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.

Validation of "Neurit.Space": Three Digital Tests for the Neuropsychological Evaluation of Unilateral Spatial Neglect.

Patients suffering from Unilateral Spatial Neglect (USN) fail to pay attention to, respond to, and report sensory events occurring in the contralesional side of space. The traditional neuropsychological assessment of USN is based on paper-and-pencil tests, whose data recording and scoring may be subjected to human error. The utilization of technological devices can be expected to improve the assessment of USN. Therefore, we built Neurit.Space, a modified digital version of three paper-and-pencil tests, widely used to detect signs of USN, namely: Bells Cancellation, Line Bisection and Five Elements Drawing Test. Administration and data processing is fully automatic. Twelve right brain-damaged patients (six with and six without USN) and 12 age- and education-balanced healthy participants were enrolled in the study. All participants were administered both the computerized and the paper-and-pencil versions of the tests. The results of this preliminary study showed good sensitivity, specificity, and usability of Neurit.Space, suggesting that these digital tests are a promising tool for the evaluation of USN, both in clinical and in research settings.

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.

Exploring the Effects of Brain Stimulation on Musical Taste: tDCS on the Left Dorso-Lateral Prefrontal Cortex-A Null Result.

Humans are the only species capable of experiencing pleasure from esthetic stimuli, such as art and music. Neuroimaging evidence suggests that the left dorsolateral prefrontal cortex (DLPFC) plays a critical role in esthetic judgments, both in music and in visual art. In the last decade, non-invasive brain stimulation (NIBS) has been increasingly employed to shed light on the causal role of different brain regions contributing to esthetic appreciation. In Experiment #1, musician (N = 20) and non-musician (N = 20) participants were required to judge musical stimuli in terms of "liking" and "emotions". No significant differences between groups were found, although musicians were slower than non-musicians in both tasks, likely indicating a more analytic judgment, due to musical expertise. Experiment #2 investigated the putative causal role of the left dorsolateral pre-frontal cortex (DLPFC) in the esthetic appreciation of music, by means of transcranial direct current stimulation (tDCS). Unlike previous findings in visual art, no significant effects of tDCS were found, suggesting that stimulating the left DLPFC is not enough to affect the esthetic appreciation of music, although this conclusion is based on negative evidence,.

Aftereffects to Prism Exposure without Adaptation: A Single Case Study.

Visuo-motor adaptation to optical prisms (Prism Adaptation, PA), displacing the visual scene laterally, is a behavioral method used for the experimental investigation of visuomotor plasticity, and, in clinical settings, for temporarily ameliorating and rehabilitating unilateral spatial neglect. This study investigated the building up of PA, and the presence of the typically occurring subsequent Aftereffects (AEs) in a brain-damaged patient (TMA), suffering from apperceptive agnosia and a right visual half-field defect, with bilateral atrophy of the parieto-occipital cortices, regions involved in PA and AEs. Base-Right prisms and control neutral lenses were used. PA was achieved by repeated pointing movements toward three types of stimuli: visual, auditory, and bimodal audio-visual. The presence and the magnitude of AEs were assessed by proprioceptive, visual, visuo-proprioceptive, and auditory-proprioceptive straight-ahead pointing tasks. The patient's brain connectivity was investigated by Diffusion Tensor Imaging (DTI). Unlike control participants, TMA did not show any adaptation to prism exposure, but her AEs were largely preserved. These findings indicate that AEs may occur even in the absence of PA, as indexed by the reduction of the pointing error, showing a dissociation between the classical measures of PA and AEs. In the PA process, error reduction, and its feedback, may be less central to the building up of AEs, than the sensorimotor pointing activity per se.

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.

Investigating visuo-spatial neglect and visual extinction during intracranial electrical stimulations: The role of the right inferior parietal cortex.

