UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study
Phase: PHASE4
Conditions: Unconsciousness, Consciousness
Sponsor: University of Wisconsin, Madison

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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UNderstanding CONSciousness Connectedness and 
Intraoperative Unresponsiveness Study (UN-ConsCIOUS) 
 
 
 
 
 
 
 
 
University of Wisconsin – Madison 
School of Medicine and Public Health 
Department of Anesthesiology 
 
 
 
 
 

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UN-CONSCIOUS Protocol 
 
UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness 
Study (UN-CONSCIOUS) 
 
 
 
Authors 
 
Principal Investigator:  
Robert Pearce, MD, PHD* 
Co-Investigators:  
 
Robert  D. Sanders, MBBS, PHD 
 
Giulio Tononi M.D., Ph.D. 
Aeyal Raz M.D. Ph.D. 
Melanie Boly M.D. Ph.D. 
Matthew Banks PhD 
Brady Riedner PhD 
Ari Rosenberg 
Yuri Saalmann 
Heidi Lindroth 
 
 
 
 
 
Version Date: 1/11/2023 
 
 
 
 

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Investigator's Agreement 
1. I have read this protocol and agree to conduct this trial in accordance with Good Clinical Practice 
(GCP), all stipulations of the protocol, the Declaration of Helsinki, and applicable regulatory 
requirements as stated by my human subjects testing oversight body [e.g., independent ethics 
committee (IEC) or institutional review board (IRB)]. 
2. I will personally conduct or supervise the described investigation(s). This includes informing all 
associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments. 
3. I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
4. I agree that all electronic signatures will be considered the equivalent of a handwritten 
signature and will be legally binding. 
 
Protocol Title: UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness 
Study (UN-CONSCIOUS) 
Protocol Number: 2015-1399 
Version Number: 5.0 
Version Date: 1/11/2023 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
 
 

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Summary 
 
The aim of the proposed research is to measure the effect of drug-induced sedation on delta power 
(also known as slow wave activity) of posterior cortex (overlying the precuneus brain region) and the 
functional and effective connectivity between brain regions as indicated by high density EEG 
transmission within the human brain.  The results of this study will help to identify the 
neurophysiological correlates of changes in conscious experience that occur during drug-induced 
sedation informing clinical practice of sedation and anesthesiology as well as consciousness science. 
 
The study will employ auditory stimuli and high-density electroencephalography (HD-EEG) in 
combination. We hypothesize that consciousness during sedation will be associated with lower delta 
power at the CPz electrode than unconsciousness.  HD-EEG allows non-invasive recording and mapping 
of brain responses. Transmission of signals within the brain will be evaluated in normal subjects by 
recording the time course and spatial distribution auditory stimuli-evoked EEG signals during different 
states of sedation i.e., wakefulness, responsive sedation, and unresponsive sedation.  Sedation will be 
induced with FDA-approved, clinical sedatives, dexmedetomidine, ketamine, midazolam and propofol. 
All these drugs have distinct mechanisms of action. We will study 20 patients for each drug. Hence 60 
subjects will be recruited in total. We will compare these responses from those obtained from natural 
sleep with sleep data acquired at the Wisconsin Psychiatric Institute and Clinics (WISPIC). 
 
We have previously shown that midazolam, a short-acting benozodiazepine that is commonly used for 
procedural sedation and before and during surgery is safe. Herein we seek to develop these same 
findings throughout the study of the other sedative drugs.  In the proposed doses, there is a very small 
risk of prolonged sedation and loss of airway control. All drugs will be administered by an 
anesthesiologist with clinical grade equipment and facilities. The sedative drugs (dexmedetomidine, 
ketamine, midazolam and propofol) have very low allergic potential.   
 
 
 
 

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Schedule of activities 
 
 
Screening 
Baseline 
Sedation 
Window 
Up to 30 days prior 
Up to 30 days prior 
 
INFORMED CONSENT  
X 
X 
X 
ELIGIBILITY REVIEW  
X 
 
X 
OBTAIN HISTORY & 
DEMOGRAPHICS 
X 
 
X 
VITAL SIGN MEASUREMENT 
X 
 
X 
ANESTHESIOLOGIST REVIEW1 
X 
 
X 
REVIEW OF CONCOMITANT 
MEDICATIONS 
X 
 
X 
HD-EEG 
 
X 
X 
Predictive Coding and Cognitive 
tasks 
 
X 
X 
Auditory Stimuli 
 
X 
X 
Sleep Study 
 
X 
 
Brice Questionnaire 
 
 
X 
Blood Collection2 
 
 
X 
SEDATION3  
 
 
X 
Patient Reimbursement 
none 
$50 for sleep study 
$200 for each 
sedation visit 
1 History and Physical, Neurologic and Anesthesiologic examinations for candidacy will be performed. 
2 Blood samples will be taken intraoperatively from the indicated intravenous line.  
3 Sedation will be with dexmedetomidine, ketamine, midazolam or propofol. We will recruit 20 subjects 
per sedative. All subjects will have the option to complete all sedation tests. Each sedation will be at 
least 28 days apart.  
*MRI might be performed on a subsequent day, depending on the availability of the MRI machines.  
 
 

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Introduction 
 
1.1. 
Background 
‘Consciousness’ is synonymous with ‘subjective experience’: it can be summarized as “what abandons us 
every night when we fall into dreamless sleep and returns the next morning when we wake up or when 
we dream.” Similarly, patients typically report the absence of subjective experience upon recovering 
from anesthesia (though they sometimes also report dreams). It is evident that sleep and anesthesia are 
not the same. But, they do share certain behavioral features, such as unresponsiveness and loss of 
muscular tone. They also share a number of neurophysiological characteristics, including EEG slowing 
and synchronization, characteristic events such as “K-complexes” and “spindles”, and partially 
overlapping patterns of subcortical activity patterns revealed by microelectrode and imaging methods. 
Although there are similarities, there are also several notable differences between sleep and anesthesia. 
For example, whereas sleep may be interrupted by a noxious stimulus or even a loud noise, anesthesia – 
at clinical doses - survives these challenges. Does this mean that the unconscious state produced by 
sleep and anesthesia are fundamentally different? This is one of the fundamental questions we will 
address.  
 
Anesthetics appear to produce a reversible state of unconsciousness accompanied by amnesia1. This 
remarkable phenomenon brings great relief to surgical patients and wonder to clinicians and scientists. 
However consciousness also occurs during anesthesia: dreaming is common under clinical conditions 
(33% of patients) and in laboratory studies (up to 80% of subjects2) but subjects typically remain 
“disconnected” from their environment (ie. they may be in a dream-state, unaware of their environment 
and the external sensory world)1. This complex pharmacological state mirrors that of sleep but to date, 
we do not fully understand the mechanisms by which anesthetics ablate conscious sensation and 
memory. Nor do we have a deep understanding of consciousness itself or how to measure it – a 
shortcoming that hinders progress in the newly emerging science of consciousness, and has prevented 
the development of an effective diagnostic tool or monitor that can be applied in clinical settings. 
 
The intense interest in “depth-of-anesthesia” monitors demonstrates its perceived importance among 
practicing clinicians. Just as monitors of cardio-respiratory function dramatically improved patient 
safety, a reliable monitor of consciousness has the potential to reduce the incidence of awareness with 
recall, which remains unacceptably high (up to 0.2%) and can lead to adverse psychological sequelae, 
such as symptoms of post-traumatic stress disorder. At the same time, there is a concern that many 
patients may be “overdosed” in an attempt to minimize awareness with recall. 
 
Current approaches to measuring depth-of-anesthesia suffer from significant inter-patient variability in 
response properties. They also lack predictive power: although valid on average, they fail too often to 
report the level of consciousness in individual patients1. We suggest that an approach based on a 
fundamental understanding of consciousness is an essential path to identifying a universally applicable 
measure that can be used to guide drug administration in the perioperative setting.  
 
Understanding how we may be conscious under anesthesia but unaware of our environment (sensory 
disconnection) is also critical1. Sanders et al. have discussed, achieving sensory disconnection appears 
desirable in anesthesia but may fail in approximately 37% of cases1. Our ConsCIOUS study (IRB: Bauer 
(PI) 2014: 1558) has shown that 4.6% of patients are aware of their environment following intubation 
under general anesthesia. Presently we lack a marker of disconnection that provides confidence that 
sensory stimuli will not trigger a conscious experience. Such a marker would have clinical utility to 
identify patients at risk of anesthesia awareness.  As discussed above, dreaming (disconnected 

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consciousness) is  common under clinical anesthesia. A depth of anesthesia monitor that detected 
internally-triggered dreaming (with sensory disconnection from surgery) would signal to the 
anesthesiologist to unnecessarily deepen the anesthetic state increasing the risk of the side effects of 
anesthesia. A marker of disconnection would have significant clinical utility to signify the lack of 
perception of surgery. Any insights afforded into the mechanisms of disconnection could lead to 
developments of improved anesthesia or sedation in the critical care unit as well as development of 
further sleep aids for use in the community. 
 
Patterns of brain activity during anesthesia can be recorded using electroencephalography (EEG). EEG 
reflects the electrical activity of the brain, and is characterized by fundamental oscillatory patterns, 
including slow waves and spindles. A more complete understanding of these patterns will elucidate both 
normal brain function, and alterations in these patterns may be sensitive indicators of disrupted brain 
function in disorders of brain function. This aim will be supported by studying four clinical drugs with 
diverse mechanisms of action: dexmedetomidine (an alpha2 adrenergic agonist), propofol  and 
midazolam (GABAmimetics), and ketamine (NMDA antagonist). While midazolam and propofol both 
affect GABAA receptor function, midazolam targets synaptic (benzodiazepine sensitive channels) while 
propofol also targets extrasynaptic channels (and HCN-1 channels in addition). These differences 
necessitate individual studies of those drugs. We will study the EEG correlates of conscious experience 
and lack of conscious experience under sedation. In order to obtain report of consciousness, we will 
wake patients from the sedated state and ask them questions to gain insights into the experience – if 
any – they were having at the time. We will compare the responses obtained during sedation with those 
collected during natural sleep. We will test whether EEG responses during sleep correlate with changes 
during sedation. In the future we envision that sleep data can be used to develop personalized 
thresholds for an EEG consciousness monitor to be used during sedation and anesthesia and we will test 
this proposal in a subsequent application based on the data acquired herein.  
 
We will also test the cognitive state when aroused from sedation that we expect will be associated with 
impaired feedback processing in the brain and therefore disturbed predictive coding3. We have recently 
shown that feedback connections are particularly susceptible to sub-anesthetic concentrations of drugs4 
and we will therefore test whether cognitive processes that depend on feedback processing, particularly 
those dependent on predictive coding3, are affected during sedation. We will then titrate the anesthetic 
to a state of unresponsiveness to verbal command and repeat the experiment (but not the predictive 
coding tasks requiring the subject to respond).  
 
Our laboratory has pioneered such approaches, particularly in advancing the use of high-density EEG 
(HD-EEG) in the study of sleep, especially in combination with transcranial magnetic stimulation – a non-
invasive method for stimulating specific brain regions and auditory stimuli (IRB: Tononi (PI) 2013-0019). 
We have successfully and safely used this technology during HD-EEG during sleep and anesthesia5 (IRB: 
Pearce (PI) 2008-0018). The combination of HD-EEG,  and auditory stimuli, will provide novel insights 
into EEG and connectivity changes in the brain under varying depths of anesthesia.  
 
 
1.2. 
Rationale and hypothesis 
This study will be a single-site, controlled, unblinded study at the University of Wisconsin to examine 
changes in posterior cortical delta power of the HD-EEG during anesthesia and waking. We hypothesize 
that sedation, with different agents, will increase posterior cortical delta power, interrupting the 
conscious experience, testing this using several anesthetic drugs. 
 

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We will apply high-density electroencephalography (HD-EEG) to assess waking and anesthetized brain 
activity in response to non-invasive brain stimulation techniques, such as auditory stimulation.  
 
2. Objectives 
 
2.1. 
Primary outcome and endpoint (endpoint bulleted below) 
The study primary outcome is the difference in spontaneous EEG delta power over posterior cortex 
between consciousness and unconsciousness during sedation.  
 
2.2. 
Secondary outcomes and endpoints (endpoints bulleted below) 
  
1. The incidence of disconnected conscious experience (dreaming) versus connected conscious 
experience (awareness of the external world) during sedation. 
2. The ability to identify shapes/images in visual illusions and match sounds and images during 
sedation. 
3. The ability to hear words and form implicit memory during sedation tested using a two-alternative 
forced choice word task. 
 
