Coherent activity within and between hemispheres: cortico-cortical connectivity revealed by rTMS of the right posterior parietal cortex.

Introduction: Low frequency (1 Hz) repetitive transcranial stimulation (rTMS) applied over right posterior parietal cortex (rPPC) has been shown to reduce cortical excitability both of the stimulated area and of the interconnected contralateral homologous areas. In the present study, we investigated the whole pattern of intra- and inter-hemispheric cortico-cortical connectivity changes induced by rTMS over rPPC. Methods: To do so, 14 healthy participants underwent resting state EEG recording before and after 30 min of rTMS at 1 Hz or sham stimulation over the rPPC (electrode position P6). Real stimulation was applied at 90% of motor threshold. Coherence values were computed on the electrodes nearby the stimulated site (i.e., P4, P8, and CP6) considering all possible inter- and intra-hemispheric combinations for the following frequency bands: delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12Hz), low beta (12-20 Hz), high beta (20-30 Hz), and gamma (30-50 Hz). Results and discussion: Results revealed a significant increase in coherence in delta, theta, alpha and beta frequency bands between rPPC and the contralateral homologous sites. Moreover, an increase in coherence in theta, alpha, beta and gamma frequency bands was found between rPPC and right frontal sites, reflecting the activation of the fronto-parietal network within the right hemisphere. Summarizing, subthreshold rTMS over rPPC revealed cortico-cortical inter- and intra-hemispheric connectivity as measured by the increase in coherence among these areas. Moreover, the present results further confirm previous evidence indicating that the increase of coherence values is related to intra- and inter-hemispheric inhibitory effects of rTMS. These results can have implications for devising evidence-based rehabilitation protocols after stroke.

Motor Pathways Reorganization following Surgical Decompression for Degenerative Cervical Myelopathy: A Combined Navigated Transcranial Magnetic Stimulation and Clinical Outcome Study.

(1) Background: Degenerative cervical myelopathy is one of the main causes of disability in the elderly. The treatment of choice in patients with clear symptomatology and radiological correlation is surgical decompression. The application of navigated transcranial magnetic stimulation (nTMS) techniques has the potential to provide additional insights into the cortical and corticospinal behavior of the myelopathic cord and to better characterize the possible extent of clinical recovery. The objective of our study was to use nTMS to evaluate the effect of surgical decompression on neurophysiological properties at the cortical and corticospinal level and to better characterize the extent of possible clinical recovery. (2) Methods: We conducted a longitudinal study in which we assessed and compared nTMS neurophysiological indexes and clinical parameters (modified Japanese Orthopedic Association score and nine-hole pegboard test) before surgery, at 6 months, and at 12 months' follow-up in a population of 15 patients. (3) Results: We found a significant reduction in resting motor threshold (RMT; average 7%), cortical silent period (CSP; average 15%), and motor area (average 25%) at both 6 months and 12 months. A statistically significant linear correlation emerged between recruitment curve (RC) values obtained at follow-up appointments and at baseline (r = 0.95 at 6 months, r = 0.98 at 12 months). A concomitant improvement in the mJOA score and in the nine-hole pegboard task was observed after surgery. (4) Conclusions: Our results suggest that surgical decompression of the myelopathic spinal cord improves the neurophysiological balance at the cortical and corticospinal level, resulting in clinically significant recovery. Such findings contribute to the existing evidence characterizing the brain and the spinal cord as a dynamic system capable of functional and reversible plasticity and provide useful clinical insights to be used for patient counseling.

Influence of frontal-to-parietal connectivity in pseudoneglect: A cortico-cortical paired associative stimulation study.

