Longitudinal data of neuropsychological profile in a cohort of Duchenne muscular dystrophy boys without cognitive impairment.

The aim of the study was to re-assess neuropsychological profile in a group of boys with Duchenne muscular dystrophy without intellectual disability and neuropsychiatric disorder three years apart from a previous evaluation, to establish possible changes over time. We were also interested in defining more in detail correlation between genotype and neuropsychological phenotype. Thirty-three of the previous 40 subjects (mean age at follow up: 10 years and 7 months) agreed to participate in the follow up study and to perform the new assessment. The results confirm a typical neuropsychological profile, with difficulty in the manipulation of stored information, poor abstract reasoning and planning capacity and impulsiveness, supporting the involvement of a cerebellar striatal cortical network for these children. The more detailed description of subgroups of subjects, according to the real expression of Dp140, let to reveal possible genotype-neuropsychological phenotype correlations, and a more general neuropsychological impairment emerged in boys without Dp140 expression.

A new protocol for assessing action observation and imitation abilities in children with Developmental Coordination Disorder: A feasibility and reliability study.

AIMS: To develop a new protocol for the assessment of action observation (AO) abilities and imitation of meaningful and non-meaningful gestures, to examine its psychometric properties in children with DCD and typically developing (TD) children. BACKGROUND: For learning manual skills, AO and imitation are considered fundamental abilities. Knowledge about these modalities in children with DCD is scarce and an assessment protocol is lacking. METHOD: The protocol consists of 2 tests. The AO test consists of two assembly tasks. The imitation test includes 12 meaningful and 20 non-meaningful gestures. Items of both tests are rated on a 4-point scale. Twelve children with DCD (mean age 8y3m, SD, 1.30) and 11 TD children (mean age 8y2m, SD 1.52) were enrolled. For inter-rater reliability, intraclass correlation coefficients (ICC) were calculated for the total score, weighted kappa and percentage agreement for single items. Known group validity was assessed by comparison of DCD and TD group (Wilcoxon rank sum test). For construct validity, the mABC-2 test was used. The protocol was adapted and confirmed by an intra and inter-rater reliability study (new sample of 11 DCD children, mean age 7y5m, SD 1.37). RESULTS: Excellent ICCs were reported for intra and inter-rater reliability for the final protocol. A significant difference between DCD and TD group was found for AO abilities (p < .01), for nonmeaningful gestures (p < .001). A significant correlation was reported between the AO test and the mABC-2 test (r = 56;p ≤0.0001). No significant correlations were revealed for the imitation tests. DISCUSSION AND CONCLUSION: The results support the psychometric properties of this protocol. When fully validated, it may contribute to map the deficits in AO abilities and imitation, to evaluate treatment effects of imitation and AO interventions.

Cognitive profile in Duchenne muscular dystrophy boys without intellectual disability: The role of executive functions.

The aim of our prospective observational study was to assess profiles of cognitive function and a possible impairment of executive functions in a cohort of boys with Duchenne muscular dystrophy without intellectual and behavior disability. Forty Duchenne boys (range of age: 6 years to 11 years and 6 months) were assessed by Wechsler Intelligence scale and battery of tests including tasks assessing working memory and executive functions (inhibition and switching, problem solving and planning). In our cohort some aspects of cognitive function were often impaired. These included multitasking, problem solving, inhibition and working memory necessary to plan and direct goal oriented behavior. Our results support the suggestion that aspects of cognitive function could be impaired even in boys without intellectual disability and support the hypothesis that executive functions may play an important role in specific aspects of cognitive impairment in Duchenne muscular dystrophy.

Network over-connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study.

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P < 0.05. No contra-comparison results were found. The over-connectivity pattern in ASD occurred in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network-based diffusion study comparing toddlers with ASD and those with other-DD. Results indicate the detection of different connectivity patterns in ASD and other-DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333-2344, 2017. © 2017 Wiley Periodicals, Inc.

Diffusion Tractography Biomarkers of Pediatric Cerebellar Hypoplasia/Atrophy: Preliminary Results Using Constrained Spherical Deconvolution.

