Tumor electroporation (EP) refers to the permeabilization of the cell membrane by means of short ... more Tumor electroporation (EP) refers to the permeabilization of the cell membrane by means of short electric pulses thus allowing the potentiation of chemotherapeutic drugs. Standard plate adhesion 2D cell cultures can simulate the in vivo environment only partially due to lack of cell–cell interaction and extracellular matrix (ECM). In this study, we assessed a novel 3D scaffold for cell cultures based on hyaluronic acid and ionic-complementary self-assembling peptides (SAPs), by studying the growth patterns of two different breast carcinoma cell lines (HCC1569 and MDA-MB231). This 3D scaffold modulates cell shape and induces extracellular matrix deposit around cells. In the MDA-MB 231 cell line, it allows three-dimensional growth of structures known as spheroids, while in HCC1569 it achieves a cell organization similar to that observed in vivo. Interestingly, we were able to visualize the electroporation effect on the cells seeded in the new scaffold by means of standard propidium io...
To date, behavioural procedures adopted to assess sound preferences in young children have evalua... more To date, behavioural procedures adopted to assess sound preferences in young children have evaluated the responses of participants while listening to the stimuli administered by the experimenter. Due to the difficulties which may arise in the interpretation of the results, recent studies have suggested some limitations to these procedures, stimulating the further development of behavioural methods. Here, we introduce a new method for testing sound preferences in children, in which participants actively produce the stimuli during the experimental session. The apparatus consists of a musical lever which emits different sounds depending on its rotation around a hinge. The device was programmed to emit consonant and dissonant harmonic intervals. The procedure has been tested with 22 participants from 19 to 40 months of age. Results show that: (a) sound emission strongly stimulates toy manipulation; (b) the examined participants distinguished the two types of sounds, showing a preference...
The First IEEE/RAS-EMBS International Conference on Biomedical Robotics and Biomechatronics, 2006. BioRob 2006.
AbstractMovement and behaviour analysis is a key re-search area in the domain of biomedical engi... more AbstractMovement and behaviour analysis is a key re-search area in the domain of biomedical engineering and in many other medical research domains aiming at the under-standing of physiological motor and cognitive basic mecha-nisms. The systematic application of robotic and ...
Proceedings 2007 IEEE International Conference on Robotics and Automation, 2007
Neuro-Developmental Engineering is a new interdisciplinary research area at the intersection of d... more Neuro-Developmental Engineering is a new interdisciplinary research area at the intersection of developmental neuroscience and bioengineering. Applications can be found in early detection of neuro-developmental disorders via a new generation of mechatronic toys for assessing the regular development of perceptual and motor skills in infants, in particular coordination of mobile and multiple frames of reference during manipulation. This paper focuses on the design of a novel mechatronic toy, shaped as a 5 cm (diameter) ball, i.e. small enough to be grasped with a single hand by a 1 year old child. The sensorized ball is designed to embed a kinematics sensing unit, able to sense both the orientation in 3D space and linear accelerations, as well as a force sensing unit, to detect grasping patterns during manipulation. Dimensioning of batteries able to operate for 1 hour during experimental sessions as well as a wireless communication unit are also included in the design.
Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizo... more Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizophrenia. Reelin haploinsufficiency in the heterozygous rl/+ mouse causes behavioral abnormalities soon after birth, consisting of decreased ultrasound vocalizations (USV) emitted by pups upon maternal separation, as well as in adult life, producing behavioral rigidity in a task requiring a change in strategy. At the anatomical level, reelin haploinsufficiency causes a loss of GABAergic inhibitory neurons, e.g. parvalbumin-positive neurons in limbic areas and basal ganglia, and Purkinje cells (PC) in the cerebellum. This PC loss is more evident in male than female mice. Objectives: 1) To characterize brain circuit abnormalities of heterozygous reeler (rl/+) mice, and their sex-dependency; 2) To unravel the mechanisms of neuronal loss in brain areas that are relevant for autism, like the cerebellum and limbic system, focusing on interactions between decreased reelin levels and sex steroids...
