Time scales in cognitive neuroscience

Cognitive neuroscience boils down to describing the ways in which cognitive function results from brain activity. In turn, brain activity shows complex fluctuations, with structure at many spatio-temporal scales. Exactly how cognitive function inherits the physical dimensions of neural activity, though, is highly non-trivial, and so are generally the corresponding dimensions of cognitive phenomena. As for any physical phenomenon, when studying cognitive function, the first conceptual step should be that of establishing its dimensions. Here, we provide a systematic presentation of the temporal aspects of task-related brain activity, from the smallest scale of the brain imaging technique's resolution, to the observation time of a given experiment, through the characteristic time scales of the process under study. We first review some standard assumptions on the temporal scales of cognitive function. In spite of their general use, these assumptions hold true to a high degree of approximation for many cognitive (viz. fast perceptual) processes, but have their limitations for other ones (e.g., thinking or reasoning). We define in a rigorous way the temporal quantifiers of cognition at all scales, and illustrate how they qualitatively vary as a function of the properties of the cognitive process under study. We propose that each phenomenon should be approached with its own set of theoretical, methodological and analytical tools. In particular, we show that when treating cognitive processes such as thinking or reasoning, complex properties of ongoing brain activity, which can be drastically simplified when considering fast (e.g., perceptual) processes, start playing a major role, and not only characterize the temporal properties of task-related brain activity, but also determine the conditions for proper observation of the phenomena. Finally, some implications on the design of experiments, data analyses, and the choice of recording parameters are discussed.

Estudio Multimodal de la Funcionalidad Cortical en ratones Transgénicos con Síndrome X Frágil y la modulación del dolor