Pseudoneglect is a set of visuospatial biases that entails a behavioral advantage for stimuli appearing in the left hemifield compared to the right one. Although right hemisphere dominance for visuospatial processing has been invoked to explain this phenomenon, its neurophysiological mechanisms are still debated, and the role of intra- and inter-hemispheric connectivity is yet to be defined. The present study explored the possibility of modulating pseudoneglect in healthy participants through a cortico-cortical paired associative stimulation protocol (ccPAS): a non-invasive brain stimulation protocol that manipulates the interplay between brain regions through the repeated, time-locked coupling of two transcranial magnetic stimulation (TMS) pulses. In the first experiment, healthy participants underwent a frontal-to-parietal (FP) and a parietal-to-frontal (PF) ccPAS. In the FP protocol, the first TMS pulse targeted the right frontal eye field (FEF), and the second pulse the right inferior parietal lobule (IPL), two critical areas for visuospatial and attentional processing. In the PF condition, the order of the pulses was reversed. In both protocols, the inter-stimulus interval (ISI) was 10 ms. Before and after stimulation, pseudoneglect was assessed with a landmark task and a manual line bisection task. A second experiment controlled for ccPAS timing dependency by testing FP-ccPAS with a longer ISI of 100 ms. Results showed that after administering the FP-ccPAS with the ISI of 10 ms, participants' leftward bias in the landmark task increased significantly, with no effects in the manual line bisection task. The other two protocols tested were ineffective. Our findings showed that ccPAS could be used to modulate pseudoneglect by exploiting frontal-to-parietal connectivity, possibly through increased top-down attentional control. FP-ccPAS could represent a promising tool to investigate connectivity properties within visuospatial and attentional networks in the healthy and as a potential rehabilitation protocol in patients suffering from severe visuospatial pathologies.

Opposite pattern of transcranial direct current stimulation effects in middle-aged and older adults: Behavioral and neurophysiological evidence.

Introduction: Episodic memory (EM) exhibits an age-related decline, with overall increased impairment after the age of 65. The application of transcranial direct current stimulation (tDCS) to ameliorate cognitive decline in ageing has been extensively investigated, but its efficacy has been reported with mixed results. In this study, we aimed to assess whether age contributes to interindividual variability in tDCS efficacy. Methods: Thirty-eight healthy adults between 50 and 81 years old received anodal tDCS over the left prefrontal cortex during images encoding and then performed an EM recognition task while event-related potentials (ERPs) were recorded. Results: Our results showed an opposite pattern of effect between middle-aged (50-64 years) and older (65-81 years) adults. Specifically, performance in the recognition task after tDCS was enhanced in older adults and was worsened in middle-aged adults. Moreover, ERPs acquired during the recognition task showed that two EM components related to familiarity and post-retrieval monitoring, i.e., Early Frontal and Late Frontal Old-New effects, respectively, were significantly reduced in middle-aged adults after anodal tDCS. Discussion: These results support an age-dependent effect of prefrontal tDCS on EM processes and its underlying electrophysiological substrate, with opposing modulatory trajectories along the aging lifespan.

Connectivity alterations underlying the breakdown of pseudoneglect: New insights from healthy and pathological aging.

A right-hemisphere dominance for visuospatial attention has been invoked as the most prominent neural feature of pseudoneglect (i.e., the leftward visuospatial bias exhibited in neurologically healthy individuals) but the neurophysiological underpinnings of such advantage are still controversial. Previous studies investigating visuospatial bias in multiple-objects visual enumeration reported that pseudoneglect is maintained in healthy elderly and amnesic mild cognitive impairment (aMCI), but not in Alzheimer's disease (AD). In this study, we aimed at investigating the neurophysiological correlates sustaining the rearrangements of the visuospatial bias along the progression from normal to pathological aging. To this aim, we recorded EEG activity during an enumeration task and analyzed intra-hemispheric fronto-parietal and inter-hemispheric effective connectivity adopting indexes from graph theory in patients with mild AD, patients with aMCI, and healthy elderly controls (HC). Results revealed that HC showed the leftward bias and stronger fronto-parietal effective connectivity in the right as compared to the left hemisphere. A breakdown of pseudoneglect in patients with AD was associated with both the loss of the fronto-parietal asymmetry and the reduction of inter-hemispheric parietal interactions. In aMCI, initial alterations of the attentional bias were associated with a reduction of parietal inter-hemispheric communication, but not with modulations of the right fronto-parietal connectivity advantage, which remained intact. These data provide support to the involvement of fronto-parietal and inter-parietal pathways in the leftward spatial bias, extending these notions to the complex neurophysiological alterations characterizing pathological aging.

