Electroconvulsive therapy, or ECT for short, can be an effective treatment for severe depression. Many patients who do not respond to medication find that their symptoms improve after ECT. During an ECT session, the patient is placed under general anesthesia and two electrodes are attached to the scalp to produce an electric field that generates currents within the brain. These currents activate neurons and make them fire, causing a seizure, but it remains unclear how this reduces symptoms of depression.

For many years, researchers thought that the induced seizure must be key to the beneficial effects of ECT, but recent studies have cast doubt on this idea. They show that increasing the strength of the electric field alters the clinical effects of ECT, without affecting the seizure. This suggests that the benefits of ECT depend on the electric field itself.

Argyelan et al. now show that electric fields affect the brain by making a part of the brain known as the gray matter expand. In a large multinational study, 151 patients with severe depression underwent brain scans before and after a course of ECT. The scans revealed that the gray matter of the patients’ brains expanded during the treatment. The patients who experienced the strongest electric fields showed the largest increase in brain volume, and individual brain areas expanded if the electric field within them exceeded a certain threshold. This effect was particularly striking in two areas, the hippocampus and the amygdala. Both of these areas are critical for mood and memory.

Further studies are needed to determine why the brain expands after ECT, and how long the effect lasts. Another puzzle is why the improvements in depression that the patients reported after their treatment did not correlate with changes in brain volume. Disentangling the relationships between ECT, brain volume and depression will ultimately help develop more robust treatments for this disabling condition.

Electroconvulsive therapy (ECT) remains the most effective approach for treatment resistant depressive episodes, as well as the most established neuromodulation technique (UK ECT Review Group, 2003; Fink and Taylor, 2007). Despite intensive research, however, the mechanism of action for ECT remains unknown, but does involve at least two potentially therapeutic components: electric perturbation and/or seizure activity. One common element across various neuromodulation techniques is the application of different intensities of electric field (EF) on the human brain. Understanding how ECT-induced EF interacts with the cortex and subcortical structures can both advance our mechanistic understanding of ECT and enrich our understanding of other neuromodulation approaches such as magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).

A recent longitudinal ECT-imaging study from the Global ECT-MRI Collaboration (GEMRIC) (Oltedal et al., 2018) assessed hippocampal volume changes in a large cohort of subjects (N = 268) receiving right unilateral (RUL) or bilateral (BL) electrode placements. The results demonstrated that the volume of the hippocampus increased over the course of ECT treatment and correlated with the number of ECT sessions administered during the ECT series. In addition, the subjects receiving RUL electrode placement had a significantly larger volume change ipsilateral to the side of stimulation, consistent with previous ECT-neuroimaging observations (Abbott et al., 2014; Dukart et al., 2014; Pirnia et al., 2016; Bouckaert et al., 2016; Sartorius et al., 2016; Cano et al., 2018). Our most recent study of 331 subjects with longitudinal MRI scanning pre- and post-ECT showed brain volume increases across several subcortical and cortical regions with strong lateralization of the effects if the electrode placement was RUL (Ousdal et al., 2019). Contrary to a priori expectations (Joshi et al., 2016; Cano et al., 2017), increased volume in these key areas did not translate to better clinical outcome. While the association between the number of ECT sessions and volume change and the laterality of the volume changes all implied a dose–response causative relationship, the role of ECT-mediated neuroplasticity and the underlying mechanism for antidepressant response remains elusive. Furthermore, given the naturalistic design of the studies included for mega-analysis (e.g., non-responders had a longer ECT course and were frequently switched to bilateral treatment at varying intervals), both the number of ECT sessions and electrode placement varied depending on the clinical response, further confounding the dose-response association and its interpretation.

Recent research has challenged the notion that a primary purpose of electric stimulation in treating depression is to generate widespread seizure activity (Sackeim, 2015; Regenold et al., 2015). Alternatively, electric stimulation may be a therapeutic component of ECT and similar to other non-convulsive neuromodulation treatments. Finite-element simulation was developed to estimate the spatial distribution of the electric field on a voxel-wise basis (Lee et al., 2012; Bikson et al., 2012). The technique was recently validated in humans (Huang et al., 2017). Preliminary computational analyses based on three realistic head models suggested that the ECT electric field distribution had a direct association with clinical and cognitive outcomes, explaining the rationale behind different electrode placement strategies in ECT treatment (Bai et al., 2017). This finding is in agreement with our previous observation where RUL treatment induced higher volumetric changes in the right hippocampus compared to the left (Oltedal et al., 2018), implying that more lateralized electric stimulation rather than a global generalized seizure, may be responsible at least for part of the antidepressant effects of ECT. However, to date, no study has demonstrated the relationship between ECT electric field distribution and treatment response. In this study, we used the large Global ECT-MRI Research Collaboration (GEMRIC) ECT-imaging data set to explicitly determine the relationships between regional 1) electric field strength and volume changes, 2) volume changes and antidepressant response, and 3) electric field and antidepressant response. For the purpose of our primary research question and in contrast to previous GEMRIC investigations, we limited the analyses to subjects that only received right unilateral electrode placement.

