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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.

Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state (maintenance) and a process that operates on these activated representations (manipulation). We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. We found that both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Both structural and functional architecture of these systems suggested that these cognitive functions are supported by two dissociable brain networks. Critically, maintenance and manipulation functional networks became increasingly segregated with increasing demand, an effect that was positively associated with individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.

Background: Emotional dysregulation is a serious and impairing mental health problem. We examined functional activity and connectivity of neural networks involved in emotional dysregulation at baseline and following a pilot neurostimulation-enhanced cognitive restructuring intervention in a transdiagnostic clinical adult sample., Methods: Neuroimaging data were analyzed from adults who scored 89 or higher on the Difficulties with Emotion Regulation (DERS) scale and had at least one DSM-5 diagnosis. These participants were part of a pilot randomized, double-blind, placebo-controlled trial combining a single therapeutic session of cognitive restructuring with active or sham transcranial magnetic stimulation over the dorsolateral prefrontal cortex. During the study, participants engaged in an emotional regulation task using personalized autobiographical stressors while undergoing functional magnetic resonance imaging (fMRI) before and after the pilot intervention. The fMRI task required participants to either experience the emotions associated with the memories or apply cognitive restructuring strategies to reduce their distress., Results: Whole-brain fMRI results during regulation at baseline revealed increased activation in the dorsal frontoparietal network but decreased activation in the supplementary motor area, cingulate cortex, insula, and ventrolateral prefrontal cortex (vlPFC). Emotion dysregulation was associated with greater vmPFC and amygdala activation and functional connectivity between these regions. The strength of functional connectivity between the dlPFC and other frontal regions was also a marker of emotional dysregulation. Preliminary findings from a subset of participants who completed the follow-up fMRI scan showed that active neurostimulation improved behavioral indices of emotion regulation more than sham stimulation. A whole-brain generalized psychophysiological interaction analysis indicated that active neurostimulation selectively increased occipital cortex connectivity with both the insula and the dlPFC. Region-of-interest functional connectivity analyses showed that active neurostimulation selectively increased dlPFC connectivity with the insula and orbitofrontal cortex (OFC)., Conclusion: Insufficient neural specificity during the emotion regulation process and over-involvement of frontal regions may be a marker of emotional dysregulation across disorders. OFC, vlPFC, insula activity, and connectivity are associated with improved emotion regulation in transdiagnostic adults. In this pilot study, active neurostimulation led to neural changes in the emotion regulation network after a single session; however, the intervention findings are preliminary, given the small sample size. These functional network properties can inform future neuroscience-driven interventions and larger-scale studies., Competing Interests: Declaration of competing interest The authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, repetitive transcranial magnetic stimulation was applied to either the right inferior frontal junction or the right inferior parietal cortex during a difficult aerial reconnaissance search task to test its capacity to improve search performance. Two stimulation strategies previously found to enhance cognitive performance were tested: The first is called "addition by subtraction," and the second condition utilizes a direct excitatory approach by applying brief trains of high-frequency repetitive transcranial magnetic stimulation immediately before task trials. In a within-subjects design, participants were given active or sham repetitive transcranial magnetic stimulation at either 1 Hz or at 1 Hz above their individual peak alpha frequency (IAF + 1, mean 11.5 Hz), delivered to either the right inferior frontal junction or the right inferior parietal cortex, both defined with individualized peak functional magnetic resonance imaging (fMRI) activation obtained during the visual search task. Results indicated that among the 13 participants who completed the protocol, only active IAF + 1 stimulation to inferior frontal junction resulted in significant speeding of reaction time compared to sham. This site- and frequency-specific enhancement of performance with IAF + 1 repetitive transcranial magnetic stimulation applied immediately prior to task trials provides evidence for the involvement of inferior frontal junction in guiding difficult visual search, and more generally for the use of online repetitive transcranial magnetic stimulation directed at specific functional networks to enhance visual search performance., (Published by Oxford University Press 2024.)

