State-dependent effectiveness of cathodal transcranial direct current stimulation on cortical excitability.

The extensive use of transcranial direct current stimulation (tDCS) in experimental and clinical settings does not correspond to an in-depth understanding of its underlying neurophysiological mechanisms. In previous studies, we employed an integrated system of Transcranial Magnetic Stimulation and Electroencephalography (TMS-EEG) to track the effect of tDCS on cortical excitability. At rest, anodal tDCS (a-tDCS) over the right Posterior Parietal Cortex (rPPC) elicits a widespread increase in cortical excitability. In contrast, cathodal tDCS (c-tDCS) fails to modulate cortical excitability, being indistinguishable from sham stimulation. Here we investigated whether an endogenous task-induced activation during stimulation might change this pattern, improving c-tDCS effectiveness in modulating cortical excitability. In Experiment 1, we tested whether performance in a Visuospatial Working Memory Task (VWMT) and a modified Posner Cueing Task (mPCT), involving rPPC, could be modulated by c-tDCS. Thirty-eight participants were involved in a two-session experiment receiving either c-tDCS or sham during tasks execution. In Experiment 2, we recruited sixteen novel participants who performed the same paradigm but underwent TMS-EEG recordings pre- and 10 min post- sham stimulation and c-tDCS. Behavioral results showed that c-tDCS significantly modulated mPCT performance compared to sham. At a neurophysiological level, c-tDCS significantly reduced cortical excitability in a frontoparietal network likely involved in task execution. Taken together, our results provide evidence of the state dependence of c-tDCS in modulating cortical excitability effectively. The conceptual and applicative implications are discussed.

The Neuropsychological Assessment of Unilateral Spatial Neglect Through Computerized and Virtual Reality Tools: A Scoping Review.

Unilateral Spatial Neglect is a disabling neuropsychological deficit. Patients with spatial neglect fail to detect and report events, and to perform actions in the side of space contralateral to a hemispheric cerebral lesion. Neglect is assessed by evaluating the patients' abilities in daily life activities and by psychometric tests. Computer-based, portable and Virtual Reality technologies may provide more and precise data, and be more sensitive and informative, compared to current paper-and-pencil procedures. Studies since 2010, in which such technologies have been used, are reviewed. Forty-two articles meeting inclusion criteria are categorized according to their technological approaches (computer-, graphics tablet or tablet-, virtual reality-based assessment, and other). The results are promising. However, a definite golden standard, technologically based procedure cannot be still established. Developing technologically based tests is a laborious process, which requires technical and user experience improvements as well as normative data, to increase the evidence of efficacy for clinical evaluation of at least some of the tests considered in this review.

The Semantic Association Test (SAT): normative data from healthy Italian participants and a validation study in aphasic patients.

The Semantic Association Test assesses several aspects of Semantic Memory (Categorical, Encyclopedic, Functional, and Visual Encyclopedic associations: CAs, EAs, FAs and VEAs), using a picture-to-picture matching paradigm. Normative data were collected from a group of 329 healthy participants (178 females) with mean 51.1 (range 20-90) years of age and mean 11.89 (range 5-19) years of education. Raw scores of healthy participants, pre-calculated correction factors for age and educational level, and Equivalent Scores are provided. The SAT was validated in a sample of 139 left brain-damaged persons with aphasia (PWA). Both groups (healthy participants and PWA) scored worse in the CA and EA conditions. The performance of the PWA group was overall defective, and global aphasics scored worse than persons with other types of aphasia. However, several PWA did not show impairments in the SAT. Dissociations were also found, with individual PWA showing defective performance confined to a single category. These results present the SAT as a tool that is useful to detect impairments of visual Semantic Memory, providing normative data from healthy participants and a validation study in PWA.

Abnormal multisensory integration in relapsing-remitting multiple sclerosis.

