The effects of ECT stimulus dose and electrode placement on the Ictal electroencephalogram: An intraindividual crossover study

BIOL PSYCHIATRY 1993;34:759-76"/

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The Effects of ECT Stimulus Dose and Electrode Placement on the Ictal Electroencephalogram: An Intraindividual Crossover Study Andrew D. Krystal, Richard D. Weiner, W. Vaughn McCall, Frank E. Shelp, Rebecca Arias, and Pamela Smith

Recent evidence suggests that electroconvulsive therapy (ECT) efficacy depends upon both electrode placement and the degree to which stimulus dosage exceeds seizure threshold (T), and not simply on surpassing a minimum seizure duration as has been assumed. In light of these findings and studies reporting ictal electroencephalogram (EEG) differences between bilateral and unilateral ECT, we performed this 19-subject intraindividual crossover study of the effects of dose and electrode placement on the ictal EEG. We found ictal EEG evidence of greater seizure intensity with bilateral than unilateral ECT and with higher dosage (2.25 7")compared with barely suprathreshold stimuli. Seizure duration was not longer with bilateral than unilateral ECT and actually decreased with increased dose. A number of ictal EEG variables separated the unilateral 2.25 T and unilateral T conditions, which reportedly differ in efficacy, and therefore, these EEG measures show promise as markers of treatment adequacy. Key Words: ECT, EEG, electrode placement, stimulus dose, seizure adequacy

Introduction The ability to surpass a minimum seizure duration has generally been held as the standard of seizure adequacy with electroconvulsive therapy (ECT) (Ottosson 1960; Abrams 1992). However, this measure now appears to be a poor predictor of therapeutic response (Weiner and Krystal 1993; Sackeim et al 1991), and we have postulated that other electrophysiologic characteristics of the induced seiFrom the Department of Psychiatry (ADK, RDW. PS, RA). Duke University Medical Center, Durham, and the Department of Psychiatry (WVM), the Bowman Gray School of Medicine, Winston-Salem, NC, and United Health Care (FES), Louisville, KY. Address reprint requests to Dr. Andrew Krystal, Department of Psychiatry, Box 3309. Duke University Medical Center. Durham. NC, 27710. Received October 15, 1992; revised August 20, 1993.

© 1993 Society of Biological Psychiatry

zure activity may be more important (Krystal et al 1992; Weiner et al 1991; Weiner and Krystal 1993). Recent evidence that the efficacy of ECT may depend on both electrode placement (ELPL) and dose, the degree to which stimulus dosage exceeds seizure threshold (T) (Sackeim et al 1987, 1991, 1993) led us to wonder whether such effects might operate via differences in the induced seizure activity, as recorded on the scalp electroencephalogram (EEG). Based on earlier reports of ictal EEG amplitude and symmetry differences between unilateral nondominant (UL) ,~nd bilateral (BL) ECT (d'Elia and Penis 1970; Abrams et ai 1973; Kriss et ai 1978; Staton et al 1981; Brumback and Staton 1982), we developed a variety of ictal EEG manual and computer measures and conducted a pilot study in which subjects were randomized

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to one of these ECT modalities for their entire treatment course (Krystal et al 1992). We found that BL seizures had greater ictal EEG amplitude, symmetry, coherence, morphologic regularity, and postictal suppression than the UL seizures. it is perhaps even more clinically important to be able to separate seizures on the basis of dose than ELPL. This is because although antidepressant potency and adverse effects have been shown to be strongly dependent on dose (Sackeim et al 1987, 1991, 1993), a highly variable rise in seizure threshold takes place over the ECT treatment course that renders the practitioner's ability to accurately assess relative dosage in an ongoing fashion uncertain at best (Sackeim et al 1983, 1991). To this end, we carried out the present investigation of the relationship of both manually rated and computer-derived ictal EEG variables to ELPL and Dose in subjects involved in an intraindividual crossover comparison of UL versus BL effects on seizure threshold (McCall et al 1993). This pilot study also contrasted barely suprathreshold with moderately suprathreshold (2.25 times initial seizure threshold) stimulus intensities, thereby allowing dose-dependent effects to be investigated. It is, therefore, the first intraindividual investigation to directly assess the effects of both electrode placement and stimulus dosage on the ictal EEG while controlling for the degree to which stimuli are suprathreshold.

