Test-retest reliability of intrahemispheric dorsal premotor and primary motor cortex dual-site TMS connectivity measures.

OBJECTIVE: Investigating the optimal interstimulus interval (ISI) and the 24-hour test-retest reliability for intrahemispheric dorsal premotor cortex (PMd) - primary motor cortex (M1) connectivity using dual-site transcranial magnetic stimulation (dsTMS). METHODS: In 21 right-handed adults, left intrahemispheric PMd-M1 connectivity has been investigated with a stacked-coil dsTMS setup (conditioning stimulus: 75% of resting motor threshold; test stimulus: eliciting MEPs of 1-1.5 mV) at ISIs of 3, 5-8, and 10 ms. Additionally, M1-M1 short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were investigated to assess comparability to standard paired-pulse setups. RESULTS: Conditioning PMd led to significant inhibition of M1 output at ISIs of 3 and 5 ms, whereas 10 ms resulted in facilitation (all, p < 0.001), with a fair test-retest reliability for 3 (ICC: 0.47) and 6 ms (ICC: 0.44) ISIs. Replication of SICI (p < 0.001) and ICF (p = 0.017) was successful, with excellent test-retest reliability for SICI (ICC: 0.81). CONCLUSION: This dsTMS setup can probe the inhibitory and facilitatory PMd-M1 connections, as well as reliably replicate SICI and ICF paradigms. SIGNIFICANCE: The stacked-coil dsTMS setup for investigating intrahemispheric PMd-M1 connectivity offers promising possibilities to better understand motor control.

Adverse event monitoring and reporting in pediatric neuromodulatory studies: A systematic review.

Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good Clinical Practice and the Harms Extension of the CONSORT (Consolidated Standards of Reporting Trials) Statement, we identified how adverse events are measured, assessed, and reported in studies evaluating neuromodulation for the treatment of mental and neurodevelopmental disorders among children and adolescents. A systematic literature review identified 56 experimental and quasi-experimental studies evaluating transcranial magnetic stimulation (TMS), transcranial alternating (tACS) or direct (tDCS) current stimulation, transcranial pulse stimulation (TPS), and vagus or trigeminal nerve stimulation (VNS or TNS). For 22 studies (39%), the types of adverse events to be monitored were identified, and for 31 studies (55%), methods for collecting adverse event data were described. Methods for assessing adverse events were less commonly described with 23 studies (41%) having details on assessing event severity, and 11 studies (20%) having details on assessing event causality. Among 31 studies with reported results, headache, skin irritation, and general pain or discomfort were the most reported across studies. Seizure, untoward medical occurrences, and intracranial bleeding, edema, or other intracranial pathology were considered serious events, but these events were not reported as occurring in any results-based papers. Taken together, the findings from this review indicate that most studies of pediatric neuromodulatory interventions did not include descriptions of adverse event monitoring and evaluation. Comprehensive event monitoring and reporting across studies can significantly augment the current knowledge base.

Royal Australian and New Zealand College of Psychiatrists professional practice guidelines for the administration of repetitive transcranial magnetic stimulation.

OBJECTIVES: To provide guidance for the optimal administration of repetitive transcranial magnetic stimulation, based on scientific evidence and supplemented by expert clinical consensus. METHODS: Articles and information were sourced from existing guidelines and published literature. The findings were then formulated into consensus-based recommendations and guidance by the authors. The guidelines were subjected to rigorous successive consultation within the RANZCP, involving the Section of ECT and Neurostimulation (SEN) Committee, its broader membership and expert committees. RESULTS: The RANZCP professional practice guidelines (PPG) for the administration of rTMS provide up-to-date advice regarding the use of rTMS in clinical practice. The guidelines are intended for use by psychiatrists and non-psychiatrists engaged in the administration of rTMS to facilitate best practice to optimise outcomes for patients. The guidelines strive to find the appropriate balance between promoting best evidence-based practice and acknowledging that evidence for rTMS use is a continually evolving. CONCLUSION: The guidelines provide up-to-date advice for psychiatrists and non-psychiatrists to promote optimal standards of rTMS practice.

Topography and lateralization of long-latency trigeminal somatosensory evoked potentials.

