Electroconvulsive Therapy Amplitude Titration for Improved Clinical Outcomes in Late Life Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of New Mexico

 
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Version Date: 11/19/2020 
PROTOCOL TITLE: Electroconvulsive therapy amplitude titration for improved clinical 
outcomes in late-life depression 
 
NCT number: NCT04621786 
 
Date of document: 11/19/2020 
 
 

 
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Version Date: 11/19/2020 
PROTOCOL TITLE: 
Electroconvulsive therapy amplitude titration for improved clinical outcomes in 
late-life depression 
PRINCIPAL INVESTIGATOR: 
Chris Abbott, MD, MS 
Department of Psychiatry 
 
ADMINISTRATIVE CONTACT: 
 
Kenia Aguilar-Pineda 
 
Department of Psychiatry 
 
VERSION NUMBER: 
v.1 
DATE: 
November 19, 2020 
REGULATORY FRAMEWORK: 
Please indicate all that apply: 
 
DOD (Department of Defense) 
 
DOE (Department of Energy) 
 
DOJ (Department of Justice) 
 
ED (Department of Education) 
 
EPA (Environmental Protection Agency) 
 
FDA (Food and Drug Administration) 
 
HHS (Department of Health and Human Services) 
 
VA 
 
Other:       
 
FUNDING: 
The protocol is funded by the National Institutes of Health (NIH).   
Sponsor number: 
SPO Click ERA record number: FP00008135 
 
CLINICAL TRIALS 
Is this a clinical trial per the NIH definition of a Clinical Trial?   
 Yes   
 No 

 
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Version Date: 11/19/2020 
Use the following four questions to determine the difference between a clinical study 
and a clinical trial:        
 
Does the study involve human participants? 
 Yes   
 No 
 
Are the participants prospectively assigned to an intervention? 
 Yes   
 No 
 
Is the study designed to evaluate the effect of the intervention on the participants? 
 Yes   
 No  
 
 Is the effect being evaluated a health-related biomedical or behavioral outcome? 
 Yes   
 No 
 
If yes to all 4 questions, please confirm that the research team is familiar with and agrees 
to comply with the investigator requirement to register the study on the ClinicalTrials.gov 
database. Additionally, the approved consent document(s) must be uploaded to the 
ClinicalTrials.gov database    
 Yes   
 No  
For any assistance with registration of your trial or the requirements, please contact HSC-
CTSCResearchConcierge@salud.unm.edu  
 

 
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Table of Contents 
1. 
Objectives .................................................................................................................... 6 
2. 
Background .................................................................................................................. 7 
3. 
Study Design................................................................................................................ 8 
4. 
Inclusion and Exclusion Criteria ................................................................................. 9 
5. 
Number of Subjects ..................................................................................................... 9 
6. 
Study Timelines ........................................................................................................... 9 
7. 
Study Endpoints ........................................................................................................... 9 
8. 
Research Setting .......................................................................................................... 9 
9. 
Resources Available .................................................................................................. 10 
10. 
Prior Approvals ...................................................................................................... 11 
11. 
Multi-Site Research ............................................................................................... 11 
12. 
Study Procedures ................................................................................................... 11 
13. 
Data Analysis ......................................................................................................... 14 
14. 
Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 18 
15. 
Withdrawal of Subjects .......................................................................................... 19 
16. 
Data Management/Confidentiality ......................................................................... 19 
17. 
Data and Specimen Banking .................................................................................. 20 
18. 
Risks to Subjects .................................................................................................... 21 
19. 
Potential Benefits to Subjects ................................................................................ 22 
20. 
Recruitment Methods ............................................................................................. 22 
21. 
Provisions to Protect the Privacy Interests of Subjects .......................................... 22 
22. 
Economic Burden to Subjects ................................................................................ 22 
23. 
Compensation ........................................................................................................ 22 
24. 
Compensation for Research-Related Injury ........................................................... 23 
25. 
Consent Process ..................................................................................................... 23 
26. 
Documentation of Consent .................................................................................... 23 
27. 
Study Test Results/Incidental Findings ................................................................. 23 
28. 
Sharing Study Progress or Results with Subjects .................................................. 24 
29. 
Inclusion of Vulnerable Populations ...................................................................... 24 
30. 
Community-Based Participatory Research ............................................................ 24 
31. 
Research Involving American Indian/Native Populations ..................................... 24 
32. 
Transnational Research .......................................................................................... 25 
33. 
Drugs or Devices.................................................................................................... 25 
34. 
Principal Investigator’s Assurance ........................................................................ 25 
35. 
CHECKLIST SECTION ........................................................................................ 27 
36. 
Partial Waiver of Consent for Screening/Recruitment .......................................... 27 
37. 
Partial Waiver of HIPAA Authorization for Screening/Recruitment .................... 27 
38. 
Waiver of Documentation of Consent ................................................................... 27 
39. 
Alteration of Consent ............................................................................................. 27 
40. 
Full Waiver of Consent/Parental Permission ......................................................... 27 
41. 
Full Waiver of Consent/Parental Permission (Public Benefit or Service Programs)
 
27 
42. 
Full Waiver of HIPAA Authorization (Checklist) ................................................. 27 
43. 
Other Waiver Types (Checklist) ............................................................................ 27 
44. 
Vulnerable Populations (Checklist) ....................................................................... 27 

 
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45. 
Medical Devices (Checklist) .................................................................................. 29 
46. 
Export Control (Checklist) ..................................................................................... 30 
47. 
Data Transfer/Sharing (Checklist) ......................................................................... 30 
48. 
Specimen Transfer/Sharing (Checklist) ................................................................. 32 
 
 

 
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1. Objectives 
 
Electroconvulsive therapy (ECT) stimulation parameter selection reflects a balance 
between efficacy and cognitive adverse effects. ECT stimulation parameters associated 
with more antidepressant efficacy (non-focal electrode placement, longer pulse width) are 
associated with increased risk of cognitive adverse effects. Amplitude is currently fixed at 
800 or 900 milliamperes (mA) in standard clinical practice with no clinical or scientific 
basis. Amplitude determines the intensity of the induced electric field (E-field). With a 
fixed extracranial amplitude, the ECT “dose” as represented by the E-field is highly 
variable due to anatomic differences in skin, skull, fluid, and brain tissue. This anatomic 
variability is prominent in older (age 50+) depressed patients and can compromise both 
antidepressant efficacy (insufficient stimulation of mood-related circuitry) and safety 
(inducing cognitive impairment due to excessive stimulation of cognitive related circuitry). 
 
Our long-term goal is focused on advancing treatment for older adults with depressive 
disorders by refining neuromodulation stimulus parameters to improve efficacy and 
cognitive safety. Our BRAIN Initiative project (MH111826) used right unilateral electrode 
placement (RUL) and randomized older ECT subjects to 600, 700, and 800 mA treatment 
arms. Our results demonstrated a trade-off between antidepressant (improved with higher 
amplitudes) and cognitive (improved with lower amplitudes) outcomes. Subjects in the 
600 mA arm had worse depression outcomes, less neuroplasticity, and cognitive safety, 
while subjects in the higher amplitude arms (700 and 800 mA) had improved 
antidepressant outcomes, more neuroplasticity, and cognitive deficits. 
 
Amplitude titration, as proposed here, can reduce the variability related to fixed amplitude 
dosing and optimize clinical and cognitive outcomes. The goal of this project is to change 
standard ECT parameter selection from a fixed amplitude with variable pulse number 
(combination of pulse train duration and frequency) to an individualized and empirically 
determined amplitude with fixed pulse number. To achieve this goal, we will focus on the 
relationship between amplitude titrated seizure threshold and treatment-responsive changes 
in hippocampal neuroplasticity with RUL fixed amplitude ECT. Fixed amplitude ECT 
results in variable E-fields and inconsistent changes in hippocampal neuroplasticity. In 
contrast, computational and pre-translational investigations have demonstrated that 
amplitude titration results in consistent E-fields. Seizure titration amplitudes (based on 
historic data, 233 to 544 mA) are below the amplitude range of FDA-approved ECT 
devices (500 to 900 mA) and will require an adaptor to reduce the amplitude (FDA 
Investigational Device Exemption). Amplitude titration will also be below the 
hippocampal neuroplasticity threshold and insufficient for antidepressant response. The 
difference between RUL amplitude titration and RUL fixed amplitude (800 mA) ECT will 
determine the degree of target engagement with the hippocampus. To illustrate, subjects 
with low amplitude seizure threshold of ~250 mA (800/250, high fixed/titration amplitude 
ratio) will have significant changes in hippocampal neuroplasticity. Subjects with high 
amplitude ~500 mA (800/500, low fixed/titration ratio) will have minimal changes in 
hippocampal neuroplasticity. The relationship between amplitude titration and fixed 
amplitude hippocampal neuroplasticity will be used to develop the amplitude multiplier 
required for consistent and clinically effective ECT dosing. Amplitude titration with 

 
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multiplier will be associated with the “sweet spot” for hippocampal neuroplasticity: 
sufficient for antidepressant response but not excessive thus resulting in cognitive safety. 
 