ECT Administration

Methods

unchanged throughout the study treatments for each subject.

Subjects Nineteen patients clinically referred for ECT were included (13 female and six male). Twelve met DSM-III-R (APA 1987) criteria for major depression (unipolar), three met criteria for major depression (bipolar), three satisfied cfitefia for schizophrenia, and one met criteria for a diagnosis of schizoaffective disorder. Data from nine other subjects in the parent study were excluded before analysis by R.D.W. because of inadequacies in the technical quality of the recording, primarily due to artefact. All subjects gave informed consent, were between ages 21 and 75 years (mean = 46.5 years, SD = 16.3 years), were strongly right body dominant by history, had a negative neurologic history and examination, and had not had ECT in the past 6 months. Psychoactive medications were reduced as far as possible prior to study entry. All subjects were free of antidepressants, lithium, and agents with anticonvulsant properties for a minimum of 3 days before the fust ECT treatment. Two individuals with a diagnosis of schizophrenia remained on fixed doses of neuroleptic agents over the series of treatments, and one depressed subject was maintained on hydroxyzine.

All subjects underwent estimation of seizure threshold at treatments 1 and 2 (see below), followed by treatments at 2.25 times seizure threshold at treatments 3 and 4. Subjects were randomized ds to the order in which they received BL or right UL electrode placement (d'Elia 1970). Stimuli at 2.25 times seizure threshold were chosen because this is the middle of the range recommended for clinical practice by the American Psychiatric Association ECq" task force (1.5 to 3 times threshold) (APA 1990) and is very close to what was used in the work of Sackeim described above (Sackeim et al 1991, 1993). All stimulus waveforms were bidirectional pulses. The seizure threshold titration protocol used an initial stimulus of 32 m e for all subjects at treatments 1 and 2, using a Mecta SRI device (Mecta Corporation). If restimulation was necessary (absence of tonic-clonic convulsive activity of greater than 20 sec in the cuffed fight ankle), a treatment was delivered at a level 50% higher in charge. Up to three such restimulations (each involving an approximately 50% increase in dosage) were allowed at each of the titration treatments. The mean number of restimulations was !.3 for UL titration and 2.0 for BL titration. No subjects failed to seize by the fourth stimulus. No adverse effects accompanied the restimulations. All of the 2.25-T treatments were accompanied by more than 20 see of convulsive activity on the first stimulation. The dosages of anesthetic, muscle relaxant, and anticholinergic medications remained

EEG Recording Two channels of EEG were recorded from left and fight prefrontal-to-mastoid derivations using Ag/AgC! electrodes. Prefrontal electrodes were positioned 1 cm rostral to standard Fpl and Fp2 locations (International 10-20 System). The EEG, amplified by a Mecta Corporation SRI ECT device (1- to 40-Hz passband) was both recorded onto paper during the seizures for manual analysis and input to a Vetter Model C-4 multichannel FM audiotape recorder (0- to 100-Hz passband). The analog recordings were later digitized off-line onto a microcomputer at a resolution of 256 samples/sec for subsequent computer analysis.

Computer EEG Analysis The digitized ictal EEG data underwent Fourier decomposition using a standard FFT algorithm (Cooley and Tukey 1965) into three frequency bands: 2-5 Hz, 5.5-13 HZ, and 13.5-30 Hz (Krystal et al 1992). This analysis was performed on 6-sec portions of the seizure from the

The lctal EEG Effects of ECT Stimulus Type

immediate poststimulus, midictal, and immediate postictal segments of the seizure. A.D.K., who remained blind to treatment type, first manually artefacted the ictal EEG and then chose these 6-see (three 2-see epoch) segments, according to the fixed protocols described below (Figure 1). The early segment was chosen as the first six artefactfree seconds of data within the initial 10 see after the stimulus artefact. If 6 see of artefact-free data were not available within this period, no early spectral analysis was performed. The midictal portion of the seizure was chosen by an automated computer algorithm that detected the maximum amplitude portion of the seizure. The ictal EEG underwent sp':ctral amplitude calculation in sequential, overlapping 3-epoch (6-see) artefact.free portions (epochs 1-3, 2-4, 3-5, etc.). The highest amplitude segment was used for all midictal calculations. The po~tictal portion of the seizure was defined as the first three artefact-free postictal epochs. The EEG seizure cndpoint was manually determined by A.D.K. The spectral amplitude, interhemispheric coherence (the frequency domain analogue of correlation, which reflects the degree of physiologic coupling between the EEG activity in both hemispheres in each of the three frequency bands), and interhemispheric amplitude symmetry were computed for each of these three temporal portions at all three frequency bands in the same manner as previously reported (Krystal et al 1992).