Temporal Binding Window (TBW) represents a reliable index of efficient multisensory integration process, which allows individuals to infer which sensory inputs from different modalities pertain to the same event. TBW alterations have been reported in some neurological and neuropsychiatric disorders and seem to negatively affects cognition and behavior. So far, it is still unknown whether deficits of multisensory integration, as indexed by an abnormal TBW, are present even in Multiple Sclerosis. We addressed this issue by testing 25 participants affected by relapsing-remitting Multiple Sclerosis (RRMS) and 30 age-matched healthy controls. Participants completed a simultaneity judgment task (SJ2) to assess the audio-visual TBW; two unimodal SJ2 versions were used as control tasks. Individuals with RRMS showed an enlarged audio-visual TBW (width range = from - 166 ms to + 198 ms), as compared to healthy controls (width range = - 177/ + 66 ms), thus showing an increased tendency to integrate temporally asynchronous visual and auditory stimuli. Instead, simultaneity perception of unimodal (visual or auditory) events overall did not differ from that of controls. These results provide first evidence of a selective deficit of multisensory integration in individuals affected by RRMS, besides the well-known motor and cognitive impairments. The reduced multisensory temporal acuity is likely caused by a disruption of the neural interplay between different sensory systems caused by multiple sclerosis.

A novel computerized assessment of manual spatial exploration in unilateral spatial neglect.

Unilateral spatial neglect is a neuropsychological syndrome commonly observed after stroke and defined by the inability to attend or respond to contralesional stimuli. Typically, symptoms are assessed using clinical tests that rely upon visual/perceptual abilities. However, neglect may affect high-level representations controlling attention in other modalities as well. Here we developed a novel manual exploration test using a touch screen computer to quantify spatial search behaviour without visual input. Twelve chronic stroke patients with left neglect and 27 patients without neglect (based on clinical tests) completed our task. Four of the 12 "neglect" patients exhibited clear signs of neglect on our task as compared to "non-neglect" patients and healthy controls, and six other patients (from both groups) also demonstrated signs of neglect compared to healthy controls only. While some patients made asymmetrical responses on only one task, generally, patients with the strongest neglect performed poorly on multiple tasks. This suggests that representations associated with different modalities may be affected separately, but that severe forms of neglect are more likely related to damage in a common underlying representation. Our manual exploration task is easy to administer and can be added to standard neglect screenings to better measure symptom severity.

Explicit motor sequence learning after stroke: a neuropsychological study.

Motor learning interacts with and shapes experience-dependent cerebral plasticity. In stroke patients with paresis of the upper limb, motor recovery was proposed to reflect a process of re-learning the lost/impaired skill, which interacts with rehabilitation. However, to what extent stroke patients with hemiparesis may retain the ability of learning with their affected limb remains an unsolved issue, that was addressed by this study. Nineteen patients, with a cerebrovascular lesion affecting the right or the left hemisphere, underwent an explicit motor learning task (finger tapping task, FTT), which was performed with the paretic hand. Eighteen age-matched healthy participants served as controls. Motor performance was assessed during the learning phase (i.e., online learning), as well as immediately at the end of practice, and after 90 min and 24 h (i.e., retention). Results show that overall, as compared to the control group, stroke patients, regardless of the side (left/right) of the hemispheric lesion, do not show a reliable practice-dependent improvement; consequently, no retention could be detected in the long-term (after 90 min and 24 h). The motor learning impairment was associated with subcortical damage, predominantly affecting the basal ganglia; conversely, it was not associated with age, time elapsed from stroke, severity of upper-limb motor and sensory deficits, and the general neurological condition. This evidence expands our understanding regarding the potential of post-stroke motor recovery through motor practice, suggesting a potential key role of basal ganglia, not only in implicit motor learning as previously pointed out, but also in explicit finger tapping motor tasks.

Rivermead assessment of somatosensory performance: Italian normative data.

The Rivermead assessment of somatosensory performance (RASP) provides a quantitative assessment of somatosensory processing, suitable for brain-damaged patients suffering from stroke. It consists of seven subcomponents: Subtest 1 (sharp/dull discrimination), Subtest 2 (surface pressure touch), Subtest 3 (surface localization), Subtest 4 (sensory extinction), Subtest 5 (2-point discrimination), Subtest 6 (temperature discrimination), and Subtest 7 (proprioception). Overall, the RASP assesses 5 bilateral body regions: face (cheek), hand (palm and back), and foot (sole and back). This study aimed at providing normative data and cut-off scores for RASP subtests, for each body region, in a large Italian population sample. We present results from 300 healthy Italian individuals aged 19 to 98 years. Data represent a comprehensive set of norms that cover each subtest and each body region tested. Performance in Subtests 1, 5, and 6 decreased, for some body regions, with increasing age. Based on these results, norms were stratified for age (seven groups), with the pathological/non-pathological cut-off coinciding with the 5th percentile. Conversely, other results were not influenced by age; in such cases, a single error, in each body region, has to be considered indicative of pathological performance. This independent investigation of all subcomponents of the somatosensory system, for each body region, further confirms RASP's potential in clinical practice, for neurological assessment, as well as in research settings.

