Extra-powerful on the visuo-perceptual space, but variable on the number space: Different effects of optokinetic stimulation in neglect patients

We studied the effects of optokinetic stimulation (OKS; leftward, rightward, control) on the visuo-perceptual and number space, in the same sample, during line bisection and mental number interval bisection tasks. To this end, we tested six patients with right-hemisphere damage and neglect, six patients with right-hemisphere damage but without neglect, and six neurologically healthy participants. In patients with neglect, we found a strong effect of leftward OKS on line bisection, but not on mental number interval bisection. We suggest that OKS influences the number space only under specific conditions

Multi-tasking uncovers right spatial neglect and extinction in chronic left-hemisphere stroke patients

open7noUnilateral Spatial Neglect, the most dramatic manifestation of contralesional space unawareness, is a highly heterogeneous syndrome. The presence of neglect is related to core spatially lateralized deficits, but its severity is also modulated by several domain-general factors (such as alertness or sustained attention) and by task demands. We previously showed that a computer-based dual-task paradigm exploiting both lateralized and non-lateralized factors (i.e., attentional load/multitasking) better captures this complex scenario and exacerbates deficits for the contralesional space after right hemisphere damage. Here we asked whether multitasking would reveal contralesional spatial disorders in chronic left hemisphere damaged (LHD) stroke patients, a population in which impaired spatial processing is thought to be uncommon. Ten consecutive LHD patients with no signs of right-sided neglect at standard neuropsychological testing performed a computerized spatial monitoring task with and without concurrent secondary tasks (i.e., multitasking). Severe contralesional (right) space unawareness emerged in most patients under attentional load in both the visual and auditory modalities. Multitasking affected the detection of contralesional stimuli both when presented concurrently with an ipsilesional one (i.e., extinction for bilateral targets) and when presented in isolation (i.e., left neglect for right-sided targets). No spatial bias emerged in a control group of healthy elderly participants, who performed at ceiling, as well as in a second control group composed of patients with Mild Cognitive Impairment. We conclude that the pathological spatial asymmetry in LHD patients cannot be attributed to a global reduction of cognitive resources but it is the consequence of unilateral brain damage. Clinical and theoretical implications of the load-dependent lack of awareness for contralesional hemispace following LHD are discussed.embargoed_20180601Blini, Elvio; Romeo, Zaira; Spironelli, Chiara; Pitteri, Marco; Meneghello, Francesca; Bonato, Mario; Zorzi, MarcoBlini, ELVIO ADALBERTO; Romeo, Zaira; Spironelli, Chiara; Pitteri, Marco; Meneghello, Francesca; Bonato, Mario; Zorzi, Marc

Optokinetic Stimulation Modulates Neglect for the Number Space: Evidence from Mental Number Interval Bisection

Behavioral, neuropsychological, and neuroimaging data support the idea that numbers are represented along a mental number line (MNL), an analogical, visuospatial representation of number magnitude. The MNL is left-to-right oriented in Western cultures, with small numbers on the left and larger numbers on the right. Left neglect patients are impaired in the mental bisection of numerical intervals, with a bias toward larger numbers that are relatively to the right on the MNL. In the present study we investigated the effects of optokinetic stimulation (OKS) – a technique inducing visuospatial attention shifts by means of activation of the optokinetic nystagmus – on number interval bisection. One patient with left neglect following right-hemisphere stroke (BG) and four control patients with right-hemisphere damage, but without neglect, performed the number interval bisection task in three conditions of OKS: static, leftward, and rightward. In the static condition, BG misbisected to the right of the true midpoint. BG misbisected to the left following leftward OKS, and again to the right of the midpoint following rightward OKS. Moreover, the variability of BG’s performance was smaller following both leftward and rightward OKS, suggesting that the attentional bias induced by OKS reduced the “indifference zone” that is thought to underlie the length effect reported in bisection tasks. We argue that shifts of visuospatial attention, induced by OKS, may affect number interval bisection, thereby revealing an interaction between the processing of the perceptual space and the processing of the number space