BACKGROUND AND PURPOSE: Advances in MR imaging modeling have improved the feasibility of reconstructing crossing fibers, with increasing benefits in delineating angulated tracts such as cerebellar tracts by using tractography. We hypothesized that constrained spherical deconvolution-based probabilistic tractography could successfully reconstruct cerebellar tracts in children with cerebellar hypoplasia/atrophy and that diffusion scalars of the reconstructed tracts could differentiate pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia, and progressive cerebellar atrophy. MATERIALS AND METHODS: Fifteen children with cerebellar ataxia and pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia or progressive cerebellar atrophy and 7 controls were included in this study. Cerebellar and corticospinal tracts were reconstructed by using constrained spherical deconvolution. Scalar measures (fractional anisotropy and mean, axial and radial diffusivity) were calculated. A general linear model was used to determine differences among groups for diffusion MR imaging scalar measures, and post hoc pair-wise comparisons were performed. RESULTS: Cerebellar and corticospinal tracts were successfully reconstructed in all subjects. Significant differences in diffusion MR imaging scalars were found among groups, with fractional anisotropy explaining the highest variability. All groups with cerebellar pathologies showed lower fractional anisotropy compared with controls, with the exception of cerebellar hypoplasia. CONCLUSIONS: This study shows the feasibility of constrained spherical deconvolution to reconstruct cerebellar and corticospinal tracts in children with morphologic cerebellar pathologies. In addition, the preliminary results show the potential utility of quantitative analysis of scalars of the cerebellar white matter tracts in children with cerebellar pathologies such as cerebellar hypoplasia and atrophy. Further studies with larger cohorts of patients are needed to validate the clinical significance of our preliminary results.

Brain reorganization following intervention in children with congenital hemiplegia: a systematic review.

Noninvasive rehabilitation strategies for children with unilateral cerebral palsy are routinely used to improve hand motor function, activity, and participation. Nevertheless, the studies exploring their effects on brain structure and function are very scarce. Recently, structural neuroplasticity was demonstrated in adult poststroke patients, in response to neurorehabilitation. Our purpose is to review current evidence on the effects of noninvasive intervention strategies on brain structure or function, in children with unilateral cerebral palsy. The main literature databases were searched up to October 2013. We included studies where the effects of upper limb training were evaluated at neurofunctional and/or neurostructural levels. Only seven studies met our selection criteria; selected studies were case series, six using the intervention of the constraint-induced movement therapy (CIMT) and one used virtual reality therapy (VR). CIMT and VR seem to produce measurable neuroplastic changes in sensorimotor cortex associated with enhancement of motor skills in the affected limb. However, the level of evidence is limited, due to methodological weaknesses and small sample sizes of available studies. Well-designed and larger experimental studies, in particular RCTs, are needed to strengthen the generalizability of the findings and to better understand the mechanism of intervention-related brain plasticity in children with brain injury.

Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency.

We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.

Thyroid-stimulating hormone levels in the first days of life and perinatal factors associated with sub-optimal neuromotor outcome in pre-term infants.

AIM: To identify perinatal factors associated with sub-optimal neuromotor outcome in infants without evident central nervous system lesions (intraventricular hemorrhage/ periventricular leukomalacia), with gestational age ≤30 (group I) and of 31-32 weeks (group II). PATIENTS AND METHODS: A total of 102 premature infants admitted to the Neonatal Intensive Care Unit of Pisa, at 26-32 weeks of gestation, were studied. Data about perinatal factors and TSH values at 3-4 days of life were collected. The assessment of neuromotor development was performed at 18 months of corrected age, using the locomotor subscale of the Griffiths Scales of Mental Development. RESULTS: Risk factors supposed to be predictive of sub-optimal neuromotor outcome (odds ratio >1) were at ≤30 weeks: male sex, small for gestational age, patent duct arterious, respiratory distress syndrome, and at 31-32 weeks: Apgar at 5 min <7, respiratory distress syndrome, patent duct arterious and birth weight <1500 g. A strong correlation was also found between TSH screening values >4,3 mU/l and suboptimal neuromotor outcome in both groups. CONCLUSIONS: Several perinatal factors, acting on an immature and more vulnerable nervous system, such as the pre-term one, different for different gestational ages, are associated with a sub-optimal neuromotor outcome. Higher, but within the normal range, TSH values at screening seem to be a strong risk factor for neuromotor outcome in preterm infants without intraventricular hemorrhage or periventricular leukomalacia.

Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia.