El dolor es un síntoma frecuente en la práctica médica. En España, un estudio realizado en el año 2000 demostró que cada médico atiende un promedio de 181 pacientes con dolor por mes, la mayoría de ellos con dolor crónico moderado1. Del 7%-8% de la población europea está afectada y hasta el 5% puede ser grave2-3, se estima, que afecta a más de dos millones de españoles4. En la consulta de Atención Primaria, los pacientes con dolor neuropático tienen tasas de depresión mucho mayores 5-6-7. El dolor neuropático8 es el dolor causado por daño o enfermedad que afecta al sistema somato-sensorial, es un problema de salud pública con un alto coste laboral, debido a que existe cierto desconocimiento de sus singularidades, tanto de su diagnóstico como de su tratamiento, que al fallar, el dolor se perpetúa y se hace más rebelde a la hora de tratarlo, en la mayoría de las ocasiones pasa a ser crónico. Los mecanismos fisiopatológicos son evolutivos, se trata de un proceso progresivo e integrado que avanza si no recibe tratamiento, ocasionando graves repercusiones en la calidad de vida de los pacientes afectados9. De acuerdo a Prusiner (premio nobel de medicina 1997), en todas las enfermedades neurodegenerativas hay algún tipo de proceso anormal de la función neuronal. Las enfermedades neurodegenerativas son la consecuencia de anormalidades en el proceso de ciertas proteínas que intervienen en el ciclo celular, por lo tanto da lugar al cúmulo de las mismas en las neuronas o en sus proximidades, disminuyendo o anulando sus funciones, como la enfermedad de Alzheimer y el mismo SXF. La proteína FMRP (Fragile Mental Retardation Protein), esencial para el desarrollo cognitivo normal, ha sido relacionada con la vía piramidal del dolor10-11-12. El Síndrome de X Frágil13-14 (SXF), se debe a la mutación del Gen (FMR-1). Como consecuencia de la mutación, el gen se inactiva y no puede realizar la función de sintetizar la proteína FMRP. Por su incidencia se le considera la primera causa de Deficiencia Mental Hereditaria sólo superada por el Síndrome de Down. La electroencefalografía (EEG) es el registro de la actividad bioeléctrica cerebral que ha traído el desarrollo diario de los estudios clínicos y experimentales para el descubrimiento, diagnóstico y tratamiento de un gran número de anormalidades neurológicas y fisiológicas del cerebro y el resto del sistema nervioso central (SNC) incluyendo el dolor. El objetivo de la presente investigación es por medio de un estudio multimodal, desarrollar nuevas formas de presentación diagnóstica mediante técnicas avanzadas de procesado de señal y de imagen, determinando así los vínculos entre las evaluaciones cognitivas y su correlación anatómica con la modulación al dolor presente en patologías relacionadas con proteína FMRP. Utilizando técnicas biomédicas (funcionalestructural) para su caracterización. Para llevar a cabo esta tarea hemos utilizado el modelo animal de ratón. Nuestros resultados en este estudio multimodal demuestran que hay alteraciones en las vías de dolor en el modelo animal FMR1-KO, en concreto en la modulación encefálica (dolor neuropático), los datos se basan en los resultados del estudio estructural (imagen histología), funcional (EEG) y en pruebas de comportamiento (Laberinto de Barnes). En la Histología se muestra una clara asimetría estructural en el modelo FMR1 KO con respecto al control WT, donde el hemisferio Izquierdo tiene mayor densidad de masa neuronal en KO hembras 56.7%-60.8%, machos 58.3%-61%, en WT hembras 62.7%-62.4%, machos 55%-56.2%, hemisferio derecho-izquierdo respectivamente, esto refleja una correlación entre hemisferios muy baja en los sujetos KO (~50%) con respecto a los control WT (~90%). Se encontró correlación significativa entre las pruebas de memoria a largo plazo con respecto a la asimetría hemisférica (r = -0.48, corregido <0,05). En el estudio de comportamiento también hay diferencias, los sujetos WT tuvieron 22% un de rendimiento en la memoria a largo plazo, mientras que en los machos hay deterioro de memoria de un 28% que se corresponden con la patología en humanos. En los resultados de EEG estudiados en el hemisferio izquierdo, en el área de la corteza insular, encuentran que la latencia de la respuesta al potencial evocado es menor (22vs32 15vs96seg), la intensidad de la señal es mayor para los sujetos experimentales FMR1 KO frente a los sujetos control, esto es muy significativo dados los resultados en la histología (140vs129 145vs142 mv). Este estudio multimodal corrobora que las manifestaciones clínicas del SXF son variables dependientes de la edad y el sexo. Hemos podido corroborar en el modelo animal que en la etapa de adulto, los varones con SXF comienzan a desarrollar problemas en el desempeño de tareas que requieren la puesta en marcha de la función ejecutiva central de la memoria de trabajo (almacenamiento temporal). En el análisis del comportamiento es difícil llegar a una conclusión objetiva, se necesitan más estudios en diferentes etapas de la vida corroborados con resultados histológicos. Los avances logrados en los últimos años en su estudio han sido muy positivos, de tal modo que se están abriendo nuevas vías de investigación en un conjunto de procesos que representan un gran desafío a problemas médicos, asistenciales, sociales y económicos a los que se enfrentan los principales países desarrollados, con un aumento masivo de las expectativas de vida y de calidad. Las herramientas utilizadas en el campo de las neurociencias nos ofrecen grandes posibilidades para el desarrollo de estrategias que permitan ser utilizadas en el área de la educación, investigación y desarrollo. La genética determina la estructura del cerebro y nuestra investigación comprueba que la ausencia de FMRP también podría estar implicada en la modulación del dolor como parte de su expresión patológica siendo el modelo animal un punto importante en la investigación científica fundamental para entender el desarrollo de anormalidades en el cerebro. ABSTRACT Pain is a common symptom in medical practice. In Spain, a study conducted in 2000 each medical professional treats an average of 181 patients with pain per month, most of them with chronic moderate pain. 7% -8% of the European population is affected and up to 5% can be serious, it is estimated to affect more than two million people in Spain. In Primary Care, patients with neuropathic pain have much higher rates of depression. Neuropathic pain is caused by damage or disease affecting the somatosensory system, is a public health problem with high labor costs, there are relatively unfamiliar with the peculiarities in diagnosis and treatment, failing that, the pain is perpetuated and becomes rebellious to treat, in most cases becomes chronic. The pathophysiological mechanisms are evolutionary, its a progressive, if untreated, causing severe impact on the quality of life of affected patients. According to Prusiner (Nobel Prize for Medicine 1997), all neurodegenerative diseases there is some abnormal process of neuronal function. Neurodegenerative diseases are the result of abnormalities in the process of certain proteins involved in the cell cycle, reducing or canceling its features such as Alzheimer's disease and FXS. FMRP (Fragile Mental Retardation Protein), is essential for normal cognitive development, and has been linked to the pyramidal tract pain. Fragile X Syndrome (FXS), is due to mutation of the gene (FMR-1). As a consequence of the mutation, the gene is inactivated and can not perform the function of FMRP synthesize. For its incidence is considered the leading cause of Mental Deficiency Hereditary second only to Down Syndrome. Electroencephalography (EEG) is the recording of bioelectrical brain activity, is a advancement of clinical and experimental studies for the detection, diagnosis and treatment of many neurological and physiological abnormalities of the brain and the central nervous system, including pain. The objective of this research is a multimodal study, is the development of new forms of presentation using advanced diagnostic techniques of signal processing and image, to determine the links between cognitive evaluations and anatomic correlation with pain modulation to this protein FMRP-related pathologies. To accomplish this task have used the mouse model. Our results in this study show alterations in multimodal pain pathways in FMR1-KO in brain modulation (neuropathic pain), the data are based on the results of the structural study (histology image), functional (EEG) testing and behavior (Barnes maze). Histology In structural asymmetry shown in FMR1 KO model versus WT control, the left hemisphere is greater density of neuronal mass (KO females 56.7% -60.8%, 58.3% -61% males, females 62.7% -62.4 WT %, males 55% -56.2%), respectively right-left hemisphere, this reflects a very low correlation between hemispheres in KO (~ 50%) subjects compared to WT (~ 90%) control. Significant correlation was found between tests of long-term memory with respect to hemispheric asymmetry (r = -0.48, corrected <0.05). In the memory test there are differences too, the WT subjects had 22% yield in long-term memory, in males there memory impairment 28% corresponding to the condition in humans. The results of EEG studied in the left hemisphere, in insular cortex area, we found that the latency of the response evoked potential is lower (22vs32 15vs96seg), the signal strength is higher for the experimental subjects versus FMR1 KO control subjects, this is very significant given the results on histology (140vs129 145vs142 mv). This multimodal study confirms that the clinical manifestations of FXS are dependent variables of age and sex. We have been able to corroborate in the animal model in the adult stage, males with FXS begin developing problems in the performance of tasks that require the implementation of the central executive function of working memory (temporary storage). In behavior analysis is difficult to reach an objective conclusion, more studies are needed in different life stages corroborated with histologic findings. Advances in recent years were very positive, being opened new lines of research that represent a great challenge to physicians, health care, social and economic problems facing the major developed countries, with a massive increase in life expectancy and quality. The tools used in the field of neuroscience offer us great opportunities for the development of strategies to be used in the area of education, research and development. Genetics determines the structure of the brain and our research found that the absence of FMRP might also be involved in the modulation of pain as part of their pathological expression being an important animal model in basic scientific research to understand the development of abnormalities in brain.

