Bruce Luber

Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials

Testing the therapeutic potential of transcranial magnetic stimulation (TMS) in controlled trials requires a valid sham condition. Sham TMS is typically administered by tilting the coil 45--90 degrees off the scalp, with one or two wings of the coil touching the scalp. Lack of cortical effects has not been verified. We compared sham manipulations in their thresholds for eliciting motor-evoked potentials (MEPs) in human volunteers and in intracerebral measurements of voltage induced in the prefrontal cortex of a rhesus monkey. Three types of sham (one-wing 45 degrees and 90 degrees and two-wing 90 degrees tilt) induced much lower voltage in the brain than active TMS (67--73% reductions). However, the two-wing 45 degrees sham induced values just 24% below active TMS. This sham was about half as potent in inducing MEPs over the motor cortex as active TMS. Some sham TMS conditions produce substantial cortical stimulation, making it critical to carefully select the sham manipulation for clinical trials.

Safety and Feasibility of Magnetic Seizure Therapy (MST) in Major Depression: Randomized Within-Subject Comparison with Electroconvulsive Therapy

Magnetic seizure therapy (MST) is a novel means of performing convulsive therapy using rapidly alternating strong magnetic fields. MST offers greater control of intracerebral current intensity than is possible with electroconvulsive therapy (ECT). These features may result in a superior cognitive side effect profile for MST, while possibly retaining the efficacy of ECT. The objective of this study was to determine whether MST and ECT differ in seizure characteristics, and acute objective and subjective cognitive side effects. A total of 10 inpatients in a major depressive episode referred for ECT were enrolled in this randomized, within-subject, double-masked trial. Seizure threshold was determined with MST and ECT in the first two sessions of a course of convulsive therapy, with order randomized. The remaining two sessions consisted of suprathreshold stimulation with MST and ECT. A neuropsychological battery and side effect rating scale were administered by a masked rater before and after each session. Tonic-clonic seizures were elicited with MST in all patients. Compared to ECT, MST seizures had shorter duration, lower ictal EEG amplitude, and less postictal suppression. Patients had fewer subjective side effects and recovered orientation more quickly with MST than ECT. MST was also superior to ECT on measures of attention, retrograde amnesia, and category fluency. Magnetic seizure induction in patients with depression is feasible, and appears to have a superior acute side effect profile than ECT. Future research will be needed to establish whether MST has antidepressant efficacy.

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects.

Although improvements in performance due to TMS have been demonstrated with some cognitive tasks, performance improvement has not previously been demonstrated with working memory tasks. In the present study, a delayed match-to-sample task was used in which repetitive TMS (rTMS) at 1, 5, or 20 Hz was applied to either left dorsolateral prefrontal or midline parietal cortex during the retention (delay) phase of the task. Only 5 Hz stimulation to the parietal site resulted in a significant decrease in reaction time (RT) without a corresponding decrease in accuracy. This finding was replicated in a second experiment, in which 5 Hz rTMS at the parietal site was applied during the retention phase or during presentation of the recognition probe. Significant speeding of RT occurred in the retention phase but not the probe phase. This finding suggests that TMS may improve working memory performance, in a manner that is specific to the timing of stimulation relative to performance of the task, and to stimulation frequency.

Transcranial magnetic stimulation: applications in basic neuroscience and neuropsychopharmacology

Introduced 15 years ago, transcranial magnetic stimulation (TMS) is a non-invasive means of stimulating the cortex that has proved to be a unique tool for probing brain-behaviour relationships. While a therapeutic role for TMS in neuropsychiatry is uncertain, the utility of TMS in studying brain function has been demonstrated in diverse neuroscience applications. We review studies in animals on the mechanisms of action of TMS, and present a summary of the applications of TMS in basic neuroscience. TMS is still a relatively young technique, and unanswered questions remain regarding its acute and chronic impact on neural excitability and various aspects of brain function. Nonetheless, recent work with TMS has demonstrated its unique role in complementing other tools for studying brain function. As a brain intervention tool, TMS holds the promise of moving beyond correlative studies to help define the functional role of cortical regions in selected cognitive and affective processes.

Differential effects of high-dose magnetic seizure therapy and electroconvulsive shock on cognitive function.

BACKGROUND Magnetic seizure therapy (MST) is under investigation as an alternative form of convulsive therapy that induces more focal seizures and spares cortical regions involved in memory. With a newly expanded version of the Columbia University Primate Cognitive Profile, we compared the cognitive effects of high-dose MST delivered at 100 Hz (6 x seizure threshold) with electroconvulsive shock (ECS) delivered at 2.5 x seizure threshold. METHODS Daily high-dose MST, ECS, and sham (anesthesia-only) were administered for 4 weeks each in a within-subject crossover design. Rhesus macaques (n = 3) were trained on five cognitive tasks assessing automatic memory, anterograde learning and memory, combined anterograde and retrograde simultaneous chaining, and spatial and serial working memory. Acutely after each intervention, monkeys were tested on the cognitive battery twice daily, separated by a 3-hour retention interval. RESULTS Subjects were slower to complete criterion tasks (p values < .0001) after ECS, compared with sham and high-dose MST. Moreover, time to task-completion after high-dose MST did not differ from sham. Of six measures of accuracy, treatment effects were found in four; in all of these, ECS but not MST fared worse than sham. On all accuracy and time to completion measurements, subjects performed as well after high-dose MST as subjects from a previous study on moderate-dose MST. CONCLUSIONS These findings provide evidence that high-dose MST results in benign acute cognitive side-effect profile relative to ECS and are in line with our previous studies.

