suggesting enhanced metaplasticity) Enticott et al. [2010], Develop- n/a n/a 120 1 None Online Reduced intracortical inhibition in the Not Indicated mental Medicine and Child HFA group as compared to the AS or Neurology control group Jung et al. [2012], Developmen- 13.3 min (PAS) n/a 200 1 None Before, after, 30 min No LTP-like MEP facilitation in ASD – tal Medicine and Child after, 60 min after (group difference signiﬁcant at 60 Neurology PAS min). No group difference in response to ppTMS. Oberman et al. [2012], European 190 s (iTBS), iTBS: 20 3 2s, 600 1 or 2 Data analysis Before, 5, 10, 20, 30, Longer lasting facilitation None Journal of Neuroscience 40 s (cTBS) 10 s ISI; cTBS (patient group) 40, 50, 60, 75, 90, (enhanced MEP) following iTBS in 105, 120 min after 1 train of 40 s cTBS ASD Longer lasting inhibition (suppressed MEP) following TBS in ASD Enticott et al. [2012], Biological n/a n/a 50 1 None Online No group difference in degree of Not Indicated Psychiatry corticospinal excitability in response to observation of single static hand stimuli. Impaired corticospinal facilitaiton in response to single hand transitive hand actions in the ASD group. Enticott et al. [2013], Frontiers n/a n/a 50 1 None Online No group difference in degree of Not Indicated in Human Neuroscience corticospinal excitability in response to single static hand stimuli or two person interactive hands. Enticott et al. [2013], n/a n/a 170 1 None Online No group difference in RMT. Not Indicated Neuropharmacology Heterogeneous response to paired pulse TMS in the ASD group. Oberman et al. [2014], Frontiers 40 s cTBS 1 train of 40 s 600 1 Data analysis Before, 5, 10, 20, 30, Positive linear relationship between age mild headache, in Human Neuroscience (patient group) 40, 50, 60, 75, 90, and duration of modulation of TBS mild fatigue. 105, 120 min after after effects in children and cTBS adolescents with ASD. A subgroup of the ASD participants showed paradoxical facilitation. Oberman et al., [2014], Medical 40 s cTBS 1 train of 40 s 600 1 Data analysis Before, 5, 10, 20, 30, Longer lasting inhibition (suppressed None Hypotheses (patient group) 40, 50, 60, 75, 90, MEP) and greater degree of inhibition 105, 120 min after (area under the curve) following TBS cTBS in ASD. Age did not signiﬁcantly contribute to the model.

All studies used TMS-evoked MEP amplitude as outcome measures. All Studies used Figure of 8 coils. ASD, Autism Spectrum Disorder; HFA, High Functioning Autism; PDD-NOS, Pervasive Develop- mental Disorder, Not Otherwise Speciﬁed; AS, Asperger’s Syndrome; M1, Primary Motor Cortex; Fo8, Figure of 8 coil; ISI, Interstimulus Interval; ppTMS, Paired Pulse TMS; rTMS, Repetitive Transcra-

INSAR nial Magnetic Stimulation; PAS, Paired Associative Stimulation; iTBS, Intermittant Theta Burst Stimulation; cTBS, Continuous Theta Burst Stimulation; RMT, Resting Motor Threshold; AMT, Active Motor Threshold; MEP, Motor Evoked Potential; LTP, Long Term Potentiation; SSRI, Selective Serotonin Reuptake Inhibitor. response to visually presented stimuli. Six independent receptors [Ziemann, Tergau, Wischer, Hildebrandt, & studies have shown no difference in either motor Paulus, 1998], GABAA receptors [Inghilleri, Berardelli, threshold (the lowest intensity of stimulation required Marchetti, & Manfredi, 1996; Mohammadi, et al., 2006; to induce a MEP) or size of MEP in response to a supra- Ziemann, Lonnecker, Steinhoff, & Paulus, 1996], and threshold pulse of TMS between individuals with ASD noradrenaline (NA) receptors [Boroojerdi, Battaglia, and neurotypical individuals [Enticott, Kennedy, Muellbacher, & Cohen, 2001; Gilbert et al., 2006; Her- Rinehart, Bradshaw, et al., 2013; Enticott, Kennedy, wig, Brauer, Connemann, Spitzer, & Schonfeldt-Lecuona, Rinehart, Tonge, et al., 2013; Enticott, Rinehart, Tonge, 2002; Kirschner et al., 2003; Moll, Heinrich, & Rothen- Bradshaw, & Fitzgerald, 2010; Minio-Paluello, Baron- berger, 2003; Plewnia, Bartels, Cohen, & Gerloff, 2001; Cohen, Avenanti, Walsh, & Aglioti, 2009; Oberman Plewnia et al., 2002]. Two suprathreshold pulses deliv- et al., 2012; Theoret et al., 2005]. These published data ered at an interpulse interval of 50–200 msec is used to suggest that baseline M1 excitability is not affected in evaluate GABA mediated long interval intracortical inhi- ASD. bition (LICI) [McDonnell, Orekhov, & Ziemann, 2006; Several other studies [Enticott, Kennedy, Rinehart, Pierantozzi et al., 2004; Valls-Sole et al., 1992; Werhahn, Bradshaw, et al., 2013; Enticott, Kennedy, et al., 2012; Kunesch, Noachtar, Benecke, & Classen, 1999; Hsieh Minio-Paluello et al., 2009; Theoret et al., 2005] et al., 2012]. assessed modulation of M1 excitability in individuals A number of studies have been conducted using these with ASD as measured by single pulse TMS during the paradigms to probe intracortical inhibition and facilita- observation of another person’s actions. In neurotypical tion in ASD. Two studies report no significant differ- individuals the observation of another person’s actions ence in response to the SICI paradigm between ASD results in a simultaneous activation of the observer’s and neurotypical individuals [Jung et al., 2013; Theoret sensorimotor system. This phenomenon is referred to as et al., 2005]. Three studies employed the ICF paradigm interpersonal motor resonance (IMR) and is considered and found no significant difference between ASD and a putative index of mirror neuron system activity neurotypical controls [Enticott, Kennedy, Rinehart, [Uithol, van Rooij, Bekkering, & Haselager, 2011]. Stud- Tonge, et al., 2013; Enticott et al., 2010; Theoret et al., ies evaluating IMR in individuals with ASD have 2005]. Three studies have reported mixed results with reported mixed results that appear to be dependent on some ASD individuals showing impaired intracortical the properties of the stimuli such as the presentation inhibition and others showing typical responses [Enti- from egocentric or allocentric perspectives, transitive cott, Kennedy, Rinehart, Tonge, et al., 2013; Enticott versus intransitive actions, or the social or emotional et al., 2010; Oberman et al., 2010]. Thus, abnormal content of the stimulus. These findings suggest that the intracortical inhibition may be present in a subgroup, aberrant IMR responses may be a result of differences in but this alteration of cortical physiology does not visual processing or attention to certain stimuli, but appear to be consistently demonstrable in all individu- typical responses to other stimuli in ASD [Enticott, Ken- als with ASD. nedy, Rinehart, Bradshaw, et al., 2013]. rTMS. The effects of single and paired pulses are short Paired Pulse TMS. In the conventional paired pulse lasting (on the order of milliseconds), however, when TMS protocol, two consecutive magnetic pulses are pulses are applied in repeated trains, such as in the case applied through the same TMS coil in rapid succession of rTMS, there is the potential to affect cortical excit- over primary motor cortex at various interpulse inter- ability for several minutes following a single session, or vals. The outcome measure is the degree of effect of the several days to months following a series of daily ses- first pulse “conditioning stimulus” (CS) on the second sions. Thus, rTMS can be used to provide a measure of pulse “test stimulus” (TS) [Claus et al., 1992; Kujirai cortical plasticity (the degree to which the excitability et al., 1993; Valls-Sole et al., 1992; Ziemann, 1999]. of the cortex changes following these rTMS trains) When the interpulse interval between a subthreshold [Pascual-Leone et al., 2011]. Depending on the parame- CS and suprathreshold TS is 1–6 msec, the resulting ters of stimulation, focal cortical excitability can be

