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Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker

Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker ORIGINAL STUDY Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker A Pilot Study Jeremy Miller, MD, MS,* Tom Jones, MS,* Joel Upston, MS,* Zhi-De Deng, PhD,†‡ Shawn M. McClintock, PhD, MSCS,‡§ Sephira Ryman, PhD, MS,† Davin Quinn, MD,* and Christopher C. Abbott, MD, MS* Key Words: electroconvulsive therapy, E-field modeling, ictal theta power, Objective: Electroconvulsive therapy (ECT) remains the benchmark for letter fluency, ECT safety biomarker treatment resistant depression, yet its cognitive adverse effects have a neg- (JECT 2022;38: 88–94) ative impact on treatment. A predictive safety biomarker early in ECT treat- ment is needed to identify patients at cognitive risk to maximize therapeutic outcomes and minimize adverse effects. We used ictal electroencephalog- HIGHLIGHTS raphy frequency analysis from suprathreshold treatments to assess the rela- tionships between ECT dose, ictal power across different frequency do- mains, and cognitive outcomes. • Ictal theta power may be a convenient and reliable safety bio- Methods: Seventeen subjects with treatment resistant depression received marker for electroconvulsive therapy (ECT). right unilateral ECT. Structural magnetic resonance imaging was obtained • Increased ictal theta power early in right unilateral ECT treatment pre-ECT for electric field modeling to assess ECT dose. Serial assessments may be associated with cognitive outcomes. with 24-lead electroencephalography captured ictal activity. Clinical and • Ictal power with different frequency bands does not seem to be cognitive assessments were performed before and after ECT. The primary associated with ECT's antidepressant effect. cognitive outcome was the change in Delis Kaplan Executive Function • Electroconvulsive therapy dose as measured by electric field model- Verbal Fluency Letter Fluency. ing is associated with ictal theta power and cognitive outcomes. Results: Ictal theta (4–8 Hz) power in the Fp1/Fp2 channels was associ- ated with both whole-brain electric field strength (t =19.5, P = 0.007)/ (2,12) Electroconvulsive therapy (ECT) is effective for treatment re- (t = 21.85, P = 0.02) and Delis Kaplan Executive Function Verbal Flu- (2,10) sistant depression and is widely used in the United States. The ency Letter Fluency scores (t = −2.05, P =0.05)/(t = −2.20, (2,12) (2,10) therapeutic effect of ECT is achieved by administering a stimulus P = 0.01). Other frequency bands (beta, alpha, delta, and gamma) did not substantially above the seizure threshold, yet as the stimulus in- demonstrate this relationship. 1 creases, it can worsen cognitive outcomes. Although most ECT- Conclusions: This pilot data identify ictal theta power as a potential associated cognitive adverse effects are acute and transient, some safety biomarker in ECTand is related to the strength of the ECT dose. Ictal 2–4 effects can persist for 6 months or longer. These adverse effects theta power could prove to be a convenient and powerful tool for clinicians include changes in attention, verbal fluency, memory, and execu- to identify those patients most susceptible to cognitive impairment early in tive function and can lead to suboptimal outcomes and worsening the treatment series. Additional studies are needed to assess the role of lon- 5,6 stigma toward the procedure. Present day dosing algorithms, gitudinal changes in ictal theta power throughout the ECT series. such as seizure threshold titration and formula dosing based on age and sex, lack scientific rationale as they are unable to account From the *Department of Psychiatry, University of New Mexico School of for individual variability to electric current (head shape, skull Medicine, Albuquerque, NM; †Noninvasive Neuromodulation Unit, Experimental 7,8 Therapeutics and Pathophysiology Branch, National Institute of Mental thickness, tissue composition, etc). Furthermore, ECT dosing Health, National Institutes of Health, Bethesda, MD; ‡Duke Psychiatry and algorithms rely on frequency and train duration to increase total Behavioral Sciences, Duke University School of Medicine, Durham, NC; charge, while amplitude, which is directly proportional to the in- §Division of Psychology, Department of Psychiatry, UT Southwestern Medical duced electric field (E-field) and offers the most direct control Center, Dallas, TX; and ||The Mind Research Network, Albuquerque, NM. Received for publication May 18, 2021; accepted September 6, 2021. in the volume of tissue stimulated, remains fixed. A safety bio- Reprints: Christopher C. Abbott, MD, MS, Department of Psychiatry, marker rooted in individual variability is needed to identify a University of New Mexico School of Medicine, 2400 Tucker Avenue N.E., patient's susceptibility to cognitive adverse effects so that optimal 1 University of New Mexico, MSC09-5030, Albuquerque, NM 87131 treatment settings can be identified early in the treatment course to (e‐mail: CAbbott@salud.unm.edu). S.W.M. is a consultant to Pearson Assessment. The other authors have no maximize both clinical and cognitive safety. conflicts of interest or financial disclosures to report. Despite decades of research to define seizure adequacy, ictal Supported by the National Institute of Mental Health, the National Institute of electroencephalography (EEG) has been infrequently assessed as General Medical Sciences, and the UNM Clinical and Translational Science a cognitive biomarker. A recent meta-analysis on ictal EEG in Center (MH125126, MH111826, 1P30GM122734, and CTSC017-10). Z.- D.D. is supported by the Intramural Research Program of the National ECT found that just 1 of 44 studies that met inclusion criteria re- Institute of Mental Health, National Institutes of Health (ZIAMH002955). ported cognitive outcomes. That study found no significant asso- J.M. and C.C.A. completed initial draft of manuscript. J.M. performed literature 10 ciation between peri-ictal EEG features and cognitive outcomes. search. J.M., T.J., J.U., and C.A. did data retrieval and analysis. J.M. and Another study examined differences in ketamine and methohexital C.C.A. conceptualized manuscript. All authors reviewed final draft. