Occipital transcranial direct current stimulation in episodic migraine patients: effect on cerebral perfusion.

Cerebral blood flow differs between migraine patients and healthy controls during attack and the interictal period. This study compares the brain perfusion of episodic migraine patients and healthy controls and investigates the influence of anodal transcranial direct current stimulation (tDCS) over the occipital cortex. We included healthy adult controls and episodic migraineurs. After a 28-day baseline period and the baseline visit, migraine patients received daily active or sham anodal tDCS over the occipital lobe for 28 days. All participants underwent a MRI scan at baseline; migraineurs were also scanned shortly after the stimulation period and about five months later. At baseline, brain perfusion of migraine patients and controls differed in several areas; among the stimulated areas, perfusion was increased in the cuneus of healthy controls. At the first visit, the active tDCS group had an increased blood flow in regions processing visual stimuli and a decreased perfusion in other areas. Perfusion did not differ at the second follow-up visit. The lower perfusion level in migraineurs in the cuneus indicates a lower preactivation level. Anodal tDCS over the occipital cortex increases perfusion of several areas shortly after the stimulation period, but not 5 months later. An increase in the cortical preactivation level could mediate the transient reduction of the migraine frequency.Trial registration: NCT03237754 (registered at clincicaltrials.gov; full date of first trial registration: 03/08/2017).

The impact of levamisole and alcohol on white matter microstructure in adult chronic cocaine users.

Previous brain imaging studies with chronic cocaine users (CU) using diffusion tensor imaging (DTI) mostly focused on fractional anisotropy to investigate white matter (WM) integrity. However, a quantitative interpretation of fractional anisotropy (FA) alterations is often impeded by the inherent limitations of the underlying tensor model. A more fine-grained measure of WM alterations could be achieved by measuring fibre density (FD). This study investigates this novel DTI metric comparing 23 chronic CU and 32 healthy subjects. Quantitative hair analysis was used to determine intensity of cocaine and levamisole exposure-a cocaine adulterant with putative WM neurotoxicity. We first assessed the impact of cocaine use, levamisole exposure and alcohol use on group differences in WM integrity. Compared with healthy controls, all models revealed cortical reductions of FA and FD in CU. At the within-patient group level, we found that alcohol use and levamisole exposure exhibited regionally different FA and FD alterations than cocaine use. We found mostly negative correlations of tract-based WM associated with levamisole and weekly alcohol use. Specifically, levamisole exposure was linked with stronger WM reductions in the corpus callosum than alcohol use. Cocaine use duration correlated negatively with FA and FD in some regions. Yet, most of these correlations did not survive a correction for multiple testing. Our results suggest that chronic cocaine use, levamisole exposure and alcohol use were all linked to significant WM impairments in CU. We conclude that FD could be a sensitive marker to detect the impact of the use of multiple substances on WM integrity in cocaine but also other substance use disorders.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Enhancing reappraisal of negative emotional memories with transcranial direct current stimulation.

Reappraisal of negative memories and experiences is central for mental health and well-being. Deficiency of reappraisal lies at the core of many psychiatric disorders and is a key target for treatment. Here we apply transcranial direct current stimulation (tDCS) to enhance reappraisal of negative emotional memories. In a randomised, sham-controlled, 2 × 2 between-subject and double-blinded study, we applied single sessions of anodal and sham tDCS over the right dorsolateral prefrontal cortex (dlPFC) of 101 healthy participants while reappraising a personal negative memory or engaging in a control task. We hypothesised that (i) reappraisal decreases negative valence, arousal and evaluations of the memory and leads to improved decision making, and (ii) tDCS leads to additional changes in these reappraisal outcomes. In line with these hypotheses, participants' personal memories were rated as less negative and less arousing following reappraisal. Anodal tDCS during reappraisal was associated with significant short-term reductions in negative valence compared to sham stimulation. Our results indicate that tDCS may enhance some of the effects of reappraisal. If replicated, our findings suggest potential benefits elicited by tDCS stimulation that may help optimise current treatment approaches for psychiatric disorders.

Frontopolar theta oscillations link metacognition with prospective decision making.

