Boosting Learning Efficacy with Noninvasive Brain Stimulation in Intact and Brain-Damaged Humans.

Numerous behavioral studies have shown that visual function can improve with training, although perceptual refinements generally require weeks to months of training to attain. This, along with questions about long-term retention of learning, limits practical and clinical applications of many such paradigms. Here, we show for the first time in female and male human participants that just 10 d of visual training coupled with transcranial random noise stimulation (tRNS) over visual areas causes dramatic improvements in visual motion perception. Relative to control conditions and anodal stimulation, tRNS-enhanced learning was at least twice as fast, and, crucially, it persisted for 6 months after the end of training and stimulation. Notably, tRNS also boosted learning in patients with chronic cortical blindness, leading to recovery of motion processing in the blind field after just 10 d of training, a period too short to elicit enhancements with training alone. In sum, our results reveal a remarkable enhancement of the capacity for long-lasting plastic and restorative changes when a neuromodulatory intervention is coupled with visual training.SIGNIFICANCE STATEMENT Our work demonstrates that visual training coupled with brain stimulation can dramatically reduce the training period from months to weeks, and lead to fast improvement in neurotypical subjects and chronic cortically blind patients, indicating the potential of our procedure to help restore damaged visual abilities for currently untreatable visual dysfunctions. Together, these results indicate the critical role of early visual areas in perceptual learning and reveal its capacity for long-lasting plastic changes promoted by neuromodulatory intervention.

Rapid Improvement on a Temporal Attention Task within a Single Session of High-frequency Transcranial Random Noise Stimulation.

This study explored the modulatory effects of high-frequency transcranial random noise stimulation (tRNS) on visual sensitivity during a temporal attention task. We measured sensitivity to different onset asynchronies during a temporal order judgment task as a function of active stimulation relative to sham. While completing the task, participants were stimulated bilaterally for 20 min over either the TPJ or the human middle temporal area. We hypothesized that tRNS over the TPJ, which is critical to the temporal attention network, would selectively increase cortical excitability and induce cognitive training-like effects on performance, perhaps more so in the left visual field [Matthews, N., & Welch, L. Left visual field attentional advantage in judging simultaneity and temporal order. Journal of Vision, 15, 1-13, 2015; Romanska, A., Rezlescu, C., Susilo, T., Duchaine, B., & Banissy, M. J. High-frequency transcranial random noise stimulation enhances perception of facial identity. Cerebral Cortex, 25, 4334-4340, 2015]. In Experiment 1, we measured the performance of participants who judged the order of Gabors temporally imbedded in flickering discs, presented with onset asynchronies ranging from -75 msec (left disc first) to +75 msec (right disc first). In Experiment 2, we measured whether each participant's temporal sensitivity increased with stimulation by using temporal offsets that the participant initially perceived as simultaneous. We found that parietal cortex stimulation temporarily increased sensitivity on the temporal order judgment task, especially in the left visual field. Stimulation over human middle temporal area did not alter cortical excitability in a way that affected performance. The effects were cumulative across blocks of trials for tRNS over parietal cortex but dissipated when stimulation ended. We conclude that single-session tRNS can induce temporary improvements in behavioral sensitivity and that this shows promising insight into the relationship between cortical stimulation and neural plasticity.

The Pivotal Role of the Right Parietal Lobe in Temporal Attention.