Functional Imaging to Guide Network-Based TMS Treatments: Toward a Tailored Medicine Approach in Alzheimer's Disease.

A growing number of studies is using fMRI-based connectivity to guide transcranial magnetic stimulation (TMS) target identification in both normal and clinical populations. TMS has gained increasing attention as a potential therapeutic strategy also in Alzheimer's disease (AD), but an endorsed target localization strategy in this population is still lacking. In this proof of concept study, we prove the feasibility of a tailored TMS targeting approach for AD, which stems from a network-based perspective. Based on functional imaging, the procedure allows to extract individual optimal targets meanwhile accounting for functional variability. Single-subject resting-state fMRI was used to extract individual target coordinates of two networks primarily affected in AD, the default mode and the fronto-parietal network. The localization of these targets was compared to that of traditional group-level approaches and tested against varying degrees of TMS focality. The distance between individual fMRI-derived coordinates and traditionally defined targets was significant for a supposed TMS focality of 12 mm and in some cases up to 20 mm. Comparison with anatomical labels confirmed a lack of 1:1 correspondence between anatomical and functional targets. The proposed network-based fMRI-guided TMS approach, while accounting for inter-individual functional variability, allows to target core AD networks, and might thus represent a step toward tailored TMS interventions for AD.

Enhancing cognitive training effects in Alzheimer's disease: rTMS as an add-on treatment.

The treatment of Alzheimer's disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning. The present study provides important hints on the promising therapeutic use of rTMS in AD.

Predicting Alzheimer's disease severity by means of TMS-EEG coregistration.

Clinical manifestations of Alzheimer's disease (AD) are associated with a breakdown in large-scale communication, such that AD may be considered as a "disconnection syndrome." An established method to test effective connectivity is the combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) because the TMS-induced cortical response propagates to distant anatomically connected regions. To investigate whether prefrontal connectivity alterations may predict disease severity, we explored the relationship of dorsolateral prefrontal cortex connectivity (derived from TMS-EEG) with cognitive decline (measured with Mini Mental State Examination and a face-name association memory task) in 26 patients with AD. The amplitude of TMS-EEG evoked component P30, which was found to be generated in the right superior parietal cortex, predicted Mini Mental State Examination and face-name memory scores: higher P30 amplitudes predicted poorer cognitive and memory performances. The present results indicate that advancing disease severity might be associated with effective connectivity increase involving long-distance frontoparietal connections, which might represent a maladaptive pathogenic mechanism reflecting a damaged excitatory-inhibitory balance between anterior and posterior regions.

Pseudoneglect is maintained in aging but not in mild Alzheimer's disease: new insights from an enumeration task.

Neurologically healthy young adults display a behavioral bias, called pseudoneglect, which favors the processing of stimuli appearing in the left visual field. Pseudoneglect arises from the right hemisphere dominance for visuospatial attention. Previous studies investigating the effects of normal aging on pseudoneglect in line bisection and greyscale tasks have produced divergent results. In addition, scarce systematic investigations of visual biases in dementia have been reported. The aim of the present study was to evaluate whether the leftward bias appearing during an enumeration task in young adults would be preserved in normal aging and at different stages of severity of Alzheimer's disease. In Experiment 1, young and older healthy adults showed a comparable pseudoneglect, performing better when targets appeared in the left visual field. In Experiment 2, the leftward bias was maintained in amnesic mild cognitive impairment patients (aMCI), but it vanished in mild Alzheimer's disease patients (AD). The maintenance of pseudoneglect in normal aging and in aMCI patients is consistent with compensatory phenomena involving the right fronto-parietal network, which allow maintaining the right hemisphere dominance. Conversely, the lack of pseudoneglect in the sample of AD patients likely results from a loss of the right hemisphere dominance, caused by the selective degeneration of the right fronto-parietal network. These results highlight the need of further systematic investigations of visuospatial biases along the continuum of normal and pathological aging, both for a better understanding of the changes characterizing cognitive aging and for improvements in the evaluation of neglect in Alzheimer's disease.

