Neuromodulation Augmented Cognitive Remediation to Improve Executive Dysfunction in Fetal Alcohol Spectrum Disorder (FASD)
Phase: NA
Conditions: Fetal Alcohol Spectrum Disorders
Sponsor: University of Minnesota

PROTOCOL TITLE: Neuromodulation augmented cognitive remediation to improve 
executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
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PROTOCOL TITLE: 
Neuromodulation augmented cognitive remediation to improve executive 
dysfunction in fetal alcohol spectrum disorder 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Jeffrey R. Wozniak, Ph.D. 
Department of Psychiatry 
612-273-9741
jwozniak@umn.edu
STUDENT INVESTIGATOR: 
NA 
VERSION NUMBER/DATE: 
Version 1: 11-2-2017 
REVISION HISTORY 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
NCT03361293

PROTOCOL TITLE: Neuromodulation augmented cognitive remediation to improve 
executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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Table of Contents 
 
1.0 
Objectives ................................................................................................................ 4 
2.0 
Background .............................................................................................................. 4 
3.0 
Study Endpoints/Events/Outcomes .......................................................................... 8 
4.0 
Study Intervention(s)/Investigational Agent(s)........................................................ 8 
5.0 
Procedures Involved................................................................................................. 9 
6.0 
Data and Specimen Banking .................................................................................. 13 
7.0 
Sharing of Results with Participants ...................................................................... 14 
8.0 
Study Duration ....................................................................................................... 14 
9.0 
Study Population .................................................................................................... 14 
10.0 Vulnerable Populations .......................................................................................... 14 
11.0 Local Number of Participants ................................................................................ 15 
12.0 Local Recruitment Methods ................................................................................... 16 
13.0 Withdrawal of Participants .................................................................................... 16 
14.0 Risks to Participants ............................................................................................... 17 
15.0 Potential Benefits to Participants ........................................................................... 19 
16.0 Data Management .................................................................................................. 19 
17.0 Confidentiality ....................................................................................................... 19 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 20 
19.0 Provisions to Protect the Privacy Interests of Participants .................................... 20 
20.0 Compensation for Research-Related Injury ........................................................... 20 
21.0 Consent Process ..................................................................................................... 20 
22.0 Setting .................................................................................................................... 21 
23.0 Multi-Site Research ............................................................................................... 21 
24.0 Resources Available............................................................................................... 21 
25.0 References .............................................................................................................. 22 
 

PROTOCOL TITLE: Neuromodulation augmented cognitive remediation to improve 
executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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ABBREVIATIONS/DEFINITIONS 
 PAE: Prenatal Alcohol Exposure  
 FASD: Fetal Alcohol Spectrum Disorders 
 MRI: Magnetic Resonance Imaging 
 tDCS: Transcranial Direct Current Stimulation   
 
STUDY SUMMARY 
 
Study Title 
Neuromodulation augmented cognitive remediation 
to improve executive dysfunction in fetal alcohol 
spectrum disorder 
Study Design 
Randomized, double-blind, placebo (sham) trial   
Primary Objective 
Establish feasibility of tDCS for enhancing the 
efficacy of cognitive training in FASD youth.  
Secondary Objective(s) 
 
Research 
Intervention(s)/Investigational 
Agents 
Transcranial direct current stimulation (tDCS) 
Magnetic Resonance Imaging (MRI) 
IND/IDE # (if applicable) 
N/A 
Investigational Drug Services 
# (if applicable) 
N/A 
Study Population 
Children and adolescents with Fetal Alcohol 
Spectrum Disorders 
Sample Size (number of 
participants) 
40 
Study Duration for Individual 
Participants 
4-8 weeks 
 
 
 

PROTOCOL TITLE: Neuromodulation augmented cognitive remediation to improve 
executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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1.0 
Objectives 
1.1 Purpose:  
 Aim 1: Characterize the feasibility and tolerability of 
combined cognitive remediation and tDCS in children ages 
10-16 with FASD. 
o Hypothesis 1: Children with FASD will tolerate the 
procedures and remain in the study with less than 
20% dropout over the course of cognitive 
remediation and tDCS 
 Aim 2: Evaluate the potential additive benefits of tDCS to 
the base cognitive remediation program. 
o Hypothesis 2: Cognitive remediation with active 
tDCS vs. sham tDCS will result in greater gains 
over the courses of treatment.  
 Aim 3: Examine the brain circuitry changes following the 
intervention. 
o Resting and task fMRI will demonstrate greater 
change with active compared with sham tDCS. 
 
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
 
Prenatal alcohol exposure (PAE) has profound detrimental effects on 
brain development and, as a result, has permanent consequences for 
cognition, learning, and behavior. Individuals with Fetal Alcohol 
Spectrum Disorders (FASD) commonly have a range of 
neurocognitive impairments that directly lead to practical problems 
with learning, attention, working memory, task planning/execution, 
and decision making, among other areas of functioning. Recent data 
indicate that 2-5% of the U.S. population has FASD (May & 
Gossage, 2001).  
 