2008 International Conference on Technology and Applications in Biomedicine, 2008
In this work, a novel technological approach to the early diagnosis of neuro-developmental disord... more In this work, a novel technological approach to the early diagnosis of neuro-developmental disorders is presented. Disorders such as Autism are typically diagnosed after language development, i.e. after the 2-3 years of age. In this paper, three different typologies of instruments are presented which are designed to assess infants behavior in different perceptual and motor domains. The first is an
2006 IEEE/RSJ International Conference on Intelligent Robots and Systems, 2006
In this work the problem of orientation tracking based on inertial/magnetic sensors is restated i... more In this work the problem of orientation tracking based on inertial/magnetic sensors is restated in geometric terms, in particular an intrinsic observer, i.e. an observer whose performance does not depend on a specific choice of coordinates, is derived on the Lie group of rigid body rotations SO(3). Measurements of the gravitational and geomagnetic fields are used to estimate orientation errors. A coordinate-free control law is defined on the Lie algebra and fed back in terms of angular velocity that steers the observer towards the correct attitude. A proof of stability for the proposed estimator is provided which relies on the natural (bi-invariant) metric of SO(3). The observer results stable for almost the whole configuration space. Presence of unstable equilibria as a limitation for global stability is also discussed. Based on the proposed intrinsic control law, a filter is designed which implements the observer. Simulations are presented that test the numerical implementation of the proposed observer.
The development of sensorimotor coordination in infancy is fundamental for regulating interaction... more The development of sensorimotor coordination in infancy is fundamental for regulating interactional dynamics with peers and adults. In this work we present a multimodal device to systematically assess children's orienting behavior in social situations. Technological choices are emphasized with respect to ecological requirements. Also ad-hoc calibration procedures are presented which are suitable to unstructured environments. Preliminary tests carried out at a
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2011
This study analyzes motor adaptation during a redundant tasks with the wrist. The goal is threefo... more This study analyzes motor adaptation during a redundant tasks with the wrist. The goal is threefold: (i) understanding if motor adaptation also occurs when CNS is involved in the solution of the redundancy problem; (ii) addressing whether motor strategies used to solve redundancy (i.e Donders' law) are disrupted or not during adaptation; (iii) verifying if motor strategies remain the same during adaptation and washout or they themselves adapt. First of all, our data confirm that CNS adapts its movements to the perturbation also when it is committed in the execution of a redundant task. Secondly, we showed that motor strategies used to solve redundancy (i.e Donders' law) are not disrupted during adaptation, since absolute values of thickness during the whole protocol remain in the range of physiological values. Lastly, analysis of the curvature of Donders' surfaces suggests that motor strategies, such as Donders' law, remain invariant during motor adaptation in redund...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2009
This paper describes an interdisciplinary approach to the assessment on infants' behavior, wi... more This paper describes an interdisciplinary approach to the assessment on infants' behavior, with a focus on the technology. The goal is an objective, quantitative analysis of concurrent maturation of sensory, motor and cognitive abilities in young children, in relation to the achievement of developmental milestones. An instrumented block-box toy specifically developed to assess the ability to insert objects into holes is presented. The functional specifications are derived from experimental protocols devised by neuroscientists to assess spatial cognition skills. Technological choices are emphasized with respect to ecological requirements. An ad-hoc calibration procedure is also presented which is suitable to unstructured environments. Finally, preliminary tests carried out at a local day-care with 12-24 months old infants are presented which prove the in-field usability of the proposed technology.
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2008
In this work, a novel technological approach to the early diagnosis of neuro-developmental disord... more In this work, a novel technological approach to the early diagnosis of neuro-developmental disorders is presented. Disorders such as Autism are typically diagnosed after language development, i.e. after the 2-3 years of age. In this paper, three different typologies of instruments are presented which are designed to assess infants behavior in different perceptual and motor domains. The first is an instrumented toy embedding kinematic and force sensors for studying grasping and manipulation in infants as young as 6 months old. The second is a wearable device for sensing the kinematics of the upper and lower limbs of infants, designed to assess spontaneous movements in premature babies. The third is a multimodal audio-visuo-vestibular cap which was designed to assess infants orienting behaviors in social situations in response to audio and visual stimuli.