Prospective decision making considers the future consequences of actions and therefore requires agents to represent their present subjective preferences reliably across time. Here, we test the link of frontopolar theta oscillations to both metacognitive ability and prospective choice behavior. We target these oscillations with transcranial alternating current stimulation while participants make decisions between smaller-sooner and larger-later monetary rewards and rate their choice confidence after each decision. Stimulation designed to enhance frontopolar theta oscillations increases metacognitive accuracy in reports of subjective uncertainty in intertemporal decisions. Moreover, the stimulation also enhances the willingness of participants to restrict their future access to short-term gratification by strengthening the awareness of potential preference reversals. Our results suggest a mechanistic link between frontopolar theta oscillations and metacognitive knowledge about the stability of subjective value representations, providing a potential explanation for why frontopolar cortex also shields prospective decision making against future temptation.

Long-Term Effects of Self-Administered Transcranial Direct Current Stimulation in Episodic Migraine Prevention: Results of a Randomized Controlled Trial.

BACKGROUND: Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively. OBJECTIVE: To test the hypothesis that self-administered anodal tDCS over the visual cortex significantly decreases the number of monthly migraine days in episodic migraine. MATERIALS AND METHODS: The study was single-blind, randomized, and sham-controlled. Inclusion criteria were age 18-80 years and an ICHD-3 diagnosis of episodic migraine. Exclusion criteria were pregnancy, presence of a neurodegenerative disorder, a contraindication against MRI examinations, and less than two migraine days during the 28-day baseline period. Patients in whom the baseline period suggested chronic migraine were excluded. After baseline, participants applied daily either verum (anodal-1 mA to 20 min) or sham tDCS (anodal-1 mA to 30 sec) at Oz (reference Cz electrode) for 28 days. Headache diaries were used to record the number of migraine days at baseline, during the stimulation period, and during four subsequent 28-day periods. RESULTS: Twenty-eight patients were included; two were excluded after the baseline period because less than two migraine days occurred; three were excluded because their headache diaries suggested the diagnosis of chronic migraine. Twenty-three datasets were taken for further analysis. Compared to sham tDCS (n = 12), verum tDCS (n = 11) resulted in a lower number of migraine days (p = 0.010) across all follow-up periods. We found no significant change in total headache days (p = 0.165), anxiety (p = 0.884), or depression scores (p = 0.535). No serious adverse events occurred; minor side effects were similar in both groups. CONCLUSIONS: This study provides Class II evidence that self-administered anodal tDCS over the visual cortex in episodic migraine results in a significantly lower number of monthly migraine days. However, it has neither an immediate nor a long-term effect.

The right temporoparietal junction enables delay of gratification by allowing decision makers to focus on future events.

Studies of neural processes underlying delay of gratification usually focus on prefrontal networks related to curbing affective impulses. Here, we provide evidence for an alternative mechanism that facilitates delaying gratification by mental orientation towards the future. Combining continuous theta-burst stimulation (cTBS) with functional neuroimaging, we tested how the right temporoparietal junction (rTPJ) facilitates processing of future events and thereby promotes delay of gratification. Participants performed an intertemporal decision task and a mental time-travel task in the MRI scanner before and after receiving cTBS over the rTPJ or the vertex (control site). rTPJ cTBS led to both stronger temporal discounting for longer delays and reduced processing of future relative to past events in the mental time-travel task. This finding suggests that the rTPJ contributes to the ability to delay gratification by facilitating mental representation of outcomes in the future. On the neural level, rTPJ cTBS led to a reduction in the extent to which connectivity of rTPJ with striatum reflected the value of delayed rewards, indicating a role of rTPJ-striatum connectivity in constructing neural representations of future rewards. Together, our findings provide evidence that the rTPJ is an integral part of a brain network that promotes delay of gratification by facilitating mental orientation to future rewards.

Causal contributions of human frontal eye fields to distinct aspects of decision formation.

Several theories propose that perceptual decision making depends on the gradual accumulation of information that provides evidence in favour of one of the choice-options. The outcome of this temporally extended integration process is thought to be categorized into the 'winning' and 'losing' choice-options for action. Neural correlates of corresponding decision formation processes have been observed in various frontal and parietal brain areas, among them the frontal eye-fields (FEF). However, the specific functional role of the FEFs is debated. Recent studies in humans and rodents provide conflicting accounts, proposing that the FEF either accumulate the choice-relevant information or categorize the outcome of such evidence integration into discrete actions. Here, we used transcranial magnetic stimulation (TMS) on humans to interfere with either left or right FEF activity during different timepoints of perceptual decision-formation. Stimulation of either FEF affected performance only when delivered during information integration but not during subsequent categorical choice. However, the patterns of behavioural changes suggest that the left-FEF contributes to general evidence integration, whereas right-FEF may direct spatial attention to the contralateral hemifield. Taken together, our results indicate an FEF involvement in evidence accumulation but not categorization, and suggest hemispheric lateralization for this function in the human brain.

