Cortical excitation/inhibition ratios in patients with major depression treated with electroconvulsive therapy: an EEG analysis

Patients with major depression. This is a post hoc analysis of data from depressed patients treated with ECT in Rijnstate Hospital (Arnhem, The Netherlands) and who participated in the StudY of effect of Nimodipine and Acetaminophen on Postictal Symptoms after ECT (SYNAPSE; NCT04028596). SYNAPSE is a randomized controlled trial with a three-condition cross-over design. Patients received nimodipine, acetaminophen, or a placebo (water) in random and counterbalanced order at a maximum of 2 h before each ECT session. The order of the treatment conditions was randomized and differed across patients [16]. Repeated EEG measures before, during, and until one hour after the ECT sessions were collected. Inclusion criteria for patients were age ≥ 18 years and having a current clinical diagnosis of major depression (i.e., classified as unipolar, bipolar, schizoaffective disorder in DSM-5). The local medical ethical committee approved the study protocol (NCT04028596) and all included patients provided oral and written informed consent.

Healthy controls. To correct for test–retest variability of fE/I ratios, we included a public EEG dataset of healthy controls (HC) with repeated EEG recordings at two different time points [17]. None of these participants reported psychiatric or neurological symptoms. HC were aged ≥ 18 years and provided oral and written informed consent [18].

ECT was administered according to the standard treatment guidelines in The Netherlands [19], mostly twice weekly. The Thymatron System IV device (Somatics Incorporation Lake Bluff, Illinois, USA) was used to administer ECT stimuli with a constant-current (0.9 Ampère), bidirectional, square wave and brief pulse (1 ms). Electrodes were placed either unilateral (right [RUL]) or bi(fronto)temporal (BL). Dose titration or age-based dosage were used to choose the stimulus charge, which was adjusted during the course according to the psychiatrist’s discretion. In case patients did not improve after six sessions, unilateral placement was switched to BL during the ECT course. Anesthesia was mostly provided with etomidate (0.2–0.3 mg/kg body weight) for sedation and succinylcholine (0.5–1 mg/kg body weight) for muscle relaxation. Cessation of the ECT course was decided based on the treatment response, estimated by clinical judgement of the treating psychiatrist and clinically rated by using the Hamilton Depression Rating Scale (HDRS) [20].

Healthy controls. Four-minute EEG recordings with eyes closed were used. EEG data were recorded using a 64-channel (silver/silver chloride) BioSemi ActiveTwo system (BioSemi B.V., Amsterdam) and were sampled at 1024 Hz [18], at two time points (i.e., T₁ and T₂). The available channels were reduced to the similar EEG electrodes of the patients. Here, EEG electrode T4 corresponded to T8, T3 to T7, T6 to P8, and T5 to P7.

Both EEG datasets were band-pass filtered (0.5–30 Hz; first-order Butterworth filter) and visually inspected for artifacts. Cz was used as reference electrode. EEG data of HC were resampled to 256 Hz. EEG electrodes containing (excessive) noise were rejected for analysis and segments containing artifacts were removed. This was considered justified, as removing segments from a signal and constructing the remaining together does not affect the scaling behavior of positively correlated signals [21]. All pre-processing steps and analyses were conducted with MATLAB R2022b (MathWorks, Natick, MA, USA).

The power spectral density (PSD) of each EEG electrode pair was estimated using Welch’s method in five second artifact-free segments with an overlap of 50%. To compare PSD values, these were averaged in frequency bins of 1 Hz in the frequency range 0.5–30 Hz.

A requirement for estimating fE/I ratios was the existence of a co-variation between the amplitude of the spectral power and the fluctuation function. To ensure this, only data consisting of LRTC were used to estimate fE/I values. Detrended fluctuation analysis (DFA) was done to check for the existence of LRTC with DFA exponent > 0.60 as threshold [22]. When performing DFA, the fluctuation function is computed, which is plotted on logarithmic axes. The fluctuation function is expressed aswith \(F(t)\) the fluctuation function and \(\sigma\) the standard deviation of the detrended signal of a set windows (\(W\)) of separate time series of length \(t\), with an overlap of 50%. The DFA exponent is the slope of the fluctuation function calculated using linear regression. After removing segments containing artifacts, the DFA exponent was fit between 2 and 25 s. DFA analysis was performed for each individual frequency band (i.e., bins of 1 Hz in the frequency range 0.5–30 Hz).

