Mapping cortical excitability in the human dorsolateral prefrontal cortex.

BACKGROUND: Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an effective treatment for depression, but the neural effects after TMS remains unclear. TMS paired with electroencephalography (TMS-EEG) can causally probe these neural effects. Nonetheless, variability in single pulse TMS-evoked potentials (TEPs) across dlPFC subregions, and potential artifact induced by muscle activation, necessitate detailed mapping for accurate treatment monitoring. OBJECTIVE: To characterize early TEPs anatomically and temporally (20-50 ms) close to the TMS pulse (EL-TEPs), as well as associated muscle artifacts (<20 ms), across the dlPFC. We hypothesized that TMS location and angle influence EL-TEPs, and specifically that conditions with larger muscle artifact may exhibit lower observed EL-TEPs due to over-rejection during preprocessing. Additionally, we sought to determine an optimal group-level TMS target and angle, while investigating the potential benefits of a personalized approach. METHODS: In 16 healthy participants, we applied single-pulse TMS to six targets within the dlPFC at two coil angles and measured EEG responses. RESULTS: Stimulation location significantly influenced observed EL-TEPs, with posterior and medial targets yielding larger EL-TEPs. Regions with high EL-TEP amplitude had less muscle artifact, and vice versa. The best group-level target yielded 102% larger EL-TEP responses compared to other dlPFC targets. Optimal dlPFC target differed across subjects, suggesting that a personalized targeting approach might boost the EL-TEP by an additional 36%. SIGNIFICANCE: EL-TEPs can be probed without significant muscle-related confounds in posterior-medial regions of the dlPFC. The identification of an optimal group-level target and the potential for further refinement through personalized targeting hold significant implications for optimizing depression treatment protocols.

Real-time optimization to enhance noninvasive cortical excitability assessment in the human dorsolateral prefrontal cortex.

Objective: We currently lack a robust noninvasive method to measure prefrontal excitability in humans. Concurrent TMS and EEG in the prefrontal cortex is usually confounded by artifacts. Here we asked if real-time optimization could reduce artifacts and enhance a TMS-EEG measure of left prefrontal excitability. Methods: This closed-loop optimization procedure adjusts left dlPFC TMS coil location, angle, and intensity in real-time based on the EEG response to TMS. Our outcome measure was the left prefrontal early (20-60 ms) and local TMS-evoked potential (EL-TEP). Results: In 18 healthy participants, this optimization of coil angle and brain target significantly reduced artifacts by 63% and, when combined with an increase in intensity, increased EL-TEP magnitude by 75% compared to a non-optimized approach. Conclusions: Real-time optimization of TMS parameters during dlPFC stimulation can enhance the EL-TEP. Significance: Enhancing our ability to measure prefrontal excitability is important for monitoring pathological states and treatment response.

Reliability of the TMS-evoked potential in dorsolateral prefrontal cortex.

We currently lack a reliable method to probe cortical excitability noninvasively from the human dorsolateral prefrontal cortex (dlPFC). We recently found that the strength of early and local dlPFC transcranial magnetic stimulation (TMS)-evoked potentials (EL-TEPs) varied widely across dlPFC subregions. Despite these differences in response amplitude, reliability at each target is unknown. Here we quantified within-session reliability of dlPFC EL-TEPs after TMS to six left dlPFC subregions in 15 healthy subjects. We evaluated reliability (concordance correlation coefficient [CCC]) across targets, time windows, quantification methods, regions of interest, sensor- vs. source-space, and number of trials. On average, the medial target was most reliable (CCC = 0.78) and the most anterior target was least reliable (CCC = 0.24). However, all targets except the most anterior were reliable (CCC > 0.7) using at least one combination of the analytical parameters tested. Longer (20 to 60 ms) and later (30 to 60 ms) windows increased reliability compared to earlier and shorter windows. Reliable EL-TEPs (CCC up to 0.86) were observed using only 25 TMS trials at a medial dlPFC target. Overall, medial dlPFC targeting, wider windows, and peak-to-peak quantification improved reliability. With careful selection of target and analytic parameters, highly reliable EL-TEPs can be extracted from the dlPFC after only a small number of trials.

Two models of mind blanking.

