El área 5 de la corteza parietal: estudio anatómico de un área asociativa somestésica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Morfología. Fecha de lectura: 1 de Junio de 198

Unbinding forces and energies between a siRNA molecule and a dendrimer measured by force spectroscopy

We have measured the intermolecular forces between small interference RNA (siRNA) and polyamidoamine dendrimers at the single molecular level. A single molecule force spectroscopy approach has been developed to measure the unbinding forces and energies between a siRNA molecule and polyamidoamine dendrimers deposited on a mica surface in a buffer solution. We report three types of unbinding events which are characterized by forces and free unbinding energies, respectively, of 28 pN, 0.709 eV; 38 pN, 0.722 eV; and 50 pN, 0.724 eV. These events reflect different possible electrostatic interactions between the positive charges of one or two dendrimers and the negatively charged phosphate groups of a single siRNA. We have evidence of a high binding affinity of siRNA towards polyamidoamine dendrimers that leads to a 45% probability of measuring specific unbinding eventsThis work was funded by the European Research Council ERC-AdG-340177 (3DNanoMech) grant to RG and by the Spanish Ministry of Economy (MINECO) through grants CSD2010-00024, MAT2013-44858-R to RG and BFU2011-30161- C02-01 and BFU2014-59009-P to VC.Peer reviewe

Expression of type 2 iodothyronine deiodinase in hypothyroid rat brain indicates an important role of thyroid hormone in the development of specific primary sensory systems

10 pages, 6 figures.Thyroid hormone is an important epigenetic factor in brain development, acting by modulating rates of gene expression. The active form of thyroid hormone, 3,5,3'-triiodothyronine (T3) is produced in part by the thyroid gland but also after 5'-deiodination of thyroxine (T4) in target tissues. In brain, ~80% of T3 is formed locally from T4 through the activity of the 5'-deiodinase type 2 (D2), an enzyme that is expressed mostly by glial cells, tanycytes in the third ventricle, and astrocytes throughout the brain. D2 activity is an important point of control of thyroid hormone action because it increases in situations of low T4, thus preserving brain T3 concentrations. In this work, we have studied the expression of D2 by quantitative in situ hybridization in hypothyroid animals during postnatal development. Our hypothesis was that those regions that are most dependent on thyroid hormone should present selective increases of D2 as a protection against hypothyroidism. D2 mRNA concentration was increased severalfold over normal levels in relay nuclei and cortical targets of the primary somatosensory and auditory pathways. The results suggest that these pathways are specifically protected against thyroid failure and that T3 has a role in the development of these structures. At the cellular level, expression was observed mainly in glial cells, although some interneurons of the cerebral cortex were also labeled. Therefore, the T3 target cells, mostly neurons, are dependent on local astrocytes for T3 supply.This work was supported by grants from the Fundación Ramón Areces, Comision Interministerial de Ciencia y Tecnologia Grants PM95–0019 and SAF-0031, and Comunidad de Madrid.Peer reviewe

Patterns of motor signs in spinocerebellar ataxia type 3 at the start of follow-up in a reference unit

Background: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder that affects the cerebellar system and other subcortical regions of the brain. As for other cerebellar diseases, the severity of this type of ataxia can be assessed with the Scale for Assessment and Rating of Ataxia (SARA) which gives a total score that reflects functional impairment out of 8 cerebellar function tests. SCA3 patients score profile is heterogeneous on at the start of follow up. This study investigates possible patterns in those profiles and analyses the impact of other usually concurrent signs of impairment of extracerebellar motor systems in that profile variability by means of multivariate statistical approaches. Methods: Seventeen patients with SCA3 underwent systematic anamnesis, neurological and SARA assessment, visual evaluation of 123I-Ioflupane (DaTSCAN) single-photon emission computed tomography (SPECT) imaging and electrophysiological studies (nerve conduction and electromyography). Patterns in the profiles of SARA item scores were investigated by hierarchical clustering after multivariate correspondence analysis. A network analysis was used to represent relationships between SARA item scores, clinical, genetic and neurological examination parameters as well as abnormalities of DaTSCAN SPECT imaging and electrophysiological studies. Results: The most frequently altered SARA items in all patients are gait and stance, and three profiles of SCA3 patients can be distinguished depending mainly on their degree of impairment in those two items. Other SARA items like the score on heel-shin slide contribute less to the classification. Network analysis shows that SARA item scores configure a single domain that is independent of the size of the mutated expanded allele and age of onset, which are, in turn closely and inversely correlated. The severity of cerebellar dysfunction is correlated with longer disease duration, altered visual evaluation of DaTSCAN SPECT imaging and decreased patellar reflexes. Neither the presence of pyramidal or extrapyramidal signs nor the intensity of polyneuropathy is correlated with the SARA items scores. Conclusions: Pattern recognition approaches are useful tools to describe clinical phenotypes of ataxias and to identify particular configurations of cerebellar signsDr. Arpa has received grant funding from TRA-052 (MSPSI) and EFACTS 242.19

