The parietal cortex has a causal role in ambiguity computations in humans.

Humans often face the challenge of making decisions between ambiguous options. The level of ambiguity in decision-making has been linked to activity in the parietal cortex, but its exact computational role remains elusive. To test the hypothesis that the parietal cortex plays a causal role in computing ambiguous probabilities, we conducted consecutive fMRI and TMS-EEG studies. We found that participants assigned unknown probabilities to objective probabilities, elevating the uncertainty of their decisions. Parietal cortex activity correlated with the objective degree of ambiguity and with a process that underestimates the uncertainty during decision-making. Conversely, the midcingulate cortex (MCC) encodes prediction errors and increases its connectivity with the parietal cortex during outcome processing. Disruption of the parietal activity increased the uncertainty evaluation of the options, decreasing cingulate cortex oscillations during outcome evaluation and lateral frontal oscillations related to value ambiguous probability. These results provide evidence for a causal role of the parietal cortex in computing uncertainty during ambiguous decisions made by humans.

High-density transcranial direct current stimulation to improve upper limb motor function following stroke: study protocol for a double-blind randomized clinical trial targeting prefrontal and/or cerebellar cognitive contributions to voluntary motion.

BACKGROUND: Focal brain lesions following a stroke of the middle cerebral artery induce large-scale network disarray with a potential to impact multiple cognitive and behavioral domains. Over the last 20 years, non-invasive brain neuromodulation via electrical (tCS) stimulation has shown promise to modulate motor deficits and contribute to recovery. However, weak, inconsistent, or at times heterogeneous outcomes using these techniques have also highlighted the need for novel strategies and the assessment of their efficacy in ad hoc controlled clinical trials. METHODS: We here present a double-blind, sham-controlled, single-center, randomized pilot clinical trial involving participants having suffered a unilateral middle cerebral artery (MCA) stroke resulting in motor paralysis of the contralateral upper limb. Patients will undergo a 10-day regime (5 days a week for 2 consecutive weeks) of a newly designed high-definition transcranial direct current stimulation (HD-tDCS) protocol. Clinical evaluations (e.g., Fugl Meyer, NIHSS), computer-based cognitive assessments (visuo-motor adaptation and AX-CPT attention tasks), and electroencephalography (resting-state and task-evoked EEG) will be carried out at 3 time points: (I) Baseline, (II) Post-tDCS, and (III) Follow-up. The study consists of a four-arm trial comparing the impact on motor recovery of three active anodal tDCS conditions: ipsilesional DLPFC tDCS, contralesional cerebellar tDCS or combined DLPFC + contralesional cerebellar tDCS, and a sham tDCS intervention. The Fugl-Meyer Assessment for the upper extremity (FMA-UE) is selected as the primary outcome measure to quantify motor recovery. In every stimulation session, participants will receive 20 min of high-density tDCS stimulation (HD-tDCS) (up to 0.63 mA/[Formula: see text]) with [Formula: see text] electrodes. Electrode scalp positioning relative to the cortical surface (anodes and cathodes) and intensities are based on a biophysical optimization model of current distribution ensuring a 0.25 V/m impact at each of the chosen targets. DISCUSSION: Our trial will gauge the therapeutic potential of accumulative sessions of HD-tDCS to improve upper limb motor and cognitive dysfunctions presented by middle cerebral artery stroke patients. In parallel, we aim at characterizing changes in electroencephalographic (EEG) activity as biomarkers of clinical effects and at identifying potential interactions between tDCS impact and motor performance outcomes. Our work will enrich our mechanistic understanding on prefrontal and cerebellar contributions to motor function and its rehabilitation following brain damage. TRIAL REGISTRATION: ClinicalTrials.gov NCT05329818. April 15, 2022.

Gamma amplitude is coupled to opposed hippocampal theta-phase states during the encoding and retrieval of episodic memories in humans.