Safe return to driving following severe acquired brain injury: role of a short neuropsychological assessment.

BACKGROUND: Driving is a complex ability requiring a broad range of motor, cognitive-behavioral and visual skills that may be impaired after severe acquired brain injury (sABI). Resumption of driving is perceived as a major need by patients, being closely linked to personal autonomy, work and social activities. AIM: The objective of this study was to identify a short battery of neuropsychological tests with predictive value with regard to safe return to driving after sABI. DESIGN: Observational study. SETTING: Outpatient of a rehabilitation center for sABI. POPULATION: A continuous series of 127 patients with stable sABI, well-reintegrated at a family and social level, dismissed since at least one year from the end of their intensive rehabilitation, enrolled between 2006 and 2014. METHODS: Patients underwent an extensive battery of neuropsychological tests (pencil and paper and specific PC programs), aimed at assessing cognitive functions, in performance and verbal tasks. The results were analyzed in relation to their on-road performance during the driving test conducted by the office of the Italian Government Authority (success or failure of the test). RESULTS: No correlations were found between demographic data, etiology, driving experience, verbal competence and the decision of the competent authority. Significant correlation was found between attention, executive functions, overall visual-spatial exploration and driving performance. CONCLUSIONS: Both "pencil and paper" and computerized tests in the cognitive domains of attentive functions, and those involving performance with visual-spatial material, are significantly correlated with the driving test outcome, even if there is not enough evidence of the relative value of off-road compared to direct on-road tests. CLINICAL REHABILITATION IMPACT: We propose a small neuropsychological battery of tests with normative data for Italian population, predictive with respect to the ability to drive safely. We recommend to use it as first screening before submitting patients to more demanding and risky on-road driving tests.

Neural Dynamics of Multiple Object Processing in Mild Cognitive Impairment and Alzheimer's Disease: Future Early Diagnostic Biomarkers?

The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event-related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology.

Blind-Sight vs. Degraded-Sight: Different Measures Tell a Different Story.

Blindsight patients can detect, localize, and discriminate visual stimuli in their blind field, despite denying being able to see the stimuli. However, the literature documents the cases of blindsight patients who demonstrated a preserved degree of awareness in their impaired visual field. The aim of this study is to investigate the nature of visual processing within the impaired visual field and to ask whether it reflects pure unconscious behavior or conscious, yet degraded, vision. A hemianopic patient (SL) with a complete lesion to the left primary visual cortex was tested. SL was asked to discriminate several stimulus features (orientation, color, contrast, and motion) presented in her impaired visual field in a two-alternative forced-choice task. SL had to report her subjective experience: in the first experiment as "seen" or "guessed," whereas in the second experiment as the degree of clarity of her experience according to the perceptual awareness scale. In the first experiment, SL demonstrated a performance above-chance in the discrimination task for "guessed" trials, thus showing type 1 blindsight. In the second experiment, however, SL showed above-chance performance only when she reported a certain degree of awareness, thus showing that SL's preserved discrimination ability relies on conscious vision. These data show that graded measures to assess awareness, which can better tap on the complexity of conscious experience, need to be used in order to differentiate genuine forms of blindsight from degraded conscious vision.

Early Local Activity in Temporal Areas Reflects Graded Content of Visual Perception.