The Stroop task is a well-established tool to investigate the influence of competing visual categories on decision making. Neuroimaging as well as rTMS studies have demonstrated the involvement of parietal structures, particularly the intraparietal sulcus (IPS), in this task. Given its reliability, the numerical Stroop task was used to compare the effects of different TMS targeting approaches by Sack and colleagues (Sack AT 2009), who elegantly demonstrated the superiority of individualized fMRI targeting. We performed the present study to test whether fMRI-guided rTMS effects on numerical Stroop task performance could still be observed while using more advanced techniques that have emerged in the last decade (e.g., electrical sham, robotic coil holder system, etc.). To do so we used a traditional reaction time analysis and we performed, post-hoc, a more advanced comprehensive drift diffusion modeling approach. Fifteen participants performed the numerical Stroop task while active or sham 10 Hz rTMS was applied over the region of the right intraparietal sulcus (IPS) showing the strongest functional activation in the Incongruent > Congruent contrast. This target was determined based on individualized fMRI data collected during a separate session. Contrary to our assumption, the classical reaction time analysis did not show any superiority of active rTMS over sham, probably due to confounds such as potential cumulative rTMS effects, and the effect of practice. However, the modeling approach revealed a robust effect of rTMS on the drift rate variable, suggesting differential processing of congruent and incongruent properties in perceptual decision-making, and more generally, illustrating that more advanced computational analysis of performance can elucidate the effects of rTMS on the brain where simpler methods may not., Competing Interests: “The opinions expressed in this article are the authors’ and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Dr. Deng is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the National Institutes of Health (NIH), Columbia University, and University of New Mexico. Dr. Lisanby is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the NIH and Columbia University, with no remuneration. Our competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.”, (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Misophonia is a disorder of decreased tolerance to certain aversive, repetitive common sounds, or to stimuli associated with these sounds. Two matched groups of adults (29 participants with misophonia and 30 clinical controls with high emotion dysregulation) received inhibitory neurostimulation (1 Hz) over a personalized medial prefrontal cortex (mPFC) target functionally connected to the left insula; excitatory neurostimulation (10 Hz) over a personalized dorsolateral PFC (dlPFC) target; and sham stimulation over either target. Stimulations were applied while participants were either listening or cognitively downregulating emotions associated with personalized aversive, misophonic, or neutral sounds. Subjective units of distress (SUDS) and psychophysiological measurements (e.g., skin conductance response [SCR] and level [SCL]) were collected. Compared to controls, participants with misophonia reported higher distress (∆ SUDS  = 1.91-1.93, ps < 0.001) when listening to and when downregulating misophonic distress. Both types of neurostimulation reduced distress significantly more than sham, with excitatory rTMS providing the most benefit (Cohen's d SUDS  = 0.53; d SCL  = 0.14). Excitatory rTMS also enhanced the regulation of emotions associated with misophonic sounds in both groups when measured by SUDS (d control  = 1.28; d Misophonia  = 0.94), and in the misophonia group alone when measured with SCL (d = 0.20). Both types of neurostimulation were well tolerated. Engaging in cognitive restructuring enhanced with high-frequency neurostimulation led to the lowest misophonic distress, highlighting the best path forward for misophonia interventions., Competing Interests: Declaration of competing interest The authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD., Competing Interests: SL is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the NIH and Columbia University no royalties. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oberman, Francis, Beynel, Hynd, Jaime, Robins, Deng, Stout, van der Veen and Lisanby.)

