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.     

Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression

Aims: Low‐frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, and its antidepressant effects have proven to correlate with decreases in cerebral blood flow (CBF) in the orbitofrontal cortex and subgenual cingulate cortex. However, a predictor of treatment response to low‐frequency right prefrontal rTMS in depression has not been identified yet. The aim of this study was to estimate regional CBF in the frontal regions and investigate the correlation with treatment response to low‐frequency right prefrontal rTMS in depression. Methods: We examined 26 depressed patients for the correlation between treatment response to rTMS and regional CBF in the frontal regions, by analyzing their brain scans with ^99mTc‐ethyl cysteinate dimer before rTMS treatment. CBF in 16 brain regions was estimated using fully automated region of interest analysis software. Two principal components were extracted from CBF in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization. Results: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions) and ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was not correlated with CBF in the dorsolateral prefrontal cortex, but it was correlated with CBF in the ventromedial prefrontal cortex. Conclusion: These findings suggest that CBF in the ventromedial prefrontal cortex may be a potential predictor of low‐frequency right prefrontal rTMS, and depressed patients with increased CBF in the ventromedial prefrontal cortex may show a better response.     

Chronic repetitive transcranial magnetic stimulation alters β-adrenergic and 5-HT2 receptor characteristics in rat brain

Repetitive transcranial magnetic stimulation (rTMS) has been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for low- and high-frequency rTMS treatment. In animal behavioral models of depression magnetic stimulation of the brain induced similar effects to those of electroconvulsive shock (ECS). In this study the effects of repeated rTMS on rat brain noradrenaline, dopamine, serotonin and their metabolites levels, as well as on β-adrenergic and 5-HT₂ receptor characteristics were studied. After 10 days of treatment, β-adrenergic receptors were significantly up regulated in the frontal cortex, down regulated in the striatum and were unchanged in the hippocampus. 5-HT₂ receptors were down regulated in the frontal cortex and were not changed in the other brain areas. No change in benzodiazepine receptors in the frontal cortex and cerebellum were demonstrated. These findings demonstrate specific and selective alterations induced by repeated rTMS, which are distinct from those induced by other antidepressant treatments. TMS therapeutic effects in humans and behavioral and biochemical effects in animal, suggest that TMS has a unique mechanism of action which requires further investigation.     

Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striatum as revealed by in vivo dialysis

We have examined the effects of schizophrenomimetic drugs including phencyclidine (PCP) and methamphetamine (MAP) on cortical and striatal dopamine (DA) metabolism using an in vivo dialysis technique in the rat. An acute systemic injection of PCP (2.5–10 mg/kg, intraperitoneally (i.p.)) dramatically increased concentrations of DA, 3,4-dihydroxy-phenylacetic acid, and homovanillic acid in the dialysates from the medial frontal cortex in a dose-dependent fashion. However, PCP (2.5–10 mg/kg, i.p.) caused a much lower augmentation of extracellular DA release, with a significant decrease in dialysate DOPAC levels in the striatum. Moreover, continuous infusion of tetrodotoxin (TTX, 10⁻⁵ M) into the prefrontal or striatal region through the microdialysis tube completely blocked the ability of PCP (10 mg/kg, i.p.) to alter the extracellular release of DA and its metabolites in the respective areas. In contrast, MAP (4.8 mg/kg, i.p.) elicited a marked and tetrodotoxin-resistant increase in DA levels with a significant loss of DOPAC contents in the extracellular space of both the frontal cortex and the striatum. The present results clearly demonstrate the differential effects of PCP on cortical and striatal DA transmission, suggesting that PCP may facilitate DA release in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the cortical area, whereas PCP-induced elevation of extracellular DA in the striatum may be caused mainly by reuptake inhibition of DA liberated by basal activity of the striatal DA neurons. The regional variation in PCP-induced DA release would be due to the combination of NMDA (N-methyl-D-aspartate) receptor blocking and DA reuptake inhibition by the drug. The uniform and TTX-resistant nature of MAP-induced changes in brain DA metabolism may result from the direct actions of MAP at DA nerve terminals. © 1996 Wiley-Liss, Inc.     