BACKGROUND: hereditary spastic paraplegias (HSP) are a group of neurodegenerative disorders characterized by progressive lower extremity spastic weakness. SPG7, SPG4 and SPG3A are some of the autosomal genes recently found as mutated in recessive or dominant forms of HSP in childhood. SPG31 is more often associated with a pure spastic paraplegia phenotype, but genotype-phenotype correlation is still unclear. The aims of the current study was: (i) to verify the mutational frequency of SPG4, SPG3A, SPG31 and SPG7 genes in our very-well-selected childhood sample, and (ii) to improve our knowledge about the clinical and electrophysiological HSP phenotypes and their possible correlation with a specific mutation. METHODS: a sample of 14 Italian children affected by pure HSP (mean age at diagnosis 5.9 years) was extensively investigated with electrophysiological, neuroradiological and genetic tests. RESULTS: three SPG4 mutations were identified in three patients: two novel missense mutations, both sporadic, and one multiexonic deletion already reported. A novel large deletion in SPG31 gene involving exons 2-5 was also detected in one young patient. No mutations in the SPG7 and in the SPG3A genes were found. CONCLUSIONS: our data confirm that HSP represent a heterogeneous group of genetic neurodegenerative disorders, also in sporadic or autosomal recessive early onset forms. Multiplex Ligation-dependent Probe Amplification-based mutation screening for SPG4 and SPG31 genes would be added to sequencing-based screening of SPG4, SPG31 and SPG3A genes in the routine diagnosis of HSP children.

Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.

We describe the clinical and molecular features of a child harboring a novel mutation in SLC6A8 gene in association with a milder phenotype than other creatine transporter (CT1) deficient patients (OMIM 300352) [1-7]. The mutation c.757 G>C p.G253R in exon 4 of SLC6A8 was hemizygous in the child, aged 6 years and 6 months, who showed mild intellectual disability with severe speech and language delay. His carrier mother had borderline intellectual functioning. Although the neurochemical and biochemical parameters were fully consistent with those reported in the literature for subjects with CT1 deficit, in our patient within a general cognitive disability, a discrepancy between nonverbal and verbal skills was observed, confirming the peculiar vulnerability of language development under brain Cr depletion.

Instrumented toys for studying power and precision grasp forces in infants.

Currently the study of infants grasping development is purely clinical, based on functional scales or on the observation of the infant while playing; no quantitative variables are measured or known for diagnosis of eventually disturbed development. The aim of this work is to show the results of a longitudinal study achieved by using a "baby gym" composed by a set of instrumented toys, as a tool to measure and stimulate grasping actions, in infants from 4 to 9 months of life. The study has been carried out with 7 healthy infants and it was observed, during infants development, an increase of precision grasp and a reduction of power grasp with age. Moreover the forces applied for performing both precision and power grasp increase with age. The proposed devices represent a valid tool for continuous and quantitative measuring infants manual function and motor development, without being distressful for the infant and consequently it could be suitable for early intervention training during the first year of life. The same system, in fact, could be used with infants at high risk for developmental motor disorder in order to evaluate any potential difference from control healthy infants.

Design and development of "biomechatronic gym" for early detection of neurological disorders in infants.

The study and measurement of grasping actions and forces in humans is important in a variety of contexts. In infants, it can give insights on the typical and atypical motor development, while it poses functional and operative requirements that are not fully matched by current sensing technology. Novel approaches for measuring infants' grasping actions are based on sensorized platform usable in natural settings. A new set of instrumented toys has been designed for the assessment/stimulation of upper limbs of infants between 4 and 9 months. A purposive biomechatronic gym has been developed by integrating pressure and force sensors and visual/auditory stimulations to the usual gym structure and hanging toys (cow, flower and ring puppets), so that the infants' actions on the gym can be monitored, measured and stimulated. With the developed system, a longitudinal clinical validation has been carried out with seven healthy infants. From data analysis it is possible to identify a trend in manual forces development and this result confirms the usefulness of the system proposed as a clinical tool for monitoring infants' grasping development.

Reticulated platelets and platelet reactivity in renal transplant recipients receiving antiplatelet therapy.