MEP suppression is thought to reﬂect GABAA receptor either facilitated or suppressed [Pascual-Leone, Valls- mediated short-interval intracortical inhibition (SICI) Sole, Wassermann, & Hallett, 1994]. The degree and [Kujirai et al., 1993; Ziemann et al., 2015]. When the direction of the effect of rTMS, both at the level of the interpulse interval is increased to 10–25 msec, the net brain and behavior, depends on factors such as location result is facilitatory, making this paired pulse paradigm of stimulation, intensity of stimulation, frequency of a putative index of intracortical facilitation (ICF), which stimulation, number of sessions, and frequency of ses- is thought to be mediated by a combination of receptor sions, as well as individual symptom pathophysiology types including n-methyl-d-aspartate (NMDA) glutamate [Rotenberg, Horvath, & Pascual-Leone, 2014]. Some

INSAR Oberman et al./TMS in ASD 5 protocols appear to induce suppression or facilitation strated an increase in the duration of response across through Hebbian mechanisms of long-term depression childhood and revealed a subgroup of children who (LTD) and long-term potentiation (LTP) across popula- showed paradoxical facilitation to the typically suppres- tions of neurons [Ahmed & Wieraszko, 2006; Cardenas- sive cTBS paradigm [Oberman, Rotenberg, et al., 2014]. Morales, Gron, & Kammer, 2011; Thickbroom, 2007]. The authors suggested that their findings may reflect While others may induce these changes by modulating abnormalities in GABAergic inhibitory control in those activity in GABAergic interneurons [Funke & Benali, individuals who showed paradoxical facilitation. 2010; Trippe, Mix, Aydin-Abidin, Funke, & Benali, Although both PAS and TBS paradigms suggest abnor- 2009]. The prominent role of inhibitory interneurons in malities in cortical plasticity in ASD, initial studies have rTMS-induced modulation of cortical excitation is of yielded conflicting findings, with PAS showing impaired importance in autism as the GABAergic system has and TBS showing enhanced plasticity. These differences repeatedly been implicated in this disorder. may reflect the small sample sizes of the studies, etiolo- One rTMS protocol developed specifically to probe gic heterogeneity of the population, or paradigmatic NMDA dependent Hebbian plasticity mechanisms is differences (Hebbian vs. non-Hebbian mechanisms) and refererred to as Paired associated stimulation (PAS) highlight the need for larger-scale studies that include [Stefan, Kunesch, Cohen, Benecke, & Classen, 2000; phenotypic and if possible genotypic characterization Ziemann, 2004] This protocol involves applying pairs of of the samples [Enticott & Oberman, 2013]. electrical median nerve stimulation combined with single pulses of TMS to primary motor cortex repeatedly for 90 pairings with 20 sec between the pairings (for Summary of TMS as an Investigational Tool in approximately 30 min). In neurotypical individuals, ASD. In summary, the findings from the above men- when the peripheral median nerve stimulation and tioned literature using TMS as an investigational device TMS stimulation are timed such that the afferent signal partially support the theories suggesting excitation/ coming from the peripheral nerve stimulation to the inhibition imbalance and aberrant plasticity mecha- motor cortex arrives at the same time as the TMS pulse nisms in ASD. However, what the studies above reveal is applied over the primary motor cortex (25 msec most clearly is the variability of the findings. Other interstimulus interval), an LTP-like facilitation of corti- than no abnormality in baseline corticospinal excitabil- cal excitability, lasting up to an hour after the end of ity, all other indexes of response to TMS vary both the protocol, is induced [Classen et al., 2004]. Jung within and across studies. One should note that the et al. [2013] recently published a study reporting abnor- sample sizes in the studies are relatively small (ranging mally reduced LTP-like facilitation of MEPs following from 5 to 36) and represent a small subgroup of the the PAS paradigm in individuals with ASD, suggesting overall ASD population. Specifically, (1) the aforemen- an impairment in Hebbian plasticity mechanisms. tioned studies either did not document or did not Another common rTMS paradigm, theta burst stimu- exclude individuals on psychoactive medications; (2) all lation (TBS), has been developed to investigate nonHeb- studies excluded individuals with intellectual disability; bian plasticity mediated by changes in GABAergic tone and, (3) all studies excluded individuals with a history [Benali et al., 2011; Stagg et al., 2009]. TBS involves of seizures or abnormal electroencephaolography (EEG) application of 3 bursts of 50-Hz rTMS repeated every findings. 200 msec either continuously (cTBS) for a total of 40 A number of unanswered questions related to the use sec or intermittently (iTBS) (every 8 sec) for about 3 of TMS as an investigative device in ASD remain—Are min [Huang, Edwards, Rounis, Bhatia, & Rothwell, aberrant physiological findings causal or a consequence 2005; Huang, Rothwell, Edwards, & Chen, 2008]. When of ASD pathology? What is the impact of age or devel- applied to the motor cortex, cTBS and iTBS tend to opment on these measures? Are the effects consistent result in lasting suppression or facilitation, respectively, across the spectrum (verbal and nonverbal, with and of cortical excitability for approximately 20–40 min in without comorbidities or intellectual disability)? And neurotypical individuals [Huang et al., 2005]. Oberman what underlying mechanisms are driving the observed and coworkers recently published a series of studies heterogeneity in the population? Future research efforts where high functioning adults with ASD showed an should acquire larger, well-powered samples and increased duration of response to the TBS paradigm attempt to stratify or enrich ASD samples according to [Oberman et al., 2012; Oberman et al., 2010; Oberman clinical, genetic, or neurocognitive attributes. Addition- & Pascual-Leone, 2014]. The authors interpreted this ally, researchers should strive to adopt consistent exper- increased duration to represent hyperplasticity (seem- imental procedures including standardized pulse ingly counter to the impaired plasticity response sequences, outcome measures, and side-effect monitor- reported by Jung et al. [2013]). An additional study ing. There is intrasubject and intersubject variability in where TBS was applied to children with ASD demon- response to rTMS even when the parameters are kept