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.     

High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking

BACKGROUND: The mesolimbic dopaminergic reward system seems to play a crucial role in reinforcing effects of nicotine. Recently, acute high-frequency repetitive transcranial magnetic stimulation (rTMS) of frontal brain regions has been shown to efficiently modulate the mesostriatal and mesolimbic dopaminergic system in both animals and humans. For this reason, we investigated whether high-frequency rTMS would be able to influence nicotine-related behavior by studying rTMS effects on craving and cigarette smoking. METHOD: Fourteen treatment-seeking smokers were included in a double-blind crossover trial, conducted in 2002, comparing single days of active versus sham stimulation. Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence. RESULTS: High-frequency (20-Hz) rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly (p <.01) in an active stimulation compared with sham stimulation. Levels of craving did not change significantly. CONCLUSION: High-frequency rTMS may be useful for treatment in smoking cessation.     

Motor cortex stimulation for Parkinson's disease and dystonia: lessons from transcranial magnetic stimulation? A review of the literature

INTRODUCTION: Over the last few years, deep brain stimulation techniques, with targets such as the subthalamic nucleus or the pallidum, have bee found to be beneficial in the treatment of Parkinson's disease and dystonia. Conversely, therapeutic strategies of cortical stimulation have not yet been validated in these diseases, although they are known to be associated with various cortical dysfunctions. Transcranial magnetic stimulation (TMS) is a valuable tool for non-invasive study of the role played by the motor cortex in the pathophysiology of movement disorders, in particular by assessing various cortical excitability determinants using single or paired pulse paradigms. In addition, repetitive TMS (rTMS) trains can be used to study the effects of transient activity changes of a targeted cortical area. BACKGROUND: Studies with TMS revealed significant motor cortex excitability changes, particularly regarding intracortical inhibitory pathways, both in Parkinson's disease and in dystonia, and these changes can be distinguished owing to the resting state or to the phases of movement preparation or execution. However, more specific correlation between electrophysiological features and clinical symptoms remains to be established. In addition, the stimulation of various cortical targets by rTMS protocols applied at low or high frequencies have induced some clear clinical effects. PERSPECTIVES: The TMS effects are and will remain applied in movement disorders to better understand the role played by the motor cortex, to assess various types of treatment and appraise the therapeutic potential of cortical stimulation. CONCLUSION: TMS provides evidence for motor cortex dysfunction in Parkinson's disease or dystonia. Moreover, rTMS results have opened new perspectives for therapeutic strategies of implanted cortical stimulation. By these both aspects, TMS techniques show their usefulness in the assessment of movement disorders.     

Effects of successive repetitive transcranial magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinson's disease

We studied the effects of 0.2 Hz repetitive transcranial magnetic stimulation (rTMS) successively performed 6 times for 2 weeks in 12 patients with idiopathic Parkinson's disease (PD). Ten patients received rTMS to the bilateral frontal cortex (frontal rTMS) and six patients received rTMS to the bilateral occipital cortex (occipital rTMS). Before and after rTMS, we evaluated regional cerebral blood flow (rCBF) using 99m-Tc-ECD single photon emission computed tomography (SPECT) and clinical tests.In an analysis with statistic parametric mapping, both frontal and occipital rTMS reduced rCBF in the cortical areas around the stimulated site. The activities of daily living (ADL) and motor scores of Unified Parkinson's Disease Rating Scale (UPDRS), pronation-supination movements, and buttoning up significantly improved after frontal rTMS than before it, while occipital rTMS had no significant effects in clinical tests.The findings of the present study suggest that successive 0.2 Hz rTMS has outlasting inhibitory effects on neuronal activity around the stimulated cortical areas. Because there were no significant relations between improved clinical tests and reduced rCBF, we speculate that the indirect effects of 0.2 Hz rTMS on subcortical structures are related to improved parkinsonian symptoms. Further studies recruiting large numbers of subjects are required to confirm the efficacy of 0.2 Hz rTMS on PD.     

