Individualized, connectome-based, non-invasive stimulation of OCD deep-brain targets: A proof-of-concept.

Treatment-resistant obsessive-compulsive disorder (OCD) generally improves with deep-brain stimulation (DBS), thought to modulate neural activity at both the implantation site and in connected brain regions. However, its invasive nature, side-effects, and lack of customization, make non-invasive treatments preferable. Harnessing the established remote effects of cortical transcranial magnetic stimulation (TMS), connectivity-based approaches have emerged for depression that aim at influencing distant regions connected to the stimulation site. We here investigated whether effective OCD DBS targets (here subthalamic nucleus [STN] and nucleus accumbens [NAc]) could be modulated non-invasively with TMS. In a proof-of-concept study with nine healthy individuals, we used 7T magnetic resonance imaging (MRI) and probabilistic tractography to reconstruct the fiber tracts traversing manually segmented STN/NAc. Two TMS targets were individually selected based on the strength of their structural connectivity to either the STN, or both the STN and NAc. In a sham-controlled, within-subject cross-over design, TMS was administered over the personalized targets, located around the precentral and middle frontal gyrus. Resting-state functional 3T MRI was acquired before, and at 5 and 25 min after stimulation to investigate TMS-induced changes in the functional connectivity of the STN and NAc with other regions of the brain. Static and dynamic seed-to-voxel correlation analyses were conducted. TMS over both targets was able to modulate the functional connectivity of the STN and NAc, engaging both overlapping and distinct regions, and unfolding following different temporal dynamics. Given the relevance of the engaged connected regions to OCD pathology, we argue that a personalized, connectivity-based procedure is worth investigating as potential treatment for refractory OCD.

Impact of theta transcranial alternating current stimulation on language production in adult classic galactosemia patients.

Patients with classic galactosemia (CG), an inborn error of galactose metabolism, suffer from impairments in cognition, including language processing. Potential causes are atypical brain oscillations. Recent electroencephalogram (EEG) showed differences in the P300 event-related-potential (ERP) and alterations in the alpha/theta-range during speech planning. This study investigated whether transcranial alternating current stimulation (tACS) at theta-frequency compared to sham can cause a normalization of the ERP post stimulation and improves language performance. Eleven CG patients and fourteen healthy controls participated in two tACS-sessions (theta 6.5 Hz/sham). They were engaged in an active language task, describing animated scenes at three moments, that is, pre/during/post stimulation. Pre and post stimulation, behavior (naming accuracy, voice-onset-times; VOT) and mean-amplitudes of ERP were compared, by means of a P300 time-window analysis and cluster-based-permutation testing during speech planning. The results showed that theta stimulation, not sham, significantly reduced naming error-percentage in patients, not in controls. Theta did not systematically speed up naming beyond a general learning effect, which was larger for the patients. The EEG analysis revealed a significant pre-post stimulation effect (P300/late positivity), in patients and during theta stimulation only. In conclusion, theta-tACS improved accuracy in language performance in CG patients compared to controls and altered the P300 and late positive ERP-amplitude, suggesting a lasting effect on neural oscillation and behavior.

Modulating risk-taking behavior with theta-band tACS.

