Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS–EEG study

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.     

The use of transcranial magnetic stimulation in the clinical evaluation of suspected myelopathy

Central motor conduction time (CMCT) and motor evoked potential (MEP) latencies measured by using transcranial magnetic stimulation (TMS) are parameters used to evaluate electrophysiologic function of the corticospinal motor tract. We present 5 cases to illustrate how the use of TMS had contributed to clinical management. CMCT and MEP latency measurements were found to be useful in determining the significance of lesions seen on neuroimaging and helped clinical decisions in the presence of multiple lesions or multiple clinical conditions that cause similar clinical manifestations. TMS study is particularly useful in localizing levels of conduction defect.     

Transcranial magnetic stimulation and neuroplasticity

We review past results and present novel data to illustrate different ways in which TMS can be used to study neural plasticity. Procedural learning during the serial reaction time task (SRTT) is used as a model of neural plasticity to illustrate the applications of TMS. These different applications of TMS represent principles of use that we believe are applicable to studies of cognitive neuroscience in general and exemplify the great potential of TMS in the study of brain and behavior. We review the use of TMS for (1) cortical output mapping using focal, single-pulse TMS; (2) identification of the mechanisms underlying neuroplasticity using paired-pulse TMS techniques; (3) enhancement of the information of other neuroimaging techniques by transient disruption of cortical function using repetitive TMS; and finally (4) modulation of cortical function with repetitive TMS to influence behavior and guide plasticity.     

Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review

Transcranial Magnetic Stimulation (TMS) is a non-invasive method of stimulating the brain that is increasingly being used in neuropsychiatric research and clinical psychiatry. This review examines the role of TMS in schizophrenia research as a diagnostic and a therapeutic resource. After a brief overview of TMS, we describe the application of TMS to schizophrenia in studies of cortical excitability and inhibition, and we discuss the potential confounding role of neuroleptic medications. Based on these studies, it appears that some impairment of cortical inhibition may be present in schizophrenic subjects. We then review attempts to employ TMS for treating different symptoms of schizophrenia. Some encouraging results have been obtained, such as the reduction of auditory hallucinations after slow TMS over auditory cortex and an improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. However, these results need to be confirmed using better placebo conditions. Future studies are likely to employ TMS in combination with functional brain imaging to examine the effects produced by the stimulated area on activity in other brain regions. Such studies may reveal impaired effective connectivity between specific brain areas, which could identify these regions as targets for selective stimulation with therapeutic doses of TMS.     

A new device and protocol for combining TMS and online recordings of EEG and evoked potentials

We describe an electroencephalographic (EEG) device and protocol that allows recording of electrophysiological signals generated by the human brain during transcranial magnetic stimulation (TMS) despite the TMS-induced high-voltage artifacts. The key hardware components include slew-rate limited preamplifiers to prevent saturation of the EEG system due to TMS. The protocol involves artifact subtraction to isolate the electrophysiological signals from residual TMS-induced contaminations. The TMS compatibility of the protocol is illustrated with examples of two data sets demonstrating the feasibility of the approach in the single-pulse TMS design, as well as during repetitive TMS. Our data show that both high-amplitude potentials evoked by visual checkerboard stimulation and low-amplitude steady-state oscillations induced by auditory click-trains can be retrieved with the present protocol. The signals recorded during TMS perfectly matched control EEG responses to the same visual and auditory stimuli. The main field of application of the present protocol is in cognitive neuroscience complementing behavioral studies that use TMS to induce transient, 'virtual lesions'. Combined EEG-TMS techniques provide neuroscientists with a unique method to test hypothesis on functional connectivity, as well as on mechanisms of functional orchestration, reorganization, and plasticity.     

Safety,ethical considerations,and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research

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.     

