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Objective: The extent of plastic responses of motor cortex (M1) to paired associative stimulation (PAS) varies among healthy subjects. Continuous theta-burst stimulation (cTBS) of cerebellum enhances the mean PAS-induced plasticity in groups of healthy subjects. We tested whether the initial status of Responder or Non-Responder to PAS, influenced the effect of cerebellar stimulation on PAS-induced plasticity. Methods: We assessed in 19 young healthy volunteers (8 Responders, 11 Non-Responders to PAS), how cTBS and iTBS (intermittent TBS) applied to the cerebellum before a PAS protocol influenced the plastic responsiveness of M1 to PAS. We tested whether the PAS-induced plastic effects could be depotentiated by a short cTBS protocol applied to M1 shortly after PAS and whether cerebellar stimulation influenced GABA-ergic intracortical inhibition and M1 plasticity in parallel. Results: Cerebellar cTBS restored the M1 response to PAS in Non-Responders while cerebellar iTBS turned the potentiating response to PAS to a depressive response in both groups. The depotentiation protocol abolished both responses. Conclusion: Non-Responder status to PAS is a state of M1 amenable to bidirectional plastic modulation when primed by a change in cerebello-thalamic drive. Significance: The meaning of lack of responsiveness to certain protocols probing plasticity should be reconsidered. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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.

Background Over the past decade, the number of experimental and clinical studies using theta-burst-stimulation (TBS) protocols of transcranial magnetic stimulation (TMS) to modulate brain activity has risen substantially. The use of TBS is motivated by the assumption that these protocols can reliably and lastingly modulate cortical excitability despite their short duration and low number of stimuli. However, this assumption, and thus the experimental validity of studies using TBS, is challenged by recent work showing large inter- and intra-subject variability in response to TBS protocols. Objectives To date, the reproducibility of TBS effects in humans has been exclusively assessed with motor evoked potentials (MEPs), which provide an indirect and limited measure of cortical excitability. Here we combined TMS with electroencephalography (TMS-EEG) and report the first comprehensive investigation of (1) direct TMS-evoked cortical responses to intermittent (iTBS) and continuous TBS (cTBS) of the human motor cortex, and (2) reproducibility of both iTBS- and cTBS-induced cortical response modulation against a robust sham control across repeat visits with commonly used cortical responsivity metrics. Results We show that although single pulse TMS generates stable and reproducible cortical responses across visits, the modulatory effects of TBS vary substantially both between and within individuals. Overall, at the group level, most measures of the iTBS and cTBS-induced effects were not significantly different from sham-TBS. Most importantly, none of the significant TBS-induced effects observed in visit-1 were reproduced in visit-2. Conclusions Our findings suggest that the generally accepted mechanisms of TBS-induced neuromodulation, i.e. through changes in cortical excitability, may not be accurate. Future research is needed to determine the mechanisms underlying the established therapeutic effects of TBS in neuropsychiatry and examine reproducibility of TBS-induced neuromodulation through oscillatory response dynamics.

Theta-burst transcranial magnetic stimulation (TBS) has become a standard non-invasive technique to induce offline changes in cortical excitability in human volunteers. Yet, TBS suffers from a high variability across subjects. A better knowledge about how TBS affects neural activity in vivo could uncover its mechanisms of action and ultimately allow its mainstream use in basic science and clinical applications. To address this issue, we applied continuous TBS (cTBS, 300 pulses) in awake behaving rhesus monkeys and quantified its after-effects on neuronal recordings and behavior. Guided by anatomical MRI, we recorded single-cell activity in parietal area PFG during passive fixation of real-world objects. Overall, we observed a pronounced, long-lasting and highly reproducible reduction in neuronal excitability after cTBS in individual parietal neurons, with some neurons exhibiting periods of hyperexcitability during the recovery phase. We applied the same stimulation protocol during visually-guided grasping of objects, and observed a significant grasping impairment. These results provide the first experimental evidence on the effects of cTBS on single neurons in awake behaving monkeys.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

In everyday life, risky decision-making relies on multiple cognitive processes including sensitivity to reinforcers, exploration, learning, and forgetting. Neuroimaging evidence suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in exploration and risky decision-making, but the nature of its computations and its causal role remain uncertain. We provide evidence for the role of the DLPFC in value-independent, directed exploration on the Iowa Gambling Task (IGT) and we describe a new computational model to account for the competition of directed exploration and exploitation in guiding decisions. Forty-two healthy human participants were included in a right DLPFC, left DLPFC or sham stimulation groups using continuous theta-burst stimulation (cTBS). Immediately after cTBS, the IGT was completed. Computational modelling was used to account for exploration and exploitation with different combinations with value-based and sensitivity to reinforcers for each group. Applying cTBS to the left and right DLPFC selectively decreased directed exploration on the IGT compared to sham stimulation. Model-based analyses further indicated that the right (but not the left) DLPFC stimulation increased sensitivity to reinforcers, leading to avoidance of risky choices and promoting advantageous choices during the task. Although these findings are based on small sample sizes per group, they nevertheless elucidate the causal role of the right DLPFC in governing the exploration-exploitation tradeoff during decision-making in uncertain and ambiguous contexts.

Introduction: Theta-burst stimulation (TBS) is a safe non-invasive neurostimulation technique used to improve cognitive and neuropsychiatric impairments. Combined outcome evaluation using event-related potentials (ERPs) and neuropsychological tests may allow a more thorough assessment of TBS treatment efficacy; however, some mixed results have been found, and their use remains scarce. Our main objective was to evaluate whether a session of TBS to the left dorsolateral prefrontal cortex (DLPFC) can impact upon the performance of both neuropsychological and neurophysiological tests. Methods: This double-blind sham-controlled study involved 28 healthy adults, between 18 and 30 years. Volunteers were randomly allocated to receive excitatory (intermittent [iTBS]), inhibitory (continuous TBS [cTBS]) or sham stimulation on the left DLPFC. Subjects were evaluated using ERPs (auditory oddball paradigm P300) and neuropsychological tests (Trail making test [TMT] and Stroop test of words and colours [STWC]), using a pre-post stimulation protocol. Results: Inhibitory stimulation led to significantly delayed P300 peak latencies (p < 0.001), with no consistent change in N2P3 amplitudes. cTBS also significantly influenced the expected group performance in Stroop C and Stroop interference (p = 0.025) compared to the iTBS and sham groups. No significant results were found in TMT tests after TBS. Conclusion: Our results suggest that P300 and specific Stroop colour and words test parameters can be similarly influenced by the same TBS protocol. This emphasizes the importance of mixed evaluation using neuropsychological and neurophysiological resources in research associated with the use of transcranial magnetic stimulation and cognition.

Objective The main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism. Methods Intermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers. Results We found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype. Conclusions Enhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects. Significance Since γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.

Background Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS. Objective To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS. Methods Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed. Results The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS. Conclusion QPS is more effective and stable for synaptic plasticity induction than TBS.

Motor memories become resistant to interference by the process of consolidation, which leads to long-term retention. Studies have shown involvement of the somatosensory cortex in motor learning-related plasticity, but not directly in motor memory consolidation. This Neuro Forum article reviews evidence from a continuous theta-burst transcranial magnetic stimulation (cTBS) study by Kumar and colleagues (Kumar N, Manning TF, Ostry DJ. PLoS Biol 17: e3000469, 2019) that demonstrates the role of somatosensory, rather than motor, cortex in human motor memory consolidation during implicit motor learning.

