12 Month Open Extension Study of TNS for ADHD .
Phase: NA
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Sponsor: James McGough

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Developmental Pilot Study of External Trigeminal Nerve Stimulation for 
ADHD 
 
 
NIMH R34 MH101282 
 
 
 
 
James J. McGough, M.D., M.S. and Sandra K. Loo, Ph.D. 
 
(Principal Investigators) 
 
Division of Child and Adolescent Psychiatry 
Semel Institute for Neuroscience & Human Behavior and  
David Geffen School of Medicine at UCLA 
 
 
 
 
12-Month Open Extension Study of TNS for ADHD 
Clinical Trials Registration: NCT03888391 
 
 
 
Study Protocol 
 
05/30/2018 
 

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LAY SUMMARY 
 
Attention-Deficit/Hyperactivity Disorder (ADHD) is estimated to affect up to 9.5% of school-aged children 
and 4.4% of adults. ADHD is associated with increased functional impairments, comorbid psychopathology, 
and overall health care costs.  Although various psychosocial interventions are employed, medication remains 
the mainstay of ADHD treatment. It is estimated that over 2.8 million children in the United States are 
prescribed psychostimulants, mostly for ADHD. Although these are generally safe and effective in acute 
treatment, considerable concerns remain about side effects and the absence of demonstrated long-term 
benefit. Parents are highly ambivalent about using ADHD medications. While there is great demand for non-
medication approaches to ADHD, most popular alternatives are not linked to any mechanistic understanding of 
brain processes and similarly lack significant scientific evidence to support their use.   
 
External trigeminal nerve stimulation (eTNS) is a non-invasive method of brain modulation with 
demonstrated success in treating adults with medication-resistant epilepsy and depression. In eTNS, the 
trigeminal nerve receives low current electrical stimulation via an electrode applied to the forehead and worn 
during sleep. Preliminary adult studies revealed significant improvements in mood, sleep, and attention.  PET 
imaging demonstrated acute eTNS-related activation in brain areas involved in attention and executive 
functioning. A preliminary pediatric study based on this work assessed the feasibility of eTNS for ADHD.  
Results demonstrated that eTNS was well tolerated and accepted, and was associated with significant 
improvements in ADHD symptoms and laboratory measures of response inhibition and working memory.   
 
This R34 proposes a three-year clinical trial development project to further standardize eTNS in 
preparation for definitive ADHD efficacy trials and to elucidate underlying brain mechanisms that will potentially 
support use of eTNS in ADHD as well as other behavioral, emotional, and cognitive disorders.  
 
The project is a four-week double-blind randomized trial of active vs. sham eTNS followed by one week 
follow-up after treatment discontinuation.  Participants will have repeated assessments on behavioral ratings, 
cognitive processes, and cortical activation via electroencephalography (EEG).  This study will assess 
differences in outcome trajectories by condition in the first randomized controlled trial of eTNS for ADHD, 
validity and fidelity of sham eTNS as a blinded control, time course effects regarding onset and offset of 
response, and underlying mechanisms of brain change that are associated with treatment outcomes.   
 
Following completion of the 5-week double-blind trial, participants randomized to the sham condition will be 
offered the opportunity to receive 4 weeks open-label eTNS therapy.  All participants who demonstrate positive 
clinical benefit to active eTNS, whether during the double-blind or open-label phase, will be offered an 
opportunity to receive 12 additional months of open eTNS treatment.  Open-label trial and 12-month extension 
trial results will be listed under a separate clinicaltrials.gov registration. 
 
The proposal is consistent with several NIMH priorities, including the development of innovative 
interventions and designs for intervention studies, development of an integrated understanding of brain 
disorder processes that provide the foundation for understanding mental disorders, and assessment of the 
mechanisms of action of efficacious interventions in the brain. 
 
 

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SPECIFIC AIMS 
 
This application for a Clinical Trial Planning Grant (R34) seeks to develop external trigeminal nerve 
stimulation (eTNS), a non-invasive method of direct brain modulation previously shown to be useful in the 
treatment of medication-refractory epilepsy and depression, as an innovative non-medication therapy for 
Attention-Deficit/Hyperactivity Disorder (ADHD).  The project builds on previous work that demonstrated the 
initial feasibility of eTNS research in youth with ADHD and its acceptability as an ADHD treatment.  The 
proposed study will assess: 1) the behavioral, cognitive, and cortical activation effects of eTNS in a 
randomized double-blind active vs. sham eTNS pilot study, expanding results from our previous open trial and 
assessing fidelity of our proposed sham condition; 2) time to effect-onset during acute treatment and effect-
offset following treatment discontinuation, and 3) proposed mechanisms of action and potential effects on 
cross-disorder dimensional measures of emotion and behavior consistent with Research Domain Criteria 
(RDoC).  The overall focus is to generate additional information necessary for planning and implementation of 
larger randomized controlled definitive trials for ADHD and to explore potential benefits of eTNS for difficulties 
with mood, anxiety, and sleep which occur commonly in youth across several diagnostic categories.  Our 
specific aims are:  
 
Specific Aim #1:  
To examine ADHD symptom trajectories for active vs. sham eTNS and test the 
fidelity of study blinding in a double blind randomized trial spanning four weeks of acute treatment and one-
week follow-up after treatment discontinuation. 
 
Specific hypotheses to be tested include: 1) that participant receiving active eTNS will exhibit improved 
scores on the investigator completed ADHD IV Rating Scale (ADHD-RS) compared to those assigned to the 
sham condition; 2) that ADHD-RS symptoms in the active group will decrease over time during acute 
treatment, 3) that differences on ADHD-RS ratings between active vs. sham conditions will lose significance 
over time following treatment discontinuation, and 4) that treatment fidelity will be demonstrated such that 
participants and their parents will not be able to guess assigned treatment at a rate significantly higher than 
chance.  
 
Specific Aim #2:  
To assess the underlying mechanisms of eTNS response by examining 
condition and time course effects on measures of executive functioning (response inhibition and working 
memory), reaction time, reaction time variability, and cortical activation.   
 
Specific hypotheses to be tested include: 1) that score trajectories on the parent completed Behavior 
Rating Inventory of Executive Functioning (BRIEF) will differ in active vs. sham groups; 2) that trajectories on 
measures of response inhibition (Attention Network Test) and working memory (Spatial Working Memory Task) 
reaction time and reaction time variability will differ in active vs. sham groups, and 3) that specific EEG 
changes with active vs. sham eTNS will reflect increased activation of the anterior cingulate cortex and other 
frontal regions. Specifically, EEG changes with active eTNS treatment will be: a) lower theta-band (4-7 Hertz 
(Hz)) and higher gamma-band (30-50 Hz) spectral power in fronto-central regions during working memory and 
inhibition tasks; and b) higher amplitude error-related negativity (ERN) as reflected by the P50 event-related 
potential; and c) stronger connectivity between frontal and central sources of theta- and gamma-band spectral 
power.     
 
Specific Aim #3: 
To examine the effects of eTNS on secondary measures that include parent and 
teacher Conners ADHD rating scales, a side effects rating scale, adverse event inquiry, height, weight, 
cardiovascular effects, sleep, anxiety, and mood.  
 
Specific hypotheses to be tested include: 1) that score trajectories on parent and teacher Conners 
ratings will differ by condition; 2) that side effect and adverse event frequencies are minimal and do not differ 
by condition; 3) that height and weight are functions of time without effects from assigned condition; 4) that 
improved dimensions of sleep as measured by the parent completed Children’s Sleep Habits Questionnaire 
(CSHQ) are seen in the active condition, 5) that anxiety dimensions as measured by the parent and child 
completed Manifest Anxiety Scale for Children (MASC) and mood dimensions measured by the CDI, and 6) 
that irritability measured by the parent and child completed ARI will improve in the active vs. sham eTNS 
groups.  

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Specific Aim #4: 
To assess long tern trajectories of clinical response, cognitive outcomes, safety, 
and compliance in participants who demonstrate acute positive benefits from eTNS therapy during a 12-month 
open extension. 
 
Specific hypotheses to be tested include: 1) that score trajectories on the ADHD-RS, BRIEF, MASC, 
CDI, ARI, and CSHQ will remain unchanged from the beginning to end of the open-label extension; 2) that 
trajectories on measures of working memory and response inhibition will remain unchanged from the beginning 
to end of the open-label extension; 3) that measurements of height and weight have age-appropriate increases 
over the open-label extension; 4) that side-effects remain minimal and expected; 5) that compliance remains 
high.  
 
RESEARCH STRATEGY 
 
A. 
Significance 
 
1. 
Importance of the problem to be addressed. 
 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder estimated in the 
United States to affect up to 9.5% of school age children [1] and 4.4% of adults [2].  ADHD is defined by 
clinically significant and developmentally inappropriate levels of inattentive and/or hyperactive/impulsive 
symptoms [3]. ADHD is associated with significant functional impairments, including educational 
underachievement, occupational difficulties, impaired social relationships, increased motor vehicle accidents, 
and overall increased health care costs, and risk for lifetime comorbid psychopathology, particularly disruptive 
behavior, antisocial, mood, anxiety, and substance use disorders [4, 5, 6].  A recent review of 19 studies 
estimates the national annual incremental cost of ADHD to be between $143 and $266 billion (B), with the cost 
of adult ADHD at $105 to $194B and childhood ADHD at $38 to $72B [85]. The largest costs associated with 
childhood ADHD were for healthcare ($21 to 44B) and education ($15-25B). ADHD has significant impact on 
the lives of affected individuals and their families and remains an issue of major public health importance [1]. 
 
Neuropsychological deficits are associated with ADHD throughout the lifespan, particularly in those 
abilities grouped as “executive control” or “executive functions” [8].  Although all children with ADHD do not 
exhibit full deficits in executive function [9], multiple studies reveal that ADHD-affected youth exhibit deviations 
in reaction time variability and the acquisition of cortical, top-down processes of executive control and attention 
regulation [10-12].  These differences are reflected in both structural and functional brain imaging studies that 
implicate prefrontal-striatal circuits and the frontoparietal control circuit among others [13].  The frontoparietal 
control circuit, which includes the lateral frontal pole, anterior cingulate cortex (ACC), dorsolateral prefrontal 
cortex, anterior PFC, lateral cerebellum, anterior insula, caudate and inferior parietal lobe, is thought to relate 
directly to executive function and cognitive control [14, 15].  Several studies revealed hypoactivation in 
frontostriatal and frontoparietal circuits during inhibitory tasks performed by ADHD children [16, 17]. Others 
describe hypoactivation specifically in the dorsal ACC during go/no-go, response inhibition, and attention tasks 
[18-22].  While not specific to ADHD, recognition of dysfunction in these regions provides a basis for targeted 
interventions with potential implication for treatment of ADHD and other disorders.  
 
