Clinical trial NCT02761330
Conditions: Depression Delirium Seizures Cognitive Disorders
Keywords: Anesthesia Electroconvulsive therapy Delirium Electroencephalography Seizures Depression Ketamine Etomidate Physiological Effects of Drugs Pharmacologic Actions Confusion Mental Disorders Neurobehavioral Manifestations Signs and Symptoms Neurologic Manifestations Cognitive Disorders
Sponsor: Washington University School of Medicine
Start date: 2016-04-01; Completion date: 2019-09-11
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is geared toward characterizing the recovery of brain activity and cognitive function following treatments of electroconvulsive therapy and ketamine general anesthesia.

Detailed description:
Seizures are often associated with loss of consciousness, possibly through effects on sub-cortical arousal systems, disruption of cortical-subcortical interactions, and ultimately through depressed neocortical function. Furthermore, people are often confused in the post-ictal state even when consciousness returns after a seizure. Disrupted cognitive function during the postictal phase has not been fully characterized but presents short and long-term implications. Many experience an acute disorder of attention, consciousness, and cognition, referred to as delirium. Memory deficits are also common. The neurobiology for these phenomena are incomplete and challenging to test, as seizures are typically sporadic and vary in intensity and character. In contrast, the setting of electroconvulsive therapy (ECT) provides the opportunity to study the reconstitution of consciousness and cognition following seizures in an elective and predictable context.

There is no standard agent used to induce general anesthesia during ECT. Ketamine is receiving greater attention as an infusion for treating depression and for its potential benefits on improving ECT efficacy and expediting cognitive recovery. Further data are needed to determine whether ketamine may improve recovery of cognitive function relative to etomidate, a commonly used anesthetic for general anesthesia during ECT.

The investigators will evaluate the cognition function and electroencephalographic patterns that accompany the recovery from ECT and general anesthesia. Twenty patients with refractory depression will be randomized in this interventional single-blinded randomized crossover trial. Each patient will complete seven study visits. The first visit will be conducted during the dose-charge titration ECT treatment with etomidate anesthesia. After this session, patients will be randomized to three sessions each week for two weeks (six treatments total). Over the first week patients will be randomized in order for three treatment arms: (1) etomidate general anesthesia and ECT, (2) ketamine general anesthesia and ECT, and (3) ketamine alone. Patients will be blinded to the treatment arm for each session. Baseline and post-treatment measurements of cognition and ECT will be acquired on each of the six treatment sessions.

Patients that agree will have a MRI.

Arms: arm 1: General anesthesia for ECT will be induced with etomidate, approximately 0.2 mg/kg (0.1-0.6 mg/kg). Following application of stimulation electrodes to the patients scalp, an ECT charge will be administered at the previously determined therapeutic dose. arm 2: General anesthesia for ECT will be induced with ketamine, approximately 2 mg/kg (1-2.5 mg/kg). Following application of stimulation electrodes to the patients scalp, an ECT charge will be administered at the previously determined therapeutic dose. arm 3: General anesthesia for ECT will be induced with ketamine, approximately 2 mg/kg (1-2.5 mg/kg). Following application of stimulation electrodes to the patients scalp, no ECT charge will be administered.
Interventions: intervention 1: Ketamine intervention 2: Electroconvulsive Therapy
Intervention descriptions: intervention 1: Ketamine will be used to induce general anesthesia with or without subsequent ECT. Within a single patient, the dose will remain consistent throughout the study and is estimated to be 2 mg/kg. intervention 2: Dose of the ECT charge will be determined during titration session prior to randomization.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
1
RESEARCH PROTOCOL 
 
 
 
Cognitive Recovery After Electroconvulsive Therapy and General Anesthesia 
 
Palanca BJA*, Maybrier HR, Mickle AM, Farber NB, Hogan RE, Trammel ER, Spencer JW, Bohnenkamp DD, 
Wildes TS, Ching S, Lenze EJ, Basner M, Kelz MB, Avidan MS,  
RCC2 Research Collaborative at Washington University School of Medicine 
 
This study has been scientifically reviewed and has been awarded funding for three years by the James S. 
McDonnell Foundation  
 
Washington University School of Medicine 
Department of Anesthesiology 
660 S. Euclid Ave., Campus Box 8054 
St. Louis, MO. 63110 
Voice: (314) 362-1196 
Fax: (314) 747-3977 
E-mail: palancab@wustl.edu  
            avidanm@anest.wustl.edu 
 
 
 
 
 
 
 
Version Date: 2.25.19 


 
 
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1.  STUDY SYNOPSIS 
 
Study Title 
 
 
Cognitive Recovery After Electroconvulsive Therapy and General Anesthesia 
 
 
 
 
Objectives 
 
1. Characterize the order and consistency in which cognitive function recovers following 
treatments of electroconvulsive therapy (ECT) and ketamine general anesthesia 
 
2. Characterize the electroencephalography (EEG) changes during recovery from ECT 
and ketamine anesthesia 
  
 
 
Study Period 
 
Planned enrollment duration: 3 years 
Planned study duration: 3 weeks  
 
 
Study Design 
 
 
Single academic center, prospective, longitudinal, observational 
Randomized, crossover, repeated measures 
Number of 
Patients 
Target enrollment:  15-20 patients  
 
 
Inclusion and 
Exclusion 
Criteria 
Inclusion Criteria:   
Treatment resistant unipolar or bipolar depression requiring outpatient ECT, planned right 
unilateral ECT stimulation, English speaking, 18 years of age and older, able to provide 
written informed consent. 
 
Exclusion Criteria:  
Known brain lesion or neurological illness that causes cognitive impairment, 


 
 
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schizophrenia, schizoaffective disorder, blindness or deafness or motor impediments that 
may impair performance for cognitive testing battery, inadequate ECT seizure duration 
with etomidate 
 
 
 
 
Measurements 
(1) Cognitive function (COGNITION battery) 
(2) Multichannel EEG 
(3) 3D-CAM (3D-Confusion Assessment Method) 
(4) Mood Self-Assessment Manikin (SAM) 
(5) PROMIS-CAT (Computer Adaptive Testing) for depression 
(6) Scale of Suicidal Ideation 
(7) ECT Seizure duration 
(8) ECT electrical dose 
(9) Subjective assessment of whether ECT was performed 
(10) Quick Inventory of Depressive Symptomatology, Self-Report (16-Item), QIDS-SR1 
(11) Structural MRI 
 
 
 
 
Outcomes 
 
(1) Cognitive recovery  
(2) Delta, theta, alpha, and beta EEG band power, functional connectivity, entropy, and 
phase lag measurements measures 
(3) Delirium 
(4) Mood 
(5) Depression 
(6) Suicidal ideation 
(7) Assessment of blinding quality 
(8) Satisfaction with ECT following involvement in study. 
 