Computational models and in vivo studies in rodents suggest that the emergence of gamma activity (40-140 Hz) during memory encoding and retrieval is coupled to opposed-phase states of the underlying hippocampal theta rhythm (4-9 Hz).1,2,3,4,5,6,7,8,9,10 However, direct evidence for whether human hippocampal gamma-modulated oscillatory activity in memory processes is coupled to opposed-phase states of the ongoing theta rhythm remains elusive. Here, we recorded local field potentials (LFPs) directly from the hippocampus of 10 patients with epilepsy, using depth electrodes. We used a memory encoding and retrieval task whereby trial unique sequences of pictures depicting real-life episodes were presented, and 24 h later, participants were asked to recall them upon the appearance of the first picture of the encoded episodic sequence. We found theta-to-gamma cross-frequency coupling that was specific to the hippocampus during both the encoding and retrieval of episodic memories. We also revealed that gamma was coupled to opposing theta phases during both encoding and recall processes. Additionally, we observed that the degree of theta-gamma phase opposition between encoding and recall was associated with participants' memory performance, so gamma power was modulated by theta phase for both remembered and forgotten trials, although only for remembered trials the dominant theta phase was different for encoding and recall trials. The current results offer direct empirical evidence in support of hippocampal theta-gamma phase opposition models in human long-term memory and provide fundamental insights into mechanistic predictions derived from computational and animal work, thereby contributing to establishing similarities and differences across species.

Local Alterations of Left Arcuate Fasciculus and Transcallosal White Matter Microstructure in Schizophrenia Patients with Medication-resistant Auditory Verbal Hallucinations: A Pilot Study.

Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been associated with abnormalities of the left arcuate fasciculus and transcallosal white matter projections linking homologous language areas of both hemispheres. While most studies have used a whole-tract approach, here we focused on analyzing local alterations of the above-mentioned pathways in SZ patients suffering medication-resistant AVH. Fractional anisotropy (FA) was estimated along the left arcuate fasciculus and interhemispheric projections of the rostral and caudal corpus callosum. Then, potential associations between white matter tracts and SZ symptoms were explored by correlating local site-by-site FA values and AVH severity estimated via the Auditory Hallucinations Rating Scale (AHRS). Compared to a sample of healthy controls, SZ patients displayed lower FA values in the rostral portion of the left arcuate fasciculus, near the frontal operculum, and in the left and right lateral regions of the rostral portion of the transcallosal pathways. In contrast, SZ patients showed higher FA values than healthy controls in the medial portion of the latter transcallosal pathway and in the midsagittal section of the interhemispheric auditory pathway. Finally, significant correlations were found between local FA values in the left arcuate fasciculus and the severity of the AVH's attentional salience. Contributing to the study of associations between local white matter alterations of language networks and SZ symptoms, our findings highlight local alterations of white matter integrity in these pathways linking language areas in SZ patients with AVH. We also hypothesize a link between the left arcuate fasciculus and the attentional capture of AVH.

Transcranial direct current stimulation for gait recovery following stroke: A systematic review of current literature and beyond.

Background: Over the last decade, transcranial direct current stimulation (tDCS) has set promise contributing to post-stroke gait rehabilitation. Even so, results are still inconsistent due to low sample size, heterogeneity of samples, and tDCS design differences preventing comparability. Nonetheless, updated knowledge in post-stroke neurophysiology and stimulation technologies opens up opportunities to massively improve treatments. Objective: The current systematic review aims to summarize the current state-of-the-art on the effects of tDCS applied to stroke subjects for gait rehabilitation, discuss tDCS strategies factoring individual subject profiles, and highlight new promising strategies. Methods: MEDLINE, SCOPUS, CENTRAL, and CINAHL were searched for stroke randomized clinical trials using tDCS for the recovery of gait before 7 February 2022. In order to provide statistical support to the current review, we analyzed the achieved effect sizes and performed statistical comparisons. Results: A total of 24 records were finally included in our review, totaling n = 651 subjects. Detailed analyses revealed n = 4 (17%) studies with large effect sizes (≥0.8), n = 6 (25%) studies with medium ones (≥0.5), and n = 6 (25%) studies yielding low effects sizes (≤ 0.2). Statistically significant negative correlations (rho = -0.65, p = 0.04) and differences (p = 0.03) argued in favor of tDCS interventions in the sub-acute phase. Finally, significant differences (p = 0.03) were argued in favor of a bifocal stimulation montage (anodal M1 ipsilesional and cathodal M1 contralesional) with respect to anodal ipsilesional M1. Conclusion: Our systematic review highlights the potential of tDCS to contribute to gait recovery following stroke, although also the urgent need to improve current stimulation strategies and subject-customized interventions considering stroke severity, type or time-course, and the use of network-based multifocal stimulation approaches guided by computational biophysical modeling. Systematic review registration: PROSPERO: CRD42021256347.