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is Food and Drug Administration cleared for clinical use in treatment-resistant depression and a growing list of other disorders. The clinical uptake of rTMS has been facilitated by its relatively benign adverse-effect profile compared with other treatment modalities. Seizure is a rare but serious adverse event that has been reported with rTMS, when dosage exceeds safety guidelines or in individuals at increased risk for seizure. Fortunately, most rTMS-induced seizures are typically transient, with no adverse sequelae, but they may lead to treatment discontinuation. Seizure is not the only cause of loss of conscious and abnormal movements induced by rTMS. Convulsive syncope, a more common adverse event that involves loss of consciousness associated with myoclonic movements, can be difficult to differentiate from an rTMS-induced seizure. We report the case of a 52-year-old man with no known seizure risk factors, enrolled in an institutional review board-approved research study who developed what appeared to be a convulsive syncopal episode lasting 10 to 15 seconds during day 2 of a 30-day rTMS protocol (10 Hz, 120% of motor threshold, 4-second pulse train, 26-second intertrain interval, 3000 pulses per session), with no adverse sequelae. The patient's history, screening, physical examination, pertinent laboratory, neurology consult, electroencephalogram, and imaging findings are discussed. This case demonstrates that distinguishing between convulsive syncope and rTMS-induced seizure can be a diagnostic challenge. Clinicians and researchers delivering rTMS should be familiar with the risk factors for rTMS-induced seizures and rTMS-induced convulsive syncope, to screen for predisposing factors and to manage these rare adverse events if they occur., Competing Interests: Dr Lisanby is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the National Institutes of Health (NIH) and Columbia University (no royalties). The opinions expressed in this article are the author's own and do not reflect the views of the NIH, the Department of Health and Human Services, or the United States government. All other authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression, there is a limited understanding of the mechanisms of action and how potential treatment-related brain changes help to characterize treatment response. To address this gap in understanding we investigated the effects of an approach combining rTMS with simultaneous psychotherapy on global functional connectivity., Method: We compared task-related functional connectomes based on an idiographic goal priming task tied to emotional regulation acquired before and after simultaneous rTMS/psychotherapy treatment for patients with major depressive disorders and compared these changes to normative connectivity patterns from a set of healthy volunteers (HV) performing the same task., Results: At baseline, compared to HVs, patients demonstrated hyper connectivity of the DMN, cerebellum and limbic system, and hypo connectivity of the fronto-parietal dorsal-attention network and visual cortex. Simultaneous rTMS/psychotherapy helped to normalize these differences, which were reduced after treatment. This finding suggests that the rTMS/therapy treatment regularizes connectivity patterns in both hyperactive and hypoactive brain networks., Conclusions: These results help to link treatment to a comprehensive model of the neurocircuitry underlying depression and pave the way for future studies using network-guided principles to significantly improve rTMS efficacy for depression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Transcranial magnetic stimulation (TMS) was used to test the functional role of parietal and prefrontal cortical regions activated during a playing card Guilty Knowledge Task (GKT). Single-pulse TMS was applied to 15 healthy volunteers at each of three target sites: left and right dorsolateral prefrontal cortex and midline parietal cortex. TMS pulses were applied at each of five latencies (from 0 to 480 ms) after the onset of a card stimulus. TMS applied to the parietal cortex exerted a latency-specific increase in inverse efficiency score and in reaction time when subjects were instructed to lie relative to when asked to respond with the truth, and this effect was specific to when TMS was applied at 240 ms after stimulus onset. No effects of TMS were detected at left or right DLPFC sites. This manipulation with TMS of performance in a deception task appears to support a critical role for the parietal cortex in intentional false responding, particularly in stimulus selection processes needed to execute a deceptive response in the context of a GKT. However, this interpretation is only preliminary, as further experiments are needed to compare performance within and outside of a deceptive context to clarify the effects of deceptive intent., Competing Interests: BL, LB, HG, and SL were supported by the NIMH Intramural Research Program (ZIAMH002955). This work was done while BL and SL were at Columbia University, prior to their NIMH employment. SL is an inventor on a patent on TMS technology assigned to Columbia University. SL has received grant support from the Brain and Behavior Research Foundation, the Stanley Medical Research Foundation, Neosync, Nexstim, NIH, and Brainsway. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luber, Beynel, Spellman, Gura, Ploesser, Termini and Lisanby.)