If the DFA exponent exceeded the threshold, a normalized fluctuation function nF(t) was computed by dividing each windowed signal profile by the mean amplitude of that window. Here, windows with a length of five seconds and an overlap of 80% were used. The fE/I ratio was defined as [15]with \({r}_{W\mathrm{amp},W\mathrm{nF}(t)}\) being the Pearson correlation between the set of windowed amplitude values (\({W}_{\mathrm{amp}}\)) and the set of detrended amplitude-normalized signal profiles (\({W}_{\mathrm{nF}(t)}\)). Hence, fE/I ratios below 1 indicated inhibition dominated networks, above 1 indicated excitation dominated networks, while balanced, critical networks would have a value of 1. fE/I ratios were estimated in frequency bins of 1 Hz in the frequency range 0.5–30 Hz.

Comparisons at baseline. To test whether differences existed at baseline between fE/I ratios of patients (pre-ECT) and HC (T₁), Wilcoxon rank-sum tests were performed.

Changes over time. Paired t-tests or Wilcoxon signed-rank tests were performed to test whether changes in spectral power and fE/I ratios occurred over the ECT course in patients (post-ECT–pre-ECT), as well as between the two time-point measurements in HC (T₂–T₁).

For all analyses, p-values < 0.05 were considered statistically significant. In case of multiple testing, also the false discovery rates (FDRs) were computed whereby p_FDR < 0.05 values were considered statistically significant.

We included a total of 28 patients with major depression (23 unipolar depressive disorder and five bipolar depressive disorder) and 31 HC. The SYNAPSE study consisted of 33 patients. Two patients were excluded from our current analysis, because they received maintenance ECT and therefore the HDRS scores were not suitable to study effectiveness of an index ECT course. Two patients were excluded, since they already received > 2 ECT sessions upon inclusion in SYNAPSE; therefore, their baseline EEGs were missing. One patient dropped out before the ‘end-measurement,’ two weeks after the ECT course, and therefore, the HDRS score was missing. In total, data from 28 ECT patients from the SYNAPSE trial were included in the current analyses. The original dataset of HC consisted of 41 participants with two measurements (mean 301 days ± 125 days SD in between), but 10 subjects had to be excluded because of poor data quality.

Comparisons between patients and healthy controls. Sex frequencies were equal in the patient group (n = 16 females; 57%) and the HC group (n = 18 females; 58%; χ² = 0.0051; df = 1; p = 0.94). The patient group appeared significantly older (median = 54 years; IQR = 23) compared to HC (median = 39 years; IQR = 15.8; p < 0.001). Patients received a median of 12 ECT sessions (IQR = 6) during the ECT course and 20 (71%) were treated with BL stimulation. HDRS scores decreased significantly after the ECT course (median HDRS score pre-ECT = 25; IQR = 10; median HDRS score post-ECT = 12; IQR = 11; p < 0.001). Half of the patients reached the criterion of responder after the ECT course (n = 14; 50%) and seven (25%) reached complete remission (i.e., HDRS score post-ECT ≤ 7). An overview of the characteristics and comparisons is shown in Table 1.

Comparisons between responders and non-responders. No differences in age were found between responders (median = 61 years; IQR = 20) and non-responders (median = 46 years; IQR = 21; p = 0.08). Sex frequencies were equal in both groups (χ² = 0; df = 1; p = 1). The total number of ECT sessions did not differ between responders (median = 12; IQR = 6) and non-responders (median = 12; IQR = 5; p = 0.69). No differences in concomitant medication use (i.e., antidepressants [χ² = 0.16; df = 1; p = 0.69], benzodiazepines [χ² = 0.58; df = 1; p = 0.45], and antipsychotics [χ² = 0.16; df = 1; p = 0.69]), and electrode placement ([χ² = 2.80; df = 1; p = 0.09) between responders and non-responders were found. An overview of the characteristics and comparisons is shown in Table 2.