2.3. 
Exploratory outcomes and endpoints (endpoints bulleted below) 
  
1. Difference in HD-EEG responses assessed by calculation of the Phase Locking Factor following 
auditory stimulation between conscious experience under sedation and lack of conscious 
experience. Phase locking factor is calculated by taking the Hilbert transform of the evoked response 
and quantifying the alignment of phases based on the imaginery component of the signal. PLF is 
quantified on a scale of 0 to 1. With 0 being no phase locking and 1 being maximal phase locking. 
We expect than under anesthesia PLF will decrease across the whole scalp. 
2. Drug effect on percent difference in duration of PLF between the two consciousness states. 
3. The effect of consciousness during sedation vs. unconsciousness during sedation on PLF following 
auditory stimulation. 
4. The correlation between sedation EEG responses and those from natural sleep. 
 
 

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3. Study design 
 
This study will be a single-site, controlled, unblinded study at the University of Wisconsin to examine 
changes in delta power during consciousness vs unconsciousness during sedation. We will collect data in 
wakefulness, light sedation and deep sedation. The primary outcome focuses on light sedation during 
which data will be collected divided on conscious experience present/absent.  
 
We will study four different sedatives that have different mechanisms of action, to provide a cross 
section of the drugs used in clinical practice and provide greater insight into the mechanisms through 
which consciousness may be perturbed. We will recruit 20 subjects per drug into this study. Subjects will 
not be randomized between sedatives as it is important to start with dexmedetomidine which is the 
drug that will be easiest to titrate to consciousness/unconsciousness. Drugs will be administered, on 
separate days, in the order of dexmedetomidine, ketamine, midazolam and propofol. 
 
 
4. Study population 
Patients recruited will be 18-40 years old without contraindication to anesthesia or allergy to study drug. 
We will recruit 20 subjects per drug (up to 80 total subjects). Subjects will be allowed to be participate in 
all four sedative experiments. 
 

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4.1. 
Inclusion criteria 
• 
Adults, ages ≥ 18 and ≤ 40 years old 
• 
In good health, determined by the PI on the basis of medical history and a standard assessment for 
anesthesia to be documented as part of the study record  
 
 
4.2. 
Exclusion criteria  
• 
Adults <18 years old or >40 years old 
• 
Pregnancy confirmed on pregnancy test on day of sedation 
• 
Contraindication to anesthesia or allergy to study drug 
• 
Difficult anesthesia: American Society of Anesthesiologists Physical Status greater than 1, per the 
discretion of the PI. Examples of ASA status include, but are not limited to:  
o Any systemic disease present, such as diabetes, cardiac, pulmonary, or other acute or 
chronic disorder, or history of smoking 
o Narrow angle glaucoma 
o Abnormal airway examination 
o Any abnormality on medical history and physical examination 
o Snoring or sleep disorders including apnea 
o Antecedent pulmonary aspiration risk (e.g., history GI reflux, heartburn, hiatal hernia) 
o Adverse reaction or allergy with anesthesia or other sedatives 
o Chronic medication use 
o History of difficult anesthesia, laryngoscopy or intubation 
o Family history of difficulty with anesthesia or sedation 
o History of vertigo, nausea or vomiting after anesthesia  
• 
BMI > 35 
• 
Contraindication to HD-EEG for relative parts of the procedures.  
• 
Exclusion from Dexmedetomidine: 
o Resting heart Rate<60 bpm 
o Known dexmedetomidine allergy 
• 
Exclusion from Propofol: 
o Reported egg or propofol allergy 
o Known ketamine allergy 
• 
Exclusion from Ketamine: 
o History of post-operative nausea and vomiting 
o History of motion sickness 
• 
Exclusion from midazolam 
o Known midazolam allergy 
 
Additional exclusion criteria on the day of sedation:  
• 
Anything to eat or drink for the preceding 8 hours 
• 
Any use of over-the-counter or recreational drugs (including alcohol or tobacco) within the 
preceding 24 hours 
• 
Any use of sedative or sleep agents within the preceding 24 hours 
• 
Recent change in health, including cough, cold, or fever 
• 
Exposure to anesthesia or sedation in the last 6 days 
 
 

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4.3. 
Protected populations 
Prisoners 
Due to the complexity of state and federal requirements governing the participation of prisoners in 
research, patients who are prisoners will not be considered for participation in this trial.  
 
 
5. Trial interventions 
None of the procedures in this study are considered to be standard treatments. Some of the equipment 
used in study procedures has been evaluated and approved by the FDA for other applications for other 
(clinical) applications. As all procedures are considered “research”, they do not require specific approval 
by the FDA Devices Panel, as long as subjects are informed of the nature of the study, and all devices are 
clearly labeled “WARNING - For Investigational Use”. However, most of the equipment used in this study 
has an FDA approval for clinical use AND/OR an FDA 510(k) pre-market clearance. A summary of FDA 
approvals of equipment is detailed below: 
 
Electroencephalography equipment: Most EEG equipment has been “grandfathered” by the FDA, as it 
has been used in clinical settings prior to the 1976 Medical Device Amendment to the U.S. Food and 
Drug Law. EEG devices in current use are, for the most part, substantially equivalent and maintain this 
exemption.  
 
High-density (HD) EEG equipment is identical in concept to previously existing EEG equipment. However, 
HD-EEG has many more individual electrodes placed across the scalp to allow superior spatial and 
temporal resolution in the analysis of the EEG signals. Analysis of HD-EEG data has become practical only 
with the advent and improvement of powerful personal computers. High-density EEG systems have 
been in use since at least the early 1990’s, and do not require FDA approval for research use. However, 
more recently some HD-EEG systems (electrode caps, amplifiers, recording software) have received FDA 
510(k) pre-market approval, as these companies intend to market their products for commercial clinical 
use. In addition to HD-EEG systems, multiple sensor systems used for clinical polysomnography 
(integrated systems incorporating EEG, respiratory monitoring, movement monitoring, etc. along with 
amplifier and recording/analysis software) also have 510(k) clearance.  
 
The following systems have FDA 510(k) approval: 
- Electrical Geodesics Inc., hydrocel geodesic sensor net (HCGSN) hd-EEG system (64-, 128-, and 256-
electrode systems). (http://www.egi.com) 
- Philips-Respironics Alice Diagnostic Sleep system 
(http://www.healthcare.philips.com/main/homehealth/sleep/alice5/default.wpd - current vendor for 
Wisconsin Sleep Center although other systems from Nihon-Koden, Compumedics, ViaSys, etc. may 
potentially be used in the future) 
 
The following systems do not have FDA 510(k) approval: 
- BrainAmp, BrainAmp MR Plus MRI compatible high density EEG system. 
(http://www.brainproducts.com/products/brainampmrplus/).  
- NexStim Eximia EEG system (http://www.nexstim.com/index.php?k=11139) 
 
These systems are designed and marketed exclusively for research applications, and as such do not 
require FDA approval. However, these devices are not substantially different than the other EEG 
systems, and are still considered NSR devices. Wireless EEG systems may also be used. These systems 
consists of battery powered EEG amplifiers that are not directly plugged into the power mains. Several 

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wireless EEG devices are commercially available. The wireless EEG device currently used for research in 
the laboratory and approved for use in protocol H2009-0052 was specifically designed for sleep 
according to ANSI/AAMI ES1-1985 guidelines for “Safe current limits for electro-medical apparatus” and 
safety standards for wireless communications according to the Radio and Telecommunications Terminal 
Equipment directives by Philips Applied Technologies.  
   
Auditory Stimulation: Devices that produce evoked auditory stimuli (an EEG response from an auditory 
stimulus) are described in 21CFR882.1900 as a Class II device (exempt from pre-market notification 
[510(k) clearance). Auditory stimuli will be produced on a standard personal computer through 
commonly available media software (e.g. – Windows Media Player, iTunes, etc.) and played back 
through standard commercially available small speakers or earphones connected to the computer. 
Volume of playback will be estimated before experiments using a decibel meter, and are maintained 
below 80dB (“low” volume range, corresponds to a speaking voice level). Volume will kept at the lowest 
level that still produces an auditory evoked potential (an EEG signal in response to hearing a sound). It is 
critical to keep the volume as low as possible as louder sounds could awaken a subject and disrupt the 
experiment.   
 
GE Clinical anesthesia machine: monitoring and full resuscitation equipment consistent with American 
Society of Anesthesiologists and UW-Madison guidance with FDA approval. Studies conducted in the 
MRI will have appropriate MRI approved clinical safety equipment including anesthesia apparatus and 
appropriate staff to safely conduct anesthesia. 
 
EZstim II nerve stimulator, model es400, Life Tech has 510k clearance to provide tetanic stimuli to assess 
neuromuscular function and is routinely used in clinical anesthesia. 
 
Predictive coding task. We have designed a behavioral task in which subjects use prior auditory 
information to process visual information. This task uses biomorphic visual stimuli from Michael Tarr’s 
lab, known as greebles (http://wiki.cnbc.cmu.edu/Novel_Objects). Greebles will either be colored or gray-
scale images. Each greeble is personified with a name. For example, the violet, green and yellow greebles 
shown in figure 1 are called Paluti, Kagotu and Tilado respectively. During the experimental session, the 
subject will first learn two or three pairs of name and image associations through trial and error (images 
and their names are randomly assigned each session). This phase is called the learning phase, and it will 
take place before the administration of anesthetic agents. Subjects will hear a name voiced by the 
computer followed by a visual image of a greeble on the monitor. Auditory feedback on correct and 
incorrect responses provided at the end of each trial. To confirm that subjects have learnt the correct 
associations, subjects perform a match/non-match task (figure 2A). Subjects report whether the auditory-
visual pairs matched or not using a button response device (keyboard, mouse or button box). The buttons 
signaling a match and non-match on each trial are respectively indicated by a star (or check) and null (or 
cross) symbol on the monitor (after the presentation of the greeble image). The appropriate button 
changes randomly over trials to minimize motor preparation (on half the trials, the left button will signal 
a match, and on the other half, the right button will signal a match). To allow measuring of reaction times, 
we will also use a variant of the task shown in figure 2, in which the second delay period (after the greeble 
image) is absent.   
 

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Figure 1 (left). Stimuli used in the behavioral 
task. To avoid differences in salience of 
stimuli, greeble images have similar size, 
number of extensions and contrast, and 
greeble names have the same number of 
syllables, start with a ‘hard’ consonant and 
end with a vowel.   
 
 

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Figure 2 (below). Task design. A1, A2 and A3 are computer-voiced names Paluti, Kagotu and Tilado. V1, 
V2 and V3 are greeble images. Star=match; null sign =non-match; screen position indicates left/right 
button. 
 
 
Once subjects demonstrate greater than 80% accuracy in the match/non-match task during the learning 
phase, they progress to the testing phase (figure 2B-D). In this phase, which will occur during baseline 
recordings, the administration of anesthetic agents (prior to loss of consciousness), and during recovery 
we manipulate predictions by changing the probability of a greeble visual image appearing after its 
associated auditory name. For example, whenever subjects hear the name Paluti, there will be an 85% 
chance of Paluti’s image being shown; whenever subjects hear the name Kagotu, there will be a 50% 
chance of Kagotu’s image being shown; and whenever subjects hear the name Tilado, there will be a 33% 
chance of Tilado’s image being shown. In an individual experimental session, there will be roughly equal 
numbers of match and non-match trials, to avoid response bias. In addition, there will be approximately 
equal numbers of Paluti, Kagotu and Tilado images, and their corresponding names will have similar 
probability of being presented as the auditory cue, to control for stimulus familiarity. 
To test how precision (or the reliability of sensory information) is represented, in some cases, we may 
introduce two conditions during the predictive coding testing phase. These are high noise and low noise 
conditions. White noise will be added to the greeble images to manipulate perceptual confidence.  
To rule out the possibility that expectation of a match or non-match in itself may contribute to subjects’ 
responses, we will pilot a variant of the predictive coding task in which half of trials subjects simply 
respond to the color of the visual image (or, in the case of gray-scale images, whether the image is upright 

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or inverted) rather than whether the auditory name matched the subsequent greeble image. In this 
behavioral pilot, the second delay period (after the greeble image) is absent, to allow measuring of 
reaction times. Further, on the half of trials in which subjects simply respond to the color of the visual 
image (or, in the case of gray-scale images, whether the image is upright or inverted), a colored swatch 
(or, for gray-scale images, and up/down arrow) on each side of the fixation point replace the star and null 
symbols at the end of the trial (see figure 3). Our pilot behavioral data suggests expectation of a match or 
non-match in itself contribute little to subjects’ responses.   
 
Most of this experimental phase is conducted prior to sedation commencing with the testing phase that 
will take approximately 20 minutes occurring under sedation after waking to answer commands. The 
testing will be spread over the first 2-3 epochs of arousal after the questions have been asked (equivalent 
to OAAS scale 4-5) and then the subject will be allowed to return to sleep. The duration of sedation will 
not be extended for this experimental addition. Patients will be asked to perform the 20 minute testing 
phase again after full recovery from the drug. This would allow us to look at cognitive performance 
following recovery from anesthesia.  
 
