Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates.

Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report new methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in awake monkeys (Macaca mulatta). We recorded action potentials within ∼1 ms after 0.4-ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared with sham stimulation. This methodology is compatible with standard equipment in primate laboratories, allowing easy implementation. Application of these tools will facilitate the refinement of next generation TMS devices, experiments and treatment protocols

Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper

Copyright © 2022 The Author(s) and International Federation of Clinical Neurophysiology. Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.Aman S. Aberra was supported by a U. S. A. National Science Foundation Graduate Research Fellowship (No. DGF 1106401). Andrea Antal has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01GP2124B) and by a grant of the Lower Saxony Ministry of Science and Culture (Grant 76251-12-7/19 ZN 3456). Marco Davare has been supported by a BBSRC responsive mode grant. Klaus Funke has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01EE1403B) as part of the German Center for Brain Stimulation (GCBS) and by the Deutsche Forschungsgemeinschaft (DFG) (Grants FU256/3-2; 122679504–SFB874). Mark Hallett is supported by the NINDS Intramural Program. Anke N. Karabanov holds a 4-year Sapere Aude Fellowship which is sponsored by the Independent Research Fund Denmark (Grant Nr. 0169-00027B). The sponsor had no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Giacomo Koch has been supported by na EU grant H2020-EU.1.2.2. - FET Proactive (Neurotwin ID: 101017716). Sabine Meunier is Emeritus Research Director at INSERM, this has no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Carlo Miniussi has been supported by a grant of the Caritro Foundation, Italy. Walter Paulus received grants from the Deutsche Forschungsgemeinschaft and BMBF. Angel V. Peterchev was supported by grants from the U. S. A. National Institutes of Health (Grants Nos. R01NS117405, R01NS088674, RF1MH114268, R01MH111865). Traian Popa has been supported by the Defitech Foundation and NIBS-iCog grant from the Swiss National Science Foundation. Hartwig R. Siebner holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant Nr. R186-2015-2138). The salary for Janine Kesselheim (PhD project) has been covered by a project grant “Biophysically adjusted state-informed cortex stimulation” (BASICS) funded by a synergy grant from Novo Nordisk Foundation (PI: Hartwig R Siebner, Interdisciplinary Synergy Program 2014; grant number NNF14OC001). Axel Thielscher has been supported by grants of the Lundbeck foundation (R118-A11308, R244-2017-196 and R313-2019-622). Yoshikazu Ugawa has been supported in part by grants from the Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Grants 15H05881, 16H05322, 19H01091, 20K07866). Ulf Ziemann received grants from the German Ministry of Education and Research (BMBF), European Research Council (ERC), and German Research Foundation (DFG)

Noninvasive Detection of Motor-Evoked Potentials in Response to Brain Stimulation Below the Noise Floor-How Weak Can a Stimulus Be and Still Stimulate.

Motor-evoked potentials (MEP) are one of the most important responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. The understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smallest responses, e.g., from single motor units, but available detection and quantization methods are rather simple and suffer from a large noise floor. The paper introduces a more sophisticated matched-filter detection method that increases the detection sensitivity and shows that activation occurs well below the conventional detection level. In consequence, also conventional threshold definitions, e.g., as 50 μV median response amplitude, turn out to be substantially higher than the point at which first detectable responses occur. The presented method uses a matched-filter approach for improved sensitivity and generates the filter through iterative learning from the presented data. In contrast to conventional peak-to-peak measures, the presented method has a higher signal-to-noise ratio (≥14 dB). For responses that are reliably detected by conventional detection, the new approach is fully compatible and provides the same results but extends the dynamic range below the conventional noise floor. The underlying method is applicable to a wide range of well-timed biosignals and evoked potentials, such as in electroencephalography.NI

Effects of transcranial magnetic stimulation coil orientation and pulse width on short-latency afferent inhibition