Background: 18F-fluorodeoxyglucose PET/CT is recommended as an optional study in the current NCCN Clinical Practice Guidelines in Oncology for Breast Cancer after CT of the chest, abdomen, and pelvis with contrast and bone scan (CTBS) in stage IIA–IIIC breast cancer. We evaluated our experience with the use of PET/CT in this setting before beginning primary systemic therapy (PST) prior to planned surgery. Methods: We performed medical record abstractions of all adult female patients with clinical stage IIA–IIIC breast cancer diagnosed at Montefiore Medical Center from January 1, 2014, through January 1, 2019, who underwent PET/CT before PST. We calculated the proportion of patients upstaged after PET/CT and examined the cost and radiation exposure associated with PET/CT compared with CTBS. Results: A total of 195 patients with 196 breast cancers (bilateral disease in 1 patient) met the study inclusion criteria and had PET/CT as the first imaging study before PST. The overall upstaging rate for regional nodal metastasis and/or distant metastasis was 37% (73/196), including 24% for stage IIA (9/38), 39% for stage IIB (31/79), 54% for stage IIIA (22/41), 27% for stage IIIB (8/30), and 37% for stage IIIC (3/8). The overall upstaging rate for distant metastasis was 14% (27/196), including 0% for stage IIA, 13% for stage IIB (10/79), 22% for stage IIIA (9/41), 17% for stage IIIB (5/30), and 37% for stage IIIC (3/8). Medicare reimbursement rates were $1,604.37 for PET/CT and $1,679.94 for CTBS. The radiation dose for PET/CT was 14 mSv versus 21 mSv for CTBS. Conclusions: Approximately 37% of patients with clinical stage IIA–IIIC breast cancer who underwent PET/CT before PST showed more extensive disease, including 23% with more extensive nodal metastasis and 14% with distant metastasis. Given its high detection rate, comparable cost, lower radiation dose, and greater convenience, PET/CT should be considered as an alternative to CTBS rather than “optional” after CTBS, especially in patients who require an efficient and expeditious workup before initiating PST.

Background Many studies have attempted to identify the sources of interindividual variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. Objective/Hypothesis This study brought together over 60 TMS researchers to form the ‘Big TMS Data Collaboration’, and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response variability. Methods 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response variability. Results 430 healthy participants’ TBS data was pooled across 22 studies (mean age = 41.9; range = 17–82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. Conclusions This is the largest known study of interindividual variability in TBS. Our findings indicate that a significant portion of variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of variability.

We recently proposed a neurocognitive model of distancing-an emotion regulation tactic-with a focus on the lateral parietal cortex. Although this brain area has been implicated in both cognitive control and self-projection processes during distancing, fMRI work suggests that these processes may be dissociable here. This preregistered (NCT03698591) study tested the contribution of left temporoparietal junction (TPJ) to distancing using repetitive transcranial magnetic stimulation. We hypothesized that inhibiting left TPJ would decrease the efficiency of distancing but not distraction, another regulation tactic with similar cognitive control requirements, thus implicating this region in the self-projection processes unique to distancing. Active and sham continuous theta burst stimulation (cTBS) were applied to 30 healthy adults in a single-session crossover design. Tactic efficiency was measured using online reports of valence and effort. The stimulation target was established from the group TPJ fMRI activation peak in an independent sample using the same distancing task, and anatomical MRI scans were used for individual targeting. Analyses employed both repeated-measures ANOVA and analytic procedures tailored to crossover designs. Irrespective of cTBS, distancing led to greater decreases in negative valence over time relative to distraction, and distancing effort decreased over time while distraction effort remained stable. Exploratory analyses also revealed that active cTBS made distancing more effortful, but not distraction. Thus, left TPJ seems to support self-projection processes in distancing, and these processes may be facilitated by repeated use. These findings help to clarify the role of lateral parietal cortex in distancing and inform applications of distancing and distraction.

Background Neuroimaging studies suggest that facial expression recognition is processed in the bilateral posterior superior temporal sulcus (pSTS). Our recent repetitive transcranial magnetic stimulation (rTMS) study demonstrates that the bilateral pSTS is causally involved in expression recognition, although involvement of the right pSTS is greater than involvement of the left pSTS. Objective /Hypothesis: In this study, we used a dual-site TMS to investigate whether the left pSTS is functionally connected to the right pSTS during expression recognition. We predicted that if this connection exists, simultaneous TMS disruption of the bilateral pSTS would impair expression recognition to a greater extent than unilateral stimulation of the right pSTS alone. Methods Participants attended two TMS sessions. In Session 1, participants performed an expression recognition task while rTMS was delivered to the face-sensitive right pSTS (experimental site), object-sensitive right lateral occipital complex (control site) or no rTMS was delivered (behavioural control). In Session 2, the same experimental design was used, except that continuous theta-burst stimulation (cTBS) was delivered to the left pSTS immediately before behavioural testing commenced. Session order was counter-balanced across participants. Results In Session 1, rTMS to the rpSTS impaired performance accuracy compared to the control conditions. Crucially in Session 2, the size of this impairment effect doubled after cTBS was delivered to the left pSTS. Conclusions Our results provide evidence for a causal functional connection between the left and right pSTS during expression recognition. In addition, this study further demonstrates the utility of the dual-site TMS for investigating causal functional links between brain regions., Highlights • Dual-site TMS was used to test causal functional connectivity between left and right pSTS during expression recognition. • rTMS impaired facial expression recognition when delivered to the right pSTS during a facial expression recognition task. • cTBS delivered to the left pSTS prior to the task doubled the impairment effect of rTMS to the right pSTS during the task. • The results demonstrate causal functional connectivity between the left and right pSTS during expression recognition. • The results also demonstrate the utility of dual-site TMS for investigating interregional causal functional connectivity.

Although the cerebellum is not among the most renowned brain structures affected in Alzheimer`s disease (AD), recent evidence suggest that it undergoes degenerative changes during the course of the disease. A main neurophysiological feature of AD patients is the remarkable impairment of long term potentiation (LTP)-like cortical plasticity assessed in the primary motor cortex (M1) using theta burst stimulation (TBS) protocols. In healthy conditions, continuous (cTBS) and intermittent TBS (iTBS) of the cerebellum induce respectively long term depression (LTD)-like and LTP-like after effects in the contralateral M1. Here we aimed at examining the effects of cerebellar TBS on contralateral M1 excitability in a sample of 15 AD patients and 12 healthy age matched controls (HS). Motor evoked potentials (MEPs) were obtained in the contralateral M1 before and after cerebellar cTBS and iTBS protocols. As compared to HS, AD patients showed an impairment of LTP-like cortical plasticity mechanisms following cerebellar iTBS. No difference was observed for the cTBS protocol, in which both populations exhibited the expected LTD-like after effect. This study shows that mechanisms of cerebellar-cortical plasticity are impaired in AD. Given its role in high order cognitive functions, new potential therapeutic strategies could be built up in the future to modulate neural activity in the cerebellum in AD.

Background Through transcranial magnetic stimulation (TMS) it is possible to change cortical excitability of the visual cortex, and to influence binocular balance. The main goal of our study is to assess the effect of transcranial magnetic stimulation, specifically theta burst stimulation (TBS), in a group of amblyopic volunteers measuring several visual parameters: visual acuity, suppressive imbalance, and stereoacuity. Methods Thirteen volunteers aged 19 to 24 years, randomly split in 2 groups, underwent 1 session of continuous TBS, stimulating the right occipital lobe. The first group with 8 volunteers was exposed to active stimulation with cTBS, and the other group with 5 volunteers was exposed to placebo stimulation. Results Significant improvements in visual acuity, suppressive imbalance, and stereoacuity were found in the amblyopic eye after cTBS. The average value of amblyopia in visual acuity before stimulation was 0.32 ± 0.20 logMar and after cTBS was 0.19 ± 0.17 logMar. The mean value for the control group before placebo stimulation was 0.28 ± 0.17 and after placebo stimulation was 0.28 ± 0.16. The suppressive imbalance in the group of amblyope subjects stimulated before cTBS was 0.26 ± 0.18 and after was 0.12 ± 0.12; the suppressive imbalance of the control group before the placebo stimulation was 0.34 ± 0.37 and after was 0.32 ± 0.40. Conclusions Visual acuity, suppressive imbalance, and stereoacuity had significant enhancements compared with baseline after cTBS over the right occipital lobe in an ambliopic population.