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. anesthesia induction during ECTand found that ketamine enhanced This is an open access article distributed under the Creative Commons At- ictal EEG evidence of seizure intensity. The study provided prelim- tribution License 4.0 (CCBY), which permits unrestricted use, distribution, inary evidence that ketamine may be associated with a lower level and reproduction in any medium, provided the original work is properly of ECT-related cognitive adverse effects when compared with cited. DOI: 10.1097/YCT.0000000000000812 methohexital anesthesia as measured by posttreatment time to 88 www.ectjournal.com Journal of ECT � Volume 38, Number 2, June 2022 Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker orientation. A third study with a small cohort of patients who re- randomized clinical trial that compared 3 different pulse ampli- ceived bitemporal (BT) ECT (n = 8) found that postictal suppression tudes (600, 700, and 800 mA) and antidepressant and clinical out- and slow-wave amplitude positively correlated with delayed memory, comes. The data presented in this analysis include subjects who whereas ictal slow-wave amplitude was negatively correlated with agreed to 24-lead EEG acquisitions. phonemic fluency. To our knowledge, these 3 studies constitute the corpus of literature in the past 20 years relating ictal EEG mea- Subjects surements in pulse wave ECT to ECT-induced cognitive adverse ef- The University of New Mexico Human Research Protections fects, in domains of time to orientation, memory, and verbal fluency. Office approved this investigation. All subjects signed procedural Electroconvulsive therapy dosing as measured by E-field consent or assented to the research protocol with the surrogate modeling takes into account individual variability and may be re- medical decision maker providing consent. Of the 62 subjects who lated to cognitive outcomes. Realistic computational models of completed the parent study, 17 underwent an sMRI to generate the head can predict E-field distribution in the brain induced by E-field modeling and completed 24-lead EEG capture at a RUL ECT, accounting for anatomical parameters such as tissue conduc- suprathreshold treatment. Every attempt was made to capture tivity, head and brain geometry, and also properties of the current- the earliest suprathreshold RUL treatment with 59% of captures carrying electrodes, such as size and placement on the scalp (right happening at either treatment #2 or #3. Fifteen subjects had Fp1 7,13,14 unilateral [RUL], BT). The work flow to develop realistic EEG captures and 13 subjects had Fp2 EEG captures. head models for electric stimulation include image segmentation, tessellation of volume into a mesh, electrode placement on the scalp, 13,15 Cognitive and Therapeutic Evaluations and solving for the E-fields with the finite element method. These E-field models have been validated with motor evoked poten- Subjects were recruited through the ECT service at the Uni- tials and intraoperatively with cortical EEG. By using structural versity of New Mexico. Subjects were started with RUL placement magnetic resonance imaging (sMRI) data, E-field modeling can cap- and randomized to 3 fixed amplitude arms: 600, 700, or 800 mA. ture individual anatomical differences to explain variable ECT dos- All analysis was done on only the RUL treatments. Subjects 16,17 ing. Prior work has shown that the E-field strength has a direct completed a neurocognitive battery and depression symptom relationship with hippocampal neuroplasticity and a negative relation- severity assessments before ECT (V1), during ECT (before treatment 18,19 19 ship with antidepressant response. Argyelan et al demonstrated #6, V2), and after ECT (V3). Patient's final scores were in patients receiving ECT that the amygdala and hippocampus had a assessed as the difference between pre- and post-ECT (V3-V1), strong relationship between E-field and volumetric change and unless they switched to BT at V2 secondary because of nonresponse, that high E-fields were associated with robust volume changes in which case final scores were assessed as (V2-V1). Bitemporal in a dose-dependent fashion; however, neither the E-field nor vol- treatments were excluded from the analysis because of the substantial umetric change was associated with antidepressant outcomes. difference in E-field values when modeling for BT electrode Fridgeirsson et al found that a stronger E-field in the temporal placement. A separate analysis of BT outcomes was not possible lobes was associated with decreased therapeutic response in pa- given the small sample size (n = 4). The DKEFS-VF LF was used 20,21 tients who received BT ECT. A common limitation to these model- as our primary outcome measure for cognitive impairment. The ing studies is that the E-field only describes the spatial extent of the DKEFS-VF LF raw score was converted into demographic- direct electrical stimulation. The relationship between the E-field adjusted (age) scaled scores. The 24-item Hamilton Depression and seizure expression, and the ultimate clinical and neurocognitive Rating Scale was used to measure antidepressant outcome. outcome remains unknown. The Montreal Cognitive Assessment (version 7.1) and Test of The purpose of this study was to investigate ictal EEG power Premorbid Function (TOPF) at baseline were used to screen for as a potential bridge between ECT variable dosing in the brain as global cognitive function and premorbid intellectual function 23,24 measured by E-field modeling and cognitive impairment. The respectively. data are from a parent study with a primary focus of investigating the relationship between E-field and neuroplasticity. In this Electroencephalography double-blind controlled-trial, older patients (50–80 years) were The SMARTING 24-lead channel amplifier and mobile de- randomized into 3 amplitude arms: 600, 700, and 800 mA. Electric vice was used for EEG capture (mBrainTrain, Inc, Belgrade, field models were generated in all patients as well as neurocognitive Serbia). The sampling rate was 500 Hz. The initial single batteries and mood scales before, during, and after ECT. In line with referencing node was located in the FCz position. Cleaning of data the recent advances in cognitive testing and the results of our parent consisted of excluding all channels with an impedance greater than study, the Delis Kaplan Executive Function System (DKEFS) Ver- 20 kΩ. Channels were then visually inspected and excluded if they bal Fluency Test Category and Letter Fluency (DKEFS-VF CF and were saturated or contained artifacts during the ictal period. The re- LF) tasks were found to be the most sensitive tests to amplitude- maining good channels were re-referenced to the common average mediated cognitive impairment and were used as our primary out- 25 2 reference. Power spectral density (in micro-Volts per Hertz) was 20,21 come measures for cognitive impairment. We examined 17 calculated for each channel over the range of frequency bands; delta subjects who received sMRIs, 24-lead EEG, and cognitive and ther- (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), and apeutic assessments. Linear regression models examined the rela- 26–28 gamma (30–80 Hz) with EEGLAB (version 2019.0). Ictal tionships between E-field models, ictal power in each frequency powers were then log transformed to normalize the distribution. band, and cognitive outcomes controlling for age and premorbid in- Fp1 and Fp2 channels were chosen as our primary outcome chan- tellectual function. We hypothesized that frequencies in the lower nels to align with standard ECT EEG acquisitions. bands would demonstrate an association. Magnetic Resonance Imaging MATERIALS AND METHODS T1 and T2 sMRI were captured using a 3T Siemens scanner For detailed information on study inclusion/exclusion criteria, before