High frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral cortex: EEG topography during waking and subsequent sleep

Repetitive transcranial magnetic stimulation (rTMS) is a novel research tool in neurology and psychiatry. It is currently being evaluated as a conceivable alternative to electroconvulsive therapy for the treatment of mood disorders. Eight healthy young (age range 21-25 years) right-handed men without sleep complaints participated in the study. Two sessions at a 1-week interval, each consisting of an adaptation night (sham stimulation) and an experimental night (rTMS in the left dorsolateral prefrontal cortex or sham stimulation; crossover design), were scheduled. In each subject, 40 trains of 2-s duration of rTMS (inter-train interval 28 s) were applied at a frequency of 20 Hz (i.e. 1600 pulses per session) and at an intensity of 90% of the motor threshold. Stimulations were scheduled 80 min before lights off. The waking EEG was recorded for 10-min intervals approximately 30 min prior to and after the 20-min stimulations, and polysomnographic recordings were obtained during the subsequent sleep episode (23.00-07.00 h). The power spectra of two referential derivations, as well as of bipolar derivations along the antero-posterior axis over the left and right hemispheres, were analyzed. rTMS induced a small reduction of sleep stage 1 (in min and percentage of total sleep time) over the whole night and a small enhancement of sleep stage 4 during the first non-REM sleep episode. Other sleep variables were not affected. rTMS of the left dorsolateral cortex did not alter the topography of EEG power spectra in waking following stimulation, in the all-night sleep EEG, or during the first non-REM sleep episode. Our results indicate that a single session of rTMS using parameters like those used in depression treatment protocols has no detectable side effects with respect to sleep in young healthy males.     

Positive predictors for antidepressive response to prefrontal repetitive transcranial magnetic stimulation (rTMS)

Repetitive transcranial magnetic stimulation (rTMS) is a brain stimulation technique which had recently been investigated as a putative antidepressant intervention. However, there is little agreement about clinically useful predictors of rTMS outcome. Therefore, the objective of the present study was to determine whether specific biographical, clinical, and psychopathological parameters are associated with the antidepressant response to rTMS in a large sample of 70 depressive patients. We performed a logistic regression analysis in 70 patients with major depressive disorder treated with rTMS of the left dorsolateral prefrontal cortex testing the predictive value of various domains of the depression syndrome as well as the variables episode duration, degree of treatment resistance, and CORE criteria. Response was defined as a 50% reduction of the initial Hamilton score (HAMD). After two weeks of treatment, 21% of the patients showed a response to rTMS. The binary logistic regression model correctly assigned 86.7% of the responders and 96.4% of the non-responders to their final response group. In the model, a high level of sleep disturbances was a significant predictor for treatment response to rTMS. Also, a low score of treatment resistance and a short duration of episode were positive predictors. These findings provide new evidence that especially pronounced sleep disturbances may be a significant clinical predictor of a response to rTMS. Prospective rTMS studies are necessary to validate the predictive value of the derived model.     

Reductions in CI amplitude after repetitive transcranial magnetic stimulation (rTMS) over the striate cortex

Slow repetitive transcranial magnetic stimulation (rTMS) is a method capable of transiently inhibiting cortical excitability and disrupting information processing in the visual system. This method can be used to topographically map the functional contribution of different cortical brain areas in visual processing. An early electrophysiological component, the CI is argued to reflect early visual processing. In addition, source-localization studies have provided evidence for the assumption that the striate cortex is the underlying neural generator of CI. In the present placebo-controlled, crossover study, slow rTMS was applied in order to further investigate the relationship between the striate cortex and the CI component. Based on the inhibitory effects of slow rTMS, a reduction in CI amplitude and an increase in latency were expected. Compared to placebo stimulation, slow rTMS over the striate cortex resulted in significant decreases of the CI amplitude, but did not affect latency. The present study provides causal evidence for the involvement of the striate cortex in generating the CI component.     

Subthreshold prefrontal repetitive transcranial magnetic stimulation reduces motor cortex excitability

The prefrontal cortex plays an important role in central motor control. We have examined whether prefrontal repetitive transcranial magnetic stimulation (rTMS) induces changes of motor cortex excitability determined by motor evoked potentials (MEPs) following single-pulse TMS. We studied 18 healthy volunteers stimulated at 5 Hz with 10% subthreshold prefrontal vs. occipital rTMS for 12 s. MEPs from the flexor carpi radialis muscle after single-pulse vertex stimulation were recorded during rTMS at 0, 4, 8, and 12 s. MEP areas decreased significantly after 8 s of prefrontal rTMS (P < 0. 05) but not after occipital rTMS. We conclude that rTMS of the prefrontal cortex may inhibit the primary motor areas.     

Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression

There is evidence that repetitive transcranial magnetic stimulation (rTMS) applied to the prefrontal cortex has antidepressive properties. In the present study we evaluated the clinical status and the hemodynamic responses during mental work in the prefrontal cortex before therapeutic rTMS. Twelve patients diagnosed with major depression (DSM-IV) were randomized in a sham-controlled cross-over treatment protocol of 4 weeks' duration consisting of two periods of 5 days with rTMS separated by 9 days of no stimulation. rTMS (10 Hz) was applied to the left dorsolateral prefrontal cortex. Hemodynamic changes in the prefrontal cortex during mental work were evaluated by multi-site near-infrared spectroscopy (NIRS). Scores on the Hamilton Depression Rating Scale (HAMD) decreased significantly by -5.4 points after 5 days of active stimulation, whereas it did not change (+1.6 points) after sham stimulation. Absence of a task-related increase of total hemoglobin concentrations at the stimulation site (P<0.005), but not at other locations, before the first active rTMS significantly predicted the clinical response to active rTMS. Clinical benefits of rTMS are predicted by low local hemodynamic responses and support the idea of activation-dependent targeting of rTMS location.     

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.     

High frequency repetitive transcranial magnetic stimulation (rTMS) is effective in migraine prophylaxis: an open labeled study

Abstract

Objective: To evaluate the effect of high rate repetitive transcranial magnetic stimulation (rTMS) in migraine prophylaxis in medically refractory patients.

Methods: Migraine patients above 15 years of age, having more than 7 attacks/month and refractory to at least two prophylactic drugs were included. The patients were evaluated for migraine frequency, severity, functional disability, number of rescue medications and migraine index. Three sessions of alternate day 10 Hz rTMS comprising of 600 pulses in 10 trains were delivered to left frontal cortex. The response was evaluated at the end of session and weekly for 4 weeks.

Results: Fifty-one patients aged 16–61 years and 45 females were treated. Fifty (98%) patients had more than 50% reduction of headache frequency at the end and 1 week after rTMS and the improvement persisted till the fourth week in 80·4% patients. The headache frequency, severity, functional disability, migraine index, and rescue medications significantly reduced at all time points, but the maximum benefit was observed in the first 2 weeks. There were no serious adverse events.

Conclusion: High rate rTMS in left frontal cortex is effective and well tolerated for migraine prophylaxis.     

Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex affects strategic decision-making

Although decision-making is typically seen as a rational process, emotions play a role in tasks that include unfairness. Recently, activation in the right dorsolateral prefrontal cortex during offers experienced as unfair in the Ultimatum Game was suggested to subserve goal maintenance in this task. This is restricted to correlational evidence, however, and it remains unclear whether the dorsolateral prefrontal cortex is crucial for strategic decision-making. The present study used repetitive transcranial magnetic stimulation in order to investigate the causal role of the dorsolateral prefrontal cortex in strategic decision-making in the Ultimatum Game. The results showed that repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex resulted in an altered decision-making strategy compared with sham stimulation. We conclude that the dorsolateral prefrontal cortex is causally implicated in strategic decision-making in healthy human study participants.     

Changes in regional cerebral blood flow after repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in treatment-resistant depression

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex is effective in treatment-resistant depression, although its mechanism is still not completely elucidated. To clarify the neuroanatomical alteration of function elicited by rTMS, single photon emission computed tomography (SPECT) with (99m)Tc-ECD was performed on 12 male inpatients with treatment-resistant unipolar depression before and after high-frequency rTMS of the left dorsolateral prefrontal cortex. These results suggest that the manifestation of the antidepressant effect of high-frequency rTMS is associated with changes in the neuroanatomical function of the left dorsolateral prefrontal cortex as well as of the limbic-paralimbic region, including the ipsilateral subgenual cingulate, and the basal ganglia.     

Antidepressant effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebo-controlled trial

Repetitive transcranial magnetic stimulation (rTMS) has antidepressant effects in patients with major depressive disorder. The mechanisms of action and optimal stimulation parameters remain unclear. To test the hypothesis that rTMS exerts antidepressant effects either by enhancing left dorsolateral prefrontal cortex (DLPFC) excitability or by decreasing right DLPFC excitability, the authors studied 45 patients with unipolar recurrent major depressive disorder in a double-blind, randomized, parallel group, sham-controlled trial. Patients were randomized to receive 1 Hz or 10 Hz rTMS to the left DLPFC, 1 Hz to the right DLPFC or sham TMS. Left 10 Hz and right 1 Hz rTMS showed similar significant antidepressant effects. Other parameters led to no significant antidepressant effects.     