Prior functional magnetic resonance imaging (fMRI) studies indicate that a core network of brain regions, including the hippocampus, is jointly recruited during episodic memory, episodic simulation, and divergent creative thinking. Because fMRI data are correlational, it is unknown whether activity increases in the hippocampus, and the core network more broadly, play a causal role in episodic simulation and divergent thinking. Here we employed fMRI-guided transcranial magnetic stimulation (TMS) to assess whether temporary disruption of hippocampal brain networks impairs both episodic simulation and divergent thinking. For each of two TMS sessions, continuous θ-burst stimulation (cTBS) was applied to either a control site (vertex) or to a left angular gyrus target region. The target region was identified on the basis of a participant-specific resting-state functional connectivity analysis with a hippocampal seed region previously associated with memory, simulation, and divergent thinking. Following cTBS, participants underwent fMRI and performed a simulation, divergent thinking, and nonepisodic control task. cTBS to the target region reduced the number of episodic details produced for the simulation task and reduced idea production on divergent thinking. Performance in the control task did not statistically differ as a function of cTBS site. fMRI analyses revealed a selective and simultaneous reduction in hippocampal activity during episodic simulation and divergent thinking following cTBS to the angular gyrus versus vertex but not during the nonepisodic control task. Our findings provide evidence that hippocampal-targeted TMS can specifically modulate episodic simulation and divergent thinking, and suggest that the hippocampus is critical for these cognitive functions.

Objectives: To synthesise the existing literature investigating if acute aerobic exercise enhances the response to experimentally-induced neuroplasticity paradigms. Methods: A systematic search of electronic databases Medline, PsycInfo and Embase was undertaken on 26 April 2018 and updated on 17 May 2019. Studies were included if they involved a bout of aerobic exercise; prescribed a bout of rest as a control condition; utilized a non-invasive brain stimulation paradigm to induce neuroplasticity; used TMS to assess neuroplasticity outcomes; participants were healthy 18-65 year old males and females with no diagnosed neurological/psychological impairments. Results: Eight papers (containing 12 experiments) met inclusion criteria. All studies utilized cycling or treadmill exercise as their exercise modality, and exercise intensity ranged from low intensity continuous exercise to high-intensity interval exercise. Four neuroplasticity paradigms were employed including paired associative stimulation (PAS) (n = 3), continuous theta-burst stimulation (cTBS) (n = 2), intermittent theta-burst stimulation (iTBS) (n = 2) and transcranial direct current stimulation (n = 1). Aerobic exercise enhanced neuroplastic responses (compared to rest) in seven of the 12 experiments. Conclusions: This review provides emerging evidence that acute aerobic exercise can enhance the response to experimentally-induced neuroplasticity paradigms. However, there remains great variability in the study design and reporting of effects in these studies and thus a more standardized approach is encouraged to better understand the relationship between acute aerobic exercise and neuroplasticity. Future studies should consider optimizing intensity, paradigms and duration of both exercise and neuroplasticity paradigms employed. Refereed/Peer-reviewed

Introduction The vergence oculomotor system possesses two robust adaptive mechanisms; a fast “dynamic” and a slow “tonic” system that are both vital for single, clear and comfortable binocular vision. The neural substrates underlying these vergence adaptive mechanisms in humans is unclear. Methods We investigated the role of the posterior cerebellum in convergence adaptation using inhibitory continuous theta-burst repetitive transcranial magnetic stimulation (cTBS) within a double-blind, sham controlled design while eye movements were recorded at 250hz via infrared oculography. Results In a preliminary experiment we validated our stimulation protocols by reproducing results from previous work on saccadic adaptation during the classic double-step adaptive shortening paradigm. Following this, across a series of three separate experiments we observed a clear dissociation in the effect of cTBS on convergence adaptation. Dynamic adaptation was substantially reduced while tonic adaptation was unaffected. Baseline dynamic fusional vergence response were also unaffected by stimulation. Conclusions These results indicate a differential role for the posterior cerebellum in the adaptive control of convergence eye movements and provide initial evidence that repetitive transcranial magnetic stimulation is a viable tool to investigate the neurophysiology of vergence control. The results are discussed in the context of the current models of implicit motor adaptation of vergence and their application to clinical populations and technology design in virtual and augmented head mounted display architectures. Significance statement The cerebellum plays a critical role in the adaptive control of motor systems. Vergence eye movements shift our gaze in depth allowing us to see in 3D and exhibit two distinct adaptive mechanisms that are engaged under a range of conditions including reading, wearing head-mounted displays and using a new spectacle prescription. It is unclear what role the cerebellum plays in these adaptive mechanisms. To answer this, we temporarily disrupted the function of the posterior cerebellum using non-invasive brain stimulation and report impairment of only one adaptive mechanism, providing evidence for neural compartmentalization. The results have implications for vergence control models and applications to comfort and experience studies in head-mounted displays and the rehabilitation of clinical populations exhibiting vergence dysfunctions.

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit partially distinct brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used noninvasive network-based continuous theta burst stimulation (cTBS) in human subjects (male and female) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that, relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus–outcome associations. These findings suggest that activity in the targeted OFC network supports decision-making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free control of behavior.SIGNIFICANCE STATEMENTIt is widely accepted that the orbitofrontal cortex (OFC) is important for decision-making. However, it is less clear how exactly this region contributes to behavior. Here we test the hypothesis that the human OFC is only required for decision-making when future outcomes have to be mentally simulated, but not when direct experience with stimulus–outcome associations is available. We show that targeting OFC network activity in humans using network-based continuous theta burst stimulation selectively impairs behavior that requires inference but does not affect responding that can be based solely on direct experience. These results are in line with previous findings in animals and suggest a critical role for human OFC in model-based but not model-free behavior.

Contains fulltext : 216048pub.pdf (Publisher’s version ) (Open Access) While much progress has been made in how brain organization supports language function, the language network's ability to adapt to immediate disturbances by means of reorganization remains unclear. The aim of this study was to examine acute reorganizational changes in brain activity related to conceptual and lexical retrieval in unimpaired language production following transient disruption of the left middle temporal gyrus (MTG). In a randomized single-blind within-subject experiment, we recorded the electroencephalogram from 16 healthy participants during a context-driven picture-naming task. Prior to the task, the left MTG was perturbed with real continuous theta-burst stimulation (cTBS) or sham stimulation. During the task, participants read lead-in sentences creating a constraining (e.g., "The farmer milks the") or nonconstraining context (e.g., "The farmer buys the"). The last word was shown as a picture that participants had to name (e.g., "cow"). Replicating behavioral studies, participants were overall faster in naming pictures following a constraining relative to a nonconstraining context, but this effect did not differ between real and sham cTBS. In contrast, real cTBS increased overall error rates compared to sham cTBS. In line with previous studies, we observed a decrease in alpha-beta (8-24 Hz) oscillatory power for constraining relative to nonconstraining contexts over left temporal- parietal cortex after participants received sham cTBS. However, following real cTBS, this decrease extended toward left prefrontal regions associated with both domain-general and domain-specific control mechanisms. Our findings provide evidence that immediately after perturbing the left MTG, the lexical-semantic network is able to quickly reconfigure, also recruiting domain-general regions. 11 p.

Background: Opoid use disorder (OUD) is a global illness and reduction in craving by repeatative Transcranial Magnetic Stimulation (RTMS) is one of its management approaches. Orbito-frontal Cortex is implicated in the several behavioral aspects of substance use including craving. Brain derived neurotrophic factor (BDNF) has a critical role in addictive properties of drugs of use. Previous studies have shown significant improvement in craving with RTMS and demonstrated alterations of serum BDNF levels in various substance dependent individual associated with craving. Aim: To examine the efficacy of continuous Theta Burst Stimulation RTMS (CTBS-RTMS) over the right OFC as an adjunct to Naltrexone in patients of OUD and its correlation with serum BDNF levels. Methods: Forty patients with OUD were recruited with purposive sampling. At the end of detoxification CTBS -RTMS was applied by dividing them into two equal groups as active and sham group using alternate allocation. Obsessive compulsive drug use scale (OCDUS) was applied and serum BDNF level was measured overtime till the end of CTBS-RTMS session. Data was analyzed by SPSS version 25. Results: Both groups had shown significant reduction in craving (OCDUS score) and serum BDNF from the baseline to 14th session of the RTMS. But there was no significant difference when compared between the two groups. Significant correlation was observed between serum BDNF levels overtime with different clinical variables in active group. Conclusion: The study adds to the literature in building an understanding of how rTMS could be used in reducing cravings for opioids.

