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Electroconvulsive therapy (ECT) was applied for the first time in humans in 1938: after 80 years, it remains conceptually similar today except for modifications of the original protocol aimed to reduce adverse effects (as persistent memory deficits) without losing clinical efficacy. We illustrate the stages of development as well as ups and downs of ECT use in the last eighty years, and the impact that it still maintains for treatment of certain psychiatric conditions. Targeted, individualized and safe noninvasive neuromodulatory interventions are now possible for many neuropsychiatric disorders thanks to repetitive transcranial magnetic stimulation (rTMS) that injects currents in the brain through electromagnetic induction, powerful enough to depolarize cortical neurons and related networks. Although ECT and rTMS differ in basic concepts, mechanisms, tolerability, side effects and acceptability, and beyond their conceptual remoteness (ECT) or proximity (rTMS) to "precision medicine" approaches, the two brain stimulation techniques may be considered as complementary rather than competing in the current treatment of certain neuropsychiatric disorders., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PMR and RDI do not have potential conflicts of interest to be disclosed. SR is consultant for the Neurocare Italy Group., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines., Competing Interests: Declaration of Competing Interest The content of this manuscript is solely theresponsibility of the authors and does not necessarily represent the official views of any of the institutions involved or any of the funding agencies and bodies. Peter J. Fried has nothing to disclose with regard to this manuscript. Emiliano Santarnecchi serves on the scientific advisory boards for Neuroelectrics, EBNeuro and Neurocare. He is listed as an inventor on several issued and pending patents on the application of noninvasive brain stimulation in patients with dementia and brain tumors. Andrea Antal serves as a paid consultant for NeuroConn, Ilmenau, Germany and Savir GmbH, Magdeburg, Germany. She is supported by the State of Lower Saxony, Germany (76251-12-7/19 (ZN 3456)). David Bartres-Faz has nothing to disclose with regard to this manuscript. Sven Bestmann has nothing to disclose with regard to this manuscript. Linda L. Carpenter is supportedby the National Institute of General Medical Sciencesof the National Institutes of Health under Award Number P20GM130452 (Core Resources of the Butler Hospital COBRE Center for Neuromodulation). She has received consulting income from Neuronetics, Nexstim, Janssen, AffectNeuro, and Sage Therapeutics. She has research support from Neuronetics, Neosync, AffectNeuro, and Nexstim. Pablo Celnik has nothing to disclose with regard to this manuscript. Dylan Edwards has nothing to disclose with regard to this manuscript. Faranak Farzan has nothing to disclose with regard to this manuscript. Shirley Fecteau is a deputy editor of Brain Stimulation and an editor of Scientific Reports.She is regular faculty of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education. Mark S. George is an unpaid consultant to Brainsway, Neuronetics, and Magstim. He has received loaned equipment or research grants from Mecta, Brainsway, Magstim, Magventure. He is a paid consultant to Neuralief. He does not own equity in any device company. He is the editor in chief of Brain Stimulation, with a stipend from Elsevier. Bin He has nothing to disclose with regard to this manuscript. Yun-Hee Kim has nothing to disclose with regard to this manuscript. Letizia Leocani is currently shortlisted for the European Commission expert panel on Medical Devices and in vitro diagnostic medical devices for Neurology. Sarah H. Lisanby is inventor on a patent for TMS technology, unrelated to the topic presented here, with no royalties.The opinions expressed in this article are the authors’ own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Colleen Loo has received competitive grant funding from the Australian National Health and Medical Research Council for brain stimulation research. Bruce Luber has nothing to disclose with regard to this manuscript. Michael A. Nitsche serves on the scientific advisory boards for Neuroelectrics and NeuroDevice. Walter Paulus serves as a member of the scientific advisory board of Precisis AG. Simone Rossi serves as a consultant for EB-Neuro and Neurocare Italy group. Paolo M. Rossini has nothing to disclose with regard to this manuscript. John Rothwell has nothing to disclose with regard to this manuscript. Alexander T. Sack serves as head of the scientific advisory board for AlphaSys Brain Technologies BV. He is founder of Neurowear Medical BV, and Director of the European Clinical TMS Certification Course (www.tmscourse.eu). Gregor Thut serves as a Section Editor for European Journal of Neuroscience and Brain Topography and as an Associate Editor for several Frontiers journals (Brain Imaging and Stimulation, Consciousness Research, Perception Science). Yoshikazu Ugawa has nothing to disclose with regard to this manuscript. Ulf Ziemann has received grants from European Research Council (ERC), German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Ministry of Research and Arts of the Federal State of Baden-Würrtemberg (MWK), Bristol Myers Squibb, Janssen Pharmaceutica NV, Servier, Biogen Idec GmbH, and personal fees from Bayer Vital GmbH, Pfizer GmbH, CorTec GmbH, all not related to this work. Mark Hallett was supported by the NINDS Intramural Program. He is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the Medical Advisory Boards of CALA Health and Brainsway. He has research grants from Allergan for studies of methods to inject botulinum toxins, Medtronic, Inc. for a study of DBS for dystonia, and CALA Health for studies of a device to suppress tremor. Alvaro Pascual-Leone serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim, Magventure, MedRhythms, and Cognito. He listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and novel methods for transcranial electric stimulation. He is co-founder of Linus Health and TI Solutions A.G. He serves as associate editor for Annals of Neurology. He is co-director of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education., (Copyright © 2020. Published by Elsevier B.V.)

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The goal of this review is to show how transcranial magnetic stimulation (TMS) techniques can make a contribution to the study of brain networks. Brain networks are fundamental in understanding how the brain operates. Effects on remote areas can be directly observed or identified after a period of stimulation, and each section of this review will discuss one method. EEG analyzed following TMS is called TMS-evoked potentials (TEPs). A conditioning TMS can influence the effect of a test TMS given over the motor cortex. A disynaptic connection can be tested also by assessing the effect of a pre-conditioning stimulus on the conditioning-test pair. Basal ganglia-cortical relationships can be assessed using electrodes placed in the process of deep brain stimulation therapy. Cerebellar-cortical relationships can be determined using TMS over the cerebellum. Remote effects of TMS on the brain can be found as well using neuroimaging, including both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). The methods complement each other since they give different views of brain networks, and it is often valuable to use more than one technique to achieve converging evidence. The final product of this type of work is to show how information is processed and transmitted in the brain., (Published by Elsevier B.V.)

