Translational development strategy for magnetic seizure therapy

Abstract

Electroconvulsive therapy (ECT) has unparalleled antidepressant efficacy, but its cognitive side effects may be persistent. Research suggests that the side effects may be at least partially dissociable from the therapeutic effects of ECT, suggesting that distinct cortical networks may underlie them and introducing a role for focal seizure induction as a means of minimizing side effects. In magnetic seizure therapy (MST), magnetic fields avoid tissue impedance and induce electrical currents confined to superficial cortex, facilitating focal seizure induction. The translational development strategy for MST has included: (1) device development, (2) feasibility in animals and initial human trials, (3) testing in nonhuman primates on safety and mechanisms of action (with neuroanatomical, neurophysiological and cognitive endpoints), (4) safety testing in patients, (5) initial efficacy testing in patients, (6) dosage optimization, and (7) randomized comparison with ECT. These stages have been iterative, with results of early clinical testing prompting device enhancements that were, in turn, tested in nonhuman primates prior to human trials. Safety testing was aided by development of a nonhuman primate model of human ECT, and the validation of a cognitive battery for the monkey that is sensitive to the range of effects of ECT on human memory. Human testing has been facilitated by the development of an international consortium of centers addressing various aspects of technique and dose/response relationships. Challenges facing MST are common to other device-based therapies: characterizing dose/response relationships, optimizing efficacy, and developing efficient and reliable methods to induce lasting therapeutic change in the circuitry underlying depression.

Figures

Figure 1. Stages of physiologically-informed intervention development as applied to Magnetic Seizure Therapy (MST)

The processes starts with a clinically salient physiological target, which in this case was a pattern of brain activation associated with therapeutic response to ECT, with frontal inhibitory effects as illustrated by frontal delta-band EEG activity (Luber, et al., 2000). A prototype device was designed to achieve this physiological target, which had maximal stimulator output of 50 Hz for 8 seconds, at maximal stimulator output (100% intensity). The ability of this prototype device to achieve the physiological target was tested in nonhuman primates, using intracerebral electrodes to record the strength of the induced electric field of MST, contrasting it with electroconvulsive shock, and to characterize the topography of the induced seizures. The safety and efficacy of this prototype was piloted in depressed patients, yielding supporting evidence of safety relative to ECT and encouraging signs of efficacy in open trials, however there were suggestions that output restrictions may be limiting efficacy. This led to a refined design for a high dose MST device, capable of 100 Hz for 10 seconds at 100% intensity.

Figure 2. Evolution of MST Devices for Non-Human Primate and Clinical Trials

A) First generation nonhuman primate MST device, used in the first MST feasibility trials in rhesus monkeys (Lisanby, et al., 2001) and the first depressed patient (Lisanby, et al., 2001). A conventional rTMS device was expanded by adding 4 charging units, yielding a total of 8 booster modules and a maximal stimulator output of 40 Hz. B) First generation human MST device used in the first randomized trial of MST in the treatment of depression conducted at Columbia and University of Texas Southwestern Medical Center (Lisanby, et al., 2003, White, et al., 2006). Sixteen charging units were employed, resulting in a maximal stimulator output of 50 Hz, 8 seconds, 100% intensity. C) Second generation nonhuman primate high dose MST (HD-MST) device used in the first animal studies of HD-MST (Spellman, et al., 2008). A three-phase power supply and other revisions to circuit topology were used to achieve 100 Hz, 10 second trains at 100% intensity. D) Second generation human HD-MST device used in the first human studies of HD-MST (Kirov, et al., 2008). The Magstim Theta is capable of 1000 pulses per train at 100 Hz and 100% intensity, as well at theta burst stimulation. Three coils can be connected simultaneously to facilitate seizure threshold titration. A touch screen monitor provides an interactive user interface. The self-contained console has a small footprint to fit easily in a typical clinical ECT suite.

Figure 3. MST coil design

Figure 8 coil (left), double cone coil (middle), cap coil (right). The figure 8 coil was least efficient in seizure induction. The Double cone coil conforms well to vertex and midline prefrontal placements and was more efficient in seizure induction. The cap coil, which is a round coil with concave windings to conform closely to the scalp, was highly efficient in inducing seizure with a bilateral placement.

Figure 4. Translational development strategy applied to MST

The development of MST progressed through the stages of feasibility testing, safety evaluation, and efficacy trials. At each stage, work toggled back and forth between animal testing in nonhuman primates and clinical trials. Device design was iteratively improved, incorporating results from each stage of development. Animal testing provided the unique opportunity to test the safety of MST using postmortem anatomical studies, while clinical trials provide the unique opportunity to assess efficacy in depressed patients.

Figure 5. Scalp EEG of a patient undergoing high dose MST for treatment of depression

This is a representative 2-channel, bifrontotemporal scalp EEG recording during one of the initial human HD-MST sessions from the case series reported in Kirov et al. (Kirov, et al., 2008). The period of the MST train is marked. Following the train, high frequency spiking can be seen in both channels that evolves into spike-slow wave configuration, and then slow wave activity. This was accompanied by a generalized tonic-clonic seizure as documented by motor convulsion in an unanesthetized limb, employing the cuff-technique.