Auditory time perception impairment in children with developmental dyscalculia.

Developmental dyscalculia (DD) is a specific learning disability which prevents children from acquiring adequate numerical and arithmetical competences. We investigated whether difficulties in children with DD spread beyond the numerical domain and impact also their ability to perceive time. A group of 37 children/adolescent with and without DD were tested with an auditory categorization task measuring time perception thresholds in the sub-second (0.25-1 s) and supra-second (0.75-3 s) ranges. Results showed that auditory time perception was strongly impaired in children with DD at both time scales. The impairment remained even when age, non-verbal reasoning, and gender were regressed out. Overall, our results show that the difficulties of DD can affect magnitudes other than numerical and contribute to the increasing evidence that frames dyscalculia as a disorder affecting multiple neurocognitive and perceptual systems.

Neurovisual Manifestations in Children with Mild COVID-19: An Association to Remember.

Neurovisual involvement has been reported in a number of patients with severe SARS-CoV-2 disease (COVID-19), mainly among adult patients. In children, such involvement has been reported in rare cases, often in those presenting with severe forms of COVID-19. The aim of this work is to explore the association between mild COVID-19 and neurovisual manifestations. We report the cases of three previously healthy children who developed neurovisual manifestations following mild acute COVID-19, analysing the clinical phenotype, the latency between the onset of acute COVID-19 and neurovisual involvement, and the kinetic of resolution. Our patients developed different clinical patterns, including visual impairment and ophthalmoplegia. In two cases, these clinical features occurred during acute COVID-19, while in the third patient their development was delayed after 10 days from disease onset. Furthermore, the dynamics of resolution were different, with one patient showing remission after 24 hours, the second after 30 days, and the third showing persistence of the strabismus after 2 months of follow-up. The spreading of COVID-19 among the paediatric population will probably lead to an increase of atypical disease forms, including those presenting with neurovisual involvement. Therefore, a better knowledge of the pathogenic and clinical features of these manifestations is warranted.

Sex influences on the neurocognitive outcome of preterm children.

This article presents a revision of the literature regarding the influence of sex differences on the recovery and long-term behavioral and cognitive outcomes of preterm children. After initial discussion of some methodological concerns, the literature regarding the concept of "male disadvantage," which is often used when talking about early neurological and psychomotor outcomes in preterm children, is presented. Subsequently, the literature data on sex-related differences in preterm children are discussed, focusing on their influence on the developmental pathways of cognition, language, executive function, behavior and affect, and response to rehabilitation therapies. Finally, evidence about brain structural and connectivity correlates of sex differences in the brain of preterm survivors is taken into account. Although visuo-spatial and visuo-perceptual functioning is widely studied in the preterm child and is strongly sex specific, little to no data are available regarding male-female differences in preterm children and the interaction effect between sex and preterm birth. For this reason, original data analyses of male-female differences in visuo-spatial performance from a small sample of preterm children are also presented.

Math difficulties in attention deficit hyperactivity disorder do not originate from the visual number sense.

There is ample evidence from literature and clinical practice indicating mathematical difficulties in individuals with ADHD, even when there is no concomitant diagnosis of developmental dyscalculia. What factors underlie these difficulties is still an open question. Research on dyscalculia and neurotypical development suggests visual perception of numerosity (the number sense) as a building block for math learning. Participants with lower numerosity estimation thresholds (higher precision) are often those with higher math capabilities. Strangely, the role of numerosity perception in math skills in ADHD has been neglected, leaving open the question whether math difficulties in ADHD also originate from a deficitary visual number sense. In the current study we psychophysically measured numerosity thresholds and accuracy in a sample of children/adolescents with ADHD, but not concomitant dyscalculia (N = 20, 8-16 years). Math abilities were also measured by tasks indexing different mathematical competences. Numerosity performance and math scores were then compared to those obtained from an age-matched control group (N = 20). Bayesian statistics indicated no difference between ADHD and controls on numerosity perception, despite many of the symbolic math tasks being impaired in participants with ADHD. Moreover, the math deficits showed by the group with ADHD remained substantial even when numerosity thresholds were statistically regressed out. Overall, these results indicate that math difficulties in ADHD are unlikely to originate from an impaired visual number sense.