 
 


 
 
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2.  STUDY PROTOCOL  
2.1 Background, Significance, and Preliminary Data 
2.1.1 Seizures – Unique States for Probing the Return Consciousness and Cognition 
The return of consciousness following reversible states of unresponsiveness is relevant to 
neuroscience and clinical practice. Neural mechanisms underlying these processes appear to be distinct from 
those perturbed during loss of consciousness, with implications for anesthetic practice(Kelz, Sun et al. 2008) 
and 
sleep/wake 
disorders(Trotti 
2016). 
While 
states 
incurred 
by 
general 
anesthesia(Boveroux, 
Vanhaudenhuyse et al. 2010, Palanca 2015, Ranft, Golkowski et al. 2016) and sleep(Massimini, Ferrarelli et al. 
2007, Landsness, Crupi et al. 2009) have suggested neural substrates necessary for sustaining 
consciousness(Koch, Massimini et al. 2016), the recovery from these depressed states of neural activity 
remains poorly characterized. Comparatively less is known regarding the recovery from states of highly 
synchronized neural activity incurred through generalized seizures(Yu and Blumenfeld 2009, Englot, Yang et 
al. 2010). Characterizing the recovery of neural activity and cognitive function following these states may 
provide a system to complement states of brain suppression given that: 1) action potential synchronization is a 
fundamental mode of information processing in the cerebral cortex distinct from the decrements in neuronal 
firing rates and 2) seizures arise from changes in the excitatory and inhibitory synaptic balance in different 
brain regions. 
The relationships of underlying electroencephalographic (EEG) activity and the recovery from 
generalized seizures remain unclear is currently limited and challenging to investigate(So and Blume 2010). 
Generalized seizures are characterized by the loss of consciousness coincident with ictal EEG spike-and-wave 
complexes, polyspike-and-wave complexes, and spikes(Hrachovy and Frost 2006). External phenotypes, 
ranging from convulsions to immobile staring, likely depend on the precise disruption in sub-cortical arousal 
systems, cortical-subcortical interactions, or neocortical connectivity(Yu and Blumenfeld 2009, Englot, Yang et 
al. 2010, Blumenfeld 2012). Inter-individual heterogeneity among clinical seizures may arise from diverse 
structural or metabolic derangements. Moreover, seizures are typically sporadic, unpredictable in occurrence, 
and may vary in intensity and character, making them difficult to study systematically. Following the 
disappearance of epileptiform EEG signatures, the postictal period begins and culminates in a return of 


 
 
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consciousness and cognitive function. There is little standardization of postictal clinical and behavior testing to 
facilitate objective comparison to EEG changes during the postictal period. Critical barriers to generating 
inferences from reproducible seizures may be addressed in the context of electroconvulsive therapy 
(ECT)(Fink 1979), where seizures are electrically induced under safe controlled conditions. 
 
2.1.2 EEG Activity and Cognitive Dysfunction Following ECT 
The potential of EEG to inform clinicians on the future efficacy and side effects of ECT has not been 
fully realized. EEG is commonly monitored during ECT, a proven treatment for depression, bipolar illness, and 
psychosis(Lisanby 2007). Following the delivery of the ECT stimulus charge, epileptiform activity in the bilateral 
fronto-mastoid EEG can complement the assessment of peripheral tonic-clonic muscle activity(Fink and 
Johnson 1982). Clinically relevant EEG measures beyond the length of seizure duration(Mayur 2006) have 
unclear clinical utility(Dinwiddie, Glick et al. 2012). Optimally, EEG markers would be available for predicting 
and refining ECT administration to balance efficacy and side effects that accrue over the course of therapy. 
Such advances in the field have not occurred since prior work establishing a relationship between cognitive 
performance and ECT stimulation parameters(Weiner, Rogers et al. 1986, Abrams 2002). This void may be 
due to the paucity of studies that have characterized EEG across widely distributed brain regions using either 
10-20 montages(Brumback and Staton 1982, Luber, Nobler et al. 2000, Nobler, Luber et al. 2000, Zoldi, 
Krystal et al. 2000) or high-density EEG. The spatial resolution offered by high-density EEG is likely needed to 
associate cognitive an affective perturbations to specific EEG patterns. High-density scalp EEG has shown 
superiority over standard 10-20 montage recordings in guiding surgical treatment for epileptic seizures 
(Brodbeck, Spinelli et al. 2011). Extension of this paradigm to the ECT setting may yield clinically relevant EEG 
markers for tailoring treatment at an individual patient level. 
During the ictal period, seeming stereotyped evolution EEG patterns develop and resolve(Weiner 
1982), with proposed phases of activity(Brumback and Staton 1982). Brief periods of EEG suppression or 
rhythmic bilateral 14-22 Hz oscillations may first emerge(Brumback and Staton 1982). Induction of bilateral 
poly-spike activity occurs, often with greater power on the side of the stimulation electrode in unilateral 
ECT(Brumback and Staton 1982, Gerst, Enderie et al. 1982). Spike/spike-and-wave complexes then occur, 
followed by termination within three minutes(Brumback and Staton 1982, Weiner 1982). This ictal activity may 


 
 
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be followed by postictal generalized EEG suppression, a marker associated with ECT therapeutic 
efficacy(Krystal and Weiner 1999, Mayur 2006, Azuma, Fujita et al. 2007) and with potential implications for 
understanding sudden unexpected death in epilepsy(Ryvlin, Nashef et al. 2013, Bauer, Thijs et al. 2017). Delta 
waves (<4 Hz)(Weiner 1982) emerge that are gradually replaced by theta (4-8 Hz), alpha (8-13 Hz), and beta 
(13-30 Hz) rhythms(Weiner 1982). The dynamics of these EEG changes may aid in our understanding of 
seizures in general and help to reveal the efficacy/side effects of ECT in the postictal period following future 
large-scale investigations. 
The continued resolution of postictal EEG changes may also correlate with the cognitive impairments 
incurred immediately after individual sessions and progress over the course of ECT treatments. Perturbations 
in processed EEG measures persist even when individuals appear to be awake in the postictal period 
(Thimmaiah, Thirthalli et al. 2012, Soehle, Kayser et al. 2014). Patients with greater suppression in processed 
EEG measures following ECT are more likely to experience prolonged memory impairment(Koitabashi, Oyaizu 
et al. 2009). Specific EEG markers that can be linked to both underlying neurobiology and cognitive function 
have not been developed for the acute period after ECT. Beyond individual sessions, persistent slow theta and 
delta oscillations have been observed in the EEG(Volavka, Feldstein et al. 1972) and may resolve only weeks 
following the last session(Kolbeinsson and Petursson 1988, Sackeim, Luber et al. 1996). These markers that 
remain weeks after ECT sessions may be linked to either therapeutic efficacy(Sackeim, Luber et al. 1996) or 
the extent of disorientation and retrograde amnesia(Sackeim, Luber et al. 2000). Definitive relationships remain 
speculative.  
 
The return of cognitive function following individual ECT sessions has not been fully characterized. 
Recent analyses have shed light on the incidence and persistence of cognitive side effects related to this 
procedure(Semkovska and McLoughlin 2010). Presumably, perturbations in attention, memory, and cognition 
during the postictal period have bearing on short- and long-term deficits in functionality as patients become 
rehabilitated into the community. Approximately 5-12% of patients experience postictal agitation and 
disorientation after ECT(Kranaster, Janke et al. 2012, Tzabazis, Schmitt et al. 2013) that may last 1-2 hours 
after ECT. Postictal agitation does not occur reproducibly in the same patients following subsequent 
treatments(Fink 1993). Disorientation during the early postictal recovery from ECT appears to decrease with 
number of sessions(Calev, Cohen et al. 1991). Interictal confusion accumulates prior to successive ECT 


 
 
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sessions(Calev, Cohen et al. 1991). Cognitive side effects may persist for 90 minutes following seizure 
termination(Perera, Luber et al. 2004). Cumulative treatments of ECT may be associated with 
anterograde(Sobin, Sackeim et al. 1995) and retrograde amnesia(Nobler and Sackeim 2008), primarily 
following the entire course of an ECT regimen (Semkovska and McLoughlin 2010). The extent to which these 
forms of cognitive dysfunction contribute to missed work and caregiver burden are not known. Given that each 
session of ECT requires the administration of general anesthesia during seizure induction, systematic study 
requires accounting for these potent neuromodulatory agents. 
 
