Publications by authors named "Francesca Tinelli"

49 Publications

Cortical thickness of primary visual cortex correlates with motion deficits in periventricular leukomalacia.

Neuropsychologia 2021 01 15;151:107717. Epub 2020 Dec 15.

Department of Developmental Neuroscience, Laboratory of Vision, IRCCS Fondazione Stella Maris, Pisa, Italy; Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Italy. Electronic address:

Impairments of visual motion perception and, in particular, of flow motion have been consistently observed in premature and very low birth weight subjects during infancy. Flow motion information is analyzed at various cortical levels along the dorsal pathways, with information mainly provided by primary and early visual cortex (V1, V2 and V3). We investigated the cortical stage of the visual processing that underlies these motion impairments, measuring Grey Matter Volume and Cortical Thickness in 13 children with Periventricular Leukomalacia (PVL). The cortical thickness, but not the grey matter volume of area V1, correlates negatively with motion coherence sensitivity, indicating that the thinner the cortex, the better the performance among the patients. However, we did not find any such association with either the thickness or volume of area MT, MST and areas of the IPS, suggesting damage at the level of primary visual cortex or along the optic radiation.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107717DOI Listing
January 2021

Visuo-haptic transfer for object recognition in children with peripheral visual impairment.

Vision Res 2021 Jan 15;178:12-17. Epub 2020 Oct 15.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy. Electronic address:

It is well known how early visual experience is critical for the development of multisensory processing abilities, and for this reason an early vision impairment could hinder the transfer of different sensory information during the exploration and recognition of the surrounding environment. Recently, we verified that visuo-haptic transfer for object recognition emerges early in typically developing children but matures slowly during the school-age period. Subsequently we verified the presence of a slower trend of development in unisensory and multisensory skills in children with early abnormal motor and sensory experiences due to brain lesions. Now, we investigated unimodal visual information, unimodal haptic information and visuo-haptic information transfer in children with a diagnosis of low-vision, due to congenital visual impairment. Unimodal and bimodal processes for object recognition were explored in 11 children with low-vision and the results were matched with those of 22 controls. Participants were tested using a clinical protocol involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects and visuo-haptic transfer of these two types of information. Results show a normal development in haptic unisensory processing in children with low vision and a significant difference in multisensory transfer between the two groups. In children with visual impairment, multisensory processes do not facilitate the recognition of common objects as in typical children, probably because early visual impairment may impact the cross-sensory calibration of vision and touch.
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http://dx.doi.org/10.1016/j.visres.2020.06.008DOI Listing
January 2021

Structural brain damage and visual disorders in children with cerebral palsy due to periventricular leukomalacia.

Neuroimage Clin 2020 11;28:102430. Epub 2020 Sep 11.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, Pisa, Italy.

Aim: To systematically explore the relationship between type and severity of brain lesion on Magnetic Resonance Imaging (MRI) and visual function in a large cohort of children with periventricular leukomalacia (PVL).

Methods: 94 children with bilateral cerebral palsy (CP) and history of PVL were recruited at Stella Maris Scientific Institute in Pisa (Italy). We included data of participants (72) with at least one MRI after the age of three years and an evaluation of visual function including fixation, following, saccades, nystagmus, acuity, visual field, stereopsis and color perception. Brain lesions location and extent were assessed by a semi-quantitative MRI-scale for children with CP.

Results: Brain lesion severity strongly correlated with visual function total score (global MRI score p = .000; hemispheric score p = .001 and subcortical score p = .000). Moreover, visual acuity, visual field, stereopsis and colour were compromised when a cortical damage was present, while ocular motricity (and in particular fixation and saccades) were compromised in presence of subcortical brain damage.

Interpretation: Structural MRI is valuable for understanding the relationship between brain lesion severity and visual function in children with CP.
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http://dx.doi.org/10.1016/j.nicl.2020.102430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519396PMC
September 2020

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Laboratory of Cellular Neurobiology, Neurology IX Unit, UCV, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45CD34CD133 mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
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http://dx.doi.org/10.3390/ijms21165763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460840PMC
August 2020

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Int J Mol Sci 2020 May 13;21(10). Epub 2020 May 13.

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
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http://dx.doi.org/10.3390/ijms21103435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279405PMC
May 2020

Temporal representation impairment in developmental dyslexia for unisensory and multisensory stimuli.