It was recently demonstrated that the characteristics of EEG rhythms preceding a transcranial magnetic stimulation (TMS) of the motor cortex (M1) influence the motor-evoked potential (MEP) amplitude with a peculiar pattern, thus reflecting the M1 functional state. As physiological aging is related to a decrease in motor performance and changes in excitability and connectivity strength within cerebral sensorimotor circuits, we aimed to explore whether aging affects EEG-MEP interactions. Using MRI-navigated TMS and multichannel EEG, we compared the EEG-MEP interactions observed in healthy aged subjects with those observed in young volunteers. We divided the MEPs amplitude into two different subgroups consisting of "high" and "low" MEPs, based on the 50th percentile of their amplitude distribution. Then we analysed the characteristics of the pre-stimulus EEG from M1 and correlated areas separately for the "high" and "low" MEPs, comparing the two conditions. In both young and old subjects, significantly larger MEPs were evoked when the stimulated M1 was coupled in the beta-2 band with the homolateral prefrontal cortex. Conversely, only in young participants was the MEP size modulated when the M1 and homolateral parieto-occipital cortices were coupled in the delta band. The elderly didn't show this kind of pattern. Importantly, this coupling was significantly higher in elderly brains than in young brains, both for high and low MEPs. Our results suggest an age-related significant influence of time-varying coupling of spatially patterned EEG rhythms on motor cortex excitability in response to TMS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Transcranial direct current stimulation (tDCS) is well established-among the non-invasive brain stimulation techniques-as a method to modulate brain excitability. Polarity-dependent modulations of membrane potentials are detected after the application of anodal and cathodal stimulation, leading to changes in the electrical activity of the neurons. The main aim of the present study was to test the hypothesis that tDCS can affect-in a polarity-specific manner-the functional coupling of the sensorimotor areas during the eyes-open resting condition as revealed by total EEG coherence (i.e., coherence across the average of all combinations of the electrode pairs placed around the stimulation electrode). The changes in the total EEG coherence were evaluated pre-, during, and post-anodal and cathodal tDCS. While no differences were observed in the connectivity characteristics of the two pre-stimulation periods, a connectivity increase was observed in the alpha 2 band in the post-anodal tDCS with respect to pre-anodal and post-cathodal tDCS. The present study suggests that a specific approach based on the analyses of the functional coupling of EEG rhythms might enhance understanding of tDCS-induced effects on cortical connectivity. Moreover, this result suggests that anodal tDCS could possibly modify cortical connectivity more effectively with respect to cathodal tDCS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate neurophysiological features of M1 excitability and plasticity in Subcortical Ischemic Vascular Dementia (SIVD), by means of a TMS mapping study., Methods: Seven SIVD and nine AD patients, along with nine control subjects were tested. The M1 excitability was studied by resting thresholds, area and volume of active cortical sites for forearm and hand's examined muscles. For M1 plasticity, coordinates of the hot-spot and the center of gravity (CoG) were evaluated. The correlation between the degree of hyperexcitability and the amount of M1 plastic rearrangement was also calculated., Results: Multivariate analysis of excitability measures demonstrated similarly enhanced cortical excitability in AD and SIVD patients with respect to controls. SIVD patients showed a medial and frontal shift of CoG from the hot-spot, not statistically different from that observed in AD. A significant direct correlation was seen between parameters related to cortical excitability and those related to cortical plasticity., Conclusions: The results suggest the existence of common compensatory mechanisms in different kind of dementing diseases supporting the idea that cortical hyperexcitability can promote cortical plasticity., Significance: This study characterizes neurophysiological features of motor cortex excitability and plasticity in SIVD, providing new insights on the correlation between cortical excitability and plasticity., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Introduction: Changes in cortical excitability are considered to play an important role in promoting brain plasticity both in healthy people and in neurological diseases. Hydrocephalus is a brain development disorder related to an excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. The functional relevance of cortical structural changes described in this disease is largely unexplored in human. We investigated cortical excitability using multimodal transcranial magnetic stimulation (TMS) in a case of congenital hydrocephalus with almost no neurological signs., Methods: A caucasian 40 years old, ambidextrous and multilingual woman affected by occult spina bifida and congenital symmetrical hydrocephalous underwent a TMS study. The intracortical and interhemispheric paired pulse paradigms were used, together with the mapping technique., Results: No significant differences were found in the resting motor thresholds between the two hemispheres. Instead, the intracortical excitability curves were statistically different between the two hemispheres (with short intracortical inhibition (SICI) being strongly reduced and intracortical facilitation (ICF) enhanced in the right one), and the interhemispheric curves showed a general hyper-excitability on the right hemisphere (when conditioned by the left one) and a general hypo-excitability in the left hemisphere (when conditioned by the right one). It is noteworthy that an asymmetric right hemisphere (RH) change of excitability was observed by means of mapping technique., Conclusion: We hypothesize that in this ambidextrous subject, the observed RH hyper-excitability could represent a mechanism of plasticity to preserve functionality of specific brain areas possibly devoted to some special skills, such as multilingualism.