In vivo low-intensity magnetic pulses durably alter neocortical neuron excitability and spontaneous activity.

Magnetic brain stimulation is a promising treatment for neurological and psychiatric disorders. However, a better understanding of its effects at the individual neuron level is essential to improve its clinical application. We combined focal low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons in vivo. Continuous 10 Hz LI-rTMS reliably evoked firing at ∼4-5 Hz during the stimulation period and induced durable attenuation of synaptic activity and spontaneous firing in cortical neurons, through membrane hyperpolarization and a reduced intrinsic excitability. However, inducing firing in individual neurons by repeated intracellular current injection did not reproduce the effects of LI-rTMS on neuronal properties. These data provide a novel understanding of mechanisms underlying magnetic brain stimulation showing that, in addition to inducing biochemical plasticity, even weak magnetic fields can activate neurons and enduringly modulate their excitability. KEY POINTS: Repetitive transcranial magnetic stimulation (rTMS) is a promising technique to alleviate neurological and psychiatric disorders caused by alterations in cortical activity. Our knowledge of the cellular mechanisms underlying rTMS-based therapies remains limited. We combined in vivo focal application of low-intensity rTMS (LI-rTMS) to the rat somatosensory cortex with intracellular recordings of subjacent pyramidal neurons to characterize the effects of weak magnetic fields at single cell level. Ten minutes of LI-rTMS delivered at 10 Hz reliably evoked action potentials in cortical neurons during the stimulation period, and induced durable attenuation of their intrinsic excitability, synaptic activity and spontaneous firing. These results help us better understand the mechanisms of weak magnetic stimulation and should allow optimizing the effectiveness of stimulation protocols for clinical use.

Evaluation of the effect of transcranial direct current stimulation on language impairments in the behavioural variant of frontotemporal dementia.

The behavioural variant of frontotemporal dementia is a neurodegenerative disease characterized by bilateral atrophy of the prefrontal cortex, gradual deterioration of behavioural and executive capacities, a breakdown of language initiation and impaired search mechanisms in the lexicon. To date, only a few studies have analysed the modulation of language deficits in the behavioural variant of frontotemporal dementia patients with transcranial direct current stimulation, yet with inconsistent results. Our goal was to assess the impact on language performance of a single session of transcranial direct current stimulation on patients with the behavioural variant of frontotemporal dementia. Using a sham-controlled double-blind crossover design in a cohort of behavioural frontotemporal dementia patients (n = 12), we explored the impact on language performance of a single transcranial direct current stimulation session delivering anodal or cathodal transcranial direct current stimulation, over the left and right dorsolateral prefrontal cortex, compared with sham stimulation. A Letter fluency and a Picture naming task were performed prior and following transcranial direct current stimulation, to assess modulatory effects on language. Behavioural frontotemporal dementia patients were impaired in all evaluation tasks at baseline compared with healthy controls. Computational finite element method (FEM) models of cortical field distribution corroborated expected impacts of left-anodal and right-cathodal transcranial direct current stimulation over the dorsolateral prefrontal cortex and showed lower radial field strength in case of atrophy. However, none of the two tasks showed statistically significant evidence of language improvement caused by active transcranial direct current stimulation compared with sham. Our findings do not argue in favour of pre-therapeutic effects and suggest that stimulation strategies evaluating the modulatory role of transcranial direct current stimulation in the behavioural variant of frontotemporal dementia must carefully weigh the influence of symptom severity and cortical atrophy affecting prefrontal regions to ensure clinical success.