Mind blanking is a mental state in which attention does not bring any perceptual input into conscious awareness. As this state is still largely unexplored, we suggest that a comprehensive understanding of mind blanking can be achieved through a multifaceted approach combining self-assessment methods, neuroimaging and neuromodulation. In this article, we explain how electroencephalography and transcranial magnetic stimulation could be combined to help determine whether mind blanking is associated with a lack of mental content or a lack of linguistically or conceptually determinable mental content. We also question whether mind blanking occurs spontaneously or intentionally and whether these two forms are instantiated by the same or different neural correlates.

Connectivity by the Frontal Aslant Tract (FAT) Explains Local Functional Specialization of the Superior and Inferior Frontal Gyri in Humans When Choosing Predictive over Reactive Strategies: A Tractography-Guided TMS Study.

Predictive and reactive behaviors represent two mutually exclusive strategies in a sensorimotor task. Predictive behavior consists in internally estimating timing and features of a target stimulus and relies on a cortical medial frontal system [superior frontal gyrus (SFG)]. Reactive behavior consists in waiting for actual perception of the target stimulus and relies on the lateral frontal cortex [inferior frontal gyrus (IFG)]. We investigated whether SFG-IFG connections by the frontal aslant tract (FAT) can mediate predictive/reactive interactions. In 19 healthy human volunteers, we applied online transcranial magnetic stimulation (TMS) to six spots along the medial and lateral terminations of the FAT, during the set period of a delayed reaction task. Such scenario can be solved using either predictive or reactive strategies. TMS increased the propensity toward reactive behavior if applied to a specific portion of the IFG and increased predictive behavior when applied to a specific SFG spot. The two active spots in the SFG and IFG were directly connected by a sub-bundle of FAT fibers as indicated by diffusion-weighted imaging (DWI) tractography. Since FAT connectivity identifies two distant cortical nodes with opposite functions, we propose that the FAT mediates mutually inhibitory interactions between SFG and IFG to implement a "winner takes all" decisional process. We hypothesize such role of the FAT to be domain-general, whenever competition occurs between internal predictive and external reactive behaviors. Finally, we also show that anatomic connectivity is a powerful factor to explain and predict the spatial distribution of brain stimulation effects.SIGNIFICANCE STATEMENT We interact with sensory cues adopting two main mutually-exclusive strategies: (1) trying to anticipate the occurrence of the cue or (2) waiting for the GO-signal to be manifest and react to it. Here, we showed, by using noninvasive brain stimulation [transcranial magnetic stimulation (TMS)], that two specific cortical regions in the superior frontal gyrus (SFG) and the inferior frontal gyrus (IFG) have opposite roles in facilitating a predictive or a reactive strategy. Importantly these two very distant regions but with highly interconnected functions are specifically connected by a small white matter bundle, which mediates the direct competition and exclusiveness between predictive and reactive strategies. More generally, implementing anatomic connectivity in TMS studies strongly reduces spatial noise.

Reliability of the TMS-evoked potential in dorsolateral prefrontal cortex.

Background: We currently lack a robust and reliable method to probe cortical excitability noninvasively from the human dorsolateral prefrontal cortex (dlPFC), a region heavily implicated in psychiatric disorders. We recently found that the strength of early and local dlPFC single pulse transcranial magnetic stimulation (TMS)-evoked potentials (EL-TEPs) varied widely depending on the anatomical subregion probed, with more medial regions eliciting stronger responses than anterolateral sites. Despite these differences in amplitude of response, the reliability at each target is not known. Objective: To evaluate the reliability of EL-TEPs across the dlPFC. Methods: In 15 healthy subjects, we quantified within-session reliability of dlPFC EL-TEPs after single pulse TMS to six dlPFC subregions. We evaluated the concordance correlation coefficient (CCC) across targets and analytical parameters including time window, quantification method, region of interest, sensor-vs. source-space, and number of trials. Results: At least one target in the anterior and posterior dlPFC produced reliable EL-TEPs (CCC>0.7). The medial target was most reliable (CCC = 0.78) and the most anterior target was least reliable (CCC = 0.24). ROI size and type (sensor vs. source space) did not affect reliability. Longer (20-60 ms, CCC = 0.62) and later (30-60 ms, CCC = 0.61) time windows resulted in higher reliability compared to earlier and shorter (20-40 ms, CCC 0.43; 20-50 ms, CCC = 0.55) time windows. Peak-to-peak quantification resulted in higher reliability than the mean of the absolute amplitude. Reliable EL-TEPs (CCC up to 0.86) were observed using only 25 TMS trials for a medial dlPFC target. Conclusions: Medial TMS location, wider time window (20-60ms), and peak-to-peak quantification improved reliability. Highly reliable EL-TEPs can be extracted from dlPFC after only a small number of trials. Highlights: Medial dlPFC target improved EL-TEP reliability compared to anterior targets.After optimizing analytical parameters, at least one anterior and one posterior target was reliable (CCC>0.7).Longer (20-60 ms) and later (30-60 ms) time windows were more reliable than earlier and shorter (20-40 ms or 20-50 ms) latencies.Peak-to-peak quantification resulted in higher reliability compared to the mean of the absolute amplitude.As low as 25 trials can yield reliable EL-TEPs from the dlPFC.