Gait analysis under the lens of statistical physics

Human gait; Irreversibility; Multi-fractal analysisMarcha humana; Irreversibilidad; Análisis multifractalMarxa humana; Irreversibilitat; Anàlisi multifractalHuman gait is a fundamental activity, essential for the survival of the individual, and an emergent property of the interactions between complex physical and cognitive processes. Gait is altered in many situations, due both to external constraints, as e.g. paced walk, and to physical and neurological pathologies. Its study is therefore important as a way of improving the quality of life of patients, but also as a door to understanding the inner working of the human nervous system. In this review we explore how four statistical physics concepts have been used to characterise normal and pathological gait: entropy, maximum Lyapunov exponent, multi-fractal analysis and irreversibility. Beyond some basic definitions, we present the main results that have been obtained in this field, as well as a discussion of the main limitations researchers have dealt and will have to deal with. We finally conclude with some biomedical considerations and avenues for further development.This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 851255). M.Z. and F.O. acknowledges the Spanish State Research Agency through Grant MDM-2017–0711 funded by MCIN/AEI/10.13039/501100011033. Authors acknowledge support from the Escuela Universitaria de Fisioterapia de la ONCE

Permutation entropy and irreversibility in gait kinematic time series from patients with mild cognitive decline and early alzheimer’s dementia

Gait is a basic cognitive purposeful action that has been shown to be altered in late stages of neurodegenerative dementias. Nevertheless, alterations are less clear in mild forms of dementia, and the potential use of gait analysis as a biomarker of initial cognitive decline has hitherto mostly been neglected. Herein, we report the results of a study of gait kinematic time series for two groups of patients (mild cognitive impairment and mild Alzheimer’s disease) and a group of matched control subjects. Two metrics based on permutation patterns are considered, respectively measuring the complexity and irreversibility of the time series. Results indicate that kinematic disorganisation is present in early phases of cognitive impairment; in addition, they depict a rich scenario, in which some joint movements display an increased complexity and irreversibility, while others a marked decrease. Beyond their potential use as biomarkers, complexity and irreversibility metrics can open a new door to the understanding of the role of the nervous system in gait, as well as its adaptation and compensatory mechanismsThis research was funded through the Premio del Ilustre Colegio Profesional de Fisioterapeutas de la Comunidad De Madrid, prize number ICPFM-IX-201

Characterizing Normal and Pathological Gait through Permutation Entropy

Altres ajuts: We acknowledge the contribution of the children and their families who generously collaborated to build the gait dataset used in this study. We are also grateful to Michael R. Paul for kindly editing the English style of this manuscript. The acquisition and processing of gait data were funded by Escuela de Fisioterapia de la ONCE-UAM, through a private donation, and Agencia de Evaluación de Tecnologías Sanitarias (Instituto de Salud Carlos III), .Cerebral palsy is a physical impairment stemming from a brain lesion at perinatal time, most of the time resulting in gait abnormalities: the first cause of severe disability in childhood. Gait study, and instrumental gait analysis in particular, has been receiving increasing attention in the last few years, for being the complex result of the interactions between different brain motor areas and thus a proxy in the understanding of the underlying neural dynamics. Yet, and in spite of its importance, little is still known about how the brain adapts to cerebral palsy and to its impaired gait and, consequently, about the best strategies for mitigating the disability. In this contribution, we present the hitherto first analysis of joint kinematics data using permutation entropy, comparing cerebral palsy children with a set of matched control subjects. We find a significant increase in the permutation entropy for the former group, thus indicating a more complex and erratic neural control of joints and a non-trivial relationship between the permutation entropy and the gait speed. We further show how this information theory measure can be used to train a data mining model able to forecast the child's condition. We finally discuss the relevance of these results in clinical applications and specifically in the design of personalized medicine interventions

Gait phenotypes in paediatric hereditary spastic paraplegia revealed by dynamic time warping analysis and random forests