6 Oberman et al./TMS in ASD INSAR constant, the variability of effects will be even larger with ASD. Statistically significant improvements in irri- when publications vary on other experimental proce- tability and repetitive behaviors [Baruth et al., 2010; dures. Despite the limitations of the studies to date, Casanova et al., 2012; Casanova et al., 2014; Sokhadze, results suggest that TMS-measures of brain physiology El-Baz, Sears, et al., 2014; Sokhadze, El-Baz, Tasman, may have the potential to serve as biomarkers to guide et al., 2014], normalization of (EEG) components the search for ASD subtypes. related to target detection and error monitoring [Baruth et al., 2010; Casanova et al., 2012; Sokhadze et al., TMS as a Therapeutic Intervention 2009, 2010, 2012; Sokhadze, El-Baz, Sears, et al., 2014] rTMS has been studied as a therapeutic intervention for and enhanced autonomic balance [Casanova et al., a number of neurological and psychiatric conditions 2014] have been reported following this protocol. These [Kobayashi & Pascual-Leone, 2003]. These include results have been further corroborated and improved medication-refractory major depressive disorder [Gaynes on in a pilot trial using EEG neurofeedback in combina- et al., 2014] where two different TMS devices are tion with rTMS [Sokhadze, El-Baz, Tasman, et al., 2014]. cleared by the Food and Drug Administration, stroke Though the effect sizes were large in these studies rehabilitation [Pinter & Brainin, 2013], chronic pain (d50.7–1.2), the trial designs were all open-label (with a [Galhardoni et al., 2015] Parkinson’s disease [Kimura waitlist control group), thus results may be confounded et al., 2011], Alzheimer’s disease [Freitas, Mondragon- by placebo effects or adaptation to the environment Llorca, & Pascual-Leone, 2011], and epilepsy [Sun et al., and protocol. 2012]. Additional studies have applied low-frequency rTMS A number of recent studies [Baruth et al., 2010; to other regions of prefrontal cortex to modulate func- Casanova et al., 2012; Casanova et al., 2014; Enticott tioning of different cortical circuits. Fecteau et al. [Fec- et al., 2014; Enticott, Rinehart, Tonge, Bradshaw, & teau et al., 2011] discovered that 1 Hz rTMS to Fitzgerald, 2012; Fecteau, Agosta, Oberman, & Pascual- individuals with ASD enhanced object naming when Leone, 2011; Panerai et al., 2013; Sokhadze et al., 2010; applied to left pars triangularis, but reduced object Sokhadze et al., 2012; Sokhadze et al., 2009; Sokhadze, naming when applied to left pars opercularis. Enticott El-Baz, Sears, Opris, & Casanova, 2014; Sokhadze, El- et al. [2012] reported changes in movement-related EEG Baz, Tasman, et al., 2014] and case reports [Cristancho, cortical potentials (MRCPs) that are involved in prepa- Akkineni, Constantino, Carter, & O’Reardon, 2014; ration and execution of movements. Following a single Enticott, Kennedy, Zangen, & Fitzgerald, 2011; Nie- session of 1 Hz rTMS to supplementary motor area and derhofer, 2012] have reported on the efficacy of both M1 (relative to M1 sham) ASD participants showed high and low frequency rTMS protocols in ASD (find- increases in these components, indicating increased ings summarized in Table 2). A variety of brain regions activity in supplementary motor cortex during move- and symptom domains have been targeted including: ment preparation. There were, however, no observable dorsal lateral prefrontal cortex (DLPFC) to improve irri- changes in motor behavior. tability, repetitive behaviors, and executive functioning, supplementary and primary motor cortices to improve High Frequency Stimulation. Other investigators motor behavior, medial prefrontal cortex to improve have employed high-frequency rTMS protocols in an mentalizing, and premotor cortex to improve speech attempt to enhance excitability within presumably production and eye-hand coordination. Of importance underactive cortical regions and associated networks in to note, it is unlikely that therapeutic TMS would ASD. Enticott et al. [2014] applied either active or sham reverse multiple aspects of the ASD phenotype, rather, high-frequency (5 Hz) rTMS to bilateral medial prefron- it may improve specific core or associated symptoms tal cortex among adults with ASD in a double-blind related to an alteration in the functioning of a specific randomized sham-controlled trial. This study was cortical region or circuit. designed to have an excitatory effect on networks devoted to mentalizing, which have shown reduced Low Frequency Stimulation. The earliest and activation in ASD in neuroimaging studies [Di Martino majority of the published studies on therapeutic use of et al., 2009]. The authors reported a significant rTMS in ASD have been conducted by Manuel Casanova improvement in the Social Relatedness Subscale of the and et al. [2003], who have employed low-frequency, Ritvo Autism Asperger Diagnostic Scale (RAADS) with a subthreshold rTMS to dorsolateral prefrontal cortex medium effect size, but no effect on other behavioral (DLPFC) (left or sequential bilateral) to suppress excit- scales including the Autism Spectrum Quotient (AQ), ability in ASD. This paradigm was chosen to address the Interpersonal Reactivity Index (IRI), or experimental hypothesized cortical inhibition deficits resulting from measures of mentalizing (reading the mind in the eyes suspected minicolumnar abnormalities in individuals test and animations mentalizing test). In another trial,

