Chronic rTMS Research Articles

RTMS of Motor Cortex Diminishes Gains in Maximal Voluntary Force

Repetitive transcranial magnetic stimulation (rTMS) of the human primary motor cortex (M1) at 1 Hz interferes with the acute consolidation of motor memory without affecting motor performance (Muellbacher et al. Nature 415:640, 2002). It is however unclear if the human M1 plays a role in chronic adaptations associated with exercise intended to increase maximal voluntary force (MVC). PURPOSE: To determine if 1 Hz rTMS of the human M1 affects gains in maximal voluntary force following strength training. METHODS: Healthy volunteers performed 5 bouts of 10 repetitions of index finger abduction at an intensity of 70% MVC in each of the 10 sessions over 3 weeks (VOL, n = 13). Subjects in VOL+rTMS (n = 8) also exercised but in the 1-minute-long inter-bout rest interval received 1 Hz rTMS at 120% of the resting motor threshold (rMT) targeting the M1 area of the first dorsal interosseus (FDI) (60 pulses, 5 times in a session for 10 sessions, 3,000 pulses total). The rTMS group received only 5 bouts of rTMS in 10 sessions and did not exercise (n = 8). VOL+sham RTMs (n = 6) exercised as did VOL and received sham rTMS to M1 from a coil turned perpendicular relative to M1. RESULTS: The Group by Time interaction was significant (F = 7.2, p = 0.0001) and the Tukey post-hoc contrast revealed that VOL and VOL+sham rTMS, respectively, increased MVC 39% (±19 SD) and 33% (±16). These increases were more (p < 0.05) than the 19% (±15) in VOL+rTMS, the 2% (±10) in rTMS. MVC did not change in a control muscle, the left abductor digiti minimi. rMT remained stable. There were no side effects due to chronic rTMS in these healthy volunteers. CONCLUSION: The human motor cortex may play a role in mediating neural adaptations to strength training.

Sex differences in antidepressant-like effect of chronic repetitive transcranial magnetic stimulation in rats

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurophysiological technique. Pre-clinical and clinical studies supported that rTMS might have antidepressant effects. However, whether antidepressant effect of chronic rTMS is gender-dependent is still unknown. In this study, male and female Wistar rats received 10-day rTMS (4 trains of 15 Hz; 200 stimuli/day; 1.0 T) or control condition, and then were subjected to the forced-swim test (FST). We found that female rats consistently showed higher activity levels than males in FST and revealed the significant effects of gender and rTMS as well as the interaction of gender and rTMS. The result suggested the antidepressant-like effects of chronic rTMS on behavioral components in FST are gender-dependent. The gender discrepancy related to rTMS should not be neglected in antidepressant treatment of rTMS.

Effects of repetitive transcranial magnetic stimulation on [ 11C]raclopride binding and cognitive function in patients with depression

Background Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [ 11C]raclopride. Methods Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [ 11C]raclopride PET scans and neuropsychological tests — before rTMS and 1 day after rTMS. Results In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [ 11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment. Limitations Our sample size was limited, and our study was an open trial lacking sham-treated controls. Conclusion This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [ 11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

The effect of repetitive transcranial magnetic stimulation on dystonia: a clinical and pathophysiological approach

Dystonia is characterized by sustained muscle contraction, which frequently causes repetitive, twisting movements or abnormal posture. The precise pathophysiological mechanisms of dystonia are still unknown. Several studies did demonstrate that, although motor cortex hyperexcitability appears to be responsible for abnormal co-contraction and overflow to adjacent muscles, plasticity mechanisms and integrative sensorimotor processing are also likely to be involved in this condition. Current dystonia treatments are based on oral medication, injection of botulinum toxin and, in a low proportion of cases, bi-pallidal deep brain stimulation. However, treatment outcome is generally disappointing. A few researchers have reported the application of repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex or the premotor cortex, with the goal of decreasing motor cortex hyperexcitability. This article reviews all studies using this technique in dystonia and discusses rTMS therapeutic impact and its possible mechanisms of action in this indication. Currently, the premotor cortex seems to be the best target for rTMS in dystonia. Rather than merely reducing the hyperexcitability of the primary motor cortex, this technique's clinical benefit seems to result from modifications in plasticity and restoration of sensorimotor integration. The corollary technique for chronic rTMS is electrical cortical stimulation. Even though this new therapeutic tool may have therapeutic promise, more studies are required to confirm it. In particular, we need to broaden our knowledge of rTMS impact on the various forms of dystonia and to optimize target localization.