Reliability and Validity of Transcranial Magnetic Stimulation-Electroencephalography Biomarkers.

Noninvasive brain stimulation and neuroimaging have revolutionized human neuroscience with a multitude of applications, including diagnostic subtyping, treatment optimization, and relapse prediction. It is therefore particularly relevant to identify robust and clinically valuable brain biomarkers linking symptoms to their underlying neural mechanisms. Brain biomarkers must be reproducible (i.e., have internal reliability) across similar experiments within a laboratory and be generalizable (i.e., have external reliability) across experimental setups, laboratories, brain regions, and disease states. However, reliability (internal and external) is not alone sufficient; biomarkers also must have validity. Validity describes closeness to a true measure of the underlying neural signal or disease state. We propose that these metrics, reliability and validity, should be evaluated and optimized before any biomarker is used to inform treatment decisions. Here, we discuss these metrics with respect to causal brain connectivity biomarkers from coupling transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We discuss controversies around TMS-EEG stemming from the multiple large off-target components (noise) and relatively weak genuine brain responses (signal), as is unfortunately often the case in noninvasive human neuroscience. We review the current state of TMS-EEG recordings, which consist of a mix of reliable noise and unreliable signal. We describe methods for evaluating TMS-EEG biomarkers, including how to assess internal and external reliability across facilities, cognitive states, brain networks, and disorders and how to validate these biomarkers using invasive neural recordings or treatment response. We provide recommendations to increase reliability and validity, discuss lessons learned, and suggest future directions for the field.

Mapping cortical excitability in the human dorsolateral prefrontal cortex.

Objective: To characterize early TEPs anatomically and temporally (20-50 ms) close to the TMS pulse (EL-TEPs), as well as associated muscle artifacts (<20 ms), across the dlPFC. We hypothesized that TMS location and angle influence EL-TEPs, and that EL-TEP amplitude is inversely related to muscle artifact. Additionally, we sought to determine an optimal group-level TMS target and angle, while investigating the potential benefits of a personalized approach. Methods: In 16 healthy participants, we applied single-pulse TMS to six targets within the dlPFC at two coil angles and measured EEG responses. Results: Stimulation location significantly influenced EL-TEPs, with posterior and medial targets yielding larger EL-TEPs. Regions with high EL-TEP amplitude had less muscle artifact, and vice versa. The best group-level target yielded 102% larger EL-TEP responses compared to other dlPFC targets. Optimal dlPFC target differed across subjects, suggesting that a personalized targeting approach might boost the EL-TEP by an additional 36%. Significance: Early local TMS-evoked potentials (EL-TEPs) can be probed without significant muscle-related confounds in posterior-medial regions of the dlPFC. The identification of an optimal group-level target and the potential for further refinement through personalized targeting hold significant implications for optimizing depression treatment protocols. Highlights: Early local TMS-evoked potentials (EL-TEPs) varied significantly across the dlPFC as a function of TMS target.TMS targets with less muscle artifact had significantly larger EL-TEPs.Selection of a postero-medial target increased EL-TEPs by 102% compared to anterior targets.