Although various psychosocial interventions are employed in ADHD management, pharmacotherapy 
remains at present the mainstay of treatment [23].  While there is increased availability of non-stimulant 
medications approved for ADHD, stimulants remain the most widely used class for this disorder with large 
clinical effect sizes demonstrated in several hundred well-controlled trials [6, 24, 25].  An estimated 2.8 million 
children in the U.S. receive psychostimulant medication, primarily for ADHD.  The robust short-term reduction 
in ADHD symptoms with acute psychostimulant treatment is one of the best-replicated effects in pediatric 
psychopharmacology. Numerous studies demonstrate response rates of 65-75% of school-age children during 
acute treatment [24].   
 
Several small recent studies have suggested that medication use is associated with brain plasticity 
effects in the direction of typically developing children without ADHD.  For example, fMRI studies demonstrate 
how “typical” attentional circuits are brought on-line with acute stimulant administration [26], and in some cases 

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function more efficiently [27, 28].  Stimulant use has been associated with changes in brain structure, 
particularly in frontal and parietal regions, such as increased white matter volumes, decreased gray matter 
thinning, and increased cerebellar size that more closely resemble developmental patterns seen in typically 
developing youth [29-31].  Although these findings are tentative and do not demonstrate causal effects, the 
potential for administration of medication or other interventions, particularly during critical periods of brain 
development, that could effect positive and possibly persistent changes in brain networks remains an intriguing 
area for future research.    
 
Nonetheless, medications for ADHD have notable drawbacks.  While usually manageable, stimulants 
are commonly associated with significant side effects, particularly appetite loss, sleep disturbance, irritability, 
stomachaches, headaches, and possible growth delays [25, 32]. In contrast with robust short-term 
improvements in ADHD symptoms, longer-term treatment studies suggest that response rates decrease over 
time [33, 34].  Finally, although it is necessary to stay on ADHD medication to maintain treatment effects, long-
term adherence is poor, with a majority of patients leaving treatment within a year [35, 36].  Several 
hypotheses have been offered to explain the high rates of medication discontinuation that persist in spite of 
clearly evident therapy associated improvement.  Some evidence suggests that problems with adverse events 
and tolerability substantially contribute to treatment discontinuation [36].  Others have noted the trend for 
discontinuation and noncompliance that is seen in management of most chronic conditions, particularly those 
affecting children [37].  A less discussed, but perhaps more salient reason for discontinuation, is the substantial 
ambivalence that most parents have about placing their child on ADHD medication and their clear preference 
for employment of behavioral approaches to manage the condition [38].  Of particular note, disparities in 
utilization of established pharmacotherapies for ADHD are particularly evident in some African American and 
Hispanic communities where serious concerns about medication use and safety persist [86].  In spite of this 
high public support for non-medication based ADHD therapies, traditional psychosocial interventions such as 
parent management and social skills training are now viewed as generally inferior to medication-only and 
multimodal approaches [39], and preliminary investigations of alternative therapies, such as EEG 
neurofeedback, have as yet failed to demonstrate significant benefits [40-42, 87].  
 
External trigeminal nerve stimulation (eTNS) is a 
non-invasive 
method 
of 
brain 
modulation 
under 
development at UCLA for treatment of medication-
resistant epilepsy and major depression (Fig. 1).  In 
eTNS, adhesive electrode pads are placed externally on 
the forehead over the trigeminal nerve and connected by 
thin wires to an external stimulator (approximately the 
size of an iPod) that is worn on the patient’s clothing.  
The stimulator uses a nine-volt lithium battery to emit a 
low-grade current, which subsequently stimulates the 
trigeminal nerve.  eTNS was developed as a substitute 
for two invasive methods of direct brain stimulation, 
vagus nerve stimulation and deep brain stimulation, which have proven useful in the treatment of epilepsy and 
depression, but which require surgery, with associated costs and risks, to implant electrodes directly into the 
vagus nerve or the brain itself.  The rational for development of eTNS rests in part on anatomical similarities 
between the trigeminal and vagus nerves. The trigeminal nerve conveys sensory information from the skin, 
muscles, and joints of the head [43] and projects extensively with several brainstem structures including the 
thalamus, cerebellum, and cortex [43-46].  Also like the vagus nerve, the trigeminal has connections with the 
locus coeruleus, reticular activating system, and nucleus tractus solitarious.  Based on the assumption that the 
therapeutic effects of vagus nerve stimulation rely in part on these connections, it was hypothesized that eTNS 
would have similar effects.  An anti-seizure effect of eTNS was demonstrated in one animal study [47].   
Preliminary studies in humans provide initial support for the efficacy of eTNS in treatment-refractory epilepsy 
[48-50].  Several patients in these epilepsy trials reported significant improvement in mood symptoms, 
prompting additional investigations for unipolar depression.  Small trials in adults with major depression and 
post-traumatic stress disorder have since been conducted, and suggest that eTNS leads to clinical 
improvement in patients refractory to standard pharmacotherapies [51-53].  
 

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Emerging data on eTNS supports claims of increased utility compared with other methods of 
neuromodulation, for which enthusiasm has waned.  The vagus nerve contains outflow fibers that project to the 
heart and modulate cardiac activity with potential to slow or even stop it [88]).  In response, the U.S. FDA has 
limited VNS to maximum stimulation frequencies of 30 Hz and to unilateral stimulation.  In contrast, the 
trigeminal nerve does not have any projections to the heart, and the V1 and V2 branches are entirely afferent 
fibers.  Preclinical work with a rodent seizure model demonstrated that the antiepileptic effects of eTNS were 
far greater at frequencies ≥100 Hz than at 30Hz and significantly greater with bilateral stimulation [89, 90], 
suggesting that central neuromodulation effects are dependent upon frequency of stimulation and are 
enhanced by stimulating both hemispheres [91].  These differences likely explain the improved outcomes seen 
with eTNS vs. TNS and support ongoing research efforts in eTNS.  eTNS is non-invasive, administered at 
home, requires no clinical intervention beyond assessment and monitoring.  The FDA has deemed eTNS to be 
a non-significant risk device based on safety data from our preliminary pediatric study in ADHD (preliminary 
data).  Pivotal Phase II trials are now ongoing for adult treatment refractory depression, post-traumatic stress 
disorder in veterans, and treatment refractory epilepsy in children.  Since 2013, eTNS is available as an 
approved treatment in Europe and Canada, with treatment costs comparable to costs of brand-name ADHD 
medications [92].  There is no patient burden using eTNS that exceeds routine outpatient care. 
 
Based on these findings, we conducted a preliminary feasibility study of open eTNS in children with 
ADHD to assess its potential acceptability as a treatment in the pediatric population and its effects on ADHD 
symptoms and related measures of cognition (see Preliminary Data).  The outcome of this pilot suggests that: 
1) eTNS is readily accepted by children aged 7-14 and their families with no practical impediments for 
treatment compliance; 2) open treatment with eTNS is associated with very substantial reductions in parent 
and clinician ratings of ADHD symptoms; 3) eTNS is associated with significant improvements on multiple 
indices of parent-reported executive functioning; 4) eTNS is associated with dramatic improvements in 
laboratory measures of response inhibition previously reported to rely on ACC function; 5) positive effects of 
eTNS were seen after 4 weeks of treatment – the first interval measured after baseline, and 6) eTNS is very 
well tolerated and does not appear to be associated with clinically meaningful adverse events.   
 
Although encouraging, findings suggesting the potential utility of eTNS as an intervention for ADHD 
require confirmation in blinded controlled trials.  Several impediments must be resolved prior to initiation of 
pivotal studies.  Consistent with the stated intent of the R34 mechanism, this application seeks to establish the 
additional information required for the optimal design and implementation of controlled clinical trials of eTNS for 
ADHD.  Of primary importance is the development of sham or placebo eTNS to serve as comparator with 
active treatment.  Since our initial application, technological developments have enabled creation of an 
effective inactive sham eTNS treatment, which is identical in appearance and operation to both participants 
and staff.  Use of the sham in blinded trials has now been implemented in studies for other disorders, but the 
sham has not been validated in ADHD trials nor has any assessment been done in this study group of 
participants’ ability to see through the study blind.  The randomized active vs. inactive sham eTNS trial 
proposed in this application is designed to address this question.  Second, differences in outcomes across 
active and sham conditions would provide an additional signal of potential benefit that would provide additional 
justification for larger studies beyond that suggested in our initial open trial.  Third, although our preliminary 
work demonstrated behavioral and cognitive changes after four weeks of treatment, more information 
pertaining to the onset of treatment effects is required as a prerequisite for the appropriate design of definitive 
clinical trials.  Fourth, a similarly unknown and critical issue is the time to offset of clinical effect after cessation 
of active therapy, which would also influence future trial design and approaches to clinical use of eTNS.  Fifth, 
this preliminary study will allow estimation of treatment effect sizes, which will be critical for future trial design.  
Finally, additional information regarding the mechanistic effects of eTNS will inform on its clinical application in 
ADHD as well as its potential for use in other brain-based behavioral disorders.   
 
 
B. 
Approach 
 
1. Project Overview  
 
This three-year developmental study is a double-blind randomized trial of active vs. inactive sham 
eTNS for ADHD, with four weeks acute treatment followed by an additional week of clinical observation and 

7 
testing after treatment cessation.  The study will enroll 85-90 participants aged 8-12 years to achieve a 
completion target of N=36 for each study condition (total final N = 72).  Participants will be recruited from UCLA 
clinical programs and through public advertising and will meet DSM-5 criteria for ADHD, any current 
presentation, as established by the Behavior Disorders Module of the Kiddie Schedule for Affective Disorders 
and Schizophrenia (KSADS-PL) [55] and clinical interview.  Other screening procedures include measures of 
ADHD symptom severity, other behavioral ratings, and cognitive assessments.  Once inclusion/exclusion 
criteria (see Protection of Human Subjects) have been reviewed and verified, participants will have a pre-
treatment visit to establish behavioral and cognitive baseline ratings and to obtain an EEG.  Participants and 
parents will be instructed in the use of eTNS, and participants will begin use of the eTNS as directed during 
sleep each night.  Participants will be randomized 1:1 to active or inactive sham eTNS.  Participants, families, 
and most of the study team will remain blind to treatment assignment. Participants will have weekly 
assessments over the five week study to assess behavioral, cognitive, and brain activation change and to 
monitor safety, tolerability, and compliance.  Weekly ratings will be obtained from a parent, teacher, and 
clinician investigator.  EEG will occur at baseline and end of treatment (week 4). 
 