This task requires active involvement of the subject but as they get more sedated this is not possible. 
Therefore we will also apply a passive tasks as a pilot study that involves passive audio-visual integration 
where in addition to a tone, a paired visual stimulus is provided (for example a picture of a face is provided) 
on the computer screen. Each tone and/or face is provided as a 250ms stimulus. The tone will be provided 
through the headphones as above and the face will be displayed on a computer screen as per 6. Fifteen 
minutes of data will be acquired using this paradigm under sedation. The paired visual and auditory 
stimulus produces an integrated evoked response [AV]. The interaction of the responses can be calculated 
by the difference between the AV responses and the visual (V) or auditory cue (A) i.e. (AV – (A+V)) which 
we call the AV interaction. We will model how sedation affects the AV interaction response hypothesizing 
that during states of disconnection or unconsciousness the AV interaction will disappear. 
 
Cognitive Tests: To better understand what areas of cognition are affected by anesthesia, participants 
may also complete a flanker task, verbal fluency task, and Wisconsin card-sorting task. Participants would 
complete these tasks during the HD-EEG recording. To obtain baseline cognition, these tasks will be 
completed before the start of sedation. They will also be completed during the lighter sedation period. 
Similar to the Predictive Coding task, once participants reach a deeper level of sedation, they will be 
unable to perform these tasks so they will only be done when the patient is still conscious. Subjects will be 
asked to complete them again during recovery in the CRU, taking approximately 30 minutes. If the subject 
would prefer this recovery cognitive testing may also be deferred to the following day. The time to 
complete these tasks will be included in the 4 hours of sedation and the 30 minutes allotted in the CRU. 
Sedation time will not be increased for these tasks. 
The flanker task is a test of attention, executive control, and inhibition. For this task, participants are 
instructed to focus on a central, directional, target stimulus such as an arrow.  The target stimulus will be 

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surrounded by non-target stimuli. The non-target stimuli will either have congruent or non-congruent 
directionality with the target stimulus. The participant will be told to respond with the direction of the 
target stimulus and their accuracy and reaction time will be recorded. Participants respond more quickly 
when the flanking symbols are congruent with the central target.  
For the verbal fluency task, participants will be told to think of words starting with a certain letter. They 
will be presented with the letters in four 20-s blocks with 20-s blocks of rest. The letters they will be 
presented with are “F,” “A,” “S,” and “T”. 
The Wisconsin Card Sorting Task tests executive function and cognitive flexibility. For this task images are 
presented that vary along different dimensions (e.g., shape and color). Participants are then instructed to 
sort the images along one of the dimensions. During switch trials, the dimension in which the participant 
is asked to sort changes. Their ability to quickly and accurately switch between dimensions is considered 
a measure of cognitive flexibility. 
 
Auditory Stimuli: 
 
Oddball Paradigm:  
We will use the “roving” oddball paradigm that our collaborator, Dr. Boly (UW-Madison, Neurology) 
used previously to study brain-damaged patients with altered levels of consciousness7 (Fig. 1) and that 
Dr. Tononi (UW-Madison, Psychiatry) is investigating in sleeping subjects. This paradigm has been well 
studied in other volunteer settings but not specifically in anesthesia. The stimuli comprise a structured 
sequence of pure sinusoidal tones. The loudness of the tones will be set in each subject to a comfortable 
level, which will be maintained throughout the experiment. Within each stimulus train, all tones are of 
one frequency and are followed by a train of a different frequency. The first tone of a train is a deviant, 
which becomes a standard after several repetitions. This paradigm ensures that deviant tones and 
standard tones have exactly the same physical properties, differing only in the number of times they 
have been presented, which is varied pseudo-randomly between one and eleven. The frequency of the 
tones will vary from 500 to 800 Hz, in randomly selected integer multiples of 50 Hz. Stimuli will be 
presented binaurally via headphones for 20 minutes during wakefulness. The duration of each tone will 
be 70 ms and the inter-stimulus interval is 500 ms. 200 “standard sets” ranging from 1-11 tones/set 
(also resulting in 300 deviant tones) will be presented to each subject in each condition. 
 
Local/Global Deviant Paradigm: 
Experimental stimuli are vowels /a/ and /i/, presented in a local global deviant paradigm (Bekinschtein 
et al., 20098; Fig. 1). The vowels were excised from the steady-state vowel portions of consonant-vowel 
stimuli /had/ and /hid/, spoken by a female talker (F0 = 232 Hz and 233 Hz, respectively) (Hillenbrand et 
al., 1995). On each trial, five 100 ms vowels, normalized to the same root-mean-square amplitude, gated 
with 5 ms on/off ramps and separated by 50 ms silent intervals, will be presented, with the fifth vowel 
being either the same as the first four or different (Fig. 1a). This difference constituted the local 
deviance: /aaaaa/ and /iiiii/ trials were local standards, while /aaaai/ and /iiiia/ trials were local 
deviants.  

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 17 of 52 
 
Figure 1. Local global deviant experimental paradigm. a: Schematic of the four experimental stimuli. b: 
Stimulus sequences. c: Comparisons between trials to characterize local and global deviance effect. 
 
The intertrial interval will be varied within a Gaussian distribution (onset-to-onset mean 1500 ms, S.D. = 
10 ms) to reduce heterodyning in the recordings secondary to power line noise. In each block, the 
stimuli were presented in four sequences, with the order of the sequences randomized across blocks 
(Fig. 1b). Each sequence will begin with a recorded instruction that defined the task and the target 
stimulus to the subject, e.g., for Sequence 1: “This time, press the button when you hear this sound: 
/aaaai/. Once again, press the button when you hear this sound: /aaaai/.” This will be followed by a 
sequence of 10 trials that established the global standard stimulus, and then by 72 global standard trials 
and 18 global deviant trials, presented in a pseudorandom order. The difference in presentation 
frequency thus constituted the global deviance, and the identity of the global deviant changed across 
the four sequences within each block. The duration of each block is 11 minutes (400 1.5 s trials and four 
15-second instruction segments); this will be paused during wake ups. Stimuli will be delivered to both 
ears via insert earphones that were integrated into custom-fit earmolds. Acoustic stimulation will be 
performed at a comfortable level, typically 60-65 dB SPL. Subjects will be instructed to report detection 
of the target stimuli (i.e. global deviants) by a button press if they are awake. 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 18 of 52 
Word Retrieval Task 
 
At one arousal, subjects will be presented with the following words and then, on recovery 
from sedation in the CRU, they will be tested for memory of the words using a word 
retrieval task (analogous to ConsCIOUS2). Subjects will be randomized to one of two word 
list sequences: 
 
List A: 
BIRDS  
NORTH 
TABLE 
HAT 
PENCIL  
LAMP  
FISH 
SEA 
STOVE 
STONES 
WATER 
BASKET 
INDUSTRY 
OFFICE 
EGG 
JOURNAL 
 
List B: 
BEARS  
SOUTH 
STREET 
TRUCK 
BUTTER    
BOWL 
SHEEP  
WOOL 
CLOCK 
TREES 
GLASS 
VIOLIN 
MATERIAL  
HISTORY 
FORK  
ENGINE 
 
 
 
Paradigm: 
For encoding, subjects will be presented 16 target words read from either List A or B. 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 19 of 52 
 
Memory will be assessed and analyzed using the two-alternative forced choice (2AFC) signal detection 
method in the CRU. Here, the subjects are presented with a pair of words; one is a target word, and the 
other is a foil. The subjects are asked to select the word that seems more familiar, or otherwise to choose 
randomly. The following methods are applied to minimize sources of bias: (1) 2AFC word pairs are 
balanced for linguistic characteristics of valence, arousal, dominance, frequency, and syllables1 2, and 
avoidance of semantic or phonemic similarity across pairs; (2) Alternate versions of the command 
sequence are created to balance the word used as the target and that as the foil, and applied randomly; 
(3) To avoid position effects in the 2AFC pairing, alternate versions of the retrieval list are created, and 
applied randomly. 
 
Limitations: 
The 2AFC method is a sensitive, but not specific assessment of implicit memory. Any explicit memory trace 
will also influence the discrimination of target words. This limitation is acceptable because: (1) There is a 
sound a priori hypothesis that explicit memory will be absent or rare during sedation/anesthesia; (2) In 
the context of anesthetic patients who report no spontaneous recollection, the existence of any memory 
behavior that represents performance above chance is of interest and significance; (3) Alternate methods 
that are specific to implicit memory are less robust with the limited number of patients and words 
possible, and are also less resilient to cultural linguistic heterogeneity. 
 
1 
Bradley MM, Lang PJ. Affective norms for English words (ANEW): Instruction manual and affective 
ratings. Technical Report C-1, The Center for Research in Psychophysiology, University of Florida, 
1999 
2 
Coltheart M The MRC psycholinguistic database. The Quarterly Journal of Experimental 
Psychology Section A 1981; 33: 497-505 
 
The retrieval task should occur 60 minutes after arrival in the CRU. Ideally, the person who read the 
commands should be the person who performs the retrieval task. Care should be taken to read the word 
pairs evenly, with no significant tonal or emphasis differences. Subjects should be randomized to be read 
either Sequence X or Sequence Y. 
 
Instructions: “Now, we are going to do an exercise where I read you two words. I want you to pay attention 
to whether one of these words seems to be more familiar to you than the other. If you do have a sense 
that one seems more familiar to you, tell me that word. If neither word seems more familiar, then please 
choose one of the words randomly.” 
 
RETRIEVAL LIST X 
(1) 
VIOLIN  
BASKET 
(2) 
EGG 
 
FORK 
(3) 
TRUCK  
HAT 
(4) 
SOUTH  
NORTH 
(5) 
HISTORY 
OFFICE  

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 20 of 52 
(6) 
WATER  
GLASS 
(7) 
TABLE  
STREET 
(8) 
PENCIL  
BUTTER 
(9) 
ENGINE 
JOURNAL 
(10) 
BOWL  
LAMP 
(11) 
FISH 
 
SHEEP 
(12) 
STOVE  
CLOCK 
(13) 
BIRDS  
BEARS 
(15) 
INDUSTRY 
MATERIAL 
(14) 
WOOL  
SEA 
(16) 
TREES  
STONES 
 
RETRIEVAL LIST Y 
(1) 
BASKET 
VIOLIN  
(2) 
FORK  
EGG 
(3) 
HAT 
 
TRUCK 
(4) 
NORTH  
SOUTH 
(5) 
OFFICE  
HISTORY 
 
(6) 
GLASS  
WATER 
(7) 
STREET  
TABLE 
(8) 
BUTTER 
PENCIL 
(9) 
JOURNAL 
ENGINE 
(10) 
LAMP  
BOWL 
(11) 
SHEEP  
FISH 
(12) 
CLOCK  
STOVE 
(13) 
BEARS  
BIRDS 
(15) 
MATERIAL 
INDUSTRY 
(14) 
SEA 
 
WOOL 
(16) 
STONES 
TREES 
 
 
Tetanic Stimulus: 
In deeply sedated individuals (OAA/S 1), we will apply a tetanic stimulus for 10s at 50Hz 50mAmp to the 
forearm using a clinical nerve stimulator (EZstim II, model es400, Life Tech). Peripheral nerve stimulation 
is routinely used on emergence from anesthesia to monitor return of muscle function. It is a moderately 
painful stimulus and hence we will not conduct it in wakeful individuals. However it has been used to 
assess rousability during anesthesia previously9. 
 
Video Recording: 
Participants will be video recorded during the duration of each sedation appointment to ensure quality 
of research and to aid in analysis of the timing events following sedation.  A written copy of the 
recordings will be made for use in the research. Video recordings will be stored in a secure departmental 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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drive only accessible to study team, and the video will be deleted from the video camera immediately 
following sedation.  
 
5.1. 
Allocation to intervention 
Each sedative will be administered at different sessions on different days. The first sedative session will 
be dexmedetomidine followed by ketamine, propofol (dependent on the availability of the drugs) and 
then midazolam. Allocation is not randomized to ensure that dexmedetomidine, the drug that is easiest 
to titrate, is administered first. Hence we will recruit 20 patients per drug in a non-randomized design. 
Total enrollment in the study will be 80 patients. After 20 patients are enrolled into the  
dexmedetomidine session, no further patients will be enrolled to that drug. Rather we will complete the 
sessions in order above, ensuring 20 subjects allocated to each. 
 
6. Subject recruitment and consent 
 
6.1. 
Subject identification 
Subjects will be recruited via advertisements (mass email distribution). All advertising materials will be 
submitted to the IRB for approval. Potential subjects may respond to advertisements via phone to study 
staff.  
 
 
6.2. 
Screening 
Subjects will respond to the volunteer posts for the study by calling into a study specific phone number. 
They will complete a phone screening to determine basic eligibility for the study. If they qualify, the 
volunteer will be asked to come into UWHC for an in person meeting with a Faculty anesthesiologist and 
consented, followed by a basic pre-anesthesia exam to confirm they are healthy and safe enough to take 
part in the study.  The Faculty anesthesiologist will confirm with the subject that the study could kill 
them and there is no direct benefit to the subject. 
 
