A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

A novel paired associative stimulation protocol with a high-frequency peripheral component: A review on results in spinal cord injury rehabilitation.

In recent decades, a multitude of therapeutic approaches has been developed for spinal cord injury (SCI), but few have progressed to regular clinical practice. Novel non-invasive, cost-effective, and feasible approaches to treat this challenging condition are needed. A novel variant of paired associative stimulation (PAS), high-PAS, consists of non-invasive high-intensity transcranial magnetic stimulation (TMS) and non-invasive high-frequency electrical peripheral nerve stimulation (PNS). We observed a therapeutic effect of high-PAS in 20 patients with incomplete SCI with wide range of injury severity, age, and time since injury. Tetraplegic and paraplegic, traumatic, and neurological SCI patients benefited from upper- or lower-limb high-PAS. We observed increases in manual motor scores (MMT) of upper and lower limbs, functional hand tests, walking tests, and measures of functional independence. We also optimized PAS settings in several studies in healthy subjects and began elucidating the mechanisms of therapeutic action. The scope of this review is to describe the clinical experience gained with this novel PAS approach. This review is focused on the summary of our results and observations and the methodological considerations for researchers and clinicians interested in adopting and further developing this new method.

Localization of Sensorimotor Cortex Using Navigated Transcranial Magnetic Stimulation and Magnetoencephalography.

The mapping of the sensorimotor cortex gives information about the cortical motor and sensory functions. Typical mapping methods are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG). The differences between these mapping methods are, however, not fully known. TMS center of gravities (CoGs), MEG somatosensory evoked fields (SEFs), corticomuscular coherence (CMC), and corticokinematic coherence (CKC) were mapped in ten healthy adults. TMS mapping was performed for first dorsal interosseous (FDI) and extensor carpi radialis (ECR) muscles. SEFs were induced by tactile stimulation of the index finger. CMC and CKC were determined as the coherence between MEG signals and the electromyography or accelerometer signals, respectively, during voluntary muscle activity. CMC was mapped during the activation of FDI and ECR muscles separately, whereas CKC was measured during the waving of the index finger at a rate of 3-4 Hz. The maximum CMC was found at beta frequency range, whereas maximum CKC was found at the movement frequency. The mean Euclidean distances between different localizations were within 20 mm. The smallest distance was found between TMS FDI and TMS ECR CoGs and longest between CMC FDI and CMC ECR sites. TMS-inferred localizations (CoGs) were less variable across participants than MEG-inferred localizations (CMC, CKC). On average, SEF locations were 8 mm lateral to the TMS CoGs (p < 0.01). No differences between hemispheres were found. Based on the results, TMS appears to be more viable than MEG in locating motor cortical areas.

Protocol for motor and language mapping by navigated TMS in patients and healthy volunteers; workshop report.

INTRODUCTION: Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value. METHODS: The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications. RESULTS: nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here. CONCLUSION: At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.

Neurophysiologic markers of primary motor cortex for laryngeal muscles and premotor cortex in caudal opercular part of inferior frontal gyrus investigated in motor speech disorder: a navigated transcranial magnetic stimulation (TMS) study.

Transcranial magnetic stimulation studies have so far reported the results of mapping the primary motor cortex (M1) for hand and tongue muscles in stuttering disorder. This study was designed to evaluate the feasibility of repetitive navigated transcranial magnetic stimulation (rTMS) for locating the M1 for laryngeal muscle and premotor cortical area in the caudal opercular part of inferior frontal gyrus, corresponding to Broca's area in stuttering subjects by applying new methodology for mapping these motor speech areas. Sixteen stuttering and eleven control subjects underwent rTMS motor speech mapping using modified patterned rTMS. The subjects performed visual object naming task during rTMS applied to the (a) left M1 for laryngeal muscles for recording corticobulbar motor-evoked potentials (CoMEP) from cricothyroid muscle and (b) left premotor cortical area in the caudal opercular part of inferior frontal gyrus while recording long latency responses (LLR) from cricothyroid muscle. The latency of CoMEP in control subjects was 11.75 ± 2.07 ms and CoMEP amplitude was 294.47 ± 208.87 µV, and in stuttering subjects CoMEP latency was 12.13 ± 0.75 ms and 504.64 ± 487.93 µV CoMEP amplitude. The latency of LLR in control subjects was 52.8 ± 8.6 ms and 54.95 ± 4.86 in stuttering subjects. No significant differences were found in CoMEP latency, CoMEP amplitude, and LLR latency between stuttering and control-fluent speakers. These results indicate there are probably no differences in stuttering compared to controls in functional anatomy of the pathway used for transmission of information from premotor cortex to the M1 cortices for laryngeal muscle representation and from there via corticobulbar tract to laryngeal muscles.