Purpose We used a controllable pulse parameter transcranial magnetic stimulation (cTMS) device to assess whether adjusting pulse width and coil orientation would allow more selective stimulation of different neuronal populations. Methods Young healthy subjects participated in experiments involving single pulse stimulation over the hand motor area elicited by a cTMS device connected to a figure-of-eight coil. Experiment 1 (n=10) evaluated the effect of coil orientation (posterior-anterior, PA; anterior-posterior, AP) and pulse width (30, 60 and 120 μs) on the strength-duration curve, the input-output (IO) curve and the latency of the motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Experiment 2 (n=12) evaluated the effect of coil orientations (PA, AP) and pulse width (30 and 120 μs) on short-latency afferent inhibition (SAI), tested with electrical median nerve stimulation at the wrist prior to TMS (inter-stimulus intervals: N20 latency +2 and +4 ms). All tests were completed during background contraction (∼10% maximum). Results The mean strength-duration time constants were shorter for PA than AP directed currents when estimated using motor threshold data (231 vs. 294 μs; t-test, p = 0.008) and IO data (252 vs. 296 μs; t-test, p < 0.001). ANOVA revealed an interaction of pulse width and orientation on MEP latencies (p = 0.001), due mainly to the increase in latencies with short duration AP stimuli. A similar pulse width and orientation interaction was observed for SAI (p = 0.011), resulting from the stronger inhibition with AP stimuli of short duration. Conclusion PA and AP oriented pulses appear to activate neural populations with different time constants. The AP-sensitive neural populations that elicit the longest latency MEPs are more readily stimulated by short than by long duration pulses, and appear more sensitive to SAI. Manipulating pulse width may improve the selectivity of AP stimulation

Online repetitive transcranial magnetic stimulation during working memory in younger and older adults: A randomized within-subject comparison.

Working memory is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. The ability to manipulate information in working memory is central to many aspects of human cognition, but also declines with healthy aging. Given the profound importance of such working memory manipulation abilities, there is a concerted effort towards developing approaches to improve them. The current study tested the capacity to enhance working memory manipulation with online repetitive transcranial magnetic stimulation in healthy young and older adults. Online high frequency (5Hz) repetitive transcranial magnetic stimulation was applied over the left dorsolateral prefrontal cortex to test the hypothesis that active repetitive transcranial magnetic stimulation would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in working memory manipulation conditions with the highest cognitive demand in both young and older adults. Repetitive transcranial magnetic stimulation was applied while participants were performing a delayed response alphabetization task with three individually-titrated levels of difficulty. The left dorsolateral prefrontal cortex was identified by combining electric field modeling to individualized functional magnetic resonance imaging activation maps and was targeted during the experiment using stereotactic neuronavigation with real-time robotic guidance, allowing optimal coil placement during the stimulation. As no accuracy differences were found between young and older adults, the results from both groups were collapsed. Subsequent analyses revealed that active stimulation significantly increased accuracy relative to sham stimulation, but only for the hardest condition. These results point towards further investigation of repetitive transcranial magnetic stimulation for memory enhancement focusing on high difficulty conditions as those most likely to exhibit benefits

International randomized-controlled trial of transcranial Direct Current Stimulation in depression

Background Evidence suggests that transcranial Direct Current Stimulation (tDCS) has antidepressant effects in unipolar depression, but there is limited information for patients with bipolar depression. Additionally, prior research suggests that brain derived neurotrophic factor (BDNF) Val66Met genotype may moderate response to tDCS. Objective To examine tDCS efficacy in unipolar and bipolar depression and assess if BDNF genotype is associated with antidepressant response to tDCS. Methods 130 participants diagnosed with a major depressive episode were randomized to receive active (2.5 milliamps (mA), 30 min) or sham (0.034 mA and two 60-second current ramps up to 1 and 0.5 mA) tDCS to the left prefrontal cortex, administered in 20 sessions over 4 weeks, in a double-blinded, international multisite study. Mixed effects repeated measures analyses assessed change in mood and neuropsychological scores in participants with at least one post-baseline rating in the unipolar (N = 84) and bipolar (N = 36) samples. Results Mood improved significantly over the 4-week treatment period in both unipolar (p = 0.001) and bipolar groups (p < 0.001). Among participants with unipolar depression, there were more remitters in the sham treatment group (p = 0.03). There was no difference between active and sham stimulation in the bipolar sample. BDNF genotype was unrelated to antidepressant outcome. Conclusions Overall, this study found no antidepressant difference between active and sham stimulation for unipolar or bipolar depression. However, the possibility that the low current delivered in the sham tDCS condition was biologically active cannot be discounted. Moreover, BDNF genotype did not moderate antidepressant outcome. Clinical Trials Registration www.clinicaltrials.gov, NCT01562184