This study investigated the relationship between electric field, volume change and clinical response to ECT. We used a large sample of subjects with depression receiving ECT with right unilateral electrode placement from the GEMRIC database. The key findings included a lateralization (right >left) of the electric field and changes in regional brain volume in association with ECT. The use of right unilateral electrode placement, which elicits greater right hemisphere electric fields, can thus be dissociated from generalized seizure activity such that their contributions to antidepressant mechanisms may be at least partially distinct. Further, regional volume increase and electric field distributions were strongly related, especially in the left hippocampus and left amygdala. Here, the observed relationships between electric field and volume change suggest that a minimum electric field of 30–40 V/m is necessary for subsequent changes in brain structure, and that EF may have a ‘ceiling effect’ above approximately 100 V/m as illustrated for right hippocampal volume (see Figure 3). However, volume change and electric field were not statistically related to clinical response after controlling for age, number of ECT sessions and site. Below, we discuss potential mechanisms for electric field and volume change that may be considered both independent and synergistic with seizure activity. We also discuss potential future directions to elucidate the role of electric field distributions with clinical response.

The biological underpinnings of ECT-mediated volume change (Oltedal et al., 2018; Ousdal et al., 2019) could be related to seizure activity, cerebral blood flow, electric field strength, or synergy between the generalized seizure and electric field (e.g. the electric field determines site and focality of seizure initiation, which can subsequently affect seizure propagation and termination). Several neuroplastic mechanisms including neurogenesis, angiogenesis, synaptogenesis, gliogenesis may be specific to the rapidly changing electric field (Bouckaert et al., 2014; Tang et al., 2017). Although heavily debated (Sorrells et al., 2018; Boldrini et al., 2018; Andreae, 2018), the support for adult neurogenesis is based on pre-clinical studies demonstrating neuronal division and differentiation related to suprathreshold electric stimulation (Scott et al., 2000; Madsen et al., 2000; Perera et al., 2007; Segi-Nishida, 2011). However, neurogenesis as the sole mechanism of neuroplasticity may be incompatible with the time frame and expansive volume change. Specifically, the ECT series is less than one month in duration, but pre-translational investigations have established that adult neurogenesis may take up to six months (Kohler et al., 2011). Furthermore, adult neurogenesis is limited to the hippocampus and olfactory bulb and does not support the volume change in 82 out of 85 regions demonstrated in our investigation (Kornack and Rakic, 1999). Alternatively, volume change may be related to fluid shifts due to vascularization (Hellsten et al., 2004), blood flow changes (Milo et al., 2001; Leaver et al., 2019) and inflammation (Wennström et al., 2004; Jansson et al., 2009; Fluitman et al., 2011; van Buel et al., 2015; Yrondi et al., 2018). Vasogenic edema secondary to the hypertensive surge commonly associated with electroconvulsive stimulation and possible breach of the blood brain barrier could be a potentially iatrogenic mechanism of volumetric increase, but the available pre-clinical and ECT-imaging studies (focused on T2 relaxtion time) so far have produced mixed results (Andrade and Bolwig, 2014; Kunigiri et al., 2007; Bolwig et al., 1977; Nordanskog et al., 2010; Takamiya et al., 2018). The generalized seizure and global changes in blood flow would not explain the laterality of volumetric changes (right >left) ipsilateral to the hemisphere of stimulation as seen in our current and previous investigations (Abbott et al., 2014; Dukart et al., 2014; Pirnia et al., 2016; Bouckaert et al., 2016; Sartorius et al., 2016; Cano et al., 2018). The laterality with electric field and volume change suggest a mechanistic role of the electric field that may be independent or synergistic with seizure generation. Pre-translational investigations have demonstrated that increased stimulus charge increased dendritic arborization in a dose-related fashion (Smitha et al., 2014). Furthermore, the behavioral improvement after electroconvulsive stimulation are related to increased dendritic complexity, synaptic remodeling, and neuronal survival (Jonckheere et al., 2018). However, additional pre-clinical studies are clearly needed to resolve the mechanistic link between electric field and neuroplasticity.

Our original hypothesis was that a) local electric field had a causal role in clinical outcome and that b) the corresponding volume change was mediating this relationship. In order to support this model, data analysis should have indicated 1) a significant correlation between volume change and electric field, 2) a significant correlation between clinical outcome and volume change, and 3) that only the effect of volume change is significant in a multilinear regression model when both electric field and volume change is added as covariates (outcome ~volume change + electric field). However, since volume change showed no correlation with clinical change, neither in this dataset, nor in the recently published broader dataset with more heterogeneous ECT electrode placement (Ousdal et al., 2019), only the first half of this model, namely that electric field strength was associated with volume change, was supported by our data.

The null relationship between electric field, volume change and clinical outcome may be attributed to demographic (age) and other treatment related factors (number of sessions, rate of response). For example, age-related structural brain changes may mediate these relationships and thus were an important consideration in our analysis. Our results are consistent with previous ECT investigations demonstrating that older patients often have higher response rates (O'Connor et al., 2001; Nordenskjöld et al., 2012; Brus et al., 2017). Previous electric field modeling investigations have demonstrated that age-related structural brain changes modulate the spatial distribution of the calculated electric field (Deng et al., 2009). However, when including age in the assessment with electric field, volume change and clinical outcome, our results suggest more complex or alternative mechanisms underlie differential age-related response to ECT.