Transcranial magnetic stimulation entrains alpha oscillatory activity in occipital cortex.

Parieto-occipital alpha rhythms (8-12 Hz) underlie cortical excitability and influence visual performance. Whether the synchrony of intrinsic alpha rhythms in the occipital cortex can be entrained by transcranial magnetic stimulation (TMS) is an open question. We applied 4-pulse, 10-Hz rhythmic TMS to entrain intrinsic alpha oscillators targeting right V1/V2, and tested four predictions with concurrent electroencephalogram (EEG): (1) progressive enhancement of entrainment across time windows, (2) output frequency specificity, (3) dependence on the intrinsic oscillation phase, and (4) input frequency specificity to individual alpha frequency (IAF) in the neural signatures. Two control conditions with an equal number of pulses and duration were arrhythmic-active and rhythmic-sham stimulation. The results confirmed the first three predictions. Rhythmic TMS bursts significantly entrained local neural activity. Near the stimulation site, evoked oscillation amplitude and inter-trial phase coherence (ITPC) were increased for 2 and 3 cycles, respectively, after the last TMS pulse. Critically, ITPC following entrainment positively correlated with IAF rather than with the degree of similarity between IAF and the input frequency (10 Hz). Thus, we entrained alpha-band activity in occipital cortex for ~ 3 cycles (~ 300 ms), and IAF predicts the strength of entrained occipital alpha phase synchrony indexed by ITPC.

Evaluating deep learning EEG-based mental stress classification in adolescents with autism for breathing entrainment BCI.

Mental stress is a major individual and societal burden and one of the main contributing factors that lead to pathologies such as depression, anxiety disorders, heart attacks, and strokes. Given that anxiety disorders are one of the most common comorbidities in youth with autism spectrum disorder (ASD), this population is particularly vulnerable to mental stress, severely limiting overall quality of life. To prevent this, early stress quantification with machine learning (ML) and effective anxiety mitigation with non-pharmacological interventions are essential. This study aims to investigate the feasibility of exploiting electroencephalography (EEG) signals for stress assessment by comparing several ML classifiers, namely support vector machine (SVM) and deep learning methods. We trained a total of eleven subject-dependent models-four with conventional brain-computer interface (BCI) methods and seven with deep learning approaches-on the EEG of neurotypical (n=5) and ASD (n=8) participants performing alternating blocks of mental arithmetic stress induction, guided and unguided breathing. Our results show that a multiclass two-layer LSTM RNN deep learning classifier is capable of identifying mental stress from ongoing EEG with an overall accuracy of 93.27%. Our study is the first to successfully apply an LSTM RNN classifier to identify stress states from EEG in both ASD and neurotypical adolescents, and offers promise for an EEG-based BCI for the real-time assessment and mitigation of mental stress through a closed-loop adaptation of respiration entrainment.

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.

Patterns of axono-cortical evoked potentials: an electrophysiological signature unique to each white matter functional site?

BACKGROUND: Brain-to-brain evoked potentials constitute a new methodology that could help to understand the network-level correlates of electrical stimulation applied for brain mapping during tumor resection. In this paper, we aimed to describe the characteristics of axono-cortical evoked potentials recorded from distinct, but in the same patient, behaviorally eloquent white matter sites. METHODS: We report the intraoperative white matter mapping and axono-cortical evoked potentials recordings observed in a patient operated on under awake condition of a diffuse low-grade glioma in the left middle frontal gyrus. Out of the eight behaviorally eloquent sites identified with 60-Hz electrical stimulation, five were probed with single electrical pulses (delivered at 1 Hz), while recording evoked potentials on two electrodes, covering the inferior frontal gyrus and the precentral gyrus, respectively. Postoperative diffusion-weighted MRI was used to reconstruct the tractograms passing through each of the five stimulated sites. RESULTS: Each stimulated site generated an ACEP on at least one of the recorded electrode contacts. The whole pattern-i.e., the specific contacts with ACEPs and their waveform-was distinct for each of the five stimulated sites. CONCLUSIONS: We found that the patterns of ACEPs provided unique electrophysiological signatures for each of the five white matter functional sites. Our results could ultimately provide neurosurgeons with a new tool of intraoperative electrophysiologically based functional guidance.

