Cranial Electrical Stimulation (CES) as Treatment for Insomnia in Stroke
Phase: NA
Conditions: Cerebrovascular Accident, Sleep Disorder
Sponsor: University of Texas Southwestern Medical Center

Official title: Cranial Electrical Stimulation (CES) as a First Line Treatment for 
Insomnia in Patients with Subacute Stroke 
NCT number: NCT03344562 
Document date: October 30, 2018 

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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
 
 
Cranial Electrical Stimulation (CES) as a First Line Treatment for Insomnia in Patients with 
Subacute Stroke 
 
Principal Investigator: Amy Mathews, MD 
 
Funding Sponsor: UT Southwestern Department of Physical Medicine and Rehabilitation  
 
Version number: 3  
 
Date: September 2018 
 
1. Introduction and purpose 
Sleep is crucial for the successful recovery from illness, disease or injury. Sleep is often viewed as a 
neurologic pause giving our bodies a chance to rest, yet in actuality it is a neurologically dynamic 
environment wherein the brain is continually progressing through alternating cycles of light and deep 
sleep, collectively known as sleep architecture. During deep sleep, or restorative sleep, our brains 
clear debris, consolidate memory, and form new connections through a process called neuroplasticity. 
Restorative sleep is particularly important for patients to achieve in the days and weeks following a 
stroke. Recently, researchers discovered a network of lymphatic vessels in the brain that run 
alongside glial cells 1; 2. This network is referred to as the glymphatic system and has shown to be 
utilized in the removal of neuronal debris, such as beta amyloid plaques, that build up during waking 
hours leading to fatigue and mental clouding 2.The glymphatic system is most active during deep 
sleep, reinforcing the necessity of quality sleep in individuals recovering from neuronal insults such as 
stroke.  
 
Currently, patients being treated in rehabilitation settings after acute stroke who experience difficulties 
in achieving sufficient or restful sleep are treated with environmental adaptations (such as minimizing 
nighttime interruptions in room) and frequently, with pharmacological agents.  One commonly used 
agent, trazodone, is a hypnotic antidepressant with sedative qualities. Trazodone is frequently used 
because it is viewed as being effective and relatively safe; however, this class of medications is 
known to alter sleep architecture resulting in more time in light sleep and reduced amounts in deep 
restorative sleep.  Additionally, trazodone has well documented carryover effects that are detrimental 
to stroke recovery. These carryover effects include deficits in short-term memory, verbal learning, 
equilibrium, and arm muscle endurance3. Most importantly, trazodone has been shown to significantly 
interfere with sleep-dependent consolidation of cortical plasticity 3. These effects are in stark contrast 
to the goals of rehabilitation patient who requires neuronal plasticity for his or her recovery.  
 
Conversely, cranial electrical stimulation (CES) is a safe method tested in a number of pilot studies to 
promote deep, restorative sleep that is seldom used. There are many potential advantages to using 
CES in place of medications, including safety. CES has few notable side effects and has none of the 
drug-drug interactions that are commonplace in pharmaceuticals. CES is FDA approved to treat 
insomnia, depression, anxiety and pain. Additionally, CES has been shown to increase learning, 
consolidation of memory, creativity and mood. Patients who use CES report feeling calm, focused, 
and relaxed. Side effects of CES are extremely rare and the known risks of CES are minimal and mild 
in nature 4. Skin irritation may occur at the site of sponge electrode placement when sponges 
deteriorate or if the sponges are not thoroughly wet before use. The device manufacturer also cites a 
mild headache or dizziness that may occur during use and ceases when the device is turned off. Such 
reactions are very rare.  