In visual cognitive neuroscience the debate on consciousness is focused on two major topics: the search for the neural correlates of the different properties of visual awareness and the controversy on the graded versus dichotomous nature of visual conscious experience. The aim of this study is to search for the possible neural correlates of different grades of visual awareness investigating the Event Related Potentials to reduced contrast visual stimuli whose perceptual clarity was rated on the four-point Perceptual Awareness Scale. Results revealed a left centro-parietal negative deflection (Visual Awareness Negativity; VAN) peaking at 280-320 ms from stimulus onset, related to the perceptual content of the stimulus, followed by a bilateral positive deflection (Late Positivity; LP) peaking at 510-550 ms over almost all electrodes, reflecting post-perceptual processes performed on such content. Interestingly, the amplitude of both deflections gradually increased as a function of visual awareness. Moreover, the intracranial generators of the phenomenal content (VAN) were found to be located in the left temporal lobe. The present data thus seem to suggest (1) that visual conscious experience is characterized by a gradual increase of perceived clarity at both behavioral and neural level and (2) that the actual content of perceptual experiences emerges from early local activation in temporal areas, without the need of later widespread frontal engagement.

No causal effect of left hemisphere hyperactivity in the genesis of neglect-like behavior.

Spatial neglect is traditionally explained as an imbalance of the interhemispheric reciprocal inhibition exerted by the two hemispheres: after a right lesion, the contralesional hemisphere becomes disinhibited and its enhanced activity suppresses the activity in the lesioned one. Even though the hyperexcitability of the left hemisphere is the theoretical framework of several rehabilitation interventions using non-invasive brain stimulation protocols in neglect, no study has yet investigated directly the actual state of cortical excitability of the contralesional hemisphere immediately after the brain lesion. The present study represents the first attempt to directly assess the interhemispheric rivalry model adopting a novel approach based on the induction of neglect-like biases in healthy participants. Applying repetitive transcranial magnetic stimulation (rTMS) over the right posterior parietal cortex while concurrently recording the EEG activity allows to measure specific neurophysiological markers of cortical activity (i.e. TMS-evoked potentials, TEPs) both over the stimulated right hemisphere and over the contralateral homologous area. Besides the effectiveness of the protocol used in modulating behavior, our results show an inhibition of the cortical excitability of the directly stimulated parietal cortex (right hemisphere) and, most importantly, a comparable reduction of cortical excitability of the homologous contralateral (left) area. TEPs and additional electrophysiological measures reliably provide strong evidence for a bilateral hypo-activation following TMS induction of neglect-like biases. These results suggest that the parietal imbalance typically found in neglect patients could reflect a long-term maladaptive plastic reorganization that follows a brain lesion.

Waves of awareness for occipital and parietal phosphenes perception.

Transcranial magnetic stimulation (TMS) of the occipital cortex is known to induce visual sensations, i.e. phosphenes, which appear as flashes of light in the absence of an external stimulus. Recent studies have shown that TMS can produce phosphenes also when the intraparietal sulcus (IPS) is stimulated. The main question addressed in this paper is whether parietal phosphenes are generated directly by local mechanisms or emerge through indirect activation of other visual areas. Electroencephalographic (EEG) signals were recorded while stimulating left occipital or parietal cortices inducing phosphene perception in healthy participants and in a hemianopic patient who suffered from complete destruction of the early visual cortex of the left hemisphere. Results in healthy participants showed that the onset of phosphene perception induced by occipital TMS correlated with differential cortical activity in temporal sites while the onset of phosphene perception induced by parietal TMS correlated with differential cortical activity in the stimulated parietal site. Moreover, IPS-TMS of the lesioned hemisphere of the hemianopic patient with a complete lesion to V1 showed again that the onset of phosphene perception correlated with differential cortical activity in the stimulated parietal site. The present data seem thus to suggest that temporal and parietal cortices can serve as different local early gatekeepers of perceptual awareness and that activity in the occipital cortex, although being relevant for perception in general, is not part of the neural bases of the perceptual awareness of phosphenes.