Axono-cortical evoked potentials as a new method of IONM for preserving the motor control network: a first study in three cases.

BACKGROUND: White matter stimulation in an awake patient is currently the gold standard for identification of functional pathways. Despite the robustness and reproducibility of this method, very little is known about the electrophysiological mechanisms underlying the functional disruption. Axono-cortical evoked potentials (ACEPs) provide a reliable technique to explore these mechanisms. OBJECTIVE: To describe the shape and spatial patterns of ACEPs recorded when stimulating the white matter of the caudal part of the right superior frontal gyrus while recording in the precentral gyrus. METHODS: We report on three patients operated on under awake condition for a right superior frontal diffuse low-grade glioma. Functional sites were identified in the posterior wall of the cavity, whose 2-3-mA stimulation generated an arrest of movement. Once the resection was done, axono-cortical potentials were evoked: recording electrodes were put over the precentral gyrus, while stimulating at 1 Hz the white matter functional sites during 30-60 s. Unitary evoked potentials were averaged off-line. Waveform was visually analyzed, defining peaks and troughs, with quantitative measurements of their amplitudes and latencies. Spatial patterns of ACEPs were compared with patients' own and HCP-derived structural connectomics. RESULTS: Axono-cortical evoked potentials (ACEPs) were obtained and exhibited complex shapes and spatial patterns that correlated only partially with structural connectivity patterns. CONCLUSION: ACEPs is a new IONM methodology that could both contribute to elucidate the propagation of neuronal activity within a distributed network when stimulating white matter and provide a new technique for preserving motor control abilities during brain tumor resections.

Sustained Recovery in a Treatment-Refractory Obsessive-Compulsive Disorder Patient After Deep Brain Stimulation Battery Failure.

Obsessive-compulsive disorder (OCD) is a widespread chronic neuropsychiatric disorder characterized by recurrent intrusive thoughts, images, or urges (obsessions) that typically cause anxiety or distress. Even when optimal treatment is provided, 10% of patients remain severely affected chronically. In some countries, deep brain stimulation (DBS) is an approved and effective therapy for patients suffering from treatment-resistant OCD. Hereafter, we report the case of a middle-aged man with a long history of treatment-resistant OCD spanning nearly a decade with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores oscillating between 21 and 28. The patient underwent bilateral implantation of ventral striatum/ventral capsule DBS leads attached to a battery-operated implanted pulse generator. After a 3-month postimplantation period, the DBS protocol started. Three months after the onset of DBS treatment, the patient's Y-BOCS score had dropped to 3, and he became steadily asymptomatic. However, inadvertently, at this time, it was found out that the implanted pulse generator battery had discharged completely, interrupting brain stimulation. The medical team carried on with the original therapeutic and evaluation plan in the absence of active DBS current. After 12 additional months under off-DBS, the patient remained at a Y-BOCS score of 7 and asymptomatic. To our knowledge, this is the first report that provides an opportunity to discuss four different hypotheses of long-term recovery induced by DBS in a treatment-refractory OCD patient, notably: (1) A placebo effect; (2) Paradoxical improvements induced by micro-lesions generated by DBS probe implantation procedures; (3) Unexpected late spontaneous improvements; (4) Recovery driven by a combination of active DBS-induction, the effects of medication, and DBS-placebo effects.

Network-level causal analysis of set-shifting during trail making test part B: A multimodal analysis of a glioma surgery case.