Despite the profound public health burden posed by FASD, there 
have been very few treatment studies of any sort in this population. 
Our group conducted the first randomized controlled trials of the 
nutrient choline as a neurodevelopmental intervention in 2-5 year old 
children with FASD, in which we demonstrated effects on sequential 
memory (Wozniak et al., 2015).  For older children, a very different 
neurodevelopmental target is needed, and we have narrowed our 
focus to “plasticity” (the brain’s ability to adapt) as that target.   
 

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Our group has recently shown that neuromodulation - in the form of 
transcranial direct current stimulation (tDCS) - can enhance the 
brain’s plasticity in order to increase the efficiency and 
generalization of cognitive remediation training (Nienow, 
MacDonald, & Lim, 2016).  This work has been done thus far in 
schizophrenia, which is also a neurodevelopmental disorder.  This 
approach to intervention has not yet been tested in FASD, a 
condition in which we know there are brain plasticity 
abnormalities.   
 
We propose to conduct a first-of-its-kind pilot study to examine the 
effects of a cognitive remediation training augmented with tDCS in 
children and adolescents with FASD. Functional magnetic resonance 
imaging will be collected to provide preliminary data of brain 
circuitry changes created by this intervention.   
 
2.2 Preliminary Data:  
 Engagement of population in clinical trials: The University of 
Minnesota Fetal Alcohol Spectrum Disorders Clinic (directed by 
Dr. Christopher Boys) and Research Program (directed by Dr. Jeff 
Wozniak) evaluates more than 300 children with FASD per year 
and has recruited 345 participants over the last 6 years (including 
84 children ages 2-5 for the choline clinical trial). 
 
 Clinical trial experience:  Dr. Wozniak and Dr. Lim have both 
acquired significant experience designing and conducting 
randomized controlled trials using novel interventions in clinical 
populations.  Dr. Wozniak has completed two small RCTs using a 
novel nutritional intervention (choline) in children with 
FASD.  Dr. Lim has completed two studies using tDCS in patients 
with schizophrenia (Nienow et al., 2016) and clinical impulsivity 
(in preparation).  
 
 tDCS and cognitive training: Schizophrenia has been 
demonstrated to have impaired neuronal plasticity 
(Kantrowitz et al., 2016).  Dr. Lim has conducted work 
testing the use of transcranial direct current stimulation to 
enhance cognitive training in schizophrenia (Nienow et al., 
2016).  A design similar to what is being proposed for this 
study was used; all subjects received cognitive training 
focused on working memory but were randomized to either 
active or sham tDCS.  Compared with sham tDCS, active 
tDCS was found to double the effect size of learning on the 

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executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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trained task and was also found to increase the 
generalization to untrained tasks.   
 The level of stimulation that will be used is between 1.0 to 
2.0 mA.  This is the range that has been used in other 
studies of children including a 2014 study of children ages 
5 to 12 years with language disorders (Andrade et al., 
2014). In that study, no serious adverse events were 
reported. For some participants tingling, itching, and 
discomfort were observed in some participants after 10 
sessions – but these symptoms immediately resolved upon 
discontinuation of the tDCS. Furthermore, a comprehensive 
review of pediatric tDCS studies shows that 1.0 to 2.0 mA 
stimulation consistently produces either no adverse events 
or mild tingling, itching, and discomfort as described 
(Antal et al., 2017). 
 
 Cognitive training and imaging: Drs. Wozniak and Lim 
have conducted and published multiple neuroimaging 
studies in FASD (Wozniak et al., 2006, 2016) so have 
experience in imaging this population. In a study of 
cognitive training in schizophrenia, we found that working 
memory training increased activation of the dorsolateral 
prefrontal cortex (DLPFC) compared with social skills 
training.  This has provided our rationale for our anode 
placement over the left DPLFC. In a current study of 
cognitive training involving executive function (set 
shifting), we scanned subjects before and after 10 
intervention sessions. We found that subjects who received 
active tDCS had a significant increase in thalamo-frontal 
activity compared to those with sham tDCS. This 
demonstrates the ability of the cognitive training with 
active tDCS to change resting brain circuitry. 
 
2.3 Existing Literature:  
 
Prenatal alcohol exposure disrupts plasticity in the developing 
brain: A number of pre-clinical studies have demonstrated that 
neuronal plasticity throughout the brain is affected by PAE.  For 
example, as summarized by Medina, (Medina, 2011), PAE has been 
shown to disrupt long-term potentiation in the hippocampus (Puglia 
& Valenzuela, 2010), long-term depression in the hippocampus and 
cerebellum (Servais et al., 2007), and cortical plasticity in primary 
visual and somatosensory cortex (Medina, Krahe, & Ramoa, 2005). 
In animal models, these types of developmental disturbances in 

PROTOCOL TITLE: Neuromodulation augmented cognitive remediation to improve 
executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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neuronal plasticity contribute to abnormalities in learning, memory, 
visual processing, and other cognitive functions. In fact, approaches 
to improve neuronal plasticity have been proposed as interventions 
(Medina, 2011).  
 