Functional lesions and human action monitoring: combining repetitive transcranial magnetic stimulation and event-related brain potentials.

OBJECTIVE: Electrophysiological recordings of the error-related negativity (ERN) and functional imaging data point to an involvement of medial frontal cortex (including the anterior cingulate cortex, ACC) and dorsolateral prefrontal cortex (DLPFC) in the detection and correction of performance errors. Here, we studied this network by applying trains of rapid transcranial magnetic stimulation (rTMS) prior to the recording of the ERN. METHODS: Low-frequency (0.9 Hz) rTMS was applied to medial frontal or lateral frontal regions (different sessions) for 60 s immediately before each 3 min ERN recording in 11 healthy young subjects. The ERN was obtained by multichannel recordings in a typical Eriksen flanker task with instructions calling for immediate error correction in case a performance error was detected by the subject. Event-related potentials were quantified and statistically evaluated using standard methodology. RESULTS: Compared to a no-stimulation control condition, medial frontal stimulation led to a small but reliable decrease in the number of corrected errors as well as to an attenuation of the ERN and an increase of the subsequent error-positivity (Pe). No effect on these components was seen after lateral frontal stimulation. No reliable effects on the lateralized readiness potential were observed. CONCLUSIONS: Functional lesions by rTMS appear to interfere with the functions of the medial frontal cortex in error detection and correction.     

Isatin, an endogenous MAO inhibitor, and a rat model of Parkinson's disease induced by the Japanese encephalitis virus

A single dose of isatin (indole-2,3-dione)(i.p.), an endogenous MAO inhibitor, significantly increased norepinephrine and 5-hydroxytryptamine concentrations in the rat brain and also significantly increased acetylcholine and dopamine (DA) levels in the rat striatum. Urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. We have developed a rat model of Parkinson's disease induced by the Japanese encephalitis virus (JEV). The distribution of the pathological lesions of JEV-rats resemble those found in Parkinson's disease. Significant behavioral improvement was observed in JEV-rats after isatin, L-DOPA and selegiline administration using a pole test. Both isatin and selegiline prevented the decrease in striatum DA levels of JEV-rats. The increased turnover of DA (DOPAC/DA) induced by JEV was significantly inhibited by isatin, but not selegiline. These findings suggest that JEV-infected rats may serve as a model of Parkinson's disease and that exogenously administered isatin and selegiline can improve JEV-induced parkinsonism by increasing DA concentrations in the striatum.     

Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain

Using intracerebral microdialysis in urethane-anaesthetized adult male Wistar rats, we monitored the effects of acute repetitive transcranial magnetic stimulation (rTMS; 20 trains of 20 Hz, 2.5 s) on the intrahypothalamic release of arginine vasopressin (AVP) and selected amino acids (glutamate, glutamine, aspartate, serine, arginine, taurine, gamma-aminobutyric acid) and the intrahippocampal release of monoamines (dopamine, noradrenaline, serotonin) and their metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid). The stimulation parameters were adjusted according to the results of accurate computer reconstructions of the current density distributions induced by rTMS in the rat and human brains, ensuring similar stimulation patterns in both cases. There was a continuous reduction in AVP release of up to 50% within the hypothalamic paraventricular nucleus in response to rTMS. In contrast, the release of taurine, aspartate and serine was selectively stimulated within this nucleus by rTMS. Furthermore, in the dorsal hippocampus the extracellular concentration of dopamine was elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a differentiated modulatory effect on selected neurotransmitter/neuromodulator systems in distinct brain areas.     

Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinson's disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. METHODS: We used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. RESULTS: rTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. CONCLUSIONS: Our results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.     