2006 International Conference of the IEEE Engineering in Medicine and Biology Society, 2006
This paper introduces Neurodevelopmental Engineering, a new interdisciplinary research area at th... more This paper introduces Neurodevelopmental Engineering, a new interdisciplinary research area at the intersection of developmental neuroscience and bioengineering. Specifically, it presents current results of the design and development process of a set of instrumented toys equipped with a variety of sensors for behavioral analysis of infants in minimally structured environmental conditions. First the multidisciplinary design approach is presented, then the detailed functional and technical specifications of the proposed biomechatronic toys and of their scenarios of use are described. Finally, a clear picture of ongoing implementation of the proposed technology is provided together with preliminary results of verification tests.
This technology is expected to be also useful in the long term for developing new tools, e.g. toy... more This technology is expected to be also useful in the long term for developing new tools, e.g. toys, which can sustain, in ecological scenarios, the regular development of motor and cognitive abilities of the child, based on a rigorous scientific approach. The long term goal is establishing standards against which development of infants at risk for neuro-developmental disorders, particularly autism, can be measured, with the aim of detecting early signs of disturbed development. 1.1 Sensori-Motor Integration Deficits in Neurodevelopmental Disorders Neurodevelopmental disorders such as ASD, ADHD, Tourette syndrome and others are characterized by a genetic basis. In this case behavioral analysis, or behavioral phenotyping, will be instrumental for the analysis of the roles of genes in behavior (Gerlai 2002). Autism is a behavioral disorder, with onset in childhood, which is characterized by deficits in three basic domains: social interaction, language and communication, and pattern of interests. There is no doubt that autism has a strong genetic component, and that biological disease mechanisms leading to autism are already active during foetal development and/or infancy,
Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenes... more Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenesis is severely impaired in E-reeler mice, a model of Reelin deficiency showing specific Green Fluorescent Protein expression in Rod Bipolar Cells (RBCs). Since no data are available on Reelin and NGF cross-talk, NGF and trkA NGFR /p75 NTR expression was investigated in retinas from E-reeler versus control mice, by confocal microscopy, Western blotting, and real time PCR analysis. A scattered increase of NGF protein was observed in the Ganglion Cell Layer and more pronounced in the Inner Nuclear Layer (INL). A selective increase of p75 NTR was detected in most of RBCs and in other cell subtypes of INL. On the contrary, a slight trend towards a decrease was detected for trkA NGFR , albeit not significant. Confocal data were validated by Western blot and real time PCR. Finally, the decreased trkA NGFR /p75 NTR ratio, representative of p75 NTR increase, significantly correlated with E-reeler versus E-control. These data indicate that NGF-trkA NGFR /p75 NTR is affected in E-reeler retina and that p75 NTR might represent the main NGF receptor involved in the process. This first NGF-trkA NGFR /p75 NTR characterization suggests that E-reeler might be suitable for exploring Reelin-NGF crosstalk, representing an additional information source in those pathologies characterized by retinal degeneration.
Genetic risk factors acting during pregnancy or early after birth have been proposed to account f... more Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2ppm in Dams' drinking water), or at a toxic dose (6ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2ppm MeHg does not cause PCs loss in the different animal groups, and ...
Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. He... more Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. Here, we demonstrate that Reelin functions postnatally to regulate the development of the neuromuscular junction. Reelin is required for motor end-plate maturation and proper nerve-muscle connectivity, and it directly promotes synapse elimination. Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity.
According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly exp... more According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice-a putative model of neuroanatomical and behavioral endophenotypes in ASD-show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity.
We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (... more We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (rl/+) reeler mice of either sex during early postnatal development; in parallel, we quantified levels of neuroactive steroids in the cerebellum with mass spectrometry. We also quantified reelin mRNA and protein expression with RT-PCR and Western blotting. PC numbers are selectively reduced at postnatal day 15 (P15) in rl/+ males in comparison to +/+ males, +/+ females, and rl/+ females. Administration of 17beta-estradiol (17beta-E) into the cisterna magna at P5 increases PC numbers in rl/+ males, but not in the other groups; conversely, estrogen antagonists 4-OH-tamoxifen or ICI 182,780 reduce PC numbers in +/+ and rl/+ females, but have no effect in males. Testosterone (T) levels at P5 are much higher in males than in females, reflecting the perinatal testosterone surge in males. In addition, rl/+ male cerebella at P5 show a peculiar hormonal profile in comparison with the other groups, consisting of increased levels of T and 17beta-E, and decreased levels of dihydrotestosterone. RT-PCR analysis indicated that heterozygosity leads to a 50% reduction of reelin mRNA in the cerebellum in both sexes, as expected, and that 17beta-E upregulates reelin mRNA, particularly in rl/+ males; reelin mRNA upregulation is associated with an increase of all major reelin isoforms. These effects may represent a novel model of how reelin deficiency interacts with variable perinatal levels of neuroactive steroids, leading to gender-dependent differences in genetic vulnerability.