The Brentano Illusion Test (BRIT): An implicit task of perceptual processing for the assessment of visual field defects in neglect patients.

In brain damaged patients with unilateral spatial neglect (USN), the differential diagnosis between the presence and absence of a unilateral visual half-field deficit (VHFD) is hampered by the similarity of their phenomenology. The absence of stimuli detection in the contralateral visual field, indeed, can be due to the co-occurrence of USN and VHFD or the sole presence of the USN. The disentangling of the two conditions is required to devise more specific rehabilitation programmes. Daini et al. [2002. Exploring the syndrome of spatial unilateral neglect through an illusion of length. Experimental Brain Research, 144(2), 224-237.] reported a difference in performance for the two conditions when the tasks required the bisection of Brentano illusory stimuli. Only when USN and VHFD co-occurred, the leftward illusory effect was disrupted. Based on previous findings, in this cross-sectional study, we developed the Brentano Illusion Test (BRIT), a clinical tool that helps the identification of VHFD in USN patients. The BRIT is a simple behavioural test of line bisection aimed at verifying the presence or absence of implicit processing in USN and thus helping the diagnosis of VHFD in USN patients; it also provides normative data for the line bisection task and the length effect.

Multisensory stimulation for the rehabilitation of unilateral spatial neglect.

Unilateral spatial neglect (USN) is a neuropsychological syndrome, typically caused by lesions of the right hemisphere, whose features are the defective report of events occurring in the left (contralesional) side of space and the inability to orient and set up actions leftwards. Multisensory integration mechanisms, largely spared in USN patients, may temporally modulate spatial orienting. In this pilot study, the effects of an intensive audio-visual Multisensory Stimulation (MS) on USN were assessed, and compared with those of a treatment that ameliorates USN, Prismatic Adaptation (PA). Twenty USN stroke patients received a 2-week treatment (20 sessions, twice per day) of MS or PA. The effects of MS and PA were assessed by a set of neuropsychological clinical tests (target cancellation, line bisection, sentence reading, personal neglect, complex drawing) and the Catherine Bergego Scale for functional disability. Results showed that MS brought about an amelioration of USN deficits overall comparable to that induced by PA; personal neglect was improved only by MS, not by PA. The clinical gains of the MS treatment were not influenced by duration of disease and lesion volume, and they persisted up to one month post-treatment. In conclusion, MS represents a novel and promising rehabilitation procedure for USN.

Adaptation aftereffects reveal that tactile distance is a basic somatosensory feature.

The stage at which processing of tactile distance occurs is still debated. We addressed this issue by implementing an adaptation-aftereffect paradigm with passive touch. We demonstrated the presence of a strong aftereffect, induced by the simultaneous presentation of pairs of tactile stimuli. After adaptation to two different distances, one on each hand, participants systematically perceived a subsequent stimulus delivered to the hand adapted to the smaller distance as being larger. We further investigated the nature of the aftereffects, demonstrating that they are orientation- and skin-region-specific, occur even when just one hand is adapted, do not transfer either contralaterally or across the palm and dorsum, and are defined in a skin-centered, rather than an external, reference frame. These characteristics of tactile distance aftereffects are similar to those of low-level visual aftereffects, supporting the idea that distance perception arises at early stages of tactile processing.

Somatosensory cortical representation of the body size.