2. Preliminary Studies 
 
The Co-PI’s and study team have conducted over 13 years of collaborative research on clinical 
phenomenology, genetics, neurocognitive correlates, EEG profiles, and clinical interventions of behavioral 
disorders.  Several lines of current and past research provide the foundation for the current proposal:  
 
a) Studies of eTNS in Adult Mood and Anxiety Disorders:  UCLA investigators remain at the forefront for 
developing eTNS for epilepsy and behavioral disorders.  Dr. Leuchter, project study co-investigator, is 
currently PI on several current studies examining potential roles for eTNS in treatment of adult major 
depression (MDD) and post-traumatic stress disorder (PTSD). 
Recently published studies demonstrate significant improvement in 
mood symptoms in an open-label study of MDD [56] and in a sham-
controlled treatment study in epilepsy [91]. Item-analysis of mood 
disorder rating scales in these studies suggests selective 
improvements in concentration and attention.  Another sham-
controlled study in MDD is ongoing and the blind has not yet been 
broken. According to a functional neuroimaging study using [O-15] 
positron emission tomography (PET) scans of adults with MDD with 
and without eTNS, underlying neural mechanisms of action appear 
to be increased activation of frontal and parietal regions [92] (see 
Fig. 2). Exposure to TNS resulted in significant increases in regional 
cerebral blood flow in anterior cingulate gyrus (bilateral BA 32,24) 
and medial/middle frontal gyri of the DLPFC (right BA 6,8, 45, 46), as 
well as the inferior frontal gyrus (left BA 44,6,22) and parietotemporal cortex (bilateral BA 39,40). All 
regions had peak voxels showing highly significant differences (p<0.0005) and significant cluster size 
(ppcluster corr<0.05). Results from these studies suggest efficacy of eTNS in placebo-controlled efficacy 
studies as well as a mechanism of action that may target areas (i.e., frontal and ACC regions) found to be 
under activated in ADHD [93].   
 
b) Translational Treatment Studies: The investigators have had long-standing involvement in clinical trials for 
over 15 years.  Our recently completed CIDAR Center (P50 MH077248) exceeded its original recruitment 
goal of 180 and randomized 202 children and adolescents with ADHD over a 37-month recruitment period, 
supporting the feasibility of our current recruitment targets.  We have a cadre of trained experienced 
research staff able to carry out large-scale, complex, intervention and cognitive assessment protocols 
involving children, adolescents, and adults with developmental psychopathologies.  In CIDAR, we utilized 
the Attention Network Task (ANT), Go/NoGo and Sternberg spatial working memory (SWM) task to assess 
cognitive response in a three-arm trial of guanfacine, d-methylphenidate, and the combination.  SWM 
accuracy was significantly improved in the combination group relative to the monotherapies (p < .05) and 
was no longer significantly different from controls (p>.10). Similarly, errors of commission were significantly 
reduced in the combined group when compared with the other medication groups (p < .05), but remained 
marginally different from controls (p=.08). In contrast, reaction time (RT) variability was significantly 

8 
improved in the combined and d-methylphenidate groups compared with guanfacine alone (p < .05) and 
also normalized relative to controls (p=.89). Results from this work also demonstrate that there are virtually 
no practice effects on the ANT and SWM tasks, which support their use as repeated measures in the 
currently proposed study. These studies demonstrate that the cognitive measures we plan to use are 
sensitive to ADHD medication treatment effects as well as our ability to measure and differentiate cognitive 
treatment effects in blinded clinical trials.  
 
c) EEG Studies of ADHD and Treatment Correlates: In two studies [61, 62] we have demonstrated possible 
associations with EEG change and treatment responder status during an inhibition task (Go/NoGo). 
Additionally, we have examined EEG correlates of acute medication administration on performance on the 
SWM task with the CIDAR ADHD treatment sample. Shown in Fig. 3 are the EEG effects for the Combined 
medication group, which improved significantly in SWM accuracy. 
Independent components analysis of event-related EEG during the 
maintenance (M) phase suggests that there is a frontal component 
(see inset Fig. 3), which corresponds with previous findings of 
frontal midline activation during working memory tasks [63]. In 
neuroimaging studies, frontal midline theta power has been linked 
to activation of the anterior cingulate [94]. As shown in the event-
related spectra plots (Fig. 3), significant theta band (4-8 Hz) 
synchronization and gamma (30-50 Hz) desynchronization are 
apparent during the maintenance interval among ADHD children at 
baseline relative to controls (p<.05, corrected). With acute 
medication 
administration 
in 
the 
ADHD 
group, 
theta 
synchronization and gamma desynchronization are normalized 
such that they are not significantly different from controls. Further, 
theta power is significantly associated with SWM accuracy (r=-0.23, p<.05) and number of 
hyperactive/impulsive symptoms (r=0.21, p<.05). These studies support our EEG hypotheses of decreased 
frontal midline theta power with eTNS treatment and our ability to assess treatment-associated changes in 
cortical activation in clinical intervention trials. 
 
d) Feasibility study of eTNS in pediatric ADHD: Project investigators (McGough, Loo, Leuchter) conducted an 
8 week open treatment study in 24 youth with ADHD aged 7-14 to obtain preliminary data on: 1) potential 
effects of eTNS on ADHD behavioral symptoms; 2) potential effects of eTNS on cognition and executive 
functioning, and 3) potential tolerability, acceptability, and feasibility of eTNS treatment and eTNS research 
in children diagnosed with ADHD [95, 96]  Once inclusion/exclusion criteria were met, participants had a 
pre-treatment baseline visit to assess ADHD symptom severity and several measures of executive 
functioning and cognition.  Subsequently, participants began eTNS therapy during sleep each night.  
Participants returned for 8 weekly clinic visits for repeated assessment of behavioral response, tolerability, 
and compliance.  Visits at weeks 4 and 8 also included repeated measurements of cognitive outcomes.  
The primary outcome variable established a priori was the Investigator Completed ADHD-IV Rating Scale 
(ADHD-RS), which along with CGI scores were completed at baseline, week 4, and week 8.  Parents also 
completed weekly Conners and side effects rating scales.   
 
Sample was 92% male, 75% White, 13% African American, 13% Asian, and 46% Hispanic.  Mean age was 
10.3 years and mean Full Scale IQ was 100.7.  Almost one-half had comorbid oppositional defiant disorder. 
Strong improvements were noted on the Investigator Completed ADHD-RS (p < .0001) and Conners 
Parent Index (p < .0001). On the CGI-Improvement Scale, 64 % met response criteria (improved or very 
much improved) at Week 4, and 71% met criteria at Week 8. Although participants did not have depressive 
disorders, significant improvement was noted on the 
Children’s Depression Inventory (p= .04) suggesting general 
mood improvement.  On the Children’s Sleep Habits 
Questionnaire, improvements were detected for selected 
subscales including Sleep Anxiety (p=.03), Total Bedtime 
Problems (p < .0001), and Total Sleep Problems (p < .0001). 
 

9 
eTNS effects on cognitive outcomes. Results from the Behavior Rating Inventory of Executive Functioning 
(BRIEF), a parent completed measure of participants’ executive functioning, demonstrated significant 
improvements on 7 of 11 subscales (p value range .03 to < .001). The most significant improvement on the 
BRIEF was on the Working Memory scale (F2,37=9.7, p=.0004), as shown in Figure 4. Note that 
improvement is indicated by a decrease in t-score. On a laboratory measure of executive functioning, the 
ANT, eTNS had positive effects on response inhibition (see Fig. 4). Results suggest a significant decrease 
in the reaction time to correctly respond to the ANT incongruent flanker condition (F2,37=5.9, p=.006). Over 
the course of eTNS treatment, the speed of the inhibitory process became faster and more efficient.  
Neuroimaging studies using the ANT have found that successful performance of this task is associated 
with activation of the anterior cingulate cortex [64].   
 
These preliminary results provide objective evidence of improvement among children with ADHD due to 
TNS treatment.  There were no clinically significant side effects or adverse events.  Treatment compliance 
and satisfaction were high and families were generally enthusiastic in their participation.  While it is 
acknowledged that placebo effects were not controlled for in this open trial, positive changes on several 
objective laboratory measures of cognition as well as robust improvements noted on some, but not all, 
sleep measures, provide further support to behavioral rating scales that suggest potential benefits in ADHD 
and other pediatric psychiatric conditions.  Of particular note was the strength of response demonstrated 
even in such a small sample.  This study demonstrated the feasibility of eTNS research for ADHD in 
children and points to the eventual need to conduct randomized controlled trials.   
 
3. Summary of Project Visits. 
 
A schedule of study visits and procedures appears in Table 2.  Screening procedures may be divided 
over several days at the convenience of participants, and screening measures obtained in other UCLA clinical 
or research settings may be used if they were collected within one month of the screening visit.  Study baseline 
visit will be scheduled within one week of study screening, unless participant circumstances necessitate a mild 
deviation from this timeframe.  At the baseline visit, inclusion/exclusion criteria will be verified and participants 
and parents will be instructed on the proper use of the eTNS stimulator.  Participants will be randomized to 
their study condition, and the eTNS stimulator will be programmed accordingly by the one research assistant 
privy to randomized assignment.  All other study personnel will remain blinded.  eTNS treatment will 
commence at home during sleep after the baseline visit and continue nightly for four weeks.  Afterward, data 
collection will continue for one week following treatment cessation to ascertain offset of any treatment effects.  
Behavioral ratings, safety assessments, and cognitive outcomes will be collected weekly throughout the study.  
Participants will be asked whether they believe they are on active or sham treatment after the first week of 
intervention. At the conclusion of study participation, parents will be asked to complete a questionnaire 
designed to assess their satisfaction with treatment and their involvement in research. 
 
At end of treatment (Visit 4) treatment will stop. Participants will have one week off treatment and then 
return for a final assessment visit (Visit 5).  After all procedures for Visit 5 are complete, blind will be program 
and families advised as to which treatment (active or sham) they were assigned.  Patients randomized to sham 
treatment will then have the option to begin 4 weeks of open active eTNS therapy.  These participants will 
return for two subsequent visits at two-week intervals to complete safety and behavioral measures.  
 
At Visits 2 and 3, participants who have access to the Internet can choose to complete study ratings on-
line in lieu of an in-clinic weekly visit.  If parents are agreeable, the study investigator will contact them by 
phone each week to complete the ADHD-RS, CGI ratings, concomitant medications, and adverse event 
inquiry. Height, weight, and vital signs ratings will be waived in weeks that assessments are done away from 
clinic.  
 
Participants with clinically meaningful improvement on active eTNS treatment, during either double 
blind or open treatment and defined by a CGI-I score ≤ 2, will be offered 12 additional months of eTNS therapy 
in an open extension phase (Table 3).  Data obtained at the final visit following active treatment, either Visit 4 
for those randomized to active eTNS or Visit 7 for those randomized to sham that receive 4 weeks open eTNS 
treatment, will serve as baseline for the 12 month extension. During the extension, participants will return for 

10 
study visits every 3 months to complete behavioral, safety and compliance measures.  ADHD and other 
medications with CNS effects will be permitted if clinically indicated and will be recorded as concomitant 
medications.  Cognitive testing will be repeated at the final study visit, either after 12 months or at early 
termination.   
 