6.3. 
Recruitment and consent 
The subject will meet with a staff anesthesiologist in a private room. The subject will undergo informed 
consent discussion for the study where the risks of anesthesia, and the study procedures are explained 
by an anesthesiologist. Participants will be offered informational handouts on the sedative drugs. Undue 
coercion will be prevented by stressing that the potential subject does not have to agree to participation 
and that the future care of the potential subject will not change regardless of the decision about 
participation.  
 
7. Activities and measurements 
 
Screening & Baseline:  
An informed consent discussion, reviewing the risks of participation, eligibility, and data collection will 
be completed at this visit. All questions from the potential subjects will be answered at this visit. If 
consent is provided and criteria for inclusion are met, a history and physical, neurologic and 
anesthesiologic examinations for candidacy will be performed (assessment of a normal airway and 
adequate venous access).  Vital signs will be measured and a review of concomitant medications will be 
performed. 
 
 
Sleep Study Protocol: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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This protocol mirrors IRB approved protocol (2013-0019; PI Tononi). Subjects will be reimbursed 
$50 for the nights recording. 
 
Subjects who have never had an EEG or sleep recording may be offered the option of an 
accommodation night. Subjects will either have an “accommodation” night in the sleep lab, or 
will be able to use a “demo” hd-EEG net at home prior to the sleep lab recording. 
 
Accomodation night: Subjects will have sleep hd-EEG recordings on two nights. The first night 
will be an “accommodation” night and the second will be considered the baseline recording. 
Procedures and recording equipment will be the same between the two nights. 
 
“Demo” hd-EEG nets: Another option to allow accommodation to the EEG net is the use of a 
“demo” net. The demo nets have the identical appearance and shape of the recording hd-EEG 
nets (supplied by Electrical Geodesics, Inc.). However, instead of recording electrodes, the net 
has only the plastic/rubber electrode housing, and also does not include the wires/cables 
necessary for recording. These do not require conductive gel and can be worn by subjects 
overnight. Because they do not require any setup or other hardware, the demo nets can be used 
by a subject at home. Subjects will come to the lab for an instructional session (about 15-20 
minutes) to learn how to put on and care for the net. Subjects will then be allowed to take the net 
home and use it while sleeping for 1-7 nights prior to their scheduled laboratory hd-EEG session. 
There is no risk associated with the use of or sleeping with this demo net, and has the advantage 
of improving subject comfort and accommodation to the recording net prior to the laboratory 
session. Nets that were previously used as recording nets but are no longer functional may also 
be used as “demo” nets. 
 
EEG is a non-invasive technique commonly used both in research and clinical settings to 
measure electrical activity in the brain. We will record hd-EEG while subjects are awake and 
asleep to have recordings for both states. Baseline recordings will be compared to recordings 
during other experimental procedures. The sleep hd-EEG recordings will be performed in a 
manner comparable to clinical polysomnography (PSG). The consent will instruct subjects that 
the PSG should not be considered to be a substitute for a clinical study ordered by their 
physician. Interpretation of PSG data will be supervised by Dr. Plante, a board-certified Sleep 
Medicine Specialist. Subjects will be informed of any identified sleep disorders, and assistance 
will be given with referrals for appropriate medical followup. 
 
In addition to the hd-EEG net, there will be additional electrodes/sensors to monitor other 
physiologic activity during sleep including: 
Electrodes at the corner of each eye to monitor eye movements. 
Electrode on the chin to measure muscle activity. 
Low-resolution video recording using an infrared camera to allow assessment of sleep/wake 
state, sleep-related movements, assist with sleep scoring of the EEG record, and to allow real-
time monitoring of subjects. In addition to providing important information for assessing sleep, 
video monitoring provides additional subject safety by allowing visual contact at all times 
without disrupting the subject.  
 

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The actigraph is a small device (about the size of a postage stamp) worn like a watch. The device 
registers movement, and is used to estimate how many hours a subject sleeps (e.g. – when they 
are not moving). Actigraphs are FDA approved for use in clinical sleep labs. There is no 
foreseeable risk associated with wearing this small recording unit. The actigraphic recording will 
be used to confirm daily (circadian) patterns of activity/sleep, in conjunction with subject report 
on the Sleep Diary form. 
 
After baseline waking recordings, a sleep EEG will be recorded for the subjects’ entire night of 
sleep. The experiment will be scheduled so subjects lie down and try to fall asleep within 30 
minutes of their usual bedtime. Subjects will be in a private room with the door closed and lights 
off. The subject can contact the investigator present at any time via an intercom. Thereafter the 
subject will be allowed to sleep undisturbed for 2-3 hours to establish the peak delta power slow 
wave activity power in natural sleep. After this period, The wake up procedure will be followed 
with wake ups approximately every 15-30 minutes as per our prior work with the same questions 
asked as during sedation.  After awakening, subjects will repeat the awake eyes open and eyes 
closed recordings (~10 minutes). The setup and awake recordings will take up to approximately 
2-3 hours. 
 
This pilot sub study will establish whether peak slow wave activity during sleep +/- 10% can be 
used to predict consciousness during sedation and whether EEG characteristics are similar or not 
between sedation and sleep. Subjects will be reimbursed $50 for the nights recording. 
 
Sedation Protocols: 
On a separate day to the baseline data acquisition the subjects will be invited back for the first sedation 
experiment (dexmedetomidine). Subsequent sedation experiments (for drugs in order), will occur on 
separate days at least 28 days apart for a given subject (only one study sedative will be administered on 
a given day). Subjects will be reconsented on the day of sedation. If the patient is inappropriate for one 
sedative, due to a specific contraindication to that drug (and not the study in general) but are eligible for 
another drug, then they will progress through the order of sedatives (as above). 
 
Female patients will have a pregnancy test on the day of the sedation to confirm they are not pregnant. 
 
As in our previous protocol (IRB: Pearce (PI) 2008-0018) at the beginning of this session, participants will 
affirm that in the interval since their baseline visit, they have not acquired any of the cited exclusion 
criteria that would preclude participation. A review of these exclusion criteria will be completed by the 
Anesthesiologist. A standard pre-anesthetic assessment will be performed, including confirmation of 
NPO status, and documented using the standard Department of Anesthesiology pre-operative 
evaluation form. Participants will have the EEG cap placed and will be given a clear antacid (Bicitra), and 
a 20-gauge intravenous catheter will be placed for drug delivery.  Supplemental oxygen will be provided 
at 2-10 L/minute via nasal cannula.  Many of the sedation drugs have been associated with nausea and 
vomiting, therefore each subject will be given Ondansetron (8 mg) intravenously as a nausea 
prophylactic during each procedure as required. Ondansetron has limited side effects that are rarely 
reported but include headache and constipation. The subject’s EKG, non-invasive blood pressure, SaO2, 
exhaled CO2, and axillary skin temperature will be monitored continuously.  Before each experiment, 
the anesthesia machine and drug cart will undergo routine pre-anesthetic scrutiny, and the availability 
of resuscitation drugs and equipment will be confirmed and documented. 
 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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An anesthesiologist whose sole responsibility is participant welfare will administer the sedatives and will 
be responsible for monitoring physiological status and documenting vital signs on the standard UW 
Hospital and Clinics Anesthesia Record. Level of consciousness will be assessed using the 5-point OAA/S 
scale.  The level of 1 corresponds to “no eye opening or coherent response to verbal command or mild 
physical stimulus (mild shaking or prodding)”.  At this level of responsiveness, airway patency and 
ventilation are maintained in most, if not all, patients.  Patients will not be routinely intubated for this 
study. 
 
All anesthetic drugs that are being used in this study are FDA approved clinical anesthetics (propofol, 
dexmedetomidine and ketamine) in routine clinical use with a proven track record in clinical practice. 
They will be used in a manner analogous to clinical care with appropriate safety measures, dosing and 
treatments for side effects available. Contraindications to these drugs are rare but are a critical 
exclusion criteria. Anesthesia will be administered in a designated clinical anesthesia area in UWHC 
designed for this purpose: the lithotripsy suite (C7/214) in the Ambulatory Procedure Centre (APC) or 
the Motility room (C7/201) also in the APC. Both rooms are designated clinical anesthesia areas, with 
the same access to equipment/emergency care. Drugs will be administered consistent with American 
Society of Anesthesiology and UW-Madison safety guidelines with full safety monitoring and access to 
clinical resuscitation equipment. Lactated Ringers or normal saline may also be administered anywhere 
from 25mL/hr to 1000mL/hr at any point as needed. An anesthesiologist will be present throughout the 
study procedures until the patient is awake. In the APC, other faculty will be notified of the sedation in 
case of patient safety issues. If patient safety issues arise they will be managed in the standard clinical 
manner including an “Anesthesia stat” call if required. Recovery from anesthesia will occur in a 
designated clinical area for that purpose. All the sedative agents may provoke cardiorespiratory 
disturbance hence the drugs will be administered slowly, by an anesthesiologist, in clinically approved 
environments. Full resuscitation equipment will be available throughout. 
 
In order to achieve more controlled transitions in drug concentrations, and therefore more stable 
levels of sedation when administering intravenous medications (dexmedetomidine, ketamine and 
propofol), the sedative infusion rate will be altered using information from Target Controlled 
Infusion (TCI) technology. TCI is a mature technology that is used throughout the world10-15. It 
maintains stable plasma concentrations by adjusting infusion rates according to well established 
pharmacokinetic models. In addition to providing greater stability12,13, this method minimizes the 
need for bolus administration11 and so reduces unwanted drug accumulation. We propose to use 
Rugloop TCI software, which is classified as “non-significant-risk”. It will be used only as an 
adjunct to clinical supervision of drug dosing by the anesthesiologist. TCI has been used in 
multiple volunteer and clinical studies safely10-15. Importantly, we will not deviate from 
approved FDA total drug doses. TCI will enable the subject to stay in a stable sedative state 
allowing cognition to vary while drug concentrations are held constant. We will still be able to 
use all the prior data collected in the study by retrospectively calculating the drug concentrations 
using the same pharmacokinetic models. 
 
Dexmedetomidine: 
Dexmedetomidine is an ICU sedative noted for its safety and lack of idiosyncratic drug reactions. All 
adverse effects are dose-dependent and hence dexmedetomidine will be given through slow 
intravenous infusion16. Dexmedetomidine is known for lack of respiratory depression and preservation 
of airway responses but is known to induce bradycardia and hypotension. Close attention to these 
parameters will be maintained and treated as per standard anesthesiology measures as required. If 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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interventions are required, dexmedetomidine infusion will be stopped. Dexmedetomidine has limited 
effects on seizures, though it has been used safely for resection of seizure foci in patients undergoing 
awake craniotomy17, indicating it is safe in patients prone to seizures. Severe allergic reactions to 
dexmedetomidine have not been reported however, as with all anesthesia care, full resuscitation 
equipment will be available. Allergic skin reactions to dexmedetomidine have been reported twice both 
with minimal effects 
 
Dexmedetomidine will be administered by infusion (TCI) (following 15 minutes of acquisition of data in 
wakefulness as performed previously). The infusion will be conducted consistent with FDA guidance/ 
approval of up to 1mcg/kg bolus followed by infusion between 0.2-1.4 mcg/kg/hr until the desired 
OAA/S level is achieved. Incremental changes in infusion rate will be allowed to titrate to the subject’s 
cognitive and physiological state including, for example, slowing bolus administration or bolusing in an 
incremental fashion. To aid in guiding these incremental changes, infusion rates will be adjusted 
using information from the TCI model (Dyck model18) and clinical judgment. The TCI model 
will be asked to predict plasma concentrations of dexmedetomidine at 0.5 ng/ml increments 
allowing 5-minutes to equilibrate between any step change as we used safely in prior studies. 
Clinical judgment will be used at all times to prioritise subject safety. The anesthesiologist will 
monitor the subject throughout to ensure they are safe and the drugs are being administered at an 
appropriate rate as per clinical practice.  
 
Ketamine: 
Ketamine is an anesthetic noted for producing dreaming (disconnected consciousness) that produces 
limited cardiorespiratory effects and has been used safely in prior EEG studies. Ketamine also preserves 
airway responses19. Dr. Sanders has visited Liege, Belgium to witness their use of ketamine for fMRI and 
HD-EEG experiments. In volunteer studies, ketamine has been associated with nausea and vomiting and 
hence we will administer ondansetron 8mg intravenously at the end of the ketamine infusion.  
 
Ketamine will be titrated using up to a 4.5mg/kg bolus over 10 minutes followed by 0.1-0.5mg/min 
intravenous infusion with 5 minutes between increments and titrated to OAA/S level. This infusion rate 
may be slowed further or stopped for patient safety concerns. Infusion rates will be adjusted using 
information from the TCI model (Domino model20) and clinical judgment. The TCI model will 
be asked to predict plasma concentrations of ketamine at 0.5mcg/ml increments allowing 5-
minutes to equilibrate between any step change as used safely in prior studies. Clinical judgment 
will be used at all times to prioritise subject safety. Short-lived emergence delirium (confusion on 
awakening) may occur on emergence from ketamine anesthesia and this will be managed through 
standard clinical practice including administration of midazolam (up to 4mg IV) if required. However in 
most instances these episodes are short lived and can be managed through calm reassurance of the 
subjects. Allergic reactions to ketamine are extremely rare however, as with all anesthesia care, full 
resuscitation equipment and supportive medications will be available. 
 