OBJECTIVE: Long-latency trigeminal somatosensory evoked potentials (SSEPs) have not been sufficiently studied regarding their topography and lateralization. SSEPs are hypothesized to contribute to the evoked potentials after transcranial magnetic stimulation (TMS). This study focused on trigeminal SSEPs with latencies > 100 ms, potentially overlapping with TMS-evoked N100. METHODS: In 14 healthy subjects, the trigeminus was electrically stimulated on the left and right forehead, and time-course, topography, and lateralization of trigeminal SSEPs were examined in 64-channel electroencephalogram (EEG). SSEPs were then compared to TMS-evoked potentials when TMS was applied to the left and right dorsolateral prefrontal cortex. RESULTS: Trigeminal stimulation produced a somatosensory N140 with topographic maximum over centroparietal electrodes with larger amplitudes contra- than ipsilaterally to the stimulation. Contralateral potentials after TMS were partly comparable in their topography but differed in latencies. CONCLUSIONS: SSEPs generated by electrical stimulation of the trigeminus occurred over somatosensory areas with a contralateral lateralization. Therefore, contralateral potentials after TMS should be interpreted with caution, as they may include somatosensory components. SIGNIFICANCE: The topography and lateralization of long-latency trigeminal SSEPs should be considered in future TMS-EEG designs.

Reproducing the effect of hippocampal network-targeted transcranial magnetic stimulation on episodic memory.

Repetitive transcranial magnetic stimulation (rTMS) targeted to the hippocampal network via the inferior parietal cortex (HN-Stim) can strengthen hippocampal-cortical connectivity and improve episodic memory, offering a potential clinical intervention. However, acceptance of this technique has been tempered by the infrequent reproduction of findings in rTMS research on cognitive processes. We tested the reproducibility of the HN-Stim effect on episodic memory in our laboratory using different procedures from those previously published. We tested episodic memory in 29 participants before, one day, and one week after, three consecutive days of 20 Hz HN-Stim. Participants received stimulation targeted to either the area of inferior parietal cortex maximally connected to the left anterior hippocampus (HN-Stim; N = 14) or the vertex (control; N = 15), where we expected no effect. HN-Stim increased episodic memory performance one day, but not one week, after the last stimulation session. While failing to reproduce the lasting beneficial effect on memory found by others after five days of treatment, we found robust effects on behavior 24 h after treatment. HN-Stim is a safe and reliable means of enhancing episodic memory and may have potential for boosting learning and treating memory deficits.

Sham-derived effects and the minimal reliability of theta burst stimulation.

Theta-burst stimulation (TBS) is a patterned form of repetitive transcranial magnetic stimulation (rTMS) that has been used to induce long-term modulation (plasticity) of corticospinal excitability in a drastically shorter duration protocol than conventional rTMS protocols. In this study we tested the reliability of the effects of two well defined TBS protocols, continuous TBS (cTBS) and intermittent TBS (iTBS), especially in relation to sham TBS, within and across the same 24 participants. All TBS protocols were repeated after approximately 1 month to assess the magnitude and reliability of the modulatory effects of each TBS protocol. Baseline and post-TBS changes in motor evoked potentials (MEP-measure of corticospinal excitability) amplitudes were compared across the cTBS, iTBS and sham TBS protocols and between the initial and retest visits. Overall, across participants, at the initial visit, iTBS facilitated MEPs as compared to baseline excitability, with sham eliciting the same effect. cTBS did not show a significant suppression of excitability compared to baseline MEPs at either visit, and even facilitated MEPs above baseline excitability at a single time point during the repeat visit. Otherwise, effects of TBS were generally diminished in the repeat visit, with iTBS and sham TBS replicating facilitation of MEPs above baseline excitability at similar time points. However, no protocol demonstrated consistent intra-individual modulation of corticospinal excitability upon retest. As the first study to test both iTBS and cTBS against sham TBS across repeat visits, our findings challenge the efficacy and reliability of TBS protocols and emphasize the importance of accounting for sham effects of TBS. Furthermore, given that therapeutic effects of TBS are hypothetically derived from consistent and repeated modulation of brain activity, the non-replicability of plasticity and sham effects call into question these basic mechanisms.

The reliability of cerebellar brain inhibition.