Deficits in plasticity result in significant neuropsychological 
problems related to executive function: Persons with FASD can 
manifest a wide variety of behavioral and neuropsychological 
problems depending on the timing and extent of prenatal alcohol 
exposure (Mattson, Crocker, & Nguyen, 2011).  A common 
neuropsychological finding is impairments in executive functioning - 
a broad set of skills needed for planning and carrying out of goal 
directed behavior, including working memory, response inhibition, 
etc.  Impairment in executive functioning has been shown to 
negatively impact functional outcome in many psychiatric and 
neurological disorders.  
 
Cognitive training alone has modest effects on working memory in 
neurodevelopmental disorders:  
A common deficit in people with schizophrenia is poor executive 
functioning in the form of impaired working memory.  Medications 
have not been found to improve executive functioning in 
schizophrenia.  Cognitive training, in which there is repeated drilling 
of exercises of the impaired function such as working memory, has 
been shown to improve working memory but with only a modest 
effect sizes and with considerable subject effort. Another limitation 
is the limited degree of transfer of improvement from the trained task 
to untrained task.  
 
Cognitive training alone has modest effects on working memory in 
FASD: Cognitive training has also been tried in FASD.  Kerns et al. 
(Kerns, Macsween, Vander Wekken, & Gruppuso, 2010) used 
computer based attention exercises administered by educational 
assistants, in ten children ages 6-15 years.  An average of 16 hours of 
training was provided over 9 weeks. Significant improvement was 
noted in several attention measures and there were trend 
improvements in working memory with effect size of d=0.5.   In a 
study that combined subjects with autism spectrum disorder and 
FASD (Kerns, Macoun, MacSween, Pei, & Hutchison, 2016), a 
game designed to target attention and working memory was used in 
subjects 6-11 years, administered by an educational assistant. 
Approximately 12 hours of training was provided over a 12 week 
school period.  Significant improvements were noted in attention and 
working memory.  However, since the two groups were merged, the 
specific effect for those with FASD could not be determined.  A 

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executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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limitation of both of these studies is that neither used a randomized 
controlled design.  The durability of the intervention was also not 
assessed.    
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome:  
 
The primary endpoints will be BrainHQ (Posit Science, San Francisco, CA) 
task performance measures.   
 Learning curves derived from repeated sessions of BrainHQ 
training will serve as the primary endpoints: 
o Scene Crasher; Mind Bender; Juggle Factor; Eye for Detail; 
and Divided Attention  
 
3.2 Secondary Endpoint(s)/Event(s)/Outcome(s): 
 Neurocognitive measures will be administered at baseline and 
again after completion of training:  
o Subtests from the Delis-Kaplan Executive Functioning 
System (DKEFS) 
o Delis Rating of Executive Functioning (D-REF) 
o NIH Toolbox measures (Flanker, Dimensional Card Sort 
Test, Picture Sequence Memory Test, and Oral Symbol 
Digit Test) 
 Functional Connectivity analysis of resting-state fMRI data 
o Seed-based functional connectivity measure  
o Graph theoretical analysis of connectivity 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description:  
 We will use transcranial direct current stimulation (tDCS) to 
stimulate the dorsolateral prefrontal cortex (DLPFC).   
 tDCS is a non-invasive brain stimulation technique that can 
modulate brain connectivity.  
 tDCS involves applying a weak electrical current (1 to 2mA) to the 
scalp via anodal and cathodal electrodes, causing either increases 
or decreases in cortical excitability, respectively.  
 Research has shown in both healthy subjects and patients (e.g. 
Alzheimer’s disease, Parkinson’s disease, stroke, and depression) 
that tDCS has the potential to modulate synaptic strengthening and 

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executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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neurotransmitter-dependent plasticity underlying changes in 
behavior and learning (Lang et al., 2005). 
4.2 Drug/Device Handling:  
 tDCS will be applied with a StarStim Enobio system 
(Neuroelectrics, Barcelona, Spain) using a bipolar stimulation 
montage.  
 This device has been approved for use in research without an 
investigational device exemption due to meeting criteria for non-
significant risk (NSR).  
 In addition, the device has built in safety mechanisms which allow 
for the immediate cessation of stimulation should the subject 
become uncomfortable or if the impedance of the stimulation 
electrodes is too high.  
 The current will be administered via two saline soaked sponge 
electrode sponges during each intervention session, using a current 
strength of 1.0 to 2.0 mA.  
 These administration procedures are in line with other protocols 
that have outlined the safe use of tDCS in pediatric populations 
(Antal et al., 2017).  
 The tDCS cap and stimulation electrodes/sponges will be washed 
and disinfected after each intervention session and stored under 
lock and key in 717 Delaware Street SE.  
4.3 IND/IDE: N/A 
 
5.0 
Procedures Involved 
5.1 Study Design:  
 The study will be a randomized, double-blind, placebo (sham) 
controlled trial.   
 Eligible participants will be randomized to treatment or placebo in 
a 1:1 allocation ratio (n=20 active tDCS, n=20 sham).   
 Randomization will be from a computer procedure for 
randomization and tracking.   
 All members of the team will be blinded to assignment.   
 A block randomization procedure with variable block sizes will be 
used to maximize unpredictability of assignment. 
 