Although risk is prevalent in decision-making, the specific neural processes underlying risk-taking behavior remain unclear. Previous studies have suggested that frontal theta-band activity plays a crucial role in modulating risk-taking behavior. The functional relevance of theta in risk-taking behavior is yet to be clearly established and studies using noninvasive brain stimulation have yielded inconsistent findings. We aimed to investigate this relevance using transcranial alternating current stimulation (tACS) over right or left dorsolateral prefrontal cortex (DLPFC). We also studied the influence of stimulation intensity on risk-taking behavior and electrophysiological effects. We applied theta-band (6.5 Hz) tACS over the left (F3) and right (F4) DLPFC with lower (1.5 mA) and higher (3 mA) tACS intensities. We employed a single-blinded, sham-controlled, within-subject design and combined tACS with electroencephalography (EEG) measurements and the Maastricht Gambling Task (MGT) to elicit and evaluate risk-taking behavior. Our results show an increase in risk-taking behavior after left DLPFC stimulation at both intensities and a reduction of risk-taking behavior after 3 mA (and not 1.5 mA) right DLPFC stimulation compared to sham. Further analyses showed a negative correlation between resting-state frontal theta-power and risk-taking behavior. Overall, frontal theta-power was increased after left, but not right, theta-band tACS independent of stimulation intensity. Our findings confirm the functional relevance of frontal theta-band activity in decision-making under risk and the differential role of left and right DLPFC. We also were able to show that stimulation intensity did have an effect on behavioral responses, namely risk-taking behavior. Significant right hemisphere stimulation effects were observed only after high-intensity stimulation. Nevertheless, electrophysiological effects were only significant after left DLPFC stimulation, regardless of tACS intensity. Furthermore, the results indicate the role of the baseline frontal theta-power in the direction of behavioral effects after theta-band tACS.

Hemispheric Asymmetry in TMS-Induced Effects on Spatial Attention: A Meta-Analysis.

Hemispheric asymmetry is a fundamental principle in the functional architecture of the brain. It plays an important role in attention research where right hemisphere dominance is core to many attention theories. Lesion studies seem to confirm such hemispheric dominance with patients being more likely to develop left hemineglect after right hemispheric stroke than vice versa. However, the underlying concept of hemispheric dominance is still not entirely clear. Brain stimulation studies using transcranial magnetic stimulation (TMS) might be able to illuminate this concept. To examine the putative hemispheric asymmetry in spatial attention, we conducted a meta-analysis of studies applying inhibitory TMS protocols to the left or right posterior parietal cortices (PPC), assessing effects on attention biases with the landmark and line bisection task. A total of 18 studies including 222 participants from 1994 to February 2022 were identified. The analysis revealed a significant shift of the perceived midpoint towards the ipsilateral hemifield after right PPC suppression (Cohen's d = 0.52), but no significant effect after left PPC suppression (Cohen's d = 0.26), suggesting a hemispheric asymmetry even though the subgroup difference does not reach significance (p = .06). A complementary Bayesian meta-analysis revealed a high probability of at least a medium effect size after right PPC disruption versus a low probability after left PPC disruption. This is the first quantitative meta-analysis supporting right hemisphere-specific TMS-induced spatial attention deficits, mimicking hemineglect in healthy participants. We discuss the result in the light of prominent attention theories, ultimately concluding how difficult it remains to differentiate between these theories based on attentional bias scores alone.

No evidence of rhythmic visuospatial attention at cued locations in a spatial cuing paradigm, regardless of their behavioural relevance.

Recent evidence suggests that visuospatial attentional performance is not stable over time but fluctuates in a rhythmic fashion. These attentional rhythms allow for sampling of different visuospatial locations in each cycle of this rhythm. However, it is still unclear in which paradigmatic circumstances rhythmic attention becomes evident. First, it is unclear at what spatial locations rhythmic attention occurs. Second, it is unclear how the behavioural relevance of each spatial location determines the rhythmic sampling patterns. Here, we aim to elucidate these two issues. Firstly, we aim to find evidence of rhythmic attention at the predicted (i.e. cued) location under moderately informative predictor value, replicating earlier studies. Secondly, we hypothesise that rhythmic attentional sampling behaviour will be affected by the behavioural relevance of the sampled location, ranging from non-informative to fully informative. To these aims, we used a modified Egly-Driver task with three conditions: a fully informative cue, a moderately informative cue (replication condition), and a non-informative cue. We did not find evidence of rhythmic sampling at cued locations, failing to replicate earlier studies. Nor did we find differences in rhythmic sampling under different predictive values of the cue. The current data does not allow for robust conclusions regarding the non-cued locations due to the absence of a priori hypotheses. Post-hoc explorative data analyses, however, clearly indicate that attention samples non-cued locations in a theta-rhythmic manner, specifically when the cued location bears higher behavioural relevance than the non-cued locations.