Both visuo-spatial neglect and visual extinction may occur following right-brain damage. So far, studies on brain-damaged patients have not provided definite evidence about which lesion patterns may lead to the association or dissociation of these deficits. This study was set out to address this issue using Intracranial Electrical Stimulation (IES) in a group of nine patients affected by refractory epilepsy. Cerebral regions associated with visuo-spatial neglect and visual extinction were stimulated, including the right frontal, temporal, and posterior parietal areas. During IES, patients with intracranial implantation involving at least one of these cortical regions were administered with a manual line bisection task (N = 9) to assess visuo-spatial neglect, and a computerized task (N = 8) assessing visual extinction. Results showed that parietal IES induced a rightward bias at the manual bisection task, together with a general improvement in reaction times at bilateral and unilateral visual stimuli detection at the extinction task. The occurrence of visual extinction did not vary across stimulations. By adopting a complementary approach to anatomo-clinical correlation studies, our work corroborates the notion that lesions to the right inferior parietal lobule play a pivotal role in the pathogenesis of visuo-spatial neglect. Importantly, our results also suggest that temporarily interfering with the activity of this region is not sufficient per se to generate visual extinction, which instead may involve a broader and/or different network, possibly extending beyond the cerebral regions considered here, posing important theoretical and clinical implications.

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.

Exploring the time-course and the reference frames of adaptation to optical prisms and its aftereffects.

Prism adaptation (PA) is used to investigate visuo-motor plasticity and to rehabilitate the syndrome of Unilateral Spatial Neglect (USN). After PA, participants show aftereffects (AEs), contralateral to the side of the optical displacement in several tasks. This study explored the features of these AEs, specifically the "egocentric" versus "allocentric, object-based", reference frames involved, and their time course. In three experiments, healthy participants adapted to prismatic lenses inducing a horizontal displacement of the visual field. In Experiment #1, participants adapted to rightward displacing prisms. Four tasks were used requiring repeated pointings towards the participant's subjective egocentric straight-ahead, with the availability of proprioceptive or visual-proprioceptive signals, and, in some conditions, of an external allocentric visual frame (i.e., a rectangular paper sheet). Experiment #2 explored the role of the position of the allocentric frame, with AEs being tested by straight-ahead and frame bisection tasks, requiring pointing toward the external visual frame, placed in different positions of the working space. An egocentric visual proprioceptive task was administered after prism removal and after the execution of the allocentric tasks, to assess the effectiveness of the PA, as indexed by the AEs, and their persistence up to the end of the administration of the allocentric tasks. Experiment #3 differed from #2 in that participants adapted to leftward displacing lenses. Consistent with evidence from USN patients, in Experiment #1, in the egocentric tasks, AEs lasting up to 30 min after PA were found. In Experiment #2, AEs in "allocentric" tasks did not occur, regardless of frame position. Experiment #3 showed AEs in both the "egocentric" and the "allocentric" tasks, with the latter being minor in size. These findings illustrate that the spatial reference systems modulated by PA in extra-personal space primarily operate in spatial "egocentric" reference frames, with a comparatively minor and direction-specific role of "allocentric" frames.

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.

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.

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.

The role of the right posterior parietal cortex in prism adaptation and its aftereffects.

Adaptation to optical prisms (Prismatic Adaptation, PA) displacing the visual scene laterally, on one side of visual space, is both a procedure for investigating visuo-motor plasticity and a powerful tool for the rehabilitation of Unilateral Spatial Neglect (USN). Two processes are involved in PA: i) recalibration (the reduction of the error of manual pointings toward the direction of the prism-induced displacement of the visual scene); ii) the successive realignment after prisms' removal, indexed by the Aftereffects (AEs, in egocentric straight-ahead pointing tasks, the deviation in a direction opposite to the visual displacement previously induced by prisms). This study investigated the role of the posterior parietal cortex (PPC) of the right hemisphere in PA and AEs, by means of low frequency repetitive Transcranial Magnetic Stimulation (rTMS). Proprioceptive and Visuo-proprioceptive egocentric straight-ahead pointing tasks were used to assess the presence and magnitude of AEs. The primary right visual cortex (V1) was also stimulated, to assess the selectivity of the PPC effects on the two processes of PA (recalibration and realignment) in comparison with a cortical region involved in visual processing. Results showed a slower adaptation to prisms when rTMS was delivered before PA, regardless of target site (right PPC or V1). AEs were reduced only by PPC rTMS applied before or after PA, as compared to a sham stimulation. These findings suggest a functional and neural dissociation between realignment and recalibration. Indeed, PA interference was induced by rTMS to both the PPC and V1, indicating that recalibration is supported by a parieto-occipital network. Conversely, AEs were disrupted only by rTMS delivered to the PPC, thus unveiling a relevant role of this region in the development and maintenance of the realignment.