5.2 Study Procedures:  
 Intervention (active tDCS vs. sham): There will be a total of 6 
visits for the study - an initial baseline and intervention visit; four 

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additional intervention visits and one follow-up visit (within one 
week of the last intervention session)  
o Visit 1: Baseline session; three hour visit.  
a. Obtain consent; conduct safety screen for MRI (15 
min) 
b. Baseline MRI scan (45 min) 
c. Baseline cognitive testing (60 min) 
d. First tDCS intervention session (60 min)  
i. 14 minutes set-up 
ii. 46 minutes of cognitive training interleaved 
with two 13 minute blocks of active or sham 
tDCS (26 minutes total active/sham tDCS) 
o Visits 2-5: tDCS intervention sessions; one hour visits. 
a. 14 minutes set-up 
b. 46 minutes of cognitive training interleaved with 
two 13 minute blocks of active or sham tDCS (26 
minutes total active/sham tDCS) 
o Visit 6: Follow-up; two hour visit. Within one week of the 
last intervention session 
a. Obtain consent/screen for MRI (15 min) 
b. Repeat MRI scan (45 min) 
c. Repeat cognitive testing (60 min) 
 
 Cognitive Training Description (Brain HQ):  
o 46 total minutes of cognitive training using the BrainHQ 
software (Posit Science, San Francisco, CA) will be 
completed by each subject in each intervention session.  
o The BrainHQ software includes a number of brain training 
games which focus on various aspects of attention, reaction 
time, memory and executive function.  
o Positive findings using the BrainHQ program have been 
reported in children with ADHD (Mishra, Merzenich, & 
Sagar, 2013) as well as adults with traumatic brain injury 
(Lebowitz, Dams O’Connor, & Cantor, 2012).  
o The BrainHQ program allows for real-time monitoring of 
subject performance and adjusts the difficulty level of 
individual tasks accordingly.  

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o Additionally, it allows for quantitative tracking of subject 
performance over time both within and across intervention 
sessions.  
 
 tDCS Description:  
o Two 13 minute blocks of active or sham 1.0 to 2.0 mA 
tDCS will be applied in parallel with cognitive training in 
each intervention session.  
o A 20 minute block of cognitive training without active or 
sham tDCS will separate the two 13 minute active or sham 
tDCS blocks with cognitive training.  
o The sham condition will emulate the sensation of tDCS on 
the scalp at the beginning and end of each 13 minute 
stimulation block in order to blind the subject to the 
intervention type, however, current will not be applied for 
the remainder of the 13 minute blocks.  
o tDCS will be applied with a StarStim Enobio 8 system 
(Neuroelectrics, Barcelona, Spain) using a bipolar 
stimulation montage (anode over the left DLPFC/F3 and 
cathode over the right orbitofrontal cortex/FP2).  
o The StarStim device allows for double-blinded 
administration of tDCS/sham stimulation during each 
session.  
 
 Neuroimaging:  
o Pre- and post-intervention fMRI will be collected to 
examine resting state connectivity changes and reversal 
learning task changes.  
a. Subjects will be scanned at the Center for Magnetic 
Resonance Research on a Siemens Prisma scanner 
using Human Connectome Project accelerated 
imaging (Glasser et al., 2016).  
b. A high resolution structural scan and a select period 
of resting-state fMRI (eyes open and eyes closed) 
will be collected.  
c. fMRI during a reversal learning task will also be 
collected. Our group has previously used this task to 
assess brain function related to cognitive flexibility 
and executive function.  

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o Analysis will be done using already published functional 
connectivity approaches (Haut, Lim, & MacDonald, 2010; 
Wozniak et al., 2016). 
 Assessments: Note that all instruments are to be administered for 
research purposes (not for clinical diagnostic or treatment 
purposes).  Standard precautions will be implemented to reduce 
potential frustration and fatigue (frequent breaks, positive feedback 
about performance, etc.) 
o The following assessments will be administered to the child 
using the NIH toolbox using an iPad: 
a. NIH Toolbox Flanker Inhibitory Control and 
Attention Test measures both a participant’s 
attention and inhibitory control. (Heaton et al., 
2014)   
b. NIH Toolbox Dimensional Card Sort Test (DCCS) 
is an assessment to measure of cognitive flexibility. 
c. NIH Toolbox Picture Sequence Memory Test 
(PSMT) is a measure for use in the assessment of 
episodic memory. 
d. NIH Toolbox Oral Symbol Digit Test (OSDT) is a 
measure of processing speed. (Denboer, Nicholls, 
Corte, & Chestnut, 2014). 
o The following additional assessments will be administered 
to the child:  
a. Subtests from the Delis-Kaplan Executive 
Functioning System (DKEFS): a standardized 
battery of executive functioning.   
o The following questionnaires will be administered to the 
parent: 
a. Parent and Child Questionnaire 
b. Behavior Assessment System for Children – 3nd 
Edition (BASC-3): a standardized parent-report 
questionnaire of typical and atypical child behavior. 
c. Delis Rating of Executive Functioning (D-REF): a 
standardized parent-report questionnaire of child 
planning, organization, attention, inhibition, and 
emotional control. 
o The tDCS Report of Symptoms questionnaire will be 
administered to the child before and after each tDCS/sham 
intervention: 

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executive dysfunction in fetal alcohol spectrum disorder 
VERSION DATE: 11-2-2017 
 
 
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a. Assessment tool to monitor for common, specific 
side effects noted across many existing tDCS 
studies, including but not limited to itching, 
prickling, burning sensation, nausea, fatigue and 
headache.  
b. Approximately 3-5 minutes to administer and is 
typically performed twice during each intervention 
session (once before and once after the session).  
c. Furthermore, participants will be continuously 
monitored by a member of the study staff 
throughout each intervention session to ensure 
comfort and safety.  
d. In addition, at the end of each intervention visit, the 
subject will be asked if they think they received the 
active or sham condition. 
 