Transcranial magnetic stimulation over posterior parietal cortex modulates alerting and executive control processes in attention.

Attention includes three different functional components: generating and maintaining an alert state (alerting), orienting to sensory events (orienting), and resolving conflicts between alternative actions (executive control). Neuroimaging and patient studies suggest that the posterior parietal cortex (PPC) is involved in all three attention components. Transcranial magnetic stimulation (TMS) has repeatedly been applied over the PPC to study its functional role for shifts and maintenance of visuospatial attention. Most TMS-PPC studies used only detection tasks or orienting paradigms to investigate TMS-PPC effects on attention processes, neglecting the alerting and executive control components of attention. The objective of the present study was to investigate the role of PPC in all three functional components of attention: alerting, orienting, and executive control. To this end, we disrupted PPC with TMS (continuous theta-burst stimulation), to modulate subsequent performance on the Lateralized-Attention Network Test, used to assess the three attention components separately. Our results revealed hemifield-specific effects on alerting and executive control functions, but we did not find stimulation effects on orienting performance. While this field of research and associated clinical development have been predominantly focused on orienting performance, our results suggest that parietal cortex and its modulation may affect other aspects of attention as well.

Brain stimulation reveals distinct motives underlying reciprocal punishment and reward.

Reciprocal fairness, in the form of punishment and reward, is at the core of human societal order. Its underlying neural mechanisms are, however, not fully understood. We systemize suggestive evidence regarding the involvement of the right dorsolateral prefrontal cortex (rDLPFC) and medial prefrontal cortex (mPFC) in reciprocal fairness in three cognitive mechanisms (cognitive control, domain-general and self-reference). We test them and provide novel insights in a comprehensive behavioural experiment with non-invasive brain stimulation where participants can punish greedy actions and reward generous actions. Brain stimulation of either brain area decreases reward and punishment when reciprocation is costly but unexpectedly increases reward when it is non-costly. None of the hypothesized mechanisms fully accounts for the observed behaviour, and the asymmetric involvement of the investigated brain areas in punishment and reward suggests that different psychological mechanisms are underlying punishing selfishness and rewarding generosity. We propose that, for reciprocal punishment, the rDLPFC and the mPFC process self-relevant information, in terms of both personal cost and personal involvement; for reciprocal reward, these brain regions are involved in controlling selfish and pure reciprocity motives, while simultaneously promoting the enforcement of fairness norms. These insights bear importance for endeavours to build biologically plausible models of human behaviour.

The Effects of Serum Removal on Gene Expression and Morphological Plasticity Markers in Differentiated SH-SY5Y Cells.

Despite the widespread use of the SH-SY5Y human neuroblastoma cell line in modeling human neurons in vitro, protocols for growth, differentiation and experimentation differ considerably across the literature. Many studies fully differentiate SH-SY5Y cells before experimentation, to investigate plasticity measures in a mature, human neuronal-like cell model. Prior to experimentation, serum is often removed from cell culture media, to arrest the cell growth cycle and synchronize cells. However, the exact effect of this serum removal before experimentation on mature, differentiated SH-SY5Y cells has not yet been described. In studies using differentiated SH-SY5Y cells, any effect of serum removal on plasticity markers may influence results. The aim of the current study was to systematically characterize, in differentiated, neuronal-like SH-SY5Y cells, the potentially confounding effects of complete serum removal in terms of morphological and gene expression markers of plasticity. We measured changes in commonly used morphological markers and in genes related to neuroplasticity and synaptogenesis, particularly in the BDNF-TrkB signaling pathway. We found that complete serum removal from already differentiated SH-SY5Y cells increases neurite length, neurite branching, and the proportion of cells with a primary neurite, as well as proportion of ßIII-Tubulin and MAP2 expressing cells. Gene expression results also indicate increased expression of PSD95 and NTRK2 expression 24 h after serum removal. We conclude that serum deprivation in differentiated SH-SY5Y cells affects morphology and gene expression and can potentially confound plasticity-related outcome measures, having significant implications for experimental design in studies using differentiated SH-SY5Y cells as a model of human neurons.