In patients, after the ECT course (Fig. 1a, red line), PSD values between 0.5 and 6 Hz were increased (p_FDR < 0.05) compared to baseline (black line). No changes were observed for other frequencies. In the HC group, there were differences (p_FDR < 0.05) in PSD values in frequencies 7–10 Hz and 13–17 Hz between time points T₁ (Fig. 1b, black line) and T₂ (red line).

At baseline, no differences were found between whole brain fE/I ratios of patients (pre-ECT) and HC (T₁). In Fig. 2a, the averaged fE/I ratios are shown before (solid black line) and two weeks after (solid red line) the ECT course. Whole brain analysis showed fE/I ratios close to value 1, estimated in the frequencies 0.5–30 Hz. No changes occurred in fE/I ratios over the ECT course in patients at group level. In HC, there were no differences between whole brain fE/I ratios estimated at the two different time points (i.e., T₁ and T₂), as is shown in Fig. 2b.

At baseline, no differences were found between patients and HC regarding the averaged fE/I ratios in the frontal, centrotemporal, and parieto-occipital regions. In the total patient group after the ECT course, no changes in the three regional fE/I ratios occurred. Also, no differences in fE/I ratios in these three regions were found in HC between measurement T₁ and T₂.

At baseline (pre-ECT), no differences in whole brain and spatial averaged fE/I ratios were found between the groups of responders and non-responders (p_FDR > 0.05). In responders, frontal fE/I ratios increased over the ECT course in the frequencies 12–28 Hz (p_FDR < 0.05), as is shown in Fig. 3a. In non-responders, an increasing trend in fE/I ratios in the frequencies 5–20 Hz was observed, but no significant changes were found (Fig. 3b). Also, no changes occurred in HC between measurements T₁ and T₂ (Fig. 3c).

Strengths of this study include the use of paired EEG data from depressed patients before and after the ECT course and the use of a HC group to account for test–retest variability. The strength of the fE/I measure is that it enables real-time tracking of E/I ratios and it provides an absolute value indicating a balanced or unbalanced state [15]. However, some limitations are also present. First, patients were not restricted from taking medication (apart from acetaminophen, nimodipine, and non-steroidal anti-inflammatory drugs) during the ECT course, including antidepressants and benzodiazepines. Especially benzodiazepines are known to affect EEG activity, which may have influenced our results. During their ECT course, however, most patients did not switch in type nor dosage of the concomitant medications, which may have limited its effect on their evolution of fE/I ratios. Second, the effects of the used reference electrode (i.e., Cz) compared to reference schemes such as bipolar or common average on estimation of fE/I ratios is unknown. In other methods to estimate the E/I ratio, this has been shown to have profound effects, as it affects PSD values [43]. Our used method calculates a normalized fluctuation function, nF(t), that was computed by dividing each windowed signal profile by the mean amplitude of that window. Therefore, the effects of reference schemes on the fE/I ratios may be limited. Also, the E/I ratios are based on cortical activity, measured using EEG. Therefore, no (direct) information about E/I ratios of deeper structures is provided, which may also be affected in major depression or by ECT. The HC group was significantly younger compared to the ECT patients. This may have affected our results, as it is known that PSD values may decrease with age [44, 45]. Although the fE/I calculation method is based on a normalized fluctuation function, which may correct for age-related PSD changes, future studies should investigate the effect of age on fE/I ratios. Finally, the sample size of 28 depressed patients was rather small, which hampered proper analysis of confounders like age, sex, stimulation type and number of administered ECT sessions. Taking into account our less conservative control of the alpha error (i.e., FDR instead of Bonferroni correction), the other methodological limitations of this post hoc analyses, and our consideration of confounding variables (i.e., age, sex, total ECT sessions, electrode placement, and concomitant medications), we conclude with caution that the increase in frontal fE/I ratios in the frequency range 12–28 Hz may be a biomarker of positive ECT outcome. This finding needs replication in other samples and prospective studies.