2.1.3 Control for Anesthetic Exposure 
Elucidating cognitive recovery following seizures in the context of ECT requires a control to account for the 
effects of general anesthesia. This is because modern ECT is conducted under general anesthesia and 
pharmacologic neuromuscular paralysis. Anesthetics with mechanisms invoking γ-aminobutyric acid (GABA) 
A-type receptor agonism (e.g. etomidate) or NMDA-receptor antagonism (ketamine) are commonly used. 
Ketamine has received greater attention recently since subanesthetic doses of ketamine have shown efficacy 
in treating refractory depression(Mathew, Shah et al. 2012, Mathews and Zarate 2013, Murrough, Iosifescu et 
al. 2013, Murrough, Perez et al. 2013). Relative to other anesthetics in use for ECT, ketamine may provide 
faster recovery from cognitive impairment on the day of treatment(McDaniel, Sahota et al. 2006, MacPherson 
and Loo 2008) or additive benefits on ECT efficacy(MacPherson and Loo 2008). Thus, ketamine may be useful 
in a sham ECT condition to control for anesthetic  
 
2.2 Hypotheses and Aims 
We hypothesize that the reconstitution of cognitive function will markedly vary in rate and order, depending on 
the presence of seizures induced by electrical brain stimulation. Our specific aims include: (1) assess whether 
the time to return of responsiveness will be prolonged with ketamine + ECT compared with ketamine + sham 
ECT; (2) ascertain whether the time of restoration to baseline function in each cognitive domain will take longer 
after ketamine + ECT than after ketamine + sham ECT; (3) determine if postictal delirium is associated with 
delayed restoration of baseline function in all cognitive domains; and (4) determine whether the sequence of 


 
 
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reconstitution of cognitive domains is similar to that occurring after an isoflurane general anesthetic; we also 
anticipate these cognitive disturbances 
 
2.3 Design and Participants: 
2.3.1 Study Design 
 We propose over three years to randomize fifteen to twenty patients with refractory depression to one of three 
treatments in two consecutive weeks of an ECT treatment cycle. Each patient will complete seven study visits. 
The first visit will be conducted during the dose-charge titration ECT treatment. Following the titration visit, 
there will be six separate experimental treatments per patient in two blocks of three, with a random sequence 
in each block (Figure 1). During these six visits, patients will be randomized to receive one of three treatments, 
all of which are likely to have efficacy in treating refractory depression: 1) ketamine alone, 2) ketamine plus 
ECT, or 3) standard of care anesthetic plus ECT.   
 
Figure 1: Block randomized, repeated measures, crossover experimental design for reconstitution of 
consciousness and cognition following electroconvulsive therapy (ECT) and general anesthesia. K, ketamine; 
E, etomidate, Rx, treatment.     
 
 


 
 
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2.3.2 Pre-Study Period: None 
 
2.3.3 Subject Screening, Enrollment, and Consent Process:  
Screening and informed consent will occur at Barnes-Jewish Hospital, following ECT referral by staff 
psychiatrists.  
 
2.3.4 Inclusion/Exclusion Criteria 
Inclusion criteria: Referral for ECT via right unilateral stimulation for treatment-resistant non-psychotic 
unipolar or bipolar depression, English-speaking, at least 18 years old, able to provide written informed 
consent.  
 
Exclusion criteria: Known brain lesion or neurological illness that causes cognitive impairment, 
schizophrenia, schizoaffective disorder, blindness or deafness that may impair performance for cognitive 
testing battery, inadequate seizure duration with etomidate, defined at our institution as bilateral spike-and-
wave complexes present for less than 10 seconds. 
 
2.3.5 Study Involvement 
The randomized, crossover design of the study is powerful, as it will allow several within-patient comparisons, 
which will provide optimal efficiency to address the hypotheses. Specifically, the design will allow us to 
distinguish between the effect of ketamine anesthesia alone versus the combined effect of ketamine plus ECT. 
Recovery of consciousness after etomidate is generally rapid. Therefore, the etomidate plus ECT arm should 
yield additional insights into the contribution of seizures in the form of ECT to impaired consciousness and 
cognition and provides an additional comparator condition to the ketamine + ECT arm. Intra-patient repetition 
of each of the three exposures over two weeks will help to establish the reproducible effect of each exposure 
on the outcomes of interest.  
 
2.3.6 Randomization and Blinding 


 
 
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A trained team member will use a computer-generated randomization algorithm among 18 potential 
combinations of initial cognitive task and order of study interventions. Random assignments will account for 
investigator-physician availability for ketamine + sham ECT sessions. The patient will be blind to the order of 
treatment condition. Study and clinician teams will be aware of the treatment arm at each session and maintain 
blinding by maintaining consistency of routine checks and monitoring before and after anesthetic induction. 
Thus, for all treatments sessions, patients will not be able to view the syringe during anesthetic induction. 
Furthermore, stimulation electrode and conducting gel will be placed on the scalp following loss and prior to 
return of consciousness. Post-anesthetic evaluation by anesthesiology, psychiatry, and nursing staff will be 
consistent across sessions. 
To maximize study rigor and reproducibility, investigators evaluating study measurements for data 
quality and development of analytical tools will be blinded to details of the treatment intervention, whenever 
possible(Nuzzo 2015).  
 
2.3.7 Interventions 
 
 
Each patient will be included for seven sessions. As with all non-study patients, the first sessions 
consists of a dose-charge titration that is used to determine the current required to induce the seizure. At 
Barnes-Jewish Hospital, etomidate is commonly used to induce general anesthesia for this session. During 
four of the next six sessions, the patients will receive care that is currently within the standard of care for 
refractory depression, namely general anesthesia (standard of care or ketamine) plus ECT. In addition, during 
two sessions, patients will receive only general anesthesia with ketamine, which has now been shown to have 
efficacy in treating refractory depression. Apart from these treatments, patients will be monitored with full 
montage electroencephalography and will complete tests of cognition, mood and depression before and for 
approximately two hours following the general anesthesia (with or without ECT).  
 
2.3.8 Observations and Measurements 
Dose-Charge Titration Visit (Visit 1) 
During the titration visit, the study team will assess baseline cognitive function and EEG prior to ECT, 
tolerability of cognitive testing and EEG recording. Patients will have baseline assessments, including a 


 
 
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cognitive battery (COGNITION), continuous electroencephalography, 5 minutes of resting state EEG with eyes 
open and 5 minutes for eyes closed, depression testing (PROMIS-CAT) and mood assessment (Self-
Assessment Manikin), suicidal ideation (Scale of Suicidal Ideation)(Beck, Kovacs et al. 1979), and the 3D 
Confusion Assessment Method (3D-CAM) before the ECT therapy session .ECT charge will be delivered via a 
Thymatron System IV (Somatics, LLC, Venice, FL, USA). Per ECT laboratory procedures, stimulation 
parameters include current 0.9 amperes, pulse width of 0.3 milliseconds, with escalating dosage: (5% total 
charge: 24.9 millicoulombs, 10 Hz stimulation, 4.6 second duration; 10% total charge: 50.8 millicoulombs, 20 
Hz stimulation, 4.65 second duration, 15% total charge: 75.6 millicoulombs, 20 Hz stimulation, 6.98 second 
duration). Subsequent planned ECT treatment is based on six-fold increase in charge delivery. Thus, 
individuals without suitable seizure duration at projected 100% charge will be withdrawn from the study.  
 
Experimental Treatment Visits (Visit 2-7) 
 Baseline assessments will be performed at each session immediately prior to ECT and will include a cognitive 
battery (COGNITION), electroencephalography, depression testing (PROMIS-CAT) and mood assessment 
(Self-Assessment Manikin), suicidal ideation (Scale of Suicidal Ideation)(Beck, Kovacs et al. 1979), and the 3D 
Confusion Assessment Method (3D-CAM). Details regarding these assessments are provided as an appendix 
at the end of the protocol.  
 