Motor Influence in Developing Auditory Spatial Cognition in Hemiplegic Children with and without Visual Field Disorder.

Spatial representation is a crucial skill for everyday interaction with the environment. Different factors seem to influence spatial perception, such as body movements and vision. However, it is still unknown if motor impairment affects the building of simple spatial perception. To investigate this point, we tested hemiplegic children with (HV) and without visual field (H) disorders in an auditory and visual-spatial localization and pitch discrimination task. Fifteen hemiplegic children (nine H and six HV) and twenty with typical development took part in the experiment. The tasks consisted in listening to a sound coming from a series of speakers positioned at the front or back of the subject. In one condition, subjects were asked to discriminate the pitch, while in the other, subjects had to localize the position of the sound. We also replicated the spatial task in a visual modality. Both groups of hemiplegic children performed worse in the auditory spatial localization task compared with the control, while no difference was found in the pitch discrimination task. For the visual-spatial localization task, only HV children differed from the two other groups. These results suggest that movement is important for the development of auditory spatial representation.

Feasibility of audio-motor training with the multisensory device ABBI: Implementation in a child with hemiplegia and hemianopia.

Spatial representation is crucial when it comes to everyday interaction with the environment. Different factors influence spatial perception, such as body movements and vision. Accordingly, training strategies that exploit the plasticity of the human brain should be adopted early. In the current study we developed and tested a new training protocol based on the reinforcement of audio-motor associations. It supports spatial development in one hemiplegic child with an important visual field defect (hemianopia) in the same side of the hemiplegic limb. We focused on investigating whether a better representation of the space using the sound can also improve the involvement of the hemiplegic upper limb in daily life activity. The experimental training consists of intensive but entertaining rehabilitation for two weeks, during which a child performed ad-hoc developed audio-motor-spatial exercises with the Audio Bracelet for Blind Interaction (ABBI) for 2 h/day. We administered a battery of tests before and after the training that indicated that the child significantly improved in both the spatial aspects and the involvement of the hemiplegic limb in bimanual tasks. During the assessment, ActiGraph GT3X+ was used to measure asymmetry in the use of the two upper limbs with a standardized clinical tool, the Assisting Hand Assessment (AHA), pre and post-training. Additionally, the study measured and recorded spontaneous daily life activity for at least 2 h/day. These results confirm that one can enhance perceptual development in motor and visual disorders using naturally associated auditory feedback to body movements.

Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Normal Retinotopy in Primary Visual Cortex in a Congenital Complete Unilateral Lesion of Lateral Geniculate Nucleus in Human: A Case Study.

Impairment of the geniculostriate pathway results in scotomas in the corresponding part of the visual field. Here, we present a case of patient IB with left eye microphthalmia and with lesions in most of the left geniculostriate pathway, including the Lateral Geniculate Nucleus (LGN). Despite the severe lesions, the patient has a very narrow scotoma in the peripheral part of the lower-right-hemifield only (beyond 15° of eccentricity) and complete visual field representation in the primary visual cortex. Population receptive field mapping (pRF) of the patient's visual field reveals orderly eccentricity maps together with contralateral activation in both hemispheres. With diffusion tractography, we revealed connections between superior colliculus (SC) and cortical structures in the hemisphere affected by the lesions, which could mediate the retinotopic reorganization at the cortical level. Our results indicate an astonishing case for the flexibility of the developing retinotopic maps where the contralateral thalamus receives fibers from both the nasal and temporal retinae.

Auditory time thresholds in the range of milliseconds but not seconds are impaired in ADHD.

The literature on time perception in individuals with ADHD is extensive but inconsistent, probably reflecting the use of different tasks and performances indexes. A sample of 40 children/adolescents (20 with ADHD, 20 neurotypical) was engaged in two identical psychophysical tasks measuring auditory time thresholds in the milliseconds (0.25-1 s) and seconds (0.75-3 s) ranges. Results showed a severe impairment in ADHD for milliseconds thresholds (Log10BF = 1.9). The deficit remained strong even when non-verbal IQ was regressed out and correlation with age suggests a developmental delay. In the seconds range, thresholds were indistinguishable between the two groups (Log10BF = - 0.5) and not correlated with milliseconds thresholds. Our results largely confirm previous evidence suggesting partially separate mechanisms for time perception in the ranges of milliseconds and seconds. Moreover, since the evidence suggests that time perception of milliseconds stimuli might load relatively less on cognitive control and working memory, compared to longer durations, the current results are consistent with a pure timing deficit in individuals with ADHD.

