Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections.

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Objective Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6) predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment resistant depression, and to what extent this association differed between men and women. Methods In patients (n=29) with a current major depressive episode diagnosed using DSM-IV-TR criteria, undergoing ECT at an academic referral center, levels of CRP, IL-6, IL-8, tumor necrosis factor (TNF)-α, and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale, MADRS) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between 12/2011 and 12/2014. The primary outcome was end-of-treatment MADRS score. Results In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (p=0.01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (p=0.02) but not men (p=0.1), and CRP emerged as a significant predictor for women (p=0.04) but not men (p=0.66). CRP and IL-6 increased from baseline to the second ECT session (p’s<0.01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. Conclusions Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pre-treatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment resistant depression.

Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (Po0.05). Increases in left putamen volume (Po0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.

Objectives The risk of cognitive impairment is a concern for patients with major depressive disorder (MDD) receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention. Methods Forty-four MDD patients receiving ECT (61% right unilateral (RUL), 39% mixed RUL-bitemporal, left UL and/or bitemporal lead placement underwent a cognitive battery prior to ECT (T1), after 2 sessions (T2), and at the end of the index (T3). Thirty-two patients returned for a 6-month follow-up (T4). Thirty-three controls were assessed at two times ~4 weeks apart (C1 and C2). Results At baseline, patients showed deficits in processing speed, executive function and memory compared to controls. Including depression severity and lead placement covariates, linear mixed model analysis showed significant improvement in only processing speed between T1 and T3 and between T1 and T4 in patients. An acute decline in attention and verbal memory was observed at T2, but performance returned to baseline levels at T3. Longitudinal cognitive outcomes did not differ in patients defined as ECT responders/non-responders. Limitations Episodic memory was not measured and medications were not controlled between T3 and T4. Controls also showed improvements in processing speed, suggesting practice effects for some measures. Conclusions In this naturalistic ECT treatment study, results show that the initiation of ECT may transiently affect memory and executive function, but cognition is largely unaffected during and post ECT. While some functions might improve, others will at least remain stable up to 6-months following the ECT index.

Major depressive disorder (MDD) is associated with dysfunctional corticolimbic networks, making functional connectivity studies integral for understanding the mechanisms underlying MDD pathophysiology and treatment. Resting-state functional connectivity (RSFC) studies analyze patterns of temporally coherent intrinsic brain activity in "resting-state networks" (RSNs). The default-mode network (DMN) has been of particular interest to depression research; however, a single RSN is unlikely to capture MDD pathophysiology in its entirety, and the DMN itself can be characterized by multiple RSNs. This, coupled with conflicting previous results, underscores the need for further research. Here, we measured RSFC in MDD by targeting RSNs overlapping with corticolimbic regions and further determined whether altered patterns of RSFC were restored with electroconvulsive therapy (ECT). MDD patients exhibited hyperconnectivity between ventral striatum (VS) and the ventral default-mode network (vDMN), while simultaneously demonstrating hypoconnectivity with the anterior DMN (aDMN). ECT influenced this pattern: VS-vDMN hyperconnectivity was significantly reduced while VS-aDMN hypoconnectivity only modestly improved. RSFC between the salience RSN and dorsomedial prefrontal cortex was also reduced in MDD, but was not affected by ECT. Taken together, our results support a model of ventral/dorsal imbalance in MDD and further suggest that the VS is a key structure contributing to this desynchronization.

Background Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24 hours following ketamine infusion in 10 MDD patients. Methods FSL’s Tract-Based Spatial Statistics (TBSS) established voxel-level differences in fractional anisotropy (FA) between responders (patients showing >50% improvement in symptoms 24 hours post-infusion) and non-responders in major white matter pathways. Follow-up regions-of-interest (ROI) analyses examined differences in FA and radial (RD), axial (AD) and mean diffusivity (MD) between responders and non-responders and 15 age- and sex-matched controls, with groups compared pairwise. Results Whole brain TBSS (p<0.05, corrected) and confirmatory tract-based regions-of-interest analyses showed larger FA values in the cingulum and forceps minor in responders compared to non-responders; complementary decreases in RD occurred in the cingulum (p<0.05). Only non-responders differed from controls showing decreased FA in the forceps minor, increased RD in the cingulum and forceps minor, and increased MD in the forceps minor (p<0.05). Limitations Non-responders showed an earlier age of onset and longer current depressive episode than responders. Though these factors did not interact with diffusion metrics, results may be impacted by the limited sample size. Conclusions Though findings are considered preliminary, significant differences in FA, RD and MD shown in non-responders compared to responders and controls in fronto-limbic and ventral striatal pathways suggest that the structural architecture of specific functional networks mediating emotion may predict ketamine response in MDD.

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