The Hereditary Spastic Paraplegias (HSP) are a group of heterogeneous disorders with a wide spectrum of underlying neural pathology, and hence HSP patients express a variety of gait abnormalities. Classification of these phenotypes May help in monitoring disease progression and personalizing therapies. This is currently managed by measuring values of some kinematic and spatio-temporal parameters at certain moments during the gait cycle, either in the doctor´s surgery room or after very precise measurements produced by instrumental gait analysis (IGA). These methods, however, do not provide information about the whole structure of the gait cycle. Classification of the similarities among time series of IGA measured values of sagittal joint positions throughout the whole gait cycle can be achieved by hierarchical clustering analysis based on multivariate dynamic time warping (DTW). Random forests can estimate which are the most important isolated parameters to predict the classification revealed by DTW, since clinicians need to refer to them in their daily practice. We acquired time series of pelvic, hip, knee, ankle and forefoot sagittal angular positions from 26 HSP and 33 healthy children with an optokinetic IGA system. DTW revealed six gait patterns with different degrees of impairment of walking speed, cadence and gait cycle distribution and related with patient’s age, sex, GMFCS stage, concurrence of polyneuropathy and abnormal visual evoked potentials or corpus callosum. The most important parameters to differentiate patterns were mean pelvic tilt and hip flexion at initial contact. Longer time of support, decreased values of hip extension and increased knee flexion at initial contact can differentiate the mildest, near to normal HSP gait phenotype and the normal healthy one. Increased values of knee flexion at initial contact and delayed peak of knee flexion are important factors to distinguish GMFCS stages I from II- III and concurrence of polyneuropathyDGA was in receipt of a grant from Sociedad Española de Neurología Pediátrica (SENEP). Publication fee was supported by EUF-ONCE-UAM and Asociación Española de Paraparesia Espástica Familiar (AEPEF)

RC3/neurogranin is expressed in pyramidal neurons of motor and somatosensory cortex in normal and denervated monkeys

RC3/neurogranin is a neuron-specific calpacitin located in the cytoplasm and, especially, in dendrites and dendritic spines of cortical neurons, involved in many aspects of excitatory transmission and long-term potentiation. We investigated RC3 expression in pyramidal cortical neurons and interneurons of the motor and somatosensory cortex of normal Macaca fascicularis by means of double immunofluorescence and with techniques that combine immunohistochemistry and radioactive in situ hybridization. We show that RC3 is expressed in virtually all pyramidal neurons and spiny stellate neurons of neocortical areas 4, 3b, 1, 2, 5, 7, and SII, but not in the majority of cortical interneurons. RC3 protein and mRNA are tightly colocalized with the α subunit of CaM kinase II and the 200-kD, nonphosphorylated neurofilament, whereas they are absent from cells expressing the 27-kD, vitamin D-dependent calbindin and parvalbumin. In order to investigate possible activity-dependent regulation of the expression of RC3, we compared these results with those obtained from monkeys subjected to chronic peripheral cutaneous denervation of the first finger. We found that the pattern of distribution of RC3 in motor and somatosensory cortices after nerve cut did not differ from normal. © 2005 Wiley-Liss, Inc.Funded by: Ministerio de Ciencia y Tecnología (MCyT). Grant Numbers: SAF2000-0034, BFI-2001-2412; Fondo de Investigaciones Sanitarias; Instituto de Salud Carlos III; Red de Centros RCMN (C03/08) (Spain) and MCyT (Spain).Peer Reviewe

From neuroanatomy to mechanisms of disability and treatment

Resumen del trabajo presentado al MCT8 Symposium celebrado del 12 al 14 de enero de 2015 en California (USA).Mechanisms underlying motor dysfunctions in Allan Herndon Dudley Syndrome remain largely unknown. Neuroanatomical studies performed in postmortem human brain tissue obtained from control versus MCT8-deficient patients provide a suitable strategy to further understand underlying alterations of motor system circuitries. Our recent findings indicate that normal MCT8 expression is tightly regulated, both spatially and temporally, during development of the normal motor system. Particularly, MCT8 expression increases in white matter tracts during myelination. We have also found that the motor system of MCT8 deficient brains is affected of combined gray and white matter abnormalities that can be found either in prenatal and postnatal stages, and that reveal the impairment of several key developmental processes such as neuronal differentiation, myelination and synaptogenesis. Our observations in motor cortices, cerebellum and main motor descending tracts confirm the importance of the modulation of thyroid hormones availability during motor system ontogeny. These results try to outline the intervening driver molecular processes that lead this rare disease in order to support the refining of current therapeutic approaches and to pursue therapeutic targets in the future. Our results also point to the relevance of persevering on translational research towards plausible prenatal diagnosis and treatment for these patients.Peer Reviewe