Background Electroconvulsive therapy (ECT) elicits a rapid and robust clinical response in patients with refractory depression. Neuroimaging measures of structural plasticity relating to and predictive of ECT response may point to the mechanisms underlying rapid antidepressant effects and establish biomarkers to inform other treatments. Here, we determine the effects of 1) diagnosis and 2) ECT on global and local variations of hippocampal and amygdalar structure in major depression and predictors of ECT-related clinical response Methods Longitudinal changes in hippocampal and amygdala structure were examined in patients with major depression (N= 43, scanned thrice; prior to ECT, after the 2nd ECT session, and within one week of completing the ECT treatment series) referred for ECT as part of their standard clinical care. Cross-sectional comparisons with demographically similar controls (N= 32, scanned twice) established effects of diagnosis. Results Patients showed smaller hippocampal volumes compared to controls at baseline (p<.04). Both hippocampal and amygdalar volumes increased with ECT (p<.001) and in relation to symptom improvement (p<.01). Hippocampal volume at baseline predicted subsequent clinical response (p<.05). Shape analysis revealed pronounced morphometric changes in the anterior hippocampus and basolateral and centromedial amygdala. All structural measures remained stable across time in controls. Conclusions ECT induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and is pronounced in regions with prominent connections to ventromedial prefrontal cortex and other limbic structures. Smaller hippocampal volumes at baseline predict a more robust clinical response. Neurotrophic processes including neurogenesis shown in preclinical studies may underlie these structural changes.

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm3 voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

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.

Introduction One of the most effective interventions for intractable major depressive episodes is electroconvulsive therapy (ECT). Because ECT is also relatively fast-acting, longitudinal study of its neurobiological effects offers critical insight into the mechanisms underlying depression and antidepressant response. Here we assessed modulation of intrinsic brain activity in corticolimbic networks associated with ECT and clinical response. Methods We measured resting-state functional connectivity (RSFC) in patients with treatment-resistant depression (n=30), using functional magnetic resonance imaging (fMRI) acquired before and after completing a treatment series with right-unilateral ECT. Using independent component analysis, we assessed changes in RSFC with 1) symptom improvement and 2) ECT regardless of treatment outcome in patients, with reference to healthy controls (n=33, also scanned twice). Results After ECT, consistent changes in RSFC within targeted depression-relevant functional networks were observed in the dorsal anterior cingulate (ACC), mediodorsal thalamus (mdTh), hippocampus, and right anterior temporal, medial parietal, and posterior cingulate cortex in all patients. In a separate analysis, changes in depressive symptoms were associated with RSFC changes in the dorsal ACC, mdTh, putamen, medial prefrontal, and lateral parietal cortex. RSFC of these regions did not change in healthy controls. Conclusions Neuroplasticity underlying clinical change was in part separable from changes associated with the effects of ECT observed in all patients. However, both ECT and clinical change were associated with RSFC modulation in dorsal ACC, mdTh and hippocampus, which may indicate that these regions underlie the mechanisms of clinical outcome in ECT and may be effective targets for future neurostimulation therapies.