A comparative study between state-of-the-art MRI deidentification and AnonyMI, a new method combining re-identification risk reduction and geometrical preservation.

Deidentifying MRIs constitutes an imperative challenge, as it aims at precluding the possibility of re-identification of a research subject or patient, but at the same time it should preserve as much geometrical information as possible, in order to maximize data reusability and to facilitate interoperability. Although several deidentification methods exist, no comprehensive and comparative evaluation of deidentification performance has been carried out across them. Moreover, the possible ways these methods can compromise subsequent analysis has not been exhaustively tested. To tackle these issues, we developed AnonyMI, a novel MRI deidentification method, implemented as a user-friendly 3D Slicer plugin-in, which aims at providing a balance between identity protection and geometrical preservation. To test these features, we performed two series of analyses on which we compared AnonyMI to other two state-of-the-art methods, to evaluate, at the same time, how efficient they are at deidentifying MRIs and how much they affect subsequent analyses, with particular emphasis on source localization procedures. Our results show that all three methods significantly reduce the re-identification risk but AnonyMI provides the best geometrical conservation. Notably, it also offers several technical advantages such as a user-friendly interface, multiple input-output capabilities, the possibility of being tailored to specific needs, batch processing and efficient visualization for quality assurance.

Stimulation of Different Sectors of the Human Dorsal Premotor Cortex Induces a Shift from Reactive to Predictive Action Strategies and Changes in Motor Inhibition: A Dense Transcranial Magnetic Stimulation (TMS) Mapping Study.

Delayed motor tasks require timely interaction between immobility and action. The neural substrates of these processes probably reside in the premotor and motor circuits; however, fine-grained anatomical/functional information is still lacking. Participants performed a delayed simple reaction task, structured as a ready-set-go sequence, with a fixed, predictable, SET-period. Responses were given with lip movements. During the SET-period, we performed a systematic dense-mapping of the bilateral dorsal premotor region (dPM) by means of single transcranial magnetic stimulation (TMS) pulses on an 18-spot mapping grid, interleaved with sham TMS which served as a baseline. Reaction times (RTs) in TMS trials over each grid spot were compared to RTs in sham trials to build a statistical parametric z-map. The results reveal a rostro-caudal functional gradient in the dPM. TMS of the rostral dPM induced a shift from reactive towards predictive response strategies. TMS of the caudal dPM interfered with the SET-period duration. By means of dense TMS mapping, we have drawn a putative functional map of the role of the dPM during the SET-period. A higher-order rostral component is involved in setting action strategies and a caudal, lower-order, part is probably involved in the inhibitory control of motor output.

Simultaneous human intracerebral stimulation and HD-EEG, ground-truth for source localization methods.

Precisely localizing the sources of brain activity as recorded by EEG is a fundamental procedure and a major challenge for both research and clinical practice. Even though many methods and algorithms have been proposed, their relative advantages and limitations are still not well established. Moreover, these methods involve tuning multiple parameters, for which no principled way of selection exists yet. These uncertainties are emphasized due to the lack of ground-truth for their validation and testing. Here we present the Localize-MI dataset, which constitutes the first open dataset that comprises EEG recorded electrical activity originating from precisely known locations inside the brain of living humans. High-density EEG was recorded as single-pulse biphasic currents were delivered at intensities ranging from 0.1 to 5 mA through stereotactically implanted electrodes in diverse brain regions during pre-surgical evaluation of patients with drug-resistant epilepsy. The uses of this dataset range from the estimation of in vivo tissue conductivity to the development, validation and testing of forward and inverse solution methods.

Stimulation of the Dorsal Premotor Cortex, But Not of the Supplementary Motor Area Proper, Impairs the Stop Function in a STOP Signal Task.