Cortical Excitability Measured with nTMS and MEG during Stroke Recovery.

OBJECTIVE: Stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere. Stroke recovery has been studied using transcranial magnetic stimulation (TMS). Spontaneous brain oscillations and somatosensory evoked fields (SEFs) measured by magnetoencephalography (MEG) are modified in stroke patients during recovery. METHODS: We recorded SEFs and spontaneous MEG activity and motor threshold (MT) short intracortical inhibition (SICI) and intracortical facilitation (ICF) with navigated TMS (nTMS) at one and three months after first-ever hemispheric ischemic strokes. Changes of MEG and nTMS parameters attributed to gamma-aminobutyrate and glutamate transmission were compared. RESULTS: ICF correlated with the strength and extent of SEF source areas depicted by MEG at three months. The nTMS MT and event-related desynchronization (ERD) of beta-band MEG activity and SICI and the beta-band MEG event-related synchronization (ERS) were correlated, but less strongly. CONCLUSIONS: This first report using sequential nTMS and MEG in stroke recovery found intra- and interhemispheric correlations of nTMS and MEG estimates of cortical excitability. ICF and SEF parameters, MT and the ERD of the lesioned hemisphere, and SICI and ERS of the nonlesioned hemisphere were correlated. Covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system.

Applicability of nTMS in locating the motor cortical representation areas in patients with epilepsy.

BACKGROUND: Transcranial magnetic stimulation (TMS) is increasingly used for non-invasive functional mapping in preoperative evaluation for brain surgery, and the reliability of navigated TMS (nTMS) motor representation maps has been studied in the healthy population and in brain tumor patients. The lesions behind intractable epilepsy differ from typical brain tumors, ranging from developmental cortical malformations to injuries early in development, and may influence the functional organization of the cortical areas. Moreover, the interictal cortical epileptic activity and antiepileptic medication may affect the nTMS motor threshold. The reliability of the nTMS motor representation localization in epilepsy patients has not been addressed. METHODS: We compared the nTMS motor cortical representation maps of hand and arm muscles with the results of invasive electrical cortical stimulation (ECS) in 13 patients with focal epilepsy. The nTMS maps were projected to the cortical surface segmented from preoperative magnetic resonance images (MRI), and the positions of the subdural electrodes were extracted from the postoperative low-dose computed tomography (CT) images registered with preoperative MRI. RESULTS: The 3D distance between the average nTMS site and average ECS electrode location was 11 ± 4 mm for the hand and 16 ± 7 mm for arm muscle representation areas. In all patients the representation areas defined with nTMS and ECS were located on the same gyrus, also in patients with abundant interictal epileptic activity on the motor gyrus. CONCLUSIONS: nTMS can reliably locate the hand motor cortical representation area with the accuracy needed for pre-surgical evaluation in patients with epilepsy.

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

DELMEP: a deep learning algorithm for automated annotation of motor evoked potential latencies.

The analysis of motor evoked potentials (MEPs) generated by transcranial magnetic stimulation (TMS) is crucial in research and clinical medical practice. MEPs are characterized by their latency and the treatment of a single patient may require the characterization of thousands of MEPs. Given the difficulty of developing reliable and accurate algorithms, currently the assessment of MEPs is performed with visual inspection and manual annotation by a medical expert; making it a time-consuming, inaccurate, and error-prone process. In this study, we developed DELMEP, a deep learning-based algorithm to automate the estimation of MEP latency. Our algorithm resulted in a mean absolute error of about 0.5 ms and an accuracy that was practically independent of the MEP amplitude. The low computational cost of the DELMEP algorithm allows employing it in on-the-fly characterization of MEPs for brain-state-dependent and closed-loop brain stimulation protocols. Moreover, its learning ability makes it a particularly promising option for artificial-intelligence-based personalized clinical applications.

TMS-Induced Modulation of EEG Functional Connectivity Is Affected by the E-Field Orientation.