Propuesta de integración de agentes software inteligentes sobre JADE con entornos virtuales en Unity3D

La unión de distintos sistemas software constituye un elemento principal de las nuevas Tecnologías de la Información y la Comunicación. La integración de entornos virtuales tridimensionales con agentes software inteligentes es el objetivo que persigue este trabajo de investigación. Para llevar a cabo esta integración se parte de la creación de un agente virtual, un personaje que es controlado por una mente desarrollada siguiendo un enfoque basado en agentes software. Se busca así dotar al sistema de cierto nivel de inteligencia, tomando como referencia el funcionamiento del cerebro humano. Lo que se consigue es que el agente capte los estímulos del entorno, los procese y genere comportamientos, tanto reactivos como deliberativos, que son ejecutados por el personaje. Los resultados obtenidos resaltan el dinamismo del sistema, a la vez que animan a seguir investigando en este campo lleno de aplicaciones directas y reales sobre el mundo. En conclusión, esta investigación busca y consigue un nuevo paso en el progreso de las nuevas tecnologías mediante una integración real de distintos sistemas software. ---ABSTRACT---The union of different software systems is a major element of Information and Communications Technology. The aim of this research is the integration of 3D virtual environments and intelligent software agents. This integration is based on the development of a virtual agent, a character that is controlled by a mind developed following a software agent approach. It is sought to provide the system with some intelligence level, taking the human brain function as a reference point. The consequence is that the agent captures environmental stimuli, processes them and creates reactive and deliberative behaviours that can be executed by the avatar. The findings emphasize the dynamism of the system as well as they encourage to research more in this field that has a lot of direct and real-life applications on the world. In conclusion, this research seeks and takes a new step in the progress of new technologies through a real integration of different software systems.