Being able to inhibit an impending movement in response to a contextual change is a distinctive feature of action control. Such inhibitory control relies on a complex cortical-subcortical network, including posterior prefrontal regions such as caudal inferior frontal gyrus and pre-supplementary motor area. According to hierarchical models of action control, both areas represent the intermediate level between prefronto-dependent and motor-related cortices. Going at a lower level, accumulating evidence speaks for an involvement of the primary motor cortex (M1) to dorsal premotor cortex (PMCd) or supplementary motor area proper (SMA-proper) pathways in producing inhibitory control. However, the clear-cut evidence for this conjecture is still missing. The aim of the present paper was to start filling this gap, investigating this lowest level of inhibitory control. We stimulated PMCd in a group of healthy volunteers with transcranial magnetic stimulation (TMS) or sham TMS during the response phase of a STOP-signal task performed with the lips. In a separate experimental group, we applied effective TMS/sham TMS to SMA-proper during the same task. We found that effective TMS over PMCd increased false-start errors in STOP trials (p = 0.0005), but had no effect on GO trial performance (p = 0.85). Effective TMS on SMA-proper produced no effect on STOP trials' performance (p = 0.31) nor in the GO trial performance (p = 0.56). Our data show that there is at least a portion of PMCd playing a distinctive role in the control of mouth-related M1 during instructed visuomotor inhibitory behavior. This region could therefore represent a low-level hierarchical node for externally cued action inhibition.

Spatial and Temporal Characteristics of Set-Related Inhibitory and Excitatory Inputs from the Dorsal Premotor Cortex to the Ipsilateral Motor Cortex Assessed by Dual-Coil Transcranial Magnetic Stimulation.

The capacity to produce movements only at appropriate times is fundamental in successful behavior and requires a fine interplay between motor inhibition and facilitation. Evidence in humans indicates that the dorsal premotor cortex (PMCd) is involved in such preparatory and inhibitory processes, but how PMCd modulates motor output in humans is still unclear. We investigated this issue in healthy human volunteers, using a variant of the dual-coil transcranial magnetic stimulation (TMS) technique that allows testing the short-latency effects of conditioning TMS to the left PMCd on test TMS applied to the ipsilateral orofacial primary motor cortex (M1). Participants performed a delayed cued simple reaction time task. They were asked to produce a lip movement cued by an imperative GO-signal presented after a predictable SET-period, during which TMS was applied at different intervals. Results showed that the area of motor evoked potentials (MEPs) to test TMS was modulated by conditioning TMS. A transient inhibition cortico-bulbar excitability by PMCd stimulation was observed around the middle of the SET-period. Conversely, a ramping excitatory effect of PMCd stimulation appeared towards the end of the SET-period, as the time of the predicted GO-signal approached. The time-course of PMCd-M1 activity scaled to the varying SET-period duration. Our data indicate that inhibition and excitation of motor output during a delayed reaction time task are two distinct neural phenomena. They both originate in PMCd and are conveyed via cortico-cortical connections to the ipsilateral M1, where they are integrated to produce harmonic fluctuations of motor output.

The dorsal premotor cortex exerts a powerful and specific inhibitory effect on the ipsilateral corticofacial system: a dual-coil transcranial magnetic stimulation study.

A rich pattern of connectivity is present in non-human primates between the dorsal premotor cortex (PMCd) and the motor cortex (M1). By analogy, similar connections are hypothesized in humans between the PMCd and the ipsilateral hand-related M1. However, the technical difficulty of applying transcranial magnetic stimulation (TMS) with a dual-coil paradigm to two cortical regions in such close spatial proximity renders their in vivo demonstration difficult. The present work aims at assessing in humans the existence of short-latency influences of the left PMCd on the ipsilateral corticofacial system by means of TMS. A dual-coil TMS paradigm was used with 16 participants. Test TMS pulses were applied to the left orofacial M1, and conditioning TMS pulses were applied to three distinct points of the ipsilateral PMCd along the caudal part of the superior frontal sulcus. The inter-stimulus interval (ISI) between condTMS and testTMS varied in 2-ms steps between 2 and 8 ms. Motor evoked potentials (MEPs) in the active orbicularis oris muscle were recorded. CondTMS exerted a robust effect on the corticofacial system only when applied to one specific portion of the PMCd and only at one specific ISI (6 ms). The effect consisted in a systematic suppression of facial MEPs compared to those obtained by testTMS alone. No other effect was found. We provide evidence for a specific short-latency inhibitory effect of the PMCd on the ipsilateral M1, likely witnessing direct corticocortical connectivity in humans. We also describe a novel paradigm to test ipsilateral PMCd-M1 in humans.