Shared neural mechanisms between imagined and perceived egocentric motion - A combined GVS and fMRI study.

Many cognitive and social processes involve mental simulations of a change in perspective. Behavioral studies suggest that such egocentric mental rotations rely on brain areas that are also involved in processing actual self-motion, thus depending on vestibular input. In a combined galvanic vestibular stimulation (GVS) and functional Magnetic Resonance Imaging (fMRI) study, we investigated the brain areas that underlie both simulated changes in self-location and the processing of vestibular stimulation within the same individuals. Participants performed an egocentric mental rotation task, an object-based mental rotation task, or a pure lateralization task during GVS or sham stimulation. At the neural level, we expected an overlap between brain areas activated during vestibular processing and egocentric mental rotation (against object-based mental rotation) within area OP2 and the Posterior Insular Cortex (PIC), two core brain regions involved in vestibular processing. The fMRI data showed a small overlap within area OP2 and a larger overlap within the PIC for both egocentric mental rotation against object-based mental rotation and vestibular processing. GVS did not influence the ability to perform egocentric mental rotation. Our results provide evidence for shared neural mechanisms underlying perceived and simulated self-motion. We conclude that mental rotation of one's body involves neural activity in the PIC and area OP2, but the behavioral results also suggest that those mental simulations of one's body might be robust to modulatory input from vestibular stimulation.

A causal role for right temporo-parietal junction in signaling moral conflict.

The right temporo-parietal junction (rTPJ) has been proposed to play a key role in guiding human altruistic behavior, but its precise functional contribution to altruism remains unclear. We aimed to disentangle three possible functions of the rTPJ for human altruism, namely: implementing the motivation to help, signaling conflicts between moral and material values, or representing social reputation concerns. Our novel donation-decision task consisted of decisions requiring trade-offs of either positive moral values and monetary cost when donating to a good cause, or negative moral values and monetary benefits when sending money to a bad cause. Disrupting the rTPJ using transcranial magnetic stimulation did not change the general motivation to give or to react to social reputation cues, but specifically reduced the behavioral impact of moral-material conflicts. These findings reveal that signaling moral-material conflict is a core rTPJ mechanism that may contribute to a variety of human moral behaviors.

A causal account of the brain network computations underlying strategic social behavior.

During competitive interactions, humans have to estimate the impact of their own actions on their opponent's strategy. Here we provide evidence that neural computations in the right temporoparietal junction (rTPJ) and interconnected structures are causally involved in this process. By combining inhibitory continuous theta-burst transcranial magnetic stimulation with model-based functional MRI, we show that disrupting neural excitability in the rTPJ reduces behavioral and neural indices of mentalizing-related computations, as well as functional connectivity of the rTPJ with ventral and dorsal parts of the medial prefrontal cortex. These results provide a causal demonstration that neural computations instantiated in the rTPJ are neurobiological prerequisites for the ability to integrate opponent beliefs into strategic choice, through system-level interaction within the valuation and mentalizing networks.

Concurrent tACS-fMRI Reveals Causal Influence of Power Synchronized Neural Activity on Resting State fMRI Connectivity.