Clustering basado en redes bayesianas con predictoras continuas: aplicaciones en neurociencia

Desentrañar el funcionamiento del cerebro es uno de los principales desafíos a los que se enfrenta la ciencia actual. Un área de estudio que ha despertado muchas expectativas e interés es el análisis de la estructura cortical desde el punto de vista morfológico, de manera que se cree una simulación del cerebro a nivel molecular. Con ello se espera poder profundizar en el estudio de numerosas enfermedades neurológicas y patológicas. Con el desarrollo de este proyecto se persigue el estudio del soma y de las espinas desde el punto de vista de la neuromorfología teórica. Es común en el estado del arte que en el análisis de las características morfológicas de una neurona en tres dimensiones el soma sea ignorado o, en el mejor de los casos, que sea sustituido por una simple esfera. De hecho, el concepto de soma resulta abstracto porque no se dispone de una dfinición estricta y robusta que especifique exactamente donde finaliza y comienzan las dendritas. En este proyecto se alcanza por primera vez una definición matemática de soma para determinar qué es el soma. Con el fin de simular somas se ahonda en los atributos utilizados en el estado del arte. Estas propiedades, de índole genérica, no especifican una morfología única. Es por ello que se propone un método que agrupe propiedades locales y globales de la morfología. En disposición de las características se procede con la categorización del cuerpo celular en distintas clases a partir de un nuevo subtipo de red bayesiana dinámica adaptada al espacio. Con ello se discute la existencia de distintas clases de somas y se descubren las diferencias entre los somas piramidales de distintas capas del cerebro. A partir del modelo matemático se simulan por primera vez somas virtuales. Algunas morfologías de espinas han sido atribuidas a ciertos comportamientos cognitivos. Por ello resulta de interés dictaminar las clases existentes y relacionarlas con funciones de la actividad cerebral. La clasificación más extendida (Peters y Kaiserman-Abramof, 1970) presenta una definición ambigua y subjetiva dependiente de la interpretación de cada individuo y por tanto discutible. Este estudio se sustenta en un conjunto de descriptores extraídos mediante una técnica de análisis topológico local para representaciones 3D. Sobre estos datos se trata de alcanzar el conjunto de clases más adecuado en el que agrupar las espinas así como de describir cada grupo mediante reglas unívocas. A partir de los resultados, se discute la existencia de un continuo de espinas y las propiedades que caracterizan a cada subtipo de espina. ---ABSTRACT---Unravel how the brain works is one of the main challenges faced by current science. A field of study which has aroused great expectations and interest is the analysis of the cortical structure from a morphological point of view, so that a molecular level simulation of the brain is achieved. This is expected to deepen the study of many neurological and pathological diseases. This project seeks the study of the soma and spines from the theoretical neuromorphology point of view. In the state of the art it is common that when it comes to analyze the morphological characteristics of a three dimension neuron the soma is ignored or, in the best case, it is replaced by a simple sphere. In fact, the concept of soma is abstract because there is not a robust and strict definition on exactly where it ends and dendrites begin. In this project a mathematical definition is reached for the first time to determine what a soma is. With the aim to simulate somas the atributes applied in the state of the art are studied. These properties, generic in nature, do not specify a unique morphology. It is why it was proposed a method to group local and global morphology properties. In arrangement of the characteristics it was proceed with the categorization of the celular body into diferent classes by using a new subtype of dynamic Bayesian network adapted to space. From the result the existance of different classes of somas and diferences among pyramidal somas from distinct brain layers are discovered. From the mathematical model virtual somas were simulated for the first time. Some morphologies of spines have been attributed to certain cognitive behaviours. For this reason it is interesting to rule the existent classes and to relate them with their functions in the brain activity. The most extended classification (Peters y Kaiserman-Abramof, 1970) presents an ambiguous and subjective definition that relies on the interpretation of each individual and consequently it is arguable. This study was based on the set of descriptors extracted from a local topological analysis technique for 3D representations. On these data it was tried to reach the most suitable set of classes to group the spines as well as to describe each cluster by unambiguous rules. From these results, the existance of a continuum of spines and the properties that characterize each spine subtype were discussed .