  All forms are attached to this submission 
 
5.3 
Follow-Up: Participants will be contacted by phone 30 days after the last 
intervention session.  The tDCS Report of Symptoms questionnaire will be 
administered.  
 
5.4 Individually Identifiable Health Information: See attached HIPCO Ancillary 
Review Form and HIPAA Authorization form 
 
5.5 Use of radiation: NA – neither MRI nor tDCS uses ionizing radiation   
5.6 Use of Center for Magnetic Resonance Research: This study uses the CMRR 
and follows all CMRR protocols and procedures.  
 
6.0 
Data and Specimen Banking 
6.1 Storage and Access: Storage and Access:  De-identified neuroimaging data 
will be stored locally on servers supported by the Center for Magnetic 
Resonance (CMRR).  De-identified cognitive and behavioral data will be 
stored in a secure, HIPAA-compliant RedCap database supported by the 
university of Minnesota. 
6.2 Data: Data elements to be stored will include processed, de-identified 
neuroimaging results (ex. regional brain volumes, measures of white matter 
integrity, and measures of brain connectivity), de-identified neurocognitive 
test results, and de-identified behavioral questionnaire data. 
6.3 Release/Sharing: Release/Sharing: There are no plans to share these data 
with outside entities. 
 

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7.0 
Sharing of Results with Participants 
7.1 Standardized neurocognitive test results may be shared with participants’ 
parents if requested.  Dr. Wozniak is a clinical neuropsychologist with 20 
years of experience providing clinical neuropsychological information to 
parents.  This will be done in an ethical manner, sharing only the necessary 
data and not interpreting it clinically but, rather, passing on standardized 
scores in a manner consistent with American Psychological Association 
ethical standards.  Neuroimaging results are not shared with participants 
with the exception of a single “souvenir image”.  If a potential abnormality 
is identified in the MRI scan and the radiologist review indicates that a 
clinical follow-up is needed, a full set of images will be prepared on a DVD 
for sharing with the clinician doing the follow-up. 
 
8.0 
Study Duration 
8.1 Describe: 
 
Participants will complete the 6 visits described above, typically 
within a span of 8 weeks maximum. 
 
All study participants will be enrolled within the two year timeframe 
of the study. 
 
Data analysis is expected to continue for 1-2 years post study 
conclusion. 
9.0 
Study Population 
9.1 Inclusion Criteria:  
 Documented heavy prenatal alcohol exposure (self-report, social 
service records, or adoption records) and meeting criteria for an 
associated FASD diagnosis (FAS, partial FAS, or ARND). 
 An available parent or legal guardian capable of giving informed 
consent 
 
9.2 
Exclusion Criteria:  
 All participants: Substance abuse in the participant; Neurological 
condition or other developmental disorder; Serious psychiatric 
disorder known to effect brain functioning and cognitive 
performance; Birthweight < 1500 grams; MRI contraindication, 
tDCS contraindication. 
 
9.3 Screening: Participants will be screened by telephone using the attached 
screening tool. 
 
10.0 Vulnerable Populations 

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10.1 Vulnerable Populations:  
☒ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful situation such 
as emergency room setting, childbirth (labor), etc. 
☐ Disadvantaged in the distribution of social goods and services such as 
income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory standard 
treatments 
☐ Fear of negative consequences for not participating in the research (e.g. 
institutionalization, deportation, disclosure of stigmatizing behavior) 
☐ Any other circumstance/dynamic that could increase vulnerability to 
coercion or exploitation that might influence consent to research or 
decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
10.2 Adults lacking capacity to consent and/or adults with diminished capacity to 
consent: 
 
N/A 
10.3 Additional Safeguards:  
 
Children and adolescents are the focus of this study because it is a 
study of the neurodevelopmental effects of prenatal alcohol exposure 
and the desired outcome is to learn more about the presentation of 
effects over the course of development.  Children and adolescents will 
all undergo a formal assent process at the same time as the parent 
undergoes a formal informed consent process.  Children who are 
wards of the state will not be enrolled. 
 
11.0 Local Number of Participants 

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11.1 Local Number of Participants to be Consented: Up to 60 participants will be 
consented in this study, with the goal of having 40 participants enroll and 
complete the full study.  
 