Static Field Influences on Transcranial Magnetic Stimulation: Considerations for TMS in the Scanner Environment

BackgroundTranscranial magnetic stimulation (TMS) can be combined with functional magnetic resonance imaging (fMRI) to simultaneously manipulate and monitor human cortical responses. Although tremendous efforts have been directed at characterizing the impact of TMS on image acquisition, the influence of the scanner's static field on the TMS coil has received limited attention.Objective/hypothesisThe aim of this study was to characterize the influence of the scanner's static field on TMS. We hypothesized that spatial variations in the static field could account for TMS field variations in the scanner environment.MethodsUsing an MRI-compatible TMS coil, we estimated TMS field strengths based on TMS-induced voltage changes measured in a search coil. We compared peak field strengths obtained with the TMS coil positioned at different locations (B₀ field vs fringe field) and orientations in the static field. We also measured the scanner's static field to derive a field map to account for TMS field variations.ResultsTMS field strength scaled depending on coil location and orientation with respect to the static field. Larger TMS field variations were observed in fringe field regions near the gantry as compared to regions inside the bore or further removed from the bore. The scanner's static field also exhibited the greatest spatial variations in fringe field regions near the gantry.ConclusionsThe scanner's static field influences TMS fields and spatial variations in the static field correlate with TMS field variations. Coil orientation changes in the B0 field did not result in substantial TMS field variations. TMS field variations can be minimized by delivering TMS in the bore or outside of the 0–70 cm region from the bore entrance.     

Prestimulus cortical EEG oscillations can predict the excitability of the primary motor cortex

BackgroundThe motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS) vary considerably at rest, but the mechanism underlying this amplitude variation is largely unknown. We hypothesized that prestimulus EEG oscillations modulate the subsequent MEPs in a state-dependent manner.ObjectiveWe studied the relationship between prestimulus alpha/beta oscillations and MEPs during eyes open (EO)/closed (EC) conditions, and then modulated TMS intensity in the EO condition. Furthermore, we developed an EEG-triggered TMS system (“informed open-loop”) to verify our hypothesis.MethodsTMS was applied to the left motor cortex. We first compared EEG power differences between high- and low-amplitude MEP epochs in the EO and EC conditions when using a high TMS intensity. Next, we evaluated the effects of varying TMS intensities (high vs. low) on the EEG–MEP relationship. Finally, we used EEG-triggered TMS to determine whether prestimulus EEG oscillations predicted MEP amplitudes.ResultsPrestimulus higher-power alpha/low-beta bands produced larger MEPs only in the high-intensity EO condition. A positive relationship between EEG power and MEP amplitude was observed at C3 and left frontal electrodes. This relationship was obscured when using the lower TMS intensity but was observed in the high-intensity condition at the C3 electrode. EEG-triggered TMS demonstrated that higher alpha power predicted higher MEP amplitudes, but beta power at around 20 Hz did not.ConclusionsA causal relationship between alpha/low-beta oscillations and MEP amplitudes at rest requires high TMS intensity delivered when eyes are open. This association may allow us to develop a new informed open-loop TMS protocol.     

What is said or how it is said makes a difference: role of the right fronto-parietal operculum in emotional prosody as revealed by repetitive TMS

Emotional signals in spoken language can be conveyed by semantic as well as prosodic cues. We investigated the role of the fronto-parietal operculum, a somatosensory area where the lips, tongue and jaw are represented, in the right hemisphere to detection of emotion in prosody vs. semantics. A total of 14 healthy volunteers participated in the present experiment, which involved transcranial magnetic stimulation (TMS) in combination with frameless stereotaxy. As predicted, compared with sham stimulation, TMS over the right fronto-parietal operculum differentially affected the reaction times for detection of emotional prosody vs. emotional semantics, showing that there is a dissociation at a neuroanatomical level. Detection of withdrawal emotions (fear and sadness) in prosody was delayed significantly by TMS. No effects of TMS were observed for approach emotions (happiness and anger). We propose that the right fronto-parietal operculum is not globally involved in emotion evaluation, but sensitive to specific forms of emotional discrimination and emotion types.     

