We have shown for the first time that chronic treatment with high-dose MST resulted in less cognitive impairment than ECS (see for summary) and that high-dose MST did not significantly differ from the effects of anesthesia alone. Moreover, increasing MST dosage from 2.5X seizure threshold to 6X seizure threshold did not impair cognitive performance on most measures. These results support the feasibility and safety of high-dose MST for subsequent work in humans to assess its efficacy in the treatment of depression.
Replicating our prior report, we found that ECS impaired performance on anterograde amnesia (Task 2
) and retrograde amnesia (Task 3
old list), while high-dose MST did not differ from Sham on these measures (8
). This result supports the conclusion that high-dose MST dosage at 6X seizure threshold retains cognitive advantages relative to ECS on these measures. Although we failed to replicate our previously reported finding of a difference between ECS and moderate-dose MST on the new list-learning component of Task 3
, neither ECS nor high-dose MST differed from Sham on this task in the current study, likely due to a high degree of interday variance (mean = 42% +/− 27%).
As an additional test of the cognitive impact of increasing MST dosage, we compared the current results with 100 Hz high-dose MST with results seen in our prior study with 50 Hz moderate-dose MST (8
). On the measure of reorientation time (the time required to complete Task 1
upon waking), high-dose MST did not differ from moderate-dose MST, suggesting that MST dosage within the range tested is unrelated to reorientation time. Further evidence for rapid reorientation post MST has been seen in human studies, which found ECT to result in significantly longer reorientation time than acute (9
) and chronic (12
) low-dose MST. This difference may be clinically meaningful, since prolonged time to orientation is correlated with retrograde amnesia (11
). More recently, a report on the first 11 depressed patients to receive 100 Hz MST likewise found high-dose MST to result in faster orientation recovery than ECT (28
Interestingly, we found improved accuracy on Task 2 and Task 3 old list recall in the high-dose compared to the moderate-dose study for the MST and Sham groups, but not for ECS condition. Task 3 old list accuracy also improved significantly in the second study for the MST group alone. A possible explanation is a practice effect that allowed subjects to adapt to testing after recovery from anesthesia. The two subjects in the moderate-dose study were experimentally naïve, whereas the three subjects in the current high-dose study had collectively received numerous treatment days involving methohexitol anesthesia and subsequent cognitive testing. The fact that the ECS condition failed to show this practice effect provides further evidence for ECS-related impairment not seen in the MST conditions.
The apparent lack of MST dose dependence, within the range tested here, on learning and memory functions assessed by Tasks 1, 2, and 3, warrants further discussion. Both MST conditions were given at the same intensity (e.g., strength of the magnetic field), and they differed only in frequency (50 versus 100 Hz) and the duration of each stimulation train (in seconds). Since the induced electric field generated by individual pulses within the two conditions was identical, the depth of penetration and regions of the brain directly stimulated by each pulse should be identical. We have previously reported the depth of penetration of MST to be superficial compared to ECS (6
). Thus, repeatedly stimulating superficial cortex at higher frequencies and longer train durations would not be expected to adversely affect cognitive functions subserved by brain regions remote from the site of stimulation, except by transsynaptic action. The learning and memory functions involved in Tasks 1, 2, and 3 may be expected to involve hippocampal regions, which would not be directly stimulated even in the high-dose MST condition. However, our dosage comparison was retrospective and confounded by subject age, thus a definitive test of the dose-response relationships will require random assignment to different MST dosage levels.
In this study we introduce an expanded version of the CUCPC that includes two new measures of working memory: (i) spatial working memory (Task 4
), and (ii) serial probe recognition (Task 5
). ECS significantly impaired working memory on both tasks relative to sham, while high-dose MST did not. The spatial working memory task was based upon the radial arm maze, a task which has been reported to result in increased activation of the hippocampus (29
). Because previous research has shown that MST results in less marked physiological and anatomical changes in the dentate gyrus than ECS (6
), we predicted high-dose MST would have less of an effect on this task than ECS. Further work is needed to establish the extent to which this task, as implemented here, provides a measure of hippocampal functioning in monkeys. The serial probe recognition task was modeled after the Sternberg delayed match-to-sample task, which has been reported to activate frontal, parietal, occipital and other cortical regions in humans, as well as deeper structures such as cingulate cortex, insula, and hypothalamus, and to be associated with sustained firing in parahippocampal neurons (31
). We expected that high-dose MST might impair performance on this task by virtue of its action on superficial cortex. However, high-dose MST did not impair function on this task relative to sham, and fared better than ECS, perhaps again due to their differential impact on areas that are active during the task but that fall outside the area most focally stimulated by MST. However, definitive interpretation of these differences awaits further study of the neurobiological underpinnings of these tasks in primates, e.g., via functional imaging.
Limitations of this study include the small sample size, the limited number of cognitive domains assessed, the risk of carry-over effects, practice effects, the fact that all 3 subjects were male, and the aforementioned confound between age and MST dosage in the retrospective dosage comparisons. A larger sample size would be needed before these results could be generalized. Additionally, because this is the first report of the two new working memory tasks added to the CUPCP, further work will be needed to characterize and validate their psychometric properties. A further limitation is the use of bilateral ECS, rather than unilateral, which may be expected to have fewer cognitive side effects. However, bilateral ECS was selected to match the MST placement, which was also bilateral. It should also be noted that the dosage relative to seizure threshold was imbalanced between the two conditions. Specifically, MST was given at 6X whereas ECS was given at 2.5X seizure threshold. This dosage imbalance could be expected to bias the study in favor of seeing an advantage of ECS. Our results were the opposite, further strengthening the support for the relative safety of MST.
For animal models of cognitive function to meaningfully inform the development of safer neurostimulation interventions for patient populations, it will be important to develop systematic translational techniques that allow for cross-species comparison of neurocognitive function. A potentially useful approach to such translational research would be the development of parallel animal and human models of specific neurocognitive domains (34
). Such an approach allows one to leverage invasive measures of anatomy and physiology available in the animal to elucidate mechanisms of action and the specific neurocircuitry affected by neurostimulation techniques (35
). Moreover, the parallel examination of human and nonhuman responses to neurostimulation can shed light on similar and divergent cognitive processes across species. As we learn more about the effects of various types of neurostimulation modalities, controlling for variables such as stimulation focality, current density, depth, strength and duration of seizure propagation, the neurocognitive effects of these types of stimulation can provide insight into the roles of anatomy and cross-species divergence in cognition.