The knowledge of the size of our own body parts is essential for accurately moving in space and efficiently interact with objects. A distorted perceptual representation of the body size often represents a core diagnostic criterion for some psychopathological conditions. The metric representation of the body was shown to depend on somatosensory afferences: local deafferentation indeed causes a perceptual distortion of the size of the anesthetized body part. A specular effect can be induced by altering the cortical map of body parts in the primary somatosensory cortex. Indeed, the present study demonstrates, in healthy adult participants, that repetitive Transcranial Magnetic Stimulation to the somatosensory cortical map of the hand in both hemispheres causes a perceptual distortion (i.e., an overestimation) of the size of the participants' own hand (Experiments 1-3), which does not involve other body parts (i.e., the foot, Experiment 2). Instead, the stimulation of the inferior parietal lobule of both hemispheres does not affect the perception of the own body size (Experiment 4). These results highlight the role of the primary somatosensory cortex in the building up and updating of the metric of body parts: somatosensory cortical activity not only shapes our somatosensation, it also affects how we perceive the dimension of our body.

"How Did I Make It?": Uncertainty about Own Motor Performance after Inhibition of the Premotor Cortex.

Optimal motor performance requires the monitoring of sensorimotor input to ensure that the motor output matches current intentions. The brain is thought to be equipped with a "comparator" system, which monitors and detects the congruence between intended and actual movement; results of such a comparison can reach awareness. This study explored in healthy participants whether the cathodal transcranial direct current stimulation (tDCS) of the right premotor cortex (PM) and right posterior parietal cortex (PPC) can disrupt performance monitoring in a skilled motor task. Before and after tDCS, participants underwent a two-digit sequence motor task; in post-tDCS session, single-pulse TMS (sTMS) was applied to the right motor cortex, contralateral to the performing hand, with the aim of interfering with motor execution. Then, participants rated on a five-item questionnaire their performance at the motor task. Cathodal tDCS of PM (but not sham or PPC tDCS) impaired the participants' ability to evaluate their motor performance reliably, making them unconfident about their judgments. Congruently with the worsened motor performance induced by sTMS, participants reported to have committed more errors after sham and PPC tDCS; such a correlation was not significant after PM tDCS. In line with current computational and neuropsychological models of motor control and awareness, the present results show that a mechanism in the PM monitors and compares intended versus actual movements, evaluating their congruence. Cathodal tDCS of the PM impairs the activity of such a "comparator," disrupting self-confidence about own motor performance.

Improving ideomotor limb apraxia by electrical stimulation of the left posterior parietal cortex.

Limb apraxia, a deficit of planning voluntary gestures, is most frequently caused by damage to the left hemisphere, where, according to an influential neurofunctional model, gestures are planned, before being executed through the motor cortex of the hemisphere contralateral to the acting hand. We used anodal transcranial direct current stimulation delivered to the left posterior parietal cortex (PPC), the right motor cortex (M1), and a sham stimulation condition, to modulate the ability of six left-brain-damaged patients with ideomotor apraxia, and six healthy control subjects, to imitate hand gestures, and to perform skilled hand movements using the left hand. Transcranial direct current stimulation delivered to the left PPC reduced the time required to perform skilled movements, and planning, but not execution, times in imitating gestures, in both patients and controls. In patients, the amount of decrease of planning times brought about by left PPC transcranial direct current stimulation was influenced by the size of the parietal lobe damage, with a larger parietal damage being associated with a smaller improvement. Of interest from a clinical perspective, left PPC stimulation also ameliorated accuracy in imitating hand gestures in patients. Instead, transcranial direct current stimulation to the right M1 diminished execution, but not planning, times in both patients and healthy controls. In conclusion, by using a transcranial stimulation approach, we temporarily improved ideomotor apraxia in the left hand of left-brain-damaged patients, showing a role of the left PPC in planning gestures. This evidence opens up novel perspectives for the use of transcranial direct current stimulation in the rehabilitation of limb apraxia.

Italian neuropsychology in the second half of the twentieth century.