Propofol: 
Propofol is a standard anesthetic intravenous induction agent used for sedation for minor procedures in 
ambulatory settings due to its favorable anesthetic profile and wake-up. While it may be safely 
administered through bolus injections, we again will an infusion to provide a slow titration of sedation 
and reduce any safety concerns with the drug. Infusion rates will be adjusted using information 
from the TCI model (Marsh model21) and clinical judgment. The TCI model will be asked to 
predict plasma concentrations of propofol at 0.5mcg/ml increments allowing 5-minutes to 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
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equilibrate between any step change as we used safely in prior studies. Clinical judgment will be 
used at all times to prioritise subject safety. Propofol can provoke cardiorespiratory depression and 
loss of airway reflexes if given too rapidly. We will mitigate these risks through careful drug titration 
from an anesthesiologist. Subjects will be notified that propofol can initially cause some pain on 
injection (through their IV line) and if this is not tolerable, the subject can withdraw from the study. 
Allergic reactions to propofol are rare. There have been concerns that food allergies may cross react 
with propofol but these have proven unfounded22. Nonetheless, while a reaction is considered unlikely, 
clinical grade resuscitation equipment will be available. 
 
Propofol dosing will be confined to FDA approved limits with up to a 2.5mg/kg bolus over 1 to 3 minute 
followed by an infusion of 50-200mcg/kg/min titrated to the desired OAA/S levels. 
 
Midazolam 
Midazolam is a sedative/anesthetic benzodiazepine used both for anesthetic maintenance and sedation 
in critically ill and non-critically ill patients. It is safe to administer through bolus injections or an 
infusion. We will administer midazolam in accordance with FDA guidance: initial boluses of up to 
0.35mg/kg followed by doses up to 0.1mg/kg/h as a maintenance infusion. The side effects of 
midazolam are similar to propofol, though pain on injection are not noted. Allergic reactions are rare but 
standard clinical practice measures will be employed to ensure subject safety. 
 
In this session the subject will experience both HD-EEG and auditory stimuli (the Roving Oddball or LGD 
paradigm) as described above during administration of each sedative. The drugs will be titrated initially 
to an OAA/S Score of 2-3. During this phase the subject will be asked to report whether he sees different 
perceptions on visual illusions. We hypothesize that as the subject drifts to sleep, they will lose feedback 
processing in the brain and this will lead to altered predictive coding.   
 
Observation 
OAA/S Score 
5 
Wake/responds to verbal commands 
4 
Lethargic/responds to name 
3 
Responds only after name is called loudly and/or 
repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Does not respond to mild prodding or shaking 
 
 
Once at a stable sedative OAA/S level 2-3 for 5 minutes we will rouse the patient to wakefulness though 
verbal command or mild shaking, and ask the patient to report whether they were awake prior to us 
contacting them, whether they heard the tones through headphones they were wearing and to respond 
to the questions below: 
 
1. 
What was going through your mind before awakening? 
2. 
Are you sure? Anything else to report? Did you see faces? 
3.  
Did time pass? 
4. 
Did you hear the tones/words? Were you aware of your environment? 
5. 
Were you asleep or awake? (Visual Analogue Score 0-6) 
 

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This will provide information about whether they were conscious and what they were conscious of. 
Specifically we will record whether they were conscious of their environment (connected 
consciousness), dreaming (disconnected consciousness), conscious but cannot remember details, 
unconscious (no report).  We will also ask whether they noticed time passing. We anticipate the 
questions will take 15s and in the first 4-6 arousals the predictive coding experiments will be conducted. 
The patient will then have to return to OAA/S level 2/3 for at least 45 seconds before repeating the 
questions. This will be continued with arousals at a maximum of every minute  for 60 minutes however 
we anticipate that the patients will be questioned less frequently as it will take time to fall asleep again. 
Total recording from the auditory task will be 60 minutes. An additional 60 minute period of EEG 
recordings will be undertaken immediately after. For subject comfort we will interleave these periods. 
 
The subjects will then be more deeply sedated to OAA/S 1 and 20 minutes of auditory stimulation and 
20 minutes of EEG recorded. In this section we will also conduct 20 minutes of recording of response to 
tetanic stimulus using a 10 second, 50Hz, 50mAmp forearm stimulus. 5 seconds before and after the 
tetanic stimulus the subject will be asked to squeeze the observer’s hand and open their eyes and then 
asked to squeeze again if they have pain mimicking our recent isolated forearm technique study 
demonstrating that 4.6% of subject become wakeful after intubation under general anesthesia. If they 
become awake enough to answer the questions above, these will be repeated. A maximum of 20 stimuli 
will be administered over 20 minutes (one per minute). The drugs will then be stopped and the EEG 
continued until the subject is OAA/S 5. At that point we will conduct the Confusion Assessment Method 
(CAM) to assess for delirium on awakening and monitor the patient until there is absence of delirium on 
the CAM test. We estimate the whole study duration will be five hours, four of which will be sedation. 
 
Participants will be observed in the clinical environment until they are judged by the anesthesiologist to 
be ready to move to the UW Clinical Research Unit (CRU) to complete the recovery process. We 
anticipate the full recovery from the sedatives to take at least two hours. Orders for post-sedation care 
in the CRU will follow standard post-sedation hospital guidelines for patients after surgery.  UWHC 
clinical criteria for ‘street readiness’ will be used to determine suitability for discharge after a procedure 
performed under sedation. Participants will be discharged by the faculty anesthesiologist directly or by 
delegation to the CRU nurse according to pre-determined criteria. Participants will be given a copy of 
instructions and contact information in the event that complications arise after leaving the hospital, and 
they will be mandated to be accompanied home by a companion.  Patients will be instructed not to 
drive or operate machinery, and not to consume other drugs with central nervous system activity within 
24 hours of drug-induced sedation as per standard instructions after procedural sedation.  
 
All participants will be contacted by telephone the day following sedation to confirm full recovery and 
inquire about untoward incidents (e.g. nausea, headache, mood disturbance). This information will be 
documented on a post-procedure adverse event form.  
 
If patients have been enrolled in the study previously and re-present for another sedation episode they 
will not undergo re-screening but will have a new consent completed with their prior ID – X, where X is a 
number that  refers to the number of their sedation visits. E.g. if this is the second visit study ID-2. 
 
Sedation Appointment Follow-Up 
Participants will be called by study staff the day following their sedation appointment. During this phone 
call, the participant will be asked about their recovery from sedation and any adverse events will be 
recorded. During this phone call, the participant will also be asked if they can write a summary of what 

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they remember from the sedation experiment. They will be asked to email in this reflection, and their 
response will be stored in a secure research drive within their participant folder. 
  
7.1. 
Data to be recorded 
Demographics (age, sex, right handed or left handed, ASA grade, level of anxiety prior to commencing 
drug (on visual analogue scale), physiological variables, blood samples for intravenous sedatives plasma 
concentration (ketamine, propofol, midazolam and dexmedetomidine), Intra-procedural data 
(responsiveness to questions during sedative procedures,  responses to predictive coding tasks, OAA/S 
status, etc.) Roving Oddball or LGD paradigm details and EEG data will be collected from each subject, 
recorded in the CRF (see appendix 1), and stored in an anonymized fashion on secure servers. 
 
7.2. 
Blood sample collection 
Patients sedated with ketamine, propofol, midazolam and dexmedetomidine will have two intravenous 
lines placed for administration of sedatives and rescue medications/blood draws respectively. All of the 
lines will be placed in preparation on the day of the sedative procedure.  
 
Blood samples for plasma drug levels will be drawn a drug induced OAA/S 2-3 and OAA/S 1 levels are 
reached. Two 5ml blood samples will be drawn for consistency.  Each blood sample will be a 5 mL 
sample from the intravenous line indicated for blood sampling in EDTA tubes. The total amount of blood 
drawn for this study will be approximately 80 mL (2*2*5 mL samples for each sedative drug x 4 sedative 
drugs). The samples will be stored on ice until processed in Dr. Kirk Hogan’s Lab. Samples will be spun 
down to plasma and alliquotted into separate vials labeled with coded subject data and frozen at -80° F 
until analysis. Further analyses may require processing of de-identified and anonymized data in other 
laboratories but patient confidentiality will be maintained. 
 
7.3. 
Data entry 
Data collected for this study will be recorded on electronic Case Report Forms (CRFs) (see appendix 1) 
and stored on secure servers in the Department of Anesthesology. Adverse events will also be recorded 
in OnCore to facilitate the DMC. 
 
Clinical Trials Management Software: 
Online Collaborative Research Environment-Clinical Research Management (OnCore) will serve as the 
Clinical Trial Management System for this study.  ICTR OnCore is supported by the UW School of 
Medicine and Public Health Information Technology (SMPH-IT) staff and managed by the UW ICTR 
Clinical Research Infrastructure System (CRIS).  
 
OnCore is a sophisticated, web-based data management system that: a) ensures secure, easy data entry 
at multiple sites; b) integrates multiple data sources; c) provides controlled, secure access to sensitive 
data using role-based access control; d) provides workflow automation; and e) allows export and 
reporting of data for Data and Safety Monitoring Boards and biostatisticians. This software provides 
protocol management functions (e.g. subject scheduling; screening, data organization), maintains 
updated forms, addresses budget development, billing, and fiscal management, generates summary 
reports, and provides essential links with other research administration and electronic medical records 
systems. ICTR OnCore eases the burden of the individual researcher and unifies protocol management 
within research programs and across research sites, enhancing protocol integrity and regulatory 
compliance efforts. 
 
7.4. 
Subject withdrawals 

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Subjects that do not meet the EEG signaling criteria (due to craniofacial muscle artifact) will be 
withdrawn from the study by the Investigator after the baseline visit. Their consent and data collected 
up to this point will be maintained as part of the study records. Additionally, subjects will be withdrawn 
if safety concerns arise (see adverse events below). 
 
If a subject is withdrawn from the study prior to any sedative procedures, they will not count towards 
the enrollment total of 80 subjects, and we will replace them with a complete subject. If a subject is 
withdrawn for any other reason after at least one of the sedative procedures has been completed, they 
will remain part of the study total enrollment numbers.  
 
7.5. 
Stopping rules 
 
In eventualities (such as cardiorespiratory safety effects) the study drug will be stopped immediately. If 
any degree of ventilatory insufficiency is detected, the anesthesiologist in attendance will adjust the 
position of the airway and assist ventilation with bag, mask and supplemental oxygen as necessary.  
 
Pulmonary aspiration of gastric contents:  Participants who have received an oral clear antacid after an 
8-hour fast are at very low risk for pulmonary aspiration.  Participants will be closely monitored for signs 
of nausea and vomiting, and the experiment will be terminated in the event of emesis. 
 
In the event of an allergic reaction, the study drug will be stopped immediately. The subjects will be 
given chlorpheniramine 10mg, hydrocortisone 100mg and will be reviewed for necessary anaphylaxis 
protocols. Allergic reactions/anaphylaxis to anesthetic drugs are extremely rare. 
 
If heart rate falls below 40bpm or mean arterial blood pressure falls <55 mmHg or >133 mmHg, the 
experiment will be stopped and the patient will be treated until stable.  
 
Sedation will be limited to a 4 hour maximum duration, once 4 hours has elapsed the sedation will be 
stopped and the patient will be woken up. 
 
The study will be stopped as advised by the DMC based on reporting of AQI adverse events to the DMC. 
Seizures and intubations will be notified to the ICTR DMC within 7 days of the event. The DMC will be 
informed of study progress on a monthly basis and any serious adverse events including drug reactions 
will be reported to the DMC within 24 hours of occurrence. 
 
8. Data analysis and statistical considerations 
 
8.1. 
Sample size determination 
 
Spontaneous EEG: Our primary outcome is difference in delta power (also known as slow wave activity) 
over posterior cortex between consciousness and unconsciousness during sedation. Our preliminary 
data suggest that a mean difference in 12 dB with a standard deviation of 12 dB requires 16 subjects per 
group. An additional 4 subjects per group are recruited may be to difficult to wake patients and get 
descriptions of the subjects conscious experience through questioning hence approval is sought for the 

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enrollment of 20 participants per drug in the present proposal. In total 80 subjects will be recruited.   
Secondary endpoints: All secondary endpoints are considered exploratory: 
1. The incidence of disconnected conscious experience (dreaming) versus connected conscious 
experience (awareness of the external world) during sedation. 
2. The ability to percieve visual illusions (defined as time to perceive the illusion and percentage 
accuracy of perceiving the illusion) or match auditory and visual cues (defined as the time to match 
the cues and percentage accuracy of matching the cues). 
3. Differences in auditory and visual evoked responses under sedation compared to wakefulness and 
other conscious states. 
 