Additionally, it was necessary to control in our regression models for the number of ECT treatments. In our earlier paper (Oltedal et al., 2018) we found a mild effect between hippocampus volume change and clinical response, but, counterintuitively, increased volume change was associated with worse outcomes. However, this relationship was completely absent when we controlled for the number of ECTs. We have previously demonstrated a dose-response relationship between hippocampal volume change and the number of ECT sessions (Oltedal et al., 2018). Also, due to the naturalistic design, clinical outcome correlated with the number of ECT sessions: patients with the worse or slower response received more ECT treatments. Mediation analysis supported a very similar situation in our sample with p=0.035 and p=0.034 in L and R Hippocampus reflectively (Sobel test).

It was, therefore, necessary to control for the number of ECT sessions to avoid detecting spurious correlations between clinical response and volume change. Without an earlier, fixed mid-point assessment, we are unable to assess differences in rate of change, which could be relevant to specific depression subtypes (Drysdale et al., 2017) and eventual clinical response. Notably, the overall volume changes measured in this study do not permit us to make conclusions about more structure-function relationships that might be better assessed with shape or hippocampal subfield analysis (Roddy et al., 2019; Takamiya et al., 2019).

Finally, the volume change required for response may be non-linear. A minimum electric field of 30–40 V/m may be necessary to induce neuroplasticity. Increasing the electric field between 30–40 V/m and 100 V/m is related to a monotonic increase in hippocampal volume. Electric field above 100 V/m is still associated with hippocampal neuroplasticity but the dose-response relationship may be less robust and represent a ceiling effect of electric-field induced neuroplasticity as illustrated in Figure 3. Surpassing the neurpolasticity threshold (100 V/m) appears to be unrelated to further volumetric increases and antidepressant response. Thus, the relationship between e-field and volumetric changes may be conceptualized as a ‘neuroplasticity threshold’ between 30–40 V/m and 100 V/m. This thresholding effect also preserves the laterality of electric field and neuroplasticity. Our sample was limited to right unilateral electrode placement. In the left hippocampus, the maximum electric field is ~80 V/m (Figure 3) and below the 100 V/m ‘ceiling effect’ noted in the right hemisphere. Consequently, in our right unilateral sample, hippocampal electric field and related changes in neuroplasticity will demonstrate laterality effects.

Our findings indicate widespread and robust volume changes in both cortical and subcortical regions. The GEMRIC group recently published a comprehensive paper on a larger dataset with similar volumetric findings. The processing pipeline that was used has been validated against many commonly used tools for estimating longitudinal volume change (Holland et al., 2012; Holland et al., 2011). Specifically, it was previously compared head-to-head with FreeSurfer 5.3, and we have already repeated this comparison for data from one of the GEMRIC sites (Oltedal et al., 2017). Our comparisons of power estimations based on results from the FreeSurfer longitudinal pipeline and Quarc (Table 3 in Oltedal et al., 2017) were in line with those of the earlier publications. In agreement with previous research, the effect sizes show regional differences indicating that previous studies with smaller sample sizes were underpowered to detect cortical changes, and that can explain why they only found subcortical volume increase. Furthermore, using the same methodology, we did not find any significant volume change in the 95 healthy controls (received no ECT) who were imaged at two time points (Ousdal et al., 2019).

We acknowledge several limitations that influence result interpretation. First, our approach was agnostic to seizure duration, which may contribute to the effects of EF on regional volumes and clinical response. This investigation also does not preclude the possible role of seizure in both volume changes and clinical outcomes. However, the selection of right unilateral electrode placement subjects does attempt to disentangle the impact of the generalized seizure from the lateralized electric field. Second, the electric field models a single current pulse and ignores the temporal dynamics of stimulus (pulse-width, and frequency and duration of the pulse train) (Swartz, 2006; Swartz et al., 2012). Differences in pulse width, for example, may affect volume change and clinical outcomes. Furthermore, differences in maximal charge, unrelated to current amplitude, are different between the US and Europe (Europe permits twice the US maximal charge). The analysis included patients treated with one of two different ECT devices. We controlled for the differences in current related to the two devices with the electric field modeling (800mA for the spECTrum, 900mA for the Thymatron), but we are unable to control for other differences in stimulus delivery related to the device. Third, the study sites in this mega-analysis likely include heterogeneity in patient selection and other treatment related factors that were not controlled. Despite these site differences, the large sample size and additional inclusion criteria permitted whole brain analyses with electric field, and within-subject volume change and clinical outcomes. Finally, we did not assess cognitive correlates with electric field or volume change. General clinical experience and previous results from studies investigating electrode placement strategies indicate that ECT-mediated neurocognitive side effects are influenced by electrode placement (d’Elia, 1970; Sackeim et al., 2000; Kolshus et al., 2017). Previous electric field studies on simulated head models have already shown that cognitive side effects might be attributed to the electric field spatial distributions associated with different electrode placements (Bai et al., 2017; Deng et al., 2011). These considerations would indicate that these volumetric changes might be associated with cognitive side-effects, but further studies are needed to confirm this relationship.