Caracterización de ambientes sonoros en recintos universitarios: influencia del ruido sobre procesos cognitivos básicos

El interés por el estudio de la problemática del ruido en las escuelas y sus efectos sobre los estudiantes a nivel universitarios, es un tema que no ha sido estudiado debidamente. Desgraciadamente, en el ámbito educativo universitario, no existen regulaciones específicas que permitan determinar parámetros preventivos, ni procedimientos de evaluación de ruido dentro de este tipo de instalaciones educativas. Debido a la importancia de los efectos que el ruido tiene sobre la salud y la calidad de vida de los estudiantes universitarios, y consecuentemente en el rendimiento académico; es de suma importancia desarrollar mecanismos que estudien y planteen soluciones que ayuden a garantizar la mejora de la calidad de vida de la población estudiantil. En este trabajo se ha presentado un extenso trabajo que incluye el estudio de los ambientes sonoros a los que los estudiantes universitarios se ven expuestos día a día y se proponen acciones que ayudan a mejorar la calidad acústica en instalaciones educativas. Así mismo se evidencian los efectos que tiene este contaminante sobre la salud psicológica y por consecuencia en el desarrollo intelectual de los estudiantes. Por un lado, se incluye una propuesta de metodología que ayuda a la correcta caracterización de los ambientes sonoros en los cuales se desarrollan los estudiantes a nivel universitario. Esta se realizó haciendo un completo registro de los niveles sonoros durante sus actividades diarias. Así mismo, una encuesta fue aplicada a estudiantes para conocer la percepción que se tiene sobre las condiciones sonoras en ambientes universitarios. Así mismo, se realizó un estudio de la calidad sonora en instalaciones universitarias, el cual deriva la valoración de la molestia al ruido. Se propone una escala de valoración de molestia al ruido, la cual deriva el diseño de una propuesta con acciones de bajo coste frente al ruido. Por otro lado, se evidencian los trastornos que ocasiona este contaminante sobre la salud psicológica de los estudiantes y que afectan el desarrollo académico de estos. Se realizó primeramente la valoración de la atención y la memoria por medio de test psicométricos estandarizados y otros diseñados para este estudio en particular. Por último, con la finalidad de obtener datos objetivos y confiables que permitieron relacionar la influencia negativa del ruido de fondo sobre procesos cognitivos básicos como la atención y la memoria, se llevó a cabo un estudio de la actividad cerebral. Para llevar a cabo esta evaluación se utilizó como principal herramienta el electroencefalograma (EEG), enfocándose en los cambios producidos con y sin exposición a ruido de fondo, específicamente en las bandas de frecuencia relacionadas con procesos cognitivos básicos como los son la atención y la memoria, en este caso la banda theta (4-7 Hz) y la banda beta (13-30 Hz). ABSTRACT The interest in the study of the problem of noise in schools and its impact on students at university level is a topic that has not been properly studied. Unfortunately, there are no specific regulations for determining preventive parameters or noise assessment procedures in university facilities. Due to the importance of the effects that noise has on health and on the quality of life of university students, and consequently on academic performance; is very important to develop mechanisms to evaluate and design solutions that help ensure an improvement in the quality of life of the student population. This thesis has presented an extensive work, which includes the study of the state of the art on the problem of noise in the sound environments to which university students are exposed every day, and the effects on students mainly on attention aspects. On one hand, a general study of the common noise environments of life of university students was carried out, where a methodological proposal is included and that helps in the correct characterization of the sound environments in which university students grow. This proposal includes the assessment of noise exposure, noise dose and a recording of the characteristic sound levels during their daily activities in and out spaces dedicated to their education. Also, a survey was conducted to know the perception that students have on noise conditions in university environments. Also, a method for evaluation of the noise annoyance is proposed, this is through the correlation of two known methods of evaluation. The first method is based on psychoacoustic parameters that allow the evaluation of the sound quality. These parameters were related, obtaining as a result the parameter known as psychoacoustics annoyance. The second method is based on a questionnaire in conjunction with listening tests in specific sound environments. Derived from the correlation of these two methods, a series of indicators of noise annoyance are proposed, which entails the design of a noise annoyance indicator. Furthermore, the effects of this pollutant on psychological health and therefore in the intellectual development of students has been shown. First, an evaluation of attention and memory using standardized psychometric tests were performed and others designed for this particular study. Because it has been evidenced that the use of these psychometric tests are not very reliable, we sought to obtain another objective and reliable data to show the relationship between the negative influence of background noise on basic cognitive processes such as attention and memory. This was achieved by carrying out a study of the brain activity. To carry out this evaluation the electroencephalogram (EEG) was used as the main tool, focusing on the changes produced with and without exposure to background noise, specifically in the frequency bands related to basic cognitive processes such as attention and are memory. In this case the band theta (4-7 Hz) and beta band (13-30 Hz) were studied. The purpose of this thesis is to establish the bases for future studies that allow go deep in the study of the sound conditions in school environments, and enable the design of strategies and measures against noise and the correct evaluation of the effects of noise on aspects for improving the psychological quality of life and academic performance of students.