Manual EEG Analysis Manual ratings of paper tracings of ictal EEG data were performed by A.D.K., who was blind to subject and treatment type. High interrater reliability with R.D.W. had been established in prior ratings of ictal EEO data for all measures except ictai symmetry, and therefore this vari. able was dropped from the study (duration r(20) = 0.99; p < 0.0001; regularity r(20) -- 0.88, p < 0.(,001; ictal amplitude r(20) -- 0.96, p < 0.0001; postictal amplitude r(20) = 0.77, p < 0.0004; ictal symmetry r(20) -- 0.49, p < 0.05). The ratings, which were identical to those previously reported (Krystal et al 1992), included (1) maximum peak-to-peak amplitude, (2) immediate postictal amplitude (mean over first 5 see postictally), (3) ictal symmetry (degree and duration of asymmetry throughout the seizure rated on a 7-point ordinal scale, - 3 to + 3, with 0 = symmetrical (positive means right amplitude greater than left), (4) ictal regularity (predominant midictal pattern rated according to a 7-point ordinal scale, 0 to 6, with 6 being the most regular), and (5) seizure duration (the end of paroxysmal EEG activity in either channel) (Weiner and Krystal 1993).

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Statistical Analysis Because of the large number of EEG variables, statistical analysis was focused on the following spectral amplitude measures: immediate poststimulus 5.5-13 Hz amplitude, 2-5 Hz midictal amplitude, and 2-5 Hz postictal amplitude. The amplitude indices were chosen because they have been by far the best studied (d'Elia and Perris 1970; Small et al 1970; Kriss et al 1978; Staton et al 1981, 1986; Gerst et al 1982; Brumback and Staton 1982; Robin et al 1985; Weiner et al 1986a; Krystal et al 1992), and this work suggests that large ELPL and dose differences are likely to be found with these variables. For the three amplitude variables, a single multivariate repeated measures analysis of variance (ANOVA) was conducted in which ELPL, dose, hemisphere, and time period (i.e., immediate poststimulus, midictai, or postictal) served as independent variables, along with the interactions between these variables. Subsequent univariate repeated measures ANOVAs were performed for each of the three amplitude measures for independent measures and interactions where a significant main effect was found in the multivariate analysis. In addition, intraclass correlation coefficients were computed between manually rated and computer-derived amplitude measures to reflect the degree of agreement between these forms of measurement. Also, because others have suggested that seizure intensity might be reflected in the process of seizure termination, as well as in immediate postictal amplitude (Sackeim and Mukherjee 1986; Sackeim et al 1991), we calculated correlation coefficients among major ictal amplitude measures, seizure duration, and postictal amplitude.

Results Descriptive statistics for each EEG variable for each of the four treatment conditions appear in Table 1.

Multivariate Repeated Measures/,NOVA Significant main effects were found in the multivariate repeated measures ANOVA analysis including amplitude variables for ELPL (F = 11.7, p < 0.008), Dose (F -15.3, p < 0.004), and hemisphere (F = 14.6, p < 0.004). Subsequent univ~iate repeated measures ANOVAs were carried out for each of the three amplitude measures incorporating ELPL, Dose, and hemisphere as dependent variables (see below and Table 2). No significant interactions were found in the omnibus multivariate analysis except for ELPL by hemisphere (F = 2.7, p < 0.025) and ELPL by dose by hemisphere, which significantly differed in the three time periods (F = 17.4,p < 0.001). Therefore the only interactions included in the univariate analyses were ELPL by hemisphere and ELPL by dose by