Anxiolytic suppression of repetitive transcranial magnetic stimulation-induced anxiety in the rats

Repetitive transcranial magnetic stimulation (rTMS) is effective for treatment of several psychiatric disorders such as depression and anxiety disorder. However, some reports suggest that rTMS induced anxiety in normal volunteers. Consistent with this observation, we have reported that chronic rTMS induces anxiety in normal rats which was suppressed by chronic treatment, but not acute paroxetine treatment. The current study evaluates rTMS as animal model of anxiety by investigating the effect of rTMS on anxiety behaviors and the ability of standard anxiolytics to block expression of these behaviors. We found that 10-day rTMS induced anxiety in normal rats, as evidenced by expression of anxiety behaviors in the elevated plus-maze. This anxiety was suppressed by acute treatment with diazepam, alprazolam, or buspirone suggesting that chronic rTMS treatment provides a good animal model for anxiety.

Modulation of monoamine transporter expression and function by repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a new tool for the treatment of neuropsychiatric disorders. However, the mechanisms underlying the effects of rTMS are still unclear. In this study, we analyzed mRNA expression changes of monoamine transporter (MAT) genes, which are targets for antidepressants and psychostimulants. Following a 20-day rTMS treatment, these genes were found to be differentially expressed in the mouse brain. Down-regulation of serotonin transporter (SERT) mRNA levels and the subsequent decrease in serotonin uptake and binding were observed after chronic rTMS. In contrast to the SERT changes, increased mRNA levels of dopamine transporter (DAT) and norepinephrine transporter (NET) were observed. For NET, but not DAT, there were accompanying changes in uptake and binding. Similar effect on NET was observed in PC12 cells stimulated by rTMS for 15 days. These results indicate that modulation of MATs by chronic rTMS may be one therapeutic mechanism for the treatment of neuropsychiatric disorders.

Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial?

Objective Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate neurotransmission. The aim of this preliminary study was to investigate whether rTMS of the motor cortex at low (1 Hz) or high (20 Hz) frequencies can have any beneficial effect in a transgenic rat model of amyotrophic lateral sclerosis (ALS) and in a few patients with ALS. Methods The effects of chronic rTMS were evaluated in 20 transgenic rats overexpressing the human G93A mutant superoxide dismutase 1 gene. Several cycles of rTMS were also performed in 4 ALS patients and the rate of progression of the disease before and during rTMS treatment was compared. Results No effects of rTMS was observed in transgenic rats. The rTMS treatment was well tolerated by the patients. All ALS patients continued to deteriorate. However, in the patients exposed to low-frequency rTMS the rate of progression during treatment was slightly slower than that evaluated before treatment; an opposite tendency was observed in patients exposed to high frequencies. Conclusions Though we cannot be sure whether the effects observed in the patients can be attributed to rTMS, further investigation using low-frequency motor cortex stimulation on a larger group of ALS patients is warranted. Significance The results of the pilot study in humans might open up a new therapeutic perspective in ALS based on neuromodulation.

Chronic rTMS induces subsensitivity of post-synaptic 5-HT1A receptors in rat hypothalamus.

Chronic administration of several antidepressants, notably the selective serotonin re-uptake inhibitors (SSRIs) induces sub-sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus. Chronic repetitive transcranial magnetic stimulation (rTMS) is a form of treatment for depression which is often compared to electroconvulsive shock therapy (ECT). rTMS was applied to rats either on a single occasion (acute) or daily for 8 d (chronic). Twenty-four hours after the last treatment, the rats were injected with saline or 8-OH-DPAT (50 microg/kg). The rats were killed 20 min later and trunk blood taken for measurement of corticosterone and ACTH levels. Chronic rTMS did not affect basal corticosterone or ACTH levels but significantly blunted the responses to 8-OH-DPAT, while acute rTMS had no effect on either basal or 8-OH-DPAT-stimulated responses. In common with several other antidepressant treatments, chronic rTMS reduces the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus. This effect may be significant in relation to the therapeutic mechanism of rTMS.

Effects of repetitive transcranial magnetic stimulation on behavioral and neurochemical changes in rats during an elevated plus-maze test

In transcranial magnetic stimulation (TMS) the regional electrical activity in the brain is influenced by a pulsed magnetic field. The rapidly changed magnetic field produces electrical currents that activate neurons. Repetitive TMS (rTMS) treatment can cause functional changes in the cortex. The present study clarified the effects of rTMS treatment on behavioral changes in rats, focusing on anxiety by using an elevated plus-maze (plus-maze) test. The effects of rTMS treatment on neurochemical changes during the plus-maze test were investigated by determining the extracellular levels of serotonin (5-HT) and dopamine (DA) in the prefrontal cortex by using in vivo microdialysis. Each rat received rTMS of the frontal brain for 3 days, during which 125 stimuli from five trains in a day were applied at 25 Hz for 1 s with 2-min intervals between trains. Three-day series of (chronic) rTMS treatment caused significant increases in the time spent in open arms and the number of entries into open arms of the plus-maze compared with non-treated and sham-treated rats, which were not observed in 1-day series of (acute) rTMS treatment. Chronic rTMS treatment suppressed the increases in 5-HT levels induced by the plus-maze test, but did not influence the elicited DA levels. These data suggest that chronic rTMS treatment of the frontal brain has anxiolytic effects in rats, which are related to the 5-HTergic neuronal system.

