Parsing the Network Mechanisms of Electroconvulsive Therapy

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

Using functional MRI in a large multisite sample of more that 1,000 patients, four distinct neurophysiological biotypes of depression are defined. These biotypes are used to develop diagnostic classifiers that distinguish patients with depression from controls in separate multisite validation and replication cohorts, and can predict patient responsiveness to therapy.

Investigation of the hippocampus has historically focused on computations within the trisynaptic circuit. However, discovery of important anatomical and functional variability along its long axis has inspired recent proposals of long-axis functional specialization in both the animal and human literatures. Here, we review and evaluate these proposals. We suggest that various long-axis specializations arise out of differences between the anterior (aHPC) and posterior hippocampus (pHPC) in large-scale network connectivity, the organization of entorhinal grid cells, and subfield compositions that bias the aHPC and pHPC towards pattern completion and separation, respectively. The latter two differences give rise to a property, reflected in the expression of multiple other functional specializations, of coarse, global representations in anterior hippocampus and fine-grained, local representations in posterior hippocampus. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.