Study protocol of transcranial electrical stimulation at alpha frequency applied during rehabilitation: A randomized controlled trial in chronic stroke patients with visuospatial neglect.

BACKGROUND: A frequent post stroke disorder in lateralized attention is visuospatial neglect (VSN). As VSN has a strong negative impact on recovery in general and independence during daily life, optimal treatment is deemed urgent. Next to traditional stroke treatment, non-invasive brain stimulation offers the potential to facilitate stroke recovery as a complementary approach. In the present study, visual scanning training (VST; the current conventional treatment) will be combined with transcranial alternating current stimulation (tACS) to evaluate the additive effects of repeated sessions of tACS in combination with six-weeks VST rehabilitation. METHODS: In this double-blind randomized placebo-controlled intervention study (RCT), we will compare the effects of active tACS plus VST to sham (placebo) tACS plus VST, both encompassing 18 VST training sessions, 40 minutes each, during 6 weeks. Chronic stroke patients with VSN (> 6 months post-stroke onset) are considered eligible for study participation. In total 22 patients are needed for the study. The primary outcome is change in performance on a cancellation task. Secondary outcomes are changes in performance on a visual detection task, two line bisection tasks, and three measures to assess changes in activities of daily living. Assessment is at baseline, directly after the first and ninth training session, after the last training session (post training), and 1 week and 3 months after termination of the training (follow-up). DISCUSSION: If effective, a tACS-VST rehabilitation program could be implemented as a treatment option for VSN. TRIAL REGISTRATION: ClinicalTrials.gov ; registration number: NCT05466487; registration date: July 18, 2022 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT05466487.

Relating alpha power modulations to competing visuospatial attention theories.

Visuospatial attention theories often propose hemispheric asymmetries underlying the control of attention. In general support of these theories, previous EEG/MEG studies have shown that spatial attention is associated with hemispheric modulation of posterior alpha power (gating by inhibition). However, since measures of alpha power are typically expressed as lateralization scores, or collapsed across left and right attention shifts, the individual hemispheric contribution to the attentional control mechanism remains unclear. This is, however, the most crucial and decisive aspect in which the currently competing attention theories continue to disagree. To resolve this long-standing conflict, we derived predictions regarding alpha power modulations from Heilman's hemispatial theory and Kinsbourne's interhemispheric competition theory and tested them empirically in an EEG experiment. We used an attention paradigm capable of isolating alpha power modulation in two attentional states, namely attentional bias in a neutral cue condition and spatial orienting following directional cues. Differential alpha modulations were found for both hemispheres across conditions. When anticipating peripheral visual targets without preceding directional cues (neutral condition), posterior alpha power in the left hemisphere was generally lower and more strongly modulated than in the right hemisphere, in line with the interhemispheric competition theory. Intriguingly, however, while alpha power in the right hemisphere was modulated by both, cue-directed leftward and rightward attention shifts, the left hemisphere only showed modulations by rightward shifts of spatial attention, in line with the hemispatial theory. This suggests that the two theories may not be mutually exclusive, but rather apply to different attentional states.

The Role of Inhibitory Control Mechanisms in the Regulation of Sexual Behavior.