Effect of Some Psychoactive Drugs Used as ‘Legal Highs’ on Brain Neurotransmitters

New psychoactive “designer drugs” are synthetic compounds developed to provide similar effects to illicit drugs of abuse, but not subjected to legal control. The rapidly changing legal status of novel psychoactive drugs triggers the development of new compounds, analogs of well-known amphetamine or mescaline. New designer drugs used as substitutes in ecstasy pills are the least investigated and can cause life-threatening effects on users. The aim of our research was to examine the effects of acute administration of 4-methoxyamphetamine (PMA, 5 and 10 mg/kg), 4-methoxy-N-methylamphetamine (PMMA, 5 and 10 mg/kg), and mephedrone (MEPH, 5, 10 and 20 mg/kg) on extracellular and tissue level of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in rat brain, by microdialysis method in freely moving animals and HPLC. Similarly to 3,4-methylenedioxymethamphetamine (MDMA, 5 and 10 mg/kg) PMA, PMMA and MEPH enhanced the release of DA and 5-HT in rat striatum, nucleus accumbens, and frontal cortex. DA tissue content was increased by MEPH and PMMA in striatum, by MEPH, PMA, and PMMA in nucleus accumbens, and by PMA in frontal cortex. Instead, cortical DA level was decreased by MEPH and PMMA. MEPH did not influence 5-HT tissue level in striatum and nucleus accumbens, but decreased its level in frontal cortex. PMMA increased 5-HT content in striatum, while PMA enhanced it in nucleus accumbens and frontal cortex. Observed changes in brain monoamines and their metabolites by new psychoactive drugs suggest that these drugs may be capable of development of dependence. Further experiments are needed to fully investigate the neurotoxic and abuse potential of those drugs.     

Effect of repetitive transcranial magnetic stimulation on the cognitive impairment induced by sleep deprivation: a randomized trial

ObjectiveCurrently, an efficient method for improving cognitive impairment due to sleep deprivation (SD) is lacking. The aim of this study is to evaluate the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) during SD on reversing the adverse effects of SD.MethodsA total of 66 healthy people were randomized into the rTMS group and sham group. Both groups were deprived of sleep for 24 h. During SD, participants were asked to complete several cognitive tasks and underwent mood assessments. Saliva cortisol levels, plasma concentrations of brain-derived neurotrophic factor (BDNF), precursor BDNF (proBDNF), and tissue-type plasminogen activator (tPA), and frontal blood activation were detected before and after SD. The rTMS group received real rTMS stimulation for 2 sessions of 10 Hz rTMS (40 trains of 50 pulses with a 20-second intertrain interval) to the left dorsolateral prefrontal cortex and the sham group received sham stimulation during SD.ResultsTwenty-four hours of SD induced a reduced accuracy in the n-back task, increases in both anxiety and depression, increased cortisol levels, decreased frontal blood activation and decreased BDNF levels in healthy people. Notably, rTMS improved the hyperactivity of the hypothalamic-pituitary-adrenal axis and decreased frontal blood activation induced by SD, and reduced the consumption of plasma proBDNF.ConclusionsTwenty-four hours of SD induced a cognitive impairment. The administration of high-frequency rTMS during sleep deprivation exerted positive effects on HPA axis and frontal activation and might help alleviate cognitive impairment in the long term.     

Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

Impairment of executive performance after transcranial magnetic modulation of the left dorsal frontal‐striatal circuit

The dorsal frontal‐striatal circuit is implicated in executive functions, such as planning. The Tower of London task, a planning task, in combination with off‐line low‐frequency repetitive transcranial magnetic stimulation (rTMS), was used to investigate whether interfering with dorsolateral prefrontal function would modulate executive performance, mimicking dorsal frontal‐striatal dysfunction as found in neuropsychiatric disorders. Eleven healthy controls (seven females; mean age 25.5 years) were entered in a cross‐over design: two single‐session treatments of low‐frequency (1 Hz) rTMS (vs. sham rTMS) for 20 min on the left dorsolateral prefrontal cortex (DLPFC). Directly following the off‐line rTMS treatment, the Tower of London task was performed during MRI measurements. The low‐frequency rTMS treatment impaired performance, but only when the subjects had not performed the task before: we found a TMS condition‐by‐order effect, such that real TMS treatment in the first session led to significantly more errors (P = 0.032), whereas this TMS effect was not present in subjects who received real TMS in the second session. At the neural level, rTMS resulted in decreased activation during the rTMS versus sham condition in prefrontal brain regions (i.e., premotor, dorsolateral prefrontal and anterior prefrontal cortices) and visuospatial brain regions (i.e., precuneus/cuneus and inferior parietal cortex). The results show that low‐frequency off‐line rTMS on the DLPFC resulted in decreased task‐related activations in the frontal and visuospatial regions during the performance of the Tower of London task, with a behavioral effect only when task experience is limited. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity

Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5-hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity.     

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation

Transcranial magnetic stimulation has evolved into a powerful neuroscientific tool allowing to interfere transiently with specific brain functions. In addition, repetitive TMS (rTMS) has long-term effects (e.g. on mood), probably mediated by neurochemical alterations. While long-term safety of rTMS with regard to cognitive functioning is well established from trials exploring its therapeutic efficacy, little is known on whether rTMS can induce changes in cognitive functioning in a time window ranging from minutes to hours, a time in which neurochemical effects correlated with stimulation have been demonstrated. This study examined effects of rTMS on three measures of executive function in healthy subjects who received one single rTMS session (40 trains of 2 s duration 20 Hz stimuli) at the left dorsolateral prefrontal cortex (DLPFC). Compared to a sham condition one week apart, divided attention performance was significantly impaired about 30-60 min after rTMS, while Stroop-interference and performance in the Wisconsin Card Sorting Test was unaffected after rTMS. Repetitive TMS of the left DLPFC, at stimulation parameters used in therapeutic studies, does not lead to a clinically relevant impairment of executive function after stimulation. However, the significant effect on divided attention suggests that cognitive effects of rTMS are not limited to the of acute stimulation, and may possibly reflect known neurochemical alterations induced by rTMS. Sensitive cognitive measures may be useful to trace those short-term effects of rTMS non-invasively in humans.     

Acute modulation of cortical oscillatory activities during short trains of high-frequency repetitive transcranial magnetic stimulation of the human motor cortex: a combined EEG and TMS study

In this study, a combined repetitive transcranial magnetic stimulation/electroencephalography (rTMS/EEG) method was used to explore the acute changes of cortical oscillatory activity induced by intermittent short trains of high-frequency (5-Hz) rTMS delivered over the left primary motor cortex (M1). We evaluated the electrophysiological reaction to magnetic stimulation during and 2-4 s after 20 trains of 20-pulses rTMS, using event-related power (ERPow) that reflects the regional oscillatory activity of neural assemblies, and event-related coherence (ERCoh) that reflects the interregional functional connectivity of oscillatory neural activity. These event-related transformations were for the upper alpha (10-12 Hz) and beta (18-22 Hz) frequency ranges, respectively. For the alpha band, threshold rTMS and subthreshold rTMS induced an ERPow increase during the trains of stimulation mainly in frontal and central regions ipsilateral to stimulation. For the beta band, a similar synchronization of cortical oscillations for both rTMS intensities was seen. Moreover, subthreshold rTMS affected alpha-band activity more than threshold rTMS, inducing a specific ERCoh decrease over the posterior regions during the trains of stimulation. For beta band, the decrease in functional coupling was observed mainly during threshold rTMS. These findings provide a better understanding of the cortical effects of high-frequency rTMS, whereby the induction of oscillations reflects the capacity of electromagnetic pulses to alter regional and interregional synaptic transmissions of neural populations.     

High-frequency rTMS improves time perception in Parkinson disease

Patients with Parkinson disease (PD) are impaired in time processing. The authors investigated the effects of high-frequency (5 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with PD performing a time reproduction task. The authors found significant improvement in time processing induced by rTMS when trains were applied over the right dorsolateral prefrontal cortex (DLPFC) but not over the supplementary motor area, suggesting that the circuit involving the basal ganglia and the DLPFC might constitute the neural network subserving time perception.