Older depressed subjects (n = 40) will first receive RUL amplitude titration (first treatment) 
and then RUL fixed amplitude (800 mA) and fixed pulse number ECT (subsequent 
treatments). We will 1) verify results from pre-translational investigations that 
demonstrated the relationship between current pulse amplitude and a whole brain E-field 
metric (I/Ebrain), and 2) determine the relationship between current pulse amplitude and 
treatment-responsive changes in hippocampal neuroplasticity from RUL fixed-amplitude 
(800 mA) ECT. 
 
H1:  Amplitude seizure titration will have a positive correlation with I/Ebrain.  
 
H2, Go/No-Go criterion: The ratio of amplitude titrated seizure threshold to fixed 
amplitude ECT will demonstrate a linear relationship with treatment-responsive changes 
in hippocampal neuroplasticity. This relationship will determine the “neuroplasticity 
multiplier” to bridge from amplitude titration to hippocampal neuroplasticity. 
 
2. Background 
 
Electroconvulsive therapy (ECT) stimulation parameter selection reflects a balance 
between efficacy and cognitive adverse effects. ECT stimulation parameters associated 
with more antidepressant efficacy (non-focal electrode placement, longer pulse width) are 
associated with increased risk of cognitive adverse effects. Amplitude is currently fixed at 
800 or 900 milliamperes (mA) in standard clinical practice with no clinical or scientific 
basis. Amplitude determines the intensity of the spatial distribution of the electric field (E-
field). With a fixed extracranial amplitude, the ECT “dose” as represented by the E-field is 
highly variable due to anatomic differences in skin, skull, fluid, and brain tissue. This 
anatomic variability is prominent in older (age 50+) depressed patients and can 
compromise both antidepressant efficacy (insufficient stimulation of mood-related 
circuitry) and safety (inducing cognitive impairment due to excessive stimulation of 
cognitive related circuitry). Amplitude titration, as proposed in this current proposal, can 
reduce the variability related to fixed amplitude dosing and optimize clinical and cognitive 
outcomes. The goal of this project is to change standard ECT parameter selection from a 
fixed amplitude to an individualized and empirically determined amplitude. To achieve this 
goal, we will focus on the relationship between amplitude titration and treatment-
responsive changes in hippocampal neuroplasticity with RUL fixed amplitude ECT. Fixed 
amplitude ECT results in variable E-field or ECT dose. Over the course of an ECT series, 
the variable ECT dose will result in inconsistent changes in hippocampal neuroplasticity. 
In contrast, pre-translational investigations have demonstrated that amplitude titration 
results in a consistent E-field or ECT “dose”. Seizure titration amplitudes (based on historic 
data, 233 to 544 mA) are below the amplitude range of FDA-approved ECT devices (500 
to 900 mA) and will require an adaptor to reduce the output amplitude (Investigational 
Device Exemption). Amplitude titration will also be below the hippocampal 
neuroplasticity threshold and insufficient for antidepressant response. The difference 
between RUL amplitude titration and RUL fixed amplitude (800 mA) ECT will determine 

 
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the degree of target engagement with the hippocampus. To illustrate, subjects with low 
amplitude titration of ~250 mA (800/250, high fixed/titration amplitude ratio) will have 
significant changes in hippocampal neuroplasticity. Subjects with high amplitude titration 
~500 mA (800/500, low fixed/titration ratio) will have minimal changes in hippocampal 
neuroplasticity. The relationship between amplitude titration and fixed amplitude 
hippocampal neuroplasticity will be used to develop the amplitude multiplier required for 
consistent and clinically effective ECT dosing. A randomized controlled trial will then 
compare hippocampal neuroplasticity, antidepressant, and cognitive outcomes between 
amplitude titration with neuroplasticity multiplier (fixed pulse number) and traditional 
fixed amplitude ECT (800 mA, variable pulse number) in older depressed subjects. 
 
3. Study Design 
 
Subjects will receive their baseline imaging, clinical, and neuropsychological assessment 
24 to 48 hours prior to the first ECT session (V1). Subjects will first receive RUL amplitude 
titration (first treatment) and then RUL fixed amplitude (800 mA) and fixed pulse number 
ECT (subsequent treatments). We will 1) verify results from pre-translational 
investigations that demonstrated the relationship between current pulse amplitude and a 
whole brain E-field metric (I/Ebrain), and 2) determine the relationship between current 
pulse amplitude and treatment-responsive changes in hippocampal neuroplasticity from 
RUL fixed-amplitude (800 mA) ECT. Treatments will continue thrice weekly until clinical 
response, which typically occurs between six and twelve treatments 14. Subjects will 
receive their second assessment (V2) one day after the sixth ECT treatment and the final 
assessment (V3) one day after the ECT series. Subjects who do not demonstrate 
improvement by the V2 assessment (< 25% reduction from baseline IDS-C30 total score) 
will transition to traditional BT for the remainder of the ECT series. The anesthesiologist 
will determine the appropriate dose of methohexital (general anesthetic) and 
succinylcholine 
(depolarizing 
neuromuscular 
blocker). 
Anesthetic 
medications, 
electroencephalographic seizure duration, motor seizure duration, and maximum ictal heart 
rate will be recorded for each treatment. 
 
Subjects (n = 40) will receive amplitude titrated seizure threshold during the first treatment 
with RUL 105. The Soterix 4X1 High Definition ECT Multi-channel Stimulation Interface 
(“Soterix Interface”) is a passive amplitude reducer for the MECTA 5000Q. The Soterix 
Interface reduces the amplitude range to 200 mA and permits 50 mA incremental dosing 
throughout the 200 to 900 mA dosing range. Pulse width (1.0 ms), pulse train duration 
(8 s), and frequency (20 Hz, 320 pulses) will be fixed for amplitude titration. Subjects will 
receive stimulations starting with 200 mA with 50 mA increases until seizure activity is 
initiated. Clinical judgement will define seizure adequacy based on duration and 
morphology. In addition, subjects will receive amplitude titrated motor threshold after 
administration of general anesthesia during the second ECT treatment (exploratory aim, 
see “Motor Titration” below). After amplitude titrated seizure threshold, subsequent 
treatments will be completed with RUL fixed 800 mA with the same pulse width (1.0 ms) 
and pulse number (8 s, 20 Hz, and 320 pulses). If the subject fails to demonstrate 
improvement at V2 (< 25% reduction from baseline IDS-C30 total score), the subject will 
then receive traditional BT for the remainder of the ECT series. 

 
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Version Date: 11/19/2020 
 
4. Inclusion and Exclusion Criteria 
 
Entry criteria will include men and women of all backgrounds.  
 
Inclusion criteria: 1) Structured Clinical Interview for DSM-5 (SCID-5) will confirm 
diagnosis of major depressive disorder (MDD; with or without psychotic features); 2) 
clinical indications for ECT with right unilateral electrode placement including treatment 
resistance or a need for a rapid and definitive response, 3) right-handedness,  4) age range 
between 50 and 80 years, and 5) English-speaking (many of the neuropsychological tests 
are only available in English). Antidepressant medications will be continued as clinically 
indicated. To maintain feasibility and retention, as needed medications will be permitted 
for anxiety (lorazepam, total dose 2mg/day) and insomnia (trazodone, total dose: 
150mg/day). Late-life depression is often associated with cognitive impairment. 
Cognitive impaired older adults will be included in the study sample.  
 
Exclusion criteria: 1) Defined neurological or neurodegenerative disorder (e.g., 
traumatic brain injury, epilepsy, Alzheimer’s disease); 2) other psychiatric conditions 
(e.g., schizophrenia, bipolar disorder); 3) current drug or alcohol use disorder (except 
for nicotine); 4) contraindications to MRI; 5) prisoners; and 6) pregnancy (pre-
menopausal participants will receive pregnancy test, which is clinically indicated for 
ECT and not part of study protocol).  
 
5. Number of Subjects 
 
We will recruit 40 subjects who meet inclusion criteria.  
 
6. Study Timelines 
 
Our total sample size (n = 40) allows for a conservative 20% attrition rate leaving a final 
sample size of 32. This recruitment rate of 20 subjects per year will complete subject 
recruitment 2 years after study initiation. We have a successful recruitment and retention 
history for ECT-imaging investigations of approximately 20 subjects per year with this 
demographic for the last decade and are well poised to meet the recruitment/enrollment 
goals delineated in this project proposal. 
 
7. Study Endpoints 
 
After recruiting a minimum of 32 subjects, we will assess the following relationships: 1) 
amplitude-determined seizure threshold and whole brain conductivity metrics (I/Ebrain); 
and 2) amplitude titration and changes in right hippocampal volume with 800 mA ECT. 
 