Since the early 1960s, human neuropsychology, the study of brain-behavior interrelations, mainly based on the analysis of their pathological variations, brought about by brain damage, has had a remarkable systematical development in Italy. All this started in Milan, with the neurologist Ennio de Renzi, and his collaborators (Luigi Vignolo, then Anna Basso, Pietro Faglioni, Hans Spinnler, François Boller, and, more autonomously, Edoardo Bisiach), in the Clinic of Nervous and Mental Diseases. Scientists of the "Milan group" investigated several neuropsychological deficits caused by focal hemispheric lesions in large series of left- and right-brain-damaged patients, and control participants, comparable for cultural and demographic variables. Standardized tests and advanced statistical methods were used, which also applied to the diagnosis and rehabilitation of aphasia. Subsequently, neuropsychology developed in Italy extensively, reaching high international reputation. Leading neuropsychologists have been the neurologists Guido Gainotti (Rome), and Franco Denes (Padua), the physicians and psychologists Luigi Pizzamiglio (Rome), and Carlo Umiltà (Parma, with fruitful interactions with the neurophysiologists Giovanni Berlucchi, Giacomo Rizzolatti, and Carlo Marzi, from the school of Giuseppe Moruzzi in Pisa) A second scientific generation of neuropsychologists has then developed in the 1970s, trained by the abovementioned scientists, further boosting and spreading high-level basic and applied research (diagnosis and rehabilitation of neuropsychological deficits of patients with brain damage or dysfunction throughout the life span, from childhood to the elderly). Available techniques include structural and functional imaging (CT, PET, SPET, MRI and fMRI Scans, DTI), electrophysiological recording (EEG, ERPs), non-invasive brain stimulation (TMS, tES), and their combined use.

Understanding others' feelings: the role of the right primary somatosensory cortex in encoding the affective valence of others' touch.

Brain imaging studies in humans have shown the existence of a shared somatosensory representation in the primary somatosensory cortex (S1), putatively involved in understanding others' sensations (Keysers et al., 2010); however, the role of S1 in such a high-level process is still unknown. To ascertain the causal involvement of S1, and its possible hemispheric lateralization, in encoding the affective valence of emotional scenes, depicting, or not, a tactile event, we gave to healthy participants a picture-based affective go/no-go task and low-frequency repetitive transcranial magnetic stimulation (rTMS). The dorsolateral prefrontal cortex (DLPFC) was chosen as control site. rTMS over the right, but not the left, S1 selectively increased the participants' latencies in the affective go/no-go task, but only when the affective state was conveyed by touch; intriguingly, this interfering effect was associated with the empathic ability to adopt the subjective perspective of others. The left, not the right, DLPFC is also involved in affective go/no-go performance, but regardless of the sight of touch, and independently of empathic abilities. This novel evidence demonstrates the crossmodal role of right S1 in encoding the pleasant and aversive consequences of others' sensations evoked by touch.

A neurocomputational analysis of the sound-induced flash illusion.

Perception of the external world is based on the integration of inputs from different sensory modalities. Recent experimental findings suggest that this phenomenon is present in lower-level cortical areas at early processing stages. The mechanisms underlying these early processes and the organization of the underlying circuitries are still a matter of debate. Here, we investigate audiovisual interactions by means of a simple neural network consisting of two layers of visual and auditory neurons. We suggest that the spatial and temporal aspects of audio-visual illusions can be explained within this simple framework, based on two main assumptions: auditory and visual neurons communicate via excitatory synapses; and spatio-temporal receptive fields are different in the two modalities, auditory processing exhibiting a higher temporal resolution, while visual processing a higher spatial acuity. With these assumptions, the model is able: i) to simulate the sound-induced flash fission illusion; ii) to reproduce psychometric curves assuming a random variability in some parameters; iii) to account for other audio-visual illusions, such as the sound-induced flash fusion and the ventriloquism illusions; and iv) to predict that visual and auditory stimuli are combined optimally in multisensory integration. In sum, the proposed model provides a unifying summary of spatio-temporal audio-visual interactions, being able to both account for a wide set of empirical findings, and be a framework for future experiments. In perspective, it may be used to understand the neural basis of Bayesian audio-visual inference.

Cerebral correlates of visuospatial neglect: a direct cerebral stimulation study.

