Visuospatial Neglect - a Theory-Informed Overview of Current and Emerging Strategies and a Systematic Review on the Therapeutic Use of Non-invasive Brain Stimulation.

Visuospatial neglect constitutes a supramodal cognitive deficit characterized by reduction or loss of spatial awareness for the contralesional space. It occurs in over 40% of right- and 20% of left-brain-lesioned stroke patients with lesions located mostly in parietal, frontal and subcortical brain areas. Visuospatial neglect is a multifaceted syndrome - symptoms can be divided into sensory, motor and representational neglect - and therefore requires an individually adapted diagnostic and therapeutic approach. Several models try to explain the origins of visuospatial neglect, of which the "interhemispheric rivalry model" is strongly supported by animal and human research. This model proposes that allocation of spatial attention is balanced by transcallosal inhibition and both hemispheres compete to direct attention to the contralateral hemi-space. Accordingly, a brain lesion causes an interhemispheric imbalance, which may be re-installed by activation of lesioned, or deactivation of unlesioned (over-activated) brain areas through noninvasive brain stimulation. Research in larger patient samples is needed to confirm whether noninvasive brain stimulation can improve long-term outcomes and whether these also affect activities of daily living and discharge destination.

Pre-stimulus theta power is correlated with variation of motor evoked potential latency: a single-pulse TMS study.

There has been a growing interest in the role of pre-stimulus oscillations on cortical excitability in visual and motor systems. Prior studies focused on the relationship between pre-stimulus neuronal activity and TMS-evoked motor evoked potentials (MEPs) have reported heterogeneous results. We aimed to assess the role of pre-stimulus neural activity on the latency of MEPs, which might enhance our understanding of the variability of MEP signals, and potentially provide information on the role played by cortical activity fluctuations in the excitability of corticospinal pathways. Near-threshold single-pulse TMS (spTMS) was applied at random intervals over the primary motor cortex of 14 healthy participants while they sat passively, to trigger hand muscle contractions. Multichannel EEG was recorded during spTMS blocks. Spearman correlations between both the variation in MEP onset latencies and peak-to-peak MEP amplitudes, and the pre-stimulus power of EEG oscillations were calculated across participants. We found that the variation in MEP latency was positively correlated with pre-stimulus power in the theta range (4-7 Hz) in a broad time window (- 3.1 to - 1.9 s) preceding the spTMS generating the MEP. No correlation between pre-stimulus power in any frequency band and MEP amplitude was found. Our results show that pre-stimulus theta oscillations are correlated with the variation in MEP latency, an outcome measure determined by fiber conduction velocity and synaptic delays along the corticospinal tract. This finding could prove useful for clinicians using MEP latency-based information in pre- or intra-operative diagnostics of corticospinal impairment.

Direct current stimulation over the anterior temporal areas boosts semantic processing in primary progressive aphasia.

OBJECTIVE: Noninvasive brain stimulation in primary progressive aphasia (PPA) is a promising approach. Yet, applied to single cases or insufficiently controlled small-cohort studies, it has not clarified its therapeutic value. We here address the effectiveness of transcranial direct current stimulation (tDCS) on the semantic PPA variant (sv-PPA), applying a rigorous study design to a large, homogeneous sv-PPA cohort. METHODS: Using a double-blind, sham-controlled counterbalanced cross-over design, we applied three tDCS conditions targeting the temporal poles of 12 sv-PPA patients. Efficiency was assessed by a semantic matching task orthogonally manipulating "living"/"nonliving" categories and verbal/visual modalities. Conforming to predominantly left-lateralized damage in sv-PPA and accounts of interhemispheric inhibition, we applied left hemisphere anodal-excitatory and right hemisphere cathodal-inhibitory tDCS, compared to sham stimulation. RESULTS: Prestimulation data, compared to 15 healthy controls, showed that patients had semantic disorders predominating with living categories in the verbal modality. Stimulation selectively impacted these most impaired domains: Left-excitatory and right-inhibitory tDCS improved semantic accuracy in verbal modality, and right-inhibitory tDCS improved processing speed with living categories and accuracy and processing speed in the combined verbal × living condition. INTERPRETATION: Our findings demonstrate the efficiency of tDCS in sv-PPA by generating highly specific intrasemantic effects. They provide "proof of concept" for future applications of tDCS in therapeutic multiday regimes, potentially driving sustained improvement of semantic processing. Our data also support the hotly debated existence of a left temporal-pole network for verbal semantics selectively modulated through both left-excitatory and right-inhibitory brain stimulation. Ann Neurol 2016;80:693-707.