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,oo Figure i. A comparison of the UL T and 2,25-T BL spectral analysis results for the three temporal seizure phasesstudied for subject 3. Arrows indicate seizure portion chosen for analysis, (A) UL T immediate lmststimulus: left 2-5 Hz amplitude = 29 ~,,V, d~!'~Z 2-5 Hz amplitude -= 25 ixV, 2-5 Hz coherence -- 0.79, left 5,5-13 Hz amplitude -26 p.V, right 5,5-13 Hz amplitude --- 25 p,V. (n) UL T midicta]: left 2-5 Hz amplitude -- 116 p,V, right 2-5 Hz amplitude = 136 IxV, 2-5 Hz coherence -- 0.94. (C) UL T postietul: left 2-5 Hz amplitude -- 9.4 IxV, right 2-5 Hz amplitude = 8.2 p,V, 2-5 Hz coherence = 0.40. (D) BL 2,25-T immediate poststimulus: left 2-5 Hz amplitude = 16I I~V, right 2-5 Hz amplitude -- 156 I~V, 2-5 Hz coherence = 0.95, left 5.5-13 Hz amplitude -- 56 ItV, right 5,5-13 Hz amplitude --- 57 ItV. (E) UL T midictal: left 2 5 Hz amplitude -- 219 ixV, right 2-5 Hz amplitude --- 215 ItV, 2-5 Hz coherence -0.97. (F) UL T postictul: left 2-5 Hz amplitude -- 2.2 ptV, right 2-5 Hz amplitude -3.8 ItV, 2-5 Hz coherence --- 0.20.

The Ictal EEG Effects of ECT Stimulus Type

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763

Table l. Group Means and Standard Deviations~ Measure (n) fetal amplitude (~V) Left spectral 2-5 Hz early (! I) Right spectral 2-5 Hz early (! 1) Left spectral 5.5-13 Hz early (11) Right spectral 5.5-13 Hz early (ll) Left spectral 2-5 Hz middle (18) Right spectral 2-5 Hz middle (18) Left manual ietal amplitude (19) Right manual ictal amplitude (19) Postictal amplitude (pV) Left spectral 2-5 Hz (17) Right spectral 2-5 Hz (17) Left manual postictal (19) Right manual postictal 09)

Coherence 2-5 Hz early (11) 2--5 Hz middle 08) 2-5 Hz postictal (17) Morphologic reguimity lctal manual regularity (18) Seizure duration (sec) (~9)

T UL, mean (SD)

2,25-T UL, mean (SD)

T BL, mean (SD)

2.25-T BL, mean (SD)

22 (12) 24 (13) 27 (12) 29 (17) 91 (52) 105 (48) 302 (139) 300(89)

28 (12) 41 (29) 36 (15) 46 (20) 109 (51) 125 (47) 368 (155) 384 (129)

29 (14) 28 (16) 39 (22) 40 (21) 119 (57) 116 (53) 359 (170) 380 (180)

94(72) 69(65) 52 (26) 54 (22) 170 (76) 173 (80) 457 (138) 482 (156)

6.7 5.7 43.3 41.7

11.3 11.3 55.9 58.2

4.9 (3.0) 5.2 (3.4) 27.6 (16) 30,0 (17)

10.8 il.4 73.3 71,7

(5.6) (6.6) (30) (31)

(3.5) (2.8) (26) (28)

(6.2) (6.8) (32)

(40)

0.38 (0,25) 0.87 (0.18) 0.39 (0.24)

0.52 (0.28) 0.88 (0. !) 0.31 (0.19)

0,58 (0.16) 0,80 (0.2) 0.38 (0.23)

0.77 (0,17) 0.88 (0,2) 0,20 (0.16)

3.3 (2.0) 98.7 (52)

4.3 (1.5) 71.3 (25)

3.9 (1.6) 81.6 (31)

4.8 (1.5) 67.5 (23)

or, threshold; UL, unilateral; BL, bilateral.

Table 2. Repeated Measures ANOVA Significance Values for Spectral Amplitude Measures

Measure

ELPL

Dose

Hemisphere

ELPL × hemisphere

ELPL × Dose × hemisphere

5.5-13 Hz early amplitude 2-5 Hz midictal amplitude 2-5 Hz postictal amplitude

0.02 0,01 NS

0.006 0.006 0.0001

0.006 0,01 NS

0.09 0.0008 NS

0.05 NS 0,04

hemisphere. For these three variables, the degree of significance of the difference in the UL T and UL 2.25-T conditions is also reported in Table 2. This was done because UL T and 2.25-T ECT have been reported to differ in efficacy (Sackeim et al 1987, 1991, 1993), and therefore measures differing in these conditions show promise as markers of UL ECT treatment efficacy.