8. Research Setting 
 
All data collection will take place at the UNM Center for Psychiatric Research, the Mind 
Research Network or the ECT service at the University of New Mexico. All clinical 

 
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assessments and neuropsychological testing will be conducted in an interview room. These 
rooms are scheduled by research staff. The MRI scanner is located at the Mind Research 
Network. The optional EEG monitoring will be conducted at the ECT clinical services: the 
UNMH Post Anesthesia Care Unit (inpatient) or UNM Outpatient Surgical Imaging 
Services (outpatient). 
 
9. Resources Available 
 
Investigators:  
• The PI (Dr. Abbott) has recently completed a NIH U01 BRAIN Initiative project 
(MH111826) focused on ECT amplitude and medial temporal lobe engagement that 
provided the preliminary data for this protocol.  Dr. Abbott has received extramural 
funding focused on ECT-neuroimaging investigations since 2012. He is the UNM 
Neuromodulation Division Chief, Medical Director of the UNM ECT Service, and a 
member of the Global ECT MRI Research Collaboration (GEMRIC) steering 
committee. He has completed career training awards focused on neuroimaging 
biomarkers associated with late-life depression and has numerous peer-reviewed 
publications on neuroimaging correlates of ECT response. ECT, clinical and cognitive 
assessments and neuroimaging data acquisition will be conducted at the UNM/Mind 
Research Network in Albuquerque, New Mexico.  
• Dr. Davin Quinn (UNM), Medical Director of the UNM Consultation Liaison Service, 
has an extramural funding focused on neurostimulation in neuropsychiatric disorders, 
including late-life depression. He is the UNM Psychosomatics Division Chief, Medical 
Director of the UNM TMS Service, and the UNM Chief of Staff. He has worked with 
Dr. Abbott on the UNM ECT service for the last ten years and will assist with subject 
recruitment and assessments.  
• Dr. Erik Erhardt (Co-I, UNM) has expertise in neuroimaging and statistical expertise. 
He has been a key collaborator with past and current investigations with study design, 
statistical analysis, and result interpretation.  
 
Soterix High Definition ECT Multi-
channel 
Stimulation 
Interface 
(information from Soterix Operator’s 
Manual): The Soterix 4X1 HD-ECT Multi-
Channel Stimulation Interface (“Soterix 
Interface”) is an accessory to a 2-channel 
ECT stimulator and does not function as a 
stand-alone 
electrical 
stimulator 
or 
generator. The Soterix Interface is designed 
to be used as an interface device and the 
stimulation leads. The device is designed to 
be operated in either SCAN or PASS 
modes. The SCAN mode is used to 
determine lead quality values prior to switching to the PASS mode. The PASS mode 
provides the option for attenuating ECT device output. When the attenuation feature is 
enabled, the PASS mode only attenuates the stimulus current amplitude leaving other 
 
Figure 2. Soterix 4X1 High Definition ECT 
Multi-channel Stimulation Interface 

 
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treatment parameters unchanged (pulse width, frequency and pulse train duration). The 
attenuated current range is between 200 – 500 mA with 2 mA increments (50 mA dose 
increments will be used in this proposal). The Patient Stimulus cable (output cable of the 
ECT device) is used to connect the device to the Soterix Interface, which will then connect 
to right unilateral stimulation electrodes (traditional stimulation handles with 5 cm 
spherical diameter). The Research Strategy delineates how the Soterix Interface will be 
used in this project. We have received FDA Investigational Device Exemption approval to 
use the Soterix Interface for this investigation.  
 
MRI: Siemens 3T Trio with Total Imaging Matrix (TIM) Application Suite (Mind 
Research Network): The Trio 32-channel system represents state of the art in MRI 
hardware. It is capable of BOLD EPI, diffusion tensor imaging, perfusion and diffusion 
imaging, and spectroscopy. With 32 usable receiver channels as standard, the system 
allows for the use of current phased array coils (from 4 to 16) to improve sensitivity and 
speed of acquisition and is ready for future coil designs with more than 16 elements. This 
system is interfaced to an MR-compatible patient monitoring. The MRI is non-contrast. 
 
10. Prior Approvals 
 
Departmental Review Form signed by Department Chair is uploaded into Click under 
“supporting documents.” Investigational Device Exemption approval from the Food and 
Drug Administration for the Soterix Interface was received on July 10, 2020 (see 
“supporting documents”). Additionally, we have obtained a letter of support from Dr. 
Abhishek Datta, Scientist and Chief Technology Officer of Soterix Medical. 
 
11. Multi-Site Research 
 
N/A 
 
12. Study Procedures  
 
Study Protocol: Subjects will receive their baseline imaging, clinical, and 
neuropsychological assessment 24 to 48 hours prior to the first ECT session (V1). 
Treatments will continue thrice weekly until clinical response, which typically occurs 
between six and twelve treatments 14. Subjects will receive their second assessment (V2) 
one day after the sixth ECT treatment and the final assessment (V3) one day after the ECT 
series. Subjects who do not demonstrate improvement by the V2 assessment (< 25% 
reduction from baseline IDS-C30 total score) will transition to traditional BT for the 
remainder of the ECT series. The anesthesiologist will determine the appropriate dose of 
methohexital (general anesthetic) and succinylcholine (depolarizing neuromuscular 
blocker). Anesthetic medications, electroencephalographic seizure duration, motor seizure 
duration, and maximum ictal heart rate will be recorded for each treatment. 
 
Subjects (n = 40) will receive amplitude titrated seizure threshold during the first treatment 
with RUL 105. The Soterix 4X1 High Definition ECT Multi-channel Stimulation Interface 
(“Soterix Interface”) is a passive amplitude reducer for the MECTA 5000Q. The Soterix 

 
Page 12 of 32 
Version Date: 11/19/2020 
Interface reduces the amplitude range to 200 mA and permits 50 mA incremental dosing 
throughout the 200 to 900 mA dosing range. Pulse width (1.0 ms), pulse train duration (8 s) 
frequency (20 Hz, 320 pulses) and will be fixed for amplitude titration. Subjects will 
receive stimulations starting with 200 mA with 50 mA increases until seizure activity is 
initiated. Clinical judgement will define seizure adequacy based on duration and 
morphology. In addition, subjects will receive amplitude titrated motor threshold after 
administration of general anesthesia during the second ECT treatment (exploratory aim, 
see “Motor Titration” below). After amplitude titrated seizure threshold, subsequent 
treatments will be completed with RUL fixed 800 mA (traditional amplitude) with the same 
pulse width (1.0 ms) and pulse number (8 s, 20 Hz, and 320 pulses). If the subject fails to 
demonstrate improvement at V2 (< 25% reduction from baseline IDS-C30 total score), the 
subject will then receive traditional bitemporal electrode placement for the remainder of 
the ECT series. 
 
Clinical 
Assessments: 
The 
clinician-rated 
30-item 
Inventory 
of 
Depressive 
Symptomatology (IDS-C30) will be the primary depression severity measure 83. The 
number of subjects transitioning to bitemporal electrode placement after the mid-ECT 
assessment (V2, see Study Protocol) will be the secondary depression outcome. The IDS-
C30 includes depressive items in accordance with the DSM-5. Each item is scored from 0 - 
3 and summed for a total score between 0 – 84. The initial visit (V1) will also include the 
Maudsley Staging Method to measure antidepressant treatment resistance within the 
current depressive episode 84, ECT Appropriateness Scale to assess the indication for ECT 
85, Medical History form to gauge overall medical burden, Framingham Stroke Risk Profile 
to measure vascular burden 86, and Edinburgh Handedness Inventory to define handedness 
87. Additional characteristics of the current and past depressive episodes will also be 
recorded during the initial visit: age of onset, age of first treatment, number of depressive 
episodes, and depressive episode duration.  
Rationale: The IDS-C30 has excellent psychometric properties 88, includes symptoms 
relevant to depression subtypes (melancholic and atypical), and converts to other 
depression rating scales relevant to NIH data sharing. 
 
Neuropsychological Assessments: The Delis Kaplan Executive Function System (DKEFS) 
Verbal Fluency test will be the primary cognitive measure 89. The Montreal Cognitive 
Assessment (MOCA), a measure of global cognitive function that is sensitive to gross 
neurocognitive abnormalities, will screen for preexisting cognitive impairment 90,91. The 
Test of Premorbid Function (TOPF) will estimate premorbid intellectual function for use 
as a covariate in cognitive analyses 92. The Dot Counting Test will measure performance 
validity 93. The Autobiographical Memory Test will assess multiple aspects (free recall, 
retrieval pattern, cognitive efficiency) of retrospective autobiographical memory 94-96. The 
Hopkins Verbal Learning Test-Revised (HVLT-R) will measure verbal learning and 
memory 97,98. To minimize practice effects, each time point will use a different published 
HVLT-R version 99. The DKEFS Color-Word Interference test will measure processing 
speed, inhibition, initiation, and cognitive flexibility 89,100-103. The DKEFS Verbal Fluency 
test will measure phonemic and semantic fluency, and cognitive flexibility. The DKEFS 
Tower Test will measure planning and problem solving 89. Lastly, the NIH Toolbox Flanker 
Inhibitory Control and Attention Test will measure attention and inhibition 104. 