ECT initiation. neurocognitive and clinical assessments, ECT treatment parame- T1 parameters were as followed: repetition time = 2530 ms; ters, and study design, we refer to the published findings of our echo time = 1.64, 3.5, 5.36, 7.22, 9.08 ms; inversion time © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. www.ectjournal.com 89 Miller et al Journal of ECT Volume 38, Number 2, June 2022 (TI) = 1200 ms; flip angle = 7.0 degrees; slices = 192; field of TABLE 1. Demographic and Clinical Characteristics view = 256; matrix 256  256; voxel size = 1.0  1.0 1.0 mm; and total acquisition time = 6:03 (minutes:seconds). Clinical and Demographic Features N = 17 T2 parameters were as followed: repetition time = 2530 ms, echo time = 474 ms, flip angle = 120.0 degrees, slices = 192, field Age 65.1 (8.4) of view = 256, matrix 256  256, voxel size = 1.0  1.0 Sex: male/female 6/11 1.0 mm, and total acquisition time = 5:09. TOPF 108.1 (12.1) Baseline MOCA 24.5 (2.6) Electric Field Modeling E , mean (SD) 111.9 (22.8) brain We used Simulation of Non-Invasive Brain Stimulation Baseline DKEFS Category Fluency Scaled Score 8.2 (3.9) (SimNIBS, version 2.1.2) for E-field modeling. SimNIBS cre- Post RUL ECT DKEFS Category Fluency Scaled 7.0 (2.9) ates a subject specific, anatomically realistic volume conductor Score model. The T1- and T2-weighted scans are segmented into skin, Change in DKEFS Category Fluency Scaled Score −1.6 (2.2) bone, eyes, cerebral spinal fluid, ventricles, and gray and white Baseline DKEFS Letter Fluency Scaled Score 8.7 (3.2) matter with a combination of FMRIB Software Library (FSL) Post RUL ECT DKEFS Letter Fluency Scaled Score 7.7 (3.2) and Statistical Parametric Mapping 12 (SPM12) Computational 31,32 Change in DKEFS Letter Fluency Scaled Score −1(2.7) Anatomy Toolbox. SimNIBS then turns this segmentation Baseline Hamilton Depression Rating Scale 36.7 (5.3) into a tetrahedral head mesh using GMSH, a 3-dimensional finite Post RUL ECT Hamilton Depression Rating Scale 19.0 (13.8) element mesh generator, with unique conductivity values for each tissue type. Electrodes are added to the head mesh in either RUL Change in Hamilton Depression Rating Scale 0.489 (0.365) orientation and simulated with corresponding current. SimNIBS Log of Fp1 ictal theta power (n = 15) 37.8 (29.1) then uses a finite element solver to calculate the voltages and E- Log of Fp2 ictal theta power (n = 13) 46.3 (33.2) fields corresponding to the stimulation throughout the head mesh. Responder/nonresponder 3/14 Simulations were performed using unit current, the resultant E- Remitter/nonremitter 6/11 fields were then scaled to the assigned ECT current amplitudes RUL only/bitemporal switch 13/4 (600, 700, or 800 mA). Whole-brain E-field strength, E ,was brain RUL suprathreshold treatment captured by EEG 4.6 (3.3) calculated at 90th percentile of E-field magnitudes as an estimate of peak induced field strength, while avoiding the influence of tis- Format is mean (SD) or to indicate proportion. sue boundary effects that could bias the absolute maximum E- MoCA indicates Montreal Cognitive Assessment. field values. Statistical Analysis when controlling for age in delta (t = −27.04, P =0.17)/ (2,12) Our data passed normality testing. Linear regression models (t = 38.22, P = 0.10), alpha (t = 11.44, P = 0.27)/ (2,10) (2,12) comparing the relationships between E , ictal frequency power, brain (t = 17.96, P = 0.12), beta (t = 11.46, P =0.36)/ (2,10) (2,12) and cognitive outcomes were performed using R (version (t = 16.97, P = 0.20), and gamma (t = 9.03, (2,10) (2,12) 33–36 4.0.2). First, the relationship between ictal frequency power P =0.62)/(t =11.08, P = 0.56) frequency bands. In contrast, (2,10) and E controlling for age was assessed. Second, the relation- brain E was significantly associated with ictal theta power in both brain ship between the ΔDKEFS-VF LF scaled score and ictal fre- Fp1 (t =19.5, P = 0.007) and Fp2 (t =21.85, P =0.02) (2,12) (2,10) quency power controlling for premorbid intelligence (TOPF) channels when controlling for age (Figs. 1A, B). A whole-brain was assessed. Third, the relationship between ΔDKEFS-VF LF exploratory analysis demonstrated that E was related to ictal brain scaled score and ΔDKEFS-VF CF scaled scores and E con- brain theta power in 75% of the remaining 20 channels ( P <0.05in trolling for premorbid intelligence (TOPF) was assessed. An ex- green; Fig. 1C). No particular area of strength was noted, but ploratory whole-brain analyses on the remaining 20 EEG chan- the midline channels (Fz, Cz, and Cpz) demonstrated the weakest nels were done (the 2 mastoid channels were excluded from anal- association ( P >0.05). ysis) and compared E , ictal power, and antidepressant outcomes brain with similar regression models. Given the exploratory nature of our study, no mathematical corrections were made for multiple Ictal Theta Power and Cognitive Outcomes comparisons. There was no statistically significant relationship between ictal power and category fluency in any bands. We focused on letter fluency as our primary cognitive outcome. Ictal power and letter RESULTS fluency demonstrated no statistically significant relationships when controlling for premorbid intelligence in both Fp1/Fp2 Clinical and Demographic Characteristics channels in delta (t = −0.13, P =0.78)/(t = −0.66, P =0.15), (2,12) (2,10) Demographics, clinical, and neuropsychological data are alpha (t = −1.07, P = 0.23)/(t = −1.93, P = 0.024), beta (2,12) (2,10) summarized in Table 1. The average age for the subjects (N = 17) (t = −0.22, P = 0.77)/(t = −1.34, P = 0.12), and gamma (2,12) (2,10) was 65.1 years with a standard deviation of 8.4. Six of the 17 sub- (t =0.13, P = 0.80)/(t = −0.24, P = 0.72) frequency (2,12) (2,10) jects were male. Four, 6, and 7 subjects received 600, 700, and bands. In contrast, ictal theta power was associated with cognitive 800 mA RUL ECT, respectively. Thirteen of the 17 subjects re- outcomes in Fp1 (t = −2.05, P = 0.05) with Fp2 demonstrat- (2,12) mained in RUL ECT throughout the ECT series. ing a stronger relationship (t = −2.20, P = 0.01; Figs. 2A, B). (2,10) A whole-brain exploratory analysis demonstrated that ictal theta Whole-Brain E-Field Strength and Ictal power was related to cognitive outcomes when controlling for Theta Power premorbid intelligence in 70% of the remaining 20 channels Whole-brain E-field strength and ictal power demonstrated ( P < 0.05 in green; Fig. 2C). The midline and right hemisphere no statistically significant relationships in both Fp1/Fp2 channels (Fz, Pz, POz, O2, T8) demonstrated the strongest association 90 www.ectjournal.com © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker FIGURE 1. A, Left. Ictal theta power versus E in the Fp1 channel. B, Middle. Theta power versus E in the Fp2 channel. C, Right. Whole- brain brain brain exploratory analysis of ictal theta power and E with standard 19-lead EEG map shown (CPz, P7, P8, and mastoid channels not brain shown). Green leads denote statistical significance ( P <0.05). ( P < 0.01) and the left temporal-occipital area (P3, T3, T5, P7, strength (E ) was associated with ictal power in different fre- brain O1) demonstrated the weakest ( P > 0.05). quency bands. We then examined the relationship between E brain and ictal power and cognitive outcomes as measured by the change in letter and category fluency scores before and after Whole-Brain E-Field Strength and RUL ECT. Ictal theta power (4–8 Hz) was associated with E brain Cognitive Outcomes in 17 of 22 EEG channels (77%), including Fp1/Fp2, the 2 chan- Linear models showed no statistically significant relationship nels used to monitor seizure activity during routine ECT. Further- between E and letter fluency (t = −2.06, P = 0.06; Fig. 3). brain (2,14) more, an association was found in 16 of 22 EEG channels (73%), Linear regression results are summarized in Table 2. including Fp1/Fp2, between ictal theta power and the ΔDKEFS- VF LF scaled score (letter fluency). This association was noted Whole-Brain E-Field Strength, Ictal Theta Power, to a much lesser extent in the alpha band, with 11 of 22 EEG chan- and Antidepressant Outcomes nels (50%) reaching statistical significance, including Fp1, and Whole-brain E-field strength showed no statistically sig- were absent in the delta, beta, and gamma bands. No association nificant association with antidepressant outcomes (% change was observed between ictal theta power and antidepressant out- in the Hamilton Depression Rating Scale) when controlling for comes in the Fp1/Fp2 channels. Neither E nor ictal power brain age (t =0.005, P = 0.25). Ictal theta power in the Fp1/Fp2 (1,15) were associated with the change in category fluency. Meanwhile, (t =0.07, P = 0.65)/(t =0.22, P = 0.06) channels showed (2,12) (2,10) adirectrelationshipbetween E and the change in letter fluency brain no statistically significant association with antidepressant out- was insignificant ( P = 0.06). Our results align with a previous in- comes when controlling for age. A whole-brain exploratory anal- vestigation and provide evidence that ictal theta power may act as ysis demonstrated that ictal theta power was significantly associ- an ECT safety biomarker by bridging ECT dosing as measured by ated with antidepressant outcomes when controlling for age in E and cognitive impairment as measured by phonemic (letter) brain CPz and P8 ( P <0.05). fluency. Ictal theta power is a measure that is easily accessible on most ECT devices and could identify excessive dosing and cognitive DISCUSSION risk early on in treatment. Unlike postictal recovery time, ictal We obtained baseline sMRI and 24-lead EEG in a suprathreshold theta power will not be confounded by emergent agitation and re- treatment in 17 older subjects with major depressive disorder lated treatments, which affects approximately 10% of patients. who were treated with RUL ECT. We examined whether E-field Evidence suggests that early ECT dosing impacts cognitive FIGURE 2. A, Left. Letter fluency versus ictal theta power in the Fp1 channel. B, Middle. Letter fluency versus ictal theta power in the Fp2 channel. C, Right. Whole-brain exploratory analysis of cognitive performance and ictal theta power with standard 19-lead EEG map shown (CPz, P7, P8, and mastoid channels not shown). Green leads denote statistical significance ( P <0.05). © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. www.ectjournal.com 91 Miller et al Journal of ECT Volume 38, Number 2, June 2022 FIGURE 3. Letter fluency versus E (P = 0.06). brain outcomes with a significant lag time between initial parameter se- impairment. Thus, early identification of cognitive risk at the first 1,38–40 lection and eventual cognitive impairment. In the context of suprathreshold treatment has clinical translational implications for nonresponse, the ECT clinician can increase the ECT dose for immediate corrective action to mitigate the onset of cognitive im- eventual therapeutic response without potential adverse conse- pairment. Based on our results, increased ictal theta power may be quences other than prolonging the ECT series. In contrast, reduc- suggestive of excessive E-field strength. Electric field strength is 7,15 ing the ECT dose in the context of ECT-induced cognitive impair- proportional to pulse amplitude. If the first suprathreshold ment may minimize, although not completely eliminate, cognitive treatments generates excessive ictal theta power, the ECT clinician TABLE 2. Regression Results Log of Fp1 Log of Fp2 ΔLetter Fluency Theta Power Theta Power ΔLetter Fluency OLS OLS OLS OLS 12 3 4 5 Constant 3.60 (−8.70 to 15.89) 6.76 (−7.49 to 21.00) 2.27 (0.16 to 4.38) 3.49* (1.12 to 5.85) 5.52 (−7.50 to 18.54) Log of Fp1 theta −2.05* (−3.90 to −0.21) power Log of Fp2 theta −2.20* (−3.63 to −0.78) power TOPF 0.02 (−0.08 to 0.12) 0.00 (−0.11 to 0.12) −0.00 (−0.10 to 0.10) E 0.03† (0.02 to 0.04) 0.03† (0.02 to 0.04) −0.06 (−0.11 to −0.00) brain Age −0.03 (−0.06 to 0.00) −0.05* (−0.08 to −0.01) Observations 15 13 15 13 17 R 0.29 0.48 0.70 0.74 0.23 Adjusted R 0.17 0.38 0.65 0.69 0.12 Residual SE 2.44 (df = 12) 2.16 (df = 10) 0.41 (df = 12) 0.48 (df = 10) 2.54 (df =14) F statistic 2.41 (df = 2, 12) 4.69* (df = 2, 10) 14.02† (df = 2, 12) 14.57‡ (df = 2, 10) 2.13 (df =2, 14) See the 5 models presented in the rows above. The outcome variable is listed across the top. The variables and covariables are listed on the left side of the column. An example of how to read the first model under column 1 is provided. Example: ΔLetter fluency = 3.60–2.05  (log of Fp1 theta power) + 0.02  (TOPF). *P <0.05. †P < 0.001. ‡P <0.01. OLS indicates ordinary least squares. 92 www.ectjournal.com © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker may elect to decrease the E-field with a reduced amplitude in sub- cognitive testing may illuminate the interplay between electric dos- sequent treatments to reduce cognitive risk. The specific threshold ing and the resulting seizure, while disentangling therapeutic and for the amount of theta power from the first suprathreshold treat- cognitive outcomes. In conclusion, ictal theta power could provide ment that is associated with cognitive risk needs to be determined, clinicians with an immediately available tool to identify early on but the premise could be a useful and accessible tool for the ECT in the ECT course those patients most at risk of cognitive impair- clinician. ment, resulting in measurement-based care precision ECT dosing. The interaction between ictal theta power and cognitive im- pairment remains unclear. Increases in theta oscillations in the REFERENCES resting state are associated with executive function and decreased 41–43 1. Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and vigilance. In addition, anatomical correlates of theta oscilla- electrode placement on the efficacy and cognitive effects of tion activity include deep brain structures like the hippocampus, electroconvulsive therapy. 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Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker

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Wolters Kluwer Health