Neurobiological mechanisms of repetitive transcranial magnetic stimulation on the underlying neurocircuitry in unipolar depression

For nearly two decades now, transcranial magnetic stimulation (TMS) has been available as a noninvasive clinical tool to treat patients suffering from major depression. In this period, a bulk of animal and human studies examined TMS parameters to improve clinical outcome. However, the neurobiological mechanisms underlying mood changes remain an important focus of research. In addition to having an effect on neuroendocrinological processes, neurotransmitter systems, and neurotrophic factors, TMS may not only affect the stimulated cortical regions, but also those connected to them. Therefore, we will review current human data on possible neurobiological mechanisms of repetitive (r) TMS implicated in the deregulated neurocircuitry present in unipolar depression. Furthermore, as the rTMS application can be considered as a "top-down" neuronal intervention, we will focus on the neuronal pathways linked with the stimulated area and we will present an integrative model of action.     

Ventral and dorsal stream contributions to the online control of immediate and delayed grasping: A TMS approach

According to Milner and Goodale's theory of the two visual streams, the dorsal (action) stream controls actions in real-time, whereas the ventral (perceptual) stream stores longer-term information for object identification. By this account, the dorsal stream subserves actions carried out immediately. However, when a delay is required before the response, the ventral (perceptual) stream is recruited. Indeed, a neuroimaging study from our lab has found reactivation of an area within the ventral stream, the lateral occipital (LO) cortex, at the time of action even when no visual stimulus was present. To tease apart the contribution of specific areas within the dorsal and ventral streams to the online control of grasping under immediate and delayed conditions, we used transcranial magnetic stimulation (TMS) to the anterior intraparietal sulcus (aIPS) and to LO. We show that while TMS to aIPS affected grasp under both immediate and delayed conditions, TMS to LO influenced grasp only under delayed movement conditions. The effects of TMS were restricted to early movement kinematics (i.e. within 300 ms) due to the transient nature of TMS, which was always delivered simultaneous with movement onset. We discuss the implications of our findings in relation to interactions between the dorsal and ventral streams.     

Clinical application of single-pulse transcranial magnetic stimulation for the treatment of depression

Transcranial magnetic stimulation (TMS) has been recently suggested for the treatment of patients with major depression. Based on the results of the authors' pilot study showing a possible antidepressive effect of single-pulse TMS, a clinical trial was conducted involving patients with major depression. For the present study single-photon emission computed tomography (SPECT) was recorded for six of the target patients to study the effects of TMS on the local blood flow volume. Twenty-three inpatients meeting the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for major depression were invited to participate in the study. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM-D). Patients were given 10 stimuli over the frontal area of both sides for a total of 20 stimuli in a session. The subjects had daily TMS session for 5 days as an add-on therapy. In addition, six patients had their quantitative (99m)Tc-ethyl cysteinate dimer SPECT images measured before and after TMS treatment. Compared with the value 2 days prior to the start of TMS therapy (24.2 +/- 4.9), the average HAM-D scale dropped significantly to 15.3 +/- 6.6 on the day after completion of such therapy. The results of SPECT showed that the regional cerebral blood flow (rCBF) of the bilateral frontal region had increased in four out of six patients when comparing before and after treatment. The present study shows that single-pulse TMS, which is widely used as a neurological test method, possesses a wide range of antidepressive effects without inducing adverse reactions. The results suggest that although repetitive TMS is steadily becoming the mainstay technique today, single-pulse TMS also possesses sufficient antidepressive effects.     