OBJECTIVE: To assess the role of the superior longitudinal fascicle, the inferior fronto-occipital fascicle, and the posterior parietal lobe in visuospatial attention in humans during awake brain surgery. EXPERIMENTAL DESIGN: Seven patients with hemispheric gliomas (six in the right hemisphere) entered the study. During surgery in asleep/awake anesthesia, guided by Diffusion Tensor Imaging Fiber Tractography, visuospatial neglect was assessed during direct electrical stimulation by computerized line bisection. PRINCIPAL OBSERVATIONS: A rightward deviation, indicating left visuospatial neglect, was induced in six of seven patients by stimulation of the parietofrontal connections, in a location consistent with the trajectory of the second branch of the superior longitudinal fascicle. Stimulation of the medial and dorsal white matter of the superior parietal lobule (corresponding to the first branch of the superior longitudinal fascicle), of the ventral and lateral white matter of the supramarginal gyrus (corresponding to the third branch of the superior longitudinal fascicle), and of the inferior occipitofrontal fasciculus, was largely ineffective. Stimulation of the superior parietal lobule (Brodmann's area 7) caused a marked rightward deviation in all of the six assessed patients, while stimulation of Brodmann's areas 5 and 19 was ineffective. CONCLUSIONS: The parietofrontal connections of the dorso-lateral fibers of the superior longitudinal fascicle (i.e., the second branch of the fascicle), and the posterior superior parietal lobe (Brodmann's area 7) are involved in the orientation of spatial attention. Spatial neglect should be assessed systematically during awake brain surgery, particularly when the right parietal lobe may be involved by the neurosurgical procedure.

Line and word bisection in right-brain-damaged patients with left spatial neglect.

Right-brain-damaged patients with left unilateral spatial neglect typically set the mid-point of horizontal lines to the right of the objective center. By contrast, healthy participants exhibit a reversed bias (pseudoneglect). The same effect has been described also when bisecting orthographic strings. In particular, for this latter kind of stimulus, some recent studies have shown that visuo-perceptual characteristics, like stimulus length, may contribute to both the magnitude and the direction bias of the bisection performance (Arduino et al. in Neuropsychologia 48:2140-2146, 2010). Furthermore, word stress was shown to modulate reading performances in both healthy participants, and patients with left spatial neglect and neglect dyslexia (Cubelli and Beschin in Brain Lang 95:319-326, 2005; Rusconi et al. in Neuropsychology 18:135-140, 2004). In Experiment I, 22 right-brain-damaged patients (11 with left visuo-spatial neglect) and 11 matched neurologically unimpaired control participants were asked to set the subjective mid-point of word letter strings, and of lines of comparable length. Most patients exhibited an overall disproportionate rightward bias, sensitive to stimulus length, and similar for words and lines. Importantly, in individual patients, biases differed according to stimulus type (words vs. lines), indicating that at least partly different mechanisms may be involved. In Experiment II, the putative effects on the bisection bias of ortho-phonological information (i.e., word stress endings), arising from the non-neglected right hand side of the stimulus were investigated. The orthographic cue induced a rightward shift of the perceived mid-point in both patients and controls, with short words stressed on the antepenultimate final sequence inducing a smaller rightward deviation with respect to short words stressed on the penultimate final sequence. In conclusion, partly different mechanisms, including both visuo-spatial and lexical factors, may support line and word bisection performance of right-brain-damaged patients with left spatial neglect, and healthy participants.

Neuromodulation of early multisensory interactions in the visual cortex.

Merging information derived from different sensory channels allows the brain to amplify minimal signals to reduce their ambiguity, thereby improving the ability of orienting to, detecting, and identifying environmental events. Although multisensory interactions have been mostly ascribed to the activity of higher-order heteromodal areas, multisensory convergence may arise even in primary sensory-specific areas located very early along the cortical processing stream. In three experiments, we investigated early multisensory interactions in lower-level visual areas, by using a novel approach, based on the coupling of behavioral stimulation with two noninvasive brain stimulation techniques, namely, TMS and transcranial direct current stimulation (tDCS). First, we showed that redundant multisensory stimuli can increase visual cortical excitability, as measured by means of phosphene induction by occipital TMS; such physiological enhancement is followed by a behavioral facilitation through the amplification of signal intensity in sensory-specific visual areas. The more sensory inputs are combined (i.e., trimodal vs. bimodal stimuli), the greater are the benefits on phosphene perception. Second, neuroelectrical activity changes induced by tDCS in the temporal and in the parietal cortices, but not in the occipital cortex, can further boost the multisensory enhancement of visual cortical excitability, by increasing the auditory and tactile inputs from temporal and parietal regions, respectively, to lower-level visual areas.