Source data files (.csv) including processed data have been provided for Figures 1–4, Figure 3—figure supplement 1 and Figure 4—figure supplement 1. Raw data cannot be made available publicly because we do not have consent or ethical approval for this and the data cannot be anonymised. The data are stored on a secure centralized server at the University of Bergen, Norway. Participating GEMRIC sites have access to the raw data according to specific data policy and safety rules of the consortium, and in accord with the approval from the ethical committee. The GEMRIC consortium welcomes new members who are interested in the neuroimaging research of ECT. We hold board meetings twice a year when new members can apply to join and gain access to the database available on the GEMRIC servers. For more about the application process please visit https://mmiv.no/how-to-join-gemric/ or write to Leif Oltedal (leif.oltedal@uib.no). General information about the consortium can be found on the following website: https://mmiv.no/gemric/. For transparency and reproducibility, the entire analytical approach is uploaded to the https://github.com/argyelan/Publications/tree/master/ECTEFvsVOLUME (R scripts in org mode), and also was uploaded to eLife.

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Acceptance summary:

This analysis of data from the GEMRICS consortium on electroconvulsive therapy (ECT) investigates the potential links between electric field, brain volume change, and antidepressant response. Using data from 151 patients, the study finds a significant volume increase in the large majority of brain regions examined and a significant relation between electric field and volume change, particularly in left hippocampus and left amygdala. By contrast, it fails to find a significant relation between either electric field or volume change and clinical response. Given the importance of ECT as a last resort for treating severe depression and the necessity of better understanding its mechanisms, this study contributes important biological findings that will guide future investigations on the mechanisms of ECT.

Decision letter after peer review:

Thank you for submitting your article "Electric field causes volumetric changes in the human brain" for consideration by eLife. Your article has been reviewed by two peer reviewers, including Klaas Enno Stephan as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by Christian Büchel as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Juergen Dukart (Reviewer #2).

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

Summary:

This paper reports an analysis of data from the GEMRICS consortium on electroconvulsive therapy (ECT), investigating the potential links between electric field, brain volume change, and antidepressant response. Using data from 151 patients, the study finds a significant volume increase in 82 of 85 brain regions examined and a significant relation between electric field and volume change in left hippocampus and left amygdala. By contrast, it fails to find a significant relation between either electric field or volume change and clinical response.

Given the importance of ECT as a last resort for treating severe depression and the necessity of better understanding its mechanisms, this study addresses a highly relevant and timely issue. Both reviewers were generally positive about this paper. However, they also identified several issues that would require revisions and additional analyses.

Essential revisions:

1) It did not get entirely clear to me whether overlapping questions (or perhaps even the same) have been asked in previous analyses using data from the GEMRICS consortium. I do not necessarily consider this a problem, as long as the data are different, but it should be transparent for the reader.

2) Results section: the descriptions of the findings in Figure 4 (i.e., the alleged ceiling effect in the right hemisphere) are rather cryptic in the main text and deserve more explanation. I also wondered whether the difference between volume changes in left and right hemisphere (the right panel of Figure 4) is actually significant? Also, it would be helpful if you could comment on how this putative ceiling effect is compatible with the findings presented in Figure 3.

3) The central findings reported in the subsection "Electric field, volume change, and clinical response" would deserve a considerably more detailed description. There are no space constraints in eLife, and it would be helpful to see a detailed breakdown of the statistical analyses in the main text (not just in the supplementary material). In particular, it would be nice to see the relative influence of each component of the regression model. For example, one would like to see in the main text how strong the effect of age was on clinical response to ECT.

4) The authors used% changes in MADRS as the outcome. This choice is problematic as a reduction from 2 to 1 point is a 50% reduction whilst a reduction from 40 to 30 is only 25%. This choice may therefore create quite a biased evaluation of clinical improvement. The authors are therefore advised to repeat the analyses using the absolute scores as more unbiased measurement of clinical response.

5) In the model evaluating the effects of volume change on MADRS the authors also include number of ECT sessions as a covariate. This is problematic from a conceptual point of view. The authors aim to study the mediating effect of volume changes induced by ECT on clinical symptoms. Controlling for the number of ECT sessions removes exactly this variance of interest from volume changes. The authors should therefore repeat the analyses without adjusting for this covariate, or perhaps even more convincingly, perform a mediation analysis that disentangles the direct and indirect (via volume changes) effects of number of ECT sessions on MADRS scores. Similar concern applies to age as a mediator of the effect of ECT.

6) Please add a more detailed description of the overall cohort (i.e. sex, medication status.…) to Table 1A, also not only per site but for the whole cohort and move it to the main body as it is important for a clinical study to have this information in the main body.

7) At least some studies suggest potentially differential relationship between volume changes upon ECT and clinical response in bipolar and unipolar depression. Whilst the bipolar group may be not large enough it makes sense to test for this relationship separately for both diagnostic groups, or at least for major depression.

8) Lastly, I am concerned by the highly significant volume increases in basically all brain regions in both hemispheres reported in Supplementary file 2 (excluding only the cerebellum). These effects go basically against all previous studies reporting rather quite specific structural changes upon ECT. The authors seem to use some very specific and a rather uncommon software package to compute these changes which raises the question of a methodological issue with the respective software. As the authors already have the free surfer estimates, I would ask them to compute directly the volume changes from those just to confirm that the effects are not dependent on the respective software choice.