Resting state fMRI (rs-fMRI) is commonly used to study the brain's intrinsic neural coupling, which reveals specific spatiotemporal patterns in the form of resting state networks (RSNs). It has been hypothesized that slow rs-fMRI oscillations (<0.1 Hz) are driven by underlying electrophysiological rhythms that typically occur at much faster timescales (>5 Hz); however, causal evidence for this relationship is currently lacking. Here we measured rs-fMRI in humans while applying transcranial alternating current stimulation (tACS) to entrain brain rhythms in left and right sensorimotor cortices. The two driving tACS signals were tailored to the individual's α rhythm (8-12 Hz) and fluctuated in amplitude according to a 1 Hz power envelope. We entrained the left versus right hemisphere in accordance to two different coupling modes where either α oscillations were synchronized between hemispheres (phase-synchronized tACS) or the slower oscillating power envelopes (power-synchronized tACS). Power-synchronized tACS significantly increased rs-fMRI connectivity within the stimulated RSN compared with phase-synchronized or no tACS. This effect outlasted the stimulation period and tended to be more effective in individuals who exhibited a naturally weak interhemispheric coupling. Using this novel approach, our data provide causal evidence that synchronized power fluctuations contribute to the formation of fMRI-based RSNs. Moreover, our findings demonstrate that the brain's intrinsic coupling at rest can be selectively modulated by choosing appropriate tACS signals, which could lead to new interventions for patients with altered rs-fMRI connectivity.SIGNIFICANCE STATEMENT Resting state fMRI (rs-fMRI) has become an important tool to estimate brain connectivity. However, relatively little is known about how slow hemodynamic oscillations measured with fMRI relate to electrophysiological processes. It was suggested that slowly fluctuating power envelopes of electrophysiological signals synchronize across brain areas and that the topography of this activity is spatially correlated to resting state networks derived from rs-fMRI. Here we take a novel approach to address this problem and establish a causal link between the power fluctuations of electrophysiological signals and rs-fMRI via a new neuromodulation paradigm, which exploits these power synchronization mechanisms. These novel mechanistic insights bridge different scientific domains and are of broad interest to researchers in the fields of Medical Imaging, Neuroscience, Physiology, and Psychology.

Brain Network Mechanisms Underlying Motor Enhancement by Transcranial Entrainment of Gamma Oscillations.

Gamma and beta oscillations are routinely observed in motor-related brain circuits during movement preparation and execution. Entrainment of gamma or beta oscillations via transcranial alternating current stimulation (tACS) over primary motor cortex (M1) has opposite effects on motor performance, suggesting a causal role of these brain rhythms for motor control. However, it is largely unknown which brain mechanisms characterize these changes in motor performance brought about by tACS. In particular, it is unclear whether these effects result from brain activity changes only in the targeted areas or within functionally connected brain circuits. Here we investigated this issue by applying gamma-band and beta-band tACS over M1 in healthy humans during a visuomotor task and concurrent functional magnetic resonance imaging (fMRI). Gamma tACS indeed improved both the velocity and acceleration of visually triggered movements, compared with both beta tACS and sham stimulation. Beta tACS induced a numerical decrease in velocity compared with sham stimulation, but this was not statistically significant. Crucially, gamma tACS induced motor performance enhancements correlated with changed BOLD activity in the stimulated M1. Moreover, we found frequency- and task-specific neural compensatory activity modulations in the dorsomedial prefrontal cortex (dmPFC), suggesting a key regulatory role of this region in motor performance. Connectivity analyses revealed that the dmPFC interacted functionally with M1 and with regions within the executive motor system. These results suggest a role of the dmPFC for motor control and show that tACS-induced behavioral changes not only result from activity modulations underneath the stimulation electrode but also reflect compensatory modulation within connected and functionally related brain networks. More generally, our results illustrate how combined tACS-fMRI can be used to resolve the causal link between cortical rhythms, brain systems, and behavior. SIGNIFICANCE STATEMENT: Recent research has suggested a causal role for gamma oscillations during movement preparation and execution. Here we combine transcranial alternating current stimulation (tACS) with functional magnetic resonance imaging (fMRI) to identify the neural mechanisms that accompany motor performance enhancements triggered by gamma tACS over the primary motor cortex. We show that the tACS-induced motor performance enhancements correlate with changed neural activity in the stimulated area and modulate, in a frequency- and task-specific manner, the neural activity in the dorsomedial prefrontal cortex. This suggests a regulatory role of this region for motor control. More generally, we show that combined tACS-fMRI can elucidate the causal link between brain oscillations, neural systems, and behavior.

The precision of value-based choices depends causally on fronto-parietal phase coupling.

Which meal would you like today, chicken or pasta? For such value-based choices, organisms must flexibly integrate various types of sensory information about internal states and the environment to transform them into actions. Recent accounts suggest that these choice-relevant processes are mediated by information transfer between functionally specialized but spatially distributed brain regions in parietal and prefrontal cortex; however, it remains unclear whether such fronto-parietal communication is causally involved in guiding value-based choices. We find that transcranially inducing oscillatory desynchronization between the frontopolar and -parietal cortex leads to more inaccurate choices between food rewards while leaving closely matched perceptual decisions unaffected. Computational modelling shows that this exogenous manipulation leads to imprecise value assignments to the choice alternatives. Thus, our study demonstrates that accurate value-based decisions critically involve coherent rhythmic information transfer between fronto-parietal brain areas and establishes an experimental approach to non-invasively manipulate the precision of value-based choices in humans.