Dev Sci 2020 09 14;23(5):e12977. Epub 2020 Jun 14.

The Neuropsychological Laboratory, CNS-Fed, Paris, France.

Dyslexia has been associated with a problem in visual-audio integration mechanisms. Here, we investigate for the first time the contribution of unisensory cues on multisensory audio and visual integration in 32 dyslexic children by modelling results using the Bayesian approach. Non-linguistic stimuli were used. Children performed a temporal task: they had to report whether the middle of three stimuli was closer in time to the first one or to the last one presented. Children with dyslexia, compared with typical children, exhibited poorer unimodal thresholds, requiring greater temporal distance between items for correct judgements, while multisensory thresholds were well predicted by the Bayesian model. This result suggests that the multisensory deficit in dyslexia is due to impaired audio and visual inputs rather than impaired multisensory processing per se. We also observed that poorer temporal skills correlated with lower reading skills in dyslexic children, suggesting that this temporal capability can be linked to reading abilities.
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http://dx.doi.org/10.1111/desc.12977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507191PMC
September 2020

Early Childhood Attention Battery: Italian adaptation and new expanded normative data.

Early Hum Dev 2020 05 13;144:105013. Epub 2020 Mar 13.

Pediatric Neurology Unit, Catholic University of Sacred Heart, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy; National Centre of Services and Research for the Prevention of Blindness and Rehabilitation of Low Vision Patients - IAPB Italia onlus, Italy.

Background: The Early Childhood Attention Battery (ECAB) has been used to assess three different components of attention in preschool children, namely, selective, sustained and attentional control.

Aim: The aim of the study was: I) to adapt the ECAB to the Italian language; II) to collect Italian reference data using the translated version and III) to expand the available reference data using 6-month age intervals.

Study Design: The adaptation of the ECAB to Italian language and the collection of Italian reference data was performed in four phases: translation and identification of the manual and subtests that needed adaptation; interobserver reliability and feasibility of the Italian version; application of the Italian ECAB; statistical analysis.

Subjects: The ECAB was performed on a low risk population between 3 and 5 years, 11 months.

Results: Statistical analysis was conducted subdividing the cohort in 6-month age groups. The final cohort included 300 low-risk typically developing children. The assessment was well accepted and enjoyed by most of the children except for some in the youngest group who refused to complete all of the tests. Our data showed a progressive improvement in attention across age in seven of the eight subtests of the ECAB.

Conclusion: The ECAB is a feasible battery in Italian as in the English version, for the assessment of early attention in preschool children, allowing the assessment of the different components of attention and a specific maturation follow up with increasing age.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105013DOI Listing
May 2020

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Neurol Sci 2020 Aug 12;41(8):2193-2200. Epub 2020 Mar 12.

Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.
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http://dx.doi.org/10.1007/s10072-020-04306-8DOI Listing
August 2020

The development of vision between nature and nurture: clinical implications from visual neuroscience.

Childs Nerv Syst 2020 05 5;36(5):911-917. Epub 2020 Mar 5.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, Pisa, Italy.

Background: Vision is an adaptive function and should be considered a prerequisite for neurodevelopment because it permits the organization and the comprehension of the sensory data collected by the visual system during daily life. For this reason, the influence of visual functions on neuromotor, cognitive, and emotional development has been investigated by several studies that have highlighted how visual functions can drive the organization and maturation of human behavior. Recent studies on animals and human models have indicated that visual functions mature gradually during post-natal life, and its development is closely linked to environment and experience.

Discussion: The role of vision in early brain development and some of the neuroplasticity mechanisms that have been described in the presence of cerebral damage during childhood are analyzed in this review, according to a neurorehabilitation prospective.
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http://dx.doi.org/10.1007/s00381-020-04554-1DOI Listing
May 2020

Visual Function Classification System for children with cerebral palsy: development and validation.

Dev Med Child Neurol 2020 01 10;62(1):104-110. Epub 2019 Jun 10.

National Centre of Services and Research for Prevention of Blindness and Rehabilitation of Visually Impaired, Rome, Italy.

Aim: To develop and validate the Visual Function Classification System (VFCS), which was created to classify how children with cerebral palsy (CP) use visual abilities in daily life.