The visual system is extremely efficient at detecting events across time even at very fast presentation rates; however, discriminating the identity of those events is much slower and requires attention over time, a mechanism with a much coarser resolution [Cavanagh, P., Battelli, L., & Holcombe, A. O. Dynamic attention. In A. C. Nobre & S. Kastner (Eds.), The Oxford handbook of attention (pp. 652-675). Oxford: Oxford University Press, 2013]. Patients affected by right parietal lesion, including the TPJ, are severely impaired in discriminating events across time in both visual fields [Battelli, L., Cavanagh, P., & Thornton, I. M. Perception of biological motion in parietal patients. Neuropsychologia, 41, 1808-1816, 2003]. One way to test this ability is to use a simultaneity judgment task, whereby participants are asked to indicate whether two events occurred simultaneously or not. We psychophysically varied the frequency rate of four flickering disks, and on most of the trials, one disk (either in the left or right visual field) was flickering out-of-phase relative to the others. We asked participants to report whether two left-or-right-presented disks were simultaneous or not. We tested a total of 23 right and left parietal lesion patients in Experiment 1, and only right parietal patients showed impairment in both visual fields while their low-level visual functions were normal. Importantly, to causally link the right TPJ to the relative timing processing, we ran a TMS experiment on healthy participants. Participants underwent three stimulation sessions and performed the same simultaneity judgment task before and after 20 min of low-frequency inhibitory TMS over right TPJ, left TPJ, or early visual area as a control. rTMS over the right TPJ caused a bilateral impairment in the simultaneity judgment task, whereas rTMS over left TPJ or over early visual area did not affect performance. Altogether, our results directly link the right TPJ to the processing of relative time.

The Default Computation of Negated Meanings.

Negation is a fundamental component of human reasoning and language. Yet, current neurocognitive models, conceived to account for the cortical representation of meanings (e.g., writing), hardly accommodate the representation of negated meanings (not writing). One main hypothesis, known as the two-step model, proposes that, for negated meanings, the corresponding positive representation is first fully activated and then modified to reflect negation. Recast in neurobiological terms, this model predicts that, in the initial stage of semantic processing, the neural representation of a stimulus' meaning is indistinguishable from the neural representation of that meaning following negation. Although previous work has shown that pragmatic and task manipulations can favor or hinder a two-step processing, we just do not know how the brain processes an utterance as simple as "I am not writing." We implemented two methodologies based on chronometric TMS to measure motor excitability (Experiment 1) and inhibition (Experiment 2) as physiological markers of semantic access to action-related meanings. We used elementary sentences (Adverb + Verb) and a passive reading task. For the first time, we defined action word-related motor activity in terms of increased excitability and concurrently reduced inhibition. Moreover, we showed that this pattern changes already in the earliest stage of semantic processing, when action meanings were negated. Negation modifies the neural representation of the argument in its scope, as soon as semantic effects are observed in the brain.

Human movements and abstract motion displays activate different processes in the observer's motor system.

Brain imaging studies have shown that observation of both bodily movements and abstract motion displays complying with human kinematics activate the observer's motor cortex. However, it is unknown whether the same processes are active in the two conditions. Here, we addressed this issue using transcranial magnetic stimulation (TMS) to directly compare cortico-spinal excitability during observation of actions and motion stimuli that complied with or violated normal human kinematics. We found that kinematics significantly modulated the motor-evoked potentials (MEPs) produced by TMS during observation of both human and abstract motion stimuli. However, only the temporal unfolding of cortico-spinal excitability during observation of human movements significantly correlated with instantaneous stimulus velocity. This correlation was present for normal movements and also for a subset of the movements having unnatural kinematics. Furthermore, bodily movements for which we found no correlation between MEPs and stimulus velocity produced significantly higher MEPs. Our novel results suggest a dissociation in how human movements and abstract motion displays engage the observer's motor system. Specifically, while both stimulus types significantly activate the observer's motor cortex, only bodily movements produce patterns of cortico-spinal excitability that closely follow the velocity profile of the observed movement. This internal "re-enactment" of observed bodily movements seems to be only partially attuned to normal human kinematics.

The origin of word-related motor activity.

Conceptual processing of verbs consistently recruits the left posterior middle temporal gyrus (lpMTG). The left precentral motor cortex also responds to verbs, with higher activity for action than nonaction verbs. The early timing of this effect has suggested that motor features of words' meaning are accessed directly, bypassing access to conceptual representations in lpMTG. An alternative hypothesis is that the retrieval of conceptual representations in lpMTG is necessary to drive more specific, motor-related representations in the precentral gyrus. To test these hypotheses, we first showed that repetitive transcranial magnetic stimulation (rTMS) applied to the verb-preferring lpMTG site selectively impoverished the semantic processing of verbs. In a second experiment, rTMS perturbation of lpMTG, relative to no stimulation (no-rTMS), eliminated the action-nonaction verb distinction in motor activity, as indexed by motor-evoked potentials induced in peripheral muscles with single-pulse TMS over the left primary motor cortex. rTMS pertubation of an occipital control site, relative to no-rTMS, did not affect the action-nonaction verb distinction in motor activity, but the verb contrast did not differ reliably from the lpMTG effect. The results show that lpMTG carries core semantic information necessary to drive the activation of specific (motor) features in the precentral gyrus.