Background: Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex activates corticospinal neurons mainly through the depolarization of cortico-cortical axons belonging to interneurons of superficial layers., Objective: We used single-fiber electromyography (SFEMG) to estimate the "central jitter" of activation latency of interneural pools from one pulse of TMS to another., Methods: We evaluated 10 healthy subjects and one patient with multiple sclerosis. By recording SFEMG evoked activity from the left first dorsal interosseous (FDI), we first used a standard repetitive electrical 3 Hz stimulation of the ulnar nerve at the wrist to calculate the mean consecutive difference from at least 10 different potentials. The same procedure was applied during 3 Hz repetitive TMS of the contralateral motor cortex. The corticospinal monosynaptic connection of the FDI and the selectivity of SFEMG recording physiologically justified the subtraction of the "peripheral jitter" from the whole cortico-muscular jitter, obtaining an estimation of the actual "central jitter.", Results: All subjects completed the study. The peripheral jitter was 28 μs ± 6 and the cortico-muscular jitter was 344 μs ± 97. The estimated central jitter was 343 ± 97 μs. In the patient the central jitter was 846 μs, a value more than twice the central jitter in healthy subjects., Conclusion: Current results demonstrate that the evaluation of the central component of the cumulative cortico-muscular latency variability in healthy subjects is feasible with a minimally invasive approach. We present and discuss this methodology and provide a "proof of concept" of its potential clinical applicability in a patient with multiple sclerosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Electroconvulsive therapy (ECT) is the most effective treatment of depression. During the last decades repetitive transcranial magnetic stimulation (rTMS), an alternative method using electric stimulation of the brain, has revealed possible alternative to ECT in the treatment of depression. There are some clinical trials comparing their efficacies and safeties but without clear conclusions, mainly due to their small sample sizes. In the present study, a meta-analysis had been carried out to gain statistical power. Outcomes were response, remission, acceptability and cognitive effects in depression. Following a comprehensive literature search that included both English and Chinese language databases, we identified all randomized controlled trials that directly compared rTMS and ECT for major depression. 10 articles (9 trials) with a total of 425 patients were identified. Methodological quality, heterogeneity, sensitivity and publication bias were systematically evaluated. ECT was superior to high frequency rTMS in terms of response (64.4% vs. 48.7%, RR = 1.41, p = 0.03), remission (52.9% vs. 33.6%, RR = 1.38, p = 0.006) while discontinuation was not significantly different between the two treatments (8.3% vs. 9.4%, RR = 1.11, p = 0.80). According to the subgroup analysis, the superiority of ECT was more apparent in those with psychotic depression, while high frequency rTMS was as effective as ECT in those with non-psychotic depression. The same results were obtained in the comparison of ECT with low frequency rTMS. ECT had a non-significant advantage over high frequency rTMS on the overall improvement in HAMD scores (p = 0.11). There was insufficient data on medium or long term efficacy. Both rTMS and ECT were well tolerated with only minor side effects reported. Results based on 3 studies suggested that specific cognitive domains such as visual memory and verbal fluency were more impaired in patients receiving ECT. In conclusion, ECT seemed more effective than and at least as acceptable as rTMS in the short term, especially in the presence of psychotic depression. This review identified the lack of good quality trials comparing the long-term outcome and cognitive effects of rTMS and ECT, especially using approaches to optimize stimulus delivery and reduce clinical heterogeneity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Motor evoked potentials (MEPs) elicited by a train of consecutive, individual transcranial magnetic stimuli demonstrate fluctuations in amplitude with respect to time when recorded from a relaxed muscle. The influence of time-varying, instantaneous modifications of the electroencephalography (EEG) properties immediately preceding the transcranial magnetic stimulation (TMS) has rarely been explored. The aim of this study was to investigate the influence of the pre-TMS motor cortex and related areas EEG profile on time variants of the MEPs amplitude., Method: MRI-navigated TMS and multichannel TMS-compatible EEG devices were used. For each experimental subject, post-hoc analysis of the MEPs amplitude that was based on the 50th percentile of the MEPs amplitude distribution provided two subgroups corresponding to "high" (large amplitude) and "low" (small amplitude). The pre-stimulus EEG characteristics (coherence and spectral profile) from the motor cortex and related areas were analyzed separately for the "high" and "low" MEPs and were then compared., Results: On the stimulated hemisphere, EEG coupling was observed more often in the high compared to the low MEP trials. Moreover, a paradigmatic pattern in which TMS was able to lead to significantly larger MEPs was found when the EEG of the stimulated motor cortex was coupled in the beta 2 band with the ipsilateral prefrontal cortex and in the delta band with the bilateral centro-parietal-occipital cortices., Conclusion: This data provide evidence for a statistically significant influence of time-varying and spatially patterned synchronization of EEG rhythms in determining cortical excitability, namely motor cortex excitability in response to TMS., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Deafferentation pain secondary to brachial plexus avulsion, spinal cord injury, and other peripheral nerve injuries is often refractory to conventional treatments. Stimulation of the primary motor cortex (M1) has been proven to be an effective treatment for intractable deafferentation pain. The mechanisms underlying the attenuation of deafferentation pain by motor cortex stimulation remain hypothetical., Objectives: The purpose of this case report is to: (1) summarize a case in which a patient suffering chronic intractable deafferentation pain for 25 years underwent rTMS treatment over M1, (2) describe the evidence from PET imaging, and (3) reveal a possible relief mechanism with cortical plasticity., Study Design: Case report., Setting: University hospital., Results: This patient had successful pain control with no transient or lasting side effects. The pain relief remained stable for at least one week. At the end of the 20-day procedure, pain relief was obtained according to the Visual Analog Scale (VAS) (-34.6%) and the McGill Pain Questionnaire (MPQ) (-31.6%). In the PET/CT scans, the glucose metabolism was significantly reduced contralaterally to the pain side in the anterior cingulate cortex (ACC), insula, and caudate nucleus. There was no statistically significant difference in any other cortical area., Limitations: Single case of a patient with long-term intractable deafferentation pain having a PET study., Conclusion: This study implies that a single session of 20 Hz rTMS over the motor cortex could reduce the pain level in patients suffering from long-term, intractable deafferentation pain. The stimulation of the M1 induces deactivation in the ACC, insula, and caudate nucleus. The changes in these pain-related regions may mirror an adaptive mechanism to pain relief after rTMS treatment.

Background: Electromagnetic fields (EMFs) emitted by mobile phones had been shown to increase cortical excitability in healthy subjects following 45 min of continuous exposure on the ipsilateral hemisphere., Objective: Using Transcranial Magnetic Stimulation (TMS), the current study assessed the effects of acute exposure to mobile phone EMFs on the cortical excitability in patients with focal epilepsy., Methods: Ten patients with cryptogenic focal epilepsy originating outside the primary motor area (M1) were studied. Paired-pulse TMS were applied to the M1 of both the hemisphere ipsilateral (IH) and contralateral (CH) to the epileptic focus before and immediately after real/sham exposure to the GSM-EMFs (45 min). The TMS study was carried out in all subjects in three different experimental sessions (IH and CH exposure, sham), 1 week apart, according to a crossover, double-blind and counter-balanced paradigm., Results: The present study clearly demonstrated that an acute and relatively prolonged exposure to GSM-EMFs modulates cortical excitability in patients affected by focal epilepsy; however, in contrast to healthy subjects, these effects were evident only after EMFs exposure over the hemisphere contralateral to the epileptic focus (CH). They were characterized by a significant cortical excitability increase in the exposed hemisphere paired with slight excitability decrease in the other one (IH). Both sham and real EMFs exposure of the IH did not affect brain excitability., Conclusion: Present results suggest a significant interaction between the brain excitability changes induced by EMFs and the epileptic focus, which eliminated the excitability enhancing effects of EMFs evident only in the CH., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