Exploratory endpoints: 
1. Difference in HD-EEG responses assessed by calculation of the Phase Locking Factor following 
auditory stimulation between conscious experience under sedation and lack of conscious 
experience. Phase locking factor is calculated by taking the Hilbert transform of the evoked response 
and quantifying the alignment of phases based on the imaginery component of the signal. PLF is 
quantified on a scale of 0 to 1. With 0 being no phase locking and 1 being maximal phase locking. 
We expect than under anesthesia PLF will decrease across the whole scalp. In our experience evoked 
potentials have a high signal-to-noise ratio, and statistically valid responses at single sites may be 
obtained in a single subject by averaging less than 150 single responses. In an earlier TMS 
investigation of hd-EEG changes during sleep complete response sets from only 6 subjects were 
required to detect statistically significant differences in hd-EEG results. In our study we will contrast 
consciousness under sedation (confirmed by report of participant) with lack of report 
(unconsciousness). The percent difference in duration of Phase Locking Factor (PLF) following 
auditory stimuli in the consciousness state (PLFc) of anesthesia compared to the unconsciousness 
state (PLFu) of anesthesia (100*[PLFu-PLFc]/PLFc).  Duration of PLF from the conscious and 
unconscious states will be a single value which has been averaged over all measurements from all 
channels across the scalp.  The primary hypothesis is that at least one of the drugs will show a 
significant difference in percent difference in duration of PLF between the two consciousness states. 
 
2. Drug effect on percent difference in duration of PLF between the two consciousness states. 
3. The effect of consciousness during sedation vs. unconsciousness during sedation on PLF following 
auditory stimulation. 
4. Differences in connectivity between conscious states. 
  
8.2         Sample size and Statistical Analysis Plan 
Our primary endpoint as defined above is a single value per subject within drug that takes into account 
the two different states of consciousness during anesthesia.  Splitting our alpha evenly between all 4 
drugs leaves us with an alpha level of 0.0125 for each test.  If we recruit 16 patients who complete each 
drug session, we will have 80% power at an alpha level of 0.0125 to identify a 12 dB difference in the 
delta power between consciousness to unconscious during anesthesia with an expected standard 
deviation of 12dB using a single sample t-test against a null hypothesis of 0 dB difference. These 
estimates are made based on pre-acquired data comparing consciousness in ketamine sedation with 

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deep anesthesia (propofol). We anticipate that in 25% of subjects it may be to difficult to wake patients 
and get descriptions of the subjects conscious experience through questioning hence approval is sought 
for the enrollment of 20 participants per drug in the present proposal. In total 80 subjects will be 
recruited.   
A similar power analysis for TMS, which is likely to be similar to auditory stimuli, suggests that we will 
have 86% power to show a 20% difference in the Phase Locking Factor using a single sample t-test 
against a null hypothesis of 0% difference. These estimates are made based on pre-acquired data 
comparing consciousness in wakefulness with deep anesthesia (propofol).  
Sedation will be recorded as the Observer Assessment of Alertness/Sedation (OAA/S) scale. Standard 
clinical monitoring of physiological variables (heart rate, blood pressure, oxygen saturation, respiratory 
rate, and oxygen saturation) will be recorded. The imaging and EEG endpoints will be analyzed by 
standard analytical techniques such as Statistical Parametric Mapping to analyze different evoked and 
induced power between conscious report and lack of conscious report. Following FIR filtering we will 
calculate the spontaneous delta power at CPz (as well as in the precuneus in source space) as well as PLF 
per channel as calculated previously23 and then average all channels across the scalp to get a single 
value per subject. The difference in delta power (primary endpoint) and the percent difference in 
duration of PLF following the auditory stimuli between consciousness and unconsciousness will be 
compared against a null hypothesis of 0dB or 0% difference respectively with single sample t-tests for 
each drug individually with an alpha level of 0.0125.  An exploratory analysis will look for a drug effect in 
the percent difference in duration of PLF, or other evoked response changes, between the two 
consciousness states with a repeated measures ANOVA with drug as a fixed effect and subject as a 
random effect.  If we report this analysis we will explicitly state that the subjects were not randomized 
to each sedative. Other exploratory analysis will look at possible differences in percent difference in 
duration of PLF following auditory stimulation. This will be analyzed in the same methods as the primary 
endpoint. Secondary and exploratory analyzes will be conducted at a significance level of 0.05.  We 
acknowledge that we are likely under powered to detect statistically significant differences in our 
secondary analyses however the results can be foundation blocks for further studies on the differences 
between consciousness and unconsciousness states of anesthesia. Underpowered exploratory analyses 
may not be completed if the analysis would not yield meaningful results for future studies. 
 
 
5. Risks and benefits of trial participation 
Overall, risks in this study should be infrequent. Specific risks for individual study procedures are 
detailed below. 
 
None of the procedures included in this study are considered to be therapeutic or diagnostic, as detailed 
for each specific procedure. Each of the procedures has minimal risks associated with them, and have 
been employed successfully, without incident, by our research group for the last 10 years in sleep 
[Protocols H-2001-456, H-2002-414, H-2003-238, H-2004-0023, H-2004-444, H-2007-0150]. Furthermore 
we have specifically applied HD-EEG safely during anesthesia (IRB: Pearce (PI) 2008-0018) and seek to 
extend these findings here. 
 
a. Potential risks 
 
DRUGS 
Bicitra 

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Bicitra may cause diarrhea, nausea and vomiting, hypernatremia and convulsions. Bicitra may also decre 
serum calcium levels. 
 
Ondansetron 
Ondansetron can cause constipation, diarrhea, and headache. 
 
Propofol 
Propofol can provoke cardiorespiratory depression and loss of airway reflexes resulting in airway 
obstruction if given too rapidly. Propofol may also cause hypotension, hypertension, apnea, oxygen 
desaturation, arrhythmia, stinging at injection site, rash and pruritus. Allergy to propofol has been 
reported but is rare. 
 
Ketamine 
Short-lived emergence delirium (confusion on awakening) may occur on emergence from ketamine 
anesthesia and this will be managed through standard clinical practice including administration of 
midazolam (up to 4mg IV) if required. Other common side effects may include hypotension, bradycardia, 
arrhythmia, apnea, laryngospasms, diplopia, nystagmus, increased intraocular pressure, and aspiration.  
 
Dexmedetomidine 
Dexmedetomidine is known for lack of respiratory depression and preservation of airway responses but 
is known to induce bradycardia, dry mouth and hypotension. Close attention to these parameters will be 
maintained and treated as per standard anesthesiology measures as required. If interventions are 
required, dexmedetomidine infusion will be stopped.  
 
Midazolam 
Midazolam may cause cardiorespiratory depression and loss of airway reflexes resulting in airway 
obstruction if given too rapidly. Other common side effects include hiccoughs, headache, nausea, 
vomiting, coughing and drowsiness. 
 
DRUGS TO COUNTERACT COMMON SIDE EFFECTS: 
Bradycardia: 
Glycopyrrolate 
Atropine 
 
Tachycardia: 
Labetralol 
Metoprolol 
 
Hypotension: 
Ephedrine 
Phenylephrine 
 
Hypertension: 
Labetralol 
Metroprolol 
Hydrazine 
 
 

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EEG: 
Electroencephalography is a technique commonly used to non-invasively measure electric brain activity 
both in research and in clinic. There is no risk from EEG recording.  However, individuals with very 
sensitive skin may experience, on rare occasion, a slight irritation at the site of sensor application due to 
the use of mildly conductive saline gel and site preparation for EEG recording.  Continuous EEG 
monitoring during auditory stimulation represents an additional safety factor allowing the early 
detection of any sign of EEG abnormality.  The hd-EEG recording device will be screened for current leak 
before use in the operating room. 
 
Intravenous Catheters:   
Intravenous catheters will be placed by the attending anesthesiologist using local anesthesia before 
needle placement.  Nevertheless there may be some discomfort to participants upon insertion, and 
there may be a slight risk of bruising, and inflammation after removal.  In normal subjects subcutaneous 
infiltration and induration are very rare complications, and are easily managed with warm packs and 
oral analgesics. 
 
Respiratory depression / loss of patent airway:  
Because the anesthetics will be administered incrementally under close observation, we expect that if 
respiratory depression occurs it will be limited in depth and duration.  In general, a reposition of the 
airway (i.e., jaw thrust) and assisted ventilation with bag and mask will be sufficient to return the 
participant to full ventilatory control within several minutes.  If greater assistance is required, a standard 
oral, nasal and laryngeal mask airways will be immediately available. Caregivers are skilled in their use.  
Full resuscitation equipment will also be available if required. 
 
Pulmonary aspiration of gastric contents:  
Participants who have received an oral clear antacid after an 8-hour fast are at very low risk for 
pulmonary aspiration.  Participants will be closely monitored for signs of nausea and vomiting, and the 
experiment will be terminated in the event of emesis.  Participants will be sedated in the operating 
room on tables allowing positions that reduce the risk of aspiration even further, and a fully operational 
suction apparatus will be available at all times.  During recovery, participants will be closely observed for 
signs of aspiration, and instructed in the steps to take if signs of aspiration appear after discharge. 
 
Cardiovascular Effects: 
All the sedative drugs can provoke cardiovascular changes including hypotension and hypertension, 
bradycardia and tachycardia and arrhythmias. These may be most pronounced for dexmedetomidine. If 
these arise they will be treated in line with standard clinical care including administration of medications 
and fluids as clinically appropriate. 
 
Prolonged sedation:  
It is anticipated that most, if not all, participants will have fully recovered within 5 hours after receiving 
the sedative drugs.  Patients will be instructed not to drive or operate machinery, and not to consume 
other drugs with central nervous system activity within 24 hours of drug-induced sedation as per 
standard instructions after procedural sedation. 
 
Drug allergy and other side effects:   
Allergies to ondansetron, propofol, ketamine, midazolam and dexmedetomidine  administration are 
extremely rare. Patients with known allergy will be excluded.  While a number of side effects have been 
report with acute and chronic use, they are very uncommon.  Common or serious risks include residual 

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'hangover' after administration of midazolam, such as sleepiness, and impaired psychomotor and 
cognitive functions that may persist into the next day, and may impair the ability of users to drive safely.   
 
Risks associated with loss of confidentiality 
There is a risk that information recorded about subjects will be shared with people who would not 
normally have access to this information.  
 
Unknown risks 
This study may involve risks to the subject which are currently unforeseeable. We will inform subjects as 
soon as possible if we discover any information that may affect the subject's health, welfare, or decision 
to be in this study. 
 
b. Mitigation of potential risks 
An anesthesiologist will ensure that subjects fit the inclusion criteria for the study and should not be 
excluded for safety reasons. The Anesthesiologist will be present throughout the study to ensure safety 
at clinical standards. If it is judged the patient is at risk from continuation of the study, the study will be 
stopped. Patients who are at risk from seizure induction will be excluded. 
 
 
Mitigation of risks associated with EEG: There are no known risks from EEG. 
 
Mitigation of risks associated with Sedation:  The Anesthesiologist will be present throughout the study 
to ensure safety at clinical standards including administration of required medications and fluids to 
maintain subject safety. Clinical grade anesthesia and resuscitation equipment will be available 
throughout the study. Subjects will be instructed not to drive or operate heavy machinery and must be 
accompanied by someone who can take them home or schedule a ride from another service. The study 
coordinator will verbally confirm this with the subject. The study coordinator will also instruct the 
subject to be accompanied overnight and verbally confirm this will happen with the subject. 
 
Mitigation of risks associated with Blood Draws: Staff obtaining blood samples will have the necessary 
training and draw samples from existing venous catheters. 
 
 
 

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c. Potential benefits and risk-to-benefit ratio 
No direct benefit will accrue to participants. We anticipate that society may benefit from the possible 
development of a new diagnostic technique (i.e., a monitor of sedation and anesthesia), and because 
information may be obtained regarding the mechanisms of conscious experience that has important 
ramifications for detecting/preventing consciousness during anesthesia and sedation and in neurological 
conditions such as unresponsive wakefulness syndrome and coma. Furthermore in our recent 
ConsCIOUS study, 4% of patients during routine general anesthesia were aware of intubation 
(connected consciousness). Half of these, 2% of all people were in pain. This is a good example of why it 
is important for us to understand the mechanisms and markers for conscious experience that is related 
to the external world (connected consciousness). In order to identify the markers and mechanisms of 
connected consciousness, it is important to perform “within state” experiments such as probing 
conscious experience during sedation, as we plan here. If we are able to identify a marker of sensory 
disconnection or unconsciousness in these studies this will have great potential importance for the 
clinical care of patients under anesthesia and sedation. These potential benefits go beyond 
anesthesiology and may inform diverse fields from the disorders of consciousness (such as coma or 
delirium) to sleep. Finally once we identify a potential marker, studies can be undertaken to understand 
the mechanisms of sensory connectedness under anesthesia/sedation followed by studies to prevent 
sensory connectedness under anesthesia/sedation through targeting these mechanisms. It is also 
important to separate connected consciousness (experience of external world) from disconnected 
consciousness (dreams). If an anesthesia monitor could detect disconnected consciousness (e.g. 
dreaming as occurs in 10-30% of people during emergence from anesthesia) then this might imply to the 
care provider that they should deepen the anesthetic but this would not be necessary as the patient is 
unaware of the surgery. Hence a marker of sensory disconnection/connectedness (to provide an index 
of likelihood of awareness of surgery) will provide important information to guide the clinical care of 
patients undergoing anesthesia and sedation. Overall our work aims to identify markers of conscious 
experience under anesthesia, whether it is connected or disconnected, and use these markers to define 
clinical monitoring devices and novel pharmacological strategies to reduce patient experience of surgery 
under anesthesia. 
 