Method: The process of development and validation of the VFCS involved four phases: (1) drafting of the five levels from the analysis of literature and clinical experience; (2) validation of constructs and revision of the levels for concept meaningfulness, using nominal group process; (3) refinement by international Delphi survey; and(4) assessment of interrater reliability among professionals and with caregivers, and of test-retest reliability.

Results: Five nominal groups involved 29 participants; 65 people completed the first round and 51 the second round of the Delphi survey. Construct validity was demonstrated within an expert group and external validation through several stakeholders, with the involvement of patients and families to ensure meaningfulness of the concept. Discussions continued until consensus was reached about the construct and content of the five levels. Participants in the reliability study included 29 professionals, 39 parents, and a total sample of 160 children with CP (mean age [SD] 6y 6mo [3y 4mo]; median 5y 7mo, range 1-19y). Absolute interrater agreement among professionals was 86% (weighted κ=0.88; 95% confidence interval [CI] 0.83-0.93). Test-retest reliability was high (weighted κ=0.97; 95% CI 0.95-0.99). Parent-professional interrater reliability on 39 children was moderate (weighted κ=0.51; 95% CI 0.39-0.63).

Interpretation: The VFCS has been appropriately constructed and provides a reliable system to classify visual abilities of children with CP both in clinical and in research settings.

What This Paper Adds: The Visual Function Classification System is a valid and reliable system. It classifies visual abilities of children with cerebral palsy in clinical and research settings. At a clinical level, it can be used to harmonize communication among professionals and identify patients' strengths and weaknesses. In research settings, it can be used to stratify patients, define natural history evolution, and interpret intervention studies.
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http://dx.doi.org/10.1111/dmcn.14270DOI Listing
January 2020

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review.

J Clin Med 2019 05 26;8(5). Epub 2019 May 26.

Molecular medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes () have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in , and gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in and a lower frequency of mutations in than those seen in international series. mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.
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http://dx.doi.org/10.3390/jcm8050750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572054PMC
May 2019

Visuo-haptic transfer for object recognition in children with periventricular leukomalacia and bilateral cerebral palsy.

Child Neuropsychol 2019 11 24;25(8):1084-1097. Epub 2019 Apr 24.

a Department of Developmental Neuroscience, IRCCS Stella Maris Foundation , Pisa , Italy.

Object recognition is a complex adaptive process that can be impaired in children with neurodevelopmental disabilities. Recently, we found a significant effect of time on the development of unimodal and crossmodal recognition skills for common objects in typical children and this was a starting point for the study of visuo-haptic object recognition skills in impaired populations. In this study, we investigated unimodal visual information, unimodal haptic information and visuo-haptic information transfer in 30 children, from 4.0 to 10.11 years of age, with bilateral Periventricular Leukomalacia (PVL) and bilateral cerebral palsy. Results were matched with those of 116 controls. Participants were tested using a clinical protocol, adopted in the previous study, involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects and visuo-haptic transfer of these two types of information. Results show that in the PVL group as in controls, there is an age-dependent development of object recognition abilities for visual, haptic and visuo-haptic modalities, even if PVL children perform worse in all the three conditions, in comparison with the typical group. Furthermore, PVL children have a specific deficit both in visual and haptic information processing, that improves with age, probably thanks to everyday experience, but the visual modality shows a better and more rapid maturation, remaining more salient compared to the haptic one. However, multisensory processes partially facilitate recognition of common objects also in PVL children and this finding could be useful for planning early intervention in children with brain lesion.
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http://dx.doi.org/10.1080/09297049.2019.1602599DOI Listing
November 2019

A New Approach for Glyco-Functionalization of Collagen-Based Biomaterials.

Int J Mol Sci 2019 Apr 9;20(7). Epub 2019 Apr 9.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.

The cell microenvironment plays a pivotal role in mediating cell adhesion, survival, and proliferation in physiological and pathological states. The relevance of extracellular matrix (ECM) proteins in cell fate control is an important issue to take into consideration for both tissue engineering and cell biology studies. The glycosylation of ECM proteins remains, however, largely unexplored. In order to investigate the physio-pathological effects of differential ECM glycosylation, the design of affordable chemoselective methods for ECM components glycosylation is desirable. We will describe a new chemoselective glycosylation approach exploitable in aqueous media and on non-protected substrates, allowing rapid access to glyco-functionalized biomaterials.
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http://dx.doi.org/10.3390/ijms20071747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480084PMC
April 2019

Visual assessment in Down Syndrome: The relevance of early visual functions.