When linking in time electrical stimulation of the peripheral nerve with transcranial magnetic stimulation (TMS), the excitability of the motor cortex can be modulated to evoke clear inhibition, as reflected by the amplitude decrement in the motor-evoked potentials (MEPs). This specific property, designated short-latency afferent inhibition (SAI), occurs when the nerve-TMS interstimulus interval (ISI) is approximately 25 ms and is considered to be a corticothalamic phenomenon. The aim of the present study was to use the electroencephalographic (EEG) responses to navigated-TMS coregistration to better characterize the neuronal circuits underlying SAI. The present experimental set included magnetic resonance imaging (MRI)-navigated TMS and 60-channel TMS-compatible EEG devices. TMS-evoked EEG responses and MEPs were analyzed in eight healthy volunteers; ISIs between median nerve and cortical stimulation were determined relative to the latency of the individual N20 component of the somatosensory-evoked potential (SEP) obtained after stimulation of the median nerve. ISIs from the latency of the N20 plus 3 ms and N20 plus 10 ms were investigated. In all experimental conditions, TMS-evoked EEG responses were characterized by a sequence of negative deflections peaking at approximately 7, 44, and 100 ms alternating with positive peaks at approximately 30, 60, and 180 ms post-TMS. Moreover, ISI N20+3 ms modulated both EEG-evoked activity and MEPs. In particular, it inhibited MEP amplitudes, attenuated cortical P60 and N100 responses, and induced motor cortex beta rhythm selective decrement of phase locking. The findings of the present experiment suggest the cortical origin of SAI that could result from the cortico-cortical activation of GABAergic-mediated inhibition onto the corticospinal neurons modulated by cholinergic activation able to reducing intralaminar inhibition and promoting intracolumnar inhibition.

Repetitive transcranial magnetic stimulation (rTMS) can generate an increase or a decrease of neuronal excitability, which can modulate cognition and behaviour. Transcranial magnetic stimulation-induced cortical changes have been shown to result in neural plasticity. Thus, TMS provides an important opportunity to gain more insight into the mechanisms responsible for the remarkable flexibility of the central nervous system. The aim of this review was to cover the topics that could be useful when using TMS in the cognitive rehabilitation field after brain damage. The basic TMS principles are introduced, together with the clinical application for diagnosis and prognosis, the biological aspects, and the use in cognitive neuroscience studies. Finally, several hypotheses are discussed to explain the likely mechanisms induced by TMS that favour the recovery of a function after brain damage and cause the adult brain to undergo plasticity. The possibility of non-invasively interacting with the functioning of the brain and its plasticity mechanisms - a possibility that may eventually lead to cognitive and behavioural modifications - opens new and exciting scenarios in the cognitive neurorehabilitation field.

Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: Intracortical inhibition (SICI) and facilitation (ICF) in the human motor cortex can be measured using a paired pulse transcranial magnetic stimulation (ppTMS) protocol. Recently, a technical device has been introduced, which allows recording electroencephalographic (EEG) responses to TMS of a given scalp site. The latency, amplitude and scalp topography of such responses are considered a reflection of cortico-cortical connectivity and functional state. The aim of the present study is to better characterize the neuronal circuits underlying motor cortex connectivity as well as the mechanisms regulating its balance between inhibition and facilitation by means of EEG navigated-ppTMS coregistration., Methods: Sub-threshold and supra-threshold single and ppTMS of the left primary motor cortex were carried out during a multi-channel EEG recording on 8 healthy volunteers; the between-pulse intervals used in the paired pulse trials were 3 (for SICI) and 11 ms (for ICF). Motor evoked potentials (MEPs) from the opposite hand were simultaneously recorded., Results: Single and ppTMS induced EEG responses characterized by a sequence of negative deflections peaking at approximately 7, 18, 44, 100 and 280 ms alternated with positive peaks at approximately 13, 30, 60 and 190 ms post-TMS. Moreover, ppTMS modulated both EEG evoked activity and MEPs. Amplitude variability of EEG responses was correlated with - and therefore might partially explain - amplitude variability of MEPs., Interpretation: EEG-ppTMS is a promising tool to better characterize the neuronal circuits underlying cortical effective connectivity as well as the mechanisms regulating the balance between inhibition and facilitation within the human cortices and the corticospinal pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The primary motor cortex (M1) area recruitment enlarges while learning a finger tapping sequence. Also M1 excitability increases during procedural consolidation. Our aim was to investigate whether increasing M1 excitability by anodal transcranial DC stimulation (AtDCS) when procedural consolidation occurs was able to induce an early consolidation improvement. Forty-seven right-handed healthy participants were trained in a nine-element serial finger tapping task (SFTT) executed with the left hand. Random series blocks were interspersed with training series blocks. Anodal or sham tDCS was administered over the right M1 after the end of the training session. After stimulation, the motor skills of both trained and a new untrained sequential series blocks were tested again. For each block, performance was estimated as the median execution time of correct series. Early consolidation of the trained series, assessed by the performance difference between the first block after and the last block before stimulation normalized by the random, was enhanced by anodal and not by sham tDCS. Stimulation did not affect random series execution. No stimulation effect was found on the on-line learning of the trained and new untrained series. Our results suggest that AtDCS applied on M1 soon after training improves early consolidation of procedural learning. Our data highlight the importance of neuromodulation procedures for understanding learning processes and support their use in the motor rehabilitation setting, focusing on the timing of the application.

Transcranial direct current stimulation (tDCS) is able to generate a long-term increase or decrease in the neuronal excitability that can modulate cognitive tasks, similar to repetitive transcranial magnetic stimulation. The aim of this study was to explore the effects of tDCS on a language task in young healthy subjects. Anodal, cathodal and sham tDCS were applied to the left dorsolateral prefrontal cortex (DLPFC) before two picture naming experiments, a preliminary study (i.e., experiment 1) and a main study (i.e., experiment 2). The results show that anodal tDCS of the left DLPFC improves naming performance, speeding up verbal reaction times after the end of the stimulation, whereas cathodal stimulation had no effect. We hypothesize that the cerebral network dedicated to lexical retrieval processing is facilitated by anodal tDCS to the left DLPFC. Although the mechanisms responsible for facilitation are not yet clear, the results presented herein implicate a facilitation lasting beyond the end of the stimulation that imply cortical plasticity mechanisms. The opportunity to non-invasively interact with the functioning of these plasticity mechanisms will surely open new and promising scenarios in language studies in basic and clinical neuroscience fields., (Copyright 2010. Published by Elsevier B.V.)