Transcranial electrical stimulation nomenclature

Transcranial electrical stimulation (tES) aims to alter brain function non-invasively by applying current to electrodes on the scalp. Decades of research and technological advancement are associated with a growing diversity of tES methods and the associated nomenclature for describing these methods. Whether intended to produce a specific response so the brain can be studied or lead to a more enduring change in behavior (e.g. for treatment), the motivations for using tES have themselves influenced the evolution of nomenclature, leading to some scientific, clinical, and public confusion. This ambiguity arises from (i) the infinite parameter space available in designing tES methods of application and (ii) varied naming conventions based upon the intended effects and/or methods of application. Here, we compile a cohesive nomenclature for contemporary tES technologies that respects existing and historical norms, while incorporating insight and classifications based on state-of-the-art findings. We consolidate and clarify existing terminology conventions, but do not aim to create new nomenclature. The presented nomenclature aims to balance adopting broad definitions that encourage flexibility and innovation in research approaches, against classification specificity that minimizes ambiguity about protocols but can hinder progress. Constructive research around tES classification, such as transcranial direct current stimulation (tDCS), should allow some variations in protocol but also distinguish from approaches that bear so little resemblance that their safety and efficacy should not be compared directly. The proposed framework includes terms in contemporary use across peer-reviewed publications, including relatively new nomenclature introduced in the past decade, such as transcranial alternating current stimulation (tACS) and transcranial pulsed current stimulation (tPCS), as well as terms with long historical use such as electroconvulsive therapy (ECT). We also define commonly used terms-of-the-trade including electrode, lead, anode, and cathode, whose prior use, in varied contexts, can also be a source of confusion. This comprehensive clarification of nomenclature and associated preliminary proposals for standardized terminology can support the development of consensus on efficacy, safety, and regulatory standards

Individualized Low-Amplitude Seizure Therapy: Minimizing Current for Electroconvulsive Therapy and Magnetic Seizure Therapy

Electroconvulsive therapy (ECT) at conventional current amplitudes (800–900 mA) is highly effective but carries the risk of cognitive side effects. Lowering and individualizing the current amplitude may reduce side effects by virtue of a less intense and more focal electric field exposure in the brain, but this aspect of ECT dosing is largely unexplored. Magnetic seizure therapy (MST) induces a weaker and more focal electric field than ECT; however, the pulse amplitude is not individualized and the minimum amplitude required to induce a seizure is unknown. We titrated the amplitude of long stimulus trains (500 pulses) as a means of determining the minimum current amplitude required to induce a seizure with ECT (bilateral, right unilateral, bifrontal, and frontomedial electrode placements) and MST (round coil on vertex) in nonhuman primates. Furthermore, we investigated a novel method of predicting this amplitude-titrated seizure threshold (ST) by a non-convulsive measurement of motor threshold (MT) using single pulses delivered through the ECT electrodes or MST coil. Average STs were substantially lower than conventional pulse amplitudes (112–174 mA for ECT and 37.4% of maximum device amplitude for MST). ST was more variable in ECT than in MST. MT explained 63% of the ST variance and is hence the strongest known predictor of ST. These results indicate that seizures can be induced with less intense electric fields than conventional ECT that may be safer; efficacy and side effects should be evaluated in clinical studies. MT measurement could be a faster and safer alternative to empirical ST titration for ECT and MST