Safety aspects of chronic low-frequency transcranial magnetic stimulation based on localized proton magnetic resonance spectroscopy and histology of the rat brain

Because repetitive transcranial magnetic stimulation (rTMS) is capable of inducing lasting alterations of cortical excitability, it represents a promising therapeutic tool in several neuropsychiatric disorders. However, rTMS, especially when applied chronically, may cause harmful effects in the stimulated tissue. To study the safety of chronic rTMS we used a novel small stimulation coil, which was specially designed to treat rats, and investigated brain tissue using in vivo localized proton magnetic resonance spectroscopy (MRS) and post mortem histological analysis. Histology was based on a modified stereology method in combination with immunohistochemistry applying antibodies against OX-6, OX-42, ED, and GFAP to detect any microglial and/or astrocytic activation 48 h after the last TMS session. Conscious rats were treated with a daily suprathreshold rTMS regimen of 1000 stimuli applied on 5 consecutive days at a frequency of 1 Hz. In comparison with control animals receiving magnetic stimulation over the lumbar spine, quantitative evaluations of cerebral metabolite concentrations by proton MRS revealed no significant alterations of N-acetyl-aspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, glucose and lactate after chronic rTMS. Similarly to the in vivo results, post mortem histology revealed no changes in microglial and astrocytic activation after rTMS. In conclusion, these data provide support for the safety of chronic rTMS. However, they do not exclude acute changes on neurotransmitters systems or other physiologic responses during or directly after the rTMS treatment.

Anxiety induced by repetitive transcranial magnetic stimulation is suppressed by chronic treatment of paroxetine in rats.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to have a therapeutic effect on affective disorder and anxiety disorders. However, some reports have linked rTMS to a significant increase in anxiety in normal volunteers. This study investigates the effect of rTMS on anxiety and the use of acute and chronic paroxetine treatment on this animal model of anxiety. In normal rats, rTMS for 10 days induced anxiety, as shown by elevated plus maze, black and white box, and conditioned fear tests. This anxiety was suppressed by chronic, but not acute, paroxetine. These results suggest that rats receiving chronic rTMS treatment can be used as a model of anxiety and that the anxiety induced by rTMS might involve the serotonergic system.

Effect of repetitive transcranial magnetic stimulation on forced swimming test

Repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) have been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for rTMS and electroconvulsive therapy (ECT). The present experiment, aimed at comparing the effects of ECS and rTMS in rats, employed one test used for screening of antidepressant activity: the forced swimming test (FST). In this study, the authors investigated whether chronic rTMS influenced active behavior in the rat FST, similar to ECS. Male Wistar rats received rTMS treatment daily, for 10 days as is commonly used for ECT treatment. Control rats received sham treatment by placing the stimulation coil in a perpendicular position to the rat's head. Passing a current through earclip electrodes for 1 s induced ECS. The control animals were treated identically, but current was not applied. The FST was carried out 24 h after the last rTMS or ECS. The immobility time in the FST was not significantly affected by rTMS and ECS for 1 day. The immobility time in the FST was significantly shortened at rTMS and ECS for 10 days. Chronic treatment with rTMS, similar to chronic treatment with ECS, decreased the immobility time in the FST. These results indicate that chronic treatment with rTMS might have antidepressant effect similar to chronic treatment with ECS.

Chronic repetitive transcranial magnetic stimulation induces subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain

Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effective in the treatment of major depression. We administered rTMS chronically to rats in order to determine whether this procedure affected serotonergic neurotransmission in the prefrontal cortex. Basal 5-HT levels, and the effects of challenges with the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1B antagonist GR 127935 on 5-HT levels were determined using in vivo microdialysis. Rats which had undergone chronic rTMS showed reduced responses to both challenges, indicating subsensitivity of both the presynaptic 5-HT1A autoreceptors situated somatodendritically in the raphe nuclei and the 5-HT1B autoreceptors situated on nerve terminals. Since such subsensitivity has been demonstrated after other antidepressant treatments, our results indicate that these treatments and rTMS may have a common mechanism of action.