 
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Version Date: 11/19/2020 
 
Neuroimaging Acquisition and Data Processing 
Imaging data will be collected on a 3-Tesla Siemens PRISMA scanner with strong 
gradients and minimal shading artifact and a 32-channel coil using multiband sequences 
at the Mind Research Network (MRN). The imaging acquisitions relevant to this project 
include the following: 
1. sMRI (T1): Repetition time (TR) = 2530 milliseconds (ms), echo time (TE) = 1.64, 3.5, 
5.36, 7.22, 9.08 ms, Inversion time (TI) = 1200 ms, flip angle = 7.0 °, slices = 192, field 
of view = 256, matrix 256 × 256,  voxel size = 1.0 × 1.0 × 1.0 millimeter (mm) and 
total acquisition time 6:03 (minutes: seconds). 
2. sMRI (T2): TR = 2530 ms, TE = 474 ms, flip angle = 120.0 °, slices = 192, field of 
view = 256, matrix 256 × 256, voxel size = 1.0 × 1.0 × 1.0 mm and total acquisition 
time = 5:09. 
3. High-resolution T2: TR = 8020 ms, TE = 80 ms, flip angle = 150.0 °, slices = 30, field 
of view = 150, matrix 384 × 384, voxel size = 0.4 × 0.4 × 0.2 mm and total acquisition 
time = 7:05. 
 
Preprocessing steps with each imaging modality include the following: 
1. FreeSurfer Segmentation (T1 and T2): FreeSurfer 6.0 is a set of software tools that 
utilize the T1 and T2 weighted scans to study the cortical and subcortical anatomy. In 
the cortical surface stream, the tools construct models of the boundary between white 
matter and cortical gray matter as well as the pial surface. Once these surfaces are 
known, an array of anatomical measures becomes possible, including subcortical 
volumes, cortical thickness, surface area, curvature, and surface normal at each point 
on the cortex. 
2. Medial Temporal Lobe Segmentation (High resolution T2): The Automatic 
Segmentation of Hippocampal Subfields (ASHS) uses T1- and high-resolution T2-
weighted MRI to segment and label hippocampal subfields and medial temporal lobe 
cortices. The automatic labeling technique uses multi-atlas segmentation and 
similarity-weighted voting with a learning-based correction 110,111. An unbiased 
deformation-based morphometry pipeline will then estimate longitudinal changes in 
hippocampal subfields 112. Deformable image registration with a cross-correlation 
similarity metric generates a point-by-point correspondence map between images at 
two time points (baseline and follow-up). To avoid bias, registration is performed in a 
“half-way” space, and equal amounts of deformation and interpolation are applied to 
the baseline and follow-up images. A mesh representation of the ASHS segmentation 
of the medial temporal lobe substructures in the baseline image is used to measure 
change in volume between baseline and follow-up. 
3. Electric Field Modeling: Our research team has extensive experience with t E-field 
modeling approaches. The Realistic vOlumetric Approach to Simulate Transcranial 
Electric Stimulation (ROAST) and Simulation of Non-Invasive Brain Stimulation 
(SimNIBS) were both used for our preliminary data 30,31. Here, we describe the 
SimNIBS methods, which informed our power analyses. SimNIBS creates subject 
specific, anatomically realistic volume conductor model. The T1 and T2-weighted 
scans are segmented into skin, bone, eyes, cerebral spinal fluid, ventricles, and grey 
and white matter with a combination of FMRIB Software Library (FSL) 113 and 

 
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Version Date: 11/19/2020 
Statistical Parametric Mapping 12 (SPM12) Computational Anatomy Toolbox 114,115. 
SimNIBS then turns this segmentation into a tetrahedral head mesh using GMSH, a 
three-dimensional finite element (FE) mesh generator, with unique conductivity values 
for each tissue type. Electrodes are added to the head mesh in either RUL or BT 
orientation and simulated with corresponding current. SimNIBS then uses a FE solver 
to calculate the voltages and electric fields corresponding to the stimulation throughout 
the head mesh. 
 
FDA Investigational Device Exemption:  Investigational Device Exemption approval from 
the Food and Drug Administration for the Soterix Interface was received on July 10, 2020. 
Additionally, we have obtained a letter of support from Dr. Abhishek Datta, Scientist and 
Chief Technology Officer of Soterix Medical. We have a successful recruitment and 
retention history for ECT-imaging investigations of approximately 20 subjects per year 
with this demographic for the last decade and are well poised to meet the 
recruitment/enrollment goals delineated in this project proposal. Future investigations will 
focus on the optimal strength of hippocampal volumetric increases to further clarify the 
“sweet spot” of antidepressant response in conjunction with cognitive safety. 
 
13. Data Analysis 
 
Preliminary Data: Amplitude titration has been completed with non-human primates but 
has yet to be completed with human subjects and modern ECT parameters. I/Ebrain bridges 
the gap from amplitude titration in non-human primates to changes in hippocampal 
neuroplasticity in human subjects.  I/Ebrain is the ratio of electrode current strength (I) to 
the E-field strength in the brain (Ebrain) 21. Ebrain will be computed as the 90th percentile of 
E-field magnitudes from all voxels in the brain, serving as an estimate of the peak induced 
field strength while avoiding the influence of tissue boundary effects that could bias the 
absolute maximum E-field values. For example, one subject with 800 mA extracranial 
amplitude produces 0.8 V/cm 90th percentile E-field strength. The ratio would be 
1000 mA/V/cm, which means 1000 mA produces 1 V/cm. A second subject with the same 
800 mA extracranial amplitude produces 1.2 V/cm 90th percentile E-field. The ratio would 
be 667 mA/V/cm, which means 667 mA produces 1 V/cm. Ebrain is a whole brain E-field 
metric as the location of seizure duration is unknown. 
 
The relationship from amplitude titration to hippocampal neuroplasticity is 
illustrated here (Figure 4). First, we demonstrate that amplitude-titrated seizure threshold 
increases with I/Ebrain in non-human primates (4A). Second, we demonstrate that increased 
I/Ebrain is related to decreased hippocampal E-field (current dependent metric, input current 
set here at 1 mA) (4B1). For fixed amplitude ECT, I/Ebrain is inversely related to 
hippocampal volume change. Ehippo is the 95th percentile E-field in the hippocampus and 
will be an exploratory measure of this investigation. However, the focus on amplitude 
titrated seizure threshold requires Ebrain, a whole brain E-field metric, as the regions 
involved in seizure induction are unknown. Third, we demonstrate that increased 
hippocampal E-field is related to increased hippocampal neuroplasticity across all 
amplitudes (600, 700, and 800 mA) and electrode placements (RUL and BT) (4B2). This 
relationship is a replication of the GEMRIC data (Figure 2) with our U01 data. Fourth, we 

 
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performed an analysis of a subset of our data comparing I/Ebrain with hippocampal 
volumetric change with 800 mA subjects (4B3). 
 
 

 
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Figure 4: The multi-step relationship from amplitude titration to hippocampal neuroplasticity. 
A) Non-human primate data. Ielectrode/Ebrain (see description in Preliminary Data). Increased 
I/Ebrain is related to increased amplitude required for seizure titration (r = 0.84, p < 0.0001). 
B1) U01 data, all subjects. Ielectrode/Ebrain is inversely related to hippocampal E-field magnitude 
with an amplitude intensity of 1 mA, which is baseline for E-field modeling (r =-0.79, Cohen’s 
f2 =1.66). 
B2) U01 data, all subjects. Electrode placement (RUL and BT) and amplitude (600, 700, 
800 mA) are based on the subject’s last treatment. Right hippocampal E-field magnitude is 
directly related to right hippocampal neuroplasticity for all amplitude strengths (600, 700, and 
800 mA) and electrode placements (right unilateral and bitemporal) (r = 0.49, Cohen’s f2 = 
0.33). 
B3) U01 data, subjects from the 800 mA arm. Ielectrode/Ebrain is inversely related to right 
hippocampal neuroplasticity for 800 mA subjects (r = -0.62, Cohen’s f2 = 0.62). 
C1) Hypothesized relationship. Increased Ielectrode/Ebrain is related to increased amplitude 
required for seizure titration (verification of non-human primate data depicted in 4A). 
C2) Hypothesized relationship (Go-No-go). The ratio of fixed amplitude ECT (800 mA) relative 
to amplitude seizure titration will be associated with right hippocampal neuroplasticity. 
A
B1
B3
B2
C1
C2
Seizure threshold (mA)
IElectrode/Ebrain