Early Hum Dev 2019 04 26;131:21-28. Epub 2019 Feb 26.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.

Background: Children with Down Syndrome (DS) have a high prevalence of ocular disorders, and even when ophthalmological deficits (i.e. refractive errors or strabismus) are corrected, visual acuity seems to have a different developmental trend compared to typical children. Unfortunately, there is no consensus about the age at which it is fundamental to perform a first comprehensive visual assessment in this population.

Aims: We analyzed early visual functions in a sample of 42 Italian children with DS, in order to achieve new insights for early surveillance and intervention.

Material And Methods: DS children were evaluated with the Early Neurovisual Assessment, including Teller Acuity Cards (at 6, 12 and 18 months of age) and the Pediatric Ophthalmological Examination (within the 36th months of age).

Results: Visual acuity in our sample was lower than findings reported in the literature on healthy Italian children, but the values were within the confidence interval reported in previous studies on DS children. Moderate or severe refractive errors (> 3diopters) were present in five children (four had hyperopia and one myopia). Abnormalities in ocular motility were observed in 15 children and pathological findings for fundus oculi or lens were found in another eight. Furthermore, ophthalmological findings correlated with visual acuity at 18 months of age.

Conclusion: According to our results, the Early Neurovisual Assessment at 18 months of life is a reliable tool for early detection of visual disorders in children with DS and it is useful for programming early intervention to promote their neurodevelopment.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.01.020DOI Listing
April 2019

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

Front Neurol 2018 4;9:981. Epub 2018 Dec 4.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel () comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.
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http://dx.doi.org/10.3389/fneur.2018.00981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289125PMC
December 2018

Supramodal agnosia for oblique mirror orientation in patients with periventricular leukomalacia.

Cortex 2018 06 22;103:179-198. Epub 2018 Mar 22.

Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Department of Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy. Electronic address:

Periventricular leukomalacia (PVL) is characterized by focal necrosis at the level of the periventricular white matter, often observed in preterm infants. PVL is frequently associated with motor impairment and with visual deficits affecting primary stages of visual processes as well as higher visual cognitive abilities. Here we describe six PVL subjects, with normal verbal IQ, showing orientation perception deficits in both the haptic and visual domains. Subjects were asked to compare the orientation of two stimuli presented simultaneously or sequentially, using both a two alternative forced choice (2AFC) orientation-discrimination and a matching procedure. Visual stimuli were oriented gratings or bars or collinear short lines embedded within a random pattern. Haptic stimuli comprised two rotatable wooden sticks. PVL patients performed at chance in discriminating the oblique orientation, both for visual and haptic stimuli. Moreover when asked to reproduce the oblique orientation, they often oriented the stimulus along the symmetric mirror orientation. The deficit generalized to stimuli varying in many low level features, was invariant for spatiotopic object orientation, and also occurred for sequential presentations. The deficit was specific to oblique orientations, and not for horizontal or vertical stimuli. These findings show that PVL can affect a specific network involved with the supramodal perception of mirror symmetry orientation.
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http://dx.doi.org/10.1016/j.cortex.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004039PMC
June 2018

Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis.

Cell Death Dis 2018 03 7;9(3):377. Epub 2018 Mar 7.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, 20126, Italy.

Cancer aberrant N- and O-linked protein glycosylation, frequently resulting from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP), play different roles in tumor progression. However, the low specificity and toxicity of the existing HBP inhibitors prevented their use for cancer treatment. Here we report the preclinical evaluation of FR054, a novel inhibitor of the HBP enzyme PGM3, with a remarkable anti-breast cancer effect. In fact, FR054 induces in different breast cancer cells a dramatic decrease in cell proliferation and survival. In particular, in a model of Triple Negative Breast Cancer (TNBC) cells, MDA-MB-231, we show that these effects are correlated to FR054-dependent reduction of both N- and O-glycosylation level that cause also a strong reduction of cancer cell adhesion and migration. Moreover we show that impaired survival of cancer cells upon FR054 treatment is associated with the activation of the Unfolded Protein Response (UPR) and accumulation of intracellular ROS. Finally, we show that FR054 suppresses cancer growth in MDA-MB-231 xenograft mice, supporting the advantage of targeting HBP for therapeutic purpose and encouraging further investigation about the use of this small molecule as a promising compound for breast cancer therapy.
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http://dx.doi.org/10.1038/s41419-018-0405-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841296PMC
March 2018

Development and Implementation of a New Telerehabilitation System for Audiovisual Stimulation Training in Hemianopia.