 
Table 2. Double Blind Study Procedures. 
Visit Number 
Screen Base 
1 
2 
3 
4 
5 
6 
7 
 
 
Study Week 
-1 
0 
1 
2 
3 
4 
5 
7 
9 
 
 
General 
 
 
 
 
 
 
 
 
 
 
 
Informed permission/assent  
X 
 
 
 
 
 
 
 
 
 
MD 
Verify inclusion/exclusion 
 
X 
 
 
 
 
 
 
 
 
MD 
Med History/Demographics 
X 
 
 
 
 
 
 
 
 
 
Parent 
Height/Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RA 
Pulse, Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RA 
TNS Randomization 
 
X 
 
 
 
 
 
 
 
 
RA 
TNS Training 
 
X 
 
 
 
 
 
 
 
 
RA 
TNS Diary 
 
 
X 
X 
X 
X 
 
X 
X 
 
Parent 
TNS Compliance 
 
 
X 
X 
X 
X 
 
X 
X 
 
RA 
Early Impression Question 
 
 
X 
 
 
 
 
 
 
 
Parent 
End double-blind 
 
 
 
 
 
X 
 
 
 
 
MD 
Break blind 
 
 
 
 
 
 
X 
 
 
 
MD 
Begin open treatment 
 
 
 
 
 
 
X 
 
 
 
MD 
End open treatment 
 
 
 
 
 
 
 
 
X 
 
MD 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
 
 
 
 
 
 
 
 
 
 
 
KSADS-PL 
X 
 
 
 
 
 
 
 
 
 
MD 
Clinical Interview 
X 
 
 
 
 
 
 
 
 
 
MD 
Saliva Sampling 
X 
 
 
 
 
 
 
 
 
 
Child 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MD 
Adverse event inquiry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
MD 
Side effects rating scale 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Parent 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
MD 
 
 
 
 
 
 
 
 
 
 
 
 
Behavioral Ratings 
 
 
 
 
 
 
 
 
 
 
 
CBCL 
X 
 
 
 
 
 
 
 
 
 
Parent 
ADHD-RS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MD 
CGI-Severity 
X 
X 
 
 
 
X 
X 
 
X 
 
MD 
CGI-Improvement 
 
 
X 
X 
X 
X 
X 
X 
X 
 
MD 
BRIEF 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Parent 
Conners Global Index-P 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Parent 
Conners Global Index-T 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Teacher 
CSHQ 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Parent 
Affective Reactivity Index-C 
X 
 
 
 
 
X 
X 
 
X 
 
Child 
Affective Reactivity Index-P 
X 
 
 
 
 
X 
X 
 
X 
 
Parent 
MASC-child report 
 
X 
 
 
 
X 
X 
 
X 
 
Child 
MASC-parent report 
 
X 
 
 
 
X 
X 
 
X 
 
Parent 
Child Depression Inventory 
 
X 
 
 
 
X 
X 
 
X 
 
Child 

11 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Assessments 
 
 
 
 
 
 
 
 
 
 
 
WISC subtests 
X 
 
 
 
 
 
 
 
 
 
RA 
WASI subtests 
X 
 
 
 
 
 
 
 
 
 
RA 
WRAT quick screen 
X 
 
 
 
 
 
 
 
 
 
RA 
Spatial Working Memory 
 
X 
X 
 
 
X 
X 
 
 
 
RA 
Attention Network Test 
 
X 
X 
 
 
X 
X 
 
 
 
RA 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
EEG 
 
X 
 
 
 
X 
 
 
 
 
RA 
HappyCaFe 
 
X 
 
 
 
X 
 
 
 
 
RA 
Affective Posner Task 
 
 
 
 
 
X 
 
 
 
 
RA 
 
 
Table 3: Procedures for 12 month Extension. 
Visit Number 
Base 
1 
2 
3 
4 
 
 
Study Month 
0 
3 
6 
9 
12 
 
 
General 
 
 
 
 
 
 
 
Height/Weight 
X 
X 
X 
X 
X 
 
RA 
Pulse, Blood Pressure 
X 
X 
X 
X 
X 
 
RA 
Device check 
X 
X 
X 
X 
X 
 
RA 
TNS Diary 
X 
X 
X 
X 
X 
 
Parent 
TNS Compliance 
X 
X 
X 
X 
X 
 
RA 
Replace supplies 
X 
X 
X 
X 
 
 
Parent 
Begin open treatment 
X 
 
 
 
 
 
MD 
End open treatment 
 
 
 
 
X 
 
MD 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
Concomitant meds 
X 
X 
X 
X 
X 
 
MD 
Adverse event inquiry 
X 
X 
X 
X 
X 
 
MD 
Side effects rating scale 
X 
X 
X 
X 
X 
 
Parent 
 
 
 
 
 
 
 
 
Behavioral Ratings 
 
 
 
 
 
 
 
CBCL 
 
 
 
 
X 
 
Parent 
ADHD-RS 
X 
X 
X 
X 
X 
 
MD 
CGI-Severity 
X 
X 
X 
X 
X 
 
MD 
CGI-Improvement 
X 
X 
X 
X 
X 
 
MD 
BRIEF 
X 
X 
X 
X 
X 
 
Parent 
Conners Global Index-P 
X 
X 
X 
X 
X 
 
Parent 
Conners Global Index-T 
X 
X 
X 
X 
X 
 
Teacher 
CSHQ 
X 
X 
X 
X 
X 
 
Parent 
Affective Reactivity Index-C 
X 
X 
X 
X 
X 
 
Child 
Affective Reactivity Index-P 
X 
X 
X 
X 
X 
 
Parent 
MASC-child report 
X 
X 
X 
X 
X 
 
Child 
MASC-parent report 
X 
X 
X 
X 
X 
 
Parent 
Child Depression Inventory 
X 
X 
X 
X 
X 
 
Child 
 
 
 
 
 
 
 
 
Cognitive Assessments 
 
 
 
 
 
 
 
WISC subtests 
 
 
 
 
X 
 
RA 

12 
WASI subtests 
 
 
 
 
X 
 
RA 
WRAT quick screen 
 
 
 
 
X 
 
RA 
Spatial Working Memory 
X 
 
 
 
X 
 
RA 
Attention Network Test 
X 
 
 
 
X 
 
RA 
 
 
 
 
 
 
 
 
* Visit 4 cognitive assessments will be conducted at final visit in case of early termination. 
 
4. TNS Therapy 
Equipment - Stimulation is supplied using a CE-mark approved neurostimulator, the Monarch eTNS 
SystemTM (NeuroSigma, Inc., Los Angeles CA); NeuroSigma is the exclusive licensee of UCLA's intellectual 
property around trigeminal nerve stimulation and in August 2012 received CE mark certification for use of the 
Monarch for adjunctive treatment in epilepsy and major depression in adults and children age 9 and older.  The 
Monarch comprises two elements: the electrical pulse generator and the hypoallergenic, self-adhering custom 
electrodes for delivery of the signal to the supraorbital and supratrochlear branches of the V1 division of the 
trigeminal nerve.  The system offers features not available in off-the-shelf transcutaneous nerve stimulators, 
such as limiting the applied current to known safe ranges and two levels of lock-out codes to prevent the  
device from being used or reprogrammed by the patient.  As well, the composition and geometry of the 
electrodes have been engineered to provide the optimal amount of adhesion to be worn for 7-9 hours with a 
gel devoid of volatile compounds that are present in most surface electrodes used for nerve stimulation that 
lead to skin irritation.   
 
The same devices are used for the active and sham treatment conditions.  To maintain blinding, the 
sham system is identical in appearance and in operation: each night the participant applies a patch to the 
forehead, attaches the patch to the generator with lead wires, turns the device on (after putting in a new 
battery), presses the “up” button until the stimulation is uncomfortable and then presses “down” to reduce it, or 
reaches the maximum current the device is programmed to supply. In active units, current flows to the patch 
and is limited to a safe range.  It is likely to produce some sensation, albeit not for everyone.  Any sensation 
experienced generally fades with time.  In the sham unit, no current flows, so participants adjust settings 
without actually controlling current.  For this reason, all participants are informed: “pulses may come so fast or 
so slowly that the nerves in the forehead might or might not detect a sensation.” The active condition will 
employ the same parameters previously studied in ADHD, epilepsy, and major depression:  120 Hz repetition 
rate, 250 μs pulse width, duty cycle of 30s on: 30s off. The sham is currently being used in a study of PTSD 
with no evidence that blinding is compromised.  
 
If devices break or malfunction, they will be replaced upon return to study staff.  Devices will be 
returned at the end of study participation. 
 
Randomization - A web-based randomization tool will be implemented by the Semel Institute’s Statistics 
Core (SIStat) as part of the project’s centralized data system.  Participants will be block-randomized in a 1:1 
ratio to active or sham eTNS to maintain group balance throughout the study.  A random mixture of block 
lengths of 4 and 6 will be employed to further ensure preservation of the blind.  Randomization will be further 
stratified by high vs. low screening ARI scores.  Access to the randomization system will be restricted via 
password- protected login, with privileges limited to one designated member of the study team who is 
responsible for adjusting device settings  
 
Procedures- Procedures for eTNS are based on previous work in epilepsy and depression [48-54].  
After collection of baseline measures, a RA will instruct participants in the use of the device, including replacing 
the batteries, applying the forehead electrode, and general operation of the device.  The RA will conduct a brief 
trial of the stimulator, gradually increasing current to find a level of perceptible stimulation that remains 
comfortable.  The RA will check the device settings and review system use at each subsequent visit.  
Participants use new electrodes each day.  Study staff will provide adequate study supplies at each weekly 
visit. Parents will maintain a daily diary to quantify nightly use of eTNS, and the RA will confirm compliance at 
weekly at visits 1 – 4.  Additionally, after the first week of treatment at Visit 1, participants and parents will be 
asked to complete the Early Impressions Questionnaire, a measure designed to assess ability to guess or 
detect treatment assignment [97] allows us to assess the fidelity of condition blinding. This is administered after 

13 
the first week of treatment to avoid judgments about treatment assignment once efficacy differences might 
emerge. 
 
 
Participants will receive devices and supplies without cost.  If devices break, they should be returned to 
the study staff and will be replaced.  Participants will return the device and any remaining supplies to study 
staff at the conclusion of their involvement in the study.   
 