The "special effect" of case mixing on word identification: neuropsychological and transcranial magnetic stimulation studies dissociating case mixing from contrast reduction

We present neuropsychological and transcranial magnetic stimulation (TMS) evidence with normal readers, that the effects of case mixing and contrast reduction on word identification are qualitatively different. Lesions and TMS applied to the right parietal lobe selectively disrupted the identification of mixed relative to single-case stimuli. Bilateral lesions and TMS applied to the occipital cortex selectively disrupted the identification of low-contrast words. These data suggest that different visual distortions (case mixing, contrast reduction) exert different effects on reading, modulated by contrasting brain regions. Case mixing is a "special" distortion and involves the recruitment of processes that are functionally distinct, and dependent on different regions in the brain, from those required to deal with contrast reduction.     

Linking cortical and behavioural inhibition: Testing the parameter specificity of a transcranial magnetic stimulation protocol

Across a series of studies, our laboratory has shown that the efficiency of action stopping is associated with the strength of GABA_A-mediated short-intracortical inhibition (SICI) as measured using transcranial magnetic stimulation (TMS). However, these studies used fixed TMS parameters, which may not optimally probe GABA_A receptor activity for each individual. In the present study, we measured the relationship between stopping efficiency and SICI using a range of TMS parameters. Participants completed a right-hand unimanual stop signal task to obtain a measure of stopping efficiency. Resting-state SICI was measured from the left primary motor cortex using six combinations of interstimulus intervals and conditioning pulse intensities. We also established the parameters which generated the strongest SICI (SICI_max) and weakest SICI (SICI_min) for each individual. We found that stopping efficiency was significantly predicted by SICI using various TMS parameters, including SICI_max. Interestingly, SICI_min accounted for a similar proportion of variance in stopping efficiency as SICI measured using other TMS parameters. The findings suggest that the relationship between stopping efficiency and SICI is robust, reliable, and not influenced by the extent to which SICI is optimally probed.     

The effect of transcranial magnetic stimulation over the cerebellum on the synkinesis of coordinated eye and head movements

We made a study of coordinated saccadic eye and head movements following random and predictable horizontal visual targets by applying transcranial magnetic stimulation (TMS) over the cerebellum before the start of the gaze movement. We have found three effects of TMS on eye/head movements under these conditions. SACCADIC LATENCY-EFFECT: When stimulation took place shortly before movements commenced, significantly shorter latencies were found between target presentation and commencement of saccades: For predictable, to a lesser extent for random targets and TMS up to 75 ms before start of the saccade, latencies were significantly decreased when compared with no application of TMS. Without stimulation, latencies to random targets were within a range of 120-200 ms. EYE-HEAD INTERACTION-EFFECT: Without TMS, for amplitudes greater than 25 degrees, head movements usually preceded eye movements, as expected, especially for predictive responses. With the application of TMS shortly after the target display, the number of eye movements which preceded head movements, was significantly increased (p<0.001), and the delay between eye and head movements was reduced or reversed (p<0.001), compared with gaze movements without the use of TMS. SACCADIC PEAK VELOCITY-EFFECT: Applying transcranial magnetic stimulation at 5-25 ms after the position change of the 60 degrees target, and 50-5 s before the start of eye movement, mean peak velocity of synkinetic saccades increased up to 600 degrees/s, compared with 350-400 degrees/s without the use of TMS.We conclude that transient functional cerebellar deficits caused by the application of TMS can change the central synkinesis of eye-head coordination.     

Right prefrontal TMS versus sham treatment of mania: a controlled study

Objective:  Left prefrontal transcranial magnetic stimulation (TMS) has been reported to have ECT-like effects in depression and we therefore planned a study of TMS in mania. Sixteen patients completed trial of right versus left prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for 10 treatment days. Mania was evaluated using the Mania Scale, the Brief Psychiatric Rating Scale and the Clinical Global Impression. Significantly more improvement was observed in patients treated with right prefrontal TMS than with left prefrontal. We now report a follow-up study of right active TMS versus right sham TMS with the same indications and parameters.
Methods:  Twenty-five patients entered and 19 completed right TMS versus sham right TMS.
Results:  Right TMS was no more effective than sham TMS.
Conclusions:  It is possible that the previous results were due to an effect of left TMS to worsen mania. Alternatively, it is noted that the present patient group had much more psychosis than the previous study of TMS in mania, and depression studies have reported that psychosis is a poor prognostic sign for TMS response.     