[Editors' note: further revisions were requested prior to acceptance, as described below.]

Thank you for resubmitting your work entitled "Electric field causes volumetric changes in the human brain" for further consideration at eLife. Your revised article has been favorably evaluated by Christian Büchel (Senior Editor) and Klaas Enno Stephan (Reviewing Editor).

The manuscript has been improved but there are some remaining issues that need to be addressed before acceptance, as outlined below:

Point 4: In your response, you referred to a "complementary analysis with baseline MADRS score as a covariate" which "resulted in similar findings to our% MADRS." We may have overlooked this but failed to find this analysis. We would like to ask that this complimentary analysis is included in the main text (or in the supplementary material, with a direct reference in the main text) so that reviewers and readers can see the similarities directly.

Point 5: Given that this is a question many readers may wonder about, it would be worth to include your detailed explanations (why no mediation analysis was performed and why "number of ECT sessions" was included as a covariate in the statistical model) in the Discussion section of the paper.

Point 8: We would suggest that the previous validation of the analysis pipeline against other software packages is described in the Discussion section of the paper, together with your interpretation why previous studies failed to find widespread volume changes, in order to make this issue transparent.

Essential revisions:

1) It did not get entirely clear to me whether overlapping questions (or perhaps even the same) have been asked in previous analyses using data from the GEMRICS consortium. I do not necessarily consider this a problem, as long as the data are different, but it should be transparent for the reader.

The EF modeling data has not been included in previous GEMRIC analyses; the analysis of EF modeling with volume change (the main finding) and clinical response is completely new. It is correct that the broad distribution of volume change and relation to clinical response was described in more detail in a separate recent GEMRIC paper (Ousdal et al., 2019). However, that analysis also included patients stimulated with bilateral electrode placements. The present investigation includes only subjects treated with right unilateral electrode placement and e-field analysis. We have clarified the differences with the current work from previous work as follows in the concluding sentence of our Introduction: “For the purpose of our primary research question and in contrast to previous GEMRIC investigations, we limited the analyses to subjects that only received right unilateral electrode placement.”

2) Results section: the descriptions of the findings in Figure 4 (i.e., the alleged ceiling effect in the right hemisphere) are rather cryptic in the main text and deserve more explanation. I also wondered whether the difference between volume changes in left and right hemisphere (the right panel of Figure 4) is actually significant? Also, it would be helpful if you could comment on how this putative ceiling effect is compatible with the findings presented in Figure 3.

We have added to our Discussion section to further explain the non-linear relationship between EF and ∆Vol as follows: “Finally, the volume change required for response may be non-linear. A minimum electric field of 30-40 V/m may be necessary to induce neuroplasticity. Increasing the electric field between 30-40 V/m and 100 V/m is related to a monotonic increase in hippocampal volume. Electric field above 100 V/m is still associated with hippocampal neuroplasticity but the dose-response relationship may be less robust and represent a ceiling effect of electric-field induced neuroplasticity as illustrated in Figure 4. Surpassing the neurpolasticity threshold (100 V/m) appears to be unrelated to further volumetric increases and antidepressant response. Thus, the relationship between e-field and volumetric changes may be conceptualized as a “neuroplasticity threshold” between 30-40 V/m and 100 V/m. This thresholding effect also preserves the laterality of electric field and neuroplasticity. Our sample was limited to right unilatleral electrode placement. In the left hippocampus, the maximum electric field is ~ 80 V/m (Figure 3) and below the 100 V/m “ceiling effect” noted in the right hemisphere. Consequently, in our right unilateral sample, hippocampal electric field and related changes in neuroplasticity will demonstrated laterality effects.”

The difference in right and left hippocampal volume changes (right panel of Figure 4) is signficant (t = 7.76, df = 150, mean difference = 0.011, p < 0.0001). We have changed the Figure text for more clarity.

Figure 3 demonstrates laterality differences in EF and ∆Vol (upper panel) as well as the relationship between laterality between EF/∆Vol (lower panel). We have added to our Discussion section to furhter describe this relationship as noted above.

3) The central findings reported in the subsection "Electric field, volume change, and clinical response" would deserve a considerably more detailed description. There are no space constraints in eLife, and it would be helpful to see a detailed breakdown of the statistical analyses in the main text (not just in the supplementary material). In particular, it would be nice to see the relative influence of each component of the regression model. For example, one would like to see in the main text how strong the effect of age was on clinical response to ECT.

We agree with this suggestion, so we made the following changes:

a) We moved Supplementary file 4, which is our main finding, to Table 1, making the relative influence of the covariates more transparent. Also we extended the previous paragraph as follows: “Age was a necessary covariate since it was a confound in our model: both the spatial distribution of EF and volume changes correlate with age (30). We add number of ECT as a covariate to the model to be able to compare the relative influence of EF and number of ECT on volume change. In both left hippocampus and amygdala the effect size of EF was the largest (hippocampus: t_EF = 4.5, t_Age = -2.7, t_ECTnum = 3.3, amygdala: t_EF = 3.9, t_Age = -1.1, t_ECTnum = 2.1; Table 1).”