More than a decade of neuroimaging and brain stimulation studies point to a crucial role for the right dorsolateral prefrontal cortex (rDLPFC) in prosocial behavior. The intuitive prosociality model postulates that the rDLPFC controls intuitive prosocial behavior, whereas the reflective model assumes that the rDLPFC controls selfish impulses during prosocial behavior. The intuitive prosociality model implies that the transient disruption of the rDLPFC should increase voluntary transfers in both dictator and generosity games. In contrast, the reflective model suggests that the transient disruption of the rDLPFC should decrease transfers in the dictator game, without affecting voluntary transfers in the generosity game, in which selfish motives are minimized. The aim of this paper was to compare predictions of the intuitive and reflective models using the classic dictator game and generosity game and continuous theta burst stimulation (cTBS). In this study, two groups of healthy participants (dictators) received either cTBS over the rDLPFC or right extrastriate visual areas. As shown by the results, the transient disruption of the rDLPFC significantly promoted prosocial motives in the dictator game only, particularly in the trials with the lowest dictator’s costs. These findings partially support the notion that the rDLPFC controls intuitive prosocial behavior.

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta burst stimulation (cTBS) is a form of TMS which has been observed to reduce motor evoked potentials (MEPs) for 60 minutes or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral or in subjects receiving a sham stimulation.One Sentence SummaryWe used glutamate-weighted Chemical Exchange Saturation Transfer (GluCEST) imaging to detect changes in glutamate contrast in the brains of young, healthy adults undergoing transcranial magnetic stimulation (TMS) to the motor cortex.

Attentive motion tracking deficits measured using multiple object tracking (MOT) tasks have been identified in a number of neurodevelopmental disorders such as amblyopia and autism. These deficits are often attributed to the abnormal development of high-level attentional networks. However, neuroimaging evidence from amblyopia suggests that reduced MOT performance can be explained by impaired function in motion-sensitive area MT+ alone. To test the hypothesis that a subtle disruption of MT+ function could cause MOT impairment, we assessed whether continuous theta burst stimulation (cTBS) of MT+ influenced MOT task accuracy in individuals with normal vision. The MOT stimulus consisted of four target and four distractor dots and was presented at ±10° eccentricity (right/left hemifield). fMRI-guided cTBS was applied to left MT+. Participants (n = 13, age: 27 ± 3) attended separate active and sham cTBS sessions where the MOT task was completed before, 5-min post- and 30-min post-cTBS. Active cTBS significantly impaired MOT task accuracy relative to baseline for the right (stimulated) hemifield 5-min (10 ± 2% reduction) and 30-min (14 ± 3% reduction) post-stimulation. No impairment occurred within the left (control) hemifield after active cTBS or for either hemifield after sham cTBS. These results highlight the importance of lower level motion processing for MOT, suggesting that a minor disruption of MT+ function alone is sufficient to cause a deficit in MOT performance.

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS., Placenta accreta spectrum (PAS) is a high-risk obstetrical complication associated with significant morbidity and mortality. Here the authors discover a uniquely high prevalence of circulating trophoblasts clusters in PAS and explore their diagnostic potential to augment current diagnostic modalities for the early detection of PAS.

IntroductionPostoperative delirium is one of the most common postoperative complications among elderly patients (65 years old or older). However, there are no effective treatments for this condition. Recent research suggests that continuous theta burst stimulation (cTBS), a non-invasive brain stimulation, can reduce pain level, improve cognitive function and affective symptoms in multiple diseases or dysfunctions, including anxiety disorders, major depressive disorder, sleep disorders and pain. But the potential benefits of cTBS in reducing postoperative delirium have not been investigated. Therefore, we propose determining whether cTBS can prevent and/or treat postoperative delirium in senior patients.Methods and analysisThe study will be a double-blind, randomised controlled trial. Participants (65 years old or older) undergoing scheduled orthopaedic surgery (≥2 hours, general anaesthesia) will be randomised to receive either cTBS or sham stimulation with a focal figure-of-eight coil over the right dorsolateral prefrontal cortex at 80% of the resting motor threshold. Every patient will receive 2–3 sets of stimulations during postoperative days (40 s per session, 3 sessions per set, 1 set per day). Participants will be assessed twice daily by a research assistant blinded to allocation. The primary outcome will be the incidence of postoperative delirium measured by the Confusion Assessment Method on postoperative days 1, 2 and 3. The secondary outcomes will be the severity and duration of postoperative delirium, cognitive function, pain, sleep quality, activities of daily living, length of hospital stay, discharge-to-facility or home, and rate of complication and mortality during the hospital stay.Ethics and disseminationEthical approval has been obtained from the ethics committee of Shanghai 10th People’s Hospital. The principal investigator will submit a research progress report to the ethics committee regularly. All participants will provide written informed consent. Study results will be published in a peer-reviewed journal.Trial registration numberNCT04661904.

Problem Cell-free fetal DNA (cffDNA) shed from the placenta can be detected in maternal blood and increases incrementally during gestation. Concentrations are further elevated with pregnancy complications. Specific activators of cffDNA release in such complications have not been identified. Here, we use trophoblast cells from early and term placenta to examine cffDNA release following apoptosis, infection, and sterile inflammatory stress. Method of study HTR8/SVneo cells were used to model first-trimester trophoblasts, and term cytotrophoblasts (CTBs) were isolated from placentae collected after uncomplicated deliveries. Trophoblasts were treated with varying concentrations of doxorubicin (DOX), lipopolysaccharide (LPS), or high-mobility group box protein 1 (HMGB1) for 18 h. Cells or supernatants were quantified for caspase-3/7 cleavage, pro-inflammatory cytokine secretion, and cffDNA release. Results Both HTR8/SVneo and CTBs underwent caspase-3/7 cleavage following DOX treatment, with HTR8/SVneo cells more sensitive to apoptosis than term CTBs. Apoptotic cells released more cffDNA in a dose-dependent manner. Treatment with LPS resulted in an increase in pro-inflammatory IL-6 release, particularly in term CTBs compared to early trophoblasts; however, LPS did not affect cffDNA release. Lastly, while neither cell released more TNF-α following stimulation with HMGB1, both HTR8/SVneo and CTBs released significantly more cffDNA in the presence of HMGB1. Conclusions These data show that apoptosis and sterile inflammation induced by DOX and HMGB1, respectively, cause an increase in cffDNA concentrations in both first-trimester and term trophoblasts. Understanding physiologic release of cffDNA during healthy and complicated pregnancy can identify new targets for the diagnosis and treatment of gestational complications.

Human cognition is often biased. It is a fundamental question in psychology how cognitive bias is modulated in the human brain. Automatic action tendency is a typical cognitive bias. The dorsolateral prefrontal cortex (DLPFC) is a crucial area for processing various behavioral tasks. We investigated the functional role of DLPFC in the modulation of cognitive bias by testing the automatic action tendency during automatic and regulated behavioral tasks. Unilateral intermittent or continuous theta burst stimulation (excitatory iTBS or inhibitory cTBS) was used to manipulate the left or right DLPFC excitability and assess the changes in automatic action tendency during a manikin task. An approaching behavior with positive stimulus and avoiding behavior with negative stimulus were performed in an automatic task. An approaching behavior with negative stimulus and avoiding behavior with positive stimulus were performed in a regulated task. Reaction time was measured. We confirmed the automatic action tendency that reaction time for performing an automatic task was shorter than that for performing a regulated task. The automatic action tendency was enhanced after left DLPFC excitatory iTBS and was abolished after left DLPFC inhibitory cTBS stimulation. On the other hand, right DLPFC excitatory iTBS accelerated the avoiding behaviors and right DLPFC inhibitory cTBS accelerated approaching behaviors. The results suggest that left DLPFC modulates the automatic action tendency while the right DLPFC modulates the direction of behavioral tasks. We conclude that left DLPFC and right DLPFC are key nodes in modulating the cognitive bias while their functional roles are different.