Decrease of middle cerebral artery blood flow velocity after low-frequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in a variety of neuropsychiatric disorders. Both, inhibition and activation of cortical areas may be achieved using different stimulation parameters. Using low-frequency rTMS (0.9 Hz), inhibition of cortical areas can be observed. METHODS: In the present study, 38 right-handed, healthy, normotensive subjects (aged 21-50 years, mean 30.2 years, SD=4.9; 17 women) were enrolled. Twenty-five participants received active rTMS (5 min of 0.9 Hz rTMS, stimulus intensity 90% of motor threshold) of the right dorsolateral prefrontal cortex. Sham stimulation (n=13 subjects) occurred in the same manner as active rTMS, except that the angle of the coil was at 45 degrees off the skull. Simultaneously, ipsilateral and contralateral maximal middle cerebral artery (MCA) flow velocity (and pulsatility index, PI) was monitored using transcranial Doppler sonography. RESULTS: In the group with active rTMS, maximal MCA flow velocity decreased from a baseline (before rTMS) of 101.6 cm/s (SD=26.0) to a mean of 92.6 cm/s (SD=23.7) immediately after rTMS, T=5.06, P<0.001. This equals a mean decrease of 9.0 cm/s (SD=8.3) or approximately 8.9% of baseline flow. Five and 10 min after rTMS, there was a return to baseline. PI significantly decreased 10 min after rTMS (mean difference -0.05, SD=0.05, T=2.29, P<0.05). In the contralateral MCA, maximal flow velocity tended to increase 10 min after rTMS (mean difference +7.4 cm/s, SD=17.5; T=-2.03, P=0.054). With sham rTMS, no significant changes occurred. CONCLUSIONS: The results from our study support the hypothesis that low-frequency rTMS may influence cerebral blood flow (CBF) over short periods of time, inducing a temporary decrease of maximal CBF in the ipsilateral MCA followed by an increase in the contralateral MCA.     

Release of premotor activity after repetitive transcranial magnetic stimulation of prefrontal cortex

In the present study we aimed to explore by means of repetitive transcranial magnetic stimulation (rTMS) the reciprocal influences between prefrontal cortex (PFC) and premotor cortex (PMC). Subjects were asked to observe on a computer monitor different pictures representing manipulations of different kind of tools. They had to produce a movement (go condition) or to keep the resting position (no-go condition) at the appearance of different cue signals represented by different colors shown alternatively on the hands manipulating the tools or on the picture background. Motor evoked potentials (MEPs) were collected at the offset of the visual stimuli before and after a 10 minute, 1 Hz rTMS train applied to the dorsolateral PFC (Experiment 1), to the PMC (Experiment 2) or to the primary motor cortex (Experiment 3). Following rTMS to the PFC, MEPs increased in the go condition when the cue for the go command was presented on the hand. In contrast, following rTMS to the PMC, in the same condition, MEPs were decreased. rTMS to the primary motor cortex did not produce any modulation. Results are discussed according to the presence of a visual-motor matching system in the PMC and to the role of the PFC in the attention-related processes. We hypothesize that the perceptual analysis for action selection within the PFC was modulated by rTMS and its temporary functional inactivation in turn influenced the premotor areas for motor programming.     

Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression

Objectives:  The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in bipolar depression. The present study aimed to assess the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) combined with brain navigation in a sample of bipolar depressed subjects.
Methods:  Eleven subjects with bipolar I or bipolar II disorder and major depressive episode who did not respond to previous pharmacological treatment were treated with three weeks of open-label rTMS at 1 Hz, 110% of motor threshold, 300 stimuli/day.
Results:  All subjects completed the trial showing a statistically significant improvement on the 21-item Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale, and Clinical Global Impression severity of illness scale (ANOVAs with repeated measures: F  =   22.36, p < 0.0001; F  =   12.66, p < 0.0001; and F  =   10.41, p < 0.0001, respectively). In addition, stimulation response, defined as an endpoint HAM-D score reduction of ≥50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score ≤ 8). Partial response (endpoint HAM-D score reduction between 25% and 50%) was achieved by 3/11 patients. No manic/hypomanic activation was detected during the treatment according to Young Mania Rating Scale scores (ANOVAs with repeated measures: F  =   0.62, p = 0.61). Side effects were slight and were limited to the first days of treatment.
Conclusions:  Augmentative low-frequency rTMS of the right DLPFC combined with brain navigation was effective and well tolerated in a small sample of drug-resistant bipolar depressive patients, even though the lack of a sham controlled group limits confidence in the results.     

Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia

In a double-blind, controlled study, we examined the therapeutic effects of high-frequency left prefrontal repetitive transcranial magnetic stimulation (rTMS) on schizophrenia symptoms. A total of 22 chronic hospitalized schizophrenia patients were randomly assigned to 2 weeks (10 sessions) of real or sham rTMS. rTMS was given with the following parameters: 20 trains of 5-second 10-Hz stimulation at 100 percent motor threshold, 30 seconds apart. Effects on positive and negative symptoms, self-reported symptoms, rough neuropsychological functioning, and hormones were assessed. Although there was a significant improvement in both groups in most of the symptom measures, no real differences were found between the groups. A decrease of more than 20 percent in the total PANSS score was found in 7 control subjects but only 1 subject from the real rTMS group. There was no change in hormone levels or neuropsychological functioning, measured by the MMSE, in either group. Left prefrontal rTMS (with the used parameters) seems to produce a significant nonspecific effect of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia patients.     

Daily prefrontal closed-loop repetitive transcranial magnetic stimulation (rTMS) produces progressive EEG quasi-alpha phase entrainment in depressed adults

BackgroundTranscranial magnetic stimulation (TMS) is a non-invasive neuromodulation modality that can treat depression, obsessive-compulsive disorder, or help smoking cessation. Research suggests that timing the delivery of TMS relative to an endogenous brain state may affect efficacy and short-term brain dynamics.ObjectiveTo investigate whether, for a multi-week daily treatment of repetitive TMS (rTMS), there is an effect on brain dynamics that depends on the timing of the TMS relative to individuals’ prefrontal EEG quasi-alpha rhythm (between 6 and 13 Hz).MethodWe developed a novel closed-loop system that delivers personalized EEG-triggered rTMS to patients undergoing treatment for major depressive disorder. In a double blind study, patients received daily treatments of rTMS over a period of six weeks and were randomly assigned to either a synchronized or unsynchronized treatment group, where synchronization of rTMS was to their prefrontal EEG quasi-alpha rhythm.ResultsWhen rTMS is applied over the dorsal lateral prefrontal cortex (DLPFC) and synchronized to the patient's prefrontal quasi-alpha rhythm, patients develop strong phase entrainment over a period of weeks, both over the stimulation site as well as in a subset of areas distal to the stimulation site. In addition, at the end of the course of treatment, this group's entrainment phase shifts to be closer to the phase that optimally engages the distal target, namely the anterior cingulate cortex (ACC). These entrainment effects are not observed in the group that is given rTMS without initial EEG synchronization of each TMS train.ConclusionsThe entrainment effects build over the course of days/weeks, suggesting that these effects engage neuroplastic changes which may have clinical consequences in depression or other diseases.     

Theta-patterned, frequency-modulated priming stimulation enhances low-frequency, right prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) in depression: a randomized, sham-controlled study

Efficacy of repetitive, transcranial magnetic stimulation (rTMS) has been found in depression; however, doubt still remains about its effectiveness in clinical practice. In this context, results are being explored. The authors, describing new techniques to improve response rates to rTMS treatment, compared the efficacy of adjuvant, frequency-modulated, active-priming rTMS with sham-priming stimulation in the theta range in patients with moderate-to-severe depression receiving low-frequency rTMS. Forty patients with moderate-to-severe depression (ICD-10 DCR) were alternately assigned to receive add-on, active-priming rTMS (4-8 Hz; 400 pulses, at 90% of motor threshold [MT]) or sham-priming stimulation followed by low-frequency rTMS (1-Hz; 900 pulses at 110% of MT) over the right dorsolateral prefrontal cortex. They were rated with the Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impression-Severity of Illness (CGI-S) scale at baseline, after the 5th and 10th rTMS, and 2 weeks post-rTMS. For SIGH-D scores, there was significant improvement in the active group over time. Stepwise linear-regression analysis showed that age at onset significantly predicted SIGH-D scores after the 5th rTMS session in the active-priming group. Pre-stimulation with frequency-modulated priming stimulation in the theta range has greater antidepressant effect than low-frequency stimulation alone.