This paper describes an interdisciplinary approach to the assessment of children development of s... more This paper describes an interdisciplinary approach to the assessment of children development of spatial cognition, with a focus on the technology. An instrumented toy (blockbox) is presented which embeds magneto-inertial sensors for orientation tracking, specifically developed to assess the ability to insert objects into holes. The functional specifications are derived from experimental protocols devised by neuroscientists to assess spatial cognition skills in children. Technological choices are emphasized with respect to ecological requirements. Adhoc calibration procedures are presented which are suitable to unstructured environments. Preliminary results based on experimental trials carried out at a day-care on typically developing children (12-36 months old) show how the instrumented objects can be used effectively in a semi-automatic fashion (i.e. rater-independent) to derive accurate measurements such as orientation errors and insertion time which are relevant to the object insertion task. This study indicates that a technological approach to ecological assessment of spatial cognition in children is indeed feasible and maybe useful for identification and early assessment of developmental delay.
Tumor electroporation (EP) refers to the permeabilization of the cell membrane by means of short ... more Tumor electroporation (EP) refers to the permeabilization of the cell membrane by means of short electric pulses thus allowing the potentiation of chemotherapeutic drugs. Standard plate adhesion 2D cell cultures can simulate the in vivo environment only partially due to lack of cell–cell interaction and extracellular matrix (ECM). In this study, we assessed a novel 3D scaffold for cell cultures based on hyaluronic acid and ionic-complementary self-assembling peptides (SAPs), by studying the growth patterns of two different breast carcinoma cell lines (HCC1569 and MDA-MB231). This 3D scaffold modulates cell shape and induces extracellular matrix deposit around cells. In the MDA-MB 231 cell line, it allows three-dimensional growth of structures known as spheroids, while in HCC1569 it achieves a cell organization similar to that observed in vivo. Interestingly, we were able to visualize the electroporation effect on the cells seeded in the new scaffold by means of standard propidium io...
To date, behavioural procedures adopted to assess sound preferences in young children have evalua... more To date, behavioural procedures adopted to assess sound preferences in young children have evaluated the responses of participants while listening to the stimuli administered by the experimenter. Due to the difficulties which may arise in the interpretation of the results, recent studies have suggested some limitations to these procedures, stimulating the further development of behavioural methods. Here, we introduce a new method for testing sound preferences in children, in which participants actively produce the stimuli during the experimental session. The apparatus consists of a musical lever which emits different sounds depending on its rotation around a hinge. The device was programmed to emit consonant and dissonant harmonic intervals. The procedure has been tested with 22 participants from 19 to 40 months of age. Results show that: (a) sound emission strongly stimulates toy manipulation; (b) the examined participants distinguished the two types of sounds, showing a preference...
The First IEEE/RAS-EMBS International Conference on Biomedical Robotics and Biomechatronics, 2006. BioRob 2006.
AbstractMovement and behaviour analysis is a key re-search area in the domain of biomedical engi... more AbstractMovement and behaviour analysis is a key re-search area in the domain of biomedical engineering and in many other medical research domains aiming at the under-standing of physiological motor and cognitive basic mecha-nisms. The systematic application of robotic and ...
Proceedings 2007 IEEE International Conference on Robotics and Automation, 2007
Neuro-Developmental Engineering is a new interdisciplinary research area at the intersection of d... more Neuro-Developmental Engineering is a new interdisciplinary research area at the intersection of developmental neuroscience and bioengineering. Applications can be found in early detection of neuro-developmental disorders via a new generation of mechatronic toys for assessing the regular development of perceptual and motor skills in infants, in particular coordination of mobile and multiple frames of reference during manipulation. This paper focuses on the design of a novel mechatronic toy, shaped as a 5 cm (diameter) ball, i.e. small enough to be grasped with a single hand by a 1 year old child. The sensorized ball is designed to embed a kinematics sensing unit, able to sense both the orientation in 3D space and linear accelerations, as well as a force sensing unit, to detect grasping patterns during manipulation. Dimensioning of batteries able to operate for 1 hour during experimental sessions as well as a wireless communication unit are also included in the design.
Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizo... more Background: Reelin is a candidate gene for neurodevelopmental disorders such as autism and schizophrenia. Reelin haploinsufficiency in the heterozygous rl/+ mouse causes behavioral abnormalities soon after birth, consisting of decreased ultrasound vocalizations (USV) emitted by pups upon maternal separation, as well as in adult life, producing behavioral rigidity in a task requiring a change in strategy. At the anatomical level, reelin haploinsufficiency causes a loss of GABAergic inhibitory neurons, e.g. parvalbumin-positive neurons in limbic areas and basal ganglia, and Purkinje cells (PC) in the cerebellum. This PC loss is more evident in male than female mice. Objectives: 1) To characterize brain circuit abnormalities of heterozygous reeler (rl/+) mice, and their sex-dependency; 2) To unravel the mechanisms of neuronal loss in brain areas that are relevant for autism, like the cerebellum and limbic system, focusing on interactions between decreased reelin levels and sex steroids...
2008 International Conference on Technology and Applications in Biomedicine, 2008
In this work, a novel technological approach to the early diagnosis of neuro-developmental disord... more In this work, a novel technological approach to the early diagnosis of neuro-developmental disorders is presented. Disorders such as Autism are typically diagnosed after language development, i.e. after the 2-3 years of age. In this paper, three different typologies of instruments are presented which are designed to assess infants behavior in different perceptual and motor domains. The first is an
2006 IEEE/RSJ International Conference on Intelligent Robots and Systems, 2006
In this work the problem of orientation tracking based on inertial/magnetic sensors is restated i... more In this work the problem of orientation tracking based on inertial/magnetic sensors is restated in geometric terms, in particular an intrinsic observer, i.e. an observer whose performance does not depend on a specific choice of coordinates, is derived on the Lie group of rigid body rotations SO(3). Measurements of the gravitational and geomagnetic fields are used to estimate orientation errors. A coordinate-free control law is defined on the Lie algebra and fed back in terms of angular velocity that steers the observer towards the correct attitude. A proof of stability for the proposed estimator is provided which relies on the natural (bi-invariant) metric of SO(3). The observer results stable for almost the whole configuration space. Presence of unstable equilibria as a limitation for global stability is also discussed. Based on the proposed intrinsic control law, a filter is designed which implements the observer. Simulations are presented that test the numerical implementation of the proposed observer.
The development of sensorimotor coordination in infancy is fundamental for regulating interaction... more The development of sensorimotor coordination in infancy is fundamental for regulating interactional dynamics with peers and adults. In this work we present a multimodal device to systematically assess children's orienting behavior in social situations. Technological choices are emphasized with respect to ecological requirements. Also ad-hoc calibration procedures are presented which are suitable to unstructured environments. Preliminary tests carried out at a
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2011
This study analyzes motor adaptation during a redundant tasks with the wrist. The goal is threefo... more This study analyzes motor adaptation during a redundant tasks with the wrist. The goal is threefold: (i) understanding if motor adaptation also occurs when CNS is involved in the solution of the redundancy problem; (ii) addressing whether motor strategies used to solve redundancy (i.e Donders' law) are disrupted or not during adaptation; (iii) verifying if motor strategies remain the same during adaptation and washout or they themselves adapt. First of all, our data confirm that CNS adapts its movements to the perturbation also when it is committed in the execution of a redundant task. Secondly, we showed that motor strategies used to solve redundancy (i.e Donders' law) are not disrupted during adaptation, since absolute values of thickness during the whole protocol remain in the range of physiological values. Lastly, analysis of the curvature of Donders' surfaces suggests that motor strategies, such as Donders' law, remain invariant during motor adaptation in redund...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2009
This paper describes an interdisciplinary approach to the assessment on infants' behavior, wi... more This paper describes an interdisciplinary approach to the assessment on infants' behavior, with a focus on the technology. The goal is an objective, quantitative analysis of concurrent maturation of sensory, motor and cognitive abilities in young children, in relation to the achievement of developmental milestones. An instrumented block-box toy specifically developed to assess the ability to insert objects into holes is presented. The functional specifications are derived from experimental protocols devised by neuroscientists to assess spatial cognition skills. Technological choices are emphasized with respect to ecological requirements. An ad-hoc calibration procedure is also presented which is suitable to unstructured environments. Finally, preliminary tests carried out at a local day-care with 12-24 months old infants are presented which prove the in-field usability of the proposed technology.
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2008
In this work, a novel technological approach to the early diagnosis of neuro-developmental disord... more In this work, a novel technological approach to the early diagnosis of neuro-developmental disorders is presented. Disorders such as Autism are typically diagnosed after language development, i.e. after the 2-3 years of age. In this paper, three different typologies of instruments are presented which are designed to assess infants behavior in different perceptual and motor domains. The first is an instrumented toy embedding kinematic and force sensors for studying grasping and manipulation in infants as young as 6 months old. The second is a wearable device for sensing the kinematics of the upper and lower limbs of infants, designed to assess spontaneous movements in premature babies. The third is a multimodal audio-visuo-vestibular cap which was designed to assess infants orienting behaviors in social situations in response to audio and visual stimuli.
2006 International Conference of the IEEE Engineering in Medicine and Biology Society, 2006
This paper introduces Neurodevelopmental Engineering, a new interdisciplinary research area at th... more This paper introduces Neurodevelopmental Engineering, a new interdisciplinary research area at the intersection of developmental neuroscience and bioengineering. Specifically, it presents current results of the design and development process of a set of instrumented toys equipped with a variety of sensors for behavioral analysis of infants in minimally structured environmental conditions. First the multidisciplinary design approach is presented, then the detailed functional and technical specifications of the proposed biomechatronic toys and of their scenarios of use are described. Finally, a clear picture of ongoing implementation of the proposed technology is provided together with preliminary results of verification tests.
This technology is expected to be also useful in the long term for developing new tools, e.g. toy... more This technology is expected to be also useful in the long term for developing new tools, e.g. toys, which can sustain, in ecological scenarios, the regular development of motor and cognitive abilities of the child, based on a rigorous scientific approach. The long term goal is establishing standards against which development of infants at risk for neuro-developmental disorders, particularly autism, can be measured, with the aim of detecting early signs of disturbed development. 1.1 Sensori-Motor Integration Deficits in Neurodevelopmental Disorders Neurodevelopmental disorders such as ASD, ADHD, Tourette syndrome and others are characterized by a genetic basis. In this case behavioral analysis, or behavioral phenotyping, will be instrumental for the analysis of the roles of genes in behavior (Gerlai 2002). Autism is a behavioral disorder, with onset in childhood, which is characterized by deficits in three basic domains: social interaction, language and communication, and pattern of interests. There is no doubt that autism has a strong genetic component, and that biological disease mechanisms leading to autism are already active during foetal development and/or infancy,
Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenes... more Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenesis is severely impaired in E-reeler mice, a model of Reelin deficiency showing specific Green Fluorescent Protein expression in Rod Bipolar Cells (RBCs). Since no data are available on Reelin and NGF cross-talk, NGF and trkA NGFR /p75 NTR expression was investigated in retinas from E-reeler versus control mice, by confocal microscopy, Western blotting, and real time PCR analysis. A scattered increase of NGF protein was observed in the Ganglion Cell Layer and more pronounced in the Inner Nuclear Layer (INL). A selective increase of p75 NTR was detected in most of RBCs and in other cell subtypes of INL. On the contrary, a slight trend towards a decrease was detected for trkA NGFR , albeit not significant. Confocal data were validated by Western blot and real time PCR. Finally, the decreased trkA NGFR /p75 NTR ratio, representative of p75 NTR increase, significantly correlated with E-reeler versus E-control. These data indicate that NGF-trkA NGFR /p75 NTR is affected in E-reeler retina and that p75 NTR might represent the main NGF receptor involved in the process. This first NGF-trkA NGFR /p75 NTR characterization suggests that E-reeler might be suitable for exploring Reelin-NGF crosstalk, representing an additional information source in those pathologies characterized by retinal degeneration.
Genetic risk factors acting during pregnancy or early after birth have been proposed to account f... more Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2ppm in Dams' drinking water), or at a toxic dose (6ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2ppm MeHg does not cause PCs loss in the different animal groups, and ...
Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. He... more Reelin is an extracellular protein that is crucial for layer formation in the embryonic brain. Here, we demonstrate that Reelin functions postnatally to regulate the development of the neuromuscular junction. Reelin is required for motor end-plate maturation and proper nerve-muscle connectivity, and it directly promotes synapse elimination. Unlike layer formation, neuromuscular junction development requires a function of Reelin that is not mediated by Disabled1 or very-low-density lipoprotein receptors and apolipoprotein E receptor 2 receptors but by a distinct mechanism involving its protease activity.
According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly exp... more According to the ''extreme-male brain'' theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice-a putative model of neuroanatomical and behavioral endophenotypes in ASD-show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbuminpositive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-toinhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity.
We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (... more We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (rl/+) reeler mice of either sex during early postnatal development; in parallel, we quantified levels of neuroactive steroids in the cerebellum with mass spectrometry. We also quantified reelin mRNA and protein expression with RT-PCR and Western blotting. PC numbers are selectively reduced at postnatal day 15 (P15) in rl/+ males in comparison to +/+ males, +/+ females, and rl/+ females. Administration of 17beta-estradiol (17beta-E) into the cisterna magna at P5 increases PC numbers in rl/+ males, but not in the other groups; conversely, estrogen antagonists 4-OH-tamoxifen or ICI 182,780 reduce PC numbers in +/+ and rl/+ females, but have no effect in males. Testosterone (T) levels at P5 are much higher in males than in females, reflecting the perinatal testosterone surge in males. In addition, rl/+ male cerebella at P5 show a peculiar hormonal profile in comparison with the other groups, consisting of increased levels of T and 17beta-E, and decreased levels of dihydrotestosterone. RT-PCR analysis indicated that heterozygosity leads to a 50% reduction of reelin mRNA in the cerebellum in both sexes, as expected, and that 17beta-E upregulates reelin mRNA, particularly in rl/+ males; reelin mRNA upregulation is associated with an increase of all major reelin isoforms. These effects may represent a novel model of how reelin deficiency interacts with variable perinatal levels of neuroactive steroids, leading to gender-dependent differences in genetic vulnerability.
This paper describes an interdisciplinary approach to the assessment of children development of s... more This paper describes an interdisciplinary approach to the assessment of children development of spatial cognition, with a focus on the technology. An instrumented toy (blockbox) is presented which embeds magneto-inertial sensors for orientation tracking, specifically developed to assess the ability to insert objects into holes. The functional specifications are derived from experimental protocols devised by neuroscientists to assess spatial cognition skills in children. Technological choices are emphasized with respect to ecological requirements. Adhoc calibration procedures are presented which are suitable to unstructured environments. Preliminary results based on experimental trials carried out at a day-care on typically developing children (12-36 months old) show how the instrumented objects can be used effectively in a semi-automatic fashion (i.e. rater-independent) to derive accurate measurements such as orientation errors and insertion time which are relevant to the object insertion task. This study indicates that a technological approach to ecological assessment of spatial cognition in children is indeed feasible and maybe useful for identification and early assessment of developmental delay.
Note: the full version of this paper, including illustrations, has been published in pH 1/2017 de... more Note: the full version of this paper, including illustrations, has been published in pH 1/2017 destitute of hands, the various parts of his face would certainly have been arranged like those of the quadrupeds, to suit the purpose of his feeding: so that its form would have been lengthened out and pointed towards the nostrils, and his lips would have projected from his mouth, lumpy, and stiff, and thick, fitted for taking up the grass, and his tongue would either have lain between his teeth, of a kind to match his lips, fleshy, and hard, and rough, assisting his teeth to deal with what came under his grinder… If, then, our body had no hands, how could articulate sound have been implanted in it, seeing that the form of the parts of the mouth would not have had the configuration proper for the use of speech. (Gregory of Nyssa, cit., p 619)
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Papers by Flavio Keller