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Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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10.1097/yct.0000000000000812
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Abstract

ORIGINAL STUDY Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker A Pilot Study Jeremy Miller, MD, MS,* Tom Jones, MS,* Joel Upston, MS,* Zhi-De Deng, PhD,†‡ Shawn M. McClintock, PhD, MSCS,‡§ Sephira Ryman, PhD, MS,† Davin Quinn, MD,* and Christopher C. Abbott, MD, MS* Key Words: electroconvulsive therapy, E-field modeling, ictal theta power, Objective: Electroconvulsive therapy (ECT) remains the benchmark for letter fluency, ECT safety biomarker treatment resistant depression, yet its cognitive adverse effects have a neg- (JECT 2022;38: 88–94) ative impact on treatment. A predictive safety biomarker early in ECT treat- ment is needed to identify patients at cognitive risk to maximize therapeutic outcomes and minimize adverse effects. We used ictal electroencephalog- HIGHLIGHTS raphy frequency analysis from suprathreshold treatments to assess the rela- tionships between ECT dose, ictal power across different frequency do- mains, and cognitive outcomes. • Ictal theta power may be a convenient and reliable safety bio- Methods: Seventeen subjects with treatment resistant depression received marker for electroconvulsive therapy (ECT). right unilateral ECT. Structural magnetic resonance imaging was obtained • Increased ictal theta power early in right unilateral ECT treatment pre-ECT for electric field modeling to assess ECT dose. Serial assessments may be associated with cognitive outcomes. with 24-lead electroencephalography captured ictal activity. Clinical and • Ictal power with different frequency bands does not seem to be cognitive assessments were performed before and after ECT. The primary associated with ECT's antidepressant effect. cognitive outcome was the change in Delis Kaplan Executive Function • Electroconvulsive therapy dose as measured by electric field model- Verbal Fluency Letter Fluency. ing is associated with ictal theta power and cognitive outcomes. Results: Ictal theta (4–8 Hz) power in the Fp1/Fp2 channels was associ- ated with both whole-brain electric field strength (t =19.5, P = 0.007)/ (2,12) Electroconvulsive therapy (ECT) is effective for treatment re- (t = 21.85, P = 0.02) and Delis Kaplan Executive Function Verbal Flu- (2,10) sistant depression and is widely used in the United States. The ency Letter Fluency scores (t = −2.05, P =0.05)/(t = −2.20, (2,12) (2,10) therapeutic effect of ECT is achieved by administering a stimulus P = 0.01). Other frequency bands (beta, alpha, delta, and gamma) did not substantially above the seizure threshold, yet as the stimulus in- demonstrate this relationship. 1 creases, it can worsen cognitive outcomes. Although most ECT- Conclusions: This pilot data identify ictal theta power as a potential associated cognitive adverse effects are acute and transient, some safety biomarker in ECTand is related to the strength of the ECT dose. Ictal 2–4 effects can persist for 6 months or longer. These adverse effects theta power could prove to be a convenient and powerful tool for clinicians include changes in attention, verbal fluency, memory, and execu- to identify those patients most susceptible to cognitive impairment early in tive function and can lead to suboptimal outcomes and worsening the treatment series. Additional studies are needed to assess the role of lon- 5,6 stigma toward the procedure. Present day dosing algorithms, gitudinal changes in ictal theta power throughout the ECT series. such as seizure threshold titration and formula dosing based on age and sex, lack scientific rationale as they are unable to account From the *Department of Psychiatry, University of New Mexico School of for individual variability to electric current (head shape, skull Medicine, Albuquerque, NM; †Noninvasive Neuromodulation Unit, Experimental 7,8 Therapeutics and Pathophysiology Branch, National Institute of Mental thickness, tissue composition, etc). Furthermore, ECT dosing Health, National Institutes of Health, Bethesda, MD; ‡Duke Psychiatry and algorithms rely on frequency and train duration to increase total Behavioral Sciences, Duke University School of Medicine, Durham, NC; charge, while amplitude, which is directly proportional to the in- §Division of Psychology, Department of Psychiatry, UT Southwestern Medical duced electric field (E-field) and offers the most direct control Center, Dallas, TX; and ||The Mind Research Network, Albuquerque, NM. Received for publication May 18, 2021; accepted September 6, 2021. in the volume of tissue stimulated, remains fixed. A safety bio- Reprints: Christopher C. Abbott, MD, MS, Department of Psychiatry, marker rooted in individual variability is needed to identify a University of New Mexico School of Medicine, 2400 Tucker Avenue N.E., patient's susceptibility to cognitive adverse effects so that optimal 1 University of New Mexico, MSC09-5030, Albuquerque, NM 87131 treatment settings can be identified early in the treatment course to (e‐mail: CAbbott@salud.unm.edu). S.W.M. is a consultant to Pearson Assessment. The other authors have no maximize both clinical and cognitive safety. conflicts of interest or financial disclosures to report. Despite decades of research to define seizure adequacy, ictal Supported by the National Institute of Mental Health, the National Institute of electroencephalography (EEG) has been infrequently assessed as General Medical Sciences, and the UNM Clinical and Translational Science a cognitive biomarker. A recent meta-analysis on ictal EEG in Center (MH125126, MH111826, 1P30GM122734, and CTSC017-10). Z.- D.D. is supported by the Intramural Research Program of the National ECT found that just 1 of 44 studies that met inclusion criteria re- Institute of Mental Health, National Institutes of Health (ZIAMH002955). ported cognitive outcomes. That study found no significant asso- J.M. and C.C.A. completed initial draft of manuscript. J.M. performed literature 10 ciation between peri-ictal EEG features and cognitive outcomes. search. J.M., T.J., J.U., and C.A. did data retrieval and analysis. J.M. and Another study examined differences in ketamine and methohexital C.C.A. conceptualized manuscript. All authors reviewed final draft. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. anesthesia induction during ECTand found that ketamine enhanced This is an open access article distributed under the Creative Commons At- ictal EEG evidence of seizure intensity. The study provided prelim- tribution License 4.0 (CCBY), which permits unrestricted use, distribution, inary evidence that ketamine may be associated with a lower level and reproduction in any medium, provided the original work is properly of ECT-related cognitive adverse effects when compared with cited. DOI: 10.1097/YCT.0000000000000812 methohexital anesthesia as measured by posttreatment time to 88 www.ectjournal.com Journal of ECT � Volume 38, Number 2, June 2022 Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker orientation. A third study with a small cohort of patients who re- randomized clinical trial that compared 3 different pulse ampli- ceived bitemporal (BT) ECT (n = 8) found that postictal suppression tudes (600, 700, and 800 mA) and antidepressant and clinical out- and slow-wave amplitude positively correlated with delayed memory, comes. The data presented in this analysis include subjects who whereas ictal slow-wave amplitude was negatively correlated with agreed to 24-lead EEG acquisitions. phonemic fluency. To our knowledge, these 3 studies constitute the corpus of literature in the past 20 years relating ictal EEG mea- Subjects surements in pulse wave ECT to ECT-induced cognitive adverse ef- The University of New Mexico Human Research Protections fects, in domains of time to orientation, memory, and verbal fluency. Office approved this investigation. All subjects signed procedural Electroconvulsive therapy dosing as measured by E-field consent or assented to the research protocol with the surrogate modeling takes into account individual variability and may be re- medical decision maker providing consent. Of the 62 subjects who lated to cognitive outcomes. Realistic computational models of completed the parent study, 17 underwent an sMRI to generate the head can predict E-field distribution in the brain induced by E-field modeling and completed 24-lead EEG capture at a RUL ECT, accounting for anatomical parameters such as tissue conduc- suprathreshold treatment. Every attempt was made to capture tivity, head and brain geometry, and also properties of the current- the earliest suprathreshold RUL treatment with 59% of captures carrying electrodes, such as size and placement on the scalp (right happening at either treatment #2 or #3. Fifteen subjects had Fp1 7,13,14 unilateral [RUL], BT). The work flow to develop realistic EEG captures and 13 subjects had Fp2 EEG captures. head models for electric stimulation include image segmentation, tessellation of volume into a mesh, electrode placement on the scalp, 13,15 Cognitive and Therapeutic Evaluations and solving for the E-fields with the finite element method. These E-field models have been validated with motor evoked poten- Subjects were recruited through the ECT service at the Uni- tials and intraoperatively with cortical EEG. By using structural versity of New Mexico. Subjects were started with RUL placement magnetic resonance imaging (sMRI) data, E-field modeling can cap- and randomized to 3 fixed amplitude arms: 600, 700, or 800 mA. ture individual anatomical differences to explain variable ECT dos- All analysis was done on only the RUL treatments. Subjects 16,17 ing. Prior work has shown that the E-field strength has a direct completed a neurocognitive battery and depression symptom relationship with hippocampal neuroplasticity and a negative relation- severity assessments before ECT (V1), during ECT (before treatment 18,19 19 ship with antidepressant response. Argyelan et al demonstrated #6, V2), and after ECT (V3). Patient's final scores were in patients receiving ECT that the amygdala and hippocampus had a assessed as the difference between pre- and post-ECT (V3-V1), strong relationship between E-field and volumetric change and unless they switched to BT at V2 secondary because of nonresponse, that high E-fields were associated with robust volume changes in which case final scores were assessed as (V2-V1). Bitemporal in a dose-dependent fashion; however, neither the E-field nor vol- treatments were excluded from the analysis because of the substantial umetric change was associated with antidepressant outcomes. difference in E-field values when modeling for BT electrode Fridgeirsson et al found that a stronger E-field in the temporal placement. A separate analysis of BT outcomes was not possible lobes was associated with decreased therapeutic response in pa- given the small sample size (n = 4). The DKEFS-VF LF was used 20,21 tients who received BT ECT. A common limitation to these model- as our primary outcome measure for cognitive impairment. The ing studies is that the E-field only describes the spatial extent of the DKEFS-VF LF raw score was converted into demographic- direct electrical stimulation. The relationship between the E-field adjusted (age) scaled scores. The 24-item Hamilton Depression and seizure expression, and the ultimate clinical and neurocognitive Rating Scale was used to measure antidepressant outcome. outcome remains unknown. The Montreal Cognitive Assessment (version 7.1) and Test of The purpose of this study was to investigate ictal EEG power Premorbid Function (TOPF) at baseline were used to screen for as a potential bridge between ECT variable dosing in the brain as global cognitive function and premorbid intellectual function 23,24 measured by E-field modeling and cognitive impairment. The respectively. data are from a parent study with a primary focus of investigating the relationship between E-field and neuroplasticity. In this Electroencephalography double-blind controlled-trial, older patients (50–80 years) were The SMARTING 24-lead channel amplifier and mobile de- randomized into 3 amplitude arms: 600, 700, and 800 mA. Electric vice was used for EEG capture (mBrainTrain, Inc, Belgrade, field models were generated in all patients as well as neurocognitive Serbia). The sampling rate was 500 Hz. The initial single batteries and mood scales before, during, and after ECT. In line with referencing node was located in the FCz position. Cleaning of data the recent advances in cognitive testing and the results of our parent consisted of excluding all channels with an impedance greater than study, the Delis Kaplan Executive Function System (DKEFS) Ver- 20 kΩ. Channels were then visually inspected and excluded if they bal Fluency Test Category and Letter Fluency (DKEFS-VF CF and were saturated or contained artifacts during the ictal period. The re- LF) tasks were found to be the most sensitive tests to amplitude- maining good channels were re-referenced to the common average mediated cognitive impairment and were used as our primary out- 25 2 reference. Power spectral density (in micro-Volts per Hertz) was 20,21 come measures for cognitive impairment. We examined 17 calculated for each channel over the range of frequency bands; delta subjects who received sMRIs, 24-lead EEG, and cognitive and ther- (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), and apeutic assessments. Linear regression models examined the rela- 26–28 gamma (30–80 Hz) with EEGLAB (version 2019.0). Ictal tionships between E-field models, ictal power in each frequency powers were then log transformed to normalize the distribution. band, and cognitive outcomes controlling for age and premorbid in- Fp1 and Fp2 channels were chosen as our primary outcome chan- tellectual function. We hypothesized that frequencies in the lower nels to align with standard ECT EEG acquisitions. bands would demonstrate an association. Magnetic Resonance Imaging MATERIALS AND METHODS T1 and T2 sMRI were captured using a 3T Siemens scanner For