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Despite the potential benefits of CES over medications such as trazodone, this technology is seldom 
used. One reason for this is the paucity of rigorous research proving its benefit. There have been 
many studies since the technology was first introduced in the 1950’s, but there are very few modern 
well-controlled and powered studies with conclusive evidence for or against CES as a treatment for 
sleep. Nearly all studies examined cite deficits in power or adequate blinding. Furthermore, there are 
no studies using CES as a treatment for insomnia in stroke patients. The purpose of this study is to 
determine if CES is a reasonable first line alternative to the current standard of care (SOC) which 
relies on the use of trazodone for patients with subacute stroke. This objective will be answered by 
addressing the following: 
 
• 
Specific Aim 1: To determine if stroke patients with insomnia who receive CES treatment sleep more 
hours than stroke patients treated with sham CES. 
Hypothesis: Stroke patients with insomnia who are treated with CES will accumulate more 
sleeping hours than patients who are treated with sham CES. 
• 
Specific Aim 2: To determine if stroke patients with insomnia who receive CES treatment have better 
sleep efficiency than stroke patients treated with sham CES. 
Hypothesis: Stroke patients with insomnia who are treated with CES will demonstrate 
significantly better sleep efficiency than stroke patients treated with shame CES. 
 
Our study will take place at Zale Lipshy Hospital and Parkland Hospital in Dallas, TX. The study will 
enroll 85 stroke patients who score 7 or higher on the Insomnia Severity Scale. Patients will be 
randomized to a control group or CES treatment group. Patients will receive CES or sham CES for 7 
days after a 24-hour washout period. Objective and subjective sleep assessments will be conducted 
daily during the 7-day study period.  Endpoints will be total time spent sleeping, sleep efficiency and 
daytime drowsiness.  
 
The known risks of CES are minimal and mild in nature. They include potential for headache, irritation 
at the site of electrode placement and dizziness. These adverse reactions are rare and in most cases 
there are no immediate or delayed side effects. 
 
Compared to the known adverse reactions of the current standard of care, trazodone, the known 
adverse events of CES are considerable less severe. Known adverse reactions of trazodone include 
black box warnings for risk of suicidal thinking and behavior in patients less than 24 years of age. In 
addition, trazodone has a long list of potential adverse events, most involving anticholinergic effects 
(sedation, dry mouth, blurred vision) and must be used with caution with platelet inhibitors, MAO 
inhibitors, and other drugs causing prolonged QT intervals. 
 
2. Background 
 
Cranial Electrical Stimulation (CES) is safe and potentially effective way to promote restorative sleep 
without the carryover effects of pharmaceuticals. CES introduces miniscule electric currents, often no 
more than 1-2 mA to the head of individuals suffering from depression, anxiety and insomnia5; 6. While 
the exact mechanism is unknown, it is generally accepted that CES acts through direct action on the 
brain at the limbic system, thalamus, hypothalamus, and reticular activating system7. In these areas, 
the penetrating micro-currents stimulate the release of neurotransmitters such as serotonin, beta-
endorphin, and GABA (FW manual). The overall effect of this is increased alpha brain wave activity 
and decreased delta wave activity which translates to feelings of serenity, relaxation and reduced 
agitation7. In addition to insomnia, CES is FDA approved to treat anxiety and depression, much like 
trazodone which is the most commonly used hypnotic at this time.  
 
Trazodone is widely used, but its mechanism of action is not fully understood either. What is known is 
that it exerts its antidepressant effect as a serotonin (5-HT2) antagonist and reuptake inhibitor8. 

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Serotonin is an important chemical neurotransmitter which has functions in both the central nervous 
system and the peripheral nervous system. Alterations in levels of serotonin by trazodone therefore 
cause widespread effects as detailed previously. 
 
Low intensity current has the potential to modulate the release of neurotransmitters but since the 
reuptake mechanisms are not affected there is little risk in overstimulation.  The CES device we will 
be using is an alternating current (AC) stimulator. This means that each electrode rapidly switches 
between being the cathode and the anode. The electronic waveform generated from the device is a 
15,000Hz square wave carrier which is rectified, varying from zero to a maximum of 4 milliamperes. 
This device is a bipolar version of a TENS device, where there is a brief burst (50 milliseconds) of 
positive energy [above the zero axis], followed by a 16.7 millisecond “OFF” time, followed by a 50 
millisecond burst of negative energy [below the zero axis], followed by a 16.7 millisecond “OFF” time. 
In this manner consecutive positive burst and off time is followed by an equal and opposite negative 
burst and off time, thereby generating alternating current4.  
 
The output amplitude is 0-4 milliamperes at a cycling rate of 15/500/15,000 Hz with a pulse width of 
33 microseconds. The maximum charge per pulse is 0.13 microcoulombs. The output voltage is 
variable from zero to 40 volts and then the voltage limited, first positive and then negative. This allows 
for load impedances of up to 10,000 ohms to be able to have a constant current of up to 4 
milliamperes4.  
 