During human pregnancy, cytotrophoblasts (CTBs) from the placenta differentiate into specialized subpopulations that play crucial roles in proper fetal growth and development. A subset of these CTBs differentiate along an invasive pathway, penetrating the decidua and anchoring the placenta to the uterus. A crucial hurdle in pregnancy is the ability of these cells to migrate, invade and remodel spiral arteries, ensuring adequate blood flow to nourish the developing fetus. Although advances continue in describing the molecular features regulating the differentiation of these cells, assessment of their global proteomic changes at mid-gestation remain undefined. Here, using sequential window acquisition of all theoretical fragment-ion spectra (SWATH), which is a data-independent acquisition strategy, we characterized the protein repertoire of second trimester human CTBs during their differentiation towards an invasive phenotype. This mass spectrometry-based approach allowed identification of 3026 proteins across four culture time points corresponding to sequential stages of differentiation, confirming the expression dynamics of established molecules and offering new information into other pathways involved. The availability of a SWATH CTB global spectral library serves as a beneficial resource for hypothesis generation and as a foundation for further understanding CTB differentiation dynamics., Summary: The generation of a publicly available SWATH-MS global spectral library of human second-trimester primary villous cytotrophoblasts differentiating along an invasive pathway.

Background Congenital tracheobronchial stenosis (CTBS) is a rare congenital condition characterized by complete cartilage rings covering varying lengths of the major airway. In this study, we reviewed the outcomes of patients with CTBS receiving surgical tracheoplasty in our institute. Methods We retrospectively analyzed the outcomes of consecutive patients with CTBS operated between 2006 and 2017 when extracorporeal membrane oxygenation (ECMO) was used perioperatively. Results In total, 11 patients (median follow-up period, 4.2 years; interquartile range, 1.6–5.4) were included. Seven were symptomatic in the neonatal period, 10 had cardiorespiratory anomalies, 7 required preoperative bronchoscopic balloon dilatation, and 1 required preoperative stent placement. Slide tracheoplasty (STP) was performed in 9 patients, and 2 underwent pericardial patch tracheoplasty. Seven patients required postoperative balloon dilatation, and 6 required postoperative stent placement. Early stenting provided immediate ventilatory improvement in all patients and facilitated successful extubation in a median of 4 days after stenting in 80% of the patients. Conclusions Under ECMO, severe CTBS could be successfully treated through a combination of tracheoplasty and bronchoscopic management. STP provided excellent results for solitary trachea stenosis with a minimum diameter of ≥ 3 mm. In selected patients, postoperative tracheobronchial stent placement was crucial in minimizing the ECMO duration and facilitating extubation. Level of Evidence IV

Intergroup bias, which is the tendency to behave more positively toward an in‐group member than toward an out‐group member, is pervasive in real life. In particular, intergroup bias in trust decisions substantially influences multiple areas of life and thus better understanding of this tendency can provide significant insights into human social behavior. Although previous functional magnetic resonance imaging studies showed the involvement of the right temporoparietal junction (TPJ) in intergroup trust bias, a causal relationship between the two has rarely been explored. By combining repetitive transcranial magnetic stimulation and a newly developed trust game task, we investigated the causal role of the right TPJ in intergroup bias in trust decisions. In the trust game task, the counterpart's group membership (in‐group or out‐group) and reciprocity were manipulated. We applied either neuronavigated inhibitory continuous theta burst stimulation (cTBS) or sham stimulation over the right TPJ before performing the trust game task in healthy volunteers. After the sham stimulation, the participants' degrees of investments with in‐group members were significantly higher than those with out‐group members. However, after cTBS to the right TPJ, this difference was not observed. The current results extend previous findings by showing that the causal roles of the right TPJ can be observed in intergroup bias in trust decisions. Our findings add to our understanding of the mechanisms of human social behavior.

Background Cortical oscillatory activities play a role in regulating several brain functions in humans. However, whether motor resonant oscillations (i.e. β and γ) modulate long-term depression (LTD)-like plasticity of the primary motor cortex (M1) is still unclear. Objective To address this issue, we combined transcranial alternating current stimulation (tACS), a technique able to entrain cortical oscillations, with continuous theta burst stimulation (cTBS), a transcranial magnetic stimulation (TMS) protocol commonly used to induce LTD-like plasticity in M1. Methods Motor evoked potentials (MEPs) elicited by single-pulse TMS, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated before and 5, 15 and 30 min after cTBS alone or cTBS delivered during β-tACS (cTBS-β) or γ-tACS (cTBS-γ). Moreover, we tested the effects of β-tACS (alone) on short-latency afferent inhibition (SAI) and γ-tACS on SICI in order to verify whether tACS-related interneuronal modulation contributes to the effects of tACS-cTBS co-stimulation. Results cTBS-γ turned the expected after-effects of cTBS from inhibition to facilitation. By contrast, responses to cTBS-β were similar to those induced by cTBS alone. β- and γ-tACS did not change MEPs evoked by single-pulse TMS. β-tACS reduced SAI and γ-tACS reduced SICI. However, the degree of γ-tACS-induced modulation of SICI did not correlate with the effects of cTBS-γ. Conclusion γ-tACS reverses cTBS-induced plasticity of the human M1. γ-oscillations may therefore regulate LTD-like plasticity mechanisms.

The period immediately after the offset of visual training is thought to be critical for memory consolidation. Nevertheless, we still lack direct evidence for the causal role of this period to perceptual learning of either previously or subsequently trained material. To address these issues, we had human subjects complete two consecutive trainings with different tasks (detecting different Gabor orientations). We applied continuous theta burst stimulation (cTBS) to either the visual cortex or a control site (vertex) immediately after the offset of the first training. In the vertex cTBS condition, subjects showed improvement on the first task but not on the second task, suggesting the presence of anterograde interference. Critically, cTBS to the visual cortex abolished the performance improvement on the first task and released the second training from the anterograde interference. These results provide causal evidence for a role of the immediate post-training period in the consolidation of perceptual learning., Ji Won Bang et al. test the importance of the immediate post-visual training period for memory consolidation in human subjects. They apply continuous theta burst stimulation (cTBS) directly following a learning task and show that this does affect memory consolidation, and that this effect relies on the visual cortex.

Functional connectivity (FC) is fundamental to brain function and has been implicated in many neuropsychological and neuropsychiatric disorders. It is then of great scientific and clinical interest to find a non-invasive approach to modulate FC. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulational tool that can affect the target region and remote brain areas. While the distributed effects of TMS are postulated to be through either structural or functional connectivity, an understudied but of great scientific interest question is whether TMS can change the FC between these regions. The purpose of this study was to address this question in normal healthy brain using TMS with continuous theta burst stimulation (cTBS) pulses, which are known to have long-lasting inhibition function. FC was calculated from resting state fMRI before and after real and control (SHAM) stimulation. Compared to SHAM, the repetitive TMS (rTMS) reduces FC between the cTBS target: the left dorsolateral prefrontal cortex (lDLPFC) and brain regions within the default mode network (DMN), proving the effects of rTMS on FC. The reduction of FC might be the results of the inhibitory effects of cTBS rTMS.