Distinct neural mechanisms for body form and body motion discriminations.

Actions can be understood based on form cues (e.g., static body posture) as well as motion cues (e.g., gait patterns). A fundamental debate centers on the question of whether the functional and neural mechanisms processing these two types of cues are dissociable. Here, using fMRI, psychophysics, and transcranial magnetic stimulation (TMS), all within the same human participants, we show that mechanisms underlying body form and body motion processing are functionally and neurally distinct. Multivoxel fMRI activity patterns in the extrastriate body area (EBA), but not in the posterior superior temporal sulcus (pSTS), carried cue invariant information about the body form of an acting human. Conversely, multivoxel patterns in pSTS, but not in EBA, carried information about the body motion of the same actor. In a psychophysical experiment, we selectively impaired body form and body motion discriminations by manipulating different visual cues: misaligning the ellipses that made up a dynamic walker stimulus selectively disrupted body form discriminations, while varying the presentation duration of the walker selectively affected body motion discriminations. Finally, a TMS experiment revealed causal evidence for a double-dissociation between neural mechanisms underlying body form and body motion discriminations: TMS over EBA selectively disrupted body form discrimination, whereas TMS over pSTS selectively disrupted body motion discrimination. Together, these findings reveal complementing but dissociable functions of EBA and pSTS during action perception. They provide constraints for theoretical and computational models of action perception by showing that action perception involves at least two parallel pathways that separately contribute to the understanding of others' behavior.

A chronometric study of the posterior cerebellum's function in emotional processing.

The posterior cerebellum is a recently discovered hub of the affective and social brain, with different subsectors contributing to different social functions. However, very little is known about when the posterior cerebellum plays a critical role in social processing. Due to its location and anatomy, it has been difficult to use traditional approaches to directly study the chronometry of the cerebellum. To address this gap in cerebellar knowledge, here we investigated the causal contribution of the posterior cerebellum to social processing using a chronometric transcranial magnetic stimulation (TMS) approach. We show that the posterior cerebellum is recruited at an early stage of emotional processing (starting from 100 ms after stimulus onset), simultaneously with the posterior superior temporal sulcus (pSTS), a key node of the social brain. Moreover, using a condition-and-perturb TMS approach, we found that the recruitment of the pSTS in emotional processing is dependent on cerebellar activation. Our results are the first to shed light on chronometric aspects of cerebellar function and its causal functional connectivity with other nodes of the social brain.

The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders.

Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.

Improved motion perception and impaired spatial suppression following disruption of cortical area MT/V5.

As stimulus size increases, motion direction of high-contrast patterns becomes increasingly harder to perceive. This counterintuitive behavioral result, termed "spatial suppression," is hypothesized to reflect center-surround antagonism-a receptive field property ubiquitous in sensory systems. Prior research proposed that spatial suppression of motion signals is a direct correlate of center-surround antagonism within cortical area MT. Here, we investigated whether human MT/V5 is indeed causally involved in spatial suppression of motion signals. The key assumption is that a disruption of neural mechanisms that play a critical role in spatial suppression could allow these normally suppressed motion signals to reach perceptual awareness. Thus, our hypothesis was that a disruption of MT/V5 should weaken spatial suppression and, consequently, improve motion perception of large, moving patterns. To disrupt MT/V5, we used offline 1 Hz transcranial magnetic stimulation (TMS)-a method that temporarily attenuates normal functioning of the targeted cortex. Early visual areas were also targeted as a control site. The results supported our hypotheses and showed that disruption of MT/V5 improved motion discrimination of large, moving stimuli, presumably by weakening surround suppression strength. This effect was specific to MT/V5 stimulation and contralaterally presented stimuli. Evidently, the critical neural constraints limiting motion perception of large, high-contrast stimuli involve MT/V5. Additionally, our findings mimic spatial suppression deficits that are observed in several patient populations and implicate impaired MT/V5 processes as likely neural correlates for the reported perceptual abnormalities in the elderly, patients with schizophrenia and those with a history of depression.