12.0 Local Recruitment Methods 
12.1 Recruitment Process: Families of potential participants will be contacted by 
research staff or will initiate contact themselves.  Visitors to the clinics 
described below may see flyers and brochures describing the study at the 
time of their clinic appointment although they will not be recruited directly 
by their clinician.  Mailings will also be sent to families of children with 
FASD via lists provided by the Minnesota Organization on Fetal Alcohol 
Syndrome (MOFAS).  MOFAS has close working relationships with Dr. 
Wozniak, Dr. Eckerle, Dr. Boys, Dr. Gross and both clinics. All recruitment 
materials will be submitted for IRB approval upon development, before use 
in the study. Telephone scripts will be utilized. 
12.2 Source of Participants: Participants will be recruited from two University of 
Minnesota Medical Center Clinics in which co-investigators see patients: 
The Fetal Alcohol Spectrum Disorders clinic (Dr. Christopher Boys, Ph.D., 
Dr. Amy Gross, Ph.D) and the International Adoption Clinic (directed by 
Dr. Judith Eckerle, M.D.). 
12.3 Identification of Potential Participants: Potential participants will self-
identify in some cases based on advertisements.  In other cases, participants 
will be recruited based on having been seen for an evaluation for FASD.  
Participants will not be recruited by a clinician (to avoid potential coercion 
and/or confusion about clinical care vs. research.  Instead, research staff will 
contact families and will conduct telephone screens to determine eligibility.  
Access to contact information for potential participants will be obtained 
from the clinicians who are co-investigators on the study (Dr. Boys, Dr. 
Gross, and Dr. Eckerle).  Patients who “opted out” of allowing their clinical 
data to be utilized for research via the standard UMMC / Fairview clinical 
consent form will not be recruited. 
12.4 Recruitment Materials: See attached recruitment materials in ETHOS. 
12.5 Payment: Participant families will receive payment (check or pre-paid card) 
for participation.  Because the participants are children, the payment will be 
provided to the parent on behalf of the child.  Payment will be made at the 
completion of the study (final visit) or at the time of a participant dropping 
out of the study.  Payment will be based on procedures attempted and/or 
completed as follows: 
 
$50 for the neuropsychological testing and parent rating forms 
 
$50 for each MRI scan ($100 total) 
 
$25 for each tDCS session ($125 total) 

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 
The maximum payment per participant will be $275. 
 
13.0 Withdrawal of Participants 
13.1 Withdrawal Circumstances: Participants may withdraw or be withdrawn 
from the study at any point.  Participants may be withdrawn for MRI 
contraindications (ex. metal implanted in body between visit 1 and 2), tDCS 
contraindications (ex. seizures, brain trauma), failure to complete study 
procedures, or loss to follow-up. 
13.2 Withdrawal Procedures: Participants who withdraw or are withdrawn from 
the study will not be followed further.  Payment will be provided for all 
attempted and/or completed procedures. 
13.3 Termination Procedures: Data collected prior to withdrawal may be used 
from withdrawn participants. 
14.0 Risks to Participants 
14.1 Foreseeable Risks:  
The risks of MRI are as follows: 
 Projectiles:  Objects with magnetic properties can be pulled into 
the magnet and turn into projectiles. To minimize this risk we ask 
that subjects remove all metallic items (watches, cell phones, hair 
pins, etc.) prior to entering the scanner and by controlling access to 
the scanner. 
 Claustrophobia:  The scanner is a long narrow tube that may cause 
some people to feel claustrophobic. 
 Hearing Damage:  The noise generated by the operation of the 
scanner during a study is loud enough to cause hearing damage if 
you do not wear hearing protection. Hearing protection is required 
and is provided by the investigator. 
 Nerve Stimulation:  Some people experience localized tingling, 
twitching, or muscle contractions during MRI scans. This is 
expected, but if it is uncomfortable, the scan can be stopped 
immediately. 
 Disruption of Devices:  Some devices can be damaged by magnetic 
fields and should not be brought into the scanner room. This 
includes some implanted devices such as pacemakers, cochlear 
implants, insulin pumps, nerve stimulators, etc. Participants will be 
screened thoroughly prior to scanning to ensure that they do not 
have such implanted devices. 
 Heating of Devices:  The radiofrequency waves used in MRI can 
heat conductive materials such as metal implants (screws, plates, 

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rods, wires, artificial joints, etc.), certain tattoo inks, certain 
clothing fabrics, jewelry, medication patches, wigs, etc. 
Participants will be asked to remove these items if possible. If they 
cannot be removed they will be asked to provide more information 
to allow MRI staff to be able to make determination on the safety 
of proceeding with the scan. 
 