Visual Contrast Sensitivity Improvement by Right Frontal High-Beta Activity Is Mediated by Contrast Gain Mechanisms and Influenced by Fronto-Parietal White Matter Microstructure.

Behavioral and electrophysiological studies in humans and non-human primates have correlated frontal high-beta activity with the orienting of endogenous attention and shown the ability of the latter function to modulate visual performance. We here combined rhythmic transcranial magnetic stimulation (TMS) and diffusion imaging to study the relation between frontal oscillatory activity and visual performance, and we associated these phenomena to a specific set of white matter pathways that in humans subtend attentional processes. High-beta rhythmic activity on the right frontal eye field (FEF) was induced with TMS and its causal effects on a contrast sensitivity function were recorded to explore its ability to improve visual detection performance across different stimulus contrast levels. Our results show that frequency-specific activity patterns engaged in the right FEF have the ability to induce a leftward shift of the psychometric function. This increase in visual performance across different levels of stimulus contrast is likely mediated by a contrast gain mechanism. Interestingly, microstructural measures of white matter connectivity suggest a strong implication of right fronto-parietal connectivity linking the FEF and the intraparietal sulcus in propagating high-beta rhythmic signals across brain networks and subtending top-down frontal influences on visual performance.

Physiological consequences of abnormal connectivity in a developmental epilepsy.

OBJECTIVE: Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. METHODS: We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. RESULTS: Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. INTERPRETATION: Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions.

Fronto-Parietal Anatomical Connections Influence the Modulation of Conscious Visual Perception by High-Beta Frontal Oscillatory Activity.

May white matter connectivity influence rhythmic brain activity underlying visual cognition? We here employed diffusion imaging to reconstruct the fronto-parietal white matter pathways in a group of healthy participants who displayed frequency-specific ameliorations of visual sensitivity during the entrainment of high-beta oscillatory activity by rhythmic transcranial magnetic stimulation over their right frontal eye field. Our analyses reveal a strong tract-specific association between the volume of the first branch of the superior longitudinal fasciculus and improvements of conscious visual detection driven by frontal beta oscillation patterns. These data indicate that the architecture of specific white matter pathways has the ability to influence the distributed effects of rhythmic spatio-temporal activity, and suggest a potentially relevant role for long-range connectivity in the synchronization of oscillatory patterns across fronto-parietal networks subtending the modulation of conscious visual perception.

No evidence in favor of the existence of "intentional" binding.

Intentional binding refers to the subjective temporal compression between a voluntary action and its subsequent sensory outcome. Despite some studies challenging the link between temporal compression and intentional action, intentional binding is still widely used as an implicit measure for the sense of agency. The debate remains unsettled primarily because the experimental conditions used in previous studies were confounded with various alternative causes for temporal compression, and action intention has not yet been tested comprehensively against all potential alternative causes in a single study. Here, we solve this puzzle by jointly comparing participants' estimates of the interval between three types of triggering events with comparable predictability-voluntary movement, passive movement, and external sensory event-and an external sensory outcome (auditory or visual across experiments). The results failed to show intentional binding, that is, no shorter interval estimation for the voluntary than the passive movement conditions. Instead, we observed temporal (but not intentional) binding when comparing both movement conditions with the external sensory condition. Thus, temporal binding appears to originate from sensory integration and temporal prediction, not from action intention. As such, these findings underscore the need to reconsider the use of "intentional binding" as a reliable proxy of the sense of agency. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Insights on the neural basis of motor plasticity induced by theta burst stimulation from TMS-EEG.

Transcranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor-evoked potentials (MEPs) reflective of modulation of cortico-spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta-burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults, and we measured modulation of (i) MEPs, (ii) TMS-induced EEG evoked potentials (TEPs), (iii) TMS-induced EEG synchronization and (iv) eyes-closed resting EEG. Our results show the expected cTBS-induced decrease in MEP size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes-closed resting EEG, whereas it decreased single-pulse TMS-induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes-closed resting EEG, whereas it increased single-pulse TMS-induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low-frequency (theta and/or alpha) oscillators and desynchronizes high-frequency (beta) oscillators. These results provide novel insight into the cortical effects of cTBS and could be useful for exploring cTBS-induced plasticity outside of the motor cortex.

Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI.

Brain plasticity can be conceptualized as nature's invention to overcome limitations of the genome and adapt to a rapidly changing environment. As such, plasticity is an intrinsic property of the brain across the lifespan. However, mechanisms of plasticity may vary with age. The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) enables clinicians and researchers to directly study local and network cortical plasticity, in humans in vivo, and characterize their changes across the age-span. Parallel, translational studies in animals can provide mechanistic insights. Here, we argue that, for each individual, the efficiency of neuronal plasticity declines throughout the age-span and may do so more or less prominently depending on variable 'starting-points' and different 'slopes of change' defined by genetic, biological, and environmental factors. Furthermore, aberrant, excessive, insufficient, or mistimed plasticity may represent the proximal pathogenic cause of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorders or Alzheimer's disease.

Causal modulation of right hemisphere fronto-parietal phase synchrony with Transcranial Magnetic Stimulation during a conscious visual detection task.

Correlational evidence in non-human primates has reported increases of fronto-parietal high-beta (22-30 Hz) synchrony during the top-down allocation of visuo-spatial attention. But may inter-regional synchronization at this specific frequency band provide a causal mechanism by which top-down attentional processes facilitate conscious visual perception? To address this question, we analyzed electroencephalographic (EEG) signals from a group of healthy participants who performed a conscious visual detection task while we delivered brief (4 pulses) rhythmic (30 Hz) or random bursts of Transcranial Magnetic Stimulation (TMS) to the right Frontal Eye Field (FEF) prior to the onset of a lateralized target. We report increases of inter-regional synchronization in the high-beta band (25-35 Hz) between the electrode closest to the stimulated region (the right FEF) and right parietal EEG leads, and increases of local inter-trial coherence within the same frequency band over bilateral parietal EEG contacts, both driven by rhythmic but not random TMS patterns. Such increases were accompained by improvements of conscious visual sensitivity for left visual targets in the rhythmic but not the random TMS condition. These outcomes suggest that high-beta inter-regional synchrony can be modulated non-invasively and that high-beta oscillatory activity across the right dorsal fronto-parietal network may contribute to the facilitation of conscious visual perception. Our work supports future applications of non-invasive brain stimulation to restore impaired visually-guided behaviors by operating on top-down attentional modulatory mechanisms.

Statistical learning occurs during practice while high-order rule learning during rest period.

Knowing when the brain learns is crucial for both the comprehension of memory formation and consolidation and for developing new training and neurorehabilitation strategies in healthy and patient populations. Recently, a rapid form of offline learning developing during short rest periods has been shown to account for most of procedural learning, leading to the hypothesis that the brain mainly learns during rest between practice periods. Nonetheless, procedural learning has several subcomponents not disentangled in previous studies investigating learning dynamics, such as acquiring the statistical regularities of the task, or else the high-order rules that regulate its organization. Here we analyzed 506 behavioral sessions of implicit visuomotor deterministic and probabilistic sequence learning tasks, allowing the distinction between general skill learning, statistical learning, and high-order rule learning. Our results show that the temporal dynamics of apparently simultaneous learning processes differ. While high-order rule learning is acquired offline, statistical learning is evidenced online. These findings open new avenues on the short-scale temporal dynamics of learning and memory consolidation and reveal a fundamental distinction between statistical and high-order rule learning, the former benefiting from online evidence accumulation and the latter requiring short rest periods for rapid consolidation.

[Preservation of automatic ocular saccades in healthy elderly: alteration in patients with dementia with Lewy body]. / Longévité et robustesse de la saccade oculaire automatique chez le sujet âgé sain : atteinte dans des cas de démence à corps de Lewy.

