Tolerability and safety of high daily doses of repetitive transcranial magnetic stimulation in healthy young men.

Repetitive transcranial magnetic stimulation (rTMS) is an experimental technology that involves a powerful magnetic pulse applied to the scalp, which is sufficient to cause neuronal depolarization. Transcranial magnetic stimulation has been used in treatment studies for psychiatric disorders, primarily unipolar depression, and as a tool to map brain function. Although thousands of rTMS sessions have been given with few side effects, rTMS can produce serious adverse effects such as an unintended seizure. Safety guidelines for frequency, duration, and intensity of rTMS have aided in the prevention of such adverse side effects. However, the total dose (number of stimuli) able to be delivered safely to human subjects within a day or within a week has not been established. For example, previous rTMS studies as a treatment for depression consisted of delivering 800 to 3,000 magnetic pulses per day, with 8000 to 30,000 magnetic pulses over 2 to 3 weeks. This study examined whether high doses of rTMS within a day or over a week would produce significant side effects. As part of a study to examine rTMS effects in sleep deprivation, we exposed healthy men to 12,960 magnetic pulses a day for up to 3 days in 1 week. This equals 38,880 magnetic pulses over 1 week, which is likely one of the largest exposures of TMS to date. Despite this intense treatment regimen, we failed to produce significant side effects. Doses of up to 12,960 pulses per day appear safe and tolerable in healthy young men.

Decreased brain activation during a working memory task at rested baseline is associated with vulnerability to sleep deprivation.

STUDY OBJECTIVE: To examine whether differences in patterns of brain activation under baseline conditions relate to the differences in sleep-deprivation vulnerability. DESIGN: Using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging, we scanned 33 healthy young men while they performed the Sternberg working memory task following a normal night of sleep and again following 30 hours of sleep deprivation. From this initial group, based on their Sternberg working memory task performance, we found 10 subjects resilient to sleep deprivation (sleep deprivation-resilient group) and then selected 10 age- and education-matched subjects vulnerable to sleep deprivation (sleep deprivation-vulnerable group). SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Data from 10 young men (mean age 27.8 +/- 1.7 years) in the sleep deprivation-resilient group and 10 young men (mean age 28.2 +/- 1.9 years) in the sleep deprivation-vulnerable group were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We compared functional magnetic resonance imaging BOLD signal at rested baseline and sleep deprivation states in the 2 groups. As hypothesized, following sleep deprivation, both groups showed significant decreases in global brain activation compared to their rested group baseline. At rested baseline and in the sleep-deprivation state, the sleep deprivation-resilient group had significantly more brain activation than did the sleep deprivation-vulnerable group. There were also differences in functional circuits within and between groups in response to sleep deprivation. CONCLUSIONS: These preliminary data suggest that patterns of brain activation during the Sternberg working memory task at the rested baseline and the sleep-deprivation state, differ across individuals as a function of their sleep-deprivation vulnerability.

Are individual differences in fatigue vulnerability related to baseline differences in cortical activation?

Recent evidence suggests that underlying patterns of cortical activation may partially account for individual differences in susceptibility to the effects of sleep deprivation. Here, functional magnetic resonance imaging (fMRI) was used to examine the activation of military pilots whose sleep-deprivation vulnerability previously was quantified. A Sternberg Working Memory Task (SWMT; S. Sternberg, 1966) was completed alternately with a control task during a 13-min blood oxygen level-dependent fMRI scan. Examination of the activated voxels in response to SWMT indicated that, as a group, the pilots were more similar to fatigue-resistant nonpilots than to fatigue-vulnerable nonpilots. Within the pilots, cortical activation was significantly related to fatigue vulnerability on simulator-flight performance. These preliminary data suggest that baseline fMRI scan activation during a working memory task may correlate with fatigue susceptibility.

Decreased cortical response to verbal working memory following sleep deprivation.