Repetitive transcranial magnetic stimulation induces active coping strategies and attenuates the neuroendocrine stress response in rats

The effects of repetitive transcranial magnetic stimulation (rTMS) on various brain functions were investigated in adult male Wistar rats. The stimulation parameters were adjusted according to the results of accurate computer-assisted, magnetic resonance imaging-based reconstructions of the current density distributions induced by rTMS in the rat and human brain, ensuring comparable stimulation patterns in both cases. The animals were subjected to daily rTMS-treatment (three trains of 20 Hz; 2.5 s) for 8 weeks from the age of 4 weeks on. In the forced swim test these rats showed a more active stress coping strategy than the control rats. This was accompanied by a significantly attenuated stress-induced elevation of plasma ACTH concentrations. Pituitary changes accounting for the attenuation were ruled out by the corticotropin-releasing hormone test. Baseline concentrations of ACTH and corticosterone were indistinguishable in the two groups. No changes were found in the anxiety-related behavior of the rats on the elevated plus-maze or in behavior during the social interaction test. Accordingly, the binding characteristics of the benzodiazepine agonist [ 3H]flunitrazepam at the benzodiazepine/γ-aminobutyric acid type A receptor complex were similar in the rTMS and control groups. In summary, chronic rTMS treatment of frontal brain regions in rats resulted in a change in coping strategy that was accompanied by an attenuated neuroendocrine response to stress, thus revealing parallels to the effects of antidepressant drug treatment.

Chronic repetitive transcranial magnetic stimulation enhances c-fos in the parietal cortex and hippocampus

Repetitive transcranial magnetic stimulation (rTMS) is a novel non-invasive method with anti-depressant properties. However, the mechanism of activation on the cellular level is unknown. Twelve hours after the last chronic rTMS treatment (14 days, once per day, 20 Hz, 10 s, 75% machine output, the transcription factor c-fos was markedly increased in neurons in layers I–IV and VI of the parietal cortex and in few scattered neurons in the hippocampus of Sprague–Dawley rats. The cortical activation was not blocked by the NMDA antagonist MK-801. The increase of c-fos was not paralleled by an increased glial response and activation of cortical growth factors. Thus, it is concluded that chronic rTMS differentially activates parietal cortical layers and this might be involved in mediating anti-depressant activity in other brain areas.

Chronic treatment with repetitive transcranial magnetic stimulation inhibits seizure induction by electroconvulsive shock in rats

Background: Studies in laboratory animals suggest that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) increase seizure inhibition acutely. This study was designed to explore whether chronic rTMS would also have seizure inhibition properties. Methods: To this purpose we administered rTMS (Magstim Rapid) and sham rTMS twice daily (2.5 T, 4-sec train duration, 20 Hz) to two groups of 10 rats for 16 days. The rTMS coil was a 50-mm figure-8 coil held directly over the rat’s head. Raters were blind to experimental groups. On days 11, 17, and 21 (5 days after the last rTMS) ECS was administered with a Siemens convulsator using three electrical charge levels. Variables examined were the presence or absence of seizures and seizure length (measured from the initiation of the tonic contraction until the end of the limb movement). Results: At day 11 rTMS had no effect on seizures, and both rTMS and sham rTMS animals convulsed equally. At day 17, however, rTMS-treated animals convulsed significantly less (both at presence/absence of seizures, and at seizure length) than sham rTMS animals. At day 21 the effects of rTMS had disappeared. Conclusions: These findings suggest that rTMS administered chronically leads to changes in seizure threshold similar to those reported for ECS and ECT; however, these effects were short-lived.

Transcranial magnetic stimulation induces alteration in brain monoamines and β-adrenergic receptor levels

The effects of repetitive transcranial magnetic stimulation (rTMS) on various brain functions were investigated in adult male Wistar rats. The stimulation parameters were adjusted according to the results of accurate computer-assisted, magnetic resonance imaging-based reconstructions of the current density distributions induced by rTMS in the rat and human brain, ensuring comparable stimulation patterns in both cases. The animals were subjected to daily rTMS-treatment (three trains of 20 Hz; 2.5 s) for 8 weeks from the age of 4 weeks on. In the forced swim test these rats showed a more active stress coping strategy than the control rats. This was accompanied by a significantly attenuated stress-induced elevation of plasma ACTH concentrations. Pituitary changes accounting for the attenuation were ruled out by the corticotropin-releasing hormone test. Baseline concentrations of ACTH and corticosterone were indistinguishable in the two groups. No changes were found in the anxiety-related behavior of the rats on the elevated plus-maze or in behavior during the social interaction test. Accordingly, the binding characteristics of the benzodiazepine agonist [3H]flunitrazepam at the benzodiazepine/γ-aminobutyric acid type A receptor complex were similar in the rTMS and control groups. In summary, chronic rTMS treatment of frontal brain regions in rats resulted in a change in coping strategy that was accompanied by an attenuated neuroendocrine response to stress, thus revealing parallels to the effects of antidepressant drug treatment.