Front Neurol 2017 21;8:621. Epub 2017 Nov 21.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.

Telerehabilitation, defined as the method by which communication technologies are used to provide remote rehabilitation, although still underused, could be as efficient and effective as the conventional clinical rehabilitation practices. In the literature, there are descriptions of the use of telerehabilitation in adult patients with various diseases, whereas it is seldom used in clinical practice with child and adolescent patients. We have developed a new audiovisual telerehabilitation (AVT) system, based on the multisensory capabilities of the human brain, to provide a new tool for adults and children with visual field defects in order to improve ocular movements toward the blind hemifield. The apparatus consists of a semicircular structure in which visual and acoustic stimuli are positioned. A camera is integrated into the mechanical structure in the center of the panel to control eye and head movements. Patients can use this training system with a customized software on a tablet. From hospital, the therapist has complete control over the training process, and the results of the training sessions are automatically available within a few minutes on the hospital website. In this paper, we report the AVT system protocol and the preliminary results on its use by three adult patients. All three showed improvements in visual detection abilities with long-term effects. In the future, we will test this apparatus with children and their families. Since interventions for impairments in the visual field have a substantial cost for individuals and for the welfare system, we expect that our research could have a profound socio-economic impact avoiding prolonged and intensive hospital stays.
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http://dx.doi.org/10.3389/fneur.2017.00621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702450PMC
November 2017

Autism is associated with reduced ability to interpret grasping actions of others.

Sci Rep 2017 10 4;7(1):12687. Epub 2017 Oct 4.

Department of Neuroscience, Psychology, Pharmacology and Child Health, University of Florence, Florence, Italy.

We investigated the ability of children with ASD to discriminate a small cylinder from a large cube by observing a point-light movie of an actor grasping the object, either from an allocentric or egocentric viewpoint (observing action of others or self). Compared with typically developing controls, high functioning autistic children showed a strong selective impairment in this task, but only with the allocentric viewpoint, where thresholds were twice as high: egocentric thresholds were similar to age- and ability-matched controls. The magnitude of the impairment correlated strongly with the degree of symptomology (R = 0.5). The results suggest that children with ASD might be impaired in their ability to predict and infer the consequences of others' movements, which could be related to the social-communicative deficits often reported in autism.
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http://dx.doi.org/10.1038/s41598-017-12995-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627240PMC
October 2017

Multisensory-Based Rehabilitation Approach: Translational Insights from Animal Models to Early Intervention.

Front Neurosci 2017 26;11:430. Epub 2017 Jul 26.

Department of Developmental Neuroscience, Fondazione Stella Maris (IRCCS)Pisa, Italy.

Multisensory processes permit combinations of several inputs, coming from different sensory systems, allowing for a coherent representation of biological events and facilitating adaptation to environment. For these reasons, their application in neurological and neuropsychological rehabilitation has been enhanced in the last decades. Recent studies on animals and human models have indicated that, on one hand multisensory integration matures gradually during post-natal life and development is closely linked to environment and experience and, on the other hand, that modality-specific information seems to do not benefit by redundancy across multiple sense modalities and is more readily perceived in unimodal than in multimodal stimulation. In this review, multisensory process development is analyzed, highlighting clinical effects in animal and human models of its manipulation for rehabilitation of sensory disorders. In addition, new methods of early intervention based on multisensory-based rehabilitation approach and their applications on different infant populations at risk of neurodevelopmental disabilities are discussed.
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http://dx.doi.org/10.3389/fnins.2017.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526840PMC
July 2017

Development of visuo-haptic transfer for object recognition in typical preschool and school-aged children.

Child Neuropsychol 2018 07 20;24(5):657-670. Epub 2017 Apr 20.

a Department of Developmental Neuroscience , IRCCS Stella Maris Foundation , Pisa , Italy.