INSAR Oberman et al./TMS in ASD 7 bra ta.TSi ASD in al./TMS et Oberman 8 Table 2. Published Reports of Therapeutic Use of TMS in ASD

Intellectual Mean age Paper Diagnosis Disability n (ASD) (years) Gender Medication Site Coil Frequency Intensity Duration

Sokhadze et al. [2009], Journal of Autism None 13 (8rTMS, 17 M – L dlPFC (5cm anterior to Fo8 0.5 Hz 90% RMT 10 min Autism and Developmental Disorders 5waitlist) M1) (RCT with waitlist control) Baruth et al. [2010], Journal of ASD 2 25 (16rTMS, 14 M/F – L & R dlPFC (5cm ante- Fo8 1 Hz 90% RMT 10 min Neurotherapy (RCT with waitlist control) 9waitlist) rior to M1) Sokhadze et al. [2010], Applied Autism None 13 16 M/F – L dlPFC (5cm anterior to Fo8 0.5 Hz 90% RMT 10 min Psychophysiology and Biofeedback M1) (Clinical trial with no control) Enticott et al. [2011], Journal of ECT AS None 1 20 F None Bilateral dmPFC (7cm H-coil 5 Hz 100% RMT 15 min (Single case study) anterior to M1) Fecteau et al. [2011], European Journal AS None 10 37 M/F None L & R pars opercularis, L Fo8 1 Hz 70% of 30 min of Neuroscience (Crossover trial with & R par triangularis stimulator sham control) (MRIneuronaviga output tion), sham (central lobe midline) Casanova et al. [2012], Translational ASD None 45 (25 rTMS, 13 M/F - L & R dlPFC (5cm ante- Fo8 1 Hz 90% RMT 10 min Neuroscience (RCT with waitlist control) 20waitlist) rior to M1) Enticott et al. [2012], Brain Stimulation ASD (6 None 11 18 M/F - SMA (15%of nasion to Fo8 1 Hz 100% RMT 15 min (Crossover trial with sham control) HFA, 5 AS) inion anterior to Cz), L M1, Sham (M1) Niederhofer [2012], Clinical Neuropsychiatry Autism Not reported 1 42 F None M1 – 1 Hz – 1 hr (Single case study with placebo) Sokhadze et al. [2012], Applied Psychophysiology ASD (36 None 40 (20 rTMS, 14 M/F – L & R dlPFC (5cm ante- Fo8 1 Hz 90% RMT 10 min and Biofeedback (RCT with waitlist control) HFA, 4 AS) 20waitlist) rior to M1) Panerai et al. [2013], Autism ((i) Crossover trial Autism Severe to (i) 9 (i)14 M– (i) left and right PrMC Fo8 (i)8 Hz, 1 Hz 90% RMT 8 Hz 30min, with sham; (ii) RCT with sham; (iii) crossover profound (ii) 17 (ii)13 (2.5 cm anterior to (ii)8 Hz, 1Hz trial with shamiv) RCT (TMS, EHItraining, (iii) 4 (iii)16 M1) 1 Hz (iii), 15 min; TMS 1 EHItraining)) (iv) 13 (iv) 13 (ii), (iii), iv) left PrMC (iv) 8 Hz Enticott et al. [2014], Brain Stimulation ASD (4 None 28 (15active, 33 M/F Yes (39%) dmPFC (7cm anterior to H-coil 5 Hz 100% RMT 15 min (RCT with sham control) HFA, 24 AS) 13sham) M1) Cristancho et al. [2014], Journal of ECT Autism, Not reported 1 15 M olanzapine, (i) R DLPFC Fo8 1 Hz 0% RMT Variable (Single case study) Depression ﬂuoxetine, (6cm anterior to M1), (between guanfacine, (ii) L DLPFC 5 to 25 min) (6cm anterior to M1) clonazepam Casanova et al. [2014], Frontiers in Human ASD None 18 13 M/F – L & R dlPFC (5cm ante- Fo8 5 Hz 90% RMT 10 min Neuroscience (Proof of feasibility study, rior to M1) no control) Sokhadze et al. [2014a], Frontiers in ASD None 27 14.5 M/F – L & R dlPFC (5cm ante- Fo8 1 Hz 90% RMT 10 min Systems Neuroscience (RCL with rior to M1) waitlist control) Sokhadze et al. [2014b], Appl Psychophysiol ASD None 42 14.5 M/F – L & R dlPFC (5cm ante- Fo8 1 Hz 90% RMT 10 min Biofeedback (Clinical trial with waitlist rior to M1)

INSAR control) INSAR Table 2. Continued

Pulses Paper Trains Delivered Sessions Blinding Measures Assessment Times Reported Effects Side Effects

Sokhadze et al. [2009], 15 3 10 sec, 150 6 None EEG Gamma power Accuracy, Before and two Decreased frontal EEG P3a amplitude – Journal of Autism and 20–30 sec ISI RT (Kanizsa), Abberant weeks after treat- to non-targets following TMS Developmental Behavior Checklist (ABC), ment course Decreased centro-parietal latency Social Responsiveness EEG P3b to nontarget and non- Disorders Scale (SRS) (Caregiver- Kanizsa following TMS report), Decrease in gamma power for non- Repetitive Behavior Scale- target and non-Kanizsa following Revised (RBS-R) TMS Reduced repetitive behavior (RBS-R) following TMS Baruth et al. [2010], 15 3 10 sec, 150 12 (6 L, 6 R) None EEG Gamma power Accuracy, Before and two Increased EEG gamma power to tar- Itching sensation at Journal of 20–30 s ISI RT (Kanizsa), Abberant weeks after treat- gets, decrease to nontargets nose (5) Neurotherapy Behavior Checklist (ABC), ment course Reduced repetitive behavior (RBS-R) Mild headache (1) Social Responsiveness Reduced irritability (ABC) Scale (SRS) (Caregiver- report),