Coregistration of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows non-invasive probing of brain circuits: TMS induces brain activation due to the generation of a properly oriented focused electric field (E-field) using a coil placed on a selected position over the scalp, while EEG captures the effects of the stimulation on brain electrical activity. Moreover, the combination of these techniques allows the investigation of several brain properties, including brain functional connectivity. The choice of E-field parameters, such as intensity, orientation, and position, is crucial for eliciting cortex-specific effects. Here, we evaluated whether and how the spatial pattern, i.e., topography and strength of functional connectivity, is modulated by the stimulus orientation. We systematically altered the E-field orientation when stimulating the left pre-supplementary motor area and showed an increase of functional connectivity in areas associated with the primary motor cortex and an E-field orientation-specific modulation of functional connectivity intensity.

TMS combined with EEG: Recommendations and open issues for data collection and analysis.

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS-EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS-EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS-EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS-EEG covered all aspects that should be considered in TMS-EEG experiments, providing methodological recommendations (when possible) for effective TMS-EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS-EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

Probing modifications of cortical excitability during stroke recovery with navigated transcranial magnetic stimulation.

OBJECTIVE: To follow cortical excitability changes during recovery from stroke with navigated transcranial magnetic stimulation (nTMS), in particular, to characterize changes of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), to correlate them with recovery of upper extremity function, and to detect possible shifts of cortical hand representations. METHODS: Single and paired pulse nTMS were delivered to the hemisphere with infarction and to the hemisphere without infarction in 14 first-ever stroke patients at 1 (T1) and 3 months (T2) after stroke. Electromyographic responses to nTMS stimulation were recorded from the first dorsal interosseus muscles. nTMS was used to ensure an accurate coil repositioning in repeated measurements. Hand function recovery was clinically evaluated using the Action Research Arm Test (ARAT) and 9-hole peg test (9-HPT). RESULTS: SICI and ICF were modulated in both hemispheres during recovery. Inhibition in the hemisphere without infarction correlated significantly with the affected hand performance at T2; stronger disinhibition (poor inhibition) was associated with worse hand performance. Location of hand muscle representations was shifted in 3 well-recovered patients out of 14 patients at T2. CONCLUSIONS: In line with earlier studies, disinhibition in the hemisphere without infarction may be related to poor recovery of the affected hand. Usage of the affected hand during stroke recovery seems to influence these cortical excitability changes. nTMS is a valuable tool for tracking muscle cortical representation changes during brain reorganization.

The role of neuronavigation in TMS-EEG studies: Current applications and future perspectives.

Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) allows measuring non-invasively the electrical response of the human cerebral cortex to a direct perturbation. Complementing TMS-EEG with a structural neuronavigation tool (nTMS-EEG) is key for accurately selecting cortical areas, targeting them, and adjusting the stimulation parameters based on some relevant anatomical priors. This step, together with the employment of visualization tools designed to perform a quality check of TMS-evoked potentials (TEPs) in real-time during TMS-EEG data acquisition, is pivotal for maximizing the impact of the TMS pulse on the cortex and in ensuring highly reproducible measurements within sessions and across subjects. Moreover, storing stimulation parameters in the neuronavigation system can help in replicating the stimulation parameters within and across experimental sessions and sharing them across research centers. Finally, the systematic employment of neuronavigation in TMS-EEG studies is also critical to standardize measurements in clinical populations in search for reliable diagnostic and prognostic TMS-EEG-based biomarkers for neurological and psychiatric disorders.

Stochastic resonance at early visual cortex during figure orientation discrimination using transcranial magnetic stimulation.

Visual noise usually reduces the visibility of stimuli. However, very low contrast or subliminal visual noise can sometimes enhance the visibility of low-contrast stimuli. It has been suggested that this enhancement occurs at the visual cortex. The aims of this study are to clarify the role of the early visual cortex (V1/V2) in the enhancement effect and to clarify the relationship of the SR characteristics among different experiments. Noise was added directly to the visual cortex by using transcranial magnetic stimulation (TMS) with randomly varying intensity. The location on the scalp and the timing (stimulus onset asynchrony, SOA) of TMS were specifically adjusted to target the early visual cortex. Contrast thresholds for figure orientation discrimination were measured as a function of TMS noise intensity. With increasing TMS noise intensity the contrast threshold for figure discrimination first decreased (enhancement) and then increased (impairment). These effects were clearly dependent both on scalp location and timing (SOA). The optimum SOA was around 60 ms, while the optimum location varied across participants. Outside the optimum location and SOA values, no TMS effects were found. The enhancement effect can be accounted for by the stochastic resonance (SR) theory based on a threshold device. In addition, we reveal similarity in characteristics of the SR phenomenon between different experiments.