Complex neurodevelopmental disorder in a preterm child with unilateral cerebellar hemorrhage.

BACKGROUND: Cerebellar hemorrhage (CBH) represents the main form of direct cerebellar injury in preterm infants. Most CBHs occur bilaterally, while isolated unilateral hemorrhages are less frequent and often associated with focal atrophy. Limited and heterogeneous data exist on preterm birth, unilateral CBH and consequent long-term neurodevelopmental and non-motor outcomes. CASE REPORT: This is the case of a six-year-old child, born preterm, diagnosed with a complete atrophy of the right cerebellar hemisphere through brain MRI and presenting mild social atypies, visuo-perceptive and pragmatic language impairment, but only minor neurological signs. DISCUSSION: Despite the large extension of the patient's CBH neurological sequelae were mild, likely due to cerebellar plasticity, and only specific deficits in non-motor, behavioral and social skills were shown. Evidence exists on cerebellar contribution to dynamic visual information processing and to perceptual signals detection and prediction, that might explain the presence of non-motor signs.

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.

Tele-Rehabilitation for Postural Control by Means of Virtual Reality Rehabilitation System in an Adolescent With Motor Disorder: A Case Study.

The coming of an unforeseen and hostile event such as the COVID-19 pandemic has brought about various changes in everyone's daily life. During the lockdown period, a huge number of restrictions were imposed, hence interrupting a wide range of activities previously proven to be necessary for some people. Due to the circumstances, rehabilitation treatments for children with neurodevelopmental disorders have been suspended, resulting in consequent distress for the children themselves and their parents. To overcome this problem, a tele-rehabilitation approach has proven to be an excellent solution to give continuity to children's rehabilitation. The tele-rehabilitation approach allows access to rehabilitation services directly from home. During lockdown due to the COVID-19 pandemic, the Virtual Reality Rehabilitation System (VRRS) HomeKit, developed by Khymeia, was employed as a rehabilitation system for the treatment of posture and balance of an adolescent with disabilities for the first time ever. Specifically, a 17-year-old female patient was enrolled and evaluated by the clinical staff before and after the home-training sessions. The system was delivered to the patient's home so that she could perform the tasks in a familiar environment, while under the supervision of the clinical staff. Through a specific platform, using different modules of the system, therapists could remotely check that the proposed exercises were properly performed and provide feedback and/or increase the difficulty according to the patient's needs and progress. Therefore, the treatment performed was carried out at home in a personalized, intensive, and playful way; characteristics do not present in a traditional treatment. Our results are promising and demonstrate both the efficacy of rehabilitation exercises carried out at home and the feasibility of home-based rehabilitation, when using the VRRS HomeKit even with adolescents. The VRRS HomeKit presents some limitations, such as the need to have the line connection and free space at home, the presence of technical issues, and the education of parents and patients to understand the instructions. Despite the limitations, this study provides the basis for continuing the experience of tele-rehabilitation on patients with a motor disorder also by customizing the exercises to their characteristics.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Typical Crossmodal Numerosity Perception in Preterm Newborns.

Premature birth is associated with a high risk of damage in the parietal cortex, a key area for numerical and non-numerical magnitude perception and mathematical reasoning. Children born preterm have higher rates of learning difficulties for school mathematics. In this study, we investigated how preterm newborns (born at 28-34 weeks of gestation age) and full-term newborns respond to visual numerosity after habituation to auditory stimuli of different numerosities. The results show that the two groups have a similar preferential looking response to visual numerosity, both preferring the incongruent set after crossmodal habituation. These results suggest that the numerosity system is resistant to prematurity.

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

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.

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

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.

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

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.

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

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 CD45dimCD34+CD133+ 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; p = 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.

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

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 (Aß) 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.