detailed information on study inclusion/exclusion criteria, before ECT initiation. neurocognitive and clinical assessments, ECT treatment parame- T1 parameters were as followed: repetition time = 2530 ms; ters, and study design, we refer to the published findings of our echo time = 1.64, 3.5, 5.36, 7.22, 9.08 ms; inversion time © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. www.ectjournal.com 89 Miller et al Journal of ECT Volume 38, Number 2, June 2022 (TI) = 1200 ms; flip angle = 7.0 degrees; slices = 192; field of TABLE 1. Demographic and Clinical Characteristics view = 256; matrix 256  256; voxel size = 1.0  1.0 1.0 mm; and total acquisition time = 6:03 (minutes:seconds). Clinical and Demographic Features N = 17 T2 parameters were as followed: repetition time = 2530 ms, echo time = 474 ms, flip angle = 120.0 degrees, slices = 192, field Age 65.1 (8.4) of view = 256, matrix 256  256, voxel size = 1.0  1.0 Sex: male/female 6/11 1.0 mm, and total acquisition time = 5:09. TOPF 108.1 (12.1) Baseline MOCA 24.5 (2.6) Electric Field Modeling E , mean (SD) 111.9 (22.8) brain We used Simulation of Non-Invasive Brain Stimulation Baseline DKEFS Category Fluency Scaled Score 8.2 (3.9) (SimNIBS, version 2.1.2) for E-field modeling. SimNIBS cre- Post RUL ECT DKEFS Category Fluency Scaled 7.0 (2.9) ates a subject specific, anatomically realistic volume conductor Score model. The T1- and T2-weighted scans are segmented into skin, Change in DKEFS Category Fluency Scaled Score −1.6 (2.2) bone, eyes, cerebral spinal fluid, ventricles, and gray and white Baseline DKEFS Letter Fluency Scaled Score 8.7 (3.2) matter with a combination of FMRIB Software Library (FSL) Post RUL ECT DKEFS Letter Fluency Scaled Score 7.7 (3.2) and Statistical Parametric Mapping 12 (SPM12) Computational 31,32 Change in DKEFS Letter Fluency Scaled Score −1(2.7) Anatomy Toolbox. SimNIBS then turns this segmentation Baseline Hamilton Depression Rating Scale 36.7 (5.3) into a tetrahedral head mesh using GMSH, a 3-dimensional finite Post RUL ECT Hamilton Depression Rating Scale 19.0 (13.8) element mesh generator, with unique conductivity values for each tissue type. Electrodes are added to the head mesh in either RUL Change in Hamilton Depression Rating Scale 0.489 (0.365) orientation and simulated with corresponding current. SimNIBS Log of Fp1 ictal theta power (n = 15) 37.8 (29.1) then uses a finite element solver to calculate the voltages and E- Log of Fp2 ictal theta power (n = 13) 46.3 (33.2) fields corresponding to the stimulation throughout the head mesh. Responder/nonresponder 3/14 Simulations were performed using unit current, the resultant E- Remitter/nonremitter 6/11 fields were then scaled to the assigned ECT current amplitudes RUL only/bitemporal switch 13/4 (600, 700, or 800 mA). Whole-brain E-field strength, E ,was brain RUL suprathreshold treatment captured by EEG 4.6 (3.3) calculated at 90th percentile of E-field magnitudes as an estimate of peak induced field strength, while avoiding the influence of tis- Format is mean (SD) or to indicate proportion. sue boundary effects that could bias the absolute maximum E- MoCA indicates Montreal Cognitive Assessment. field values. Statistical Analysis when controlling for age in delta (t = −27.04, P =0.17)/ (2,12) Our data passed normality testing. Linear regression models (t = 38.22, P = 0.10), alpha (t = 11.44, P = 0.27)/ (2,10) (2,12) comparing the relationships between E , ictal frequency power, brain (t = 17.96, P = 0.12), beta (t = 11.46, P =0.36)/ (2,10) (2,12) and cognitive outcomes were performed using R (version (t = 16.97, P = 0.20), and gamma (t = 9.03, (2,10) (2,12) 33–36 4.0.2). First, the relationship between ictal frequency power P =0.62)/(t =11.08, P = 0.56) frequency bands. In contrast, (2,10) and E controlling for age was assessed. Second, the relation- brain E was significantly associated with ictal theta power in both brain ship between the ΔDKEFS-VF LF scaled score and ictal fre- Fp1 (t =19.5, P = 0.007) and Fp2 (t =21.85, P =0.02) (2,12) (2,10) quency power controlling for premorbid intelligence (TOPF) channels when controlling for age (Figs. 1A, B). A whole-brain was assessed. Third, the relationship between ΔDKEFS-VF LF exploratory analysis demonstrated that E was related to ictal brain scaled score and ΔDKEFS-VF CF scaled scores and E con- brain theta power in 75% of the remaining 20 channels ( P <0.05in trolling for premorbid intelligence (TOPF) was assessed. An ex- green; Fig. 1C). No particular area of strength was noted, but ploratory whole-brain analyses on the remaining 20 EEG chan- the midline channels (Fz, Cz, and Cpz) demonstrated the weakest nels were done (the 2 mastoid channels were excluded from anal- association ( P >0.05). ysis) and compared E , ictal power, and antidepressant outcomes brain with similar regression models. Given the exploratory nature of our study, no mathematical corrections were made for multiple Ictal Theta Power and Cognitive Outcomes comparisons. There was no statistically significant relationship between ictal power and category fluency in any bands. We focused on letter fluency as our primary cognitive outcome. Ictal power and letter RESULTS fluency demonstrated no statistically significant relationships when controlling for premorbid intelligence in both Fp1/Fp2 Clinical and Demographic Characteristics channels in delta (t = −0.13, P =0.78)/(t = −0.66, P =0.15), (2,12) (2,10) Demographics, clinical, and neuropsychological data are alpha (t = −1.07, P = 0.23)/(t = −1.93, P = 0.024), beta (2,12) (2,10) summarized in Table 1. The average age for the subjects (N = 17) (t = −0.22, P = 0.77)/(t = −1.34, P = 0.12), and gamma (2,12) (2,10) was 65.1 years with a standard deviation of 8.4. Six of the 17 sub- (t =0.13, P = 0.80)/(t = −0.24, P = 0.72) frequency (2,12) (2,10) jects were male. Four, 6, and 7 subjects received 600, 700, and bands. In contrast, ictal theta power was associated with cognitive 800 mA RUL ECT, respectively. Thirteen of the 17 subjects re- outcomes in Fp1 (t = −2.05, P = 0.05) with Fp2 demonstrat- (2,12) mained in RUL ECT throughout the ECT series. ing a stronger relationship (t = −2.20, P = 0.01; Figs. 2A, B). (2,10) A whole-brain exploratory analysis demonstrated that ictal theta Whole-Brain E-Field Strength and Ictal power was related to cognitive outcomes when controlling for Theta Power premorbid intelligence in 70% of the remaining 20 channels Whole-brain E-field strength and ictal power demonstrated ( P < 0.05 in green; Fig. 2C). The midline and right hemisphere no statistically significant relationships in both Fp1/Fp2 channels (Fz, Pz, POz, O2, T8) demonstrated the strongest association 90 www.ectjournal.com © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker FIGURE 1. A, Left. Ictal theta power versus E in the Fp1 channel. B, Middle. Theta power versus E in the Fp2 channel. C, Right. Whole- brain brain brain exploratory analysis of ictal theta power and E with standard 19-lead EEG map shown (CPz, P7, P8, and mastoid channels not brain shown). Green leads denote statistical significance ( P <0.05). ( P < 0.01) and the left temporal-occipital area (P3, T3, T5, P7, strength (E ) was associated with ictal power in different fre- brain O1) demonstrated the weakest ( P > 0.05). quency bands. We then examined the relationship between E brain and ictal power and cognitive outcomes as measured by the change in letter and category fluency scores before and after Whole-Brain E-Field Strength and RUL ECT. Ictal theta power (4–8 Hz) was associated with E brain Cognitive Outcomes in 17 of 22 EEG channels (77%), including Fp1/Fp2, the 2 chan- Linear models showed no statistically significant relationship nels used to monitor seizure activity during routine ECT. Further- between E and letter fluency (t = −2.06, P = 0.06; Fig. 3). brain (2,14) more, an association was found in 16 of 22 EEG channels (73%), Linear regression results are summarized in Table 2. including Fp1/Fp2, between ictal theta power and the ΔDKEFS- VF LF scaled score (letter fluency). This association was noted Whole-Brain E-Field Strength, Ictal Theta Power, to a much lesser extent in the alpha band, with 11 of 22 EEG chan- and Antidepressant Outcomes nels (50%) reaching statistical significance, including Fp1, and Whole-brain E-field strength showed no statistically sig- were absent in the delta, beta, and gamma bands. No association nificant association with antidepressant outcomes (% change was observed between ictal theta power and antidepressant out- in the Hamilton Depression Rating Scale) when controlling for comes in the Fp1/Fp2 channels. Neither E nor ictal power brain age (t =0.005, P = 0.25). Ictal theta power in the Fp1/Fp2 (1,15) were associated with the change in category fluency. Meanwhile, (t =0.07, P = 0.65)/(t =0.22, P = 0.06) channels showed (2,12) (2,10) adirectrelationshipbetween E and the change in letter fluency brain no statistically significant association with antidepressant out- was insignificant ( P = 0.06). Our results align with a previous in- comes when controlling for age. A whole-brain exploratory anal- vestigation and provide evidence that ictal theta power may act as ysis demonstrated that ictal theta power was significantly associ- an ECT safety biomarker by bridging ECT dosing as measured by ated with antidepressant outcomes when controlling for age in E and cognitive impairment as measured by phonemic (letter) brain CPz and P8 ( P <0.05). fluency. Ictal theta power is a measure that is easily accessible on most ECT devices and could identify excessive dosing and cognitive DISCUSSION risk early on in treatment. Unlike postictal recovery time, ictal We obtained baseline sMRI and 24-lead EEG in a suprathreshold theta power will not be confounded by emergent agitation and re- treatment in 17 older subjects with major depressive disorder lated treatments, which affects approximately 10% of patients. who were treated with RUL ECT. We examined whether E-field Evidence suggests that early ECT dosing impacts cognitive FIGURE 2. A, Left. Letter fluency versus ictal theta power in the Fp1 channel. B, Middle. Letter fluency versus ictal theta power in the Fp2 channel. C, Right. Whole-brain exploratory analysis of cognitive performance and ictal theta power with standard 19-lead EEG map shown (CPz, P7, P8, and mastoid channels not shown). Green leads denote statistical significance ( P <0.05). © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. www.ectjournal.com 91 Miller et al Journal of ECT Volume 38, Number 2, June 2022 FIGURE 3. Letter fluency versus E (P = 0.06). brain outcomes with a significant lag time between initial parameter se- impairment. Thus, early identification of cognitive risk at the first 1,38–40 lection and eventual cognitive impairment. In the context of suprathreshold treatment has clinical translational implications for nonresponse, the ECT clinician can increase the ECT dose for immediate corrective action to mitigate the onset of cognitive im- eventual therapeutic response without potential adverse conse- pairment. Based on our results, increased ictal theta power may be quences other than prolonging the ECT series. In contrast, reduc- suggestive of excessive E-field strength. Electric field strength is 7,15 ing the ECT dose in the context of ECT-induced cognitive impair- proportional to pulse amplitude. If the first suprathreshold ment may minimize, although not completely eliminate, cognitive treatments generates excessive ictal theta power, the ECT clinician TABLE 2. Regression Results Log of Fp1 Log of Fp2 ΔLetter Fluency Theta Power Theta Power ΔLetter Fluency OLS OLS OLS OLS 12 3 4 5 Constant 3.60 (−8.70 to 15.89) 6.76 (−7.49 to 21.00) 2.27 (0.16 to 4.38) 3.49* (1.12 to 5.85) 5.52 (−7.50 to 18.54) Log of Fp1 theta −2.05* (−3.90 to −0.21) power Log of Fp2 theta −2.20* (−3.63 to −0.78) power TOPF 0.02 (−0.08 to 0.12) 0.00 (−0.11 to 0.12) −0.00 (−0.10 to 0.10) E 0.03† (0.02 to 0.04) 0.03† (0.02 to 0.04) −0.06 (−0.11 to −0.00) brain Age −0.03 (−0.06 to 0.00) −0.05* (−0.08 to −0.01) Observations 15 13 15 13 17 R 0.29 0.48 0.70 0.74 0.23 Adjusted R 0.17 0.38 0.65 0.69 0.12 Residual SE 2.44 (df = 12) 2.16 (df = 10) 0.41 (df = 12) 0.48 (df = 10) 2.54 (df =14) F statistic 2.41 (df = 2, 12) 4.69* (df = 2, 10) 14.02† (df = 2, 12) 14.57‡ (df = 2, 10) 2.13 (df =2, 14) See the 5 models presented in the rows above. The outcome variable is listed across the top. The variables and covariables are listed on the left side of the column. An example of how to read the first model under column 1 is provided. Example: ΔLetter fluency = 3.60–2.05  (log of Fp1 theta power) + 0.02  (TOPF). *P <0.05. †P < 0.001. ‡P <0.01. OLS indicates ordinary least squares. 92 www.ectjournal.com © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. Journal of ECT Volume 38, Number 2, June 2022 Ictal Theta Power as an ECT Safety Biomarker may elect to decrease the E-field with a reduced amplitude in sub- cognitive testing may illuminate the interplay between electric dos- sequent treatments to reduce cognitive risk. The specific threshold ing and the resulting seizure, while disentangling therapeutic and for the amount of theta power from the first suprathreshold treat- cognitive outcomes. In conclusion, ictal theta power could provide ment that is associated with cognitive risk needs to be determined, clinicians with an immediately available tool to identify early on but the premise could be a useful and accessible tool for the ECT in the ECT course those patients most at risk of cognitive impair- clinician. ment, resulting in measurement-based care precision ECT dosing. The interaction between ictal theta power and cognitive im- pairment remains unclear. Increases in theta oscillations in the REFERENCES resting state are associated with executive function and decreased 41–43 1. Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and vigilance. In addition, anatomical correlates of theta oscilla- electrode placement on the efficacy and cognitive effects of tion activity include deep brain structures like the hippocampus, electroconvulsive therapy. 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