It is well described how depolarizations of neuronal membranes lead to release of chemical 
neurotransmitters; therefore, one could potentially modulate the cerebral chemical environment by 
electrical intervention. Research from the University of Texas at Austin indicated that indeed external 
electrical stimulation can readily alter the deep brain electrical environment. In their 1996 publication, 
Ferdjallah et all reported that 1 mA of current from CES reaches the thalamic area at a radius of 13.30 
mm and may facilitate the release of neurotransmitters9.   
 
The structures that CES is believed to affect are centrally located in the brain and are known to be 
involved in regulation of emotions. These subcortical brain structures are the reticular activating 
system, thalamus, and hypothalamus, and the limbic system. As the low intensity external charge 
supplied by CES reaches these deep brain structures there is a measurable physiologic result. 
Researchers from the University of North Texas used electroencephalogram (EEG) to show that CES 
is able to increase alpha brain waves (8–12 Hz) and decrease delta (0–3.5 Hz) and beta (12.5–30 Hz) 
brain waves. Increased alpha correlates with improved relaxation and increased mental alertness or 
clarity. Decreased delta waves indicate a reduction in fatigue. Beta-wave reductions between 20 and 
30 Hz correlate with decreases in anxiety, ruminative thoughts, and obsessive/compulsive-like 
behaviors10.  
 
While CES has been shown to be clinically effective in multiple studies, there are equal numbers of 
studies showing no effect or an indeterminate effect11. In nearly all these studies the researchers call 
for further study with higher patient numbers and rigorous blinding. This study will be an extension of 
previous work showing potential efficacy in sleep, while introducing a new population in subacute 
stroke patients. We anticipate our findings will benefit future patients by providing an alternative to 
hypnotics which may have negative effects that are detrimental to the recovery of the stroke patient.  
 
3. Concise Summary of Project  
 
This will be a double blinded randomized clinical trial carried out at Zale-Lipshy and Parkland Hospital 
Inpatient Rehabilitation Facilities. Acute stroke patients with insomnia, identified by the Insomnia 
Severity Index (ISI), and who choose to participate in this study will be randomized to CES or sham 
CES. Patients who do not feel they are getting adequate sleep but want to continue in the study will 
be given the option to receive the standard of care medication as a rescue starting on the 3rd night.  

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Patients will receive treatment with a Fisher-Wallace CES device or Sham CES. Treatment with CES 
will be for 20 minutes once a day, and the treatment period will be for 7 days.  Patients will be allowed 
to increase the intensity of the device from the suggested starting point of level 2 if they feel no 
improvement in sleep on night 1. Groups will be monitored with a wrist worn actigraph that records the 
patient’s activity for the duration of the period of study and provides data on sleep latency, time spent 
asleep, and sleep efficiency. The outcome measures will be total minutes/hours of sleep, sleep 
efficiency and subjective reports of drowsiness using the Karolinska Sleepiness Scale. Actigraphic 
data will be collected 24 hours a day for 7 days. The total length of study will be 4-12 months with a 
target N of 100 consented individuals and 85 participants. Patients will be allowed to exit the study at 
any time on their own choosing. To minimize loss of subjects, patients will have the option to choose 
SOC rescue starting on the third night. Patients who choose the SOC rescue will continue to be 
monitored with an actigraph for data collection purposes.  
 
The investigator should discontinue study participation for a given subject or withdraw the subject 
from study if he/she believes that continuation would be detrimental to the subject’s well-being. A 
subject can decide to withdraw from the study at any time and for any reason.  
 
4. Study procedures 
 
This randomized controlled trial is designed to meet two study objectives related to quality of sleep 
and daytime drowsiness.  
 
Demographic data will be collected from the hospital record and will include age, gender, type of 
stroke, self-reported history of insomnia or other sleep disorder, prior use of sleep medications, in-
hospital use of sleep medications, co-morbid medical conditions. 
 