We studied, in healthy elderly subjects (aged from 63 to 83 years) and adults (aged from 20 to 32 years), ocular saccades in two conditions: one the one hand, the gap condition, where the central target disappears; then follows a period of 200 ms during which the fixation and attention were disengaged; finally, a visual target appears in the periphery. On the other hand, the overlap condition, in which the peripheral target appears when the central target is still present, the subject should voluntarily disengage his attention and fixation to orient them toward the peripheral target. These paradigms stimulate automatic versus controlled triggering of saccades. The average saccade latency (measured by video-oculography) was longer in the elderly, and irrespectively of the condition. However, the elderly as the young subjects produced shorter latencies in the gap condition than in the overlap condition. Moreover, in the gap condition, we observed the emergence of a considerable number of reflex saccades with very short latency (between 80 and 120 ms, minimal conduction time) called "express saccades". The occurrence rate of such saccades was similar in the young and the elderly subjects. These results suggest the existence of separate circuits, one non-being sensitive to age (express saccades), the other suffering the effects of aging (controlled saccades). In another ongoing study, this methodology has been applied to patients with Lewy body dementia. The preliminary results from three patients showed an abnormal slowness of latencies, even in the gap condition expected to promote automatic and reflex saccades. Furthermore, we observed a total absence of saccades with express latency. These promising results suggest a deficit even for automatic and express saccades in these patients.

Corrigendum: Interhemispheric and Intrahemispheric Connectivity From the Left Pars Opercularis Within the Language Network Is Modulated by Transcranial Stimulation in Healthy Subjects.

[This corrects the article DOI: 10.3389/fnhum.2020.00063.].

Interhemispheric and Intrahemispheric Connectivity From the Left Pars Opercularis Within the Language Network Is Modulated by Transcranial Stimulation in Healthy Subjects.

Neural activity related to language can be modulated within widespread networks following learning or in response to disruption-including the experimental application of noninvasive brain stimulation. However, the spatiotemporal characteristics of such modulation remain insufficiently explored. The present study combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to explore the modulation of activity across the language network following continuous theta-burst stimulation (cTBS) of the left pars opercularis. In 10 healthy subjects (21 ± 2 years old, four females), neuronavigated cTBS was delivered over the left pars opercularis of the frontal operculum (part of the traditional Broca's area) at 80% of active motor threshold (AMT) stimulation intensity. Real cTBS and sham cTBS were performed in two different visits separated by at least 48 h. Before, immediately, and 10 min after cTBS, 30 single pulses of TMS were delivered to the left pars opercularis at 80% of the resting motor threshold (RMT), whereas EEG was simultaneously recorded. We examined the cTBS-induced modulation of phase locking values (PLVs) between the TMS-evoked potentials (TEPs) recorded over the pars opercularis and those recorded over its right-hemispheric homolog area, the left supramarginal area, and the left superior temporal area in different EEG frequency bands and different time windows following cTBS. cTBS to the left pars opercularis induced within the gamma band: (1) a significant increase in TEP phase synchronization between the left and right pars opercularis at an early time window (250-350 ms) following cTBS; and (2) significantly increased PLV with the left supramarginal area and the left superior temporal area at a later time window (600-700 ms). In the theta and delta band, cTBS to the left pars opercularis induced significantly increased phase synchronization of TEPs between the left pars opercularis and the posterior left hemispheric language areas at a late time window. In sham condition, there was a significant decrease in TEP phase synchronization of the high beta band between left pars opercularis and left superior temporal area at 200-300 ms. These results contribute to characterize the dynamics of the language network and may have implications in the development of noninvasive stimulation protocols to promote the language rehabilitation in aphasia patients.

Switching between gap and overlap pro-saccades: cost or benefit?

Triggering of saccades depends on the task: in the gap task, fixation point switches off and target appears after a gap period; in the overlap task, target appears while fixation point is still on. Saccade latencies are shorter in the gap task, due to fixation disengagement and advanced movement preparation during the gap. The two modes of initiation are also hypothesized to be subtended by different cortical-subcortical circuits. This study tested whether interleaving the two tasks modifies latencies, due to switching between different modes of triggering. Two groups of healthy participants (21-29 vs. 39-55 years) made horizontal and vertical saccades in gap, overlap, and mixed tasks; saccades were recorded with the Eyelink. Both groups showed shorter latencies in the gap task, i.e. a robust gap effect and systematic differences between directions. For young adults, interleaving tasks made the latencies shorter or longer depending on direction, while for middle-age adults, latencies became longer for all directions. Our observations can be explained in the context of models such as that of Brown et al. (Neural Netw 17:471-510, 2004), which proposed that different combinations of frontal eye field (FEF) layers, interacting with cortico-subcortical areas, control saccade triggering in gap and overlap trials. Moreover, we suggest that in early adulthood, the FEF is functioning optimally; frequent changes of activity in the FEF can be beneficial, leading to shorter latencies, at least for some directions. However, for middle-age adults, frequent changes of activity of a less optimally functioning FEF can be time consuming. Studying the alternation of gap and overlap tasks provides a fine tool to explore development, aging and disease.