During four of these six sessions, the patients will receive care that is currently within standard practice for 
ECT: general anesthesia (standard of care or ketamine), muscle paralysis (succinylcholine), and electrical 
stimulation. For the remaining two sessions, patients will undergo a ketamine general anesthetic without 
muscle paralysis or ECT stimulation.  
 
High-density EEG, bilateral fronto-mastoid clinical EEG, and full American Society of Anesthesiologists (ASA) 
monitoring will commence prior to the induction of general anesthesia. Prior to induction, audible squeeze toys 
will be placed in each hand of the patient, who will be instructed to follow serial commands to either “Squeeze 
your left hand twice” or “Squeeze your right hand twice.” Every 30 seconds, one of these commands will be 
played at random, to monitor loss and return of consciousness. Patients will be pre-oxygenated by mask and 


 
 
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anesthesia will be induced with ketamine, approximately 2 mg/kg, or standard of care. Following bolus of the 
induction agent, loss of responsiveness and eyelash reflex will be confirmed. Loss of consciousness will be 
recorded as the first time when a subject fails to correctly respond to the command. Care adherent to the ASA 
guidelines will be performed regardless of treatment session. For sessions with ECT, pre-stimulation 
hyperventilation and assisted ventilation will also be performed. Central seizure duration will be assessed from 
bilateral fronto-mastoid EEG by the psychiatry team. Peripheral seizure duration will be determined through 
monitoring of tonic-clonic activity(Fink and Johnson 1982). During the sessions that subjects receive ECT, 
other drugs will also be administered according to current practice and as clinically indicated. The return of eye 
opening will be assessed every 30 seconds and defined for the initial time at which the patient opens his eyes 
to verbal command. The ability to extend the thumb to verbal command (“thumbs up”) will be assayed every 30 
seconds. Return of responsiveness to auditory command will be defined as the first time at which the patient 
has squeeze his correct hand the number of times instructed via auditory commands. At this time, defined as t 
= 0 minutes, the subject will begin a series of cognitive and behavioral assessments, which are repeated every 
30 minutes up to two hours after return of responsiveness. Patients will be permitted to take brief breaks to use 
the restroom and eat or drink, as necessary. At the conclusion of each treatment session, depression testing 
(PROMIS-CAT) and mood assessment (Self-Assessment Manikin) will be performed to assess for early 
improvements in mood. To assess blinding quality, the patient will be asked their impression of whether they 
received ECT that day. They will be discharged according to standard post-anesthesia care unit discharge 
criteria upon completing the last neurocognitive test battery. A study site coordinator will contact each subject 
within 24 hours of the study day to assess and document any adverse events. 
EEG and Video Acquisition  
 
EEG will be collected during the dose-charge titration session and during all treatment sessions to 
assess pre-ECT and pre-anesthetic baseline EEG recordings. An appropriately fitted 64-channel EEG 
Geodesics Sensor Net (Electrical Geodesics, Inc. Eugene, OR, USA) will be affixed to the scalp. Elefix 
electrode paste (Nihon Kohden America, Inc., Irvine, CA, USA) will be injected to maintain conductivity to the 
silver/silver-chloride electrodes. Electrode impedances on each channel will be optimized to be less than 100 
kOhms/channel, per manufacturer’s suggestions. Data (DC to 2000 Hz bandwidth 500 Hz sampling rate) will 
be acquired with a Net Amps 400 amplifier and Net Station version 5.0 and above (Electrical Geodesics, Inc. 


 
 
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Eugene, OR, USA) via a Late 2012 Mac Pro Workstation (Apple Cupertino, CA, USA). Whenever possible, 
video synchronized to EEG will be acquired using an Axis P3364LV network camera (Axis Communications, 
Lund, Sweden). 
 
2.4.7.1 Outcomes (Further details on instruments are provided in appendices) 
Primary and Secondary Outcomes  
Primary outcomes include: the temporal recovery profiles for cognitive task performance, as measured 
using the Cognition assessment battery (Basner, Savitt et al. 2015); times for the return of responsiveness to 
auditory command; and the presence of delirium, evaluated through the 3-Minute Diagnostic Assessment for 
CAM-defined delirium (3D-CAM)(Marcantonio, Ngo et al. 2014). 
Secondary outcome measures based on the EEG will include definitions of the seizures by standard 
techniques using both expert reader interpretation and quantitative techniques (Haider, Esteller et al. 2016). 
Central seizure duration will be visually determined by clinician evaluation of the frontal-mastoid bipolar EEG 
ictal complexes. Additional measures will be calculated from windowed analyses of the high-density EEG: 
power spectral measures of the interval between anesthetic induction to delivery of ECT stimulus charge; the 
seizure envelope for 1-12 Hz EEG power; peak-to-peak amplitude, calculated from the difference in maximum 
and minimum voltages within 300 millisecond time; periodicity of epileptiform discharges; inter-hemispheric 
symmetry of seizure discharges; intra- and inter-hemispheric coherence. When possible, these measures and 
power spectral estimates will be derived different phase of the ictal waveforms(Gerst, Enderie et al. 1982). The 
following postictal EEG measures will be assessed: duration of postictal EEG suppression; power spectral 
parameters flanking the return of responsiveness to verbal command; power spectral parameters from eyes 
open and closed epochs, including assessments of the posterior dominant rhythm. Spatiotemporal analyses 
will also focus on the propagation of EEG signatures during the ictal and early postictal period. 
 2.4.7.2 Data Collection 
 
Outcomes, such as delirium assessments, will be entered into the Washington University School of Medicine 
Research Electronic Data Capture (REDCap) application. The baseline medications will be collected from the 
electronic medical record. The anesthetic and recovery record will be retrieved from the hospital’s perioperative 
electronic medical record (Metavision by iMDsoft®, Needham, MA). The cognitive assessments will be 


 
 
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completed using the COGNITION cognitive battery designed at the University of Pennsylvania(Basner, Savitt 
et al. 2015). The computer-based depression questionnaire will be completed through assessmentcenter.net 
developed by Northwestern University’s Department of Medical Social Sciences. As standard care for tracking 
depression symptoms during an ECT course, treating psychiatry teams will administer the Quick Inventory of 
Depressive Symptomatology, Self-Report (16-Item), QIDS-SR16(Rush, Trivedi et al. 2003). To fully assess 
each patient’s treatment response to ECT, the research team will use the electronic, as well as paper, medical 
records to access and record the following information for each treatment from the patients’ entire ECT 
treatment course at Barnes-Jewish Hospital: QIDS scores, reason for treatment (diagnosis), the method of 
ECT (right-unilateral, bilateral, or bifrontal), treatment number, date of treatment, any medications including 
doses, charge/treatment parameters, central and peripheral seizure duration, any adverse events from the 
sessions, and any clinical notes regarding treatment efficacy or recovery from each procedure.  
 
2.4.7.3 Optional Magnetic Resonance Imaging 
In addition to the above procedures listed, patients will be given the option to undergo non-contrast magnetic 
resonance imaging (MRI). The MRI data will better allow interpretation of the EEG signals in relation to 
structural brain anatomy. The MRI scan will take place following completion of the patient’s ECT treatment 
course at Barnes-Jewish Hospital. Structural MRI will be performed at the 10th floor West Pavilion Center for 
Clinical Imaging Research (CCIR). The MRI scan will use clinical sequences and will be read by board-certified 
neuroradiologist. The reading and images with be placed in the electronic medical record. Significant incidental 
findings will be disclosed to the patient and his/her physician. The patient will decide s(he) on disclose of 
Incidental findings of unclear clinical significance.  Patients will be compensated $50 for their time. There will 
be no charge to the patient for the MRI scan. If patients are unable to arrange transportation to/from Barnes-
Jewish Hospital for pre-treatment testing, the study team will provide patients with such transportation through 
cab vouchers. 
 