Ictal Amplitude Significant ELPL and Dose effects were present for both early 5.5-13 Hz and midictal 2-5 Hz amplitude (Table 2). Table 1 reveals that greater amplitude accompanied the 2.25-T dose and BL ELPL conditions for these variables and that effects in the same direction were seen with all other ictal amplitude variables that were not among the

ULT versus UL 2,25 T Left

Right

0,03 NS 0.0004

0.008 0,07 0.0003

subset included in repeated measures ANOVA analysis. In this regard, manually derived midictal amplitude measures were significantly correlated with 2-5 Hz computer spectral midictai measures (left, R = 0.80, p < 0.001; right, R = 0.81, p < 0.001). A significant hemisphere effect for both 5.5-13 early and 2-5 Hz midictal amplitude (Table 2) was due to greater amplitude in the stimulated hemisphere (Table l). For 2-5 Hz midictal amplitude, there was a significant ELPL by hemisphere interaction (Table 2), reflecting that substantial interhemispheric asymmetry was present only for UL ECI" (Table 1), whereas for 5.5-13 Hz early amplitude a significant ELPL by dose by hemisphere interaction was found (Table 2) because substantial right > left asymmetry only accompanied 2.25T UL ECT (Table 1). Also, significantly greater early 5.513 Hz amplitude was found for UL 2.25 T as compared with UL T data for both hemispheres (Tables 1 and 2). A

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trend in the same direction was found for 2-5 Hz midictal amplitude.

Postictal Amplitude A signi~cant dose effect for 2-5 Hz postictal amplitude (Table 2) reflects a prominent decrease in amplitude with increasing dose (greater postictal suppression) (Table 1). Table 2 also reveals a significant ELPL by Dose by hemisphere interaction (Table 2), which is due to a left > right interhemispheric asymmetry, which was seen only in the UL 2.25-T condition (Table !). Greater postictal suppression was seen in both hemispheres in the UL 2.25 T as compared with the UL T ECT (Tables I and 2). lntraclass correlation coefficients relating manual and computer postictal amplitude measures showed a trend toward significant correlation (left, R = 0.54, p < 0.075; right, R = 0.49, p < 0.09).

Coherence Mean values in the four treatment conditions (Table 1) are qualitatively suggestive of greater 2-5 Hz early coherence with increasing stimulus intensity and in BL as compared with UL ECT, and decreasing 2-5 Hz postictal coherence in 2.25-T as opposed to T ECT.

Morphologic Regularity Greater mean ictal manual regularity qualitatively appears to accompany BL as compared with UL ECT and 2.25-T versus T stimuli (Table 1).

Seizure Duration A decrease in mean seizure duration with increasing dose was seen, which was larger than an apparent tendency for BL ECT seizures to be shorter in duration than UL ECT seizures (Table I).

lntermeasure Correlations The two types of variables studied that had the most consistent relationships were midictal amplitude and postictal amplitude. For left 2-5 Hz spectral amplitude, significant negative correlations with left 2-5 Hz postictal amplitude were found for the T UL (R = - 0.53, p < 0.02), T BL (R = -0.42, p < 0.09), 2.25-T UL (R = -0.53, p < 0.03) and 2.25-T BL (R = -0.54, p < 0.02) conditions. The relationship between 2-5 Hz left midictal amplitude and seizure duration differed among the four treatment conditions. A strong positive correlation was seen in the T UL (R = 0.65, p < 0.004) group, a trend toward a

Krystal et al

positive correlation existed for the T BL (R = 0.44, p < 0.066) condition, whereas no substantive relationship was seen for the UL 2.25-T condition (R = 0.05), and there was a trend toward a negative correlation in the 2.25-T BL treatments (R = -0.44, p < 0.07). An additional finding was that no substantive relationship existed between postictal amplitude and seizure duration for any of the treatment conditions. Also no significant correlation was found between the number of restimulations and any EEG measure.