Binocular motor coordination during saccades and fixations while reading: a magnitude and time analysis.

Reading involves saccades and fixations. Misalignment of the eyes should be small enough to allow sensory fusion. Recent studies reported disparity of the eyes during fixations. This study examines disconjugacy, i.e. change in disparity over time, both during saccades and fixations. Text reading saccades and saccades to single targets of similar sizes (2.5 degrees ) are compared. Young subjects were screened to avoid problems of binocular vision and oculomotor vergence. The results show high quality of motor binocular coordination in both tasks: the amplitude difference between the saccade of the eyes was approximately 0.16 degrees ; during the fixation period, the drift difference was only 0.13 degrees . The disconjugate drift occurred mainly during the first 48 ms of fixation, was equally distributed to the eyes and was often reducing the saccade disconjugacy. Quality of coordination regardless of the task is indicative of robust physiological mechanisms. We suggest the existence of active binocular control mechanisms in which vergence signals may have a central role. Even computation of saccades may be based on continuous interaction between saccade and vergence.

Entrainment of local synchrony reveals a causal role for high-beta right frontal oscillations in human visual consciousness.

Prior evidence supports a critical role of oscillatory activity in visual cognition, but are cerebral oscillations simply correlated or causally linked to our ability to consciously acknowledge the presence of a target in our visual field? Here, EEG signals were recorded on humans performing a visual detection task, while they received brief patterns of rhythmic or random transcranial magnetic stimulation (TMS) delivered to the right Frontal Eye Field (FEF) prior to the onset of a lateralized target. TMS entrained oscillations, i.e., increased high-beta power and phase alignment (the latter to a higher extent for rhythmic high-beta patterns than random patterns) while also boosting visual detection sensitivity. Considering post-hoc only those participants in which rhythmic stimulation enhanced visual detection, the magnitude of high-beta entrainment correlated with left visual performance increases. Our study provides evidence in favor of a causal link between high-beta oscillatory activity in the Frontal Eye Field and visual detection. Furthermore, it supports future applications of brain stimulation to manipulate local synchrony and improve or restore impaired visual behaviors.

Endogenous visuospatial attention increases visual awareness independent of visual discrimination sensitivity.

Visuospatial attention often improves task performance by increasing signal gain at attended locations and decreasing noise at unattended locations. Attention is also believed to be the mechanism that allows information to enter awareness. In this experiment, we assessed whether orienting endogenous visuospatial attention with cues differentially affects visual discrimination sensitivity (an objective task performance) and visual awareness (the subjective feeling of perceiving) during the same discrimination task. Gabor patch targets were presented laterally, either at low contrast (contrast stimuli) or at high contrast embedded in noise (noise stimuli). Participants reported their orientation either in a 3-alternative choice task (clockwise, counterclockwise, unknown) that allowed for both objective and subjective reports, or in a 2-alternative choice task (clockwise, counterclockwise) that provided a control for objective reports. Signal detection theory models were fit to the experimental data: estimated perceptual sensitivity reflected objective performance; decision criteria, or subjective biases, were a proxy for visual awareness. Attention increased sensitivity (i.e., improved objective performance) for the contrast, but not for the noise stimuli. Indeed, with the latter, attention did not further enhance the already high target signal or reduce the already low uncertainty on its position. Interestingly, for both contrast and noise stimuli, attention resulted in more liberal criteria, i.e., awareness increased. The noise condition is thus an experimental configuration where people think they see the targets they attend to better, even if they do not. This could be explained by an internal representation of their attentional state, which influences awareness independent of objective visual signals.