In recent years, noninvasive brain stimulation methods have been proposed as the next-generation technology to probe and eventually interfere with brain function. Transcranial magnetic stimulation (TMS) is a 20-year-old technique originally introduced to investigate nervous propagation along the corticospinal tract, spinal roots, and peripheral nerves in humans. TMS is extensively used in clinical neurophysiology, including rehabilitation and intraoperative monitoring.

This article is based on a consensus conference, which took place in Certosa di Pontignano, Siena (Italy) on March 7-9, 2008, intended to update the previous safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings. Over the past decade the scientific and medical community has had the opportunity to evaluate the safety record of research studies and clinical applications of TMS and repetitive TMS (rTMS). In these years the number of applications of conventional TMS has grown impressively, new paradigms of stimulation have been developed (e.g., patterned repetitive TMS) and technical advances have led to new device designs and to the real-time integration of TMS with electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Thousands of healthy subjects and patients with various neurological and psychiatric diseases have undergone TMS allowing a better assessment of relative risks. The occurrence of seizures (i.e., the most serious TMS-related acute adverse effect) has been extremely rare, with most of the few new cases receiving rTMS exceeding previous guidelines, often in patients under treatment with drugs which potentially lower the seizure threshold. The present updated guidelines review issues of risk and safety of conventional TMS protocols, address the undesired effects and risks of emerging TMS interventions, the applications of TMS in patients with implanted electrodes in the central nervous system, and safety aspects of TMS in neuroimaging environments. We cover recommended limits of stimulation parameters and other important precautions, monitoring of subjects, expertise of the rTMS team, and ethical issues. While all the recommendations here are expert based, they utilize published data to the extent possible.

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

Background: Sleep electroencephalogram (EEG) brain oscillations in the low-frequency range show local signs of homeostatic regulation after learning. Such increases and decreases of slow wave activity are limited to the cortical regions involved in specific task performance during wakefulness. Here, we test the hypothesis that reorganization of motor cortex produced by long-term potentiation (LTP) affects EEG activity of this brain area during subsequent sleep., Methodology/principal Findings: By pairing median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex, one can potentiate the motor output, which is presumed to reflect plasticity of the neural circuitry. This paired associative stimulation increases M1 cortical excitability at interstimulus intervals of 25 ms. We compared the scalp distribution of sleep EEG power following paired associative stimulation at 25 ms to that following a control paradigm with 50 ms intervals. It is shown that the experimental manipulation by paired associative stimulation at 25 ms induces a 48% increase in amplitude of motor evoked potentials. This LTP-like potentiation, induced during waking, affects delta and theta EEG power in both REM and non-REM sleep, measured during the following night. Slow-wave activity increases in some frontal and prefrontal derivations and decreases at sites neighboring and contralateral to the stimulated motor cortex. The magnitude of increased amplitudes of motor evoked potentials by the paired associative stimulation at 25 ms predicts enhancements of slow-wave activity in prefrontal regions., Conclusions/significance: An LTP-like paradigm, presumably inducing increased synaptic strength, leads to changes in local sleep regulation, as indexed by EEG slow-wave activity. Enhancement and depression of slow-wave activity are interpreted in terms of a simultaneous activation of both excitatory and inhibitory circuits consequent to the paired associative stimulation at 25 ms.

Transcranial magnetic stimulation (TMS) can transiently modulate cortical excitability, with a net effect depending on the stimulation frequency (< or =1 Hz inhibition vs. > or =5 Hz facilitation, at least for the motor cortex). This possibility has generated interest in experiments aiming to improve deficits in clinical settings, as well as deficits in the cognitive domain. The aim of the present study was to investigate the on-line effects of low frequency (1 Hz) TMS on the EEG oscillatory activity in the healthy human brain, focusing particularly on the outcome of these modulatory effects in relation to the duration of the TMS stimulation. To this end, we used the event-related desynchronization/synchronization (ERD/ERS) approach to determine the patterns of oscillatory activity during two consecutive trains of sham and real TMS. Each train of stimulation was delivered to the left primary motor cortex (MI) of healthy subjects over a period of 10 min, while EEG rhythms were simultaneously recorded. Results indicated that TMS induced an increase in the power of brain rhythms that was related to the period of the stimulation, i.e. the synchronization of the alpha band increased with the duration of the stimulation, and this increase was inversely correlated with motor-evoked potentials (MEPs) amplitude. In conclusion, low frequency TMS over primary motor cortex induces a synchronization of the background oscillatory activity on the stimulated region. This induced modulation in brain oscillations seems to increase coherently with the duration of stimulation, suggesting that TMS effects may involve short-term modification of the neural circuitry sustaining MEPs characteristics., ((Copyright) 2006 Wiley-Liss, Inc.)

The functional organization of working memory (WM) in the human prefrontal cortex remains unclear. The present study used repetitive transcranial magnetic stimulation (rTMS) to clarify the role of the dorsolateral prefrontal cortex (dlPFC) both in the types of information (verbal vs. spatial), and the types of processes (maintenance vs. manipulation). Subjects performed three independent experiments (1-back and 2-back tasks) while rTMS was applied over dlPFC for 500 ms in the last period of the delay. In two experiments (1 and 2) physically identical stimuli (letters shown at different locations on a screen) under different domain conditions (letters or locations) were employed. Under these conditions, we discovered a double dissociation only in the 2-back task: during the letter condition, when applied to the right dlPFC, rTMS significantly delayed task performance, whereas, the same result was present during the location condition, but only when rTMS was applied to the left dlPFC. The other 2-back task (experiment 3), in which we had eliminated the task-irrelevant information (i.e. we used stimuli that varied only in one domain), did not show significant results. We propose that the functional dichotomy of the hemispheres may be due to mechanisms of cognitive control on interference, which resolve conflict through the inhibition of task-irrelevant information only during high WM load. In conclusion, these findings confirm the role of dlPFC in implementing top-down attentional control, and provide evidence for the theoretical suggestion that working memory serves to control selective attention in the normal human brain.