Distinct cerebellar regions for body motion discrimination.

Visual processing of human movements is critical for adaptive social behavior. Cerebellar activations have been observed during biological motion discrimination in prior neuroimaging studies, and cerebellar lesions may be detrimental for this task. However, whether the cerebellum plays a causal role in biological motion discrimination has never been tested. Here, we addressed this issue in three different experiments by interfering with the posterior cerebellar lobe using transcranial magnetic stimulation (TMS) during a biological discrimination task. In Experiments 1 and 2, we found that TMS delivered at onset of the visual stimuli over the vermis (vermal lobule VI), but not over the left cerebellar hemisphere (left lobule VI/Crus I), interfered with participants' ability to distinguish biological from scrambled motion compared to stimulation of a control site (vertex). Interestingly, when stimulation was delivered at a later time point (300 ms after stimulus onset), participants performed worse when TMS was delivered over the left cerebellar hemisphere compared to the vermis and the vertex (Experiment 3). Our data show that the posterior cerebellum is causally involved in biological motion discrimination and suggest that different sectors of the posterior cerebellar lobe may contribute to the task at different time points.

The benefits of simultaneous tDCS and working memory training on transfer outcomes: A systematic review and meta-analysis.

BACKGROUND: Transcranial direct current stimulation (tDCS) has shown potential as an effective aid to facilitate learning. A popular application of this technology has been in combination with working memory training (WMT) in order to enhance transfer effects to other cognitive measures after training. OBJECTIVE: This meta-analytic review aims to synthesize the existing literature on tDCS-enhanced WMT to quantify the extent to which tDCS can improve performance on transfer tasks after training. Furthermore, we were interested to evaluate the moderating effects of assessment time point (immediate post-test vs. follow-up) and transfer distance, i.e., the degree of similarity between transfer and training tasks. METHODS: Using robust variance estimation, we performed a systematic meta-analysis of all studies to date that compared WMT with tDCS to WMT with sham in healthy adults. All procedures conformed to PRISMA guidelines. RESULTS: Across 265 transfer measures in 18 studies, we found a small positive net effect of tDCS on improving overall performance on transfer measures after WMT. These effects were sustained at follow-up, which ranged from 1 week to one year after training, with a median of 1 month. Additionally, although there were no significant differences as a function of transfer distance, effects were most pronounced for non-trained working memory tasks. CONCLUSIONS: This review provides evidence that tDCS can be effective in promoting learning over and above WMT alone, and can durably improve performance on trained and untrained measures for weeks to months after the initial training and stimulation period. In particular, boosting performance on dissimilar working memory tasks may present the most promising target for tDCS-augmented WMT.

Behavioral gain following isolation of attention.

Stable sensory perception is achieved through balanced excitatory-inhibitory interactions of lateralized sensory processing. In real world experience, sensory processing is rarely equal across lateralized processing regions, resulting in continuous rebalancing. Using lateralized attention as a case study, we predicted rebalancing lateralized processing following prolonged spatial attention imbalance could cause a gain in attention in the opposite direction. In neurotypical human adults, we isolated covert attention to one visual field with a 30-min attention-demanding task and found an increase in attention in the opposite visual field after manipulation. We suggest a gain in lateralized attention in the previously unattended visual field is due to an overshoot through attention rebalancing. The offline post-manipulation effect is suggestive of long-term potentiation affecting behavior. Our finding of visual field specific attention increase could be critical for the development of clinical rehabilitation for patients with a unilateral lesion and lateralized attention deficits. This proof-of-concept study initiates the examination of overshoot following the release of imbalance in other lateralized control and sensory domains, important in our basic understanding of lateralized processing.