The approved CMRR screening procedures will be employed prior 
to scanning.  The participant will undergo thorough screening for 
metal at the time of scheduling and, again, prior to entering the 
MRI suite.  During the scan, the participant will have a squeeze 
ball to signal a desire to stop the scan and the participant will also 
be in voice communication with the scanner operator. 
The risks of tDCS are as follows:  
 This study involves the use of a tDCS device, which is considered 
to be a safe brain stimulation technique that rarely results in 
adverse events.  
 There is currently no evidence of serious side effects.  
 Criteria for discontinuation that may rarely occur are sores at the 
tDCS administration site, and headaches that temporarily affect 
comfort / functioning.  
 Mild side effects that typically resolve upon discontinuation of 
tDCS include light itching under the electrode at the beginning of 
administration, headache, fatigue, and nausea.  
 The participant may also choose to discontinue stimulation at any 
time during the session if experiencing discomfort or side effects.  
 No other risks are anticipated. Nonetheless, in order to minimize 
risks, study staff will be using standards of administration that 
have been shown to be safe in numerous other studies and across 
more than 2000 studies (Liebetanz et al., 2009; Nitsche et al., 
2007; Poreisz, Boros, Antal, & Paulus, 2007) using tDCS; this 
includes length of administration, magnitude of the current, size of 
electrode sponges used, and method of applying stimulation.  
 Any unanticipated problems or adverse events will be reported to 
the IRB  
The risks of neurocognitive testing / checklists are as follows: 
 Neurocognitive testing can be challenging and tiring.  Children 
will be given ample opportunities for breaks and will be given 
encouragement to complete tasks to the best of their ability. 
 Checklists cover sensitive topics.  Participants have the option of 
skipping items that they are uncomfortable answering. 
 

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14.2 Reproduction Risks: There are no known risks to fetuses from MRI, but we 
will take steps to ensure that no pregnancies are exposed to MRI 
nonetheless.  Parents and participants will be told that the participant should 
not undergo MRI if there is a pregnancy or the possibility of a pregnancy 
(i.e. sexual intercourse without effective contraception taking place). There 
are no known risks to fetuses from tDCS, but we will similarly take steps to 
ensure that no pregnancies are exposed to tDCS.  
14.3 Risks to Others: Parents who accompany children to the MRI facility 
(CMRR) will be screened as though they will be entering the MRI suite 
(even though the plan will be for them to remain in the attached control 
room).  All CMRR procedures will be followed in this regard. 
15.0 Potential Benefits to Participants 
15.1 Potential Benefits: There are no direct benefits for the participant or family.  
Rather, the research is expected to benefit the population of individuals with 
FASD through the knowledge acquired. 
16.0 Data Management 
16.1 Data Analysis Plan: Data analyses will include traditional statistical analyses 
for group differences in neurocognitive and brain measures with control for 
confounding variables, multiple comparisons, etc. 
16.2 Power Analysis: We propose to compare changes in cognition and in 
brain circuitry between the two intervention arms.   With an n=20, 
alpha 0.05, power of 0.8, we have power to detect an effect size of 
0.9. 
16.3 Data Integrity: Neuroimaging data will be subjected to standard quality 
control measures (both automated and manual) including measuring and 
controlling for artefacts.  Neurocognitive data will be checked for quality by 
more than one research staff member. 
17.0 Confidentiality 
17.1 Data Security: Data will be handled by trained research staff members.  
Paper records will be stored in locked file drawers and electronic data 
storage will meet University security requirements (password protection, 
encryption, controlled access, audit trails of access, etc.).  Protected Health 
Information will be separated from research data.  Research data will be 
coded and, thus, de-identified.  De-identified data will be stored in a local 
HIPAA-compliant RedCap database managed by the University of 
Minnesota. Signed consent forms will be scanned into the OnCore system as 
required by the University.  Research information will not be placed into the 
individual’s electronic medical record. 
 

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18.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 
N/A - The principal investigator will monitor safety and data quality for this 
study. They will ensure that adverse events are reported accordingly and that data 
are generated, documented (recorded), and reported - in compliance with this 
protocol, with Good Clinical Practice, and any other applicable regulatory 
requirements. 
 
 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 Protecting Privacy: Potential participants will not be contacted to inquire 
about research participation if they have opted out of research as part of 
signing the standard UMMC/Fairview consent to treatment form.  During 
telephone screening, potential participants will be given multiple 
opportunities to decline screening and participation in research.  During the 
study itself, participants will be informed that they are free to skip questions 
on questionnaires or decline to answer interview questions if they find the 
material too sensitive or uncomfortable.  Dr. Wozniak, a licensed clinical 
psychologist, has worked extensively with patients, families, and research 
participants over the years and is acutely aware of handling sensitive topics 
in relation to child mental health and development.  He will ensure that all 
aspects of the study include the consideration of participant comfort and 
privacy as a top priority. 
19.2 Access to Participants: As part of the consenting process, participants will 
give their formal consent for the study team to collect sensitive information.  
This will include the signing of a separate HIPAA form granting the study 
team access to the participant’s medical record. 
20.0 Compensation for Research-Related Injury 
20.1 Compensation for Research-Related Injury: Compensation for Research-
Related Injury: In the event that this research study results in an injury, we 
will provide treatment including first aid, emergency care, and follow-up as 
needed.  Care for injuries would be billed in the ordinary manner and costs 
would not be covered by the research study itself. 
20.2 Contract Language: N/A 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained): 
 
The informed consent process will begin at the time of the telephone 
screening and will continue throughout participation.  During 
screening, parents will be informed about the purpose of the research, 
why their child was chosen for possible participation, what the 

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potential procedures are, and how long they will take, and payment. 
This will allow them time to formulate questions which could be 
posed to investigators at the time of the in-person enrollment visit. 
 
