Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brains.

Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway) and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain.

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters' role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.

Gait analysis under the lens of statistical physics.

Human 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.

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 polyneuropathy.

Characterizing Normal and Pathological Gait through Permutation Entropy.

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.

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 (123)I-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 signs.

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 events.

[External evaluation of gait and functional changes after a single-session multiple myofibrotenotomy in school-aged children with spastic diplegia]. / Evaluación externa de los cambios funcionales y la marcha tras una sesión de miofibrotomía múltiple en escolares con diplejía espástica.

INTRODUCTION: About 23,000 patients with spasticity voluntarily chose to undergo a multiple myofiberotomy (MMF), which is an alternative technique consisting in sectioning soft tissues in order to relieve restrictions in joint movements. This technique, first employed by Ulzibat (Russia), is performed outside orthodox clinical controls. AIMS: To perform an external evaluation of the effects of MMF on motor functionality and gait. PATIENTS AND METHODS: The study was self-controlled and observation-based and was designed to evaluate the changes in functional variables -Gross Motor Function Classification System, E-dimension of the Gross Motor Function Measure (GMFM) and the Functional Mobility Scale- and 32 gait parameters (measured using analytical instruments) in 22 school-children with spastic diplegia (mean age: 9 years and 6 months; Q1-Q3: 7 years and 11 months to 11 years and 6 months) whose parents opted for an MMF (median of observation: 4 months; range: 3-7 months). RESULTS: The analysis of hierarchical conglomerates used to determine topographic cut patterns in patients revealed that the surgeons applied one of three sets of cuts to each patient. On analysing the three groups of patients, it was observed that one group worsened overall and another underwent a general significant improvement in the E-dimension of the GMFM (difference of median: 4.86%; 95% confidence interval = 0-6.94%) after the MMF. Some of the gait parameters became significantly normalised (left: hip-flexion range, maximum dorsiflexion with support; right: speed, mean pelvic rotation with support and maximum dorsiflexion with support). CONCLUSIONS: These findings do not back up or justify the use of MMF as a therapeutic option to treat spasticity. It has to be stressed that this technique must be avoided outside study protocols. Nevertheless, results do lay an objective base that may justify a clinical trial and long-term observation-based studies.

TITLE: Evaluacion externa de los cambios funcionales y la marcha tras una sesion de miofibrotomia multiple en escolares con diplejia espastica.Introduccion. Unos 23.000 pacientes con espasticidad han optado voluntariamente por la miofibrotomia multiple (MFM), una tecnica alternativa consistente en seccionar tejidos blandos para liberar restricciones articulares. Iniciada por Ulzibat (Rusia), se realiza fuera de controles clinicos ortodoxos. Objetivo. Evaluar externamente los efectos de la MFM sobre la funcionalidad motora y la marcha. Pacientes y metodos. Estudio observacional autocontrolado que evalua cambios en variables funcionales ­Gross Motor Function Classification System, dimension E de la Gross Motor Function Measure (GMFM) y Functional Mobility Scale­ y 32 parametros de marcha (medidos mediante analisis instrumental) en 22 escolares con diplejia espastica (edad mediana: 9 años y 6 meses; Q1-Q3: 7 años y 11 meses a 11 años y 6 meses) cuyos padres optaron por una MFM (mediana de observacion: 4 meses; rango: 3-7 meses). Resultados. El analisis de conglomerados jerarquicos utilizado para determinar patrones topograficos de cortes en los pacientes detecto que los cirujanos aplicaban a cada paciente uno de tres conjuntos de cortes. Analizados los tres grupos de pacientes, se observo que un grupo empeoro globalmente y una mejora significativa general en la dimension E del GMFM (diferencia de mediana: 4,86%; intervalo de confianza al 95% = 0-6,94%) tras la MFM. Algunos parametros de la marcha se normalizaron significativamente (izquierda: rango flexion-cadera, maxima dorsiflexion en apoyo; derecha: velocidad, rotacion pelvica media en apoyo y maxima dorsiflexion en apoyo). Conclusiones. Estos resultados no apoyan ni justifican el uso de la MFM como opcion para el tratamiento de la espasticidad. Insistimos en que esta tecnica debe evitarse fuera de protocolos de estudio. Sin embargo, los resultados asientan una base objetiva para justificar la realizacion de un ensayo clinico y estudios observacionales a largo plazo.