Discussion General Comments In this pilot study, ictal EEG measures are shown to be dependent on both electrode placement and stimulus intensity. The preponderance of EEG variables studied displayed differences suggestive of greater seizure intensity with BL ECT as compared with UL ECT, as well as with 2.25 T as compared to T stimuli. In addition, notable differences between the ELPL and dose effects were found. It is important to note that the study design, in which low-intensity treatments invariably preceded treatments of higher intensity, may have influenced the results. However, for most variables, a bias would be expected to be in the direction of minimizing dose-related effects, i.e., opposite to what was found, because the initial seizures in the treatment course are generally believed to be more intense than those that follow (probably due to the rise in seizure threshold over treatments) (Sackeim et al 1991). The fact that we found such significant dose-related differences in the opposite direction, therefore, suggests that actual differences may even be greater than we observed. One exception to this rule, however, is seizure duration, which has generally been reported to diminish from the first to the second treatment (Sackeim et al 1991) and which was decreased in our higher-dose condition. The T dose condition preceded the 2.25-T condition in this study because of the necessity of estimating the initial seizure threshold (T condition) prior to subsequent 2.25-T treatments.

The Effects of ELPL on the lctal EEG The ELPL-dependent changes described herein are consistent with previous findings of greater ictal amplitude, ictal symmetry., ictal morphologic regularity, and immediate poststimulus coherence with BL ECT (d'ELIA and Penis 1970; Kriss et al 1978; Staton et al 1981, 1986; Gerst et al 1982; Brumback and Staton 1982; Krystal et al 1992). Of the differences seen, the midictal amplitude, midictal symmetry, and early amplitude effects were the most substantial. These findings support the view that sei-

The lctal EEG Effects of ECT Stimulus Type

zures with BL ECT are more intense and more symmetrical than those with UL ECT.

The Effects of Dose on the lctal EEG The effects of stimulus intensity on the ictal EEG are consistent with our hypothesis that higher-dosage treatments, like BL treatments, result in greater seizure intensity. We found evidence that higher-dose treatments were associated with greater ictal amplitude, postictal suppression, and immediate poststimulus asymmetry (for UL ECT only). Similar qualitative effects were seen for immediate poststimulus coherence, and morphologic regularity. The effects of dose on some variables differs from that observed with ELPL. The most pronounced effect was a large postictai amplitude difference with dose not seen with ELPL. However, midictal 2-5 Hz spectral amplitude symmetry also had a larger ELPL than dose effect. Though no previous work has directly focused on the effects of relative stimulus intensity on the ictal EEG, other relevant work is in agreement with our findings. Small and colleagues (1970) observed that greater postictal suppression was most common early in the treatment course of sine-wave ECT. Because it has been reported that ECT tends to result in a rise in seizure threshold over the course of treatments (Sackeim et al 1991), the work of Small and colleagues supports our contention that greater postictal suppression is associated with stimuli that are higher in intensity above threshold. Weiner and coworkers (1986a) reported that sine-wave bilateral ECT resulted in greater postictal suppression than pulse unilateral, pulse bilateral, or sine-wave unilateral treatments. A limitation in comparing these results with our findings is that the degree to which these stimuli were suprathreshold is not known (this relationship varies across different stimulus waveforms [Weiner 1980]). Another study that relates to the effects of stimulus dose on the ictal EEG is an intraindividual comparison of "high-energy" modified sine-wave and wide-pulse stimuli with "low-energy" ultrabrief-pulse stimuli (Robin et al 1985). Again, there is no clear evidence as to relative stimulus intensity, though it is likely that low-energy treatments were closer to the seizure threshold. Postictal suppression was, in fact, found to be diminished with )he low-energy treatments, and manually rated mean ictal amplitudes were lower. Both findings are consistent with our results. Ottosson (1960) reported that lidocaine-modified ECT produced w e b e r postictai suppression than ECT without lidocaine. Because lidocaine raises the seizure threshold (Weiner et al 1991), this observation also supports our finding of an increase in postictal suppression with a larger relative stimulus intensity.

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A final source of supporting data, albeit anecdotal, is the clinical observation that low-amplitude and irregular seizures may be morphologically "augmented" by an increase in stimulus intensity at the next stimulation (Weiner et al 1991; Weiner and Krystal 1993).