The trail making test part B (TMT-B) is one of the most widely used task for the assessment of set-shifting ability in patients. However, the set of brain regions impacting TMT-B performance when lesioned is still poorly known. In this case report, we provide a multimodal analysis of a patient operated on while awake for a diffuse low-grade glioma located in the right supramarginal gyrus. TMT-B performance was probed intraoperatively. Direct electrical stimulation of the white matter in the depth of the resection generated shifting errors. Using the recent methodology of axono-cortical-evoked potentials (ACEP), we demonstrated that the eloquent fibers were connected to the posterior end of the middle temporal gyrus (MTG). This was further confirmed by a tractography analysis of the postoperative diffusion MRI. Finally, the functional connectivity maps of this MTG seed were assessed in both pre- and post-operative resting state MRI. These maps matched with the Control network B (13th) and Default B (17th) from the 17-networks parcellation of (Yeo et al., 2011). Last but not least, we showed that the dorsal attention B (6th), the control A & B networks (12th and 13th) and the default A (16th) have been preserved here but disconnected after a more extensive resection in a previous glioma case within the same area, and in whom TMT-B was definitively impaired. Taken together, these data support the need of a network-level approach to identify the neural basis of the TMT-B and point to the Control network B as playing an important role in set-shifting.

"I do not feel my hand where I see it": causal mapping of visuo-proprioceptive integration network in a surgical glioma patient.

A recent tasked-based fMRI study unveiled a network of areas implicated in the process of visuo-proprioceptive integration of the right hand. In this study, we report a case of a patient operated on in awake conditions for a glioblastoma of the left superior parietal lobule. When stimulating a white matter site in the anterior wall of the cavity, the patient spontaneously reported a discrepancy between the visual and proprioceptive perceptions of her right hand. Using several multimodal approaches (axono-cortical evoked potentials, tractography, resting-state functional connectivity), we demonstrated converging support for the hypothesis that tumor-induced plasticity redistributed the left-lateralized network of right-hand visuo-proprioceptive integration towards its right-lateralized homolog.

Game theoretical mapping of white matter contributions to visuospatial attention in stroke patients with hemineglect.

White matter bundles linking gray matter nodes are key anatomical players to fully characterize associations between brain systems and cognitive functions. Here we used a multivariate lesion inference approach grounded in coalitional game theory (multiperturbation Shapley value analysis, MSA) to infer causal contributions of white matter bundles to visuospatial orienting of attention. Our work is based on the characterization of the lesion patterns of 25 right hemisphere stroke patients and the causal analysis of their impact on three neuropsychological tasks: line bisection, letter cancellation, and bells cancellation. We report that, out of the 11 white matter bundles included in our MSA coalitions, the optic radiations, the inferior fronto-occipital fasciculus and the anterior cingulum were the only tracts to display task-invariant contributions (positive, positive, and negative, respectively) to the tasks. We also report task-dependent influences for the branches of the superior longitudinal fasciculus and the posterior cingulum. By extending prior findings to white matter tracts linking key gray matter nodes, we further characterize from a network perspective the anatomical basis of visual and attentional orienting processes. The knowledge about interactions patterns mediated by white matter tracts linking cortical nodes of attention orienting networks, consolidated by further studies, may help develop and customize brain stimulation approaches for the rehabilitation of visuospatial neglect.

Low frequency transcranial magnetic stimulation of right posterior parietal cortex reduces reaction time to perithreshold low spatial frequency visual stimuli.

Research in humans and animal models suggests that visual responses in early visual cortical areas may be modulated by top-down influences from distant cortical areas, particularly in the frontal and parietal regions. The right posterior parietal cortex is part of a broad cortical network involved in aspects of visual search and attention, but its role in modulating activity in early visual cortical areas is less well understood. This study evaluated the influence of right posterior parietal cortex (PPC) on a direct measure of visual processing in humans. Contrast sensitivity (CS) and detection response times were recorded using a visual detection paradigm to two types of centrally-presented stimuli. Participants were tested on the detection task before, after, and 1 hour after low-frequency repetitive transcranial magnetic stimulation (rTMS) to the right PPC or to the scalp vertex. Low-frequency rTMS to the right PPC did not significantly change measures of contrast sensitivity, but increased the speed at which participants responded to visual stimuli of low spatial frequency. Response times returned to baseline 1-hour after rTMS. These data indicate that low frequency rTMS to the right PPC speeds up aspects of early visual processing, likely due to a disinhibition of the homotopic left posterior parietal cortex.