STUDY OBJECTIVE: To investigate the cerebral hemodynamic response to verbal working memory following sleep deprivation. DESIGN: Subjects were scheduled for 3 functional magnetic resonance imaging scanning visits: an initial screening day (screening state), after a normal night of sleep (rested state), and after 30 hours of sleep deprivation (sleep-deprivation state). Subjects performed the Sternberg working memory task alternated with a control task during an approximate 13-minute functional magnetic resonance imaging scan. SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Results from 33 men (mean age, 28.6 +/- 6.6 years) were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Subjects performed the same Sternberg working memory task at the 3 states within the magnetic resonance imaging scanner. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca's area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 hours of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Task performance also decreased. A repeated-measures analysis of variance revealed that subjects at the screening and rested states had similar activation patterns, with each having significantly more activation than during the sleep-deprivation state. CONCLUSIONS: These results suggest that human sleep-deprivation deficits are not caused solely or even predominantly by prefrontal cortex dysfunction and that the paretal cortex, in particular, and other brain regions involved in verbal working memory exhibit significant sleep-deprivation vulnerability.

The maximum-likelihood strategy for determining transcranial magnetic stimulation motor threshold, using parameter estimation by sequential testing is faster than conventional methods with similar precision.

BACKGROUND: The resting motor threshold (rMT) is the basic unit of transcranial magnetic stimulation (TMS) dosing. Traditional methods of determining rMT involve finding a threshold of either visible movement or electromyography (EMG) motor-evoked potentials, commonly approached from above and below and then averaged. This time-consuming method typically uses many TMS pulses. Mathematical programs can efficiently determine a threshold by calculating the next intensity needed based on the prior results. Within our group of experienced TMS researchers, we sought to perform an illustrative study to compare one of these programs, the Maximum-Likelihood Strategy using Parameter Estimation by Sequential Testing (MLS-PEST) approach, to a modification of the traditional International Federation of Clinical Neurophysiology (IFCN) method for determining rMT in terms of the time and pulses required and the rMT value. METHODS: One subject participated in the study. Five researchers determined the same subject's rMT on 4 separate days-twice using EMG and twice using visible movement. On each visit, researchers used both the MLS-PEST and the IFCN methods, in alternating order. RESULTS: The MLS-PEST approach was significantly faster and used fewer pulses to estimate rMT. For EMG-determined rMT, MLS-PEST and IFCN derived similar rMT, whereas for visible movement MLS-PEST rMT was higher than for IFCN. CONCLUSIONS: The MLS-PEST algorithm is a promising alternative to traditional, time-consuming methods for determining rMT. Because the EMG-PEST method is totally automated, it may prove useful in studies using rMT as a quickly changing variable, as well as in large-scale clinical trials. Further work with PEST is warranted.

Mechanisms and the current state of transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is unique among the current brain stimulation techniques because it is relatively non-invasive. TMS markedly differs from vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy, all of which require either an implanted prosthesis or general anesthesia, or both. Since its rebirth in its modern form in 1985, TMS has already shown potential usefulness in at least three important domains-as a basic neuroscience research instrument, as a potential clinical diagnostic tool, and as a therapy for several different neuropsychiatric conditions. The TMS scientific literature has now expanded beyond what a single summary article can adequately cover. This review highlights several new developments in combining TMS with functional brain imaging, using TMS as a psychiatric therapy, potentially using TMS to enhance performance, and finally recent advances in the core technology of TMS. TMS' ability to non-invasively and focally stimulate the brain of an awake human is proving to be a most important development for neuroscience in general, and neuropsychiatry in particular.

Mechanisms and state of the art of transcranial magnetic stimulation.

In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device with enough power to stimulate dorsal roots in the spine. They quickly realized that this machine could likely also noninvasively stimulate the superficial cortex in humans. They waited a while before using their device over a human head, fearing that the TMS pulse might magnetically "erase the hard-drive" of the human brain. Almost 10 years later, in 1994, an editorial in this journal concerned whether TMS might evolve into a potential antidepressant treatment. In the intervening years, there has been an explosion of basic and clinical research with and about TMS. Studies are now uncovering the mechanisms by which TMS affects the brain. It does not "erase the hard-drive" of the brain, and it has many demonstrated research and clinical uses. This article reviews the major recent advances with this interesting noninvasive technique for stimulating the brain, critically reviewing the data on whether TMS has anticonvulsant effects or modulates cortical-limbic loops.