 
6. Adverse events and unanticipated problems 
 
a. Adverse event definitions 
 
Adverse event (AE) 
An adverse event is defined as any untoward or unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease temporally associated with the subject's participation 
in the research, whether or not considered related to the subject's participation in the research. Patients 
will be phoned 24 hours after discharge to confirm a lack of adverse events.  
 
Serious adverse event (SAE) 
A serious adverse event is defined as any adverse event that meets one of the following criteria: 
• Results in death; OR 
• Is life-threatening; OR 
• Requires hospitalization or prolongs existing hospitalization; OR 
• Results in significant or persistent disability or incapacity; OR 
• Results in a congenital anomaly/birth defect; OR  
 

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Unanticipated problem (UP) 
An unanticipated problem is defined as an event that meets all of the following criteria: 
1) Unexpected in severity, nature, or frequency given the research procedures and the 
characteristics of the subject population (i.e., problems that are not described in this protocol or 
other study documents); AND 
2) Related or possible related to participation in the research; AND 
3) Suggests that research places subjects or others at a greater risk of harm related to the research 
than was previously known or recognized.  
 
b. Reporting period 
Any adverse events or serious adverse events will be reported within the timeframes outlined by UW-
Madison.  
 
c. Severity assessment 
The severity of all adverse events will be assessed according to the following scale: 
• Mild = not requiring treatment 
• Moderate = resolved with treatment 
• Severe = inability to carry on normal activities and required professional medical attention 
 
d. Causality assessment 
The Site PI will determine the relationship of adverse events to the research intervention using the 
following scale: 
• Definite = AE is clearly related to the study procedures 
• Probable = AE is likely related to the study procedures 
• Possible = AE is possibly related to the study procedures 
• Unlikely = AE is doubtfully related to the study procedures 
• Unrelated = AE is clearly not related to the study procedures 
 
e. Procedures for recording and reporting adverse events 
Adverse events will be recorded in the medical record and reported to the IRB.  AEs and UPs will also be 
entered into OnCore for review by the DMC. 
 
f. Other reportable events 
Reporting timeframes begin when the site learns of the occurrence of the event.  
 
Event 
Definition 
Reporting  
Breach of 
confidentiality 
The exposure of any study information or 
communications directly related to a study 
subject to anyone not named as study staff or the 
release of a study subject’s identifiable 
information to study staff who were not specified 
to receive such information in the protocol or IRB 
application.  
Treat as major deviation  

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Event 
Definition 
Reporting  
Protocol 
deviation 
A deviation is an incident involving a departure 
from the IRB-approved protocol in the actual 
conduct of the study. Deviations may result from 
the action of the participant, investigator, or 
staff. 
See below 
Major 
deviations 
Deviations are considered major when the 
unapproved change(s) in previously approved 
research activities, implemented without IRB 
approval, may potentially adversely affect 
subjects’ rights, safety, welfare, or willingness to 
continue participation, or affect the scientific 
design of the study and/or the integrity of the 
resultant data. 
Treat as an Unanticipated 
Problem 
Minor 
deviations  
Deviations are considered minor when the 
unapproved change(s) in previously approved 
research activities, implemented without IRB 
approval, do not adversely affect subjects or the 
integrity of the study data. 
Sites are to report cumulative 
events to AE Coordinator at 
time of continuing review.  
Protocol 
violation 
An incident involving an intentional deviation 
from the IRB-approved protocol that was not 
implemented in response to an emergency 
situation and that may impact a subject’s rights, 
safety, and/or welfare, makes a substantial 
alteration to risks to subjects, or affects the 
scientific design of the study and/or the integrity 
of the resultant data. Violations may also be 
repeated deviations (major or minor) of the same 
nature. Violations can represent serious or 
continuing non-compliance with the federal 
regulations and guidelines for ethical conduct of 
human subject research. 
Treat as an Unanticipated 
Problem 
Protocol 
Exceptions 
A protocol exception is an IRB-approved 
deviation for a single subject or a small group of 
subjects, but is not a permanent revision to the 
research protocol. 
Protocol exceptions must be 
approved by local IRB prior to 
implementation. 
 
g. Reporting by study site to local IRB 
The study site will follow their local IRBs guidance for reporting all events to the local IRB.  
 
 
7. Data Safety Monitoring 
 
We plan to utilize the UW Institute for Clinical and Translational Research (ICTR) Data Monitoring 
Committee (DMC) to oversee the study. The UW ICTR DMC is comprised of experienced members (core 
plus ad hoc) with expertise required to oversee this study. The DMC members will review protocol-
specific reports created by statisticians using data pulled from the ICTR OnCore clinical research 

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management system. These standard reports will include an overview of study objectives, a review of 
actual and projected accrual rates, an evaluation of patient demographics for balance of randomization, 
and a summary of the number and seriousness of adverse events. An interim analysis of study results 
may be performed and source documents may be reviewed to allow the DMC to independently judge 
whether the overall integrity and conduct of the protocol remain acceptable based on data provided 
and reported by the Principal Investigator. The DMC will make recommendations to the Principal 
Investigator that could include actions of continuation, modification, suspension, or termination. 
 
In providing oversight for the conduct of this study, the ICTR DMC will meet biannually. Additional 
meetings may be scheduled as determined by the DMC or as requested by the PI.  
 
 
8. Medical Monitor  
The Medical Monitor may perform oversight functions (e.g., observe recruitment, enrollment 
procedures, and the consent process for individuals, groups or units; oversee study interventions and 
interactions; review monitoring plans and reports; and oversee data matching, data collection, and 
analysis) and report their observations and findings to the sponsor or a designated official. 
 
The Medical Monitor may discuss the research protocol with the investigators, interview human 
subjects, and consult with others outside of the study about the research. The Medical Monitor shall 
have authority to stop a research protocol in progress, remove individual human subjects from a 
research protocol, and take whatever steps are necessary to protect the safety and well-being of human 
subjects. Medical Monitor shall have the responsibility to promptly report their observations and 
findings to the sponsor or other designated official. 
 
Each participating site’s local IRB must approve a written summary of the Monitors’ duties, authorities, 
and responsibilities.  
 
The Medical Monitor shall have expertise consonant with the nature of risk(s) identified within the 
research protocol, and shall be independent of the team conducting the research involving human 
subjects. 
 
The Medical Monitor is required to review reports of serious adverse events (SAEs) and unanticipated 
problems (UPs) and provide an independent evaluation and an unbiased, written report of each event. 
At a minimum, the Medical Monitor shall comment on the outcomes of the event or problem, and in the 
case of an SAE comment on the relationship to participation in the study. The Medical Monitor shall also 
indicate whether he or she concurs with the details of the report provided by the site investigator. The 
Medical Monitor’s evaluation of these events will be provided to each participating site’s local IRB. 
 
If requested, the Medical Monitor shall have access to de-identified source documents. 
 
The Medical Monitor for this trial is Dr. Corey Amlong. 
 
 
9. Administrative requirements 
 
a. Good clinical practice 

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The study will be conducted in accordance with FDA and ICH guidelines for Good Clinical Practice. All 
study staff will be thoroughly familiar with the contents of this protocol and associated trial materials. 
 
b. Data quality assurance 
Our study team will prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each study subject. Study data will be entered 
into an electronic case report form (eCRF) by site personnel.  
 
c. Ethical consideration 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. 
The IRB will review all appropriate study documentation in order to safeguard the rights, safety and 
well-being of the subjects. The study will only be conducted at sites where IRB approval has been 
obtained. The protocol, informed consent form, written information given to the patients, safety 
updates, annual progress reports and any revisions to these documents will be provided to the IRB by 
the investigator.  
 
d. Patient confidentiality 
All subjects will be assigned a study-specific ID number. We will maintain a master list linking each 
subject’s medical record number (MRN) with a study-specific ID number. This list will be maintained in a 
location separate from any study data. Only site staff listed on the IRB application shall have access to 
the list.  
 
 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
e. Investigator compliance 
The investigator will conduct the trial in compliance with the protocol approved by the IRB. Changes to 
the protocol will require written IRB approval prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to subjects.  
 
f. Subject cost and payment 
Cost  
Subjects will not incur any costs associated with their involvement in this study.  
 
Payment 
Subjects will be paid $50 at their baseline visit, $50 for the sleep study, and $200 at each of the sedative 
procedure visits.  
 
 
10. Funding sources 
The funding for this protocol will be provided by the Investigator’s start-up funds.  
 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 40 of 52 
 
11. Publication Policy 
This data from this study may be used for presentation at local, regional, national or international 
meetings or for publication in a peer-reviewed journal. 
 
 
References 
References 
 
1. 
Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness ≠ Unconsciousness 
Anesthesiology. 2012;116:946-959. 
2. 
Noreika V, Jylhankangas L, Moro L, et al. Consciousness lost and found: subjective 
experiences in an unresponsive state. Brain and cognition. 2011;77(3):327-334. 
3. 
Bastos AM, Usrey WM, Adams RA, Mangun GR, Fries P, Friston KJ. Canonical 
microcircuits for predictive coding. Neuron. 2012;76(4):695-711. 
4. 
Raz A, Grady SM, Krause BM, Uhlrich DJ, Manning KA, Banks MI. Preferential effect 
of isoflurane on top-down vs. bottom-up pathways in sensory cortex. Frontiers in systems 
neuroscience. 2014;8:191. 
5. 
Ferrarelli F, Massimini M, Sarasso S, et al. Breakdown in cortical effective connectivity 
during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A. 
2010;107(6):2681-2686. 
6. 
Vidal J, Giard MH, Roux S, Barthelemy C, Bruneau N. Cross-modal processing of 
auditory-visual stimuli in a no-task paradigm: a topographic event-related potential study. 
Clinical neurophysiology : official journal of the International Federation of Clinical 
Neurophysiology. 2008;119(4):763-771. 
7. 
Boly M, Garrido MI, Gosseries O, et al. Preserved feedforward but impaired top-down 
processes in the vegetative state. Science. 2011;332(6031):858-862. 
8. 
Bekinschtein TA, Dehaene S, Rohaut B, Tadel F, Cohen L, Naccache L. Neural signature 
of the conscious processing of auditory regularities. Proc Natl Acad Sci U S A. 
2009;106(5):1672-1677. 
9. 
Zbinden AM, Maggiorini M, Petersen-Felix S, Lauber R, Thomson DA, Minder CE. 
Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen 
anesthesia. I. Motor reactions. Anesthesiology. 1994;80(2):253-260. 
10. 
Struys MM, De Smet T, Depoorter B, et al. Comparison of plasma compartment versus 
two methods for effect compartment--controlled target-controlled infusion for propofol. 
Anesthesiology. 2000;92(2):399-406. 
11. 
Hu C, Horstman DJ, Shafer SL. Variability of target-controlled infusion is less than the 
variability after bolus injection. Anesthesiology. 2005;102(3):639-645. 
12. 
Absalom AR, Glen JI, Zwart GJ, Schnider TW, Struys MM. Target-Controlled Infusion: 
A Mature Technology. Anesth Analg. 2016;122(1):70-78. 
13. 
Schnider TW, Minto CF, Struys MM, Absalom AR. The Safety of Target-Controlled 
Infusions. Anesth Analg. 2016;122(1):79-85. 
14. 
Struys MM, De Smet T, Glen JI, Vereecke HE, Absalom AR, Schnider TW. The History 
of Target-Controlled Infusion. Anesth Analg. 2016;122(1):56-69. 
15. 
Sahinovic MM, Eleveld DJ, Miyabe-Nishiwaki T, Struys M, Absalom AR. 
Pharmacokinetics and pharmacodynamics of propofol: changes in patients with frontal 
brain tumours. Br J Anaesth. 2017;118(6):901-909. 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 41 of 52 
16. 
Sanders RD, Maze M. Alpha2-adrenoceptor agonists. Curr Opin Investig Drugs. 
2007;8(1):25-33. 
17. 
Souter MJ, Rozet I, Ojemann JG, et al. Dexmedetomidine sedation during awake 
craniotomy for seizure resection: effects on electrocorticography. J Neurosurg 
Anesthesiol. 2007;19(1):38-44. 
18. 
Dyck JB, Maze M, Haack C, Azarnoff DL, Vuorilehto L, Shafer SL. Computer-
controlled infusion of intravenous dexmedetomidine hydrochloride in adult human 
volunteers. Anesthesiology. 1993;78(5):821-828. 
19. 
Kurdi MS, Theerth KA, Deva RS. Ketamine: Current applications in anesthesia, pain, 
and critical care. Anesthesia, essays and researches. 2014;8(3):283-290. 
20. 
Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE. Plasma 
levels of ketamine and two of its metabolites in surgical patients using a gas 
chromatographic mass fragmentographic assay. Anesth Analg. 1982;61(2):87-92. 
21. 
Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of 
propofol in children. Br J Anaesth. 1991;67(1):41-48. 
22. 
Molina-Infante J, Arias A, Vara-Brenes D, et al. Propofol administration is safe in adult 
eosinophilic esophagitis patients sensitized to egg, soy, or peanut. Allergy. 
2014;69(3):388-394. 
23. 
Pigorini A, Sarasso S, Proserpio P, et al. Bistability breaks-off deterministic responses to 
intracortical stimulation during non-REM sleep. Neuroimage. 2015;112:105-113. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1: UNCONSCIOUS CRF 
 