INTRODUCTION: Renal transplant recipients are at increased risk of cardiovascular morbidity and mortality. We assessed platelet reactivity and reticulated platelets (RPs) in 90 recipients, 51 (56.6%) of whom were not receiving acetylsalicylic acid (ASA) therapy (group A) and 39 (43.3%) who were receiving ASA therapy, 100 mg (group B), and in 60 healthy controls (group C). METHODS: Reticulated platelets were measured using a hematology automated analyzer (XE-2100; Sysmex Corp, Kobe, Japan) and were expressed as the percentage of RPs in the total optical platelet count (immature platelet fraction [IPF]), as the percentage of highly fluorescent RPs, and as the absolute number of RPs (IPF#). Platelet function was assessed using optical aggregometry (platelet aggregation) induced using 1 mmol/L of arachidonic acid, 2 or 10 micromol/L of adenosine diphosphate, or 2 microg/mL of collagen. RESULTS: Group A demonstrated significantly higher values of RP compared with group B or group C. Group B demonstrated a substantially higher percentage of RPs compared with group C, which was significant only for the IPF parameter. Multiple regression analysis demonstrated that IPF and IPF# were significantly and positively related to collagen-induced platelet aggregation. CONCLUSION: We documented the presence of higher concentrations of RPs in transplant recipients compared with a control population, and a significant association between RPs and platelet function.

Muscle MRI in FHL1-linked reducing body myopathy.

Reducing body myopathy is a rare progressive myopathy identified by characteristic pathological findings and secondary to dominantly acting mutations in the X-linked FHL1 gene. We report muscle MRI findings in two patients affected by reducing body myopathy and in their carrier mothers. All four showed a distinctive pattern of muscle alteration, with a predominant involvement of postero-medial muscle at thigh level and of soleus at calf level, with a striking sparing of glutei muscles that also appeared to be hypertrophic. These findings may help in the differential diagnosis of these disorders.

Language organisation in left perinatal stroke.

Right-hemispheric organisation of language has been observed following early left-sided brain lesions. The role of the site of damage is still controversial, as other aspects influence the pattern of speech organisation including timing of the lesion and the presence of epilepsy. We studied a group of 10 term-born children homogeneous for timing/type of lesion and clinical picture. All subjects had left perinatal arterial stroke, right hemiplegia, normal cognitive functions and no or easily controlled epileptic seizures. In half the patients, the lesion clearly involved Broca's area, in the other half it was remote from it. Language lateralization was explored by an fMRI covert rhyme generation task. Eight of 10 subjects showed a right lateralisation of language, including all five patients with a damaged left Broca and 3/5 of those without it. Group analysis in patients with right hemispheric organisation showed brain activations homotopic to those found in the left hemisphere of a matched control group. Our findings confirm that, at the end of gestation, the human brain exhibits extraordinary (re-)organisational capabilities. Language organisation in the right hemisphere is favoured by the presence of destructive lesions of the left Broca's area at birth, and occurs in brain regions homotopic to those usually involved in language processing.

Transcranial magnetic stimulation mapping: a model based on spline interpolation.

Transcranial magnetic stimulation (TMS) is a non-invasive method to investigate motor pathways and to create a map of the somatotopical organization of the motor cortex: ordinary mapping procedures requires a focal brain stimulation over different spots of the scalp and electromyographic (EMG) recording from a muscle. Finding an appropriate and a valid visual representation of collected data is a crucial step in research and clinical field to allow a relatively fast, intra- and inter-patient comparison of motor cortex mapping. Aim of this study was to develop and to validate a method to map cortical representation of an intrinsic hand muscle (abductor digiti minimi, ADM) using a two-dimensional spline interpolation of EMG peak amplitudes obtained with TMS. The interpolated model will result in a graphical colour-scaled representation of the motor cortex for the investigated muscle; fitted model was finally validated by comparing derived parameters with those directly measured to ensure the strength and reliability of the model. Ten healthy volunteers (mean age+/-S.D.: 35.3+/-4.7 years, 4 males and 6 females) were enrolled in the study. Transcranial stimulation was performed by placing a figure-of-eight coil over a predefined grid on the scalp of the subject. EMG responses were recorded from the right abductor digiti minimi (ADM): averaged EMG peak amplitudes obtained at each node were then used to perform spline interpolation and to derive other parameters like center of gravity (CoG). Arithmetical mean of all resting motor threshold at the hotspot was 50.6+/-3.4% of the maximal stimulator output. Average amplitude at the hotspot was 1.72+/-0.80 mV and its coordinates, expressed as median, were x=4.5 cm and y=0.0 cm. Mean CoG was located at x=4.86+/-0.57 cm and y=0.35+/-0.10 cm. Mean interpolated peak coordinates for ADM were xf=4.86+/-0.58 cm and yf=0.36+/-0.12 cm, while mean fitted peak amplitude was 0.87+/-0.47 mV. Results suggest how it is possible to map the primary motor cortex using two-dimensional spline interpolation of peak-to-peak amplitudes obtained by single pulse TMS delivered on several scalp positions, which will result in a smooth, easy to read, colour-scaled map. However, like other visual representation modalities, the interpolation should become complementary to traditional methods and not a substitute of a precise and accurate cortical motor mapping.