Patients admitted to inpatient rehabilitation (IPR) who consent to the study will undergo an overnight 
washout period before initiation of CES or sham treatment. This allows for any sleep medication they 
might have received while in acute care to be metabolized and leave their system. On their admission 
day, day 0 (d0) patients will be asked if they want to participate in our study. If they choose to 
participate and meet medical inclusion criteria, they will be tested with ISI. Patients who meet the full 
criteria will not receive sleep medication or CES on their first night.  
 
The study will begin on day 1 (d1) with the patient receiving 20 minutes of CES/sCES in the morning. 
This time will be distraction free without the entrance of laboratory technicians, nurses, housekeeping 
or other staff members. When this period is complete, they will participate in usual care. At midday 
they will be asked to complete the Karolinska Sleepiness Scale (KSS). The patient will wear the 
actigraph throughout the study. This procedure will be repeated for 7 treatment days. All procedures 
will be carried out by research team members or a trained nurse.  
 
The intensity of the CES will begin on setting 2, standard setting recommended by the device 
manufacturer, and the patient will have the option to increase the intensity to setting 3 on the second 
treatment day if they feel they did not receive any benefit from the device.  
 
If the patient does not feel they are getting adequate sleep the patient may choose to opt out of 
CES/sCES treatment and receive the standard of care medication for the remainder of the study. 
Patients who choose the SOC rescue will continue to be monitored with the actigraph. A patient may 
choose to leave the study at any time. 
 
We will collect information on side effects for the CES treatment during the 7 days of the study.   
 

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Methods of assigning patients to treatment groups and blinding  
Patients will be randomized to the active or sham treatment group using an online randomizer, 
Research randomizer (www.randomizer.org). A list of random numbers will be generated prior to the 
study. Patients will be assigned a random number in the order that the generator produces. All even 
patients will be assigned to the control group; odd numbered patients will be assigned to the treatment 
group.     
 
Procedural responsibilities and oversight 
Nursing staff at UTSW will be educated how to administer the CES and asked to help distribute and 
collect the Karolinska Sleepiness Scale questionnaire. Photos of proper placement and instructions 
will be posted in subjects’ rooms for reference. Researchers affiliated with this project will apply and 
remove the actigraph watches and be responsible for data acquisition, cleaning and charging of the 
devices. Researchers affiliated with the study will be responsible for ensuring CES is delivered to the 
appropriate patients on the days required per protocol. Research personnel will be responsible for all 
study-related activities at Parkland. 
 
5. Inclusion criteria 
 
To be eligible for inclusion in this study, subjects must fulfill all of the following criteria at screening. 
1. Written informed consent must be obtained.  
2. Patients must be admitted to inpatient rehab. 
3. Patients must have a documented acute stroke (ischemic, hemorrhagic or embolic).  
4. Patients must have at least one fully functional arm which can be used to record actigraph 
data via a wrist worn actigraph device.  
5. Subjects must Score a 7 or higher on the ISI. 
6. Patients must be able to communicate consent and/or desire to discontinue the study. 
 
6. Exclusion criteria  
 
Subjects fulfilling any of the following criteria at screening will not be eligible for inclusion in this study. 
1. Demand or sensing type cardiac pacemaker. 
2. Known uncontrolled seizure disorder. 
3. Current history of vertigo.  
4. Need for continuous O2. 
First night: no medication or prior CES 
Day 1:  
Fit with actigraph and begin 
treatment with CES/Sham 
Day 2-7:  
Option to increase CES 
intensity to level 2 
Day 3-7:  
Option to stop using CES and 
start SOC sleep medication  
 
Day 7: Remove actigraph, download data, and allow patient unrestricted access to sleep aids at their physician’s discretion  
• 
Subacute stroke patient admitted to IPR 
• 
Screened for inclusion/exclusion criteria 

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5. Inability to communicate or provide consent. 
6. Restricted use or absence of both arms.  
 
7. Sources of research material 
 
All data will be collected prospectively through a wrist-worn actigraph and a sleep questionnaire. This 
data will be used specifically for research purposes. Demographic data will be collected from the 
hospital chart. 
 
8. Recruitment methods and consenting process: 
 
We will use verbal recruitment process for the study. The attending and resident physicians will be 
educated about the study and asked to identity patients who may be appropriate. A member of the 
research team will explain the risks, benefits and rationale for the study to patients who meet inclusion 
criteria. Patients will be enrolled when they arrive on the rehabilitation floor if they choose to 
participate. Consent will be attained via a written document in the subject’s primary language (English 
or Spanish). 
 