 
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Summary, interpretation, and alternatives: To illustrate the application of these principles, 
we use our preliminary data (4B3) and hypothesized relationships (4C1 and 4C2). We also 
use the example of 2% hippocampal growth as optimal for antidepressant response 
(optimal hippocampal growth will be determined with a receiver operating curve (ROC) 
curve predicting Inventory of Depressive Symptomatology (IDS-C30) total score decrease 
during the R61). With traditional 800 mA amplitude, the 2% volume increase is related to 
an I/Ebrain of ~ 625 mA/V/cm (4B3) and fixed/amplitude ratio of ~ 2.7 (4C2). Subject #1 
(orange star) has a low (250 mA) seizure threshold (ST) (4C1), I/Ebrain of ~ 600 mA/V/cm 
(4C2) and a fixed/amplitude ratio of 800/250 = 3.2 (4C2). Subject #1 will need an input 
current of 2.7 ×  𝑆𝑇= 2.7 × 250 𝑚𝐴= 675 𝑚𝐴 for 2% hippocampal volume increase. 
In contrast, Subject #2 (green star) has a high (350 mA) seizure threshold, I/Ebrain of ~ 
750 mA/V/cm and a fixed/amplitude ratio of 800/350 = 2.3. In order to achieve the 2% 
volumetric increase, Subject #2 will require an increased X/amplitude ratio from 2.3 to 2.7. 
Subject #2 will need an input current of 2.7 ×  𝑆𝑇= 2.7 × 350 𝑚𝐴= 950 𝑚𝐴 for 2% 
hippocampal volume increase. We stress that the fixed/amplitude ratio ~ 2.7 for 2% 
hippocampal volume increase is conceptual and will be determined during the R61. 
 
H1: Amplitude seizure titration will have a positive correlation with I/Ebrain (Figure 4C1). 
This is a replication of the data from the non-human primate data. The relationship between 
I/Ebrain and amplitude titration is the foundation for the rationale of this proposal. 
Statistical approach for H1: Let (x, y)i be the observed vector of response for I/Ebrain and 
seizure threshold for each patient, I = 1, …, n.  The Pearson correlation will be calculated 
and the standard one-sided t-test with 2 degrees-of-freedom will be conducted for testing 
whether the correlation is positive, H0: ρ > 0. 
Power calculation for H1: The observed correlation in Figure 4A is r = 0.84 for non-human 
primates and we expect that the more conservative Cohen’s “large” effect size r = 0.5 is a 
realistic lower bound for our population, thus a sample size of n = 29 provides 80% power 
at a 0.05 / 2 = 0.025 significance level. 
 
Go/No-Go criterion (H2): The ratio of amplitude titration to fixed amplitude ECT will 
demonstrate a linear relationship with treatment-responsive changes in hippocampal 
neuroplasticity. This relationship will determine the “neuroplasticity multiplier” to bridge 
from amplitude titration to hippocampal neuroplasticity. 
Statistical approach for H2: We will perform a multiple regression accounting for 
covariates age and sex, %VolScaled Change = β0 + β1 M + β2 age + β3 sex, where the effect 
size is f2 = R2 / (1 − R2), with R2 the coefficient of determination with the interpretation of 
"the proportion of variance explained" in the response by the model over the grand mean. 
We will test whether the regression model explains a significant proportion of variance in 
the response, expecting that the key relationship is between %VolScaled change and 
multiplier M. 
Power calculation for H2: The relationship we are expecting in Figure 4C2 is derived from 
Figures 4B3 and 4C1. Starting with Figure 4B3, the relationship of I/Ebrain on %VolScaled 
change has a correlation of r = −0.62 with an effect size f2 = 0.624, well above the Cohen's 
"large" effect size of f2 = 0.35. Figure 4C1 is Figure A with the axes reversed, thus the 

 
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correlation is r = 0.84. We will assume that the relationship between %VolScaled Change 
and multiplier M will remain consistent with Cohen's "large" effect size. Then a sample 
size of n = 36 provides 80% power at a 0.05 significance level. 
 
The Holm Procedure, a multi-step step-down procedure useful for endpoints with any 
degree of correlation, will adjust the two hypotheses below for multiple comparison 37. For 
our situation, this means H1 is tested at the 0.05 / 2 significance level and H2 is tested at 
0.05 / (2−1) = 0.05; however, H2 is tested only if H1 is significant. 
 
The Go/No-Go criterion is set to “Go” if we can reject the null hypothesis that H0: β1=0 at 
a 0.05 significance level in the model specified in Hypothesis H2, that is, that multiplier M 
remains a significant predictor of %VolScaled Change after adjusting for age and sex. 
 
14. Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
Data safety and monitoring will be carried out to ensure and maintain the scientific integrity 
of this project and to protect the safety of our participants. Safety monitoring is the process 
during the study that involves review of accumulated outcome data for groups of subjects 
to determine if any of the procedures practiced should be altered or stopped. Ultimately, 
the PI (Abbott) will be responsible for monitoring the safety of the study and complying 
with the reporting requirements. An independent Data Safety and Monitoring Board 
(DSMB) will review the study data on a biennial basis with the PI to ensure participant 
safety (re: subject recruitment at 20 subjects/year, DSMB meetings every ~ 10 
participants). The Data Safety and Monitoring Board will include Dr. Sarah Pirio 
Richardson (DSMB Chair/Dept. of Neurology), Dr. Kathleen Reyes (Dept. of 
Anesthesiology), and Dr. Eric Clause (PI at Mind Research Network). The board members 
have no conflicts of interest or roles with the current project. Drs. Pirio Richardson and 
Claus have experience participating in ECT-related DSMB, and Dr. Reyes has extensive 
clinical experience with ECT. Continuous, close monitoring of participant safety will 
include prompt and frequent reporting of safety data (i.e., adverse/serious adverse events) 
to the DMSB, the University of New Mexico Health Sciences Center Institutional Review 
Board (UNMHSC IRB) and/or appropriate NIH staff with oversight responsibility. The 
focus of adverse event reporting will be the first treatment of the ECT series, which is the 
only experimental treatment for this phase of the project. The first treatment will be 
amplitude titration (as opposed to the more traditional titration based on pulse number or 
frequency). The amplitude titration will result in reduced amplitudes (hypothesized range 
will be between 250 and 550mA, traditional ECT is conducted at 800mA). Adverse events 
may include expected side effects related to ECT: headaches, nausea (from anesthesia), 
and muscle aches (from anesthesia). Unexpected side effects (to be determined) will also 
be reviewed with the DSMB. In addition, relevant published data related to the study 
protocol will also be presented to the DSMB. The DSMB will evaluate the adverse effects 
of the first treatment in relation to the expected side effects related to a traditional ECT 
series. The PI will provide a summary of the safe conduct of the study to NIH and FDA on 
an annual basis as part of the progress report. All AEs occurring during the course of the 
study will be collected, documented, and reported to the UNMHSC IRB. The review of 
data may result in early termination of the study, amendment to the protocol, or changes to 

 
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the data collection plan or study forms if it appears that there are adverse events directly 
related to the first (experimental) treatment. Significant adverse events directly related to 
the experimental treatment (amplitude titration, treatment#1) such as hospitalization and 
death will warrant suspension or termination of research. Should the protocol, data 
collection plans or study forms be amended as a result of data review, the IRB will be 
notified and the amendment approved prior to study amendment implementation. In 
addition, the participants will be notified of any significant new findings that develop 
during the course of research that may affect their wish to continue participation in the 
study.  
 
15. Withdrawal of Subjects 
 
If at any time a participant decides to withdraw from the study, the participant will be 
debriefed by the study coordinator or principal investigator as to the reason for their 
withdrawal. The participant will then be thanked for their time and compensated for the 
extent of their participation. If the participant wishes to withdraw, they will be asked if they 
will allow data already collected on them to be used in the study analysis. If not, the data 
associated to their identifying code will be purged from the study database. A participant 
could be excluded and withdrawn from the research study in the event that a pre-determined 
condition exists, including a defined neurological or neurodegenerative disorder (e.g., 
traumatic brain injury, epilepsy, Alzheimer’s disease), other psychiatric conditions (e.g., 
schizophrenia, bipolar disorder), current drug or alcohol use disorder (except for nicotine), 
and/or contraindications to MRI. 
 