Hemispheric asymmetries play an important role in multiple cerebral functions. Asymmetries in prefrontal cortex (PFC) function have been suggested to regulate emotional processing in that right-hemispheric dominance biases towards negative affect, whereas left PFC dominance favors positive affect. This study used transcranial magnetic stimulation to test the causal role of prefrontal asymmetries in the processing of emotional stimuli. To experimentally induce hemispheric asymmetries, 21 healthy volunteers underwent two separate sessions of inhibitory continuous theta burst stimulation (cTBS) to the left versus right dorsolateral prefrontal cortex. Each stimulation was followed by magnetoencephalographic (MEG) recordings of event-related fields elicited by visually presented emotional words in a silent reading task and a subsequent behavioral emotion categorization task. The asymmetry manipulation influenced valence processing of words in early, mid-latency and late time intervals in right occipitotemporal and parietal brain regions. Left-sided cTBS (inducing right-hemispheric dominance) consistently resulted in enhanced brain responses to negative words, while right-sided cTBS (inducing left-hemispheric dominance) enhanced responses to positive words. On a behavioral level, right-hemispheric dominance resulted in more categorization matches of negative compared to positive words, while left-hemispheric dominance resulted in reverse effects. These results provide direct evidence that bottom-up valence processing is influenced by prefrontal hemispheric asymmetry.

Theories of emotion suggest a close relation of interoception and emotion. However, knowledge of underlying neuronal networks is still sparse. Repetitive transcranial magnetic stimulation (rTMS) is one neurostimulation method allowing causal conclusions between functions and brain regions via stimulation or inhibition of underlying brain structures. In this study, rTMS with a continuous theta burst stimulation (cTBS) protocol was used aiming for inhibition of important interoceptive network structures (frontotemporal insular network and right somatosensory cortices). Stimulation effects were investigated on interoceptive accuracy (IAc), emotional evaluation and neuronal correlates of emotional picture processing in 18 male participants. The main findings were an emotional flattening in subjective valences for affective stimuli after inhibition of the frontotemporal anterior insular network and of somatosensory cortices, being mirrored in visual evoked potentials as increased N2/decreased P3, indicating an initial orientation reaction followed by decreased attentional processing of positive stimuli. Moreover, cardiac and respiratory IAc were positively associated with P3 amplitudes and negatively related to positive valence ratings. Positive associations of decreases of cardiac/respiratory IAc with decreases of arousal ratings and decreases of P3 amplitudes for negative stimuli after inhibition of the frontotemporal insular network and after inhibition of somatosensory cortices allow the conclusion of a causal relationship between reduced activity in interoceptive network structures and blunted emotional processing of visual stimuli. Our results suggest that both arousal, and valence aspects of emotional processing are disturbed after inhibition of interoceptive network structures, confirming core assumptions of peripheral theories of emotions and models of interoceptive predictive coding.

Although an enhancing effect of reward on cognitive performance has been observed consistently, its neural underpinnings remain elusive. Recent evidence suggests that the inferior frontal junction (IFJ) may be a key player underlying such an enhancement by integrating motivational processes and cognitive control. However, its exact role and in particular a potential causality of IFJ activation is still unclear. In the present study, we therefore investigated the causal contributions of the left IFJ in motivated task switching by temporarily disrupting its activity using continuous theta burst stimulation (cTBS, Exp.1) or 1 Hz repetitive transcranial magnetic stimulation (rTMS, Exp.2). After TMS application over the left IFJ or a control site (vertex), participants performed a switch task in which numbers had to be judged by magnitude or parity. Different amounts of monetary rewards (high vs low) were used to manipulate the participants’ motivational states. We measured reaction times and error rates. Irrespective of TMS stimulation, participants exhibited slower responses following task switches compared to task repeats. This effect was reduced in high reward trials. Importantly, we found that disrupting the IFJ improved participants’ behavioral performance in the high reward condition. For high reward trials exclusively, error rates decreased when the IFJ was modulated with cTBS or 1 Hz rTMS but not after vertex stimulation. Our results suggest that the left IFJ is causally related to the increase in cognitive performance through reward.

Continuous theta burst stimulation (cTBS) is a form of noninvasive repetitive brain stimulation that, when delivered over the contralesional hemisphere, can influence the excitability of the ipsilesional hemisphere in individuals with stroke. cTBS applied prior to skilled motor practice interventions may augment motor learning; however, there is a high degree of variability in individual response to this intervention. The main objective of the present study was to assess white matter biomarkers of response to cTBS paired with skilled motor practice in individuals with chronic stroke. We tested the effects of stimulation of the contralesional hemisphere at the site of the primary motor cortex (M1c) or primary somatosensory cortex (S1c) and a third group who received sham stimulation. Within each stimulation group, individuals were categorized into responders or nonresponders based on their capacity for motor skill change. Baseline diffusion tensor imaging (DTI) indexed the underlying white matter microstructure of a previously known motor learning network, named the constrained motor connectome (CMC), as well as the corticospinal tract (CST) of lesioned and nonlesioned hemispheres. Across practice, there were no differential group effects. However, when categorized as responders vs. nonresponders using change in motor behaviour, we demonstrated a significant difference in CMC microstructural properties (as measured by fractional anisotropy (FA)) for individuals in M1c and S1c groups. There were no significant differences between responders and nonresponders in clinical baseline measures or microstructural properties (FA) in the CST. The present study identifies a white matter biomarker, which extends beyond the CST, advancing our understanding of the importance of white matter networks for motor after stroke.

Objective. Heterogeneous clinical responses to treatment with non-invasive brain stimulation are commonly observed, making it necessary to determine personally optimized stimulation parameters. We investigated neuroimaging markers of effective brain targets of treatment with continuous theta burst stimulation (cTBS) in mal de débarquement syndrome (MdDS), a balance disorder of persistent oscillating vertigo previously shown to exhibit abnormal intrinsic functional connectivity. Approach. Twenty-four right-handed, cTBS-naive individuals with MdDS received single administrations of cTBS over one of three stimulation targets in randomized order. The optimal target was determined based on the assessment of acute changes after the administration of cTBS over each target. Repetitive cTBS sessions were delivered on three consecutive days with the optimal target chosen by the participant. Electroencephalography (EEG) was recorded at single-administration test sessions of cTBS. Simultaneous EEG and functional MRI data were acquired at baseline and after completion of 10–12 sessions. Network connectivity changes after single and repetitive stimulations of cTBS were analyzed. Main results. Using electrophysiological source imaging and a data-driven method, we identified network-level connectivity changes in EEG that correlated with symptom responses after completion of multiple sessions of cTBS. We further determined that connectivity changes demonstrated by EEG during test sessions of single administrations of cTBS were signatures that could predict optimal targets. Significance. Our findings demonstrate the effect of cTBS on resting state brain networks and suggest an imaging-based, closed-loop stimulation paradigm that can identify optimal targets during short-term test sessions of stimulation. ClinicalTrials.gov Identifier: NCT02470377.

Background Repetitive transcranial magnetic stimulation (rTMS) has been reported to treat muscle spasticity in post-stroke patients. The purpose of this study was to explore whether combined low-frequency rTMS (LF-rTMS) and cerebellar continuous theta burst stimulation (cTBS) could provide better relief than different modalities alone for muscle spasticity and limb dyskinesia in stroke patients. Methods This study recruited ninety stroke patients with hemiplegia, who were divided into LF-rTMS+cTBS group (n=30), LF-rTMS group (n=30) and cTBS group (three pulse bursts at 50 Hz, n=30). The LF-rTMS group received 1 Hz rTMS stimulation of the motor cortical (M1) region on the unaffected side of the brain, the cTBS group received cTBS stimulation to the cerebellar region, and the LF-rTMS+cTBS group received 2 stimuli as described above. Each group received 4 weeks of stimulation followed by rehabilitation. Muscle spasticity, motor function of limb and activity of daily living (ADL) were evaluated by modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FMA) and Modified Barthel Index (MBI) scores, respectively. Results The MAS score was markedly decreased, FMA and MBI scores were markedly increased in the three groups after therapy than before therapy. In addition, after therapy, LF-rTMS+cTBS group showed lower MAS score, higher FMA and MBI scores than the LF-rTMS group and cTBS group. Conclusion Muscle spasticity and limb dyskinesia of the three groups are all significantly improved after therapy. Combined LF-rTMS and cTBS treatment is more effective in improving muscle spasticity and limb dyskinesia of patients after stroke than LF-rTMS and cTBS treatment alone.