Object recognition is a long and complex adaptive process and its full maturation requires combination of many different sensory experiences as well as cognitive abilities to manipulate previous experiences in order to develop new percepts and subsequently to learn from the environment. It is well recognized that the transfer of visual and haptic information facilitates object recognition in adults, but less is known about development of this ability. In this study, we explored the developmental course of object recognition capacity in children using unimodal visual information, unimodal haptic information, and visuo-haptic information transfer in children from 4 years to 10 years and 11 months of age. Participants were tested through a clinical protocol, involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects, and visuo-haptic transfer of these two types of information. Results show an age-dependent development of object recognition abilities for visual, haptic, and visuo-haptic modalities. A significant effect of time on development of unimodal and crossmodal recognition skills was found. Moreover, our data suggest that multisensory processes for common object recognition are active at 4 years of age. They facilitate recognition of common objects, and, although not fully mature, are significant in adaptive behavior from the first years of age. The study of typical development of visuo-haptic processes in childhood is a starting point for future studies regarding object recognition in impaired populations.
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http://dx.doi.org/10.1080/09297049.2017.1316974DOI Listing
July 2018

Visual information from observing grasping movement in allocentric and egocentric perspectives: development in typical children.

Exp Brain Res 2017 07 28;235(7):2039-2047. Epub 2017 Mar 28.

Department of Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy.

Development of the motor system lags behind that of the visual system and might delay some visual properties more closely linked to action. We measured the developmental trajectory of the discrimination of object size from observation of the biological motion of a grasping action in egocentric and allocentric viewpoints (observing action of others or self), in children and adolescents from 5 to 18 years of age. Children of 5-7 years of age performed the task at chance, indicating a delayed ability to understand the goal of the action. We found a progressive improvement in the ability of discrimination from 9 to 18 years, which parallels the development of fine motor control. Only after 9 years of age did we observe an advantage for the egocentric view, as previously reported for adults. Given that visual and haptic sensitivity of size discrimination, as well as biological motion, are mature in early adolescence, we interpret our results as reflecting immaturity of the influence of the motor system on visual perception.
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http://dx.doi.org/10.1007/s00221-017-4944-1DOI Listing
July 2017

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

J Matern Fetal Neonatal Med 2018 Apr 28;31(8):973-980. Epub 2017 Mar 28.

g Pediatric Neurology Unit and Laboratories , "A. Meyer" Children's Hospital, University of Florence , Florence , Italy.

Purpose: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE).

Materials And Methods: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes.

Results: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM.

Conclusions: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.
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http://dx.doi.org/10.1080/14767058.2017.1304536DOI Listing
April 2018

Numerosity but not texture-density discrimination correlates with math ability in children.

Dev Psychol 2016 08;52(8):1206-16

Department of Neuroscience, Psychology, Pharmacology and Child Health, University of Florence.

Considerable recent work suggests that mathematical abilities in children correlate with the ability to estimate numerosity. Does math correlate only with numerosity estimation, or also with other similar tasks? We measured discrimination thresholds of school-age (6- to 12.5-years-old) children in 3 tasks: numerosity of patterns of relatively sparse, segregatable items (24 dots); numerosity of very dense textured patterns (250 dots); and discrimination of direction of motion. Thresholds in all tasks improved with age, but at different rates, implying the action of different mechanisms: In particular, in young children, thresholds were lower for sparse than textured patterns (the opposite of adults), suggesting earlier maturation of numerosity mechanisms. Importantly, numerosity thresholds for sparse stimuli correlated strongly with math skills, even after controlling for the influence of age, gender and nonverbal IQ. However, neither motion-direction discrimination nor numerosity discrimination of texture patterns showed a significant correlation with math abilities. These results provide further evidence that numerosity and texture-density are perceived by independent neural mechanisms, which develop at different rates; and importantly, only numerosity mechanisms are related to math. As developmental dyscalculia is characterized by a profound deficit in discriminating numerosity, it is fundamental to understand the mechanism behind the discrimination. (PsycINFO Database Record
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055099PMC
http://dx.doi.org/10.1037/dev0000155DOI Listing
August 2016

Patient-reported outcomes measure for children born preterm: validation of the SOLE VLBWI Questionnaire, a new quality of life self-assessment tool.

Dev Med Child Neurol 2016 09 7;58(9):957-64. Epub 2016 Apr 7.

Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.

Aim: This study was conducted to develop and validate a new self-report questionnaire for measuring quality of life (QoL), at school age, in children with a very low birthweight (VLBW).

Method: Through a focus group approach, children were involved directly in defining the questionnaire items, which were presented as illustrations rather than written questions. This preliminary validation of the questionnaire was conducted in 152 participants with VLBW (aged 7-11y) randomly selected from the five participating Italian centres. The questionnaire was completed by children and parents separately; data on children's demographic and medical history, and intellectual, adaptive, and behavioural functioning were collected using standardized scales. All the children also completed the Paediatric Quality of Life Inventory (PedsQL), another Italian-language measure of QoL in children.

Results: Our questionnaire was readily accepted and understood, and quick to complete. The Cronbach's alpha value showed it to be a reliable instrument. The child-compiled version correlated well with the PedsQL, whereas no correlations emerged with the other scales used, IQ, or degree of impairment. Conversely, these variables correlated significantly with the parent-compiled version. Children's and parents' answers were divergent on practically all the items.

Interpretation: The results confirm the validity of the new instrument and highlight a poor overlap between parents' and children's perspectives.
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http://dx.doi.org/10.1111/dmcn.13122DOI Listing
September 2016

Audio-Visual Stimulation Improves Visual Search Abilities in Hemianopia due to Childhood Acquired Brain Lesions.

Multisens Res 2015 ;28(1-2):153-71

Results obtained in both animal models and hemianopic patients indicate that sound, spatially and temporally coincident with a visual stimulus, can improve visual perception in the blind hemifield, probably due to activation of 'multisensory neurons', mainly located in the superior colliculus. In view of this evidence, a new rehabilitation approach, based on audiovisual stimulation of visual field, has been proposed, and applied in adults with visual field reduction due to unilateral brain lesions. So far, results have been very encouraging, with improvements in visual search abilities. Based on these findings, we have investigated the possibility of inducing long-lasting amelioration also in children with a visual deficit due to acquired brain lesions. Our results suggest that, in the absence of spontaneous recovery, audiovisual training can induce activation of visual responsiveness of the oculomotor system also in children and adolescents with acquired lesions and confirm the putatively important role of the superior colliculus (SC) in this process.
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http://dx.doi.org/10.1163/22134808-00002484DOI Listing
September 2015

Time, number and attention in very low birth weight children.

Neuropsychologia 2015 Jul 28;73:60-9. Epub 2015 Apr 28.

Department of Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy.

Premature birth has been associated with damage in many regions of the cerebral cortex, although there is a particularly strong susceptibility for damage within the parieto-occipital lobes (Volpe, 2009). As these areas have been shown to be critical for both visual attention and magnitudes perception (time, space, and number), it is important to investigate the impact of prematurity on both the magnitude and attentional systems, particularly for children without overt white matter injuries, where the lack of obvious injury may cause their difficulties to remain unnoticed. In this study, we investigated the ability to judge time intervals (visual, audio and audio-visual temporal bisection), discriminate between numerical quantities (numerosity comparison), map numbers onto space (numberline task) and to maintain visuo-spatial attention (multiple-object-tracking) in school-age preterm children (N29). The results show that various parietal functions may be more or less robust to prematurity-related difficulties, with strong impairments found on time estimation and attentional task, while numerical discrimination or mapping tasks remained relatively unimpaired. Thus while our study generally supports the hypothesis of a dorsal stream vulnerability in children born preterm relative to other cortical locations, it further suggests that particular cognitive processes, as highlighted by performance on different tasks, are far more susceptible than others.
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http://dx.doi.org/10.1016/j.neuropsychologia.2015.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040499PMC
July 2015

Vision problems in Down syndrome adults do not hamper communication, daily living skills and socialisation.

Wien Klin Wochenschr 2015 Aug 3;127(15-16):594-600. Epub 2015 Mar 3.

Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria,

Background: Down syndrome is the most commonly occurring chromosomal condition with a prevalence of 11.2-10000 life-births in Europe. The most important concern consists of various degrees of intellectual disability and sensory deficits. The overall prevalence of ophthalmologic abnormalities has been reported to be as high as 46-100%. Impairment of vision potentially hampers the capacity of learning and communication and thus of social integration. The aim of our study is to assess prospectively the occurrence of vision problems in patients with DS with special emphasis on adaptive behaviour and cognition.