UNCONSCIOUS CRF 
Date:  
 
 
 
 
 
 
Age: 
Initials: 
 
 
 
 
 
 
 
Sex: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 42 of 52 
Study ID: 
 
 
 
 
 
 
ASA: 
 
Circle:            Right Handed               Left Handed 
  
(BASELINE)    
 TIME                     EEG TIME 
 
 
                 
COMMENTS: 
 
Start: 
 
________ EEG                 TIME 
 
   EEG TIME       EYES CLOSED? 
Start: 
End: 
________EEG 
 
   TIME                EEG TIME 
      
Start: 
End: 
________EEG  
 
  TIME               EEG TIME      
Start: 
End: 
________EEG  
 
  TIME               EEG TIME      
Start: 
End: 
________EEG  
 
  TIME               EEG TIME      
Start: 
End: 
________EEG  
 
  TIME               EEG TIME      
Start: 
End: 
________EEG  
 
  TIME               EEG TIME      
Start: 
End: 
 
 
 
 
 
 
 
 
 
(PREDICTIVE CODING) 
 
 
 
 
 
 0:00:00 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 43 of 52 
TP:___________ 
 TIME               EEG TIME       
Start: 
End: 
Break time: (                                     ) 
 
TP:___________       TIME               EEG TIME       
Start: 
End: 
Break time: (                                     ) 
 
TP:___________ 
 TIME               EEG TIME       
Start:  
End: 
Break time: (                                       ) 
 
TP:___________ 
TIME               EEG TIME       
Start: 
End: 
Break time: (                                       ) 
 
TP:___________ 
 TIME               EEG TIME       
Start: 
End: 
Break time: (                                       ) 
 
TP:___________ 
TIME               EEG TIME       
Start: 
End: 
Break time: (                                       ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(PREDICTIVE CODING)  
Strategy: 
Observations/Notes: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 44 of 52 
TP:___________ 
TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                   ) 
 
TP:___________ 
 TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                     ) 
 
TP:___________       TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                     ) 
 
TP:___________ 
 TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                       ) 
 
TP:___________ 
TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                       ) 
 
TP:___________ 
 TIME               EEG TIME
 
      
Start: 
End: 
Break time: (                                       ) 
Observations/notes: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 45 of 52 
(SEDATION START) 
 
 
Level of anxiety prior to drug administration:                      
1      2       3      4      5      6      7      8      9      10 
 
TIME  
EEG TIME  
 
 
Start: 
BOLUS 
 
INFUSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observations/notes: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 46 of 52 
 (WAKE REPORT)  
 
 
TIME  
          EEG TIME 
 
 
     
Start: 
DOSE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(RESTING EEG)   TIME 
 
         EEG TIME           
 
 
 
Start:                                            
End: 
 
(ODDBALL)    
 TIME 
          EEG 
TIME 
Start: 
End:                                                   
 
(LGD)  
TIME  
          EEG TIME 
Start: 
End: 
 
WAKE  
# ____  
 
TIME  
         EEG TIME 
Time Approached 
 (voice): 
Time Approached 
 (touch): 
Time nerve stim: 
(Duration of nerve stim_____seconds) 
 
Time Response: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observations/notes: 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 47 of 52 
WAKE  
# ____  
OAA/S SCORE:  
 
 
What was the last thing going through your mind before I spoke to you? + Were you having a 
dream or were you awake? – Do you think you were unconscious? 
 
 
 
 
 
 
Are you sure? Anything else to report? Any faces? Moving? 
 
 
 
 
 
 
Did time pass since the last time we spoke? +How much time has passed since we last spoke? 
 
 
 
Did you hear the tones/words? Were you aware of the external world? 
 
 
 
Were you asleep or awake? Yes/no +Visual Analogue Score 0-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 48 of 52 
(END SEDATION) 
 
 
 
TIME  
EEG TIME  
 
                       
End: 
 
Did you feel confused as you woke up? 
 
 
 
 
(WORD RETRIEVAL PRESENTATION)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 49 of 52 
(Wait 10s after nerve stim) Go to Command Sequence: _____ 
Number of times repeated first command until response: ______ 
COMMAND List A.: 
 “[NAME],  BIRDS fly NORTH.” 
Followed by “[NAME],  
squeeze my hand.”  
Followed by “ 
 
TABLE” 
Followed by “[NAME],  
if you are in pain squeeze my hand two times.” 
Followed by “ 
 
HAT” 
Followed by “[NAME],  
if you are ok squeeze my hand two times.” 
Followed by “ 
 
PENCIL”     
Followed by “[NAME],  
show me two fingers” 
Followed by “ 
 
LAMP”  
Followed by “[NAME],  
if FISH swim in the SEA, squeeze my hand” 
Followed by “ 
 
STOVE”  
Followed by “[NAME],  
if STONES float on WATER, squeeze my hand.” 
Followed by “ 
 
BASKET”  
Followed by “[NAME],  
squeeze my hand.”   
Followed by “ 
 
INDUSTRY” 
Followed by “ 
 
OFFICE” 
Followed by “ 
 
EGG” 
Followed by “ 
 
JOURNAL” 
Followed by “[NAME],  
squeeze my hand.”   
If the patient keeps responding, please repeat the sequence of commands and inform 
the care provider.   
COMMAND List B: 
“[NAME],  squeeze my hand.”  
Followed by “[NAME],  
BIRDS fly NORTH.” 
Followed by “ 
 
TABLE” 
Followed by “[NAME],  
if you are in pain squeeze my hand two times.” 
Followed by “ 
 
HAT” 
Followed by “[NAME],  
if you are ok squeeze my hand two times.” 
Followed by “ 
 
PENCIL”     
Followed by “[NAME],  
show me two fingers” 
Followed by “ 
 
LAMP”  
Followed by “[NAME],  
if FISH swim in the SEA, squeeze my hand” 
Followed by “ 
 
STOVE”  
Followed by “[NAME],  
if STONES float on WATER, squeeze my hand.” 
Followed by “ 
 
BASKET”  
Followed by “[NAME],  
squeeze my hand.”   
Followed by “ 
 
INDUSTRY” 
Followed by “ 
 
OFFICE” 
Followed by “ 
 
EGG” 
Followed by “ 
 
JOURNAL” 
Followed by “[NAME],  
squeeze my hand.”   
 
COMMAND List C: 
Followed by “[NAME],  
BEARS walk SOUTH.” 
Followed by “[NAME],  
squeeze my hand.”  

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 50 of 52 
Followed by “ 
 
STREET” 
Followed by “[NAME],  
if you are in pain squeeze my hand two times.” 
Followed by “ 
 
TRUCK” 
Followed by “[NAME],  
if you are ok squeeze my hand two times.” 
Followed by “ 
 
BUTTER”     
Followed by “[NAME],  
show me two fingers” 
Followed by “ 
 
BOWL”  
Followed by “[NAME],  
if SHEEP have WOOL, squeeze my hand” 
Followed by “ 
 
CLOCK”  
Followed by “[NAME],  
if TREES are made of GLASS, squeeze my hand.” 
Followed by “ 
 
VIOLIN”  
Followed by “[NAME],  
squeeze my hand.”   
Followed by “ 
 
MATERIAL” 
Followed by “ 
 
HISTORY” 
Followed by “ 
 
FORK” 
Followed by “ 
 
ENGINE” 
Followed by “[NAME], 
squeeze my hand.” 
If the patient keeps responding, please repeat the sequence of commands and inform 
the care provider.   
 
COMMAND List D: 
Followed by “[NAME],  
squeeze my hand.”  
Followed by “[NAME],  
BEARS walk SOUTH.” 
Followed by “ 
 
STREET” 
Followed by “[NAME],  
if you are in pain squeeze my hand two times.” 
Followed by “ 
 
TRUCK” 
Followed by “[NAME],  
if you are ok squeeze my hand two times.” 
Followed by “ 
 
BUTTER”     
Followed by “[NAME],  
show me two fingers” 
Followed by “ 
 
BOWL”  
Followed by “[NAME],  
if SHEEP have WOOL, squeeze my hand” 
Followed by “ 
 
CLOCK”  
Followed by “[NAME],  
if TREES are made of GLASS, squeeze my hand.” 
Followed by “ 
 
VIOLIN”  
Followed by “[NAME],  
squeeze my hand.”   
Followed by “ 
 
MATERIAL” 
Followed by “ 
 
HISTORY” 
Followed by “ 
 
FORK” 
Followed by “ 
 
ENGINE” 
Followed by “[NAME], 
squeeze my hand.” 
 
 
 
 
 
 

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 51 of 52 
(WORD RETRIEVAL TASK)  
 
“Now, we are going to do an exercise where I read you two words. I want you to pay attention to 
whether one of these words seems to be more familiar to you than the other. If you do have a sense 
that one seems more familiar to you, tell me that word. If neither word seems more familiar, then 
please choose one of the words randomly.” 
 
 
 
 
 
 
 
Time Start:________  
EEG 
time:________                       
RETRIEVAL LIST A/B 
(1) 
VIOLIN 
 
BASKET 
(2) 
EGG  
FORK 
(3) 
TRUCK 
 
HAT 
(4) 
SOUTH 
 
NORTH 
(5) 
HISTORY 
OFFICE 
 
(6) 
WATER 
 
GLASS 
(7) 
TABLE 
 
STREET 
(8) 
PENCIL 
 
BUTTER 
(9) 
ENGINE 
 
JOURNAL 
(10) 
BOWL 
LAMP 
(11) 
FISH  
SHEEP 
(12) 
STOVE 
 
CLOCK 
(13) 
BIRDS 
 
BEARS 
(15) 
INDUSTRY MATERIAL 
(14) 
WOOL 
SEA 
(16) 
TREES 
 
STONES 
 
 
RETRIEVAL LIST C/D 
(1) 
BASKET 
 
VIOLIN 
 
(2) 
FORK  
EGG 
(3) 
HAT  
TRUCK 
(4) 
NORTH 
 
SOUTH 
(5) 
OFFICE 
 
HISTORY 
 
(6) 
GLASS 
 
WATER 
(7) 
STREET 
 
TABLE 
(8) 
BUTTER 
 
PENCIL 
(9) 
JOURNAL 
ENGINE 
(10) 
LAMP  
BOWL 
(11) 
SHEEP 
 
FISH 
(12) 
CLOCK 
 
STOVE 
(13) 
BEARS 
 
BIRDS 
(15) 
MATERIAL INDUSTRY 
(14) 
SEA 
 
WOOL 
(16) 
STONES 
 
TREES 
 
Number of words identified correctly: ______ 
Did these words seem familiar to you?  

UnConsCIOUS Study| Protocol (version date: 1/11/2023) 
page 52 of 52 
(CAM ICU)                    
        Time: 
 
 
 
 
COMMENTS: 
Feature 1: Acute Onset or Fluctuating Course 
Feature 2: Inattention 
SAVEAHAART 
Feature 3: Altered Level of Consciousness 
RAAS ≠ 0  
Feature 4: Disorganized Thinking 
Will a stone float on water? 
Are there fish in the sea? 
Does one pound weigh more than two pounds? 
Can you use a hammer to pound a nail? 
 
CAM-ICU POSITIVE: 
           CAM-ICU NEGATIVE: 
 
 
 
CAM ICU                   
 
        Time: 
 
 
 
 
COMMENTS: 
Feature 1: Acute Onset or Fluctuating Course 
Feature 2: Inattention 
SAVEAHAART 
Feature 3: Altered Level of Consciousness 
RAAS ≠ 0  
Feature 4: Disorganized Thinking 
Will a stone float on water? 
Are there fish in the sea? 
Does one pound weigh more than two pounds? 
Can you use a hammer to pound a nail? 
 
CAM-ICU POSITIVE: 
           CAM-ICU NEGATIVE: