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1.  Navigation strategies as revealed by error patterns on the Magic Carpet test in children with cerebral palsy 
Introduction: Short-term memory develops differently in navigation vs. manual space. The Magic Carpet (MC) is a novel navigation test derived from the Walking Corsi Test and the manual Corsi Block-tapping Task (CBT). The MC requires mental rotations and executive function. In Cerebral Palsy (CP), CBT, and MC scores relate differently to clinical and lesional factors. Hypotheses of this study are: that frontal lesion specifically affect navigation in CP; that brain lesions affect MC cognitive strategies.
Materials and Methods: Twenty-two children with spastic CP, aged 5 to 14 years, 14 with a unilateral and 8 with a bilateral form, underwent the CBT and the MC. Errors were classified into seven patterns by a recently described algorithm. Brain lesions were quantified according to a novel semi-quantitative MRI scale. Control data were partially drawn from a previous study on 91 typically developing children.
Results: Children with CP performed worse than controls on both tests. Right hemispheric impairment correlated with spatial memory. MC span was reduced less than CBT span and was more selectively related to right middle white-matter and frontal lesions. Error patterns were differently distributed in CP and in typical development, and depended on right brain impairment: children with more extensive right lesions made more positional than sequential errors.
Discussion: In CP, navigation is affected especially by extensive lesions involving the right frontal lobe. In addition, these are associated with abnormal cognitive strategies. Whereas in typical development positional errors, preserving serial order, increase with age and performance, in CP they are associated with poorer performance and more extensive right-brain lesions. The explanation may lie in lesion side: right brain is crucial for mental rotations, necessary for spatial updating. Left-lateralized spatial memory strategies, relying on serial order, are not efficient if not accompanied by right-brain spatial functions.
PMCID: PMC4495317  PMID: 26217250
spatial memory; sequential memory; Corsi; MRI; brain lesion; hemiplegia; right hemisphere; reference frame
2.  Validity of semi-quantitative scale for brain MRI in unilateral cerebral palsy due to periventricular white matter lesions: Relationship with hand sensorimotor function and structural connectivity 
NeuroImage : Clinical  2015;8:104-109.
To provide first evidence of construct validity of a semi-quantitative scale for brain structural MRI (sqMRI scale) in children with unilateral cerebral palsy (UCP) secondary to periventricular white matter (PWM) lesions, by examining the relationship with hand sensorimotor function and whole brain structural connectivity.
Cross-sectional study of 50 children with UCP due to PWM lesions using 3 T (MRI), diffusion MRI and assessment of hand sensorimotor function. We explored the relationship of lobar, hemispheric and global scores on the sqMRI scale, with fractional anisotropy (FA), as a measure of brain white matter microstructure, and with hand sensorimotor measures (Assisting Hand Assessment, AHA; Jebsen–Taylor Test for Hand Function, JTTHF; Melbourne Assessment of Unilateral Upper Limb Function, MUUL; stereognosis; 2-point discrimination).
Lobar and hemispheric scores on the sqMRI scale contralateral to the clinical side of hemiplegia correlated with sensorimotor paretic hand function measures and FA of a number of brain structural connections, including connections of brain areas involved in motor control (postcentral, precentral and paracentral gyri in the parietal lobe). More severe lesions correlated with lower sensorimotor performance, with the posterior limb of internal capsule score being the strongest contributor to impaired hand function.
The sqMRI scale demonstrates first evidence of construct validity against impaired motor and sensory function measures and brain structural connectivity in a cohort of children with UCP due to PWM lesions. More severe lesions correlated with poorer paretic hand sensorimotor function and impaired structural connectivity in the hemisphere contralateral to the clinical side of hemiplegia. The quantitative structural MRI scoring may be a useful clinical tool for studying brain structure–function relationships but requires further validation in other populations of CP.