Somatotopic blocking of sensation with navigated transcranial magnetic stimulation of the primary somatosensory cortex

We demonstrate that spatially accurate and selective stimulation is crucial when cortical functions are studied by the creation of temporary lesions with transcranial magnetic stimulation (TMS). Previously, the interpretation of the TMS results has been hampered by inaccurate knowledge of the site and strength of the induced electric current in the brain. With a Navigated Brain Stimulation (NBS) system, which provides real-time magnetic resonance image (MRI)-guided targeting of the TMS-induced electric field, we found that TMS of a spatially restricted cortical S1 thenar area is sufficient to abolish sensation from a weak electric stimulation of the corresponding skin area. We demonstrate that with real-time navigation, TMS can be repeatably directed at millimeter-level precision to a target area defined on the MRI. The stimulation effect was temporally and spatially specific: the greatest inhibition of sensation occurred when TMS was applied 20 ms after the cutaneous test stimulus and the TMS effect was sensitive to 8-13 mm displacements of the induced electric field pattern. The results also indicate that TMS selectively to S1 is sufficient to abolish perception of cutaneous stimulation of the corresponding skin area.     

Transcranial magnetic stimulation reduces nociceptive threshold in rats

Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate or inhibit nerve cells in the brain noninvasively. TMS induces an electromagnetic current in the underlying cortical neurons. Varying frequencies and intensities of TMS increase or decrease excitability in the cortical area directly targeted. It has been suggested that TMS has potential in the treatment of some neurological disorders such as Parkinson's disease, stroke, and depression. Initial case reports and open label trials reported by several groups support the use of TMS in pain treatment. In the present study, we evaluated the effect of TMS on the nociceptive threshold in the rat. The parameters used were a frequency of 60 Hz and an intensity of 2 and 6 mT for 2 hr twice per day. After 5 days of TMS treatment, rats were evaluated for mechanical, chemical, and cold stimulation. We observed a significant reduction in the nociceptive threshold in TMS-treated rats but not in sham-treated rats in all behavioral tests evaluated. When TMS treatment was stopped, a slow recovery to normal mechanic threshold was observed. Interestingly, i.c.v. MK-801 or CNQX administration reverted the TMS-induced pronociception. The results suggest that high-frequency TMS can alter the nociceptive threshold and produce allodynia in the rats; results suggest the involvement of NMDA and AMPA/KA receptors on TMS-induced allodynia in the rat.     

Exploring the contributions of the supplementary eye field to subliminal inhibition using double‐pulse transcranial magnetic stimulation

It is widely accepted that the supplementary eye fields (SEF) are involved in the control of voluntary eye movements. However, recent evidence suggests that SEF may also be important for unconscious and involuntary motor processes. Indeed, Sumner et al. ([2007]: Neuron 54:697–711) showed that patients with micro‐lesions of the SEF demonstrated an absence of subliminal inhibition as evoked by masked‐prime stimuli. Here, we used double‐pulse transcranial magnetic stimulation (TMS) in healthy volunteers to investigate the role of SEF in subliminal priming. We applied double‐pulse TMS at two time windows in a masked‐prime task: the first during an early phase, 20–70 ms after the onset of the mask but before target presentation, during which subliminal inhibition is present; and the second during a late phase, 20–70 ms after target onset, during which the saccade is being prepared. We found no effect of TMS with the early time window of stimulation, whereas a reduction in the benefit of an incompatible subliminal prime stimulus was found when SEF TMS was applied at the late time window. These findings suggest that there is a role for SEF related to the effects of subliminal primes on eye movements, but the results do not support a role in inhibiting the primed tendency. Hum Brain Mapp 38:339–351, 2017. © 2016 Wiley Periodicals, Inc.