Attention network modulation via tRNS correlates with attention gain.

Transcranial random noise stimulation (tRNS) can enhance vision in the healthy and diseased brain. Yet, the impact of multi-day tRNS on large-scale cortical networks is still unknown. We investigated the impact of tRNS coupled with behavioral training on resting-state functional connectivity and attention. We trained human subjects for 4 consecutive days on two attention tasks, while receiving tRNS over the intraparietal sulci, the middle temporal areas, or Sham stimulation. We measured resting-state functional connectivity of nodes of the dorsal and ventral attention network (DVAN) before and after training. We found a strong behavioral improvement and increased connectivity within the DVAN after parietal stimulation only. Crucially, behavioral improvement positively correlated with connectivity measures. We conclude changes in connectivity are a marker for the enduring effect of tRNS upon behavior. Our results suggest that tRNS has strong potential to augment cognitive capacity in healthy individuals and promote recovery in the neurological population.

The 'when' parietal pathway explored by lesion studies.

The perception of events in space and time is at the root of our interactions with the environment. The precision with which we perceive visual events in time enables us to act upon objects with great accuracy and the loss of such functions due to brain lesions can be catastrophic. We outline a visual timing mechanism that deals with the trajectory of an object's existence across time, a crucial function when keeping track of multiple objects that temporally overlap or occur sequentially. Recent evidence suggests these functions are served by an extended network of areas, which we call the 'when' pathway. Here we show that the when pathway is distinct from and interacts with the well-established 'where' and 'what' pathways.

Controlling Brain State Prior to Stimulation of Parietal Cortex Prevents Deterioration of Sustained Attention.

Sustained attention is a limited resource which declines during daily tasks. Such decay is exacerbated in clinical and aging populations. Inhibition of the intraparietal sulcus (IPS), using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS), can lead to an upregulation of functional communication within the attention network. Attributed to functional compensation for the inhibited node, this boost lasts for tens of minutes poststimulation. Despite the neural change, no behavioral correlate has been found in healthy subjects, a necessary direct evidence of functional compensation. To understand the functional significance of neuromodulatory induced fluctuations on attention, we sought to boost the impact of LF-rTMS to impact behavior. We controlled brain state prior to LF-rTMS using high-frequency transcranial random noise stimulation (HF-tRNS), shown to increase and stabilize neuronal excitability. Using fMRI-guided stimulation protocols combining HF-tRNS and LF-rTMS, we tested the poststimulation impact on sustained attention with multiple object tracking (MOT). While attention deteriorated across time in control conditions, HF-tRNS followed by LF-rTMS doubled sustained attention capacity to 94 min. Multimethod stimulation was more effective when targeting right IPS, supporting specialized attention processing in the right hemisphere. Used in cognitive domains dependent on network-wide neural activity, this tool may cause lasting neural compensation useful for clinical rehabilitation.

Effects of transcranial direct current stimulation over the posterior parietal cortex on novice X-ray screening performance.

Existing theories of visual search are generally deduced from lab-based studies involving the identification of a target object among similar distractors. The role of the right parietal cortex in visual search is well-established. However, less is known about real-world visual search tasks, such as X-ray screening, which require targets to be disembedded from their background. Research has shown variations in the cognitive abilities required for these tasks and typical lab-based visual search tasks. Thus, the findings of traditional visual search studies do not always transfer into the applied domain. Although brain imaging studies have offered insights into visual search tasks involving disembedding, highlighting an association between the left parietal cortex and disembedding performance, no causal link has yet been established. To this end, we carried out a pilot study (n = 34, between-subjects) administering non-invasive brain stimulation over the posterior parietal cortex (PPC) prior to completing a security X-ray screening task. The findings suggested that anodal left PPC tDCS enhanced novice performance in X-ray screening over that of sham stimulation, in line with brain imaging findings. However, the efficacy of tDCS is under question, with a growing number of failed replications. With this in mind, this study aims to re-test our original hypothesis by examining the effects of left-side parietal stimulation on novice X-ray screener performance and comparing them to those of sham stimulation and of stimulation on a control site (right PPC). As such, this within-subjects study comprised three sessions (2 mA left PPC, 2 mA right PPC, low-intensity sham stimulation left PPC), to investigate effects of anodal tDCS on X-ray screening performance. The pre-registered analysis did not detect any significant differences between left PPC tDCS and sham tDCS or left PPC tDCS and right PPC tDCS on novice performance (d') in X-ray screening. Further exploratory analyses detected no effects of left PPC tDCS on any other indices of performance in the X-ray security screening task (c, RTs and accuracy), or a disembedding control task (RTs and accuracy). The use of alternative stimulation techniques, with replicable behavioural effects on the parietal lobe (or a multi-technique approach), and well-powered studies with a systematic variation of stimulation parameters, could help to choose between two possible interpretations: that neither left nor right PPC are causally related to either tasks or that tDCS was ineffective. Finally, low-intensity sham stimulation (.016 mA), previously shown to outperform other sham conditions in between-subjects designs, was found to be ineffective for blinding participants in a within-subjects design. Our findings raise concerns for the current lack of optimal control conditions and add to the growing literature highlighting the need for replication in the field.

