Sarah H. Lisanby

Therapeutic application of repetitive transcranial magnetic stimulation: a review.

Transcranial magnetic stimulation (TMS), a non-invasive means of electrically stimulating neurons in the human cerebral cortex, is able to modify neuronal activity locally and at distant sites when delivered in series or trains of pulses. Data from stimulation of the motor cortex suggest that the type of effect on the excitability of the cortical network depends on the frequency of stimulation. These data, as well as results from studies in rodents, have been generalized across brain areas and species to provide rationales for using repetitive TMS (rTMS) to treat various brain disorders, most notably depression. Research into clinical applications for TMS remains active and has the potential to provide useful data, but, to date, the results of blinded, sham-controlled trials do not provide clear evidence of beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. In this review, we discuss the clinical and scientific bases for using rTMS as treatment, and review the results of trials in psychiatric and neurological disorders to date.

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial.

CONTEXT Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. OBJECTIVE To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. DESIGN Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. SETTING Four US university hospital clinics. PATIENTS Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. INTERVENTION We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. MAIN OUTCOME MEASURE In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. RESULTS Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). CONCLUSION Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00149838.

Transcranial magnetic stimulation

TMS is a powerful new tool with extremely interesting research and therapeutic potentials. Further understanding of the ways by which TMS changes neuronal function, especially as a function of its use parameters, will improve its ability to answer neuroscience questions as well as to treat diseases. Because of its noninvasiveness, it does not readily fit under the umbrella of neurosurgery. Nevertheless, it is important for neurosurgeons to be aware of TMS, because findings from TMS studies will have implications for neurosurgical approaches like DBS and VNS. Indeed, it is possible to think of using TMS as a potential noninvasive initial screening tool to identify whether perturbation of a circuit has short-term clinical effects. In the example of chronic refractory depression or OCD, which is generally a chronic illness, it might then follow that rather than having daily or weekly TMS for the rest of their lives, patients would have DBS electrodes implanted in the same circuit. Whatever road the future takes, TMS is an important new tool that will likely be of interest to neurosurgeons over the next 20 years and perhaps even longer.

Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis

Transcranial magnetic stimulation (TMS) is a technology that allows for non-invasive modulation of the excitability and function of discrete brain cortical areas. TMS uses alternating magnetic fields to induce electric currents in cortical tissue. In psychiatry, TMS has been studied primarily as a potential treatment for major depression. Most studies indicate that slow-frequency repetitive TMS (rTMS) and higher frequency rTMS have antidepressant properties. A meta-analysis of controlled studies indicates that this effect is fairly robust from a statistical viewpoint. However, effect sizes are heterogeneous, and few studies have shown that rTMS results in substantial rates of clinical response or remission, and the durability of antidepressant effects is largely unknown. We review in detail rTMS studies in the treatment of depression, as well as summarize treatment studies of mania, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia. We also review the application of TMS in the study of the pathophysiology of psychiatric disorders and summarize studies of the safety of TMS in human subjects.

Lateral prefrontal cortex and self-control in intertemporal choice.

Disruption of function of left, but not right, lateral prefrontal cortex (LPFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) increased choices of immediate rewards over larger delayed rewards. rTMS did not change choices involving only delayed rewards or valuation judgments of immediate and delayed rewards, providing causal evidence for a neural lateral-prefrontal cortex–based self-control mechanism in intertemporal choice.

Vagus nerve stimulation: a new tool for brain research and therapy.

Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.

Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.

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.

Effects of Pulse Width and Electrode Placement on the Efficacy and Cognitive Effects of Electroconvulsive Therapy

BACKGROUND While electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy. METHODS In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 ms) or an ultrabrief pulse (0.3 ms). Depressive symptoms and cognition were assessed before, during, and immediately, two, and six months after therapy. Patients who responded were followed for a one-year period. RESULTS The final remission rate for ultrabrief bilateral ECT was 35 percent, compared with 73 percent for ultrabrief unilateral ECT, 65 percent for standard pulse width bilateral ECT, and 59 percent for standard pulse width unilateral ECT (all Ps<0.05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other 3 groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately following therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe following ultrabrief right unilateral ECT compared to each of the other three conditions (P<0.001). CONCLUSIONS The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.).

Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive–compulsive disorder (OCD) and Tourette's syndrome (TS)

There is evidence that motor and premotor cortex are hyperexcitable in obsessive-compulsive disorder (OCD) and Tourettes syndrome (TS). We tested whether low-frequency repetitive transcranial magnetic stimulation (rTMS) could normalize overactive motor cortical regions and thereby improve symptoms. Subjects with OCD or TS were treated with active rTMS to the supplementary motor area (SMA) for 10 daily sessions at 1 Hz, 100% of motor threshold, 1200 stimuli/day. Suggestions of clinical improvement were apparent as early as the first week of rTMS. At the second week of treatment, statistically significant reductions were seen in the YBOCS, YGTSS, CGI, HARS, HDRS, SAD, BDI, SCL-90, and SASS. Symptoms improvement was correlated with a significant increase of the right resting motor threshold and was stable at 3 months follow-up. Slow rTMS to SMA resulted in a significant clinical improvement and a normalization of the right hemisphere hyperexcitability, thereby restoring hemispheric symmetry in motor threshold.