5. Clinical Assessment 
 
Determination of eligibility to participant in the project will be based on standard approaches to clinical 
assessment of ADHD.  Diagnostic approaches proposed here are similar to those used in other NIMH funded 
research studies as well as in the UCLA clinical program: 
 
a) KSADS-PL [55]: A validated, frequently used, semi-structured clinical interview to assess pediatric 
psychopathology. Although the current instrument was designed to assess DSM-IV defined ADHD it 
remains suitable for assessment of DSM-5 ADHD as symptoms in each edition are unchanged. 
 
b) Clinical History: Standard psychiatric and medical interview used in UCLA Child and Adolescent 
Outpatient Clinics and the UCLA ADHD Program. 
 
c) Saliva/DNA sampling: Participants will be asked to provide approx. 5 cc’s of saliva in a standard 
collection tube.  Saliva will be sent for DNA isolation 
 
6. Safety Assessments 
 
Although all available evidence suggests that eTNS is acceptable and well tolerated in patient groups, 
with an absence of clinically meaningful adverse events, standard approaches to safety monitoring and 
assessment of tolerability will employ the following: 
 
a) Concomitant Medication Inquiry:  At each study visit, participants will be asked about medications they 
might have used since the previous visit. 
 
b) Adverse Event Inquiry: Open-label inquiry about any changes in medical status or behavior since the 
prior visit. 
 
c) Side Effects Rating Scale: A structured, parent completed assessment of common side effects 
associated with eTNS. 
 
d) Columbia-Suicide Severity Rating Scale (C-SSRS) [66]: A validated, semi-structured assessment of 
suicidality commonly used in clinical intervention studies. 
 
7. Behavioral Ratings 
 
Selected measures include either a commonly used instrument to better characterize patients with 
ADHD (CBCL) or ratings that are commonly used in clinical medication trials of ADHD.  Behavioral ratings to 
be used in this study are:  
 
a) Achenbach Child Behavior Checklist (CBCL) [67]: A well-normed self-report measure assessing a 
broad range of behavioral problems. 
 
b) ADHD IV Rating Scale (ADHD-RS) [68]: A DSM-IV based rating scale of ADHD symptoms used 
frequently in clinical trials. 
 
c) Clinical Global Impression-Severity (CGI-S) [69]: A clinician rating of overall illness severity. 
 
d) Clinical Global Impression-Improvement (CGI-I)[69]: A clinician rating of overall improvement from 
baseline [67]. 

14 
 
e) Behavior Rating Inventory of Executive Functioning (BRIEF) [70]: An often-used parental completed 
questionnaire that assesses a child’s executive functioning in home settings.  
 
f) Conners Global Index- parent [71]: A 10-item parent completed rating scale of ADHD-related behaviors 
with a particular emphasis on externalizing symptoms. 
 
g) Conners Global Index-teacher [71]: A 10-item teacher completed rating scale of ADHD-related 
behaviors with a particular emphasis on externalizing symptoms. 
 
h) Children’s Sleep Habits Questionnaire (Abbreviated) (CSHQ) [72]: A validated parent-report measure 
that has proved useful in quantifying sleep problems in school-aged children with ADHD 
 
i) Multidimensional Anxiety Scale for Children (MASC) [73]: A self-report scale of pediatric anxiety, both 
parent and child version will be used. 
 
j) Children’s Depression Inventory (CDI) [74]: Standard self-report ratings of depressive symptoms. 
 
k) Affective Reactivity Index (ARI): A recently validated measure of irritability based on parent and child 
self-report  [98]. 
 
8. Cognitive Measures 
 
Cognitive measures were selected to assess potential treatment-related changes in brain regions 
associated with executive functioning and identified in PET studies of adults receiving eTNS for mood 
disorders.  Test of response inhibition and working memory were also selected based on their lack of practice 
effects and their suitability for repeated testing.  A description of these cognitive tests is as follows: 
 
a) Wechsler Intelligence Scale for Children (WISC-IV), Digit Span, Coding [75]: Standardized measure of 
verbal working memory and processing speed. 
 
b) Wechsler Abbreviated Scale of Intelligence (WASI), Matrix Reasoning and Vocabulary [76]: A brief and 
reliable assessment of overall intellectual ability, validated with respect to the WISC-IV. 
 
c) Wide Range Achievement Test (WRAT III) [77]: Brief test of reading recognition, spelling, and 
arithmetic. 
 
d) Spatial Working Memory [79]: The spatial version of the Sternberg delayed match to sample task that 
provides a measure of working memory. 
 
e) Attention Network Test (ANT) [80]:  A test of cued reaction time and response inhibition (conflict 
resolution). 
 
f) HappyCaFe (Happy-Calm-Fearful) Task, a measure designed for and currently in use in the IRB 
approved high-risk bipolar disorder study in which participants view photographs of young adults with 
calm, happy, fearful, and neutral facial expressions and indicate the sex of each by pressing one of two 
buttons. The measure activates brain regions associated with emotional processing 
 
9. Laboratory Assessments 
 
EEG Acquisition- We will follow procedures used by our laboratory in previous studies.  Participants will 
undergo EEG recording for ~2 hours, which includes baseline (eyes open and eyes closed) and cognitive 
activation (SWT, ANT) conditions. A head cap fitted with 84 active electrodes positioned according to the 
International 5%-system [81] will be used, and eye movement detected at the outer canthus of each eye 
(REOG and LEOG).  Recording electrodes are connected to an isolation amplifier that is part of the MANSCAN 
EEG system (SAM Technology).  Stimuli and responses are marked on the EEG record to allow for event-
related analyses by stimulus type and response (correct/incorrect).  All EEGs will be digitized, which is a 
process of recording key landmarks (nasion, inion, preauricular notches) and electrode locations to allow 3-
dimensional reconstruction of electrode positions on the scalp.  
 

15 
EEG Data Processing- continuous EEG data will be exported from MANSCAN into MATLAB [82] where 
we will use the independent components (IC) analysis tool in EEGLAB [83] to assess for super-Gaussian (e.g. 
vertical eye movement) and sub-Gaussian (e.g. EKG) noise and remove it from the data, while maintaining the 
dataset in its entirety.  
 
 IC analyses of event-related spectra- Trials are then sorted according to event type. The data are 
segmented based on conditions of interest (e.g. SWM: encoding, maintenance, retrieval).  Group IC clusters 
will be found by applying “Measure Product Method” (as implemented in EEGLAB) to the full set of ICs across 
all subjects.  This method finds similarity measures for each pair of components based on scalp maps, ERSP 
(event-related spectra plots) and ERPs of each component.  The similarity measures are then used to identify 
clusters of components via a clustering algorithm. Treatment-group differences in event-related potentials (i.e., 
ERN), synchronization (increased gamma power) and desynchronization (decreased theta power) in the frontal 
component will be tested using permutation tests with multiple-comparison correction. 
 
EEG connectivity analyses in EEGLAB using the SIFT toolbox- The SIFT functions use time-varying 
(adaptive) multivariate autoregressive modeling to detect and measure fluctuations in event-related effective 
connectivity between sources of neural activity.  This general approach allows for implementation of a number 
of popular multivariate measures of information flow, such as Granger Causality Modeling and Directed 
Transfer Function Modeling.  To test the present model, sift functions will be constrained to examine effective 
connectivity between fronto-central theta/gamma band sources, and the time courses of particular connections 
will be tested between experimental conditions (i.e., active vs. sham treatment) using Bootstrap/resampling 
techniques to correct for multiple comparisons.   
 
Affective Posner Task -This paradigm allows measurement of brain circuits dealing with frustration and 
reward, and has previously shown effects in studies of youth with chronic irritability.  The task will be performed 
once at Visit 4, while undergoing EEG and following administration of the SWM and ANT tasks.  The paradigm 
involves 3 individual tasks. For each of these three tasks, a fixation cross will appear in the center of a 
computer screen followed by 2 boxes arranged horizontally. “Cues” will be designated as one box illuminating 
blue. Cue locations will be placed 50% in the right and left boxes. Following the cue, a target square will 
appear inside the right or left box at an unequal rate. Participants will be instructed to respond as quickly and 
as accurately to the location of the target. For Task 1, 100 trials will be presented and will serve as a non-
emotional baseline. Subjects will receive “Good job!” or “Incorrect!” feedback based on their performance.  
Prior to beginning Task 2, participants will be informed that they will be doing something similar but that they 
may be able to win some money based on how they perform. The task will consist of 50 trials where subjects 
will win or lose 25 cents on each trial based on accuracy (“Great Job! Win 25 cents” or “Wrong! Lose 25 
cents”). The final and third task will also be similar. However, the feedback will be rigged to induce frustration in 
participants. On 44% of the correctly identified trials, correct responses will be provided true feedback + 
monetary reward (“You are Quick! Win 25 cents”). On the remaining 56% of correct responses, participants 
received rigged feedback, which will inform the participant that he/she was too slow and lost 25 cents (“Too 
Slow! Lose 25 cents”).  Participants will be asked to rate happy/unhappy and calm/aroused feelings about the 
task, as well as rate their feelings about the rewards and the punishments following each task. These ratings 
will be completed using an analog scale with very happy/very unhappy or very calm/very aroused on each end. 
 
Once this task is completed, participants will be debriefed about the partial disclosure regarding this set 
of tasks. 
 
 
10. Statistical Analysis and Power Calculations 
 
Overview: As a first step we will use graphical and numerical summaries to screen the data for outliers 
and violations of model assumptions and to assess the need for transformations or non-parametric methods. 
To check the success of randomization we will compare the groups at baseline on demographic characteristics 
using t-tests and chi-square tests as appropriate. Any variables that show significant differences will be 
included as covariates in subsequent models. We will also plot each of the outcome variables as a function of 
time for each of the study arms to determine the forms of treatment trajectories (e.g. linear, quadratic, 
piecewise linear with a change in slope at the end of acute treatment.)  

16 
 
Our primary analytic tool will be the general linear mixed model (GLMM), with treatment group (active 
vs. sham), time, and a group by time interactions as the primary predictors along with subject level random 
effects. GLMMs properly account for the correlations induced by repeated measurements within subjects and 
allow for both fixed and time-varying covariates. They also automatically handle missing data, producing 
unbiased estimates as long as observations are missing at random. This allows the use of all available data 
from all subjects, thereby minimizing the effects of loss to follow-up and motion artifacts. We note that given 
the short time period of the study and low expectation of side effects that we expect minimal attrition. 
Nonetheless, we will compare drop out rates and patterns by treatment arm and if we detect differences will 
adjust the primary models using a propensity score to minimize potential bias. 
 
Using GLMMs will permit us to seamlessly integrate longitudinal and cross-sectional analyses (for 
those variables such as adverse effect counts or sessions attended which are available only at end of study), 
as well as handling both continuous and binary outcomes in a common framework.  To make the most efficient 
use of our data we will fit a single model for each outcome across all time points.  Our hypotheses correspond 
to specific follow-up contrasts concerning the differential treatment effects over the acute intervention and 
follow-up periods.  Post-hoc contrasts can similarly be used to identify the individual time-points at which there 
are significant differences between groups, which will be important for establishing the minimum necessary 
treatment period. We are well aware of multiple testing issues and minimize them by identifying a limited set of 
a priori primary measures and contrasts. However we note that this is a pilot study, designed to identify optimal 
measures, and protocols for a future definitive efficacy trial; thus identifying potentially meaningful outcome 
measures and effects is more important than minimizing Type I error.  All results will therefore be reported 
using an uncorrected significance level of α=.05. Below we present a detailed analysis plan by specific aim.  
 