The research team will protect subjects’ privacy by conducting all study related verbal interactions 
with the subject in a closed room, such as the patient’s room.  For confidentiality, each subject 
screened will be assigned a unique identification number (ID#). Subjects will only be identified by the 
unique ID # in the data. No demographic data or personal information will be used to identify subjects. 
This unique ID# will be linked to subject name and will be kept in a locked file cabinet, accessible only 
to the research team. Only the research team will have access to the data. All data for presentations 
and publications will be reported as mean ± standard error of means. Investigators will educate faculty 
and residents on each floor about the study to maintain privacy and compliance. 
 
9. Potential Risks  
 
The Fisher Wallace Cranial Electrical Stimulator is known to have the potential for very rare and mild 
adverse reactions. These include, skin irritation at the site of sponge electrode placement, especially if 
the sponges deteriorate. Per Fisher Wallace recommendations, the sponges will be replaced every 
two weeks to prevent contact between the skin and the metal part of the sponge receptacle. This risk 
will also be mitigated by ensuring the sponges are thoroughly wet before each use. In rare cases a 
mild headache or dizziness may occur, and should cease after stopping use of the device. Such 
reactions represent minimal risk. 
 
11. Subject Safety and Data Monitoring 
Study data will be accessible only to study personnel.  All paper study records will be kept in a 
secured locked location.  All electronic study data will be stored on password protected, encrypted 
computers; flash drives used for data storage will be encrypted.  Each subject will be assigned a study 
number in consecutive order. The key linking the subject identifier (name and MRN) to the subject 
study number will be kept secure and separate from the research data.  The key will be destroyed at 
the time that data entry and analysis is completed.  
 
All patient information will be de-identified prior to statistical analysis.  This spreadsheet will be 
destroyed after the data has been analyzed and PHI will not be re-used or disclosed.  A link will be 
needed to ensure accurate collection of data on subsequent visits.   
 
For participants who are screened and included in the study the essential documents will be filed with 
the individual’s research file and kept for seven years. 
 
12. Procedures to Maintain Confidentiality 

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The research team will protect subjects’ privacy by conducting all study related verbal interactions 
with the subject in a closed room, such as private space in the patient’s room. For confidentiality, each 
subject screened will be assigned a unique identification number (ID#). Subjects will only be identified 
by the unique ID # in the data. No demographic data or personal information will be used to identify 
subjects. This unique ID# will be linked to subject name and will be kept in a locked file cabinet, 
accessible only to the research team. Only the research team will have access to the data. All data for 
presentations and publications will be reported as mean ± standard error of means. 
 
13. Potential Benefits  
There are many potential benefits to this study with both immediate and long term applications in 
improving sleep and minimizing the use of sedative medications during stroke recovery. Cranial 
Electrical Stimulation is a favorable alternative to standard of care medications like trazodone 
because individual participants may experience improved sleep and it is without the many side effects 
of these medications that increase the risk of complications. Some finding suggests that CES also 
increases learning, creativity and mood, and decreases anxiety, depression, and pain. It is through 
these mechanisms that patients will benefit immediately from this study.    
 
In the long term, future patients may benefit from this study by potentially having an alternative first 
line treatment option for insomnia that does not have the negative carryover effects and plasticity 
reducing effects of hypnotics and sedatives. Additionally, treatment with CES offers the potential for 
improved functional recovery efficiency, increased patient satisfaction and increased cost 
effectiveness.  
 
14. Biostatistics  
Sample size was calculated based on several studies that measured the number of hours that 
subacute rehabilitation patients sleep in an inpatient hospital setting. Alpha levels for error probability 
were set at .05 for a two-tailed test with 80% power to detect a difference between means of control 
group compared to CES treatment group.    
 
Descriptive statistics will be used to determine differences between CES and sCES treatment groups. 
A T-test will be used to determine if sleep time means differ between groups (p≤ .05). A chi square 
analysis will be used to compare data collected from the Karolinska Sleepiness Scale. A non-
parametric test will be used if data is not able to demonstrate normal distribution. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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