Objective. Transcranial magnetic stimulation (TMS) can modulate brain function via an electric field (E-field) induced in a brain region of interest (ROI). The ROI E-field can be computationally maximized and set to match a specific reference using individualized head models to find the optimal coil placement and stimulus intensity. However, the available software lacks many practical features for prospective planning of TMS interventions and retrospective evaluation of the experimental targeting accuracy. Approach. The TMS targeting and analysis pipeline (TAP) software uses an MRI/fMRI-derived brain target to optimize coil placement considering experimental parameters such as the subject's hair thickness and coil placement restrictions. The coil placement optimization is implemented in SimNIBS 3.2, for which an additional graphical user interface (TargetingNavigator) is provided to visualize/adjust procedural parameters. The coil optimization process also computes the E-field at the target, allowing the selection of the TMS device intensity setting to achieve specific E-field strengths. The optimized coil placement information is prepared for neuronavigation software, which supports targeting during the TMS procedure. The neuronavigation system can record the coil placement during the experiment, and these data can be processed in TAP to quantify the accuracy of the experimental TMS coil placement and induced E-field. Main results. TAP was demonstrated in a study consisting of three repetitive TMS sessions in five subjects. TMS was delivered by an experienced operator under neuronavigation with the computationally optimized coil placement. Analysis of the experimental accuracy from the recorded neuronavigation data indicated coil location and orientation deviations up to about 2 mm and 2°, respectively, resulting in an 8% median decrease in the target E-field magnitude compared to the optimal placement. Significance. TAP supports navigated TMS with a variety of features for rigorous and reproducible stimulation delivery, including planning and evaluation of coil placement and intensity selection for E-field-based dosing., (© 2022 IOP Publishing Ltd.)

Background: Transdiagnostic clinical emotional dysregulation is a key component of many mental health disorders and offers an avenue to address multiple disorders with one transdiagnostic treatment. In the current study, we pilot an intervention that combines a one-time teaching and practice of cognitive restructuring (CR) with repetitive transcranial magnetic stimulation (rTMS), targeted based on functional magnetic resonance imaging (fMRI)., Methods: Thirty-seven clinical adults who self-reported high emotional dysregulation were enrolled in this randomized, double-blind, placebo-controlled trial. fMRI was collected as participants were reminded of lifetime stressors and asked to downregulate their distress using CR tactics. fMRI BOLD data were analyzed to identify the cluster of voxels within the left dorsolateral prefrontal cortex (dlPFC) with the highest activation when participants attempted to downregulate, versus passively remember, distressing memories. Participants underwent active or sham rTMS (10 Hz) over the left dlPFC target while practicing CR following emotional induction using recent autobiographical stressors., Results: Receiving active versus sham rTMS led to significantly higher high frequency heart rate variability during regulation, lower regulation duration during the intervention, and higher likelihood to use CR during the week following the intervention. There were no differences between conditions when administering neurostimulation alone without the CR skill and compared to sham. Participants in the sham versus active condition experienced less distress the week after the intervention. There were no differences between conditions at the one-month follow up., Conclusion: This study demonstrated that combining active rTMS with emotion regulation training for one session significantly enhances emotion regulation and augments the impact of training for as long as a week. These findings are a promising step towards a combined intervention for transdiagnostic emotion dysregulation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Emotional dysregulation constitutes a serious public health problem in need of novel transdiagnostic treatments., Objective: To this aim, we developed and tested a one-time intervention that integrates behavioral skills training with concurrent repetitive transcranial magnetic stimulation (rTMS)., Methods: Forty-six adults who met criteria for at least one DSM-5 disorder and self-reported low use of cognitive restructuring (CR) were enrolled in a randomized, double-blind, sham-controlled trial that used a between-subjects design. Participants were taught CR and underwent active rTMS applied at 10 Hz over the right (n = 17) or left (n = 14) dorsolateral prefrontal cortex (dlPFC) or sham rTMS (n = 15) while practicing reframing and emotional distancing in response to autobiographical stressors., Results: Those who received active left or active right as opposed to sham rTMS exhibited enhanced regulation (ds = 0.21-0.62) as measured by psychophysiological indices during the intervention (higher high-frequency heart rate variability, lower regulation duration). Those who received active rTMS over the left dlPFC also self-reported reduced distress throughout the intervention (d = 0.30), higher likelihood to use CR, and lower daily distress during the week following the intervention. The procedures were acceptable and feasible with few side effects., Conclusions: These findings show that engaging frontal circuits simultaneously with cognitive skills training and rTMS may be clinically feasible, well-tolerated and may show promise for the treatment of transdiagnostic emotional dysregulation. Larger follow-up studies are needed to confirm the efficacy of this novel therapeutic approach., (© 2021 S. Karger AG, Basel.)