The Effects of ELPL and Dose on Seizure Duration We found that seizure duration decreased, rather than increased in the more "adequate" treatment conditions, i.e., increasing dose, and that it tended to be shorter in BL than UL ECT. As noted earlier, however, the dose-dependent difference is confounded by the fact that 2.25-T treatments were always delivered after the T treatments and would, therefore, be expected to be shorter in duration as a result of order alone (Sackeim et al 1991). In order to evaluate this possibility, we compared the seizure duration of UL T at treatment 1 versus UL T at treatment 2, BL T at treatment 1 versus at treatment 2, UL 2.25 T at treatment 3 versus 4, and BL 2.25 T at treatment 3 versus 4, by Mann-Whitney U-testing, so as to assess the size and direction of order effects. We found that BL 2.25-T treatments delivered at treatment 4 were significantly shorter than those delivered at treatment 3 (mean = 57 versus 74.2 sec, p -- 0.04), but none of the other treatment conditions differed as a function of treatment order. Thus, the decrease in seizure duration seen with increasing dose is larger than would be expected on the basis of order effects. This finding is consistent with the reports of Sackeim and colleagues (1991) that substantially increasing the stimulus intensity above threshold decreases seizure duration for both BL and UL ECT. In addition, in the intraindividual comparison of three stimulus types by Robin and colleagues (1985) described above, longer seizure duration was associated with the low-energy stimuli.

Electrophysiologic Markers of Efficacy This study has identified a number of ictal EEG measures that show promise for having clinical utility in separating therapeutically adequate from inadequate seizures. Since T UL treatments have been reported to be much less efficacious than higher stimulus intensity UL treatments (Sackeim et al 1991, 1993), the ability of ictal EEG measures to differentiate UL T from UL 2.25-T treatments is of considerable clinical relevance. Postictal and immediate poststimulus amplitude were the most significantly different in UL T and 2.25-T groups. Qualitative differences were also noted for manual regularity and immediate poststimulus coherence. These measures merit fut-ther exploration as clinical tools for identifying inadequate treatments. Having such tools would allow the clinician to maintain stimulus intensity at theraputic levels while also

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minimizing adverse encephalopathic effects (Weiner and Krystal 1993),

Implications for the Neurophysiology o f ECT The present findings imply that ECT treatment types (T UL and 2.25-T UL groups) that differ in efficacy may also be characterized by electrophysiologic differences. The most consistent differences are compatible with a more rapid onset and greater intensity of ictal neuronal hypersynchrony, as well as the mobilization of a greater postictal inhibitory response. The finding of greater asymmetry (right > left) in the immediate poststimulus period with higherintensity UL stimuli is consistent with previous work suggesting that higher dosage UL ECT results in increased neuropsychological effects essentially localized to the stimulated hemisphere (Sackeim et al 1992). Although it might be inferred, on this basis, that 2.25-T UL ECT seizures are less well generalized than UL T ECT seizures, the presence of increased ictal amplitude, intcrhemispheric coherence, and postictal suppression in the 2.25-T group indicates greater generalization. Further work is needed to clarify this issue. The dependence of the relationship between midictai amplitude and seizure duration on dose and ELPL described above is compatible with the view that seizure duration increases with increasing seizure intensity for barely suprathreshold stimuli, whereas this relationship disap-

pears, and may even be reversed, with higher dosage treatments. Such findings are also consistent with the inverted "U" relationship postulated by Sackeim and colleagues (1991) to exist between stimulus intensity and seizure duration and may, again, be due to a more potent activation of endogenous inhibitory processes with higher-intensity stimuli.

Conclusion Ictal EEG measures differ as a function of both ELPL and dose. Postictai amplitude and right immediate poststimulus spectral amplitude best separated the 2.25-T UL from T UL treatments, and are therefore of potential utility as tools for assessing treatment adequacy in terms of efficacy. Longer seizure duration was not associated with more intense stimuli; in fact, the opposite appears to be true, further casting doubt on the use of duration measures as a means to characterize seizure adequacy. Overall, our findings lend support to the idea that factors other than seizure duration are important for seizure adequacy and suggest a need to further investigate ictal EEG variables as markers of treatment adequacy via studies directly correlating them with therapeutic outcome measures. The authors would like to acknowledge the support of NIMH Grants MH30723 and H41059. The data described herein were presented in part at the American

Psychiatric Association Meeting, May 1993, San Francisco.

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