b) We also extended subsection “Electric field, volume change, and clinical response” with more details: “Results indicated that none of the volume changes across the 85 ROIs had a significant relationship with clinical response (Supplementary file 4, hippocampus: t_ΔVOL = 0.2, t_Age = 5.4, t_ECTnum = -2.7, amygdala: t_ΔVOL = 0.1, t_Age = 5.6, t_ECTnum = -3.0). These results therefore contradicted the hypothesis that EF by increasing brain volume indirectly exerts its effect on clinical response, given the negative results between the volume change (mediator) and MADRS change (outcome). Testing the direct effect of the EF, we failed to find significant correlations between EF and clinical response (Supplementary Table 5, hippocampus: t_EF = 1.2, t_Age = 5.7, t_ECTnum = -3.0, amygdala: t_EF = 1.1, t_Age = 5.7, t_ECTnum = -3.0). Similar to earlier studies, age strongly correlated with both clinical response (32, 33, also see Clinical Results) and EF distribution (30), therefore we controlled for age in our model. The rationale for including the number of ECT treatments as covariate needs more explanation. Due to the naturalistic nature of the design, where most sites followed the patient until response or site-determined criteria for ECT discontinuation, we observed a negative relationship between clinical response and the number of ECT treatments. Not controlling for this variable could lead to spurious correlation between volume change and clinical response (for more on this see Oltedal et al., 2018 (3)).”

c) For more detailed rationale for controlling these covariates please see our discussion under point 5.

d) We would like to also note that in the beginning of the Results section we have already explicitly stated the relationship between age and clinical response: “Highly significant correlations between age and clinical response (t = 5.75, df = 149, r = 0.43, p < 10^-7, older patients responded better).”

4) The authors used% changes in MADRS as the outcome. This choice is problematic as a reduction from 2 to 1 point is a 50% reduction whilst a reduction from 40 to 30 is only 25%. This choice may therefore create quite a biased evaluation of clinical improvement. The authors are therefore advised to repeat the analyses using the absolute scores as more unbiased measurement of clinical response.

Based on these suggestions we used absolute scores in a complementary analsyis with baseline MADRS score as a covariate to control for baseline severity, and it resulted in similar findings to our% MADRS.

All subjects had a severe depressive episode (mean pre-ECT MADRS ~ 33.9). The rationale for modeling proportional change instead of absolute change score or outcome severity directly was to control for the pre-ECT MADRS variability. We added the following test (and reference) to our methods section: “Although more conservative than absolute change or post-ECT depression outcomes (Vickers, 2001), the rationale for the use of the proportional change score was to control for the variability of the pre-ECT MADRS.”

5) In the model evaluating the effects of volume change on MADRS the authors also include number of ECT sessions as a covariate. This is problematic from a conceptual point of view. The authors aim to study the mediating effect of volume changes induced by ECT on clinical symptoms. Controlling for the number of ECT sessions removes exactly this variance of interest from volume changes. The authors should therefore repeat the analyses without adjusting for this covariate, or perhaps even more convincingly, perform a mediation analysis that disentangles the direct and indirect (via volume changes) effects of number of ECT sessions on MADRS scores. Similar concern applies to age as a mediator of the effect of ECT.

We agree that mediation analysis would be the most interesting part of this dataset as it could support mechanistic understanding. Mediation analysis in general means that the following three conditions are met: (1) there is a significant correlation between outcome and mediator, (2) there is a significant correlation between predictor and outcome, and (3) in a multiple regression model where we model outcome~mediator + predictor the mediator’s coefficient remain significant, and at the same time the predictor’s coefficient is not significant anymore. The reviewer is correct that our original goal was to show that volume change is the mediator of the clinical effect. Our original hypothesis was that EF -> volume change -> clinical response. (-> means: cause) However, since volume change has no correlation with clinical change, neither in this dataset, nor in the recently published larger set of data with more heterogeneous ECT electrode placement (1), the first condition of mediation analysis is already invalid. Therefore, formal mediation analysis (i.e. Sobel test) is not appropriate for this dataset. In regard of the number of treatments we agree with the reviewer that careful consideration is required in adding the number of ECT treatment variable (see rationale under point 3). Here we provide extra details. Due to the naturalistic design, where most sites followed the patient until response or site-determined criteria for ECT discontinuation, “Number of ECT” could either be a mediator (Author response image 1, Model 1) or a confound (Author response image 1, Model 2). Regardless of the role of “Number of ECT” as mediator or confound, we believe that inclusion in our model is necessary because of the naturalistic, multi-site design of our dataset. The remaining correlation can reflect the direct relationship between volume change and MADRS change.

Author response image 1

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In our earlier paper (Oltedal et al., 2018) we already encountered this problem because of this relationship between number of ECT and clinical response. Originally, we found a mild effect between hippocampus change and clinical response, but, contra-intuitively, number of ECT treatments reflected increased volume change that was associated with worse outcome (Oltedal et al., 2018). However, this relationship was completely absent when we controlled for the number of ECTs. This can be demonstrated via mediation analysis similar to which the reviewer proposed. Mediation analysis in our sample resulted in p = 0.035 and p = 0.034 in L and R Hippocampus reflectively (Sobel test). These results indicate that the relationship between clinical response and volume change in these areas are fully mediated via number of ECT sessions, therefore we should control for it in subsequent analyses.