Changes of cortical and corticospinal excitability as a function of sleep deprivation have been studied, using EEG power maps and several TMS measures in 33 normal subjects before and after a 40-h sleep deprivation (SD). The effects of SD were independently assessed by subjective and EEG measures of sleepiness, the latter being represented in terms of cortical maps for different frequency bands. Short intracortical facilitation (SICF) and inhibition (SICI) were measured by the paired-pulse TMS technique with different inter-stimulus intervals. Besides standardized motor threshold (MT), lower threshold (LT) and upper threshold (UT) were also determined. Subjective sleepiness severely increased as a consequence of SD, paralleled by a drastic decrease of alertness. EEG topography showed large increases in delta and theta activity, mainly evident at fronto-central areas. Standard MTs, as well as LTs and UTs, all increased as a consequence of SD. SICF also showed a significant increase as compared to pre-deprivation values, but only in females. The increase of theta activity was strongly associated in the left frontal and prefrontal cortex to a smaller decrease of corticospinal excitability, expressed by MTs, and a larger increase of intracortical facilitation, expressed by SICF. TMS and EEG measures converge in indicating that SD has severe effects on both cortical and corticospinal excitability, as shown respectively by the increases of slow-frequency EEG power and MTs. The SICF enhancement in females and the results of the combined topographical analysis of EEG and TMS changes are coherent with the hypothesis that cortical TMS-evoked responses are higher as a consequence of a longer wakefulness. However, the lack of an increase in cortical excitability after prolonged wakefulness in males suggests some caution in the generalization of these effects, that deserve further investigation.

In this paper, we used repetitive transcranial magnetic stimulation (rTMS) in 18 normal subjects to investigate whether the ventral posterior parietal cortex (PPC) plays a causal role on visuospatial attention and primary consciousness and whether these 2 functions are linearly correlated with each other. Two distinct experimental conditions involved a similar visual stimuli recognition paradigm. In "Consciousness" experiment, number of consciously perceived visual stimuli was lower by about 10% after rTMS (300 ms, 20 Hz, motor threshold intensity) on left or right PPC than after sham (pseudo) rTMS. In "Attentional" Posner's experiment, these stimuli were always consciously perceived. Compared with sham condition, parietal rTMS slowed of about 25 ms reaction time to go stimuli, thus disclosing effects on endogenous covert spatial attention. No linear correlation was observed between the rTMS-induced impairment on attention and conscious perception. Results suggest that PPC plays a slight but significant causal role in both visuospatial attention and primary consciousness. Furthermore, these high-level cognitive functions, as modulated by parietal rTMS, do not seem to share either linear or simple relationships.

Transcranial magnetic stimulation (TMS) is a 20-year-old technique originally introduced to noninvasively investigate nervous propagation along the corticospinal tract, spinal roots, and peripheral nerves in humans. TMS is extensively used in clinical neurophysiology, including rehabilitation and intraoperative monitoring. Single-pulse TMS and other more recent versions (paired-pulse TMS, repetitive TMS, integration with structural and functional MRI, and neuronavigation) allow motor output to be mapped precisely to a given body district. Moreover, TMS can be used to evaluate excitatory/inhibitory intracortical circuits and to provide information on brain physiology and pathophysiology of various neuropsychiatric diseases as well as on the mechanisms of brain plasticity and of neuroactive drugs. TMS applied over nonmotor areas made it possible to extend research applications (often complementary with other functional neuroimaging techniques) in several fields of psychophysiology, causally testing brain-behavior relationships. Being able to induce relatively long-lasting excitability changes, repetitive TMS has made the treatment of neuropsychiatric diseases linked with brain excitability dysfunctions possible. These uses, however, warrant further large-scale studies. In emerging fields of research, TMS-EEG co-registration is considered a promising approach to evaluate corticocortical connectivity and brain reactivity with high temporal resolution. However, safety and ethical limitations of TMS technique need a high level of vigilance.

Purpose: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy., Methods: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex., Results: "Active" rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability)., Conclusions: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to "active" rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.

Objective: Electrical stimulation of the median nerve followed by a magnetic pulse on the primary motor cortex (M1) is effective to cause an increase in the amplitude of motor evoked potential (MEP) registered in the target muscle with the interstimulus interval (ISI) at 25ms (paired associative stimulation, PAS). The aim of this study is to evaluate the reproducibility of PAS with ISI 25 (PAS25), assessed in two separate sessions. Intraindividual reliability of TMS measures was also evaluated., Methods: Motor threshold of abductor pollicis brevis (APB), assessed at rest, and MEP amplitude of APB and abductor digiti minimi (ADM) were assessed before and after PAS25 in 18 healthy volunteers (nine males and nine females)., Results: Data showed a significant increase of MEP amplitude in the target muscle (APB) after PAS25 and a reproducibility of group effect in the two sessions, as assessed by ANOVA, but a lack of intraindividual reliability, as assessed by intraclass correlation coefficients (ICC)., Conclusions: The results underline the reproducibility of mean effects and the need to be careful when comparing the same subject on different days., Significance: Electrical stimulation of the median nerve followed by a magnetic pulse delivered on M1 after 25ms causes a reproducible increase in MEP amplitude, without showing an acceptable intraindividual reliability.

Objective: To assess the effect of repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) on picture naming in patients with Alzheimer disease (AD)., Design: Experimental study. Patients with AD underwent rTMS in real and control conditions during picture-naming tasks., Setting: San Giovanni di Dio Fatebenefratelli Scientific Institute in Brescia, Italy. Patients Fifteen patients with probable AD. Intervention High-frequency rTMS was applied to the left and right DLPFC during object and action naming., Main Outcome Measures: Language ability was assessed by accuracy of verbal response during online rTMS., Results: Stimulation to the left and right DLPFC improved accuracy in action naming., Conclusions: These findings indicate that rTMS to the DLPFC, which speeds up action naming in normal controls, improves performance in patients with AD. While the mechanisms of rTMS-induced naming facilitation in these patients are unknown, the procedure may be worth testing as a novel approach to the treatment of language dysfunction.