Lost in classification: lower cognitive functioning in apparently cognitive normal newly diagnosed RRMS patients

Cognitive functioning in multiple sclerosis (MS) patients is usually related to the classic, dichotomic classification of impaired vs. unimpaired cognition. However, this approach is far from mirroring the real efficiency of cognitive functioning. Applying a different approach in which cognitive functioning is considered as a continuous variable, we aimed at showing that even newly diagnosed relapsing-remitting MS (RRMS) patients might suffer from reduced cognitive functioning with respect to a matched group of neurologically healthy controls (HCs), even if they were classified as having no cognitive impairment (CI). Fifty newly diagnosed RRMS patients and 36 HCs were tested with an extensive battery of neuropsychological tests. By using Z-scores applied to the whole group of RRMS and HCs together, a measure of cognitive functioning (Z-score index) was calculated. Among the 50 RRMS patients tested, 36 were classified as cognitively normal (CN). Even though classified as CN, RRMS patients performed worse than HCs at a global level (p = 0.004) and, more specifically, in the domains of memory (p = 0.005) and executive functioning (p = 0.006). These results highlight that reduced cognitive functioning can be present early in the disease course, even in patients without an evident CI. The current classification criteria of CI in MS should be considered with caution

Visual-attentional load unveils slowed processing speed in multiple sclerosis patients: a pilot study with a tablet-based videogame

Slowing in information processing speed (IPS) is the key cognitive deficit in multiple sclerosis (MS). Testing IPS in different cognitive load conditions by using computerized tools might reveal initial IPS slowness underestimated by classic paper-and-pencil tests. To investigate the extent to which IPS can be affected by increased task demands, we developed three tasks based on the manipulation of the visual-attentional load, delivered with a home-made, tablet-based videogame. Fifty-one patients with MS (pwMS), classified as having no cognitive impairment in classic paper-and-pencil tests, and 20 healthy controls (HC) underwent the videogame tasks; reaction times (RTs) and accuracy were recorded. A significant reduced performance of pwMS as compared with HC was found on the videogame tasks, with pwMS being on average slower and less accurate than HC. Furthermore, pwMS showed a significantly more pronounced decrement in accuracy as a function of the visual-attentional load, suggesting a higher susceptibility to increased task demands. Significant correlations among the Symbol Digit Modalities Test (SDMT) and the videogame mean RTs and accuracy were found, providing evidence for the concurrent validity of the videogame as a valid tool to test IPS in pwMS. The high potential that might derive from the adoption of computerized assessment tools in clinical practice should be taken into consideration and investigated further

Microstructural MRI Correlates of Cognitive Impairment in Multiple Sclerosis: The Role of Deep Gray Matter

Although cognitive impairment (CI) is frequently observed in people with multiple sclerosis (pwMS), its pathogenesis is still controversial. Conflicting results emerged concerning the role of microstructural gray matter (GM) damage especially when involving the deep GM structures. In this study, we aimed at evaluating whether differences in cortical and deep GM structures between apparently cognitively normal (ACN) and CI pwMS (36 subjects in total) are present, using an extensive set of diffusion MRI (dMRI) indices and conventional morphometry measures. The results revealed increased anisotropy and restriction over several deep GM structures in CI compared with ACN pwMS, while no changes in volume were present in the same areas. Conversely, reduced anisotropy/restriction values were detected in cortical regions, mostly the pericalcarine cortex and precuneus, combined with reduced thickness of the superior frontal gyrus and insula. Most of the dMRI metrics but none of the morphometric indices correlated with the Symbol Digit Modality Test. These results suggest that deep GM microstructural damage can be a strong anatomical substrate of CI in pwMS and might allow identifying pwMS at higher risk of developing CI