16. Data Management/Confidentiality 
 
Every effort will be made to protect the confidentiality of participants’ records. However, 
complete confidentiality of records cannot be guaranteed as records may be examined by 
authorized personnel from the UNM Human Research and Review Committee. 
Participants will be informed of this possibility prior to signing the consent forms. 
Otherwise, records will be kept strictly confidential and will not be inspected by any other 
agency unless required by law. Behavioral and computerized data from the MRI scanning 
sessions will not contain participants’ names or any other identifying information per 
HIPAA requirements. Data will be de-identified as appropriate to the UNM Human 
Research and Review Committee and HIPPA requirements by assigning a randomized 
eight-digit number to each participant upon entry into the study. This number will be used 
for all correspondence between study investigators and all data collection and analysis after 
the initial screening visit. MRN has a state-of-the art IT network with all necessary security 
mechanisms in place. Any personal information entered into computers is password 
protected and monitored for suspicious activity. In order to contact subjects for telephone 
visits and/or other matters, it will be necessary to retain names and telephone numbers of 
active subjects. However, these direct identifiers will not be stored with any clinical data 
or subject information in order to protect confidentiality. Any direct identifiers will be 
stored in locked cabinets, on a secure MRN server, and/or the COINS database on a secure 
HIPAA compliant cloud based server, separate from any clinical data. These will only be 
accessible by key study personnel. A link between study code numbers and direct 

 
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identifiers will be retained in order to contact subjects for visit appointments or at a later 
date to inform them of newly received information. This link will be retained for the 
duration of the study. Subjects will be identified only by unique Patient ID numbers in 
Case Report Forms (CRFs) and electronic CRFs. The CRFs will be maintained in a locked 
cabinet housed in the Center for Psychiatric Research. These documents will only be 
accessible by authorized study staff and will comply with HIPPA requirements for the 
storage of health information. Moreover, all information will be in double-locked rooms 
per HIPAA specifications. At the time of study closure, all participant identifiers (name, 
address, etc.) will be made inaccessible to the research team. MRN retains the link between 
identifiers and URSI indefinitely for the potential future benefit to the research participant. 
Specifically, it may become medically advantageous in the future for a former participant 
to have access to the clinical information that may be present in radiological scans and 
reviews. The results of this research may be presented at meetings or in publications; 
however, participants’ identity will not be disclosed. The participant will be provided with 
a copy of the consent form to take home. 
 
17. Data and Specimen Banking 
 
Data will be stored in locked cabinets at the UNM Center for Psychiatric Research. 
Subjects' charts will be stored without direct identifiers. Only research staff designated by 
Dr. Abbott will have access to these records. Other than the research team, the study 
sponsor and the HRRC will be permitted access to the records. In order to contact subjects 
for telephone visits and/or other matters, it will be necessary to retain names and telephone 
numbers of active subjects. However, these direct identifiers will not be stored with any 
clinical data or subject information in order to protect confidentiality. Any direct identifiers 
will be stored in locked cabinets and on a secure MRN server, and/or the COINS database 
on a secure HIPAA compliant cloud based server, separate from any clinical data. These 
will only be accessible by key study personnel. A link between study code numbers and 
direct identifiers will be retained in order to contact subjects for visit appointments or at a 
later date to inform them of newly received information. Information collected will be 
labeled with a study number and will be entered in to a secure MRN server, and/or the 
COINS database on a secure HIPAA compliant cloud-based server. Data linking scan to 
identity will be maintained at the Mind Research Network indefinitely allowing the 
neuroradiologist to compare future scans with previous ones. Research data (not including 
scan data) will be de-identified after the study is complete and closure documents are 
submitted to the UNM IRB. 
 
Electronic Data: Collaborative Neuroinformatics Suite (COINS). This cloud-based 
neuroimaging and neuropsychology software suite offers versatile, automatable data 
upload/import/entry options, rapid and secure sharing of data among PIs, querying and 
export all data, real-time reporting, and HIPAA and IRB compliant study-management 
tools suitable to large institutions as well as smaller scale neuroscience and 
neuropsychology researchers. Network is accessed on a secure MRN server, and/or a 
HIPAA compliant cloud-based server which has firewalls in place. Controlled access is 
granted to only study team members. 
 

 
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As per NIMH mandate, the de-identified data will be submitted to the National Institute of 
Mental Health Data Archive (NDA). NDA is a data repository run by the National Institute 
of Mental Health (NIMH) that allows researchers studying mental illness to collect and 
share de-identified information with each other. During and after the study, the UNM 
research team will send de-identified information to NDA. Other researchers nationwide 
can then file an application with the NIMH to obtain access to de-identified study data for 
research purposes. Experts at the NIMH who know how to protect health and science 
information will look at every request carefully to minimize risks to your privacy. In 
addition, de-identified information will be available at the Mind Research Network Data 
Sharing Repository for future research. Both the NDA and Mind Research Network Data 
Repositories are clearly described in the “Data Sharing” section of the consent form. 
 
18. Risks to Subjects 
 
Participation in this study may involve minor risks and/or discomforts associated with 
possible breach of confidentiality risk, neuropsychological testing, MRI, and lower 
amplitude ECT. 
 
Due to the coronavirus public health crisis, participants will receive regular COVID-19 
testing as part of their standard ECT treatment procedure.  Participation in this study may 
entail increase risk of exposure to COVID-19 during interactions with research staff. 
However, research staff adhere to all safety operating procedures required by UNM HSC, 
NMDOH and the CDC.   
 
MRI: Radio and magnetic waves associated with MRI scans are not associated with any 
known adverse effects. MRI is non-invasive, non-contrast, and considered minimal risk by 
the FDA and OHRP. However, the scanner is a large magnet, so it could move objects 
containing ferrous metal in the room during the scan. All participants are screened using 
the MRI safety screening form prior to be being scanned. Participants with any MRI 
scanning contraindications will be excluded from study participation. Participants may be 
bothered by feelings of claustrophobia (uncommon). The MRI also makes loud ‘drum’ 
beating noises during the study. Headphones are provided for protection. Rarely, large or 
recent tattoos can heat up during an MRI scan and cause skin irritation like a sunburn 
(uncommon). No long-term harmful effects from MRI are known. However, since the 
effect of MRI on early development of the fetus is unknown, participants who are pregnant 
will not be allowed to go in the MRI. Females 18 years of age or older who suspect they 
may be pregnant will be asked to take a urine pregnancy test before being allowed to 
participate in the study. The test results will only be shared with participant. The MRI risks 
include identification of incidental findings and potential cost for follow-up or clinical 
scans. 
 
Neuropsychological tests and clinical assessments: The neuropsychological tasks involved 
in the protocol entail no foreseeable risk, besides perhaps fatigue or mild to moderate 
demands on attention and cognition. 
 
 

 
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19. Potential Benefits to Subjects 
 
The potential benefits of the proposed research for the research participants are minimal. 
Any abnormal findings on structural MRI scans will be reported to the participant and/or 
their doctor per the participant’s request. This may lead to early detection of previously 
unknown abnormalities. However, for the large majority of participants, the proposed 
research will not have any benefit. 
 
20. Recruitment Methods 
 
The UNM ECT Treatment Program receives referrals from inpatient and outpatient 
providers at the UNM Mental Health Center. The treatment team will clinically determine 
who will be eligible for the study and document this in the subject’s study records. The 
research team will only approach patients for the study protocol who speak English and 
have been identified by the primary treatment team. Patients diagnosed with Major 
Depression are eligible for ECT treatment will be recruited from the UNM ECT Treatment 
Program. 
 
21. Provisions to Protect the Privacy Interests of Subjects 
 
The Center for Psychiatry Research handles all confidential data carefully and works to 
maintain subject privacy and confidentiality. From the standpoint of privacy and 
confidentiality, the subject's welfare will be safeguarded by responsible, systematically 
controlled procedures in the collection of information for both clinical and research 
purposes. In terms of privacy, subjects will first arrive at the research clinic, housed in 
UNM HSC Center for Psychiatric Research in the Neurobiology Building, 1101 Yale Blvd 
NE, 2nd floor. Interaction with subjects will be in the Psychiatry Research Clinic and will 
only be with relevant staff and/or with family members that they choose to be present. 
Interviews are held in closed door offices and will be conducted in a manner most 
comfortable to subjects. Subjects may refuse to answer any question at any time. Recorded 
information for research purposes will be identified only by subject initials and a study 
code number. Subject data will be kept in locked cabinets in the research clinic with limited 
access granted only to designated research personnel. These processes will be in place 
throughout the entire research process, from initial consenting to research, through research 
procedures, and follow-up. The study PI will maintain confidentiality of all records to the 
extent permitted by applicable laws. Records may be inspected by representatives of the 
study sponsor, the HRRC and other regulatory agencies. If results are presented or 
published, subjects’ identities will remain confidential. 
 
22. Economic Burden to Subjects 
 
The costs of the MRIs and office visits required by the research will be covered by the 
study. Subjects will be not placed under economic burden due to this trial. 
 
23. Compensation 
 

 
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This study will require attending three visits that will last approximately 2.5 hours for each. 
Subjects will be compensated $50.00 for completion of each visit (total subject 
compensation will be $150 for the three assessment time-points). Subjects will receive 
compensation ($50 merchandise card) at each visit. Social security numbers will not be 
required for subject payment. The cost of gas/transportation and the inconvenience of 
participating in this study, make these compensation rates fair and reasonable.  Subjects 
will be reimbursed an additional $50 merchandise card for participating in the optional 
EEG to offset additional set-up time. 
 