Methods: Assessments included Hirschberg's corneal reflex method, eye alignment, cover test, Vineland Adaptive Behaviour Scales (VABS) for adaptive behaviour and Coloured Progressive Matrices (CPM) for cognitive abilities.

Results: We included prospectively 49 individuals from 19-52 years. Ophthalmologic problems were observed in 81.6% of our DS patients. The total number of visual disorders and symptoms was equally distributed with respect to ID-group and to levels of adaptive behaviour (p > 0.050). When comparing individuals matched for age, gender, cognitive skills and sociocultural background in a subset of individuals, vision problems did not decrease adaptive behaviour skills of our patients with visual disorders and daily living skills even fared better (p = 0.046).

Conclusions: Effective early correction and intervention on visual-motor deficits seem to be important, but nevertheless personal autonomy is not seriously detained.
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http://dx.doi.org/10.1007/s00508-015-0750-6DOI Listing
August 2015

Effect of early multisensory massage intervention on visual functions in infants with Down syndrome.

Early Hum Dev 2014 Dec 30;90(12):809-13. Epub 2014 Oct 30.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Viale del Tirreno 331, 56128 Calambrone, Pisa, Italy; Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Electronic address:

Background: Down syndrome is a frequent cause of intellectual disability, with severe impact on the quality of life of affected individuals and their families, and high social costs. Intervention programs should start soon after birth but no consensus exists on specific types and timing of early interventions in this population.

Aim: This pilot study explores the effects of an early multi-sensory intervention, based on body massage, on the development of visual function in infants with Down syndrome.

Method: Infants were randomly allocated to either a massage or a control group. Intervention consisted of only standard care (Control Group) or standard care plus infant massage (Massaged Group). Visual acuity was assessed by Teller Acuity Cards and stereopsis by the Frisby Stereopsis Screening Test at 5, 6, 9 and 12 months.

Results: Massaged Group Infants showed a significantly higher visual acuity at 6 months of age and an accelerated development up to at least 12 months; compared to Controls, stereopsis had an earlier onset in the Massaged Group followed by a faster maturation.

Conclusion: Environmental enrichment, in the tested form of infant massage, seems to affect maturation of visual functions in human infants, also in the presence of a genetic disability, when applied during a period of high brain plasticity.
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http://dx.doi.org/10.1016/j.earlhumdev.2014.08.016DOI Listing
December 2014

Ventral stream sensitivity in "healthy" preterm-born adolescents: psychophysical and neuropsychological evaluation.

Early Hum Dev 2014 Jan 25;90(1):45-9. Epub 2013 Nov 25.

Department of Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address:

Background: Deficits of motion processing have been reported in premature and very low birth-weight subjects during infancy, childhood and adolescence. Less is known about ventral stream functioning in preterms.

Aim: The aim of this study is to investigate ventral stream functioning in a sample of "healthy" adolescents born preterm with normal outcome and without brain damage.

Study Design: We enrolled thirty preterm-born adolescents (mean age: 14.2years, mean gestational age 28.9weeks, mean birth weight 1097g), and 34 age-matched term-born controls (mean age: 14.5years). All subjects were administered a psychophysical test known as "Form Coherence Task" and a comprehensive standardized battery of neuropsychological tests suitable for investigating ventral stream functioning including Street Completion Test, Poppelreuter-Ghent Test and the first part of the Visual Object and Space Perception (VOSP) battery. Dorsal stream visual functioning was investigated by the second part of the VOSP.

Results: Preterm (PT) subjects showed the same results in all "ventral" tasks with respect to full-term controls without any correlation to gestational age or birth weight. We found a significant negative correlation between Form Coherence Task and Letters Task (p=.014) and between Form Coherence and Silhouette Tasks (p=.017). No correlation was observed between Form Coherence Task and Street and Ghent Tests. A statistical difference was instead found between PTs and controls in two tasks of the VOSP battery that mostly involve the dorsal stream.

Conclusions: Preterm birth per se (in absence of evident brain lesions) is not sufficient to compromise the development of ventral pathway.
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http://dx.doi.org/10.1016/j.earlhumdev.2013.10.006DOI Listing
January 2014