Enrollment will be done in person with the parent(s) providing consent 
and the child providing assent.   
21.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained): We are requesting a waiver of documentation of the consent for 
only the phone screen portion of the study. Participants would be consented 
prior to any other study activities. We need to collect sensitive information 
from the parent/guardian prior to the first visit and documented consent 
process in order to determine basic eligibility. All parents will be read the 
attached script and asked to verbally consent to the phone screen only. 
21.3 Non-English Speaking Participants: Participants will be English speaking.  
21.4 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): 
 
The participants in this study will be minors (<18 years of age) at the 
time of enrollment.  Parental consent (from one parent) and child 
assent will be utilized in all cases at enrollment.   
 
Because this is an intervention, foster children and/or wards of the 
State will not be enrolled. 
 
Assent will be obtained from all participants; Assent will be 
documented with a signed form. 
21.5 
Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: NA 
22.0 Setting 
22.1 Research Sites:  
 
Participants will be recruited from the Fetal Alcohol Spectrum 
Disorders clinic and the International Adoption Clinic at the 
University of Minnesota. 
 
Procedures will be performed in the Center for Neurobehavioral 
Development (CNBD) and the Center for Magnetic Resonance 
Research (CMRR). 
 
23.0 Multi-Site Research 
N/A; single site only 
24.0 Resources Available 
24.1 
Prior studies by our research group, including a previous study with very 
similar methodology to this one, have demonstrated high interest on the part of 

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families in participation.  Recruitment targets have been met for all previous 
studies. 
24.2 
The principal investigator, Dr. Wozniak, will devote approximately 15% 
effort to the study over the course of the project. 
24.3 
Facilities include the CMRR (which is ideally set up for neuroimaging 
work), the CNBD (which is ideally set up for collecting neuropsychological and 
behavioral data), and the DCRU (which is ideally set up for assisting with 
biological samples. 
24.4 
Dr. Wozniak, the principal investigator, is a licensed clinical 
neuropsychologist with 19 years of experience in managing children and 
adolescents with developmental disorders and mental health conditions.  He has 
conducted numerous studies in the Academic Health Center and knows how to 
access resources relevant to clinical research as well as for managing unexpected 
events. 
24.5 
Dr. Wozniak will personally ensure that research coordinators are 
appropriately trained and overseen.  Dr. Wozniak’s Department (Psychiatry) has a 
Clinical Research Specialist (Mahyra Johnson) as well as a Regulatory Specialist 
(Patricia Carstedt) who are available to assist with training and oversight. 
 
25.0 References 
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F. (2014). Feasibility of transcranial direct current stimulation use in children 
aged 5 to 12 years. J Child Neurol, 29(10), 1360-1365. 
 
Antal, A., Alekseichuk, I., Bikson, M., Brockmoller, J., Brunoni, A. R., Chen, R., et al. 
(2017). Low intensity transcranial electric stimulation: Safety, ethical, legal 
regulatory and application guidelines. Clin Neurophysiol, 128(9), 1774-1809. 
 Denboer, John W., Christopher Nicholls, Corrine Corte, and Kali Chestnut. 2014. 
“National Institutes of Health Toolbox Cognition Battery.” Archives of Clinical 
Neuropsychology: The Official Journal of the National Academy of 
Neuropsychologists, August. doi:10.1093/arclin/acu033. 
Heaton, Robert K., Natacha Akshoomoff, David Tulsky, Dan Mungas, Sandra 
Weintraub, Sureyya Dikmen, Jennifer Beaumont, et al. 2014. “Reliability and 
Validity of Composite Scores from the NIH Toolbox Cognition Battery in Adults.” 
Journal of the International Neuropsychological Society: JINS 20 (6): 588–98. 
Kantrowitz, Joshua T., Michael L. Epstein, Odeta Beggel, Stephanie Rohrig, Jonathan M. 
Lehrfeld, Nadine Revheim, Nayla P. Lehrfeld, et al. 2016. “Neurophysiological 
Mechanisms of Cortical Plasticity Impairments in Schizophrenia and Modulation by 
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Kerns, Kimberly A., Sarah Macoun, Jenny MacSween, Jacqueline Pei, and Marnie 
Hutchison. 2016. “Attention and Working Memory Training: A Feasibility Study in 
Children with Neurodevelopmental Disorders.” Applied Neuropsychology. Child, 
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Kerns, Kimberly A., Jennifer Macsween, Shelly Vander Wekken, and Vincenza 
Gruppuso. 2010. “Investigating the Efficacy of an Attention Training Programme in 
Children with Foetal Alcohol Spectrum Disorder.” Developmental 
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Mattson, Sarah N., Nicole Crocker, and Tanya T. Nguyen. 2011. “Fetal Alcohol 
Spectrum Disorders: Neuropsychological and Behavioral Features.” 
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May, P. A., and J. P. Gossage. 2001. “Estimating the Prevalence of Fetal Alcohol 
Syndrome. A Summary.” Alcohol Research & Health: The Journal of the National 
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Medina, Alexandre E. 2011. “Fetal Alcohol Spectrum Disorders and Abnormal Neuronal 
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