6) Please add a more detailed description of the overall cohort (i.e. sex, medication status.…) to Table 1A, also not only per site but for the whole cohort and move it to the main body as it is important for a clinical study to have this information in the main body.

We added a new Table to the main text that contains the required clinical and demographic information.

7) At least some studies suggest potentially differential relationship between volume changes upon ECT and clinical response in bipolar and unipolar depression. Whilst the bipolar group may be not large enough it makes sense to test for this relationship separately for both diagnostic groups or at least for major depression.

We have tested this hypothesis, however it did not change the results if we excluded the 12 bipolar patients from our sample. We inserted the following test in the manuscript: “The results did not change if we used medication status or diagnosis (bipolar or unipolar depression) as nuisance variables in the linear models of this study.”

8) Lastly, I am concerned by the highly significant volume increases in basically all brain regions in both hemispheres reported in Supplementary file 2 (excluding only the cerebellum). These effects go basically against all previous studies reporting rather quite specific structural changes upon ECT. The authors seem to use some very specific and a rather uncommon software package to compute these changes which raises the question of a methodological issue with the respective software. As the authors already have the free surfer estimates, I would ask them to compute directly the volume changes from those just to confirm that the effects are not dependent on the respective software choice.

The processing pipeline that was used has been validated against many commonly used tools for estimating longitudinal volume change (Holland and Dale, 2011; Holland, McEvoy and Dale, 2012. Specifically, it was previously compared head-to-head with FreeSurfer 5.3, and we have already repeated this comparison for data from one of the GEMRIC sites (Oltedal et al., 2017). Our comparisons of power estimations based on results from the FreeSurfer longitudinal pipeline and Quarc (Table 3 in Oltedal et al. 2017) were in line with those of the earlier publications. The broad distribution of volume change is described in more detail in a separate recent GEMRIC paper (Ousdal et al., 2001) and was already noted in terms of effect sizes in Figure 3 in Oltedal et al., 2017, see response to question 1. In agreement with previous research, the effect sizes show regional differences indicating that earlier studies with lower sample sizes were underpowered to detect cortical changes, and that can explain why they only found subcortical volume increase.

Furthermore, using the same methodology, we did not find any significant volume change in the 95 healthy controls (received no ECT) who were imaged at two time points (Osudal et al., Supplementary Table 4).

[Editors' note: further revisions were requested prior to acceptance, as described below.]

The manuscript has been improved but there are some remaining issues that need to be addressed before acceptance, as outlined below:

Point 4: In your response, you referred to a "complementary analysis with baseline MADRS score as a covariate" which "resulted in similar findings to our% MADRS.” We may have overlooked this but failed to find this analysis. We would like to ask that this complimentary analysis is included in the main text (or in the supplementary material, with a direct reference in the main text) so that reviewers and readers can see the similarities directly.

We have included these results in the second half of the Supplementary file 3 and Supplementary file 4. It is now indicated in the Materials and methods section: “In addition to analyzing the percentage change of the clinical response, we also evaluated the same models with absolute changes, using baseline MADRS as a covariate. We provided the results of these analyses in the second half of the corresponding Supplementary files.”

Point 5: Given that this is a question many readers may wonder about, it would be worth to include your detailed explanations (why no mediation analysis was performed and why "number of ECT sessions" was included as a covariate in the statistical model) in the Discussion section of the paper.

We have included two paragraphs in the Discussion section:

“Our original hypothesis was that a) local electric field had a causal role in clinical outcome and that b) the corresponding volume change was mediating this relationship […] However, since volume change showed no correlation with clinical change, neither in this dataset, nor in the recently published broader dataset with more heterogeneous ECT electrode placement (10), only the first half of this model, namely that electric field strength was associated with volume change, was supported by our data.”

“Additionally, it was necessary to control in our regression models for the number of ECT treatments. […] Mediation analysis supported a very similar situation in our sample with p = 0.035 and p = 0.034 in L and R Hippocampus reflectively (Sobel test).

It was, therefore, necessary to control for the number of ECT sessions to avoid detecting spurious correlations between clinical response and volume change.”

Point 8: We would suggest that the previous validation of the analysis pipeline against other software packages is described in the Discussion section of the paper, together with your interpretation why previous studies failed to find widespread volume changes, in order to make this issue transparent.

We have included the following paragraph:

“Our findings indicate widespread and robust volume changes in both cortical and subcortical regions. […] Furthermore, using the same methodology, we did not find any significant volume change in the 95 healthy controls (received no ECT) who were imaged at two time points (10)”.