2.5. Analytical and Statistical Methods 
This is an exploratory study that seeks to track and characterize the reconstitution of consciousness and 
cognition following ECT coupled with general anesthesia. We hypothesize that the pattern (sequence and time 


 
 
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course) of reconstitution of consciousness and cognition following ECT with general anesthesia is different 
from general anesthesia alone. In particular, we propose that the cognitive and electroencephalographic 
features following ECT will be similar to those seen during postoperative delirium, which is a disorder of 
consciousness and cognition. 
 
2.5.1 Statistical Analysis 
We will employ mixed-effects models to quantify trajectories of cognitive recovery over time while addressing 
inter-subject variance and missing data. Linear models with appropriate transformations will be used 
preferentially over non-linear models. Time and treatment intervention group will be included as fixed effects 
while random effects will account for repeated measures provided by each participant. Day of treatment 
relative to the dose-charge titration session will allow consideration of cumulative effects of treatment order that 
may remain biased despite randomization. To address differences in ECT-stimulation responsiveness, 
regression approaches will account for dose charge, central seizure duration, and age. Models will assess for 
the effects of treatment on the timing for the return of responsiveness to verbal command and the presence of 
delirium. Separate mixed-effects models will be generated to assess task performance in a group of young 
healthy volunteers during the recovery from isoflurane general anesthesia (Maier, McKinstry-Wu et al. 2017).  
 
2.5.2 Primary Analyses: 
Recovery of Responsiveness: Given that the induction of generalized seizures by electrical stimulation may 
compound the recovery from general anesthesia, we expect that interval from loss to return of responsiveness 
following ketamine + ECT will be longer compared to the period for ketamine + sham ECT. We will determine 
the median and 95% confidence intervals for this measure in relation to the treatment intervention. 
Recovery of Cognition: Given that postictal suppression may be prolonged with ketamine than with 
etomidate(Hoyer, Kranaster et al. 2014), we hypothesize that the time needed for the return of cognition to 
baseline on individual sessions will be greatest for ketamine + ECT, followed by etomidate + ECT, and 
ketamine + sham ECT. Separate mixed-effects models will be generated based on reaction time and accuracy. 
We will determine the time of convergence for 95% confidence intervals for the marginal responses related to 


 
 
16
the three treatment groups. To determine the timing for the recovery to baseline, we will determine the time 
when the same 95% confidence intervals include 0. 
Postictal Delirium and Cognitive Recovery: We expect the incidence of delirium (3D-CAM) to be associated 
with delayed restoration of baseline function in all cognitive domains. The magnitude and significance of this 
relationship will be determined from the mixed effects models for each cognitive test. 
Comparison of Cognitive Recovery After ECT and Isoflurane General Anesthesia: We hypothesize that the 
time for recovery to baseline will be quicker for treatments involving ECT compared to that for the recovery 
from isoflurane general anesthesia. Convergence for 95% confidence intervals will be compared between 
treatment groups. 
2.5.3 Secondary Analyses 
Recovery of Cognition: Principal measures of performance are based on preliminary data(Basner, Savitt et al. 
2015) of the Cognition test battery. Additional measures include: PVT response speed, DSST throughput, PVT 
lapses, VOLT duration and accuracy, AM duration and accuracy, and DSST errors. Cognition performance 
measures associated with lower effect sizes will also be assessed. These include AM accuracy, VOLT 
accuracy, F2B reaction time, MPT accuracy, MPT duration, and F2B accuracy. Overall, we expect F2B, VOLT, 
and AMT to recover the slowest due to taxing of short-term memory after ketamine + ECT compared to 
ketamine + sham ECT. 
Recovery in the Spontaneous EEG: We will evaluate mixed-effects models to test the hypotheses that the 
predominance of frontal delta or theta power during passive eyes opening or occipital alpha power during eyes 
closed predict cognitive performance (Cognition scores) or delirium (3D-CAM scores). We will also compare 
these EEG spectral measures across treatment sessions to evaluate the impact of anesthetic and ECT. 
Relationship of ECT Seizure Duration to Return of Responsiveness to Verbal Command: We expect that the 
length of ECT-induced seizures will correlate with the intervals from the loss of responsiveness to the return of 
responsiveness. 
Mood and Depression Severity: We expect improvement in these clinical outcomes to be greatest with 
ketamine + ECT, followed by etomidate + ECT, and then ketamine + sham ECT. 


 
 
17
Treatment Satisfaction: We expect satisfaction to be greatest for ketamine + ECT, followed by ketamine + 
sham ECT, and then by etomidate + ECT. 
 
2.5.4 EEG Preprocessing and Analysis 
EEGLab will be used to assess for quality and the presence of motion and eye movement 
artifact(Delorme and Makeig 2004). Data will undergo pre-processing with band-pass filtering from 0.1-50 Hz 
with 1st order Butterworth filters.  Frontal channels will be assessed for eye movement artifact. Reduction of 
severe eye movement artifacts will employ independent component analysis approaches in EEGLab. The 
following analysis time epochs will be evaluated for secondary outcomes related to EEG activity: pre-ECT and 
post-ECT periods with either eyes open or eyes closed, the interval between anesthetic induction to and ECT 
stimulation, the period between stimulus delivery and cessation of ictal waveforms/spike-and-wave complexes, 
postictal period of EEG suppression and slowing, and both 5-minute epochs flanking the return of 
responsiveness to verbal command. 
Spectral analysis will be performed using the Chronux Toolbox(Mitra and Bokil 2008), including five 
tapers, time frequency bandwidth of 3, and 6-second non-overlapping time windows.  Total power and peak 
amplitude will be computed within the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) 
bands. Coherence and phase lag will be computed using the Chronux toolbox. Global coherence(Cimenser, 
Purdon et al. 2011) and permutation entropy will be computed(Bandt and Pompe 2002). Quantitative measures 
will be derived from spectral and time-based analyses of the ictal EEG. These measures will evaluate seizure 
energy, periodicity, and symmetry, as well as propagation, and termination. 
In parallel to power spectral analysis, we will track the time-varying connectivity between the measured 
brain regions.  Data will be windowed into 5-10 second epochs within which several cross-channel connectivity 
metrics will be computed.  These measures will include the Pearson correlation, directed entropy, and 
Shannon mutual information.  Thus, windows will manifest different ‘networks’, each describing the association 
between channels (regions) according to its respective metric.  These networks will be clustered into a set of 
distinct motifs, or microstates, by using a k-means algorithm with least-squares error criterion.  Other methods 
to characterize the time-varying dynamics of the observed brain activity, including those based on network 
control theory, will also be considered. 


 
 
18
Visualization and analyses of epileptiform EEG activity will be performed using Net Station and Persyst 
software (Persyst, Solana Beach, CA, USA), following interpolation of bad channels and re-referencing to the 
average signal. EEG dipole source localization, inter-hemispheric generalization, and phase-reversals will be 
assessed by epilepsy board-certified neurologists. Seizures will be staged according to the previously 
described three components of electrical seizures induced by ECT (phase I with initial 14-22 Hz rhythmic beta 
activity, phase II with arrhythmic polyspike activity, and phase III with rhythmic 2.5-3.5 Hz. spike/polyspike 
activity(Gerst, Enderie et al. 1982). Additionally, expanding on previous analyses of stationarity in epileptiform 
activity induced by ECT(Zoldi, Krystal et al. 2000), we will use high-density EEG to topographically map 
rhythmic sharp-wave discharges. To maintain rigor, evaluators will be blinded to the study intervention. 
 