•Validity of a novel systematic approach to MR structural imaging•Relationship between lesion severity on structural MRI, clinical measures and HARDI•Usefulness of a scale to support brain structure–function relationship research
PMCID: PMC4473818  PMID: 26106533
Brain structure; Sensorimotor function; Unilateral cerebral palsy; Magnetic resonance imaging; Diffusion; HARDI; CP, cerebral palsy; MRI, magnetic resonance imaging; sqMRI, semi-quantitative MRI; PWM, periventricular white matter; AHA, Assisting Hand Assessment; MUUL, Melbourne Assessment of Unilateral Upper Limb function; JTTHF, Jebsen–Taylor test of hand function; GMFCS, Gross Motor Function Classification System; MACS, Manual Ability Classification System; FA, fractional anisotropy
3.  The first 1000 days of the autistic brain: a systematic review of diffusion imaging studies 
There is overwhelming evidence that autism spectrum disorder (ASD) is related to altered brain connectivity. While these alterations are starting to be well characterized in subjects where the clinical picture is fully expressed, less is known on their earlier developmental course. In the present study we systematically reviewed current knowledge on structural connectivity in ASD infants and toddlers. We searched PubMed and Medline databases for all English language papers, published from year 2000, exploring structural connectivity in populations of infants and toddlers whose mean age was below 30 months. Of the 264 papers extracted, four were found to be eligible and were reviewed. Three of the four selected studies reported higher fractional anisotropy values in subjects with ASD compared to controls within commissural fibers, projections fibers, and association fibers, suggesting brain hyper-connectivity in the earliest phases of the disorder. Similar conclusions emerged from the other diffusion parameters assessed. These findings are reversed to what is generally found in studies exploring older patient groups and suggest a developmental course characterized by a shift toward hypo-connectivity starting at a time between two and four years of age.
PMCID: PMC4374458  PMID: 25859207
autism; diffusion MRI; structural connectivity; toddlers; hyperconnectivity; neurodevelopment
4.  Home-based, early intervention with mechatronic toys for preterm infants at risk of neurodevelopmental disorders (CARETOY): a RCT protocol 
BMC Pediatrics  2014;14:268.
Preterm infants are at risk for neurodevelopmental disorders, including motor, cognitive or behavioural problems, which may potentially be modified by early intervention. The EU CareToy Project Consortium ( has developed a new modular system for intensive, individualized, home-based and family-centred early intervention, managed remotely by rehabilitation staff. A randomised controlled trial (RCT) has been designed to evaluate the efficacy of CareToy training in a first sample of low-risk preterm infants.
The trial, randomised, multi-center, evaluator-blinded, parallel group controlled, is designed according to CONSORT Statement. Eligible subjects are infants born preterm without major complications, aged 3-9 months of corrected age with specific gross-motor abilities defined by Ages & Stages Questionnaire scores. Recruited infants, whose parents will sign a written informed consent for participation, will be randomized in CareToy training and control groups at baseline (T0). CareToy group will perform four weeks of personalized activities with the CareToy system, customized by the rehabilitation staff. The control group will continue standard care. Infant Motor Profile Scale is the primary outcome measure and a total sample size of 40 infants has been established. Bayley-Cognitive subscale, Alberta Infants Motor Scale and Teller Acuity Cards are secondary outcome measures. All measurements will be performed at T0 and at the end of training/control period (T1). For ethical reasons, after this first phase infants enrolled in the control group will perform the CareToy training, while the training group will continue standard care. At the end of open phase (T2) all infants will be assessed as at T1. Further assessment will be performed at 18 months corrected age (T3) to evaluate the long-term effects on neurodevelopmental outcome. Caregivers and rehabilitation staff will not be blinded whereas all the clinical assessments will be performed, videotaped and scored by blind assessors. The trial is ongoing and it is expected to be completed by April 2015.
This paper describes RCT methodology to evaluate CareToy as a new tool for early intervention in preterm infants, first contribution to test this new type of system. It presents background, hypotheses, outcome measures and trial methodology.
Trial registration NCT01990183. EU grant ICT-2011.5.1-287932.
PMCID: PMC4287225  PMID: 25319764
Early intervention; Preterm infants; RCT; Tele-rehabilitation; ICT; Medical bioengineering; Neurodevelopmental disorders
6.  A novel mouse model of creatine transporter deficiency 
F1000Research  2014;3:228.
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352).
CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT −/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.
PMCID: PMC4243761  PMID: 25485098
7.  Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum 
JIMD Reports  2014;16:81-87.
Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism presenting with heterogeneous neurological symptoms such as psychomotor delay, seizures, intellectual disability and it is characterized by increased urinary excretion of N-acetylated amino acids. We report on a new patient who presented ACY1 deficiency in association with isolated mild intellectual disability, but neither neurological symptoms nor autistic features. The child showed a compound heterozygous mutation (p.Glu233Asp) and a novel p.Ser192Arg fs*64, predicting an unstable transcript and resulting in very low protein levels.
This new ACY1 deficient child was identified through regular screening for inborn error of metabolism adopted in our department in all cases of intellectual disability. This report supports a recommendation to perform metabolic investigations in patients with isolated mild intellectual disability.
PMCID: PMC4221304  PMID: 24997716
8.  Congenital nystagmus in two infants born from mothers exposed to methadone during pregnancy 
Methadone is commonly prescribed as a substitute for illicit opioids. Use of methadone during pregnancy is associated with neonatal abstinence syndrome (NAS), reduced head circumference as well as a slight increase in neonatal mortality and morbidity. Less is known about the effects of methadone on the visual system.