24. Compensation for Research-Related Injury 
 
UNMHSC will provide subjects with emergency treatment, at their own cost. No 
commitment is made by the University of New Mexico Health Sciences Center 
(UNMHSC) to provide free medical care or money for injuries to participants in this study. 
In the event that you have an injury or illness that is caused by a subject’s participation in 
this study, reimbursement for all related costs of care will be sought from their insurer, 
managed care plan, or other benefits program. If the subject does not have insurance, they 
may be responsible for the costs. Subjects will also be responsible for any associated 
copayments or deductibles required by their insurance. 
 
25. Consent Process 
 
Discussion of the proposed study will occur separate from the evaluation for the ECT 
procedure. Potential subjects will have ample time to ask questions regarding the nature of 
this study and will be clearly informed that this imaging investigation is optional. Informed 
consent will be discussed with each participant with plenty of opportunities to ask 
questions. The study PI (Abbott) or Co-PI (Quinn), board-certified psychiatrists with 
additional fellowship training and certification, will assess decisional capacity for each 
subject during the consent process. The PI’s have extensive experience with the assessment 
of decisional capacity in both research and clinical domains. All subjects must have 
decisional capacity to consent to this protocol. Prior to discussion of research participation, 
the UNM ECT service (Board certified psychiatrists) will assess decisional capacity for the 
procedure. This assessment will include decisional capacity (ability to communicate 
choice, appreciate risks/benefits, reason, and manipulate information) and voluntarism 
capacity.  
 
26. Documentation of Consent 
 
Notes will be kept documenting the informed consent process. Narrative forms will be 
securely filed with other subject information to document each visit and contact, in addition 
to required study measures and procedures. Subjects will be given a copy of their signed 
consent form and HIPAA. A member of the research team will review the HIPAA 
authorization during the consent. 
 
27. Study Test Results/Incidental Findings 
 

 
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Subjects who receive abnormal MRI scan findings by the neuroradiologist will be notified 
of an official report by e-mail letting the participant know new results are available and the 
study PI will communicate the results to the patient. The participant can securely log in to 
the Mind Research Network COINS homepage to access their MRI radiology report. No 
sensitive or identifying information is sent via e-mail. If an abnormality that requires 
follow-up is identified, such as a Doctor Referral recommendation, a hard copy of the 
report will be mailed to the participant in addition to the e-mail notification. With the 
patient’s permission, the study PI will communicate the results to the patient’s primary care 
providers. 
 
28. Progress or Results with Subjects 
 
The MRI scan is being done to answer research questions, not to examine the subject’s 
brain for medical reasons. This MRI scan is not a substitute for a clinical scan (the type a 
doctor would order). The research scan may not show problems that may be picked up by 
a clinical MRI scan. However, all research MRI scans will be read by a neuroradiologist (a 
doctor with experience reading MRI scans) unless they have been scanned at MRN in the 
previous six months. If the scan is read, the subject will receive the official report by email. 
If we find an abnormality that requires urgent follow-up, we will contact the subject by 
phone to help answer questions and get the right follow-up care. The MRN Medical 
Director or the research team is always available to answer any questions you may have 
about the subject’s scan. 
 
29. Inclusion of Vulnerable Populations 
 
Sample inclusion will not include gender restrictions. It is expected that our sample will 
reflect the gender distribution of our ECT service over the last 5 years. Recruitment will 
reflect the demographics of the state of New Mexico. Prisoners will be excluded from the 
study. The age range of 50 to 80 years was selected because to limit the variability of age-
related volume changes. Subjects with pre-existing diagnoses of neurodegenerative 
diseases or cerebrovascular pathology will be excluded. However, some older subjects may 
have significant cognitive deficits prior to treatment related to their depressive episode 
(“pseudo-dementia”). These subjects may not have decisional capacity for this 
investigation but are representative of a community sample receiving ECT in this age 
range. Dr. Abbott (PI) and Quinn (Co-PI) will assess decisional capacity of all subjects 
participating in this investigation. Subjects that do not have decisional capacity for this 
investigation will be able to participate in this research if they can assent to the procedure 
and a legally authorized representative (court appointed mental health treatment guardian) 
consents to the research protocol. 
 
30. Community-Based Participatory Research 
 
N/A 
 
31. Research Involving American Indian/Native Populations 
 

 
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The proposed research inclusion criteria will be open to all patients with major depressive 
disorder meeting the inclusion criteria including the clinical indication for ECT. The UNM 
ECT service is part of a tertiary referral service and the demographics of this service reflect 
the state of New Mexico. This investigation will not have targeted recruitment outside of 
routine clinical referrals to the UNM ECT service. 
 
32. Transnational Research 
 
N/A 
 
33. Drugs or Devices (see section 9. Resources Available) 
 
The research involves an investigational device. The Mecta Spectrum 5000Q paired with 
Soterix Medical 4X1 HD-ECT Multi-Channel Stimulation Interface is intended to reduce 
ECT current amplitude for amplitude-seizure titration and has received approval from the 
Food and Drug Administration (refer to “supporting documents”). Digitimer DS8R 
Biphasic Constant Current Stimulator will be used for motor titration during the 
second treatment.  
 
These devices will be solely handled and operated by credentialed UNM ECT providers at 
the UNMH Post Anesthesia Care Unit (inpatient) or UNM Outpatient Surgical Imaging 
Services (outpatient). 
 
Additionally, the research proposal will use DC-EEG device. The SMARTING 
(https://mbraintrain.com/smarting/) is a small, mobile EEG device that incorporates motion 
sensors that detect head and body movements. This EEG system will include a 24-channel 
recording cap. EEG data will be wirelessly recorded to mobile app and is capable of 
measuring low frequency EEG (< 0.01) pertinent for this proposal. 
 
34. Principal Investigator’s Assurance 
By submitting this study in the Click IRB system, the principal investigator of this study 
confirms that: 
☒ The information supplied in this form and attachments are complete and correct.   
☒ The PI has read the Investigator’s Manual and will conduct this research in accordance 
with these requirements.  
 ☒ Data will be collected, maintained and archived or destroyed per HSC Data Security 
Best Practices, including: 
1. Best Practice for data collection is for it to be directly entered onto a data collection 
form that is in a secured access folder on an HS drive behind a firewall, or in a secure 
UNM Data Security approved system such as RedCap. 
2. Data collection of de-identified data, if done in a clinical setting or other setting that 
does not allow direct entry into a secured system, may be done temporarily using a 
personal or university owned electronic storage device or hard copy document. The 

 
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important security safeguard is that no identifiers be include if the data is entered 
or stored using an untrusted device or storage. 
3. Permanent (during data analysis, after study closure) storage must reside on HSC 
central IT managed storage. Processing of data (aggregation, etc.) are to be carried 
out in such a way as to avoid creating/retaining files on untrusted storage 
devices/computers. Trusted devices are HSC managed and provide one or more of 
following safeguards: access logs, encryption keys, backups, business continuity and 
disaster recovery capabilities. 
4. Alternate storage media must be approved by HSC IT Security as meeting or 
exceeding HSC central IT provided security safeguards. 
 
 

 
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35. CHECKLIST SECTION 
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research. 
36. Partial Waiver of Consent for Screening/Recruitment 
 
N/A 
 
37. Partial Waiver of HIPAA Authorization for Screening/Recruitment 
 
N/A 
 
38. Waiver of Documentation of Consent 
 
N/A 
 
39. Alteration of Consent 
 
N/A 
 
40. Full Waiver of Consent/Parental Permission 
 
N/A 
 
41. Full Waiver of Consent/Parental Permission (Public Benefit or Service 
Programs) 
 
N/A 
 
42. Full Waiver of HIPAA Authorization (Checklist) 
 
N/A 
 
43. Other Waiver Types (Checklist) 
 
N/A 
 
44. Vulnerable Populations (Checklist) 
 
A. Adults with Cognitive Impairments 
1. Describe why the objectives of the study cannot be met without inclusion of 
adults with cognitive impairments. 

 
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Older subjects with major depressive disorder often present with significant 
cognitive impairment. In the context of ECT response, these patients often have 
resolution of depression-related cognitive impairment. 
 
2. Describe how capacity to consent will be evaluated. 
Prior to discussion of research participation, the UNM ECT service (Board-
certified psychiatrists) will assess decisional capacity for the procedure. This 
assessment will include decisional capacity (ability to communicate choice, 
appreciate risks/benefits, reason, and manipulate information) and voluntarism 
capacity. If the patient does not have decisional capacity, the subject will not 
be able to participate in this research.  
 
3. If subjects may regain capacity to consent, or if subjects may have fluctuating 
capacity to consent, describe your plans to evaluate capacity to consent 
throughout the research and to obtain consent to continue participation if 
capacity is regained. 
In the context of fluctuating consent capacity, the PI and Co-PI will reassess 
decisional capacity at each study visit. If the subject maintains the minimal 
threshold to continue with the proposed study, the study team will also include 
input from surrogate decision maker (power of attorney and/or treatment 
guardian) to provide additional safeguards. If the subject no longer maintains 
decisional capacity at a study visit, the subject will be withdrawn from the 
protocol.  
 