Previous studies have shown that visuospatial working memory (VSWM) plays a key role in the encoding and processing of visuospatial information. More importantly, there is evidence suggesting the role of frontal and parietal cortical areas in VSWM and especially, the influence of the frontal cortex in regulating goal-directed behavior. However, the functional role of the right dorsolateral prefrontal cortex (rDLPFC) in visuospatial working memory is still unclear. Here, we noninvasively modulated the rDLPFC activity using continuous theta-burst stimulation (cTBS), with the vertex as the control site. Our study aimed to investigate the effects of cTBS over rDLPFC on working memory task (2- and 4-back) performance. Working memory performance was assessed at the baseline and after stimulation. We observed that the working memory performance as measured by discriminability index was impaired after cTBS over rDLPFC in 2-back task, whereas 4-back task performance was not significantly affected. More so, there was no effect on performance after cTBS over the vertex, suggesting a functional role of rDLPFC in VSWM. Our findings demonstrate the involvement of the rDLPFC in VSWM as well as the load-dependent effect of working memory performance. Taken together, our work constitutes a useful addition to the literature and underscores the effectiveness and efficiency of noninvasive brain stimulation in modulating neuro-cognitive activity.

OBJECTIVE. To test whether change in motor evoked potential (ΔMEP) induced by continuous theta-burst stimulation (cTBS) of motor cortex (M1) distinguishes adults with autism spectrum disorder (ASD) from neurotypicals, and to explore the contribution of two common polymorphisms related to neuroplasticity. METHODS. 44 adult neurotypical (NT) participants (age 21–65, 34 males) and 19 adults with ASD (age 21–58, 17 males) prospectively underwent M1 cTBS. Their data were combined with previously obtained results from 35 NT and 35 ASD adults. RESULTS. ΔMEP at 15 minutes post-cTBS (T15) was a significant predictor of diagnosis (p=0.04) in the present sample (n=63). T15 remained a significant predictor in a larger sample (n=91) and when partially imputed based on T10–T20 from a yet-greater sample (N=133). T15 also remained a significant predictor of diagnosis among brain-derived neurotrophic factor (BDNF) Met+ and apolipoprotein E (APOE) ε4− subjects (p’s0.19). CONCLUSIONS. ΔMEP at T15 post-cTBS is a significant biomarker for adults with ASD, and its utility is modulated by BDNF and APOE polymorphisms. SIGNIFICANCE. M1 cTBS response is a physiologic biomarker for adults with ASD in large samples, and controlling for BDNF and APOE polymorphisms can improve its diagnostic utility.

Aim: To evaluate the effects of a single session of non-invasive brain stimulation (NIBS) on postural balance. Introduction: The NIBS has been used widely in improving balance. However, the effect of a single session of NIBS on balance in healthy individuals has not been systemically reviewed. Methods: A systematic literature review and best evidence synthesis were conducted, according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, to determine the effects of different NIBS techniques on balance function in healthy individuals. The methodological quality of included articles was assessed by the risk of bias, and the Downs and Black tool. Data were analyzed by using the best evidence synthesis. Thirty-five articles were included that used the following NIBS techniques: anodal transcranial direct current stimulation (a-tDCS), cathodal transcranial direct current stimulation (c-tDCS), continuous theta burst stimulation (cTBS), and repetitive transcranial magnetic stimulation (rTMS) on primary motor cortex (M1), supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), and cerebellum on balance. Results: Strong evidence showed that a-tDCS of M1, SMA improve balance in healthy participants, and the a-tDCS of DLPFC induces improvement only in dual task balance indices. Also, the findings indicate that cerebellar a-tDCS might significantly improve balance, if at least 10 min cerebellar a-tDCS with an intensity of ≥1 mA, over or maximum 1.5 cm below the inion, is used. Strong evidence showed that c-tDCS, cTBS, and rTMS are not effective on the balance. Conclusion: According to the results, the a-tDCS may be a useful technique to improve balance in healthy adults. Impact statement The strong evidence found in this review indicates that single-session, stand-alone application of anodal transcranial direct current stimulation on the cerebellum, primary motor cortex (M1), and supplementary motor area can improve balance in healthy individuals. Moreover, strong evidence suggests that cathodal transcranial direct current stimulation has an adverse effect on balance and must be avoided as a technique for the treatment of balance. These results can be used to improve balance in patients with neurological disorders, and healthy older adults with balance dysfunctions.

Theta-burst stimulation (TBS) is a form of non-invasive neuromodulation which is delivered in an intermittent (iTBS) or continuous (cTBS) manner. Although 600 pulses is the most common dose, the goal of these experiments was to evaluate the effect of higher per-dose pulse numbers on cortical excitability. Sixty individuals were recruited for 2 experiments. In Experiment 1, participants received 600, 1200, 1800, or sham (600) iTBS (4 visits, counterbalanced, left motor cortex, 80% active threshold). In Experiment 2, participants received 600, 1200, 1800, 3600, or sham (600) cTBS (5 visits, counterbalanced). Motor evoked potentials (MEP) were measured in 10-min increments for 60 min. For iTBS, there was a significant interaction between dose and time (F = 3.8296, p = 0.01), driven by iTBS (1200) which decreased excitability for up to 50 min (t = 3.1267, p = 0.001). For cTBS, there was no overall interaction between dose and time (F = 1.1513, p = 0.33). Relative to sham, cTBS (3600) increased excitability for up to 60 min (t = 2.0880, p = 0.04). There were no other significant effects of dose relative to sham in either experiment. Secondary analyses revealed high within and between subject variability. These results suggest that iTBS (1200) and cTBS (3600) are, respectively, the most effective doses for decreasing and increasing cortical excitability.

Non-invasive brain stimulation techniques including repetitive transcranial magnetic stimulation (rTMS), continuous theta-burst stimulation (cTBS), paired associative stimulation (PAS), and transcranial direct current stimulation (tDCS) have been applied over the cerebellum to induce plasticity and gain insights into the interaction of the cerebellum with neo-cortical structures including the motor cortex. We compared the effects of 1 Hz rTMS, cTBS, PAS and tDCS given over the cerebellum on motor cortical excitability and interactions between the cerebellum and dorsal premotor cortex / primary motor cortex in two within subject designs in healthy controls. In experiment 1, rTMS, cTBS, PAS, and tDCS were applied over the cerebellum in 20 healthy subjects. In experiment 2, rTMS and PAS were compared to sham conditions in another group of 20 healthy subjects. In experiment 1, PAS reduced cortical excitability determined by motor evoked potentials (MEP) amplitudes, whereas rTMS increased motor thresholds and facilitated dorsal premotor-motor and cerebellum-motor cortex interactions. TDCS and cTBS had no significant effects. In experiment 2, MEP amplitudes increased after rTMS and motor thresholds following PAS. Analysis of all participants who received rTMS and PAS showed that MEP amplitudes were reduced after PAS and increased following rTMS. rTMS also caused facilitation of dorsal premotor-motor cortex and cerebellum-motor cortex interactions. In summary, cerebellar 1 Hz rTMS and PAS can effectively induce plasticity in cerebello-(premotor)-motor pathways provided larger samples are studied.