We report two Italian cases of nystagmus in infants born from mothers exposed to methadone during pregnancy. Ophthalmic or central disorders were excluded as a cause of nystagmus in both infants. The first case was followed at 3, 6 and 12 months while the second one was evaluated at 5 and 8 months. Both infants had normal neurological and cognitive development. Their first evaluation revealed different characteristics but both showed progressive improvement in ocular disorder, persistence of pendular horizontal nystagmus and nearly normal visual acuity.
This report, the first description of Italian cases of nystagmus related to use of methadone during pregnancy, underlies the importance of a careful investigation of drug use in pregnancy in cases of unexplained congenital nystagmus.
PMCID: PMC3726377  PMID: 23822191
Congenital nystagmus; Methadone; Pregnancy
9.  Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI) 
BMC Pediatrics  2012;12:144.
Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.
Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.
This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.
Trial registration
Current Controlled Trials ISRCTN62175998; Identifier NCT01241019; EudraCT Number 2010-018627-25
PMCID: PMC3478965  PMID: 22950861
Neonatal hypoxic-ischemic encephalopathy; Therapeutic hypothermia; Topiramate
10.  Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency 
SLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain–blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial.
In this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24–36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations.
During L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range.
This study provides information to support the effectiveness of L-Arg supplement treatment in CTRT-D patients; in fact the syndromic pattern of cognitive and linguistic deficit presented by CRTR-D patients was partially altered by L-Arg supplementation especially at a qualitative clinical level. Oral L-Arg may represent not only a protective factor towards a further cognitive decline, but can lead to the acquisition of new skills.
PMCID: PMC3526552  PMID: 22713831
Creatine transporter deficiency; XLMR; Speech delay; Arginine treatment; SLC6A8 gene; Magnetic resonance spectroscopy
11.  Upper limb children action-observation training (UP-CAT): a randomised controlled trial in Hemiplegic Cerebral Palsy 
BMC Neurology  2011;11:80.
Rehabilitation for children with hemiplegic cerebral palsy (HCP) aimed to improve function of the impaired upper limb (UL) uses a wide range of intervention programs. A new rehabilitative approach, called Action-Observation Therapy, based on the recent discovery of mirror neurons, has been used in adult stroke but not in children. The purpose of the present study is to design a randomised controlled trial (RCT) for evaluating the efficacy of Action-Observation Therapy in improving UL activity in children with HCP.
The trial is designed according to CONSORT Statement. It is a randomised, evaluator-blinded, match-pair group trial. Children with HCP will be randomised within pairs to either experimental or control group. The experimental group will perform an Action-Observation Therapy, called UP-CAT (Upper Limb-Children Action-Observation Training) in which they will watch video sequences showing goal-directed actions, chosen according to children UL functional level, combined with motor training with their hemiplegic UL. The control group will perform the same tailored actions after watching computer games. A careful revision of psychometric properties of UL outcome measures for children with hemiplegia was performed. Assisting Hand Assessment was chosen as primary measure and, based on its calculation power, a sample size of 12 matched pairs was established. Moreover, Melbourne and ABILHAND-Kids were included as secondary measures. The time line of assessments will be T0 (in the week preceding the onset of the treatment), T1 and T2 (in the week after the end of the treatment and 8 weeks later, respectively). A further assessment will be performed at T3 (24 weeks after T1), to evaluate the retention of effects. In a subgroup of children enrolled in both groups functional Magnetic Resonance Imaging, exploring the mirror system and sensory-motor function, will be performed at T0, T1 and T2.
The paper aims to describe the methodology of a RCT for evaluating the efficacy of Action-Observation Therapy in improving UL activity in children with hemiplegia. This study will be the first to test this new type of treatment in childhood. The paper presents the theoretical background, study hypotheses, outcome measures and trial methodology.
Trial Registration
PMCID: PMC3141400  PMID: 21711525
12.  Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome 
Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the prime animal model for DS, have severe cognitive and neural plasticity defects due to excessive inhibition. We report that increasing sensory-motor stimulation in adulthood through environmental enrichment (EE) reduces brain inhibition levels and promotes recovery of spatial memory abilities, hippocampal synaptic plasticity, and visual functions in adult Ts65Dn mice.
PMCID: PMC3245647  PMID: 22207837
Down syndrome; Ts65Dn mice; environmental enrichment; GABAergic inhibition; cerebral plasticity
13.  Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491 
BMC Pediatrics  2010;10:83.
Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.
In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.
Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.
This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.
Trial Registration
Current Controlled Trials ISRCTN18523491; Identifier NCT01079715; EudraCT Number 2010-018737-21
PMCID: PMC2993687  PMID: 21087499

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