bra ta.TSi S 9 ASD in al./TMS et Oberman Repetitive Behavior Scale- Revised (RBS-R) Sokhadze et al. [2010], 15 3 10 sec, 150 6 None EEG event-related potentials Before and two Reduced error rate – Applied Psychophysi- 20–30 sec ISI (visual oddball) Accuracy, weeks after treat- Increased frontal EEG P50 amplitude ology and RT (Kanizsa) Abberant ment course to targets Increased frontal EEG P50 latency to Biofeedback Behavior Checklist (ABC) targets Social Responsiveness Decreased frontal EEG N200 latency Scale (SRS) (Caregiver- to novel distractors report) Repetitive Behavior Decreased parieto-occipital EEG P50 Scale-Revised (RBS-R) to novel distractor Increased centro-parietal EEG P50 to targets and decreased to standard distractor Centro-parietal EEG P3b amplitude increase to targets and decrease to standard distractors Centro-parietal EEG P200 increased latency to targets Reduced repetitive behaviors (RBS- R) Enticott et al. [2011], 30 3 10 sec, 1500 10 Double IRI, AQ, RAADS Before, after, and Reduction on all measures Anecdotal None Journal of ECT 20 sec ISI one-month after reports of improvement from treatment course patient and relatives Fecteau et al. [2011], 1 1800 1 per site Double Response latency on Boston Before and after TMS Increased response latency after L Many reported, European Journal of Naming Test pars opercularis including: Sleepy, Neuroscience Decreased response latency after L Trouble concen- pars triangularis trating, Improved mood, Headache, Dizziness 0Oemne l/M nASD in al./TMS et Oberman 10

Table 2. Continued

Pulses Paper Trains Delivered Sessions Blinding Measures Assessment Times Reported Effects Side Effects

Casanova et al. [2012], 15 3 10 sec, 150 12 (6 L, 6 R) None EEG event-related potentials Before and two Reduced error rate Increased frontal – Translational 20–30 sec ISI (ERP) Accuracy, RT weeks after treat- EEG N200 to targets Neuroscience (Kanizsa), Abberant ment course Reduced frontal EEG N200 latency Increased frontal RHEEG P300 to Behavior Checklist (ABC), targets Social Responsiveness Increased parietal EEG N200 to tar- Scale (SRS) (Caregiver- gets, Reduced repetitive behavior report), Repetitive Behav- (RBS) Reduced irritability (ABC) ior Scale - Revised (RBS- R) Enticott et al. [2012], 1 900 1 per site Single EEG movement-related corti- Before and after TMS SMA: increased early EEG component – Brain Stimulation cal potentials Motor PMC: increased EEG negative slope response time Niederhofer [2012], Clin- 1 1200 5 Single Abberant Behavior Checklist Before and after ABC Irritability: Active 40 to 33, – ical Neuropsychiatry (ABC) treatment course Sham 39 to 35, ABC Sterotypy: Active 18 to 12, Sham 16 to 15 Sokhadze et al. [2012], 15 3 10 sec, 150 12 (6 L, 6 R) None EEG event-related potentials Before and after Reduced omission error rates – Applied Psychophysi- 20–30 sec ISI (ERPs) RT treatment course Increased EEG ERN amplitude ology and Accuracy (Kanizsa) Reduced EEG ERN latency Biofeedback Panerai et al. [2013], 8Hz303 3.6 sec, 900 i) 3; Double (i), (ii), (iii), (iv) Psycho- Before and after (i), (ii), (iii) improved eye-hand – Autism 56.4 sec ISI ii) 10; educational Proﬁle- treatment course coordination score following lPrMC iii) 5 active, Revised (PEP-R) eye-hand HF TMSiv) Improved eye-hand coordination score following com- 5 sham, coordination; bined TMS 1 EHI training compared 5 active, to each technique alone 5 sham;iv) 10 Enticott et al. [2014], 30 3 10 sec, 1500 10 Double Interpersonal Reactivity Before, after, and Reduced social relatedness (RAADS) 1. “light- Brain Stimulation 20 sec ISI Index (IRI) one-month after Reduced personal distress (IRI) headedness” Autism Spectrum Quotient treatment course 2. facial discomfort (AQ) during rTMS Ritvo Autism-Aspergers Diag- nostic Scale (RAADS) Reading the Mind in the Eyes Test (RMET) Mentalizing Animations Task Cristancho et al. [2014], (i) 15 3 10 sec, (i) 150–300, (i) 10, (ii) 26 None Mental status examination Before and after Anecdotal reports of improve mood, Mild headaches, jaw Journal of ECT 10–30 sec (ii) 300–600 treatment course eye contact, interpersonal commu- twiching, tran- ISI (week 1), 30 3 nication, verbal expression, focus, sient dizziness 10 sec, 10–30 sec activity ISI (week 2), (ii) 30–60 3 10 sec, 10–15 sec ISI INSAR INSAR Table 2. Continued

Pulses Paper Trains Delivered Sessions Blinding Measures Assessment Times Reported Effects Side Effects

Casanova et al. [2014], 8 3 10 sec, 160 18 None Aberrant Behavior Checklist, Before and 2 weeks Increase in R-R interval, SDNN, and None Frontiers in Human 20 sec ISI restricted Behavior Pat- after treatment HF power. Significant decrease in Neuroscience tern, Time- domain meas- the LF/HF ratio and SCL. Signifi- ures of HRV (R-R interval, cant improvements in RBS-R and SDNN, RMSSD, pNN50), ABC rating scores. Frequency –domain measures of HRV (LV and HF of HRV, LF/HF ratio index), SCL Sokhadze et al. [2014a], 9 3 20 sec, 180 18 None Aberrant Behavior Checklist Before and after Decreased irritability and hyperactiv- None Frontiers in Systems 20–30 sec ISI (ABC), Repetitive Behav- ity on the Aberrant Behavior Neuroscience ior Scale (RBS-R), EEG Checklist (ABC), and decreased event related potentials stereotypic behaviors on the (ERPs), RT and post-error Repetitive Behavior Scale (RBS-R). RT Decreased amplitude and pro- bra ta.TSi S 11 ASD in al./TMS et Oberman longed latency in the frontal and fronto-central N100, N200, and P300 (P3a) ERPs to non-targets. Increased amplitude of P2d (P2a to targets minus P2a to non-targets) and centro-parietal P100 and P300 (P3b) to targets. Decrease in latency and increase in negativity of ERN during com- mission errors. Sokhadze et al. [2014b], 9 3 20 sec, 180 18 None Aberrant Behavior Checklist, Before and after Integrated TMS-NFB treatment None Appl Psychophysiol 20–30 sec ISI Repetitive Behavior Scale- enhanced the process of target Biofeedback Revised, EEG Gamma recognition. Significant improve- power, Theta/Beta ratio, ments in RBS-R and ABC rating RT and Accuracy, Post- scores. Improvement in both early error RT, EEG event and later stage ERP indices. related potentials (ERPs)