The visuo-spatial planning process is based on an "opportunistic" combination of heuristics and strategies, carried out in small units during the execution of plans. In order to investigate the functional role of the prefrontal cortex in heuristic switching, 42 healthy controls performed a labyrinth crossing task (the Maps Test). During this computerized version of the Travelling Salesperson Problem, subjects had to decide which order of locations optimizes total travel time and distance. This task was performed with and without 1 Hz repetitive transcranial magnetic stimulation (rTMS), which exerts an inhibitory action on the targeted area, applied during the task over bilateral frontal sites (active stimulation) and parieto-occipital site (sham stimulation). Only repetitive bilateral rTMS over F3 and F4 significantly decreased the number of strategies with changes of heuristics, and increased the number of movements required to solve the task. This behaviour contrasts with the performance of healthy subjects in the planning task, but is consistent with the performance of frontal traumatic brain injury patients. The results indicate that, in a visuo-spatial problem-solving task, the prefrontal cortex is involved in the switching between heuristics during the execution of a plan.

Background: Depression has been associated with low brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs appear to mend this alteration. The purpose of this study was to assess BDNF serum levels in drug resistant depressed patients before and after repetitive Transcranial Magnetic Stimulation (rTMS) antidepressant treatment., Methods: BDNF levels were measured in serum of 16 resistant depressed patients using the ELISA technique., Results: BDNF baseline levels showed a negative correlation with illness severity measured by HDRS scores (R = -0.517, p = 0.04) and a significant increase of serum BDNF was found after rTMS treatment (t = -2.549, df = 15, p = 0.022)., Conclusions: Our findings support the relationship between decreased serum BDNF and depression symptomatology and suggest a normalizing effect of rTMS antidepressant treatment. Further replications in larger samples will help to clarify the relevance of this preliminary data in the rTMS mechanism of action.

Neuroimaging findings, including repetitive transcranial magnetic stimulation (rTMS) interference, point to an engagement of prefrontal cortex (PFC) in learning and memory. Whether parietal cortex (PC) activity is causally linked to successful episodic encoding and retrieval is still uncertain. We compared the effects of event-related active or sham rTMS (a rapid-rate train coincident to the very first phases of memoranda presentation) to the left or right intraparietal sulcus, during a standardized episodic memory task of visual scenes, with those obtained in a fully matched sample of subjects who received rTMS on left or right dorsolateral PFC during the same task. In these subjects, specific hemispheric effects of rTMS included interference with encoding after left stimulation and disruption of retrieval after right stimulation. The interference of PC-rTMS on encoding/retrieval performance was negligible, lacking specificity even when higher intensities of stimulation were applied. However, right PC-rTMS of the same intensity lengthened reaction times in the context of a purely attentive visuospatial task. These results suggest that the activity of intraparietal sulci shown in several functional magnetic resonance studies on memory, unlike that of the dorsolateral PFC, is not causally engaged to a useful degree in memory encoding and retrieval of visual scenes. The parietal activations accompanying the memorization processes could reflect the engagement of a widespread brain attentional network, in which interference on a single 'node' is insufficient for an overt disruption of memory performance.

Focal transcranial magnetic stimulation (TMS) was employed in a population of hemiparetic stroke patients in a post-acute stage to map out the abductor digiti minimi (ADM) muscle cortical representation of the affected (AH) and unaffected (UH) hemisphere at rest, during motor imagery and during voluntary contraction. Imagery induced an enhancement of the ADM map area and volume in both hemispheres in a way which partly corrected the abnormal asymmetry between AH and UH motor output seen in rest condition. The voluntary contraction was the task provoking maximal facilitation in the UH, whereas a similar degree of facilitation was obtained during voluntary contraction and motor imagery in the AH. We argued that motor imagery could induce a pronounced motor output enhancement in the hemisphere affected by stroke. Further, we demonstrated that imagery-induced excitability changes were specific for the muscle 'prime mover' for the imagined movement, while no differences were observed with respect to the stroke lesion locations. Present findings demonstrated that motor imagery significantly enhanced the cortical excitability of the hemisphere affected by stroke in a post-acute stage. Further studies are needed to correlate these cortical excitability changes with short-term plasticity therefore prompting motor imagery as a 'cortical reservoir' in post-stroke motor rehabilitation.

Neuroimaging studies and experimental data suggest that symptoms of posttraumatic stress disorder (PTSD) are associated with dysfunctions of neural circuits linking prefrontal cortex and the limbic system that have a role in autobiographic episodic memory. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) has been suggested to be beneficial to patients with PTSD, transiently alleviating re-experiencing as well as avoidance reactions and associated anxiety symptoms. In healthy humans, converging evidence suggests that rTMS of the right DLPFC interferes with episodic memory retrieval. Hence, we hypothesize that daily applications of rTMS in PTSD patients may reduce access to the set of autobiographical stored events, that, if re-experienced, may cause the overt PTSD symptoms.

Neuroimaging findings suggest that the lateralization of prefrontal cortex activation associated with episodic memory performance is reduced by aging. It is still a matter of debate whether this loss of asymmetry during encoding and retrieval reflects compensatory mechanisms or de-differentiation processes. We addressed this issue by the transient interference produced by repetitive transcranial magnetic stimulation (rTMS), which directly assesses causal relationships between performance and stimulated regions. We compared the effects of rTMS (a rapid-rate train occurring simultaneously to the presentation of memoranda) applied to the left or right dorsolateral prefrontal cortex (DLPFC) on visuospatial recognition memory in 66 healthy subjects divided in two classes of age (<45 and >50 years). In young subjects, rTMS of the right DLPFC interfered with retrieval more than left DLPFC stimulation. The asymmetry of the effect progressively vanished with aging, as indicated by bilateral interference effects on recognition performance. Conversely, the predominance of left DLPFC effect during encoding was not abolished in elders, thus probing its causal role for encoding along the life span. Findings confirm that the neural correlates of retrieval modify along aging, suggesting that the bilateral engagement of the DLPFC has a compensatory role on the elders' episodic memory performance.