For Specific Aim 1 the primary outcome measures will be the ADHD-RS, which is administered weekly 
(a total of 9 time-points starting from baseline). Our primary interest is in group by time interactions during the 
intervention and follow-up periods, although main effects of group or time would also be of interest.  We plan to 
treat time as a continuous piece-wise linear predictor, allowing for a change in slope at the end of the active 
intervention period, although as noted above we will explore other possible forms for the outcome trajectories. 
 
For Specific Aim 2 we will use the same analytic structure with measures of executive function 
(response inhibition (ANT), working memory (SWM) and the parent completed BRIEF), reaction time, reaction 
time variability and cortical activation (EEG profiles) as the primary outcome measures.  These are also 
measured weekly except for EEG which is done at baseline, end of treatment, and end of follow-up. 
 
For Specific Aim 3 we will focus on parent and teacher ratings of ADHD (Conners), physiological 
measures (height, weight, cardiovascular effects) and sleep (CHSQ), all measured weekly, as well as mood 
(CDI) and anxiety (MASC), measured 3 times. We will also examine tolerability of the intervention as measured 
by the side effects rating scale and adverse event inquiries.  For the first set of measures we will use the same 
GLMM structure as in Aims 1 and 2.  For the latter measures we will use total scores or cumulative counts over 
the study period (acute, follow-up, whole study) running standard ANCOVA or Poisson regression analyses 
with treatment group as the primary predictor.   
 
Power Considerations - We plan to recruit 85-90 subjects total to obtain 72 completers (36 per 
treatment arm). Power calculations are conservatively based on these numbers; actual power should be higher 
since our GLMM structure allows us to use information from subjects with partial data. All calculations assume 
a 2-sided significance level of α=.05 and, where applicable, a moderate correlation of r = .5 between repeated 
measurements within subjects. Contrasts will be evaluated following significant omnibus tests to minimize Type 
I error rates. The primary hypotheses for all three aims correspond to group by time interactions over either the 
acute or follow-up treatment periods covering anywhere from 2 to 5 observations depending on whether the 
measure was collected weekly or at baseline, end of treatment and end of follow-up. Our design has 80% 
power to detect an interaction corresponding to a change from no difference at baseline to a difference of d = 
.59 (with 5 observations) or d = .66 (with 2 observations) at end of treatment (or equivalently a differential 
change in effect size of that magnitude across the follow-up period).  These are just above a standard medium 
effect size using the conventions of Cohen.  We are also interested in a variety of sub-contrasts.  For example, 
we have 80% power to detect a within group change of d = .47 between any two time points and a difference 
between the treatment groups of d = .65 at any individual time point.  In our preliminary study that used the 
same a dose of eTNS as our proposed active condition, In our preliminary study using the same dose of TNS 

17 
as in the proposed active condition, we observed within subject changes of d = 1.9 on the ADHD-RS (Aim 1 
primary outcome), d = .46 on the ANT incongruent reaction time (Aim 2) and d = .84 on the Parent Conners 
ADHD rating (Aim 3) over a four week intervention. If the inactive treatment group remains stable over time 
then these within-subjects changes would be equal in magnitude to the differential treatment effects and both 
types of effects would be detectable with our sample size   Indeed, even with a substantial placebo response 
we would have adequate power for the interactions for the ADHD-RS and Conners. For the cross-sectional 
analyses in Aim 3 we have 80% power to detect a treatment effect that explains R2 = 10% of the variability in 
tolerability or side effect measures. Overall, even under conservative assumptions, we are well powered to 
detect most effects of interest, and will certainly be able to obtain estimates of effect sizes and minimum 
treatment intervals to inform a future efficacy trial.  
 
PROTECTION OF HUMAN SUBJECTS 
 
 
1. Risks to Human Subjects 
 
a. Human Subjects Involvement, Characteristics, and Design 
 
This study will recruit approximately 90 children ages 8 to 12 years who meet DSM-5 criteria for ADHD.  
After diagnostic and clinical screening, eligible participants and their parents will be trained to administer eTNS 
each night, usually during sleep.  Participants will be randomized to either active or sham eTNS treatment 
conditions.  Participants, families, and most members of the study team will remain blinded to randomized 
condition.  Participants will undergo eTNS for approximately eight hours each night, typically during sleep, for 
four weeks of acute therapy.  Participants will have weekly research visits during the four weeks of treatment 
and one additional week after active treatment ends.  Behavioral ratings and safety measures will be 
administered at each visit.  Cognitive measures will be collected at baseline, end of treatment weeks 1 and 4, 
and at end of week 5.  Additionally, participants will undergo EEG at baseline and week 4.  Participation in the 
full protocol will require a total of 7 clinic visits over a 5-7 week period.  Screening, baseline, week 4, and week 
5 visits will require between one and two hours of participant time.  Other visits will generally require less than 
one hour for parent completion of questionnaires (approx. 30 minutes).  Parent and participant procedures will 
generally occur simultaneously.   Cognitive testing and EEG will be conducted simultaneously during visits 
when EEGs are obtained.  Patients randomized to sham treatment will have the option of 4 weeks open eTNS 
treatment beginning after blind is broken at Visit 5.  Two subsequent visits at two week intervals will be 
required to assess safety and behavioral responses.  These visits should require approximately one hour of 
family time.  Participants who achieve CGI-I scores ≤ 2 at the end of active treatment will be offered the 
opportunity to continue eTNS during a 12 –month open extension phase.  Visits in this phase will occur every 3 
months. 
 
Inclusion criteria are: 1) male and female children ages 8 to 12 years with DSM-5 ADHD, any current 
presentation, as determined by KSADS and clinical interview; 2) minimum scores of 12 on both the inattentive 
and hyperactive/impulsive subscales of the baseline ADHD-RS; 3) CGI-S score at baseline ³ 4; 4) no current 
medication with CNS effects; 5) parents able and willing to monitor proper use of the stimulation device and 
complete all required rating scales; 6) estimated Full Scale IQ ³ 80 based on WASI subtests; 7) parent and 
participant able to complete rating scales and other measures in English; 8) able to cooperate during EEG.  
 
Exclusion criteria are: 1) impaired functioning to a degree that requires immediate initiation of ADHD 
medication in the opinion of the parents and/or investigator; 2) current diagnosis of autism spectrum disorder or 
major depression; 3) history of lifetime psychosis, mania, seizure disorder or head injury with loss of 
consciousness; 4) baseline suicidality.  
 
 
b. Sources of Materials 
 
Information about study participants will be obtained through clinical interviews, structured interviews, 
cognitive testing, brain imaging (EEG), and rating scales completed by the participant’s parent/guardian, 

18 
teachers, and study clinicians.  Parents/participants will be asked to provide authorization for exchange of data 
between clinical and research databases, as required by the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA).  Source documents that might contain indentifying information will be retained in the 
participant’s clinical research chart, which will be stored in a locked file cabinet in our clinical research offices.  
All data will be collected on Case Report Forms (CRFs).  Data will be entered into a password protected 
electronic database under control of the principal investigator.  All entered data will be identified only by the 
participant’s study ID number.  No personally identifying information will be entered into the electronic record.  
The link between the clinical research record and the electronic database will be kept by the PI in a separate 
locked file.  Access to the electronic database will be password protected and limited to study staff.   
 
After conclusion of all research activity and planned analyses, the link between paper based research 
records and the electronic database will be destroyed.  Subsequently, the de-identified electronic database will 
be available for additional analyses or sharing with other investigators under procedures to be approved by the 
UCLA IRB.  Participant will be informed about the possibility of future sharing of de-identified data on NIH or 
other government sponsored public research databases.  
 
c. Potential Risks 
 
Risks of Assessment Procedures: There is a chance that participants and/or parents will become upset 
during initial or subsequent evaluations.  Potential risks associated with medical and cognitive testing include 
1) embarrassment or anxiety when asked to discuss personal medical history, 2) anxiety about performance 
during completion of cognitive tests, and 3) fatigue or boredom during cognitive tests and EEG.  These risks 
are not beyond those of a standard medical and psychological assessment and are considered minimal risk.  
There is also some particular risk of getting upset after administration of the Affective Posner Task.  This risk 
will be minimized by informing participants in the ICF that some procedures won’t be explained completely and 
by debriefing participants about the partial disclosure immediately after completion of the task. 
 
Risks of eTNS: Study stimulators have been used previously and are considered by the FDA to be non-
significant risk devices.  Tingling or pressure in the scalp or teeth, headache, and eye blinking have been 
reported, but generally respond to adjustments in stimulus intensity [54].  Risk for these effects, as well as mild 
discomfort, might occur during the initial dose adjustment.  Some patients wearing the device up to 24 hours 
developed mild skin irritation which responded to decreased wear times and cortisone cream.  
 
Risks of Behavioral Worsening:  It is not known if active or sham eTNS will have any effect on ADHD 
symptoms or cognition.  While nothing suggests this is likely, ADHD symptoms could also worsen.  
Unanticipated negative changes in behavior could also occur.  Finally, participants who respond positively 
might suffer loss of benefits after their participation ends. 
 
Risks of Breaches in Confidentiality: There is a rare possibility, as with any research study, that 
participant confidentiality will be breached.  
 
The overall risk classification for this project is minimal risk with an expectation of participant benefit.   
 
2. Adequacy of Protection Against Risks 
 
a. Recruitment and Informed Consent 
 
All procedures for recruitment and informed consent will be reviewed and approved by the UCLA IRB.  
Parents will be informed about the study in several ways.  Families will be solicited through flyers posted in 
public places and referral from other UCLA ADHD research studies.  We may also actively recruit for the study 
through advertisements on television, radio, or in print media.  Once parents initiate contact with study staff 
they will be provided with a brief study overview of the project, and if interested, undergo initial eligibility 
screening using an IRB approved telephone-screening script.  Eligible families who chose to participate will be 
scheduled for an initial appointment.  It is expected that we will receive a Wavier of Signed Informed Consent 
for Screening as these procedures are generally deemed minimal risk. 
 

19 
At the initial visit, parents and potential participants will be provided with the IRB approved Parent 
Permission and Child (ages 8-12) Assent Forms and given time to read and discuss these in a private office.  
Subsequently, the PI or other physician designee will provide parents and potential participants with a thorough 
verbal explanation of study requirements, including its purpose, procedures, risks, and potential benefits.  
Written informed consent forms will be reviewed with the family by the physician investigator to ensure the 
forms are understood.  After reading the permission/assent forms, patients and their parents will queried by the 
investigator to ascertain their understanding of study requirements and will also be encouraged to ask 
questions of the investigator.  After signing the informed consent forms, families will be provided with copies to 
take home.  The process of informed consent will be documented with a note in the participant’s research 
record and in a CRF.  No study procedures will begin until after written permission/assent is obtained. 
 
b. Protections Against Risk 
 
Participants and their families will be informed of the exact nature of all study procedures prior to 
providing signed permission/assent.  All medical and other testing procedures will be conducted in private 
offices to ensure participant comfort and privacy.  A study physician will monitor participants weekly.  Parents 
will be told to contact the study coordinator or physician if the child’s behavior deteriorates between scheduled 
visits, or if unanticipated side effects or other emergencies arise.   
 