Understanding diaschisis models of attention dysfunction with rTMS.

Visual attentive tracking requires a balance of excitation and inhibition across large-scale frontoparietal cortical networks. Using methods borrowed from network science, we characterize the induced changes in network dynamics following low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as an inhibitory noninvasive brain stimulation protocol delivered over the intraparietal sulcus. When participants engaged in visual tracking, we observed a highly stable network configuration of six distinct communities, each with characteristic properties in node dynamics. Stimulation to parietal cortex had no significant impact on the dynamics of the parietal community, which already exhibited increased flexibility and promiscuity relative to the other communities. The impact of rTMS, however, was apparent distal from the stimulation site in lateral prefrontal cortex. rTMS temporarily induced stronger allegiance within and between nodal motifs (increased recruitment and integration) in dorsolateral and ventrolateral prefrontal cortex, which returned to baseline levels within 15 min. These findings illustrate the distributed nature by which inhibitory rTMS perturbs network communities and is preliminary evidence for downstream cortical interactions when using noninvasive brain stimulation for behavioral augmentations.

The role of the angular gyrus in the modulation of visuospatial attention by the mental number line.

We tend to mentally organize numbers along a left-to-right oriented horizontal mental number line, with the smaller numbers occupying the more leftward positions. This mental number line has been shown to exert an influence on the visuospatial allocation of attention, with presentation of numbers from the low and high ends of the mental number line inducing covert shifts of spatial attention to the left and right side of visual space, respectively. However, the neural basis of this modulation is not known. Here we used transcranial magnetic stimulation (TMS) to study the role of the angular gyrus in shifts in visuospatial attention induced by the mental number line. We used a priming paradigm with a line bisection task to assess the bias in spatial allocation of visual attention induced by exposure to either small (16-24) or large (76-84) ends of the mental number line. In the Small Number Prime condition, when attention is presumably biased to the left side of visual space, TMS applied over the right angular gyrus during the delay between the prime and the target line abolished the effect of number priming. In contrast, application of TMS over the left angular gyrus had no significant effect. In the Large Number Prime condition (which shifted attention to the right side of visual space) both left and right TMS over the angular gyrus modulated the effect of number priming. This pattern of results reveals the involvement of the angular gyrus in the interaction between the mental number line and visual spatial attention.

The middle range of the number line orients attention to the left side of visual space.

Mental representation of numbers is believed to be spatial in nature, with small numbers occupying the left and large numbers the right side of a putative mental number line. Consistent with this, presentation of numbers from the low and high ends of the mental number line induces covert shifts of spatial attention to the left and right side of visual space, respectively. However, the effect of the presentation of the middle range (containing numbers below and above the midpoint) of the number line on visual perception has so far not been studied. Here we show in two experiments, using a line bisection task and a simple target detection task, that processing of middle-range numbers affects allocation of visuospatial attention in a similar way as processing of small numbers, with attention shifted to the left side of space. We suggest that this pattern of results arises due to "anchoring" heuristics that participants use in number processing.