ASD, Autism Spectrum Disorder; HFA, High Functioning Autism; AS, Asperger’s Syndrome; M1, Primary Motor Cortex; dlPFC, Dorsolateral Prefrontal Cortex; dmPFC, Dorsomedial Prefrontal Cortex; Fo8, Figure of 8 coil; ISI, Interstimulus Interval; rTMS, Repetitive Transcranial Magnetic Stimulation; RMT, Resting Motor Threshold. Panerai et al. [2013] applied high frequency (8 Hz) rTMS as an intervention for multiple symptom targets rTMS to left premotor cortex in children with ASD with in ASD, three of which are using a randomized, double- intellectual disability. The authors report significant blind, sham-controlled approach (e.g., ClinicalTrials.gov improvements in eye-hand coordination that were ID: NCT02311751, NCT01388179, and NCT00808782). accentuated when paired with behavioral eye-hand It is the consensus of the authors that off-label clinical integration training. Notably, this is the only study in use of rTMS for therapeutic interventions in ASD with- the published literature that included participants with out an investigational device exemption and outside of intellectual disability. an IRB approved research trial is currently premature pending further, properly powered and well-controlled trials. Summary of TMS as a Therapeutic Intervention in ASD. Although an emerging literature, the afore- mentioned trials collectively provide preliminary sup- Development of a Roadmap for the Use of TMS port for further exploration of the potential efficacy of in ASD Research rTMS for ASD. However, no study published thus far has followed strict clinical trial protocols (e.g., random- As with any investigational or therapeutic device, appli- ization, identification of clear and objective primary cation of TMS poses both practical and ethical chal- endpoints, double-blinding with appropriate sham con- lenges that need to be addressed (see Table 3 for a ditions, sufficient power, etc.), thus the generalizability summary of challenges and recommendations). Among to clinical settings is unclear. challenges to consider when determining the research A publication [Lefaucheur et al., 2014] recently estab- utility and clinical efficacy of TMS in any population lished guidelines for evaluating the therapeutic efficacy are: (1) establishment of experimental guidelines that of rTMS in a number of indications. Four classes of should be kept uniform across studies, and how to studies were described: A Class I study is an adequately ensure adherence to such guidelines and (2) study data-supported, prospective, randomized, placebo- design, analysis, and measurement strategies to ensure controlled clinical trial with masked outcome assess- treatment and assessment blinding. This second chal- ment in a representative population (n 25 patients lenge is necessary to protect against placebo effects, receiving active treatment) and includes (a) randomiza- thus yielding valid and reliable data across studies. tion concealment; (b) clearly defined primary out- These more general challenges apply across clinical comes; (c) clearly defined exclusion/inclusion criteria; populations and have been specifically addressed in (d) adequate accounting for dropouts and crossovers recent white papers [Brunoni & Fregni, 2011; Canadian with numbers sufficiently low to have minimal poten- Agency for Drugs and Technologies in Health, 2014; tial for bias, and (e) relevant baseline characteristics Klein et al., 2015; Lefaucheur et al., 2014; Nielson, substantially equivalent among treatment groups or McKnight, Patel, Kalnin, & Mysiw, 2015]. The TMS in appropriate statistical adjustment for differences. A ASD literature would greatly benefit from applying the Class II study is a randomized, placebo-controlled trial knowledge that has been gleaned by TMS researchers performed with a smaller sample size (n < 25) or that working in other clinical applications to future studies. lacks at least one of the criteria listed above. Class III For ASD there are additional challenges to manage studies include all other controlled trials. Class IV stud- including: (1) the known behavioral, functional, and ies are uncontrolled studies, case series, and case neurological heterogeneity of the population and (2) reports. There have been 15 studies and case reports safety, tolerability and ethical concerns related to published assessing rTMS as a therapeutic intervention potentially increased risk of side effects, tolerability of in ASD, however, most would be characterized as Class these procedures, as well as developmental considera- III or IV. Thus, therapeutic use of rTMS in ASD would tions related to applying TMS to children. likely be classified as Level C: “possibly effective” Experimental Guidelines, Oversight, and Regulatory according to these guidelines [Lefaucheur et al., 2014]. Concerns As with the use of TMS as an investigational tool, there remain several gaps in knowledge with regard to A decade ago, there were only a handful of widely used the use of TMS for ASD treatment—What is an TMS protocols and a small number of laboratories and adequate “dose”? What are optimal stimulus parameters clinics using this technology. However, the field has and application sites? What are the clinical targets that grown exponentially leading to alternative experimen- TMS may be considered for? On what basis should par- tal and clinical paradigms being introduced into the lit- ticipants be selected? Are there predictors of treatment erature and a growing number of researchers and response? There are currently a small number (N 5 4) of clinicians utilizing this technology. This growth has recently completed or ongoing clinical trials using produced a rich, yet discordant literature. Given the

12 Oberman et al./TMS in ASD INSAR Table 3. A summary of the challenges and recommendations for TMS research in ASD Challenges Recommendations

Experimental Guidelines, Oversight and Regulatory Consensus should be achieved on consistent paradigms to be utilized across studies Concerns Data should be made available to others in the ﬁeld to enable metaanalysis of results across studies and across centers. Studies should be conducted by a trained expert, and involve institutional and governmental oversight and regulation Study Design and Placebo Effect Concerns Researchers should adhere to gold-standard clinical trial designs including:

Use of double blind, sham-controlled designs Use of objective primary outcome measures (behavioral or biological) Obtainment of data on a sample large enough to achieve adequate power to test the hypothesis Development of hypotheses based on current understanding of pathophysiology Heterogeneity Rigorous behavioral phenotyping of participants by reliable clinicians using standardized measures should be employed Samples should be stratiﬁed based on objective measures Safety, Tolerability, and Ethical Concerns Medication, medical history, and risk-beneﬁt ratio should be assessed to determine the safety of the TMS protocol. Feasibility and tolerability of TMS procedures in younger and lower-functioning individuals should be established. A broad range of side effects and behavioral/cognitive outcomes should be consistently assessed. Side effects and behavioral/cognitive outcomes should be assessed both immediately following the TMS session and at periodic intervals to evaluate long-term effects that may not be evi- dent immediately following the TMS administration.