Potential adverse events will be assessed and recorded at each study visit with an open-ended adverse 
event inquiry as well as a structured parent completed rating of expected side effects.  The study clinician will 
assess the severity of any reported adverse event and determine the likelihood of its relation to study 
procedures.   
 
If at any time an individual participant exhibits one of the following, s/he will be immediately withdrawn 
from the study: 1) psychiatric hospitalization; 2) CGI-I of 6 (much worse) or 7 (very much worse); 3) clinically 
significant exacerbation of suicidality as assessed by clinical interview; 4) inability to tolerate TNS; 5) risk of 
failure in the home, school, or social setting that, in the opinion of a parent or physician investigator, 
necessitates immediate titration with an approved ADHD medication.  Participants who are withdrawn from the 
study by physicians will be managed clinically in the UCLA ADHD clinical program or referred to other clinically 
indicated treatment. 
 
Strict standards of confidentiality will be maintained throughout this study.  We will take every 
reasonable precaution to avoid any possibility of unauthorized release of any information gathered in this 
study.  All data entered into the electronic database will be identified by coded participant identifiers only.   All 
paper records containing identifying information (including the participant contact list and linking codes) will be 
stored in locked files in locked offices under the PI’s jurisdiction at UCLA.  Participants will remain anonymous 
in all publications. 
 
3. Potential Benefits of the Proposed Research to Human Subjects and Others 
 
All participants will receive thorough medical and psychiatric evaluations that might assist in future 
treatment planning.  eTNS might also lead to decreases in ADHD symptoms and improved cognition.  
Ultimately, development of an efficacious non-medication treatment for ADHD will have huge societal and 
public health benefits. 
 
4. Importance of the Knowledge to be Gained 
 
The results of this study will inform the on feasibility and design choices for future definitive studies of 
TNS in ADHD.  Information derived from this study will be critical in determining whether or not additional 
research on eTNS in ADHD is warranted.  Positive outcomes would support the likelihood of developing eTNS 
as an effective non-medication treatment for ADHD.  Negative results would suggest that additional research 
on eTNS in ADHD is unlikely to provide benefit, and would therefore help to avoid the expense of larger trials 
and exposure of larger numbers of participants to an ineffective treatment.  
 
5. Data and Safety Monitoring Plan 

20 
 
The principal investigators will be responsible for monitoring the safety and wellbeing of study 
participants over the course of this investigation.  Participants will be assessed for safety at each study visit by 
a physician investigator.  Parents/patients will also be provided with 24-hour pager numbers and instructed to 
contact study staff or physician investigators immediately in case of any significant reaction or emergency.  All 
treatment emergent adverse events, side effects, or serious adverse events will be reported as required by the 
IRB.   
 
Our previous research with TNS for ADHD confirms that these procedures are minimal risk, with 
virtually no past reports of clinically meaningful adverse events.  However, if any unexpected risks are 
identified, immediate steps will be taken to protect all participants, and the IRB will be contacted according to 
regulations and requirements.   
 
6. ClinicalTrials.gov Requirements 
 
This project is registered as a clinical trial at the ClinicalTrials.gov Protocol Registration System 
Information Website (http://prsinfo.clinicaltrials.gov/).  
 
 
BIBLIOGRAPHY AND REFERENCES CITED 
 
1. Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-
deficit/hyperactivity disorder among children – United States, 2003 and 2007. MMWR Morb Mortal Wkly 
Rep. 2010;12:1439-43. 
2. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United 
States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163:716-723. 
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
– Text Revision (DSMIV-TR). Washington, D.C.: American Psychiatric Publishing, Inc.; 2000.  
4. Barkley RA. Major life activity and health outcomes associated with attention deficit/hyperactivity 
disorder. J Clin Psychiatry. 2002;63 Suppl 12:10-15. 
5. McGough JJ, Smalley SL, McCracken JT, et al. Psychiatric comorbidity in adult attention deficit 
hyperactivity disorder: findings from multiplex families. Am J Psychiatry. 2005;162:1621-1627. 
6. Wilens T, Spencer TJ. Understanding attention-deficit/hyperactivity disorder from childhood to 
adulthood. Postgrad Med. 2010;49:97-109. 
7. Hinshaw S, Peele P, Danielson L. Public health issues in ADHD: individual, system, and cost burden of 
the disorder workshop. Accessed at http:/www.cdc.gov/ncbddd/adhd/dadburden.htm, March 22, 2011.  
8. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of 
attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry. 2005;57:1136-1346. 
9. Loo SK, Humphrey LA, Tapio T, et al. Executive functioning among Finnish adolescents with attention-
deficit/hyperactivity disoder. J Am Acad Child Adolesc Psychiatry. 2007;46:1594-1604. 
10. Luman M, Oosterlaan J, Knol DL, Dergeant J. Decision-making in aDHD: sensitive to frequency but 
blind to the magnitude of penalty? J Child Psychol Psychiatry. 2009;48:837-846. 
11. Paloyelis Y, Asherson P, Kuntsi J. Are ADHD symptoms associated with delay aversion or choice 
impulsivity? A general population study. J Am Acad Child Adolesc Psychiatry. 2009;48:837-846. 
12. Scheres A, Tontsch C, Thoeny AL, Kaczuking A. Temporal reward discounting in attention-
deficit/hyperactivity disorder: the contribution of symptom domains, reward magnitude, and session 
length. Biol Psychiatry. 20120;67:641-648. 
13. Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the prefrontal-striatal model. 
Trends Cogn Sci. 2012;16:17-26.  
14. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends 
Cogn Sci. 2011;15:483-506. 
15. Vincent JL, Kahn I, Snyder AZ, Raichle ME, Buckner RL. Evidence for a frontoparietal control system 
revealed by intrinsic functional connectivity. J Neurophysiol. 2008;100:3328-3342. 
16. Nakao T, Radua J, Rubia K, Mataix-Cols D. Gray matter volume abnormalities in ADHD: Voxel-based 
meta-analysis exploring the effects of age and stimulant medication Am J Psychiatry. 2011;11:1154-
1163. 

21 
17. Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in 
attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:1361-1369. 
18. Bush G. Attention-deficit/hyperactivity disorders and attention networks. Neuropsychopharmacology. 
2010;35:278-300. 
19. Durston S, Davidson MC, Mulder MJ, et al. Neural and behavioral correlates of expectancy violations in 
attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry. 2007;48:881-889. 
20. Konrad K, Neufang S, Hanisch C, Fink GR, Berpertz-Dahlmann B. Dysfunctional attentional networks in 
children with attention-deficit/hyperactivity disorder: evidence from an event-related functional magnetic 
resonance imaging study. Biol Psychiatry. 2006;59:643-651. 
21. Rubia K. “Cool’ inferior frontostriatal dysfunction in attention-deficit/hyperactivity disorder versus ‘hot’ 
ventromedial orbitofrontal-limbic dysfunction in conduct disorder: a review. Biol Psychiatry 2011;69:e69-
e87. 
22. Smith AB, Taylor E, Brammer M, Halari R, Rubia K. Reduced activation in right lateral prefrontal cortex 
and anterior cingulate gyrus in medication-naïve adolescents with attention deficit hyperactivity disorder 
during time discrimination. J Child Psychol Psychiatry. 2008;49:977-985. 
23. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and 
treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child 
Adolesc Psychiatry. 2007;46:894-921. 
24. Spencer T, Biederman J, Wilens T, Harding M, O’Donnell D, Griffin S. Pharmacotherapy of Attention-
Deficit Hyperactivity Disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35:409-
432. 
25. Prince J. Pharmacotherapy of attention-deficit/hyperactivity disorder in children and adolescents: 
update on new stimulant preparations, atomoxetine, and novel treatments. Child Adolesc Psychiatry 
Clin N Am. 2006;15:13-50.  
26. Bush G, Spencer TJ, Holmes J, et al. Functional magnetic resonance imaging of methylphenidate and 
placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen 
Psychiatry. 2008;65:102-114. 
27. Bush G, Frazier JA, Rauch LJ, et al. Anterior cingulate cortex dysfunction in attention-
deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry. 1999;45:1542-
1552. 
28. Vaidya CJ, Austin G, Kirkorian G, et al. Selective effects of methylphenidate in attention deficit 
hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA. 
1998;95:14494-14499. 
29. Castellanos FX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in 
children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002;288:1740-1748. 
30. Shaw P, Sharp WS, Morrison M, et al. Psychostimulant treatment and the developing cortex in attention 
deficit hyperactivity disorder. Am J Psychiatry. 2009;166:58-63. 
31. Shaw P, Gilliam M, Liverpool M, et al. cortical development in typically developing children with 
symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit 
hyperactivity disorder. Am J Psychiatry. 2011;168:143-151. 
32. Kaplan G, Newcorn JH. Pharmacotherapy for child and adolescent attention-deficit/hyperactivity 
disorder. Pediatr Clin N Am. 2001;59:99-120. 
33. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child 
Adolesc Psychiatry. 2007;46:989-1002. 
34. Molina BS, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children 
treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 
2009;48:484-500. 
35. Swanson J. Compliance with stimulants for attention-deficit/hyperactivity disorder: issues and 
approaches for improvement. CNS Drugs. 2003;17:117-131. 
36. Thiruchelvam D, Charach A, Schachar RJ. Moderators and mediators of long-term adherence to 
stimulant treatment in children with ADHD. J Am Acad Child Adolesc Psychiatry. 2001;40:922-928. 
37. Van Cleave J, Leslie LK. Approaching ADHD as a chronic condition: implications for long-term 
adherence. Pediatr Ann. 2008;37:19-26. 
38. Coletti DJ, Pappadopulos E, Katsiotas NJ, Berest A, Jensen PS, Kafantaris V. Parent perspectives on 
the decision to initiate medication treatment of attention-deficit/hyperactivity disorder. J Child Adolesc 
Psychopharmacol. 2012;22:226-237. 