Study Objectives: The aim of the study is to assess, in humans, transcallosal inhibition upon awakening from rapid eye movement (REM) and non-REM sleep, by paired-pulse transcranial magnetic stimulation (TMS)., Design: During the daytime, a baseline session of motor evoked potentials (MEPs) was recorded. During the nighttime, the TMS sessions were administered just before sleep onset and upon awakenings from REM and stage 2 sleep, both in the early and final part of night., Setting: The sleep research laboratory at the University of Rome "La Sapienza.", Participants: Ten right-handed subjects participated in the experiment for 4 consecutive sleep-recording nights., Interventions: N/A., Measurements and Results: During the daytime, a robust transcallosal inhibition was found; the MEP amplitude reduction ranged from 35% to 40%. During the nighttime, a decrease of transcallosal inhibition from right-to-left motor cortex, as compared to that from left-to-right motor cortex, was observed. The direct assessment of MEP changes, as a function of sleep stage and of the time of night, pointed to a drop of transcallosal inhibition after awakening from REM sleep. Therefore, the inhibitory activity of transcallosal fibers observed after non-REM awakening almost disappeared after REM sleep awakenings., Conclusions: The drastic drop of transcallosal inhibition after awakenings from REM sleep represents the first evidence in humans of a change of interhemispheric connectivity mediated by the corpus callosum during this sleep stage and may open new avenues for a better understanding of some aspects of sleep mechanisms (ie, dreaming function and dream mentation).

Intracortical facilitation and inhibition, as assessed by the paired-pulse transcranial magnetic stimulation technique with a subthreshold conditioning pulse followed by a suprathreshold test pulse, was studied upon awakening from REM and slow-wave sleep (SWS). Ten normal subjects were studied for four consecutive nights. Intracortical facilitation and inhibition were assessed upon awakening from SWS and REM sleep, and during a presleep baseline. Independently of sleep stage at awakening, intracortical inhibition was found at 1-3-ms interstimulus intervals and facilitation at 7-15-ms interstimulus intervals. Motor thresholds were higher in SWS awakenings, with no differences between REM awakenings and wakefulness, while motor evoked potential amplitude to unconditioned stimuli decreased upon REM awakening as compared to the other conditions. REM sleep awakenings showed a significant increase of intracortical facilitation at 10 and 15 ms, while intracortical inhibition was not affected by sleep stage at awakening. While the dissociation between motor thresholds and motor evoked potential amplitudes could be explained by the different excitability of the corticospinal system during SWS and REM sleep, the heightened cortical facilitation upon awakening from REM sleep points to a cortical motor activation during this stage.

Objective: Recent functional and imaging studies have substantially contributed to extend the concept of multiple sclerosis (MS), classically regarded as a disease limited to the myelin axonal sheath. Several findings, in fact, point to a parallel involvement of neuronal components of the central nervous system (CNS) in the course of MS. In the present study, therefore, we explored, in MS patients, some characteristics of central motor pathways related to changes of neuronal excitability as measured using transcranial magnetic stimulation (TMS)., Methods: Seventy-nine patients affected by relapsing-remitting (RR) MS were examined using single and paired TMS in order to assess excitability changes in the hand motor cortex occurring during relapse and/or remission of the disease. The analyzed parameters were: motor-evoked potential (MEP) threshold, silent period (SP), intracortical inhibition (ICI) with paired pulses from 1 to 6 ms interstimulus intervals (ISIs), and central motor conduction time (CMCT)., Results: The analysis of variance exhibited a strong correlation (P<0.001) between the clinical phase and the type of excitability changes: 'relapsing' patients showed increased threshold and reduced SP duration. 'Relapsing' patients also displayed a significant lack of normal intracortical inhibition (ICI). By contrast, 'remitting' patients showed a significant SP prolongation with normal motor thresholds., Conclusions: The present findings reveal changes in cortical excitability that might play a role in the pathophysiology of MS symptoms. In particular, the relapsing phase of MS has been found to be associated with cortical hyperexcitability irrespective of the site of clinical manifestation or new plaque formation. These results might help to explain the puzzling picture of neurological symptoms observed in MS patients during different phases of the disease., Significance: Alterations of neuronal components of the CNS play a role in MS.

Transcranial magnetic stimulation (TMS) is a recently established technique in the neurosciences that allows the non-invasive assessment, among other parameters, of the excitability of motor cortex. Up to now, its application to sleep research has been very scarce and because of technical problems it provided contrasting results. In fact delivering one single suprathreshold magnetic stimulus easily awakes subjects, or lightens their sleep. For this reason, in the present study we assessed motor thresholds (MTs) upon rapid eye movement (REM) and non-rapid eye movement (NREM) sleep awakenings, both in the first and in the last part of the night. Taking into account that a full re-establishment of wake regional brain activity patterns upon awakening from sleep needs up to 20-30 min, it is possible to make inferences about the neurophysiological characteristics of the different sleep stages by analyzing the variables of interest immediately after provoked awakenings. Ten female volunteers slept in the lab for four consecutive nights. During the first night the MTs were collected, following a standardized procedure: 5 min before lights off, upon stage 2 awakening (second NREM period), upon REM sleep awakening (second REM period), upon the final morning awakening (always from stage 2). Results showed that MTs increased linearly from presleep wakefulness to REM sleep awakenings, and from the latter to stage 2 awakenings. There was also a time-of-night effect on MTs upon awakening from stage 2, indicating that MTs decreased from the first to the second part of the night. The increase in corticospinal excitability across the night, which parallels the fulfillment of sleep need, is consistent with the linear decrease of auditory arousal thresholds during the night. The maximal reduction of corticospinal excitability during early NREM sleep can be related to the hyperpolarization of thalamocortical neurons, and is in line with the decreased metabolic activity of motor cortices during this sleep stage. On the contrary, the increase of MTs upon REM sleep awakenings should reflect peripheral factors. We conclude that our findings legitimate the introduction of the TMS technique as a new proper tool in sleep research.

Motor deficits affect patients with Alzheimer's disease only at later stages. Recent studies demonstrate that the primary motor cortex is affected by neuronal degeneration accompanied by the formation of amyloid plaques and neurofibrillary tangles. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries occurring along the natural course of the disease, thereby maintaining motor performances in daily living. Cortical motor output to upper limbs was tested via motor-evoked potentials from forearm and hand muscles elicited by transcranial magnetic stimulation of motor cortex in 16 patients with mild Alzheimer's disease without motor deficits. Motor cortex excitability was increased, and the center of gravity of motor cortical output, as represented by excitable scalp sites, showed a frontal and medial shift, without correlated changes in the site of maximal excitability (hot-spot). This may indicate functional reorganization, possibly after the neuronal loss in motor areas. Hyperexcitability might be caused by a dysregulation of the intracortical GABAergic inhibitory circuitries and selective alteration of glutamatergic neurotransmission. Such findings suggest that motor cortex hyperexcitability and reorganization allows prolonged preservation of motor function during the clinical course of Alzheimer's disease.

Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8–12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS–EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae. [ABSTRACT FROM AUTHOR]