Evaluación externa de los cambios funcionales y la marcha tras una sesión de miofibrotomía múltiple en escolares con diplejía espástica / External evaluation of gait and functional changes after a single-session multiple myofibrotenotomy in school-aged children with spastic diplegia

Introducción. Unos 23.000 pacientes con espasticidad han optado voluntariamente por la miofibrotomía múltiple (MFM), una técnica alternativa consistente en seccionar tejidos blandos para liberar restricciones articulares. Iniciada por Ulzibat (Rusia), se realiza fuera de controles clínicos ortodoxos. Objetivo. Evaluar externamente los efectos de la MFM sobre la funcionalidad motora y la marcha. Pacientes y métodos. Estudio observacional autocontrolado que evalúa cambios en variables funcionales -Gross Motor Function Classification System, dimensión E de la Gross Motor Function Measure (GMFM) y Functional Mobility Scale- y 32 parámetros de marcha (medidos mediante análisis instrumental) en 22 escolares con diplejía espástica (edad mediana: 9 años y 6 meses; Q1-Q3: 7 años y 11 meses a 11 años y 6 meses) cuyos padres optaron por una MFM (mediana de observación: 4 meses; rango: 3-7 meses). Resultados. El análisis de conglomerados jerárquicos utilizado para determinar patrones topográficos de cortes en los pacien s detectó que los cirujanos aplicaban a cada paciente uno de tres conjuntos de cortes. Analizados los tres grupos de pacientes, se observó que un grupo empeoró globalmente y una mejora significativa general en la dimensión E del GMFM (diferencia de mediana: 4,86%; intervalo de confianza al 95% = 0-6,94%) tras la MFM. Algunos parámetros de la marcha se normalizaron significativamente (izquierda: rango flexión-cadera, máxima dorsiflexión en apoyo; derecha: velocidad, rotación pélvica media en apoyo y máxima dorsiflexión en apoyo). Conclusiones. Estos resultados no apoyan ni justifican el uso de la MFM como opción para el tratamiento de la espasticidad. Insistimos en que esta técnica debe evitarse fuera de protocolos de estudio. Sin embargo, los resultados asientan una base objetiva para justificar la realización de un ensayo clínico y estudios observacionales a largo plazo (AU)

Introduction. About 23,000 patients with spasticity voluntarily chose to undergo a multiple myofiberotomy (MMF), which is an alternative technique consisting in sectioning soft tissues in order to relieve restrictions in joint movements. This technique, first employed by Ulzibat (Russia), is performed outside orthodox clinical controls. Aims. To perform an external evaluation of the effects of MMF on motor functionality and gait. Patients and methods. The study was self-controlled and observation-based and was designed to evaluate the changes in functional variables -Gross Motor Function Classification System, E-dimension of the Gross Motor Function Measure (GMFM) and the Functional Mobility Scale- and 32 gait parameters (measured using analytical instruments) in 22 schoolchildren with spastic diplegia (mean age: 9 years and 6 months; Q1-Q3: 7 years and 11 months to 11 years and 6 months) whose parents opted for an MMF (median of observation: 4 months; range: 3-7 months). Results. The analysis of hierarchi l conglomerates used to determine topographic cut patterns in patients revealed that the surgeons applied one of three sets of cuts to each patient. On analysing the three groups of patients, it was observed that one group worsened overall and another underwent a general significant improvement in the E-dimension of the GMFM (difference of median: 4.86%; 95% confidence interval = 0-6.94%) after the MMF. Some of the gait parameters became significantly normalised (left: hip-flexion range, maximum dorsiflexion with support; right: speed, mean pelvic rotation with support and maximum dorsiflexion with support). Conclusions. These findings do not back up or justify the use of MMF as a therapeutic option to treat spasticity. It has to be stressed that this technique must be avoided outside study protocols. Nevertheless, results do lay an objective base that may justify a clinical trial and long-term observation-based studies (AU)

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 alpha 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.