Sexual behavior is the open manifestation of a complex interplay between psychophysiological mechanisms that either facilitate or inhibit sexual thoughts, desires, and associated behaviors. Whereas sexual excitation has been widely studied, less is known about the impact of inhibitory control mechanisms that enable individuals to refrain from sexual cognition and behavior. The present study examined: (1) the relationship between general and sexual inhibitory mechanisms (as measured through self-reports and computer-based tasks), (2) the relation between sexual inhibitory processes at cognitive and motor-motivational levels and with sexual inhibition as an individual trait, and (3) the predictive value of these parameters on sexual thoughts (cognition) and behavior. We demonstrate that general inhibitory control (i.e., the ability to suppress any preponderant response) and the specific inhibition of sexual responses represent distinct processes that require at least partly different control mechanisms. Similarly, the ability to inhibit sexual visual input and the ability to suppress sexually driven responses seem to be two independent processes. The different inhibitory processes distinctively predicted the frequency of sexual thoughts and sexual behavior. We propose that these different inhibitory mechanisms are at play during different phases of sexual regulation (before and after the generation and unfolding of sexual arousal) and that a specific deficit in one of these processes may underlie the distinctive symptomatology and comorbidity of sexual disorders.

Interindividual Variability and Intraindividual Reliability of Intermittent Theta Burst Stimulation-induced Neuroplasticity Mechanisms in the Healthy Brain.

We combined patterned TMS with EMG in several sessions of a within-subject design to assess and characterize intraindividual reliability and interindividual variability of TMS-induced neuroplasticity mechanisms in the healthy brain. Intermittent theta burst stimulation (iTBS) was applied over M1 to induce long-term potentiation-like mechanisms as assessed by changes in corticospinal excitability. Furthermore, we investigated the association between the observed iTBS effects and individual differences in prolonged measures of corticospinal excitability. Our results show that iTBS-induced measures of neuroplasticity suffer from high variability between individuals within a single assessment visit and from low reliability within individuals across two assessment visits. This indicates that both group and individual effects of iTBS on corticospinal excitability cannot be assumed to be reliable and therefore need to be interpreted with caution, at least when measured by changes in the amplitudes of motor-evoked potentials.

Moving Beyond Attentional Biases: Shifting the Interhemispheric Balance between Left and Right Posterior Parietal Cortex Modulates Attentional Control Processes.

The concept of interhemispheric competition has been very influential in attention research, and the occurrence of biased attention due to an imbalance in posterior parietal cortex (PPC) is well documented. In this context, the vast majority of studies have assessed attentional performance with tasks that did not include an explicit experimental manipulation of attention, and, as a consequence, it remains largely unknown how these findings relate to core attentional constructs such as endogenous and exogenous control and spatial orienting and reorienting. We here addressed this open question by creating an imbalance between left and right PPC with transcranial direct current stimulation, resulting in right-hemispheric dominance, and assessed performance on three experimental paradigms that isolate distinct attentional processes. The comparison between active and sham transcranial direct current stimulations revealed a highly informative pattern of results with differential effects across tasks. Our results demonstrate the functional necessity of PPC for endogenous and exogenous attentional control and, importantly, link the concept of interhemispheric competition to core attentional processes, thus moving beyond the notion of biased attention after noninvasive brain stimulation over PPC.

Identifying cognitive predictors of reactive and proactive aggression.

The aim of this study was to identify implicit cognitive predictors of aggressive behavior. Specifically, the predictive value of an attentional bias for aggressive stimuli and automatic association of the self and aggression was examined for reactive and proactive aggressive behavior in a non-clinical sample (N = 90). An Emotional Stroop Task was used to measure an attentional bias. With an idiographic Single-Target Implicit Association Test, automatic associations were assessed between words referring to the self (e.g., the participants' name) and words referring to aggression (e.g., fighting). The Taylor Aggression Paradigm (TAP) was used to measure reactive and proactive aggressive behavior. Furthermore, self-reported aggressiveness was assessed with the Reactive Proactive Aggression Questionnaire (RPQ). Results showed that heightened attentional interference for aggressive words significantly predicted more reactive aggression, while lower attentional bias towards aggressive words predicted higher levels of proactive aggression. A stronger self-aggression association resulted in more proactive aggression, but not reactive aggression. Self-reports on aggression did not additionally predict behavioral aggression. This implies that the cognitive tests employed in our study have the potential to discriminate between reactive and proactive aggression. Aggr. Behav. 41:51-64 2015. © 2014 Wiley Periodicals, Inc.