State-dependent TMS effects in the visual cortex after visual adaptation: A combined TMS-EEG study.

OBJECTIVE: The impact of transcranial magnetic stimulation (TMS) has been shown to depend on the initial brain state of the stimulated cortical region. This observation has led to the development of paradigms that aim to enhance the specificity of TMS effects by using visual/luminance adaptation to modulate brain state prior to the application of TMS. However, the neural basis of interactions between TMS and adaptation is unknown. Here, we examined these interactions by using electroencephalography (EEG) to measure the impact of TMS over the visual cortex after luminance adaptation. METHODS: Single-pulses of neuronavigated TMS (nTMS) were applied at two different intensities over the left visual cortex after adaptation to either high or low luminance. We then analyzed the effects of adaptation on the global and local cortical excitability. RESULTS: The analysis revealed a significant interaction between the TMS-evoked responses and the adaptation condition. In particular, when nTMS was applied with high intensity, the evoked responses were larger after adaptation to high than low luminance. CONCLUSION: This result provides the first neural evidence on the interaction between TMS with visual adaptation. SIGNIFICANCE: TMS can activate neurons differentially as a function of their adaptation state.

Closed-loop optimization of transcranial magnetic stimulation with electroencephalography feedback.

BACKGROUND: Transcranial magnetic stimulation (TMS) is widely used in brain research and treatment of various brain dysfunctions. However, the optimal way to target stimulation and administer TMS therapies, for example, where and in which electric field direction the stimuli should be given, is yet to be determined. OBJECTIVE: To develop an automated closed-loop system for adjusting TMS parameters (in this work, the stimulus orientation) online based on TMS-evoked brain activity measured with electroencephalography (EEG). METHODS: We developed an automated closed-loop TMS-EEG set-up. In this set-up, the stimulus parameters are electronically adjusted with multi-locus TMS. As a proof of concept, we developed an algorithm that automatically optimizes the stimulation orientation based on single-trial EEG responses. We applied the algorithm to determine the electric field orientation that maximizes the amplitude of the TMS-EEG responses. The validation of the algorithm was performed with six healthy volunteers, repeating the search twenty times for each subject. RESULTS: The validation demonstrated that the closed-loop control worked as desired despite the large variation in the single-trial EEG responses. We were often able to get close to the orientation that maximizes the EEG amplitude with only a few tens of pulses. CONCLUSION: Optimizing stimulation with EEG feedback in a closed-loop manner is feasible and enables effective coupling to brain activity.

Local brain-state dependency of effective connectivity: a pilot TMS-EEG study.

Background: Spontaneous cortical oscillations have been shown to modulate cortical responses to transcranial magnetic stimulation (TMS). However, whether these oscillations influence cortical effective connectivity is largely unknown. We conducted a pilot study to set the basis for addressing how spontaneous oscillations affect cortical effective connectivity measured through TMS-evoked potentials (TEPs). Methods: We applied TMS to the left primary motor cortex and right pre-supplementary motor area of three subjects while recording EEG. We classified trials off-line into positive- and negative-phase classes according to the mu and beta rhythms. We calculated differences in the global mean-field amplitude (GMFA) and compared the cortical spreading of the TMS-evoked activity between the two classes. Results: Phase affected the GMFA in four out of 12 datasets (3 subjects × 2 stimulation sites × 2 frequency bands). Two of the observed significant intervals were before 50 ms, two between 50 and 100 ms, and one after 100 ms post-stimulus. Source estimates showed complex spatial differences between the classes in the cortical spreading of the TMS-evoked activity. Conclusions: TMS-evoked effective connectivity seems to depend on the phase of local cortical oscillations at the stimulated site. This work paves the way to design future closed-loop stimulation paradigms.

Dose-response of intermittent theta burst stimulation of the prefrontal cortex: A TMS-EEG study.