OBJECTIVE: Connectivity between the cerebellum and primary motor cortex (M1) can be assessed by using transcranial magnetic stimulation to measure cerebellar brain inhibition (CBI). The aim of the present study was to determine the intra- and inter-day measurment error and relative reliability of CBI. The former informs the degree to which repeated measurements vary, whereas the latter informs how well the measure can distinguish individuals from one another within a sample. METHODS: We obtained CBI data from 83 healthy young participants (n = 55 retrospective). Intra-day measurements were separated by ~ 30 min. Inter-day measurmenets were separated by a minimum of 24 h. RESULTS: We show that CBI has low measurement error (~15%) within and between sessions. Using the measurment error, we demonstrate that change estimates which exceed measurment noise are large at an individual level, but can be detected with modest sample sizes. Finally, we demonstrate that the CBI measurement has fair to good relative reliability in healthy individuals, which may be deflated by low sample heterogeneity. CONCLUSIONS: CBI has low measurement error supporting its use for tracking intra- and inter-day changes in cerebellar-M1 connectivity. SIGNIFICANCE: Our findings provide clear reliability guidelines for future studies assessing modulation of cerebellar-M1 connectivity with intervention or disease progression.

Effect of racial background on motor cortical function as measured by threshold tracking transcranial magnetic stimulation.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

Large-scale analysis of interindividual variability in single and paired-pulse TMS data.

OBJECTIVE: This study brought together over 60 transcranial magnetic stimulation (TMS) researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability. METHODS: Authors of previously published studies were contacted and asked to share deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and paired-pulse TMS data. RESULTS: 687 healthy participant's data were pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual's single-pulse TMS amplitude. Baseline motor evoked potential amplitude, motor cortex hemisphere, and motor threshold (MT) significantly predicted short-interval intracortical inhibition response. Baseline motor evoked potential amplitude, test stimulus intensity, interstimulus interval, and MT significantly predicted intracortical facilitation response. Age, hemisphere, and TMS machine significantly predicted MT. CONCLUSIONS: This large-scale analysis has identified a number of factors influencing participants' responses to single and paired-pulse TMS. We provide specific recommendations to minimise interindividual variability in single and paired-pulse TMS data. SIGNIFICANCE: This study has used large-scale analyses to give clarity to factors driving variance in TMS data. We hope that this ongoing collaborative approach will increase standardisation of methods and thus the utility of single and paired-pulse TMS.

Degree of improving TMS focality through a geometrically stable solution of an inverse TMS problem.

The Transcranial Magnetic Stimulation (TMS) inverse problem (TMS-IP) investigated in this study aims to focus the TMS induced electric field close to a specified target point defined on the gray matter interface in the M1HAND area while otherwise minimizing it. The goal of the study is to numerically evaluate the degree of improvement of the TMS-IP solutions relative to the well-known sulcus-aligned mapping (a projection approach with the 90∘ local sulcal angle). In total, 1536 individual TMS-IP solutions have been analyzed for multiple target points and multiple subjects using the boundary element fast multipole method (BEM-FMM) as the forward solver. Our results show that the optimal TMS inverse-problem solutions improve the focality - reduce the size of the field "hot spot" and its deviation from the target - by approximately 21-33% on average for all considered subjects, all observation points, two distinct coil types, two segmentation types, two intracortical observation surfaces under study, and three tested values of the field threshold. The inverse-problem solutions with the maximized focality simultaneously improve the TMS mapping resolution (differentiation between neighbor targets separated by approximately 10 mm) although this improvement is quite modest. Coil position/orientation and conductivity uncertainties have been included into consideration as the corresponding de-focalization factors. The present results will change when the levels of uncertainties change. Our results also indicate that the accuracy of the head segmentation critically influences the expected TMS-IP performance.

Mapping of multiple muscles with transcranial magnetic stimulation: absolute and relative test-retest reliability.

The spatial accuracy of transcranial magnetic stimulation (TMS) may be as small as a few millimeters. Despite such great potential, navigated TMS (nTMS) mapping is still underused for the assessment of motor plasticity, particularly in clinical settings. Here, we investigate the within-limb somatotopy gradient as well as absolute and relative reliability of three hand muscle cortical representations (MCRs) using a comprehensive grid-based sulcus-informed nTMS motor mapping. We enrolled 22 young healthy male volunteers. Two nTMS mapping sessions were separated by 5-10 days. Motor evoked potentials were obtained from abductor pollicis brevis (APB), abductor digiti minimi, and extensor digitorum communis. In addition to individual MRI-based analysis, we studied normalized MNI MCRs. For the reliability assessment, we calculated intraclass correlation and the smallest detectable change. Our results revealed a somatotopy gradient reflected by APB MCR having the most lateral location. Reliability analysis showed that the commonly used metrics of MCRs, such as areas, volumes, centers of gravity (COGs), and hotspots had a high relative and low absolute reliability for all three muscles. For within-limb TMS somatotopy, the most common metrics such as the shifts between MCR COGs and hotspots had poor relative reliability. However, overlaps between different muscle MCRs were highly reliable. We, thus, provide novel evidence that inter-muscle MCR interaction can be reliably traced using MCR overlaps while shifts between the COGs and hotspots of different MCRs are not suitable for this purpose. Our results have implications for the interpretation of nTMS motor mapping results in healthy subjects and patients with neurological conditions.