Uncovering a context-specific connectional fingerprint of human dorsal premotor cortex.

Primate electrophysiological and lesion studies indicate a prominent role of the left dorsal premotor cortex (PMd) in action selection based on learned sensorimotor associations. Here we applied transcranial magnetic stimulation (TMS) to human left PMd at low or high intensity while right-handed individuals performed externally paced sequential key presses with their left hand. Movements were cued by abstract visual stimuli, and subjects either freely selected a key press or responded according to a prelearned visuomotor mapping rule. Continuous arterial spin labeling was interleaved with TMS to directly assess how stimulation of left PMd modulates task-related brain activity depending on the mode of movement selection. Relative to passive viewing, both tasks activated a frontoparietal motor network. Compared with low-intensity TMS, high-intensity TMS of left PMd was associated with an increase in activity in medial and right premotor areas without affecting task performance. Critically, this increase in task-related activity was only present when movement selection relied on arbitrary visuomotor associations but not during freely selected movements. Psychophysiological interaction analysis revealed a context-specific increase in functional coupling between the stimulated left PMd and remote right-hemispheric and mesial motor regions that was only present during arbitrary visuomotor mapping. Our TMS perturbation approach yielded causal evidence that the left PMd is implicated in mapping external cues onto the appropriate movement in humans. Furthermore, the data suggest that the left PMd may transiently form a functional network together with right-hemispheric and mesial motor regions to sustain visuomotor mapping performed with the left nondominant hand.

Interleaved TMS/CASL: Comparison of different rTMS protocols.

Continuous Arterial Spin Labeling (CASL) offers the possibility to quantitatively measure the regional cerebral blood flow (rCBF). We demonstrate, for the first time, the feasibility of interleaving Transcranial Magnetic Stimulation (TMS) with CASL at 3 T. Two different repetitive TMS (rTMS) protocols were applied to the motor cortex in 10 subjects and the effect on rCBF was measured using a CASL sequence with separate RF coils for labeling the inflowing blood. Each subject was investigated, using a block design, under 7 different conditions: continuous 2 Hz rTMS (3 intensities: 100%, 110% and 120% resting motor threshold [MT]), short 10 Hz rTMS trains at 110% MT (8 pulses per train; 3 different numbers of trains per block with 2, 4 and 12 s intervals between trains) and volitional movement (acoustically triggered by 50% MT stimuli). We show robust rCBF increases in motor and premotor areas due to rTMS, even at the lowest stimulation intensity of 100% MT. RCBF exhibited a linear positive dependency on stimulation intensity (for continuous 2 Hz rTMS) and the number of 10 Hz trains in the stimulated M1/S1 as well as in premotor and supplementary motor areas. Interestingly, the 2 different rTMS protocols yielded markedly different rCBF activation time courses, which did not correlate with the electromyographic recordings of the muscle responses. In future, this novel combination of TMS with ASL will offer the possibility to investigate the immediate and after-effects of rTMS stimulation on rCBF, which previously was only possible using PET.

New coil positioning method for interleaved transcranial magnetic stimulation (TMS)/functional MRI (fMRI) and its validation in a motor cortex study.

PURPOSE: To develop and test a novel method for coil placement in interleaved transcranial magnetic stimulation (TMS)/functional MRI (fMRI) studies. MATERIALS AND METHODS: Initially, a desired TMS coil position at the subject's head is recorded using a neuronavigation system. Subsequently, a custom-made holding device is used for coil placement inside the MR scanner. The parameters of the device corresponding to the prerecorded position are automatically determined from a fast structural image acquired directly before the experiment. The spatial accuracy of our method was verified on a phantom. Finally, in a study on five subjects, the coil was placed above the cortical representation of a hand muscle in M1 and the blood oxygenation level-dependent (BOLD) responses to short repetitive TMS (rTMS) trains were assessed using echo-planar imaging (EPI) recordings. RESULTS: The spatial accuracy of our method is in the range of 2.9 +/- 1.3 (SD) mm. Motor cortex stimulation resulted in robust BOLD activations in motor- and auditory related brain areas, with the activation in M1 being localized in the hand knob. CONCLUSION: We present a user-friendly method for TMS coil positioning in the MR scanner that exhibits good spatial accuracy and speeds up the setup of the experiment. The motor-cortex study proves the viability of the approach and validates our interleaved TMS/fMRI setup.