The role of right prefrontal and medial cortex in response inhibition: interfering with action restraint and action cancellation using transcranial magnetic brain stimulation.

The ability of inhibiting impulsive urges is paramount for human behavior. Such successful response inhibition has consistently been associated with activity in pFC. The current study aims to unravel the differential involvement of different areas within right pFC for successful action restraint versus action cancellation. These two conceptually different aspects of action inhibition were measured with a go/no-go task (action restraint) and a stop signal task (action cancellation). Localization of relevant prefrontal activation was based on fMRI data. Significant task-related activation during successful action restraint was localized for each participant individually in right anterior insula (rAI), right superior frontal gyrus, and pre-SMA. Activation during successful action cancellation was localized in rAI, right middle frontal gyrus, and pre-SMA. Subsequently, fMRI-guided continuous thetaburst stimulation was applied to these regions. Results showed that the disruption of neural activity in rAI reduced both the ability to restrain (go/no-go) and cancel (stop signal) responses. In contrast, continuous thetaburst stimulation-induced disruption of the right superior frontal gyrus specifically impaired the ability to restrain from responding (go/no-go), while leaving the ability for action cancellation largely intact. Stimulation applied to right middle frontal gyrus and pre-SMA did not affect inhibitory processing in neither of the two tasks. These findings provide a more comprehensive perspective on the role of pFC in inhibition and cognitive control. The results emphasize the role of inferior frontal regions for global inhibition, whereas superior frontal regions seem to be specifically relevant for successful action restraint.

A network approach to response inhibition: dissociating functional connectivity of neural components involved in action restraint and action cancellation.

The ability to inhibit action tendencies is vital for adaptive human behaviour. Various paradigms are supposed to assess action inhibition and are often used interchangeably. However, these paradigms are based on different conceptualizations (action restraint vs. action cancellation) and the question arises as to what extent different conceptualizations of inhibitory processing are mirrored in a distinct neural activation pattern. We used functional magnetic resonance imaging to investigate the neural correlates of action restraint vs. action cancellation. Analyses of local activity changes as well as network connectivity measures revealed a strong overlap of activation within a common action inhibition network including inferior frontal, pre-supplementary motor and thalamic brain areas as well as the anterior cingulate cortex. Furthermore, our findings pointed to additional neural networks that are distinct for action restraint (i.e. right superior frontal gyrus, left middle frontal gyrus, and bilateral anterior cingulate cortex) and action cancellation (i.e. right middle frontal gyrus, posterior cingulate cortex, and parietal regions). Our connectivity analyses showed that different inhibitory modalities largely relied on a task-independent global inhibition network within the brain. Furthermore, they suggested that the conceptually distinct inhibitory aspects of action restraint vs. action cancellation also activated additional specific brain regions in a task-dependent manner. This has implications for the choice of tasks in an empirical setting, but is also relevant for various clinical contexts in which inhibition deficits are considered a diagnostic feature.

Target Engagement and Brain State Dependence of Transcranial Magnetic Stimulation: Implications for Clinical Practice.

Transcranial magnetic stimulation (TMS) is capable of noninvasively inducing lasting neuroplastic changes when applied repetitively across multiple treatment sessions. In recent years, repetitive TMS has developed into an established evidence-based treatment for various neuropsychiatric disorders such as depression. Despite significant advancements in our understanding of the mechanisms of action of TMS, there is still much to learn about how these mechanisms relate to the clinical effects observed in patients. If there is one thing about TMS that we know for sure, it is that TMS effects are state dependent. In this review, we describe how the effects of TMS on brain networks depend on various factors, including cognitive brain state, oscillatory brain state, and recent brain state history. These states play a crucial role in determining the effects of TMS at the moment of stimulation and are therefore directly linked to what is referred to as target engagement in TMS therapy. There is no control over target engagement without considering the different brain state dependencies of our TMS intervention. Clinical TMS protocols are largely ignoring this fundamental principle, which may explain the large variability and often still limited efficacy of TMS treatments. We propose that after almost 30 years of research on state dependency of TMS, it is time to change standard clinical practice by taking advantage of this fundamental principle. Rather than ignoring TMS state dependency, we can use it to our clinical advantage to improve the effectiveness of TMS treatments.