Background: Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site-specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site-specific stimulation during an online task invoking both skills., Methods: Twenty-nine subjects completed a 4-day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants., Results: Despite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects., Conclusion: While this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

While repetitive transcranial magnetic stimulation (rTMS) is widely used to treat psychiatric disorders, innovations are needed to improve its efficacy. An important limitation is that while psychiatric disorders are associated with fronto-limbic dysregulation, rTMS does not have sufficient depth penetration to modulate affected subcortical structures. Recent advances in task-related functional connectivity provide a means to better link superficial and deeper cortical sources with the possibility of increasing fronto-limbic modulation to induce stronger therapeutic effects. The objective of this pilot study was to test whether task-related, connectivity-based rTMS could modulate amygdala activation through its connectivity with the medial prefrontal cortex (mPFC). fMRI was collected to identify a node in the mPFC showing the strongest connectivity with the amygdala, as defined by psychophysiological interaction analysis. To promote Hebbian-like plasticity, and potentially stronger modulation, 5 Hz rTMS was applied while participants viewed frightening video-clips that engaged the fronto-limbic network. Significant increases in both the mPFC and amygdala were found for active rTMS compared to sham, offering promising preliminary evidence that functional connectivity-based targeting may provide a useful approach to treat network dysregulation. Further research is needed to better understand connectivity influences on rTMS effects to leverage this information to improve therapeutic applications.

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.

The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain-behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior. SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy., (Copyright © 2020 the authors.)