OBJECTIVE: Using concurrent transcranial magnetic stimulation (TMS) and electroencephalography (TMS-EEG), this study aims to compare the effect of three intermittent theta-burst stimulation (iTBS) doses on cortical activity in the left dorsolateral prefrontal (DLPFC) cortex. METHODS: Fourteen neurotypical participants took part in the following three experimental conditions: 600, 1200 and 1800 pulses. TMS-EEG recordings were conducted on the left DLPFC pre/post iTBS, including single-pulse TMS and short- and long-interval intracortical inhibition (SICI, LICI). TMS-evoked potentials (TEP) and event-related spectral perturbation (ERSP) were quantified. Linear mixed models were used to assess the effect of iTBS on brain activity. RESULTS: The effects of iTBS on DLPFC activity did not significantly differ between the three doses. Specifically, regardless of dose, iTBS modulated the amplitude of most TEP components (P30, N45, P60, P200), reduced SICI and LICI ratios of P30 and P200, and decreased ERSP power of theta oscillations. CONCLUSIONS: In neurotypical individuals, doubling or tripling the number of iTBS pulses does not result in stronger potentiation of prefrontal activity. However, all iTBS conditions induced significant modulations of DLPFC activity. SIGNIFICANCE: Replicating the study in clinical populations could help define optimal parameters for clinical applications.

A New Paired Associative Stimulation Protocol with High-Frequency Peripheral Component and High-Intensity 20 Hz Repetitive Transcranial Magnetic Stimulation-A Pilot Study.

Paired associative stimulation (PAS) is a stimulation technique combining transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) that can induce plastic changes in the human motor system. A PAS protocol consisting of a high-intensity single TMS pulse given at 100% of stimulator output (SO) and high-frequency 100-Hz PNS train, or "the high-PAS" was designed to promote corticomotoneuronal synapses. Such PAS, applied as a long-term intervention, has demonstrated therapeutic efficacy in spinal cord injury (SCI) patients. Adding a second TMS pulse, however, rendered this protocol inhibitory. The current study sought for more effective PAS parameters. Here, we added a third TMS pulse, i.e., a 20-Hz rTMS (three pulses at 96% SO) combined with high-frequency PNS (six pulses at 100 Hz). We examined the ability of the proposed stimulation paradigm to induce the potentiation of motor-evoked potentials (MEPs) in five human subjects and described the safety and tolerability of the new protocol in these subjects. In this study, rTMS alone was used as a control. In addition, we compared the efficacy of the new protocol in five subjects with two PAS protocols consisting of PNS trains of six pulses at 100 Hz combined with (a) single 100% SO TMS pulses (high-PAS) and (b) a 20-Hz rTMS at a lower intensity (three pulses at 120% RMT). The MEPs were measured immediately after, and 30 and 60 min after the stimulation. Although at 0 and 30 min there was no significant difference in the induced MEP potentiation between the new PAS protocol and the rTMS control, the MEP potentiation remained significantly higher at 60 min after the new PAS than after rTMS alone. At 60 min, the new protocol was also more effective than the two other PAS protocols. The new protocol caused strong involuntary twitches in three subjects and, therefore, its further characterization is needed before introducing it for clinical research. Additionally, its mechanism plausibly differs from PAS with high-frequency PNS that has been used in SCI patients.

Single-Pulse Transcranial Magnetic Stimulation-Evoked Potential Amplitudes and Latencies in the Motor and Dorsolateral Prefrontal Cortex among Young, Older Healthy Participants, and Schizophrenia Patients.

BACKGROUND: The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) allows for non-invasive investigation of cortical response and connectivity in human cortex. This study aimed to examine the amplitudes and latencies of each TMS-evoked potential (TEP) component induced by single-pulse TMS (spTMS) to the left motor (M1) and dorsolateral prefrontal cortex (DLPFC) among healthy young participants (YNG), older participants (OLD), and patients with schizophrenia (SCZ). METHODS: We compared the spatiotemporal characteristics of TEPs induced by spTMS among the groups. RESULTS: Compared to YNG, M1-spTMS induced lower amplitudes of N45 and P180 in OLD and a lower amplitude of P180 in SCZ, whereas the DLPFC-spTMS induced a lower N45 in OLD. Further, OLD demonstrated latency delays in P60 after M1-spTMS and in N45-P60 over the right central region after left DLPFC-spTMS, whereas SCZ demonstrated latency delays in N45-P60 over the midline and right central regions after DLPFC-spTMS. CONCLUSIONS: These findings suggest that inhibitory and excitatory mechanisms mediating TEPs may be altered in OLD and SCZ. The amplitude and latency changes of TEPs with spTMS may reflect underlying neurophysiological changes in OLD and SCZ, respectively. The spTMS administered to M1 and the DLPFC can probe cortical functions by examining TEPs. Thus, TMS-EEG can be used to study changes in cortical connectivity and signal propagation from healthy to pathological brains.