22 
39. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-
deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086. 
40. Arnold LE, Lofthouse N, Hersch S, et al. EEG neurofeedback for ADHD: double-blind sham-controlled 
randomizes pilot feasibility trial. J Atten Disord. 2012;epub. 
41. Lansbergen MM, van Dongen-Boomsa M, Buitelaar JK, Slaats-Willemse D. ADHD and EEG-
neurofeedback: a double-blind randomized placebo-controlled feasibility study. J Neural Trransm. 
2011;118:275-284. 
42. Loo SK, Makeig S. Clinical utility of EEG in attention-deficit/hyperactivity disorder: a research update. 
Neurotherapeutics. 2012;9:569-587. 
43. Nolte J. The human brain: an introduction to its functional anatomy. 4th ed. St. Louis, MO; 1999. 
44. Caous CA, deSousa BH, Lindsey CJ. Neuronal connections of the paratrigeminal nucleus: a 
topographic analysis of neurons projecting to bulbar, pontine and thalamic nuclei related to 
cardiovascular, respiratory and sensory functions. Auton Neurosci. 2001;87:14-24. 
45. De Sousa BH, Caous CA, Lindsey CJ. Projections of the paratrigeminal nucleus to the ambiguus, 
rostroventrolateral and lateral reticular nuclei, and the solitary tract. Auton Neurosci. 1002;87:187-200. 
46. Gura EV, Garkavenko VV, Limansky YP. Influences of central gray matter stimulation on thalamic 
neuron responses to high-and low-threshold stimulation of trigeminal nerve structures. Neuroscience. 
1991;41:681-693.  
47. Fanselow EE, Reid AP, Nicolelis MA. Reuction of pentylenetetrazole-induced seizure activity in awake 
rats by seizure-triggered trigeminal nerve stimulation. J Neurosci. 2000;20:8160-8168. 
48. DeGiorgio CM, Shewman DA, Whitehurst T. Trigeminal nerve stimulation for epilepsy. Neurology. 
2003;61:421-422. 
49. DeGiorgio CM, Shewmon A, Murray D, Whitehurst T. Pilot study of trigeminal nerve stimulation (TNS) 
for epilepsy: a proof-of-concept trial. Epilepsia. 2006;47:1213-1215. 
50. DeGiorgio CM, Murray D, Markovic D, Whitehurst T. Trigeminal nerve stimulation for epilepsy: long-
term feasibility and efficacy. Neurology. 2009;72:936-938. 
51. Cook IA, Schrader ML, Geist CL, et al. Regional PET activation with trigeminal nerve stimulation in 
major depression. Poster presented at the NCDEU Annual Meeting, Boca Raton FL, June 13-16, 2011. 
52. Cook IA, DeGiorgio CM, Miller PR, Maremont ER, Schrader LM. External trigeminal nerve stimulation: 
noninvasive neuromodulation in major depression. New Research Poster Session, American 
Psychiatric Association Annual Meeting, Philadelphia PA, May 5-9, 2012. 
53. Schrader LM, Mook IA, Miller PR, Maremont ER, DiGiorgio CM. Trigeminal nerve stimulation in major 
depressive disorder: first proof of concept in an open pilot trial. Epilepsy Behav. 2011;22:475-478. 
54. DeGiorgio CM, Fanselow EE, Schrader LM, Cook IA. Trigeminal nerve stimulation: seminal animal and 
human studies for epilepsy and depression. Neurosurg Clin N Am. 2011;22:449-456. 
55. Kaufman J, Birmaher B, Brent D, et al. Schedule for affectie disorders and schizophrenia for school 
aged children – present and lifetime version (K-SADS-PL). J Am Acad Child Adolesc Psychiatry. 
1997;36:980988. 
56. Cook IA, DeGiorgio CM, Leuchter AF. Trigeminal nerve stimulation in post-traumatic stress disorder 
and major depression: a novel neuromodulation approach. Poster presented at the NCDEU Annual 
Meeting, Phoenix AZ, May 29-June 1, 2012. 
57. Loo SK, Fisher SE, Franks C, et al. Genome-wide scan of reading ability in affected sibling pairs with 
attention-deficit/hyperactivity disorder: unique and shared genetic effects. Mol Psychiatry. 2004;9:485-
493. 
58. Loo SK, Smalley SL. Preliminary report of familial clustering of EEG measures in ADHD. Am J Med 
Genet B Neuropsychiatr Genet. 2008;147B:107-109. 
59. Forssman L, Bohlin G, Lundervold AJ, et al. Independent contributions of cognitive functioning and 
social risk factors to symptoms of ADHD in two nordic populations-based cohorts. Dev Neuropsychol. 
2009;34:721-735. 
60. Del’Homme M, Kim TS, Loo SK, Yang MH, Smalley SL, Familial association and frequency of learning 
disabilities in ADHD sibling pair families. J Abnorm Child Psychol. 2007;35:55-62. 
61. Loo SK, Hopfer C, Teale PD, Reite ML. EEG correlates of methylphenidate response in ADHD: 
association with cognitive and behavioral measures. J Clin Neurophysiol. 2004;21:457-464. 
62. Loo SK, Teale PD, Reite ML. EEG correlates of methylphenidate response among children with ADHD: 
a preliminary report. Biol Psychiatry. 1999;45:1657-1660. 

23 
63. Gevins A, Smith ME, McEvoy LK, Leong H, Le J. Electroencephalographic imaging of higher brain 
function. Philos Trans R Soc Lond B Biol Sci. 1999;354:1125-1133. 
64. Brocki K, Clerkin SM, Guise KG, Fan J, Fossella JA. Assessing the molecular genetics of the 
development of executive attention in children: focus on genetic pathways related to the anterior 
cingulate cortex and dopamine. Neuroscience. 2009;164:241-246. 
65. Linden DE. The working memory networks of the human brain. Neuroscience. 2007;13:257-267. 
66. Posner K, Brown GK, Stanley B, et al. Columbia-Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168:1266-1277. 
67. Achenbach TM. Manual for the Child Behavior Checklist/4-18. Burlington, VT: University of Vermont, 
Department of Psychiatry; 1999. 
68.  DuPaul GJ, Power RJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV Checklist , Norms and 
Clinical Interpretations. New York: Guilford Press; 1998. 
69. Guy W. EDCEU Assessment Manual for Psychopharmacology (Revised). Washington, D.C.: US Dept. 
Health, Education, and Welfare; 1976. 
70. Gioia GA, Isquith PK, Guy SC, Kenworthy L. Test review Behavior Rating Inventory of Executive 
Functioning. Child Neuropsychology. 2000;6:235-238. 
71. Conners CK. Conners’ Global Index. Canada: Multi-Health Systems Inc.; 1997. 
72. Owens JA, Spiritio A, McGuinn M. The Children’s Sleep Habits Questionnaire (CSHQ): psychometric 
properties of a survey instrument for school-aged children. Sleep. 2000;15:1043-1051. 
73. March J. Multidimensional Anxiety Scale for Children. Canada: Multi-Health Systems Inc.; 1997. 
74. Saylor CF, Finch AJ, Spirito A, Bennett B. The children’s depression inventory: a systematic evaluation 
of psychometric properties. J Consult Clin Psychology. 1984;52:955-967. 
75. Wechsler Intelligence Scale for Children. New York: Psychological Corp; 1991. 
76. Wechsler Abbreviated Scale of Intelligence, 3rd Edition.  Pearson Education Inc.; 1997. 
77. Wide Range Achievement Test. Jastak Associates; 1978. 
78. Conners C. CPTII:  Conners' Continuous Performance Test. Canada: Multi-Health Systems Inc.; 2000 
79. Glahn DC, Kim J, Cohen MS, et al. Maintenance and manipulation in spatial working memory: 
dissociations in the prefrontal cortex. Neuroimage. 2002;17:201-213.  
80. Fan J, Wu Y, Fossella JA, Posner MI. Assessing the heritability of attentional networks. BMC Neurosci. 
2001;2:14.  
81. Oostenveld R, Praamstra P. The five percent electrode system for high-resolution EEG and ERP 
measurements. Clin Neurophysiol. 2001;112:713-719. 
82. Amos G. MATLAB: An Introduction with Applications 2nd Edition. John Wiley & Sons; 2004.  
83. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics. J 
Neurosci Methods. 2004;134:9-21. 
84. Cohen J, Cohen P, West SG, Aiken LS. Applied Multiple Regression Correlation Analysis for the 
Behavioral Sciences. 3rd ed. Mahwah, NJ: Erlbaum; 2003. 
85. Doshi JA, Hodgkins P, Kahle J, et al. Economic impact of childhood and adult attention-
deficit/hyperactivity disorder in the United States. J Am Acad Child Adolesc Psychiatry. 2012; 51: 990-
1002 PMID: 23021476 
86. Morgan PL. Staff J, Hillemeir MM, Farkas G, Maczuga S. Racial and ethnic disparities in ADHD 
diagnosis from kindergarten to eigth grade. Pediatrics. 2013;132:ePub. 
87. Sonuga-Barke EJ, Brandeis D, Cortese S, et al. Nonpharmacological interventions for ADHD: 
systematic review and meta-analysis of randomized controlled trials of dietary and psychological 
treatments. Am J Psychiatry. 2013;ePub.  
88. Matheny RG, Shaar CJ. Vagus nerve stimulation as a method to temporarily slow or arrest the heart. 
Ann Thorac Surg. 1997;63(6 Suppl.):S28–29. 
89. Fanselow EE, Reid AP, Nicolelis MA. Reduction of pentylenetetrazole-induced seizure activity in awake 
rats by seizure-triggered trigeminal nerve stimulation. J Neurosci. 2000;20:8160–8168. 
90. Fanselow EE. Central mechanisms of cranial nerve stimulation for epilepsy. Surg Neurol Int. 
2012;3:S247–254.  
91. DiGorgio CM, Fanselow EE, Schrader LM, Cook IA. Trigeminal nerve stimulation: seminal animal and 
human studies for epilepsy and depression. Neurosurg Clin N Am. 2011;22:449-456.  

24 
92. Cook IA, Espinoza R, Leuchter AF. Neuromodulation for depression: invasive and noninvasice (deep 
brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation). Neurosurg Clin N Am. 
2013, in press. 
93. Cortese S, Kelly C, Chabernaud C, et al. Toward a systems neuroscience of ADHD: a meta-analysis of 
55 fMRI studies. Am J Psychiatry. 2012;168:1038-55.  
94. Gevins A, Smith ME, McEvoy L, Yu D. High-resolution EEG mapping of cortical activation related to 
working memory: effects of task difficulty, type of processing, and practice. Cereb Cortex. 1997;7:374-
85.  
95. McGough J, Loo S, Leuchter A, Cook I. Trigeminal nerve stimulation (TNS) for attention-
deficit/hyperactivity disorder: a pilot feasibility study. Scientific Proceedings of the Annual Meeting of the 
American Psychiatric Association, San Francisco, CA, May 20, 2013. 
96. McGough JJ, Loo SK, Sturm A, Cowen J, Leuchter AF, Cook IA. A pilot study of trigeminal nerve 
stimulation for ADHD. Scientific Proceedings of the Annual Meeting of the American Academy of Child 
and Adolescent Psychiatry, Orlando, FL, October 24, 2013. 
97. Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy questionnaire. J Beh 
Ther Exp Psychiatry. 2000;31:73-86. 
98. Stringaris A, Goodman R, Ferdinand S, Razdan V, Muhrer E, Leibenluft E, Brotman MA: The Affective 
Reactivity Index: a concise irritability scale for clinical and research settings. J Child Psychol Psychiatry 
2012;53:1109-117.