The perception of visual motion is dependent on a set of occipitotemporal regions that are readily accessible to neuromodulation. The current study tested if paired-pulse Transcranial Magnetic Stimulation (ppTMS) could modulate motion perception by stimulating the occipital cortex as participants viewed near-threshold motion dot stimuli. In this sham-controlled study, fifteen subjects completed two sessions. On the first visit, resting motor threshold (RMT) was assessed, and participants performed an adaptive direction discrimination task to determine individual motion sensitivity. During the second visit, subjects performed the task with three difficulty levels as TMS pulses were delivered 150 and 50 ms prior to motion stimulus onset at 120% RMT, under the logic that the cumulative inhibitory effect of these pulses would alter motion sensitivity. ppTMS was delivered at one of two locations: 3 cm dorsal and 5 cm lateral to inion (scalp-based coordinate), or at the site of peak activation for "motion" according to the NeuroSynth fMRI database (meta-analytic coordinate). Sham stimulation was delivered on one-third of trials by tilting the coil 90°. Analyses showed no significant active-versus-sham effects of ppTMS when stimulation was delivered to the meta-analytic (p = 0.15) or scalp-based coordinates (p = 0.17), which were separated by 29 mm on average. Active-versus-sham stimulation differences did not interact with either stimulation location (p = 0.12) or difficulty (p = 0.33). These findings fail to support the hypothesis that long-interval ppTMS recruits inhibitory processes in motion-sensitive cortex but must be considered within the limited parameters used in this design., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The brain is organized into networks that reorganize dynamically in response to cognitive demands and exogenous stimuli. In recent years, repetitive transcranial magnetic stimulation (rTMS) has gained increasing use as a noninvasive means to modulate cortical physiology, with effects both proximal to the stimulation site and in distal areas that are intrinsically connected to the proximal target. In light of these network-level neuromodulatory effects, there has been a rapid growth in studies attempting to leverage information about network connectivity to improve neuromodulatory control and intervention outcomes. However, the mechanisms-of-action of rTMS on network-level effects remain poorly understood and is based primarily on heuristics from proximal stimulation findings. To help bridge this gap, the current paper presents a systematic review of 33 rTMS studies with baseline and post-rTMS measures of fMRI resting-state functional connectivity (RSFC). Literature synthesis revealed variability across studies in stimulation parameters, studied populations, and connectivity analysis methodology. Despite this variability, it is observed that active rTMS induces significant changes on RSFC, but the prevalent low-frequency-inhibition/high-frequency-facilitation heuristic endorsed for proximal rTMS effects does not fully describe distal connectivity findings. This review also points towards other important considerations, including that the majority of rTMS-induced changes were found outside the stimulated functional network, suggesting that rTMS effects tend to spread across networks. Future studies may therefore wish to adopt conventions and systematic frameworks, such as the Yeo functional connectivity parcellation atlas adopted here, to better characterize network-level effect that contribute to the efficacy of these rapidly developing noninvasive interventions., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that delivers constant, low electrical current resulting in changes to cortical excitability. Prior work suggests it may enhance motor learning giving it the potential to augment surgical technical skill acquisition., Objectives: The aim of this study was to test the efficacy of tDCS, coupled with motor skill training, to accelerate laparoscopic skill acquisition in a pre-registered (NCT03083483), double-blind and placebo-controlled study. We hypothesized that relative to sham tDCS, active tDCS would accelerate the development of laparoscopic technical skills, as measured by the Fundamentals of Laparoscopic Surgery (FLS) Peg Transfer task quantitative metrics., Methods: In this study, sixty subjects (mean age 22.7 years with 42 females) were randomized into sham or active tDCS in either bilateral primary motor cortex (bM1) or supplementary motor area (SMA) electrode configurations. All subjects practiced the FLS Peg Transfer Task during six 20-min training blocks, which were preceded and followed by a single trial pre-test and post-test. The primary outcome was changes in laparoscopic skill performance over time, quantified by group differences in completion time from pre-test to post-test and learning curves developed from a calculated score accounting for errors., Results: Learning curves calculated over the six 20-min training blocks showed significantly greater improvement in performance for the bM1 group than the sham group (t = 2.07, p = 0.039), with the bM1 group achieving approximately the same amount of improvement in 4 blocks compared to the 6 blocks required of the sham group. The SMA group also showed greater mean improvement than sham, but exhibited more variable learning performance and differences relative to sham were not significant (t = 0.85, p = 0.400). A significant main effect was present for pre-test versus post-test times (F = 133.2, p < 0.001), with lower completion times at post-test, however these did not significantly differ for the training groups., Conclusion: Laparoscopic skill training with active bilateral tDCS exhibited significantly greater learning relative to sham. The potential for tDCS to enhance the training of surgical skills, therefore, merits further investigation to determine if these preliminary results may be replicated and extended., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The process of manipulating information within working memory is central to many cognitive functions, but also declines rapidly in old age. Improving this process could markedly enhance the health-span in older adults. The current pre-registered, randomized and placebo-controlled study tested the potential of online repetitive transcranial magnetic stimulation (rTMS) applied at 5 Hz over the left lateral parietal cortex to enhance working memory manipulation in healthy elderly adults. rTMS was applied, while participants performed a delayed-response alphabetization task with two individually titrated levels of difficulty. Coil placement and stimulation amplitude were calculated from fMRI activation maps combined with electric field modeling on an individual-subject basis in order to standardize dosing at the targeted cortical location. Contrary to the a priori hypothesis, active rTMS significantly decreased accuracy relative to sham, and only in the hardest difficulty level. When compared to the results from our previous study, in which rTMS was applied over the left prefrontal cortex, we found equivalent effect sizes but opposite directionality suggesting a site-specific effect of rTMS. These results demonstrate engagement of cortical working memory processing using a novel TMS targeting approach, while also providing prescriptions for future studies seeking to enhance memory through rTMS., Competing Interests: A.V. Peterchev is the inventor on patents and patent applications and, in the past 5 years, has received travel support as well as patent royalties from Rogue Research; research and travel support, consulting fees, as well as equipment donation from Tal Medical/Neurex; research and patent application support from Magstim; equipment loans and hardware donations from MagVenture; and consulting fees from Neuronetics, all related to TMS technology, but not directly related to the presented work.