Primary motor cortex and phonological recoding: A TMS-EMG study.

Since the 1960s, evidence from healthy participants and brain-damaged patients, neuroimaging and non-invasive brain stimulation studies has specified the neurofunctional architecture of the short-term memory (STM) system, supporting the temporary retention of a limited amount of verbal material. Auditory-verbal, later termed Phonological (Ph) STM or Phonological Loop, comprises two sub-components: i) the main storage system, the Phonological Short-Term Store (PhSTS), to which auditory verbal stimuli have direct access and where phonologically coded information is retained for a few seconds; ii) a Rehearsal Process (REH), which actively maintains the trace held in the PhSTS, preventing its decay and conveys visual verbal material to the PhSTS, after the process of Phonological Recoding (PhREC, or Grapheme-to-Phoneme Conversion) has taken place. PhREC converts visuo-verbal graphemic representations into phonological ones. The neural correlates of PhSTM include two discrete regions in the left hemisphere: the temporo-parietal junction (PhSTS) and the inferior frontal gyrus in the premotor cortex (REH). The neural basis of PhREC has been much less investigated. A few single case studies of patients made anarthric by focal or degenerative cortical damage, who show a pattern of impairment indicative of a deficit of PhREC, sparing the REH process, suggest that the primary motor cortex (M1) might be involved. To test this hypothesis in healthy participants with a neurophysiological approach, we measured the corticospinal excitability of M1, by means of Transcranial Magnetic Stimulation (TMS)-induced Motor Evoked Potentials (MEPs), during the execution of phonological judgements on auditorily vs. visually presented words (Experiment #1). Crucially, these phonological tasks involve REH, while PhREC is required only with visual presentation. Results show MEPs with larger amplitude when stimuli are presented visually. Task difficulty does not account for this difference and the result is specific for linguistic stimuli, indeed visual and auditory stimuli that cannot be verbalized lead to different behavioral and neurophysiological patterns (Experiment #2). The increase of corticospinal excitability when words are presented visually can be then interpreted as an indication of the involvement of M1 in PhREC. The present findings elucidate the neural correlates of PhREC, suggesting an involvement of the peripheral motor system in its activity.

Multisensorial Perception in Chronic Migraine and the Role of Medication Overuse.

Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by 2 or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (ie, fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine (CM) patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in CM patients (n = 63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (P < .0001). Triptan MOH patients (n = 23) presented significantly less fission effects than other CM groups (P = .008). This exploratory study suggests that CM - both with and without medication overuse - is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI. PERSPECTIVE: This observational study shows reduced susceptibility to the SIFI in CM, confirming and extending previous results in episodic migraine. MOH contributes to this phenomenon, especially in case of triptans.

Disownership of body parts as revealed by a visual scale evaluation. An observational study.

The disownership of body parts, that most frequently occurs on the left side of the body, contralateral to right-hemispheric lesions, is an infrequent disorder, as usually assessed by interviews asking for dichotomic "yes/no" responses. This observational study in right-brain-damaged stroke patients investigated the efficacy of a continuous Visual Analog Scale (VAS) to detect body disownership after right brain damage, compared to dichotomic questions. Thirty-two right-handed right-brain-damaged stroke patients were given a Standardized Interview (SI), asking "Whose hand/arm/leg is this?", followed by a VAS (asking patients to mark on a vertical line their agreement with the statement that a body part belonged to them). The neural correlates of this disorder and measures of extra-personal and personal spatial neglect were also assessed. Control data were recorded from 18 neurologically unimpaired right-handed participants. During the interview, no patient showed disownership of body parts. Conversely, on the VAS eight out of 32 (25%) patients' scores, but none of the controls' scores, indicated a judgement of disownership for left body parts, with a left-right difference larger than that of control participants. VAS-detected disownership was not systematically associated with extra-personal and personal unilateral spatial neglect. Lesion sites associated with disownership of left body parts included the caudate nucleus and the anterior part of the internal capsule. To conclude, the VAS task, compared to the interview, is a novel tool to detect disownership of left body parts in right brain-damaged patients. A revised classification of body-ownership disorders is proposed. The present variant, assessed and detected by the VAS task, is termed Covert disownership and distinguished from the Overt disownership assessed by a SI.