The assessment of visual acuity in children with periventricular damage: a comparison of behavioural and electrophysiological techniques.

It has been controversial whether electrophysiology offers better precision than behavioural techniques in measuring visual acuity in children with brain damage. We investigated the concordance between sweep VEPs and Acuity Cards (AC) in 29 children with periventricular leukomalacia (PVL), the most common type of brain damage in preterm infants. An overall good correlation was shown but with relatively better behavioural acuity values. VEP/AC ratio was significantly correlated to corpus callosum posterior thinning. We propose that this result reflects the efficacy of the compensatory mechanisms following early brain damage which may differentially affect the two methods.

General movements in infants with autism spectrum disorders.

General movements (GMs) are a distinct movement pattern carried out spontaneously without external stimulation and seen in fetuses of 9 weeks gestational age till 21 weeks postterm. GMs are helpful in the early diagnosis of an impaired central nervous system and the specific prediction of later neurological deficits. Autism spectrum disorder (ASD) is a neurodevelopmental disorder involving a life-long deficit in several aspects of the social and communicative behavior. Recently there appeared studies proving that children with ASD demonstrate disorders of motor development. To detect whether abnormalities in spontaneous motor activity can be observed already in the first months of life in infants with ASD. A retrospective study was performed by analyzing the family videos provided by parents of 20 children (male 17, female 3) later diagnosed as ASD. Home videos provided by parents of a control group of healthy children (n=20; male 10, female 10) matched for age with the ASD subjects and recorded in similar conditions were also analysed. In total 70 sequences were studied. Two independent observers, blind of the infants' outcome (ASD or normal), assessed the cases applying a global and a more detailed assessment of GMs. Hence, the age-specific GM pattern (normal or abnormal) as well as motor optimality scores were determined for each video sequence. Cohen kappa was 0.614. During the writhing movement period 70.0% sequences of infants with ASD showed poor repertoire GMs. In the control group, poor repertoire GMs were only seen in 12.5% of the sequences. In the fidgety movement period 20.8% of sequences were assessed as absent fidgety movements, 29.2% as abnormal fidgety movements. The large majority of the videos for the control cases were scored as normal (88.9%), 11.1% had no fidgety movements. According to the Mann-Whitney U test there were significant differences between the ASD and the control groups' optimality scores. The optimality scores were lower in the ASD group. The reduced optimality scores were mainly due to a lack of variable sequences, amplitude and speed of writhing GMs and an altered quality of fidgety and other spontaneous movements in the ASD group. Infants with ASD had more often poor repertoire writhing GMs as well as abnormal or absent fidgety movements than control infants. These data encourage further studies involving a larger number of family videos.

The term diplegia should be enhanced. Part I: a new rehabilitation oriented classification of cerebral palsy.

The classification systems for cerebral palsy (CP) need to be continuously updated, according to specific aims and to significant changes observed over the years in the panorama of CP. A simplification of CP categories, abandoning the use of the term diplegia, has been recently suggested. Conversely, in this paper a new proposal for classification of CP is briefly presented, where special attention is given to diplegia which is suggested to be divided into four main clinical forms, according to the patterns of walking observable in these subjects. The proposed classification was applied to a large population of 213 subjects with diplegia, among 467 cases of CP admitted to two reference centres for this disorder. The relative incidence of the four forms is reported. The adopted classification criteria, based on a primary ability of professionals working in rehabilitation, i.e. observation capacity, makes this approach simple and easy to use at all levels of the rehabilitation services for CP.