Previous research has suggested that the lateral occipital cortex (LOC) is involved with visual decision making, and specifically with the accumulation of information leading to a decision. In humans, this research has been primarily based on imaging and electroencephalography (EEG), and as such only correlational. One line of such research has led to a model of three spatially distributed brain networks that activate in temporal sequence to enable visual decision-making. The model predicted that disturbing neural processing in the LOC at a specific latency would slow object decision-making, increasing reaction time (RT) in a difficult discrimination task. We utilized transcranial magnetic stimulation (TMS) to test this prediction, perturbing LOC beginning at 400 ms post-stimulus onset, a time in the model corresponding to LOC activation at a particular difficulty level, with the expectation of increased RT. Thirteen healthy adults participated in two TMS sessions in which left and right LOC were stimulated separately utilizing neuronavigation and robotic coil guidance. Participants performed a two-alternative forced-choice task selecting whether a car or face was present on each trial amidst visual noise pre-tested to approximate a 75% accuracy level. In an effort to disrupt processing, pairs of TMS pulses separated by 50 ms were presented at one of five stimulus onset asynchronies (SOAs): -200, 200, 400, 450, or 500 ms. Behavioral performance differed systematically across SOAs for RT and accuracy measures. As predicted, TMS at 400 ms resulted in a significant slowing of RT. TMS delivered at -200 ms resulted in faster RT, indicating early stimulation may result in priming and performance enhancement. Use of TMS thus causally demonstrated the involvement of LOC in this task, and more broadly with perceptual decision-making; additionally, it demonstrated the role of TMS in testing well-developed neural models of perceptual processing., (Copyright © 2020 Luber, Jangraw, Appelbaum, Harrison, Hilbig, Beynel, Jones, Sajda and Lisanby.)

Online repetitive transcranial magnetic stimulation (rTMS), applied while subjects are performing a task, is widely used to disrupt brain regions underlying cognition. However, online rTMS has also induced "paradoxical enhancement". Given the rapid proliferation of this approach, it is crucial to develop a better understanding of how online stimulation influences cognition, and the optimal parameters to achieve desired effects. To accomplish this goal, a quantitative meta-analysis was performed with random-effects models fitted to reaction time (RT) and accuracy data. The final dataset included 126 studies published between 1998 and 2016, with 244 total effects for reaction times, and 202 for accuracy. Meta-analytically, rTMS at 10 Hz and 20 Hz disrupted accuracy for attention, executive, language, memory, motor, and perception domains, while no effects were found with 1 Hz or 5 Hz. Stimulation applied at and 10 and 20 Hz slowed down RTs in attention and perception tasks. No performance enhancement was found. Meta-regression analysis showed that fMRI-guided targeting and short inter-trial intervals are associated with increased disruptive effects with rTMS., (Published by Elsevier Ltd.)