Transcranial magnetic stimulation is a non-invasive procedure that uses robust magnetic fields to create an electrical current in the cerebral cortex. Dual stimulation consists of administering subthre-shold conditioning stimulation (CS), then suprathreshold test stimulation (TS). When the interstimulus interval (ISI) is 1-6 msec, the motor evoked potential (MEP) decreases in amplitude; this decrease is termed "short interval intracortical inhibition" (SICI); when the ISI is 7-30 msec, an increase in MEP amplitude occurs, termed "short interval intracortical facilitation" (SICF). Continuous theta burst stimulation (cTBS), often applied at a frequency of 50 Hz, has been shown to decrease cortical excitability. The primary objective is to determine which duration of cTBS achieves better inhibition or excitation. The secondary objective is to compare 50 Hz cTBS to 30 Hz and 100 Hz cTBS.The resting motor threshold (rMT), MEP, SICI, and SICF were studied in 30 healthy volunteers. CS and TS were administered at 80%-120% and 70%-140% of rMT at 2 and 3-millisecond (msec) intervals for SICI, and 10- and 12-msec intervals for SICF. Ten individuals in each group received 30, 50, or 100 Hz, followed by administration of rMT, MT-MEP, SICI, SICF immediately and at 30 minutes.Greater inhibition was achieved with 3 msec than 2 msec in SICI, whereas better facilitation occurred at 12 msec than 10 msec in SICF. At 30 Hz, cTBS augmented inhibition and suppressed facilitation, while 50 Hz yielded less inhibition and greater inter-individual variability. At 100 Hz, cTBS provided slight facilitation in MEP amplitudes with less interindividual variability. SICI and SICF did not differ significantly between 50 Hz and 100 Hz cTBS.Our results suggest that performing SICI and SICF for 3 and 12 msec, respectively, and CS and TS at 80%-120% of rMT, demonstrate safer inhibition and facilitation. Recently, TBS has been used in the treatment of various neurological diseases, and we recommend preferentially 30 Hz over 50 Hz cTBS for better inhibition with greater safety and less inter-individual variability.A transcranialis mágneses stimuláció robusztus mágneses mezôket használó, nem invazív el­járás, amivel elektromos áramlást lehet elôidézni a nagy­agykéregben. A kettôs stimuláció küszöb alatti kondicio­náló stimulust (CS), majd küszöb feletti tesztstimulust (TS) alkalmaz. Amikor a két stimulus közötti idôtartam (interstimulus interval, ISI) 1–6 msec, a kiváltott motoros potenciál amplitúdója (MEP) csökken; ennek a csökkenésnek a neve rövid intervallumos intracorticalis gátlás (SICI). 7–30 msec ISI esetén a MEP-amplitúdó nô, ennek neve rövid intervallumos intracorticalis facilitáció (SICF). A leggyakrabban 50 Hz frekvenciával alkalmazott folyamatos θ-hullám-ingerlés (cTBS) kimutathatóan csökkenti a corticalis ingerelhetôséget. A jelen vizsgálat elsôdleges célja az volt, hogy meghatározzuk, milyen idôtartamú cTBS révén lehet jobb gátlást, illetve serkentést elérni. A vizsgálat másodlagos célja az 50 Hz-es cTBS hatásának összehasonlítása volt a 30, illetve 100 Hz-es cTBS hatásával.A nyugalmi motoros küszöb (rMT), a MEP, a SICI és a SICF értékeit 30 egészséges önkéntes esetében tanulmányoztuk. A SICI esetében 2 és 3 msec intervallummal az rMT 70–140%-át használva alkalmaztuk a CS-t és a TS-t, míg SICF esetében 10 és 12 msec intervallumokat használtunk. Minden csoportban 10 személy kapott 30, 50 vagy 100 Hz-es ingerlést, ezt követôen azonnal és 30 perc elteltével rögzítettük az rMT, az MT-MEP, a SICI és a SICF értékeit.A SICI-ben nagyobb gátlást lehetett elérni 3 msec-mal, mint 2 msec-mal, míg a SICF-ben nagyobb serkentést lehetett elérni 12 msec-mal, mint 10 msec-mal. 30 Hz-en a cTBS segítette a gátlást és gátolta a serkentést, míg az 50 Hz-es stimuláció kevesebb gátlást és nagyobb interindividuális variabilitást eredményezett. A 100 Hz-es stimuláció hatására a cTBS csekély serkentést eredmé­nye­zett a MEP-amplitúdókban, kevesebb interindividuális va­riabilitással. A SICI és a SICF nem különbözött szignifikáns mértékben 50 és 100 Hz-es cTBS esetén.Vizsgálatunk szerint a 3 és 12 msec-os SICI és SICF alkalmazása, valamint a 80–120%-os rMT-vel alkalmazott CS és TS biztonságosabb gátlást és serkentést eredményez. A közelmúltban különféle neurológiai beteg­ségek kezelésére kezdték használni a TBS-t; eredményeink alapján az 50 Hz-es helyett inkább a 30 Hz-es cTBS-sti­mu­láció használatát javasoljuk, mivel nagyobb biztonsá­gos­­ság és kisebb interindividuális variabilitás mellett nagyobb gátlást eredményez.

The left dorsolateral prefrontal cortex (dlPFC) has been implicated in the regulation of stress-related cognitive processes and physiological responses and is the principal target of noninvasive brain stimulation techniques applied to psychiatric conditions. However, existing studies are mostly correlational and causal evidence on the role of this region in mediating specific psychophysiological mechanisms underpinning stress-related responses are needed to make the application of such techniques more efficient. To fill this gap, this study used inhibitory continuous theta burst stimulation (cTBS) in healthy individuals to examine the extent to which activity of the left dlPFC is associated with cognitive (subjective focus on a tracking task), behavioral (reaction times and variability), and physiological responses (heart rate and its variability and cortisol level) following induction of perseverative cognition. Compared to sham and left ventral PreMotor area stimulation (as active control area), inhibition of left dlPFC determined sustained autonomic and neuroendocrine activation and increased the subjective perception of being task-focused, while not changing the behavioral and self-reported stress-related responses. Adopting a causative approach, we describe a role of left dlPFC in inhibitory control of the physiological stress-response associated to perseverative thinking.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique with great potential in the treatment of Parkinson's disease (PD). This study aimed to investigate the clinical efficacy of accelerated rTMS and to understand the underlying neural mechanism. In a double‐blinded way, a total of 42 patients with PD were randomized to receive real (n = 22) or sham (n = 20) continuous theta‐burst stimulation (cTBS) on the left supplementary motor area (SMA) for 14 consecutive days. Patients treated with real cTBS, but not with sham cTBS, showed a significant improvement in Part III of the Unified PD Rating Scale (p, An accelerated continuous theta‐burst stimulation protocol significantly alleviates motor symptoms in Parkinson's disease. Symptom improvement can be observed as early as 1 week after the start of treatment, and maintained 8 weeks after the end of treatment. Gray matter volume in the globus pallidus (GP) increased after treatment, and the increment was positively correlated with symptom improvement as well as baseline supplementary motor area‐GP structural connectivity.

Noninvasive detection of circulating fetal cells carrying the entire fetal genome is a promising way for prenatal testing of genetic diseases. However, ideal approaches for efficient separation of these valuable cells are not available. Here, a novel inertial microfluidic chip (CelutriateChip 1) is developed for ultra-fast, label-free enrichment of circulating trophoblasts (CTBs) from the whole blood samples of pregnant women. The unique structural design of the four-stage curved channel in CelutriateChip 1 enables CTBs with larger size to be efficiently separated from the blood samples under the effect of inertial and Dean drag forces. The transition of the target cells among the stages enables CelutriateChip 1 to achieve one or two orders of magnitude higher throughput compared to single channel inertial microfluidic chips. After optimization of conditions, CTBs can be recovered from 2 mL of whole blood within 5 min with an average recovery efficiency ranging from 52.3% to 65.8% and high white blood cell depletion (99.95%). CTBs collected from the chip can be isolated at the single-cell level and used for downstream immunofluorescence staining and genetic genotyping. Clinical tests are performed on 30 pregnant women and the results demonstrate that CTBs are obtainable in 86.67% of pregnancy cases. A single-base variant in the HBB gene can be accurately detected by sequencing of rare CTBs. This simple, antibody-free and low-cost approach holds promise for obtaining rare CTBs for prenatal detection of various genetic diseases.