Ipsilesional Impairments of Visual Awareness After Right-Hemispheric Stroke

Unilateral brain damage following stroke frequently hampers the processing of contralesional space. Whether and how it also affects the processing of stimuli appearing on the same side of the lesion is still poorly understood. Three main alternative hypotheses have been proposed, namely that ipsilesional processing is functionally (i) hyperefficient, (ii) impaired, or (iii) spared. Here, we investigated ipsilesional space awareness through a computerized paradigm that exploits a manipulation of concurrent information processing demands (i.e., multitasking). Twelve chronic right-hemisphere stroke patients with a total lack of awareness for the contralesional side of space were administered a task that required the spatial monitoring of two locations within the ipsilesional hemispace. Targets were presented immediately to the right of a central fixation point (3° eccentricity), or farther to the right toward the screen edge (17° eccentricity), or on both locations. Response to target position occurred either in isolation or while performing a concurrent visual or auditory task. Results showed that most errors occurred when two targets were simultaneously presented and patients were faced with additional task demands (in the visual or auditory modalities). In the context of concurrent visual load, ipsilesional targets presented at the rightmost location were omitted more frequently than those presented closer to fixation. This pattern qualifies ipsilesional processing in right-hemisphere stroke patients as functionally impaired, arguing against the notion of ipsilesional hyperperformance, especially when under visual load

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

Introduction and methods: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 na\uefve MS patients and in 32 controls at time of diagnosis. Results: PVALB gene expression was downregulated in MS (fold change = 3.7 \ub1 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 \ub1 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean \ub1 SEM:25.2 \ub1 7.5 ng/mL) compared to both cognitively normal (10.9 \ub1 2.4, P = 0.049) and mild cognitive impaired (10.1 \ub1 2.9, P = 0.024) patients. Conclusions: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline

Rehabilitation of unilateral left neglect: effectiveness of different treatments

REHABILITATION OF UNILATERAL LEFT NEGLECT: EFFECTIVENESS OF DIFFERENT TREATMENTS Cognitive rehabilitation is a systematically applied set of therapeutic interventions designed to improve cognitive functioning and daily living activities that may be affected by difficulties in one or more cognitive domains. Evidence-based cognitive rehabilitation treatments include strategy training for cognitive deficits and interventions for functional neuropsychological rehabilitation. Unilateral left neglect is defined as the right-brain-damaged patients’ failure to explore, respond, or orient to stimuli in the contralesional side of the space (Heilman et al., 1979). Neglect cannot be considered a unitary neuropsychological deficit, but a complex syndrome involving different functions and different space domains (personal, peripersonal, extrapersonal, and representational). Several rehabilitation approaches have been employed to treat neglect, many of them with positive and long-lasting effects (e.g., see Luauté et al., 2006). Nevertheless, some authors have recently reported no effects or only minor effects of neglect rehabilitation therapy (e.g., Cubelli et al., 1999; Rousseaux et al., 2006). Although there is substantial evidence to support cognitive rehabilitation for people who suffer from brain lesions, additional research is needed to answer the question of whether and why cognitive rehabilitation is really effective, examining the treatment factors and the patient’s characteristics to optimize clinical outcomes (Cicerone et al., 2005). The aim of the present study was to directly compare, for the first time, three neglect rehabilitation treatments already described in the literature: the Limb Activation Treatment (LAT; Robertson et al., 2002), the Prism Adaptation (PA; Rossetti et al., 1998), and the Visual Scanning (VS; Antonucci et al., 1995). In addition, the present study aimed to evaluate the effect of spontaneous recovery, in the sense of a change (improving or worsening) in the cognitive status without a specific neuropsychological intervention. For this purpose, 21 patients with unilateral right-sided lesion and left unilateral neglect were tested. Patients were treated with LAT, PA, or VS. The results showed no significant differencies among the three groups. The role of spontaneous functional reorganization and this role on effects of cognitive rehabilitation is critically discussed, considering the present data and those previously reported in the literature.RIABILITAZIONE DELLA NEGLIGENZA SPAZIALE UNILATERALE: EFFICACIA DI DIVERSI TRATTAMENTI La riabilitazione cognitiva consiste in una serie di interventi terapeutici atti a migliorare il funzionamento cognitivo e le attività di ogni giorno che possono essere deficitarie dopo danno di una o più abilità cognitive. I trattamenti riabilitativi cognitivi basati sull’evidenza includono strategie di trattamento dei deficit cognitivi ed interventi per la riabilitazione neuropsicologica. La negligenza spaziale unilaterale (NSU) è definita come l’incapacità di esplorare, reagire, oppure orientarsi verso stimoli nello spazio controlesionale in pazienti che hanno subito una lesione cerebrale all’emisfero cerebrale destro (Heilman et al., 1979). La NSU non può essere considerata un deficit neuropsicologico unitario, ma una sindrome complessa che coinvolge differenti funzioni e diversi domini spaziali (personale, peripersonale, extrapersonale, e rappresentazionale). Numerosi approcci riabilitativi sono stati impiegati nel trattamento della NSU, molti dei quali con risultati positivi, anche a lungo termine (si veda Luauté et al., 2006). Tuttavia, alcuni autori hanno mostrato come la riabilitazione della NSU possa essere di scarso effetto, se non inefficace (si vedano Cubelli et al., 1999; Rousseaux et al., 2006). Nonostante ci sia una sostanziale evidenza a supporto della riabilitazione cognitiva, è ancora forte il bisogno di condurre ulteriori ricerche per capire perché, e come, i trattamenti cognitivi si dimostrano efficaci (o inefficaci), esaminando sia i fattori intrinseci al trattamento utilizzato, che che le caratteristiche del singolo paziente (Cicerone et al., 2005). Con il presente studio abbiamo confrontato direttamente, per la prima volta, l’effetto di tre trattamenti per la NSU: l’attivazione dell’arto controlesione (LAT; Robertson et al., 2002), l’adattamento prismatico (PA; Rossetti et al., 1998), e la scansione visiva (VS; Antonucci et al., 1995). Inoltre, abbiamo valutato gli effetti del recupero spontaneo, inteso come il cambiamento (miglioramento o peggioramento) dello stato cognitivo del paziente in assenza di trattamento neuropsicologico. A questo scopo, sono stati testati 21 pazienti con NSU in seguito a lesione dell’emisfero cerebrale destro. I pazienti sono stati trattati con LAT, PA e VS. Il confronto tra i trattamenti non ha mostrato alcuna differenza significativa. Il ruolo del recupero spontaneo è stato criticamente discusso considerando sia i dati del presente studio, che i dati precedentemente discussi in letteratura

Spatial grounding of symbolic arithmetic: an investigation with optokinetic stimulation

Growing evidence suggests that mental calculation might involve movements of attention along a spatial representation of numerical magnitude. Addition and subtraction on nonsymbolic numbers (numerosities) seem to induce a "momentum" effect, and have been linked to distinct patterns of neural activity in cortical regions subserving attention and eye movements. We investigated whether mental arithmetic on symbolic numbers, a cornerstone of abstract mathematical reasoning, can be affected by the manipulation of overt spatial attention induced by optokinetic stimulation (OKS). Participants performed additions or subtractions of auditory two-digit numbers during horizontal (experiment 1) or vertical OKS (experiment 2), and eye movements were concurrently recorded. In both experiments, the results of addition problems were underestimated, whereas results of subtractions were overestimated (a pattern that is opposite to the classic Operational Momentum effect). While this tendency was unaffected by OKS, vertical OKS modulated the occurrence of decade errors during subtractions (i.e., fewer during downward OKS and more frequent during upward OKS). Eye movements, on top of the classic effect induced by OKS, were affected by the type of operation during the calculation phase, with subtraction consistently leading to a downward shift of gaze position and addition leading to an upward shift. These results highlight the pervasive nature of spatial processing in mental arithmetic. Furthermore, the preeminent effect of vertical OKS is in line with the hypothesis that the vertical dimension of space-number associations is grounded in universal (physical) constraints and, thereby, more robust than situated and culture-dependent associations with the horizontal dimension