The safety and efficacy of neuronavigated intermittent theta burst stimulation (iTBS) in patients with bipolar depression has not yet been investigated. We hypothesized the superiority of active iTBS over sham. Twenty-six patients were randomly allocated to receive either active (n=12) or sham (n=14) iTBS. Response and remission rates according to changes in depression MADRS score were high following active iTBS (72% and 42% for response and remission rates, respectively), but no significant difference was found after sham stimulation (42%and 25%). No adverse events were observed. This study revealed the safety and tolerability of twice daily iTBS in patients with bipolar depression. Larger controlled studies are warranted to prove iTBS superiority in treatment-resistant bipolar depression., (Copyright © 2019. Published by Elsevier Masson SAS.)

Brain dynamics at rest depend on the large-scale interactions between oscillating cortical microcircuits arranged into macrocolumns. Cytoarchitectonic studies have shown that the structure of those microcircuits differs between cortical regions, but very little is known about interregional differences of their intrinsic dynamics at a macro-scale in human. We developed here a new method aiming at mapping the dynamical properties of cortical microcircuits non-invasively using the coupling between robotized transcranial magnetic stimulation and electroencephalography. We recorded the responses evoked by the stimulation of 18 cortical targets largely covering the accessible neocortex in 22 healthy volunteers. Specific data processing methods were developed to map the local source activity of each cortical target, which showed inter-regional differences with very good interhemispheric reproducibility. Functional signatures of cortical microcircuits were further studied using spatio-temporal decomposition of local source activities in order to highlight principal brain modes. The identified brain modes revealed that cortical areas with similar intrinsic dynamical properties could be distributed either locally or not, with a spatial signature that was somewhat reminiscent of resting state networks. Our results provide the proof of concept of "functional cytoarchitectonics", that would guide the parcellation of the human cortex using not only its cytoarchitecture but also its intrinsic responses to local perturbations. This opens new avenues for brain modelling and physiopathology readouts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: This study aimed to assess the impact of aging and 'state-dependency' on cortical excitability. Two studies investigated these factors using a motor task and found that the age-related differences observed at rest disappeared in the task condition. However, as both their tasks and excitability measurements involved the motor cortex, their results could be specific only to the motor system. To overcome this problem, the present study used a cognitive task to control mental state., Method: Intracortical inhibition/facilitation (ICI/ICF) were assessed in young and older adults at rest and during the cognitive task. The cortical silent period (CSP) was also evaluated., Results: ICI and CSP were reduced with aging. However, ICI differences between young and old people disappeared when they performed the cognitive task., Conclusion: Age and mental state modify cortical excitability. Taking these factors into consideration is crucial to clinical research using cortical excitability as a possible biomarker of pathology., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The study assumed that the antisaccade (AS) task is a relevant psychophysical tool to assess (i) short-term neuromodulation of the dorsolateral prefrontal cortex (DLPFC) induced by intermittent theta burst stimulation (iTBS); and (ii) mood change occurring during the course of the treatment. Saccadic inhibition is known to strongly involve the DLPFC, whose neuromodulation with iTBS requires less stimulation time and lower stimulation intensity, as well as results in longer aftereffects than the conventional repetitive transcranial magnetic stimulation (rTMS). Active or sham iTBS was applied every day for 3 weeks over the left DLPFC of 12 drug-resistant bipolar depressed patients. To assess the iTBS-induced short-term neuromodulation, the saccadic task was performed just before (S1) and just after (S2) the iTBS session, the first day of each week. Mood was evaluated through Montgomery and Asberg Depression Rating Scale (MADRS) scores and the difference in scores between the beginning and the end of treatment was correlated with AS performance change between these two periods. As expected, only patients from the active group improved their performance from S1 to S2 and mood improvement was significantly correlated with AS performance improvement. In addition, the AS task also discriminated depressive bipolar patients from healthy control subjects. Therefore, the AS task could be a relevant and useful tool for clinicians to assess if the Transcranial magnetic stimulation (TMS)-induced short-term neuromodulation of the DLPFC occurs as well as a "trait vs. state" objective marker of depressive mood disorder.