Electroconvulsive Therapy (ECT) is the most effective somatic treatment for major depression. Yet, cognitive side effects limit its utility and substantial number fail to respond. Electrical dosage and current paths are critical to both the efficacy and side effects of ECT, suggesting that changes in activity of discrete neural systems underlie the behavioral effects. Thus, to ensure efficacy and limit side effects, clinicians need better control over current density and greater specificity in the brain regions targeted. Implementing these advances is hampered by the use of externally applied electricity. The impedance of the skull and scalp degrade the stimulus, resulting in poor control over the strength and distribution of stimulation and variability both between and within patients. Repetitive transcranial magnetic stimulation (rTMS) avoids these pitfalls by inducing current non-invasively using rapidly alternating magnetic fields that are transparent to tissue. Capitalizing on recent technical advances, we have induced seizures magnetically in anesthetized monkeys. Our data support the feasibility of magnetic seizure induction (MST) as a novel convulsive technique with enhanced control over dosing, offering the promise of fewer side effects and improved efficacy. While studies of subconvulsive rTMS are encouraging, antidepressant effect sizes are small and the likelihood of soon replacing ECT remains low. The goals of this project are to establish the feasibility and safety of MST, and compare its cognitive, physiological, and neuropathological effects with electroconvulsive shock (ECS). Four rhesus monkeys will be implanted with multicontact intracerebral electrodes to provide data on the spatial distribution of induced current and intracerebral electrophysiological effects of both ECS and MST, and address the surprising paucity of data on ECT. In a double-masked, parallel group, random assignment design, 24-monkeys will receive either sham, ECS or MST interventions over a 6-week period. Treatment groups will be compared in terms of acute recovery of orientation, amnesia, systemic side effects, ECG and EEG effects. Neuropathological studies will include gross and microscopic exam, hippocampal and anterior frontal cortex cell counts, and neuronal sprouting in hippocampus. This work will address the neuropathological consequences of the interventions, an issue of considerable public concern, and provide the basis for human trials contrasting the efficacy and adverse effects of ECT and MST. This research will also explore the mechanisms of action of this clinically relevant putative treatment and lay the foundation for its development as a new treatment for psychiatric patients.
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