Structural MRI scans, including T1-weighted images will be used for source localization using 
Brainstorm software. 
2.6. Sample Size 
We based our targeted enrollment on safety consideration for a ketamine general anesthetic, expected 
differences in the recovery patterns of different domains assessed by the Cognition test battery, prior 
volunteer data with isoflurane emergence(Maier, McKinstry-Wu et al. 2017). Sample size calculations are 
based on 1-way pairwise of ANOVA (Analysis of Variance) comparisons of 4 means (t = 0, 30, 60, and 90  
minutes). Expected effect sizes for differences in the modeled trajectories of cognitive function ranged from 
20-40 minutes. Standard deviations were expected to range between 20 and 40 minutes. Using conservative 
assumptions, we calculated a sample size of 24 subjects (effect size, μA-μB, of 20 minutes; standard deviation, 
σ, of 20 minutes; two-sided alpha of 0.05; power of 80%). With liberal assumptions, we estimated a sample 
size of 12 participants (μA-μB of 40 minutes; σ of 20 minutes; two-sided alpha of 0.05; power of 99%). With this 
range of estimates and expected attrition of participants, we targeted for data collection from 15-20 
participants. 
 
 
2.7. Management of Intercurrent Events 
2.7.1 Cross-over, repeated measures 


 
 
19
The study design has a built in cross-over, repeated measures to allow patients to serve as their own control 
and to experience each of the treatments twice. 
 
2.7.2 Adverse Experiences and Premature Discontinuation 
The Washington University HRPO and the Data and Safety Monitoring Committee (DSMC) oversee the study’s 
progression and adherence to protocol. Following each intervention, the principal investigators will affirm 
continued involvement or withdrawal based on patient tolerance and data quality. All adverse events will be 
reviewed by the DSMC and reported to HRPO, following the reporting policies and procedures, and followed 
until satisfactory resolution.  The description of the adverse experience will include the time of onset, duration, 
intensity, known etiology, relationship to the study, and any treatment required.  The trial steering committee 
will be responsible for all major decisions regarding changes to the protocol. The committee will communicate 
these changes to HRPO and appropriate parties. . 
 
2.7.3 Potential Risks 
Interruption of clinical care: While this is a theoretical risk, it is not envisaged that the conduct of this study 
will interfere with clinical care.   
 
Discomfort related to EEG/EMG/EOG: Skin abrasions from scalp electrode placement or discomfort on 
removal of electrodes. 
 
Non-contrast MRI: Claustrophobia, anxiety, discomfort from headphones used to shield out noise, or hearing 
loss due to hammering noise are all potential risks of undergoing non-contrast MRI. Patients with tattoos may 
experience irritation, swelling, heating, or instances of primary or secondary burns in the area of the tattoo. 
Additionally, patients with devices such as a pacemaker, bone hardware, or a device placed in their uterus may 
experience heating or movement of the device, device malfunction, or damage to the tissue that surrounds the 
device. These risks are unlikely to be common or severe. 
 


 
 
20
Breach of Confidentiality:  Another potential risk of participating in this study is that confidential information 
about the participant may be accidentally disclosed. We will use our best efforts to keep the information about 
participants secure, through de-identification of personal health information. We think the risk of accidental 
disclosure is very small. 
 
2.8 Procedures to Minimize Potential Risks 
Interruption of clinical care: The research team will be in open discussion with patients and nursing staff to 
ensure that there is no disruption in the patient’s clinical care, comfort, and recovery. 
 
EEG/EMG/EOG: Timing and manner of electrodes and adhesive removal will be based on patient’s comfort 
and convenience. Discomfort will be minimized based on the use of sticker/adhesive/gel electrodes and not 
needle electrodes. 
 
Confidentiality:  This will be maintained by assigning each participant a number to be linked with data. Any 
protected health information of patient participants will be stored in a locked drawer within the locked office of 
the PI. Electronic protected health information will be stored on a password-protected server. 
 
MRI Safety: The patient will be thoroughly screened for MRI-incompatible implants. Scans may be performed 
following completion of the patient’s ECT treatment course at Barnes-Jewish Hospital. Scans will be performed 
within the hospital (10th floor CCIR).  
 
Research Conduct: Studies are conducted at Washington University School of Medicine under the general 
supervision of a board-certified cardiac anesthesiologist who is familiar with postoperative surgical care. 
Patients will be monitored during emergence and recovery from anesthesia by the anesthetic and nursing staff 
in the ECT suite as per standard care. Additionally, research personnel trained in good clinical practices will be 
present during the acquisition of data. Monitoring and safety will be according to the current clinical standard. 
Patient confidentiality will be maintained through de-identification of personal health information. Identity and 


 
 
21
linking information will be stored in a locked cabinet within the principal investigator’s office, which is locked 
outside of business hours. Electronic data will be password-encrypted on secure servers. 
Patient satisfaction will be monitored throughout the study. Ketamine may improve the efficacy of ECT and 
recovery of cognitive function following ECT. Patients may benefit from the additional EEG monitoring in the 
postictal period during which non-convulsive status epilepticus is rarely manifested. Patients will be withdrawn 
if discontinuation is in the best interest of the patient or if the patient requests withdrawal or removal of 
treatment blinding. In the event that a patient’s condition significantly worsens and requires additional or 
different interventions from those allocated in the study, the patient will be released from the study and data 
collection will be discontinued. Participants are given a satisfaction survey to be returned by mail following the 
last study session(Sienaert, De Becker et al. 2005).  
 
Participant Satisfaction: During the follow-up phone call for the last study session, participants will be asked 
about their satisfaction in the study(Sienaert, De Becker et al. 2005).  
 
2.8.1 Adverse Event Reporting and Data and Safety Monitoring Plan 
The investigators will monitor subjects for evidence of adverse events. All adverse events will be reported to 
the IRB following the IRB reporting policies and procedures and followed until satisfactory resolution.   
 
3.  HUMAN SUBJECTS RESEARCH 
 
3.1 Protection of Human Subjects 
 
The study will be conducted with strict adherence to Washington University Institutional Review Board protocol 
and consent form approval. An American Board of Anesthesiology board-certified and GCP-certified 
anesthesiologist with experience in conducting clinical studies will lead the study. Safety and privacy of study 
participants will be safeguarded.  
 


 
 
22
Patient confidentiality will be maintained through de-identification of personal health information. Identity and 
linking information will be locked cabinet within the principal investigator’s (PI) office, which is locked outside of 
business hours. Electronic data will be password encrypted on secure servers. 
3.1.1 Indemnity 
Washington University School of Medicine is responsible for any non-negligent damage incurred as a result of 
participating in the RCC II Trial. This indemnity is renewed on an annual basis. Washington University School 
of Medicine assures that it will continue renewal of the indemnity for the duration of the trial.  
 
3.1.2 Ethics and Dissemination 
The trial investigators will be responsible for all major decisions regarding changes to the protocol. The 
committee will communicate these changes to the IRB and appropriate parties. The final trial dataset is the 
property of the investigative team and shall not be shared without permission from the principal investigator. 
Dissemination plans include presentations at local, national and international scientific conferences.  Every 
effort will be made to publish results of the RCC II trial in a peer-reviewed journal. Dissemination of results to 
study participants and their family members will be available upon request. Updates and results of the study 
will be available to the public at clinicaltrials.gov. 
 