ASD, Autism Spectrum Disorder; TMS, Transcranial Magnetic Stimulation. known variability in effect that can be seen with even tocol, the risks of TMS, the treatment of any of its pos- small changes to TMS parameters (location of stimula- sible complications and side effects, and the condition tion, coil orientation, interpulse interval, etc.), studies of any patients undergoing TMS, should be involved in must begin to utilize consistent paradigms to eliminate the design and conduct of study protocols.” Thus, con- this potential source of variability across studies. sistent with these guidelines, any application of TMS in From a regulatory standpoint, there is also a safety ASD should involve oversight and regulation at institu- concern with the growth of the field both in numbers tional and/or federal levels and be conducted by a and in novel paradigms whose safety profile (especially trained expert to ensure safe and ethical applications of in clinical populations) has not been fully established. this technology. Previously, TMS was only available in labs or clinics Study Design and Placebo Effect Concerns affiliated with hospitals. However, access to these devices has recently become more widespread and TMS The studies that have been published thus far using TMS is being applied in doctor’s offices and even by patients in ASD had a number of limitations. First, there has themselves in the home (e.g., Spring TMS, eNeura Inc., been little effort to reduce the biological or clinical het- Baltimore, MD). Compared to drugs, brain stimulation erogeneity of the samples. The inclusion criteria for is often perceived as a deceivingly simple and a more most studies have simply been either a clinical diagnosis specific way to modify brain activity. Indeed, another of ASD or at best a “high-functioning” sample (based brain stimulation technology (direct current stimula- largely on IQ score). This is especially concerning given tion) has already gained popularity in the “do-it the small sample sizes of many of the studies. This sam- yourself,” “DIY” movement resulting in a number of pling method has likely contributed to the null or con- researchers and clinicians voicing ethical concerns (Fitz flicting findings both in research and clinical use. & Reiner, 2015). However, the most recent TMS safety Second, these studies have not been designed using strict guidelines [Rossi et al., 2009] dictate that the principal clinical trial designs with clear and objective primary investigator on any TMS protocol “should be an expert clinical endpoints. The clinical outcome measures that in TMS with knowledge about principles, physiology have been utilized are often subjective self- or observer- and potential side effects of the technique” and based reports. Self or observer-based reports are often “appropriate emergency medical attention for possible highly influenced by placebo effects, which threaten to TMS complications should be planned for. A licensed mask or undermine assessment of change [King et al., physician that is intimately familiar with the study pro- 2001]. Furthermore, when physiological outcome

INSAR Oberman et al./TMS in ASD 13 measures have been evaluated, the relationship between Scheduled (ADOS) and Autism Diagnostic Interview- the physiological outcome measures (e.g., ERPs) and the Revised (ADI-R)) as well as other comorbid behavioral clinical outcome measures has not been clearly estab- and psychiatric symptoms (such as Aberrant Behavior lished. The lack of blinding or true sham control condi- Checklist (ABC), and Vineland Adaptive Behavior tions employed in the majority of extant studies further Scales, Second Edition (VABS-II), etc.) would allow for compounds these concerns. This is likely a result of the improved sample characterization, stratification, and limited availability of “true sham” TMS coils and the enrichment and less variability in baseline and outcome small sample sizes employed by the studies thus far. measures. Researchers using rTMS are also encouraged While some management of expectancy bias can be to stratify their sample based on objective brain-based achieved through the use of blinded, independent raters, measures. Recently, a number of such putative brain- further efforts are needed to identify additional objective based measures that significantly correlate with ASD outcome measures, whether behavioral or biological. behavioral measures have been evaluated including pro- Ideally, such study endpoints should be grounded by ton magnetic resonance spectroscopy [Baruth, Wall, other information which demonstrates their association Patterson, & Port, 2013], EEG [Wang et al., 2013], and to the targeted pathophysiology being studied. resting state functional magnetic resonance imaging (rsfMRI) [Plitt, Barnes, & Martin, 2015]. Heterogeneity Furthermore, in keeping with modern clinical trial One ubiquitous challenge in autism research is the con- design, studies must declare clearly formulated, primary siderable heterogeneity both in the severity and quality hypotheses to be tested, which are grounded on well- of the core and comorbid symptoms in ASD. This is a articulated understanding of pathophysiology, with an challenge for all researchers aiming to study and treat effort to identify mechanisms of change, if benefits are individuals with ASD. Two individuals could meet DSM found. For example, if the aims of a therapeutic trial or ICD criteria for ASD but present with vastly different are to enhance self-regulation and behavioral control behavioral phenotypes as well as variable psychiatric and (e.g., reduce hyperactivity), a reasonable approach medical challenges. Subjects diagnosed with ASD share would be that individuals with prominent deficits in core symptoms in the areas of social communication as behavioral control would exhibit insufficient cortical well as restricted, repetitive, and stereotyped patterns of inhibitory control in a defined neural network, based behavior, interests and activities [American Psychiatric on TMS, perhaps combined with other neuroimaging or Associaiton, 2013] that can be evaluated using DSM or neurocognitive measures. The hypothesis to be tested ICD criteria. However, the severity of ASD symptoms, the would be that active rTMS aimed at increasing inhibi- presence of comorbid symptoms (including intellectual tory control in that network would be associated with disability, epilepsy, sleep disturbance, gastrointestinal greater improvement in clinical measures of behavioral conditions, and others), and the underlying cause and inhibition versus sham treatment. Moreover, the true pathophysiology differs markedly across individuals on test of proof-of-principle would require demonstration the “spectrum” of ASD. With regard to behavior alone, that the specific behavioral effects are indeed related to individuals with ASD are well known to suffer from com- changes in network inhibition. mon comorbid psychiatric symptoms, including anxiety, Safety, Tolerability, and Ethical Concerns attention deficits, hyperactivity, depression, and irritability. These co-occurring psychiatric symptoms lead to a As noted above, TMS is considered quite safe, even in widespread use of psychotropic medication in ASD, a pediatric populations, if applied within current safety phenomenon that can likely generate confounding guidelines [Garvey & Gilbert, 2004; Rajapakse & Kirton, effects in both basic physiological research and clinical 2013]. TMS does, however, pose some risk for adverse TMS studies. side effects [Rossi et al., 2009]. Thus, factors including Though TMS studies thus far have largely limited medications and medical history need to be assessed enrollment to high functioning, verbal individuals, and the risk–benefit ratio of the procedure should be future applications of TMS both as investigational carefully considered before the patients undergo TMS. probes of physiology and as potential therapeutic inter- The most serious possible TMS-related adverse event is ventions need to carefully evaluate subject selection, induction of a seizure. To date, 16 cases of rTMS and seek to identify more homogeneous subject popula- induced seizures have been reported out of tens of tions to avoid the possible masking of TMS effects due thousands of individuals who have received rTMS over to intrinsic subject differences. In future studies, rigor- the past 25 years. Overall the risk of seizure is consid- ous behavioral phenotyping by research reliable asses- ered to be less than 0.01% across all patients and all sors using standardized measures to assess both ASD paradigms [Rossi et al., 2009], however, the risk varies symptoms (such as the Autism Diagnostic Observation based on factors including interpulse interval, intensity