Non-invasive brain stimulation in the detection of deception: Scientific challenges and ethical consequences

Tools for noninvasive stimulation of the brain, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have provided new insights in the study of brain-behavior relationships due to their ability to directly alter cortical activity. In particular, TMS and tDCS have proven to be useful tools for establishing causal relationships between behavioral and brain imaging measures. As such, there has been interest in whether these tools may represent novel technologies for deception detection by altering a persons ability to engage brain networks involved in conscious deceit. Investigation of deceptive behavior using noninvasive brain stimulation is at an early stage. Here we review the existing literature on the application of noninvasive brain stimulation in the study of deception. Whether such approaches could be usefully applied to the detection of deception by altering a persons ability to engage brain networks involved in conscious deceit remains to be validated. Ethical and legal consequences of the development of such a technology are discussed.

Remediation of Sleep-Deprivation–Induced Working Memory Impairment with fMRI-Guided Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation-induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)-identified network associated with sleep-deprivation-induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.

Differential Neurophysiological Effects of Magnetic Seizure Therapy (MST) and Electroconvulsive Shock (ECS) in Non-Human Primates

Magnetic seizure therapy (MST) is under development as a means of reducing the side effects of electroconvulsive therapy (ECT) through enhanced control over patterns of seizure induction and spread. We previously reported that chronic treatment with MST resulted in less impairment in cognitive function than electroconvulsive shock (ECS) in a non-human primate model of convulsive therapy. Here we present quantitative analyses of ictal expression and post-ictal suppression following ECS, MST, and anesthesia-alone sham in the same model to test whether differential neurophysiological characteristics of the seizures could be identified. Rhesus monkeys received 4 weeks of daily treatment with ECS, MST, and anesthesia-alone sham in a counterbalanced order separated by a recovery period. Both ECS and MST were given bilaterally at 2.5 × seizure threshold. Neurophysiological characteristics were derived from two scalp EEG electrode recording sites during and immediately following the ictal period, and were compared to sham treatment. EEG power within four frequencies (delta, theta, alpha and beta) was calculated. Our results support earlier findings from intracerebral electrode recordings demonstrating that MST- and ECS- induced seizures elicit differential patterns of EEG activation. Specifically, we found that ECS shows significantly more marked ictal expression, and more intense post-ictal suppression than MST in the theta, alpha, and beta frequency bands (Ps<.05). However, the ECS and MST were indistinguishable in the delta frequency band during both ictal and post-ictal periods. These results demonstrate that magnetic seizure induction can result in seizures that differ in some neurophysiological respects compared with ECS, but that these modalities share some aspects of seizure expression. The clinical significance of these similarities and differences awaits clinical correlation.

Revisiting the Backward Masking Deficit in Schizophrenia: Individual Differences in Performance and Modeling With Transcranial Magnetic Stimulation

BACKGROUND Deficits in backward masking have been variably reported in schizophrenia patients, but individual differences in the expression of these deficits have not been explicitly investigated. In addition, increased knowledge of the visual system has opened the door for new techniques such as transcranial magnetic stimulation (TMS) to explore these deficits physiologically. METHODS Patients with schizophrenia and healthy controls were tested using a backward masking paradigm. In order to examine the functionality of visual pathways involved in backward masking, subjects were retested on a backward masking paradigm using single pulse TMS applied to occipital cortex in lieu of the masking stimuli. RESULTS Compared with controls, patients had significantly delayed recovery from visual backward masking. However, 23.5% of patients (compared to 5% of controls) never recovered to levels approaching unmasked performance. When these subjects were segregated from the analysis, group differences vanished. In addition, stimulus masking with occipital TMS followed the same pattern in both patients and controls. CONCLUSIONS Observations of individual differences in visual masking performance may identify a subgroup of schizophrenia patients. The TMS data suggest that this deficit may not localize to the occipital cortex. However, TMS can be a useful tool for localizing processing deficits in schizophrenia.

Differential heart rate response to magnetic seizure therapy (MST) relative to electroconvulsive therapy: A nonhuman primate model

Electroconvulsive therapy (ECT) is an effective treatment for severe depression; however, the induced therapeutic seizure acts on the autonomic nervous system and results in significant cardiac effects. This is an important consideration particularly in the elderly. Magnetic seizure therapy (MST) is in development as a less invasive alternative, but its effects on cardiac function have not been studied. We sought to model those effects in nonhuman primates to inform the development of safer neurostimulation interventions. Twenty four rhesus monkeys were randomly assigned to receive 6 weeks of daily treatment with electroconvulsive stimulation (ECS), magnetic seizure therapy (MST) or anesthesia-alone sham. Digitally acquired ECG and an automated R-wave and inter-R interval (IRI) sampling were used to measure intervention effects on heart rate (HR). Significant differences between experimental conditions were found in the HR as evidenced by changes in the immediate post-stimulus, ictal and postictal epochs. Immediate post-stimulus bradycardia was seen with ECS but not with MST. ECS induced significantly more tachycardia than MST or sham in both the ictal and postictal periods. MST resulted in a small, but statistically significant increase in HR during the postictal period relative to baseline. HR was found to increase by 25% and 8% in the ECS and MST conditions, respectively. MST resulted in significantly less marked sympathetic and parasympathetic response than did ECS. This differential physiological response is consistent with MST having a more superficial cortical site of action with less impact on deeper brain structures implicated in cardiac control relative to ECT. The clinical relevance of the topographical seizure spread of MST and its associated effects on the autonomic nervous system remain to be determined in human clinical trials.