Author details

1. Miklos Argyelan

   1. Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, United States
   2. Center for Neuroscience, Feinstein Institute for Medical Research, Manhasset, United States
   3. Department of Psychiatry, Zucker School of Medicine, Hempstead, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   argyelan@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7254-1776

2. Leif Oltedal

   1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
   2. Department of Radiology, Haukeland University Hospital, Mohn Medical Imaging and Visualization Centre, Bergen, Norway

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

3. Zhi-De Deng

   Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, United States

   Contribution

   Supervision, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

4. Benjamin Wade

   Department of Neurology, Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization, Software, Formal analysis, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

5. Marom Bikson

   Department of Biomedical Engineering, The City College of the City University of New York, New York, United States

   Contribution

   Conceptualization, Software, Methodology, Writing—review and editing

   Competing interests

   reports that The City University of New York (CUNY) has intellectual property (IP) on neuro-stimulation system and methods with MB as inventor; serves on the scientific advisory boards of Boston Scientific and GSK; has equity in Soterix Medical

6. Andrea Joanlanne

   Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, United States

   Contribution

   Data curation, Writing—review and editing

   Competing interests

   No competing interests declared

7. Sohag Sanghani

   Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, United States

   Contribution

   Conceptualization, Writing—review and editing

   Competing interests

   No competing interests declared

8. Hauke Bartsch

   1. Department of Radiology, Haukeland University Hospital, Mohn Medical Imaging and Visualization Centre, Bergen, Norway
   2. Center for Multimodal Imaging and Genetics, University of California, San Diego, San Diego, United States

   Contribution

   Resources, Software, Formal analysis, Methodology, Project administration

   Competing interests

   No competing interests declared

9. Marta Cano

   1. Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Barcelona, Spain
   2. CIBERSAM, Carlos III Health Institute, Barcelona, Spain

   Contribution

   Conceptualization, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0675-9483

10. Anders M Dale

    1. Center for Multimodal Imaging and Genetics, University of California, San Diego, San Diego, United States
    2. Department of Radiology, University of California, San Diego, San Diego, United States
    3. Department of Neurosciences, University of California, San Diego, San Diego, United States

    Contribution

    Conceptualization, Resources, Data curation, Software, Methodology

    Competing interests

    reports that he is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc

11. Udo Dannlowski

    Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

    Contribution

    Conceptualization, Data curation, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

12. Annemiek Dols

    Department of Psychiatry, Amsterdam UMC, location VUmc, GGZinGeest, Old Age Psychiatry, Amsterdam Neuroscience, Amsterdam, Netherlands

    Contribution

    Conceptualization, Data curation, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

13. Verena Enneking

    Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

14. Randall Espinoza

    1. Department of Neurology, University of California, Los Angeles, Los Angeles, United States
    2. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

15. Ute Kessler

    1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Division of Psychiatry, Haukeland University Hospital, University of Bergen, Bergen, Norway

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

16. Katherine L Narr

    1. Department of Neurology, University of California, Los Angeles, Los Angeles, United States
    2. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, United States

    Contribution

    Conceptualization, Data curation, Supervision, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

17. Ketil J Oedegaard

    1. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    2. Division of Psychiatry, Haukeland University Hospital, University of Bergen, Bergen, Norway

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

18. Mardien L Oudega

    Department of Psychiatry, Amsterdam UMC, location VUmc, GGZinGeest, Old Age Psychiatry, Amsterdam Neuroscience, Amsterdam, Netherlands

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

19. Ronny Redlich

    Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

20. Max L Stek

    Department of Psychiatry, Amsterdam UMC, location VUmc, GGZinGeest, Old Age Psychiatry, Amsterdam Neuroscience, Amsterdam, Netherlands

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

21. Akihiro Takamiya

    1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
    2. Center for Psychiatry and Behavioral Science, Komagino Hospital, Tokyo, Japan

    Contribution

    Conceptualization, Writing—review and editing

    Competing interests

    No competing interests declared

22. Louise Emsell

    Department of Geriatric Psychiatry, University Psychiatric Center, KU Leuven, Leuven, Belgium

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

23. Filip Bouckaert

    1. Department of Geriatric Psychiatry, University Psychiatric Center, KU Leuven, Leuven, Belgium
    2. Academic center for ECT and Neurostimulation (AcCENT), University Psychiatric Center, KU Leuven, Kortenberg, Belgium

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

24. Pascal Sienaert

    Academic center for ECT and Neurostimulation (AcCENT), University Psychiatric Center, KU Leuven, Kortenberg, Belgium

    Contribution

    Conceptualization, Data curation, Writing—review and editing

    Competing interests

    No competing interests declared

25. Jesus Pujol

    1. CIBERSAM, Carlos III Health Institute, Barcelona, Spain
    2. MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain

    Contribution

    Conceptualization, Writing—review and editing

    Competing interests

    No competing interests declared

26. Indira Tendolkar

    1. Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands
    2. Donders Institute for Brain Cognition and Behavior, Centre for Cognitive Neuroimaging, Nijmegen, Netherlands
    3. Faculty of Medicine and LVR Clinic for Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany

    Contribution

    Conceptualization, Supervision, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

27. Philip van Eijndhoven

    1. Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands
    2. Donders Institute for Brain Cognition and Behavior, Centre for Cognitive Neuroimaging, Nijmegen, Netherlands

    Contribution

    Conceptualization, Data curation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

28. Georgios Petrides

    1. Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, United States
    2. Center for Neuroscience, Feinstein Institute for Medical Research, Manhasset, United States
    3. Department of Psychiatry, Zucker School of Medicine, Hempstead, United States

    Contribution

    Conceptualization, Resources, Data curation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

29. Anil K Malhotra

    1. Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, United States
    2. Center for Neuroscience, Feinstein Institute for Medical Research, Manhasset, United States
    3. Department of Psychiatry, Zucker School of Medicine, Hempstead, United States

    Contribution

    Conceptualization, Resources, Data curation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

30. Christopher Abbott

    Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, United States

    Contribution

    Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

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