4. Describe your plans, if any, to provide information about the research to 
subjects and the steps you will take to assess understanding. 
The study PI (Abbott) and Co-PI (Quinn) are board-certified psychiatrists with 
fellowship training in geriatric psychiatric and psychosomatic medicine and 
will be involved with the consent process for all study participants. They will 
assess decisional capacity at all three study time points. 
 
5. Describe your plans to obtain assent, including whether assent will be 
obtained from none, some, or all subjects. 
All subjects must have decisional capacity to consent to this protocol. 
 
6. Describe why risks to subjects are reasonable in relation to anticipated benefits 
to the subjects. 
The risks of low-amplitude seizure and motor titration will be minimal relative 
to the traditional (higher) ECT amplitudes. The experimental portion of this 
protocol is relevant only to the first treatment with the remaining treatments 
completed at the traditional 800 mA amplitudes. Subjects will also receive more 
comprehensive clinical and neuropsychological assessments by participating 
in this research protocol relative to routine clinical care.  

 
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7. If this study involves a health or behavioral intervention, describe why the 
relation of the anticipated benefit to the risk of the research is at least as 
favorable to the subjects as that presented by alternative procedures. 
This investigation proposes use amplitude titration relative to the traditional 
pulse-number based titration and fixed amplitude ECT. This difference is only 
relevant to the first treatment. The remaining treatments will be completed with 
traditional 800 mA ECT.  
 
8. Describe your plans for monitoring the well-being of subjects including any 
plans to withdraw subjects from the research if they appear to be unduly 
distressed. 
Subjects that appear to be distressed will be encouraged to withdraw from the 
study protocol. If subjects appear to be unduly distressed, the study PI will 
withdraw these subjects from the protocol. Data regarding subject drop-out 
will be documented and presented to the DSMB. 
 
B. Children 
 
 
N/A 
 
C. Pregnant Women and Fetuses 
 
 
N/A 
 
D. Neonates of Uncertain Viability or Nonviable Neonates 
 
N/A 
 
E. Nonviable Neonates 
 
N/A 
 
F. Biomedical and Behavioral Research Involving Prisoners 
 
  
      N/A  
 
45. Medical Devices (Checklist)  
Complete this checklist if the research evaluates the safety or effectiveness of a medical device.  
If more than one medical device is being evaluated, provide the requested information for each. 
A. Device Name:   Mecta Spectrum 5000Q paired with Soterix Medical 4X1 HD-ECT Multi-
Channel Stimulation Interface  
B. Manufacturer: Soterix Medical 
237 West 35th Street 
Suite 1401 
New York, NY 10001 
Contact: Dr. Abhishek Datta 
Email: adatta@soterixmedical.com 
 

 
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C. Does the research involve a Significant Risk Device under an IDE? 
 Yes. Include documentation of the FDA approval of the IDE with your submission.  
Acceptable methods of documentation include: (1) FDA letter noting IDE number 
and approval status; (2) Industry sponsor letter noting IDE number and FDA 
approval status; or (3) FDA-approved industry sponsor protocol with IDE number 
noted  
 No 
D. Is the research IDE-exempt? 
 Yes. Include a FDA letter with your submission noting the determination that the 
research is IDE-exempt or a letter from the sponsor (or sponsor-investigator) 
justifying why they believe the research is IDE-exempt*.   
 No 
E. Does the research involve a Non-Significant Risk (NSR) Device? 
 Yes. Include a FDA letter with your submission noting the determination that the 
research is NSR or a letter from the sponsor (or sponsor-investigator) justifying why 
they believe the research is NSR**.   
 No 
* This FDA guidance includes a description for when a device study is exempt from the 
IDE requirements: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf  
**This FDA guidance includes information on how to differentiate between Significant 
Risk and Non-Significant Risk device studies: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf  
46. Export Control (Checklist) 
 
N/A 
 
47. Data Transfer/Sharing (Checklist)  
Complete this checklist if the research involves transferring/sharing of data with an external 
entity (institution, company, etc.).  
A. Will data be transferred/shared with an external entity (institution, company, etc.)?   
 Yes 
 No. The remainder of this section does not apply.  
B. Indicate if the data is incoming and/or outgoing: Outgoing 
   

 
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C. Provide the name of the entity that data will be transferred/shared with: De-identified 
clinical and imaging data will be uploaded to the National Institute of Health National 
Data Archive at 6-month intervals. This is an NIH requirement.  
 
D. Provide the contact name, email and phone number with whom data is being transferred 
or shared with: https://nda.nih.gov 
 
E. Who is responsible for transmission of the data? Study PI (Abbott) and team 
 
F. Who is responsible for receiving the data? NIMH Data Archive 
 
G. Describe how the data will be transferred/shared. Please note data cannot be 
transferred/shared without assistance from UNM HSC IT. Requesting HSC Central IT 
Transfer is detailed on the Sponsored Projects website: De-identified data will be 
uploaded to NIMH Data Archive through the COINS (https://coins.trendscenter.org) 
system. 
 
H. For data being transferred/shared with outside locations or entities, describe the following: 
• Where is data storage and how will it be maintained in a secure manner (i.e. encryption, 
password protection, use of Qualtrics or REDCap, etc)? https://coins.trendscenter.org. 
Data is encrypted and password protected.  
• What is method in which data will be collected and stored (i.e. electronic, hard copy, 
etc)? Data will be initially recorded in paper charts and then electronically uploaded to 
COINS site.  The data will be then be uploaded at 6-month intervals from COINS to 
the NIMH Data Archive.   
• How long will the data be stored? Paper charts will be kept for the duration of the 
study. COINS and NIMH Data Archive (de-identified data) will be kept indefinitely. 
• Who will have access to data? Study team will have access to the COINS data; Other 
investigators must access NIMH Data Archive through established protocols 
(https://nda.nih.gov/get/access-data.html). 
 
I.  Please list all specific data elements, variables, etc. to be sent out and/or received. Indicate 
if the data contain identifiers and health information. Please note that identifiers that MUST 
be removed to make health information de-identified are as follows: Names, All geographic 
subdivision smaller than a State, All elements of year (except year), Telephone, Fax 
numbers, E-mail addresses, Social Security, Medical record number, Health plan 
beneficiary, Account numbers, Certificate/license numbers, Vehicle identifiers and serial 
numbers, Device identifiers and serial numbers, Web URLs, IP address numbers, 
Biometric identifiers, full face photographic images, and Any other unique identifying 
number, characteristic or code.)  All identifying elements outlined above will not be 
included in COINS or uploaded to the NIMH Data Archive.  All subjects participating in 
this protocol have provided permission for the transfer of their de-identified data to the 
NIMH Data Archive. 
 
J. If the research requires the access, use, or disclosure of any of the 18 individually 
identifiable protected health information (PHI) identifiers that can be used to identify, 

 
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contact, or locate a person (e.g., name, medical record number, etc.), are the subjects going 
to consent to or authorize the disclosure of their individually identifiable health 
information? Not applicable.   
a. Or is HIPAA authorization altered or waived? Not applicable 
 
K. What is the classification of the data: de-identified, limited data set, protected health 
information, or other type? De-identified.  
 
L. Does the request to transfer/share data include clinical data that belongs to the UNM Health 
Systems? The included information will be generated for research purposes only (including 
imaging data acquired at Mind Research) and does not belong to UNM. 
 
M. Does the data to be transferred/shared include information about patients seen at external 
health system or at a third party medical provider? Not applicable. 
  
N. Is the external entity a “covered entity”? Not applicable.  
 
O. Is the data that is going to be transferred/shared owned or partially owned by another party 
or have any type of restrictions including regulatory restrictions (i.e. HIPAA, FERPA, 
etc.)? De-identified data transferred to the NIMH Data Archive (NDA) will be coded using 
a unique code known as a Global Unique Identifier (GUID). Use of the GUID minimizes 
risks to study participants because it keeps one individual’s information separate from that 
of another person without using names, addresses, or other identifying information. The 
unique code also allows the NDA to link together all submitted information on a single 
participant, giving researchers access to information that may have been collected 
elsewhere. The GUID is a computer-generated alphanumeric code [example: NDA-
1A462BS] that is unique to each research participant (i.e., each person’s information in the 
NDA—or each subject’s record—has a different GUID). The process of assigning a GUID 
prevents direct identifiers from ever being transmitted or stored in the NDA. We will ensure 
that no direct identifiers are transmitted in this process. 
 
P. Is the data publicly available? If yes, please provide details: As per the NIMH Data Archive 
site, “Summary information on the data shared in NDA is available in the NDA Query Tool 
without the need for an NDA user account.  To request access to record-level human 
subject data, you must submit a Data Access Request. 
 
Q. Does the data include information about substance abuse treatment, sexually transmitted 
diseases, genetic testing results, HIV/AIDS testing results, and/or mental health?  Mental 
health data will be included with this data.  
 
48. Specimen Transfer/Sharing (Checklist) 
 
N/A