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

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.

Reliability of the TMS-conditioned monosynaptic reflex in the flexor carpi radialis muscle.

A subthreshold pulse of transcranial magnetic stimulation (TMS) on the motor cortex can modulate the amplitude of the monosynaptic reflex (H-reflex) elicited in the flexor carpi radialis (FCR) muscle, a method known as TMS-conditioning of the H-reflex. The purpose of this study was to establish the intersession reliability of this method over the course of three sessions. Eleven healthy participants received either peripheral nerve stimulation (PNS), TMS or a combination of the two. The intensity of the PNS stimuli was set to evoke a monosynaptic response (H-reflex) corresponding to 10 % of the maximum motor response (Mmax), HM10 %. The conditioning effect of TMS on the monosynaptic reflex was assessed by delivering subthreshold cortical pulses at different conditioning-test intervals (from -7 ms to 7 ms) from peripheral nerve stimulation. The first interval at which facilitation could be observed was deemed early facilitation (EF). Using intraclass correlation coefficients (ICCs), we found excellent reliability for Mmax amplitudes (ICC = 0.98), HM10 % amplitudes (ICC = 0.85) and TMS-conditioned H-reflexes recorded at the interval following EF (EF + 2 ms) (ICC = 0.87). Good reliability (ICCs ranging from 0.67 to 0.77) was found for the other conditioning-test intervals. We conclude that TMS-conditioned H-reflexes are reliable parameters to assess the excitability of corticospinal circuits.

Last Resort Interventions?: A Qualitative Study of Psychiatrists' Experience with and Views on Psychiatric Electroceutical Interventions.

Psychiatrists play an important role in providing access to psychiatric electrical interventions (PEIs) such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). As such, their views on these procedures likely influence whether they refer or provide these types of treatments for their clinically depressed patients. Despite this, scholars have too infrequently examined psychiatrists' views about specific PEIs and have not yet examined their views across different PEIs. To gain insight into psychiatrists' views about PEIs, we conducted a qualitative study based on semi-structured interviews with 16 psychiatrists in Michigan. The majority of psychiatrists had a positive attitude towards PEIs in general. One-third reported cautionary attitudes towards PEIs; they did not reject the interventions but were skeptical of their effectiveness or felt they needed further development. The majority of psychiatrists consider ECT and TMS to be viable therapies that they would discuss with their patients after several failed medication trials. There was a lack of knowledge about surgical PEIs, such as deep brain stimulation. This study provides insights into how psychiatrists perceive PEIs. While broadly positive attitudes exist, this research highlights certain challenges, particularly lack of knowledge and ambiguity about the use of PEIs.

Reliability of transcallosal inhibition measurements for the lower limb motor cortex in stroke.

Transcallosal inhibition (TCI) is a measure of between-hemisphere inhibitory control that can be evaluated with the ipsilateral silent period (iSP) transcranial magnetic stimulation (TMS) paradigm. The study of iSP for the lower extremity has been limited possibly due to the close orientation of the lower extremity motor representations. Change in TCI can provide insights into pathophysiological mechanisms underlying the asymmetry in corticomotor excitability in stroke. Here, we describe a method for iSP quantification and report reliability of iSP parameters for the tibialis anterior (TA) muscle in stroke. 26 individuals with stroke attended three sessions where single pulse TMS was used to measure TCI from the lesioned to non-lesioned hemisphere. A double cone coil was used for stimulating the ipsilateral motor cortex while the participant maintained an isometric contraction of the non-paretic TA. Absolute and relative reliability were computed for iSP latency, duration and area. iSP latency showed the lowest measurement error (absolute reliability) and iSP latency, duration and area showed good relative reliability (intraclass correlation coefficients > 0.6). This study suggests that iSP parameters for the tibialis anterior are reliable and attempts to provide a guideline for evaluating TCI for the lower extremity in stroke and other clinical populations.