3.2 Sources of Materials 
Patients will receive remuneration of $100 per session after the titration visit (Visit 2-7), or $600 for completion 
of the study. Patients who undergo an MRI scan will receive an additional $50 for their time. There will be no 
cost for involvement.  
 
3.3 Recruitment and Informed Consent 
 
Screening and enrollment of subjects will occur according to the protocol-defined inclusion and exclusion 
criteria.  
  


 
 
23
3.4 Potential Benefits of the Proposed Research to the Participant and Others 
This study will be the first to explore and elaborate how a seizure in the form of ECT (combined with an 
induction dose of intravenous anesthesia) impacts consciousness and cognition following termination of the 
seizure. The time course and sequence of reconstitution of consciousness and cognition will also be clarified. 
This investigation will yield novel insights into an excitatory impairment of consciousness, which has not 
previously been studied with a controlled, experimental design.  
 
Candidates for ECT are refractory to multiple medical modalities. These patients may benefit from a greater 
understanding of the relationship between anesthetics and ECT on recovery of cognitive function and efficacy 
for depression treatment. 
 
This study may benefit the patient directly. Ketamine may improve the efficacy of ECT and recovery of 
cognitive function following ECT. The patient may benefit from the additional EEG monitoring in the post-ictal 
period during which non-convulsive status epilepticus is rarely manifested.  
 
 
3.5 Inclusion of Women 
Efforts will be made to enroll patients regardless of gender. 
 
3.6 Inclusion of Minorities 
All studies in the Department of Anesthesiology encourage the participation of minorities in research.  
Our minority recruiting typically matches the demographic composition of the Washington University patient 
population (30% white, 60% Black, 6 % Hispanic, 4% Asian).  
 
3.7 Inclusion of Children 
No children will be enrolled in this study. 
 
 
 


 
 
24
Appendices:  
1. Study Day (each experimental treatment day Visit 2-Visit 7) 
Pre-Treatment: 
An appropriately fitted 64-channel (n=15-20 subjects) EEG headcap (Electrical Geodesics, Inc. Eugene OR) 
will be affixed to the scalp. The actual placement of EEG electrodes might vary, depending on the 
requirements for ECT. Electrical impedances on each channel will be confirmed to be under 
100kOhms/channel.  Subjects will complete a baseline round of neurocognitive testing with ongoing EEG 
recordings, as well as 3D-CAM (3D-Confusion Assessment Method), Self-Assessment Manikin, PROMIS-CAT 
(Patient Reported Outcomes Measurement Information Systems - Computer Adaptive Testing) for depression, 
and the Scale of Suicidal Ideation (Table 1). 
During Treatment: 
Upon completion of the neurocognitive battery, the subjects will be pre-oxygenated by mask and anesthesia 
will be induced by either ketamine, 2 mg/kg or standard of care anesthetic, depending on group assignment. 
The induction agent will be slowly titrated until there is loss of responsiveness and eyelash reflex, which is 
current practice for ECT. During this time, an audio loop command will be issued every 30 seconds asking the 
subject to randomly squeeze their left or right hand. Loss of consciousness (LOC) will be recorded as the first 
time when a subject fails to respond to two consecutive commands. Antiemetic prophylaxis will be 
administered as clinically indicated. During the sessions that subjects receive ECT, other drugs will also be 
administered according to current practice and as clinically indicated. ECT will be conducted according to 
current standard practice. EEG will be acquired after the ECT charge has been delivered or continuously for 
non-ECT ketamine sessions. After the ECT has been concluded (or after the induction dose of ketamine has 
been administered), the patient will remain in the treatment room for subsequent testing and EEG recording. 
Post-treatment: 
Recovery of consciousness (ROC) will be defined as the first time at which subjects correctly responded to two 
consecutive audio loop commands. At this time, defined as t = 0 minutes, the subject will begin the 
neurocognitive battery of tests followed by a brief resting period. Neurocognitive testing will be repeated at t= 
30, 60, and 90 minutes following emergence while the 3D-CAM will be completed at time 0 and every hour 
(Table 1) until the patient is scored negative for delirium.  Each battery of neurocognitive testing will take 


 
 
25
approximately 15-20 minutes to complete. During the rest period, EEG recording will occur with 5 minutes eyes 
open and 5 minutes eyes closed. At the 90 timepoint patients will not only complete the COGNITION cognitive 
test but also the 3D-CAM (if positive for delirium at t=60, PROMIS-CAT, Self-Assessment Manikin, and a 
questionnaire regarding patients’ subjectivity of whether they received ECT. Subjects will be permitted to take 
a brief break to use the restroom and eat or drink, as necessary. Subjects will be discharged according to 
standard post-anesthesia care unit discharge criteria upon completing the last neurocognitive test battery. A 
study site coordinator will contact each subject within 24 hours of the study day to document any adverse 
events.  
Table 1: Assessment at Each Experimental ECT Treatment (Visit 2-Visit 7): 
Assessment 
Baseline 
(Pre‐ECT) 
Time 
0 
Time 
30 
Time 
60 
Time 
90 
COGNITION 
Neurocognitive Testing  
X 
 
X 
 
X 
 
X 
 
X 
 
3D-CAM - Delirium (3D-
Confusion Assessment 
Method) 
X 
 
X 
 
X 
 
X 
 
PROMIS-CAT -
(Computer Adaptive 
Testing for depression) 
X 
 
 
 
 
X 
 
Mood Self-Assessment 
Manikin -  mood 
X 
  
  
  
X 
Scale of Suicidal 
Ideation 
X 
  
  
  
 
Assessment for 
Blinding Quality 
 
 
 
 
X 
 
2. Description of Assessments: 
Neurocognitive testing (COGNITION battery) 
 
This battery for individualized neurocognitive assessment of fatigue has been tested in the context of sleep 
deprivation and is administered via a laptop. The effects of ECT and/or an induction dose of an intravenous 
general anesthetic (ketamine or etomidate) on all the tests below have not previously been well characterized. 


 
 
26
During administration, the order will be pseudorandomized, with a full complement given at each testing block. 
Additionally, the first test for each block will be repeated at the end to address temporal order within the block. 
 
Motor Praxis Test (MPT) 
The motor praxis test (MPT) measures sensory motor speed and fluidity. Participants are presented 
with a square box that, once clicked with a track pad mouse, shrinks and moves to a different location on the 
computer screen. Participants must click the box each time it re-appears as rapidly as possible. It is expected 
that the accuracy for the MPT will be close to 100%. Therefore, the standard score for this test is determined 
solely based on the speed at which the subject is able to click each square. Previous studies have shown that 
sensorimotor function performance declines with sleep deprivation. The Motor Praxis task allows for multiple 
measures of sensorimotor function in less than 1 minute. 
 
Psychomotor Vigilance Test (PVT) 
The psychomotor vigilance test (PVT) measures sustained attention by recording reaction time to visual 
stimuli that are presented at random intervals. During the PVT, subjects are instructed to respond to a small 
red counter that appears at unpredictable intervals and reports time elapsed in milliseconds by clicking the 
space bar as soon as the counter appeared. This task is time limited as any response time greater than 500 
milliseconds is recorded as a lapse or error of omission. The standard score for the PVT is based on response 
time and false starts. Originally, the PVT was designed for administration during 10-minute sessions. However, 
a shorter, modified PVT that remains sensitive to acute total sleep deprivation and chronic partial sleep 
deprivation was developed. Therefore, the PVT component of each neurocognitive battery in this study will be 
3 minutes in duration. An advantage of using this task is that PVT is unaffected by learning and aptitude.  
 