Alpha transcranial alternating current stimulation as add-on to neglect training: a randomized trial.

Visuospatial neglect is a common and debilitating condition following unilateral stroke, significantly impacting cognitive functioning and daily life. There is an urgent need for effective treatments that can provide clinically relevant and sustained benefits. In addition to traditional stroke treatment, non-invasive brain stimulation, such as transcranial alternating current stimulation, shows promise as a complementary approach to enhance stroke recovery. In the current study, we aimed to evaluate the additive effects of multi-session transcranial alternating current stimulation at alpha frequency when combined with visual scanning training in chronic stroke patients with visuospatial neglect. In this double-blind randomized controlled trial, we compared the effects of active transcranial alternating current stimulation at alpha frequency to sham (placebo) transcranial alternating current stimulation, both combined with visual scanning training. Both groups received eighteen 40-minute training sessions over a 6-week period. A total of 22 chronic visuospatial neglect patients participated in the study (active group n = 12, sham group n = 10). The median age was 61.0 years, with a median time since stroke of 36.1 months. We assessed the patients at six time-points: at baseline, after the first, ninth and eighteenth training sessions, as well as 1 week and 3 months following the completion of the combined neuromodulation intervention. The primary outcome measure was the change in performance on a visual search task, specifically the star cancellation task. Secondary outcomes included performance on a visual detection task, two line bisection tasks and three tasks evaluating visuospatial neglect in daily living. We found significantly improved visual search (primary outcome) and visual detection performance in the neglected side in the active transcranial alternating current stimulation group, compared to the sham transcranial alternating current stimulation group. We did not observe stimulation effects on line bisection performance nor in daily living. Time effects were observed on all but one outcome measures. Multi-session transcranial alternating current stimulation combined with visual scanning training may be a more effective treatment for chronic visuospatial neglect than visual scanning training alone. These findings provide valuable insights into novel strategies for stroke recovery, even long after the injury, with the aim of enhancing cognitive rehabilitation outcomes and improving the overall quality of life for individuals affected by this condition. Trial registration: ClinicalTrials.gov; registration number: NCT05466487; https://clinicaltrials.gov/ct2/show/NCT05466487.

On the feasibility of concurrent human TMS-EEG-fMRI measurements.

Simultaneously combining the complementary assets of EEG, functional MRI (fMRI), and transcranial magnetic stimulation (TMS) within one experimental session provides synergetic results, offering insights into brain function that go beyond the scope of each method when used in isolation. The steady increase of concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI studies further underlines the added value of such multimodal imaging approaches. Whereas concurrent EEG-fMRI enables monitoring of brain-wide network dynamics with high temporal and spatial resolution, the combination with TMS provides insights in causal interactions within these networks. Thus the simultaneous use of all three methods would allow studying fast, spatially accurate, and distributed causal interactions in the perturbed system and its functional relevance for intact behavior. Concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI experiments are already technically challenging, and the three-way combination of TMS-EEG-fMRI might yield additional difficulties in terms of hardware strain or signal quality. The present study explored the feasibility of concurrent TMS-EEG-fMRI studies by performing safety and quality assurance tests based on phantom and human data combining existing commercially available hardware. Results revealed that combined TMS-EEG-fMRI measurements were technically feasible, safe in terms of induced temperature changes, allowed functional MRI acquisition with comparable image quality as during concurrent EEG-fMRI or TMS-fMRI, and provided artifact-free EEG before and from 300 ms after TMS pulse application. Based on these empirical findings, we discuss the conceptual benefits of this novel complementary approach to investigate the working human brain and list a number of precautions and caveats to be heeded when setting up such multimodal imaging facilities with current hardware.