14 Oberman et al./TMS in ASD INSAR of stimulation, and risk factors in the participants. For ment in behavior in one domain may be matched with example, no seizures have been reported during single a relative decrement in skills in another domain (see or paired-pulse TMS paradigms in neurologically [Brem, Fried, Horvath, Robertson, & Pascual-Leone, healthy individuals. TMS can also cause transient or 2014] for a review of this argument). There is also long-lasting changes in cognition or mood. These potential for symptom worsening in the target domain effects are often the desired effects of the stimulation, as the pathophysiology underlying the behavioral phe- however, one must keep in mind that any given TMS notype of ASD is likely a result of a complex balance protocol may have varying effects in both degree and within and across multiple brain regions and networks. direction in any given individual, especially when that Thus, it is important to systematically and broadly individual has a preexisting neuropsychiatric disorder. assess a range of behavioral and cognitive outcomes A gap in the preliminary studies of TMS in ASD (as well and side-effects of the stimulation. Also, both investiga- as other conditions), is the lack of a systematic effort to tional and therapeutic studies should have data safety identify, track, and report adverse events in study publi- monitoring boards to monitor side effects and adverse cations. As a result, it is possible that even though TMS events and clear stopping rules in the event of a serious appears to show a large safety margin, the risk of over- or unexpected adverse event. all adverse event burden from TMS may be underesti- Another ethical concern relates to the application of mated, especially in a vulnerable population as in rTMS in a pediatric brain that is still undergoing devel- individuals with ASD. opment. It is increasingly being recognized that the There are currently no identified ASD-specific risk fac- brain of a child is not simply a smaller version of an tors for TMS-induced adverse effects. Individuals with adult brain and that therapeutic interventions such as ASD may, however, may present added concern regard- rTMS may have distinct, unpredictable, and potentially ing relative risk of seizure due to the frequent prescrib- long-lasting effects on neurodevelopment [George ing of psychotropic medications in individuals with et al., 2007]. These effects may be the target of the ASD [Murray et al., 2014] and the increased prevalence treatment or may be an unexpected side-effect. A recent of epilepsy in the population [Spence & Schneider, meta-analysis [Rajapakse & Kirton, 2013] reviewed the 2009]. Though relatively few patients with ASD have studies to date involving all rTMS protocols in children participated in TMS protocols (<500), no seizures have (approximately 1000 children have been studied across been reported in any individual with ASD and the fre- all rTMS protocols to date) and concluded “Its minimal quency and quality of side-effects reported thus far risk, excellent tolerability and increasingly sophisticated approximates that seen in the general population ability to interrogate neurophysiology and plasticity [Oberman, Rotenberg, & Pascual-Leone, 2015]. make it an enviable technology for use in pediatric There are also concerns regarding the tolerability of research with future extension into therapeutic trials.” TMS across the autism spectrum. With the exception of However, there is some evidence suggesting that the a single study [Panerai et al., 2013] all other studies effects of stimulation change across development [Gei- have excluded individuals with intellectual disability. nisman, deToledo-Morrell, & Morrell, 1994; Oberman, Individuals with ASD often display hyperreactivity to Pascual-Leone, & Rotenberg, 2014] and few studies sensory input (1) and comorbid hyperactivity, anxiety involve long-term follow up to evaluate effects of stim- and impulsive behavior. The feasibility and tolerability ulation weeks or months after the final session. Follow of these procedures in these individuals, especially up assessments of pediatric subjects well beyond the those protocols that require long or repeated sessions end of TMS exposure may be able to track how stimula- has yet to be fully established. Some individuals may tion paradigms interact with the moving target of require additional aids including a “mock” stimulator developmental neural plasticity. (similar to what is used in MRI studies), or other interventions to reduce the stress of the procedure (weighted blanket, soothing music, electronic device, etc.) to Conclusion increase tolerability. In addition to safety and tolerability concerns, there Though all of the scientific and practical limitations are also ethical concerns that have been voiced when have yet to be fully addressed, the application of TMS considering the application of rTMS in a clinical popu- in autism research and treatment holds significant lation, particularly a vulnerable population such as promise as both an investigational and therapeutic ASD, and especially so when considering exposure in tool. Though the existing literature has some limita- children. One ethical concern is whether modulation in tions, the concerns and challenges raised here are all excitability in one direction for one brain region may addressable in future studies and many are certainly result in a compensatory modulation in another area in not unique to this population or this intervention. the opposite direction. Under this model, any improve- Through collaboration across disciplines and across

INSAR Oberman et al./TMS in ASD 15 labs, researchers and clinicians can begin to develop American Psychiatric Association. (2013). Diagnostic and statis- valid and reliable uses of TMS to both study the patho- tical manual of mental disorders (5th ed.) Arlington: Ameri- physiology and develop novel treatments for ASD. This can Psychiatric Publishing. type of collaborative effort is underway through the Barker, A.T., Jalinous, R., & Freeston, I.L. (1985). Non-invasive magnetic stimulation of human motor cortex. Lancet, establishment of the “TMS in ASD Consensus Group.” 1(8437), 1106–1107. Retrieved from http://www.ncbi.nlm. This group of researchers, clinicians, regulatory affairs nih.gov/pubmed/2860322 officers, and community partners meets annually prior Baruth, J.M., Casanova, M.F., El-Baz, A., Horrell, T., Mathai, to the International Meeting for Autism Research G., Sears, L., & Sokhadze, E.M. (2010). Low-frequency repet- (IMFAR) and convenes periodically throughout the year itive transcranial magnetic stimulation (rTMS) modulates through teleconference to facilitate ongoing discussion, evoked-gamma frequency oscillations in autism spectrum establish consensus on investigative and therapeutic disorder (ASD). Journal of Neurotherapy, 14(3), 179–194. protocols and encourage collaboration across centers. doi:10.1080/10874208.2010.501500 Using the “Fast-Fail Drug Trials” and “Research Baruth, J.M., Wall, C.A., Patterson, M.C., & Port, J.D. (2013). 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