Digit Symbol Substitution Test (DSST) 
During the digit symbol substitution test, subjects are presented with a key showing ten symbols and a 
number (0-10) that correspond with each. Symbols are presented on the center of the screen one at a time, 
and the subject must type the corresponding number as quickly as possible. This test measures complex 
scanning, visual tracking, attention, working memory, and visuomotor and visuospatial speed. The standard 


 
 
27
score for this task is determined by accuracy and speed, with a severe scoring penalty based on response 
time. While learning effects can be observed in healthy individuals, individuals who chronically receive only 6 
hours of sleep do not improve in this task over time while individuals who chronically sleep less than 6 hours 
display decline in performance over time. Similarly, acutely sleep deprived individuals display significantly 
decreased correct responses in this task.  
 
Fractal-2-Back (F2B)  
 
The fractal-2-Back (N-back) test measures attention and working memory. Subjects are presented with 
images, one at a time, at a pre-set time interval and are asked to press the space bar when the current image 
is identical to the image that was presented two images prior. This task requires temporary storage and 
manipulation of information and performance is evaluated based on accuracy, since the images are presented 
at predetermined time intervals. Previous studies have shown both that the fractal-2-back is sensitive to sleep 
inertia and that healthy individuals exhibit reduced accuracy in this task following 24 hours of sleep deprivation.  
 
Visual object learning test (VOLT) 
The visual object learning test (VOLT) examines visual-spatial learning and memory. In this 
assessment, subjects are presented with a series of visual objects (shaded geometric shapes) consecutively at 
a pre-set time interval. Following this, the subject is presented with a single visual object and asked to identify 
if this objected was presented during the learning period. The standard score for the VOLT is determined 
primarily based on accuracy; however, a penalty may be applied based on mean response time. Verbal 
learning suffers as a result of sleep deprivation. The VOLT was designed to measure visual-spatial learning 
and memory analogously to verbal learning tests. Previous work reports that there is often a gender bias on 
measures of spatial learning, as men tend to perform better on spatial memory tests. However, the VOLT as 
developed by Glahn and colleagues reveals no differences between sexes. 
 
Abstract Matching (AM) 
Abstract matching (AM) examined abstraction and cognitive flexibility. During the abstract matching task, 
participants are presented with a single colored geometric shape as well as two sets of geometric shapes. 


 
 
28
They then must choose the set that the object completes. Following each selection, the subject is told whether 
their selection was correct or not are able to use this feedback to determine the implicit rules that govern this 
task. The standard score for this task is determined by accuracy with a penalty based on mean response time. 
Cognitive flexibility or “divergent” thinking is significantly impaired by sleep deprivation. The AM task version 
used in this study was chosen because it can be completed in less than 4 minutes as compared to previous 
versions, which required 15-20 minutes for completion.  
 
 
Delirium Assessment (3D-CAM) 
The 3D-CAM is a delirium assessment tool based on the full Confusion Assessment Method (CAM) interview. 
The 3D-CAM takes approximately 3 minutes to complete. In order for a patient to be positive for delirium they 
must present 3 of the 4 features including acute onset, inattention, altered level of conscious and/or 
disorganized thinking.  


 
 
29
 


 
 
30
 


 
 
31
 


 
 
32
 


 
 
33
 


 
 
34
 


 
 
35
Depression (PROMIS-CAT)  
The assessment of depressive symptoms using the PROMIS-CAT survey will be done separately from the 
routine clinical depression assessments that will be conducted by the psychiatrists who are caring for these 
patients. This is a computer-based questionnaire accessed through REDCap. As standard care for tracking 
depression symptoms during an ECT course, treating psychiatry teams will administer the Quick Inventory of 
Depressive Symptomatology, Self-Report (16-Item), QIDS-SR16(Rush, Trivedi et al. 2003). 
 
Mood Assessment (Self-Assessment Manikin, SAM) 
This assessment has been used to assess mood and mood changes with ECT. The SAM is a brief, reliable 
scale that are sensitive to the treatment effects of ECT and that are appropriate for patients with transient 
cognitive impairment(Bradley and Lang 1994). 
 
 
We will use show the scale to the patient and read the following script: 
 “This scale asks how you are feeling right now. It ranges from a smile to a frown. This end of the scale 
(point) means you feel completely happy, pleased, satisfied, contented, hopeful. The other end of the scale 
(point) means you feel completely unhappy, annoyed, unsatisfied, melancholic, despaired, bored.  You can 
choose any of these points to describe how you feel right now. “ 
 
The patient will then place a check mark in the box below the manikin row that most accurately depicts his/her 
mood. 


 
 
36
Scale of Suicidal Ideation 
This is a rating scale to assess the subjective desire to hurt oneself. We will use the first two questions only 
(http://www.psy-world.com/ssi_print.htm). These two questions have been used previously for assessing 
changes in suicidal ideation before and after a brief ketamine infusion for major depressive disorder(Ballard, 
Ionescu et al. 2014). 
Item 
Response 
Points 
1. Wish to live 
moderate to strong 
0 
 
weak 
1 
 
none 
2 
2. Wish to die 
none 
0 
 
weak 
1 
 
moderate to strong 
2 
 
Assessment of Blinding Quality 
At the conclusion of study sessions 2-7, the patient will be asked, “Do you feel that you received ECT today? 
Was ECT painful?” 
Assessment of Patient Satisfaction 
 
1. Did you have any side effects or problems after receiving treatments? Please indicate after which treatment 
these side effects occurred (check all that apply). 
 
1st 
2
nd 3
rd 
4
th 
5
th 
6
th 
Yes, but 
not sure 
when 
Nausea 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
Confusion 
 
 
 
 
 
 
 
 
Bruising or tenderness at IV site 
 
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
Weakness 
 
 
 
 
 
 
 
 
Memory loss 
 
 
 
 
 
 
 
 
Agitation 
 
 
 
 
 
 
 
 
Hallucinations 
 
 
 
 
 
 
 
 
Jaw pain  
 
 
 
 
 
 
 
Nightmares 
 
 
 
 
 
 
 
 


 
 
37
Other:___________________________  
 
 
 
 
 
 
 
 
 
The following items refer to your experience throughout the entire study. Please rate how well you agree with 
each statement. 
 
 
 
Strongly 
agree 
Agree  Neutral  Disagree  Strongly 
disagree 
2. I was satisfied with my care.  
 
  
 
  
  
  
3. Overall, I felt comfortable throughout the study. 
 
  
 
  
  
  
4. I learned about consciousness and cognition by 
participating. 
 
  
 
  
  
  
5. I was well compensated for this study. 
 
  
 
  
  
  
6. I am satisfied with my interactions with the 
study team. 
 
  
 
  
  
  
7. I would participate in this study again.  
 
  
 
  
  
  
8. My condition improved after completing the 
treatments. 
  
 
  
  
  


 
 
38
 
9. What was the most physically uncomfortable or distressing part of the study? 
 Consent 
 Screening questionnaires (performed in the days or weeks before treatment) 
 EEG cap 
 Morning before treatment 
 Recovery from treatment 
If yes, please indicate which (check all that apply):  
 1st 
 2nd 
 3rd 
 4th 
 5th 
 6th 
 No period was particular uncomfortable or distressing 
 Other: _______________________________________________________ 
 
10. How physically uncomfortable or distressing was the experience selected in the previous question? 
 Extremely 
 A lot 
 A little 
 Not very 
 N/A 
 
11. What did the study team do well? 
______________________________________________________________________________________
____________________________________________________________________________ 
 
12. Which aspects could the study team improve? 
______________________________________________________________________________________
____________________________________________________________________________ 
 
13. Additional comments: 
_______________________________________________________________________________________
_______________________________________________________________________________________
________________________________________________________________________ 
 
 
 
 
 
 


 
 
39
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