Past, Present, and Future of Non-invasive Brain Stimulation Approaches to Treat Cognitive Impairment in Neurodegenerative Diseases: Time for a Comprehensive Critical Review.

Low birth rates and increasing life expectancy experienced by developed societies have placed an unprecedented pressure on governments and the health system to deal effectively with the human, social and financial burden associated to aging-related diseases. At present, ∼24 million people worldwide suffer from cognitive neurodegenerative diseases, a prevalence that doubles every five years. Pharmacological therapies and cognitive training/rehabilitation have generated temporary hope and, occasionally, proof of mild relief. Nonetheless, these approaches are yet to demonstrate a meaningful therapeutic impact and changes in prognosis. We here review evidence gathered for nearly a decade on non-invasive brain stimulation (NIBS), a less known therapeutic strategy aiming to limit cognitive decline associated with neurodegenerative conditions. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation, two of the most popular NIBS technologies, use electrical fields generated non-invasively in the brain to long-lastingly enhance the excitability/activity of key brain regions contributing to relevant cognitive processes. The current comprehensive critical review presents proof-of-concept evidence and meaningful cognitive outcomes of NIBS in eight of the most prevalent neurodegenerative pathologies affecting cognition: Alzheimer's Disease, Parkinson's Disease, Dementia with Lewy Bodies, Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia, Corticobasal Syndrome, Progressive Supranuclear Palsy, and Posterior Cortical Atrophy. We analyzed a total of 70 internationally published studies: 33 focusing on Alzheimer's disease, 19 on PPA and 18 on the remaining neurodegenerative pathologies. The therapeutic benefit and clinical significance of NIBS remains inconclusive, in particular given the lack of a sufficient number of double-blind placebo-controlled randomized clinical trials using multiday stimulation regimes, the heterogeneity of the protocols, and adequate behavioral and neuroimaging response biomarkers, able to show lasting effects and an impact on prognosis. The field remains promising but, to make further progress, research efforts need to take in account the latest evidence of the anatomical and neurophysiological features underlying cognitive deficits in these patient populations. Moreover, as the development of in vivo biomarkers are ongoing, allowing for an early diagnosis of these neuro-cognitive conditions, one could consider a scenario in which NIBS treatment will be personalized and made part of a cognitive rehabilitation program, or useful as a potential adjunct to drug therapies since the earliest stages of suh diseases. Research should also integrate novel knowledge on the mechanisms and constraints guiding the impact of electrical and magnetic fields on cerebral tissues and brain activity, and incorporate the principles of information-based neurostimulation.

Perturbation-driven paradoxical facilitation of visuo-spatial function: Revisiting the 'Sprague effect'.

The 'Sprague Effect' described in the seminal paper of James Sprague (Science 153:1544-1547, 1966a) is an unexpected paradoxical effect in which a second brain lesion reversed functional deficits induced by an earlier lesion. It was observed initially in the cat where severe and permanent contralateral visually guided attentional deficits generated by the ablation of large areas of the visual cortex were reversed by the subsequent removal of the superior colliculus (SC) opposite to the cortical lesion or by the splitting of the collicular commissure. Physiologically, this effect has been explained in several ways-most notably by the reduction of the functional inhibition of the ipsilateral SC by the contralateral SC, and the restoration of normal interactions between cortical and midbrain structures after ablation. In the present review, we aim at reappraising the 'Sprague Effect' by critically analyzing studies that have been conducted in the feline and human brain. Moreover, we assess applications of the 'Sprague Effect' in the rehabilitation of visually guided attentional impairments by using non-invasive therapeutic approaches such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (tDCS). We also review theoretical models of the effect that emphasize the inhibition and balancing between the two hemispheres and show implications for lesion inference approaches. Last, we critically review whether the resulting inter-hemispheric rivalry theories lead toward an efficient rehabilitation of stroke in humans. We conclude by emphasizing key challenges in the field of 'Sprague Effect' applications in order to design better therapies for brain-damaged patients.