Bases para un diseño metodológico de estimulación binaural como terapia acústica en neurología

La medicina y la ingeniería del siglo XXI han dado como fruto numerosos avances para la sociedad aunque en la mayoría de los casos los tratamientos suelen ser costosos e invasivos. La educación que recibe la sociedad sobre la salud es escasa, ya que sólo vamos al médico cuando realmente estamos enfermos. Este trabajo presenta nuestra apuesta por las terapias complementarias, para el desarrollo de una metodología terapéutica no invasiva y con un costo muy bajo. La finalidad de esta Tesis, que se enmarca en un equipo multidisciplinar, fruto de la estrecha colaboración en el que participan psicopedagogos, ingenieros y médicos, es perfilar una metodología que luego pueda ser aplicable a patologías neurológicas. Aquí, dejamos sentadas las bases. Faltarán nuevos investigadores que continúen este camino para tener una base de datos lo suficientemente extensa de registros de sujetos que hayan sido sometidos a terapia binaural, para poder sacar unas conclusiones sólidas. La aportación de esta Tesis deja cubierta la aplicación, selección, procesado de señal y desarrollo de algoritmos, test cognitivos indicados para el caso específico que nos ocupa, cálculo de incertidumbre del sistema utilizado para la aplicación del estímulo y desarrollo de un test psicoacústico específico. EL empleo del sonido en medicina como es la musicoterapia o sonoterapia ha experimentado una gran difusión en los últimos años, más de 100.000 nuevas citas bibliográficas han aparecido con respecto al año anterior. Sin embargo, son escasísimas las que hacen referencia a las características físico acústicas del sonido empleado, tan sólo hemos encontrado una par de ellas que correlacionan las características físicas del sonido con el tipo de respuesta terapéutica. No encontramos citas bibliográficas específicas que planteen un modelo experimental científico capaz de reproducir las mismas respuestas ante los mismos parámetros y estímulos. En esta Tesis proponemos el uso de estimulación sonora binaural, que consiste en la utilización de dos tonos puros idénticos pero ligeramente diferentes en frecuencia que se presentan de manera separada cada uno en un oído, como consecuencia, la persona que recibe la estimulación percibe un tercer tono, llamado tono binaural, formado por la diferencia de frecuencia de ambos variando su amplitud. Existen estudios que sugieren que dichas frecuencias binaurales pueden modificar los patrones eléctricos de la actividad cerebral y los niveles de arousal, conociéndose en la literatura bajo el nombre de “entrainment”. Tras la revisión bibliográfica del estado del arte, podemos concluir que es necesario el desarrollo de estudios doble ciego bien diseñados, con el objetivo de establecer una base sólida sobre los efectos de este tipo de estimulación, ya que la mayoría de los beneficios documentados se refieren a muestras muy pequeñas y con poco rigor científico, siendo los resultados positivos obtenidos debidos al efecto placebo. La tecnología binaural es barata siendo cualquier avance en esta dirección de interés público. El objetivo concreto de la investigación es estudiar el potencial de las ondas binaurales en un área en particular: tareas que requieren atención y concentración. Se busca obtener cualquier cambio en las ondas cerebrales que se puedan correlar con la mejoras. A la vista de los resultados de estas investigaciones se intentará aplicar esta metodología en neuropatologías que presenten alguna deficiencia en el área de atención como es el Trastorno de espectro Autista. En esta Tesis presentamos los resultados de dos estudios independientes, el primero para sentar las bases del método (tiempos, diseño de estimulaciones, procesado) en una muestra de 78 adultos sanos, el segundo a partir de los resultados obtenidos en el primero, afinando la metodología y para un grupo de 20 niños entre 8 y 12 años, los resultados del segundo estudio sirven para justificar su aplicación en niños con TEA que presenten déficit de atención. ABSTRACT Medicine and engineering in the 21st century have resulted in advances for society but in most cases the treatments are often costly and invasive. The health education society receive is scarce, since only go to the doctor when we are really sick. With this work I present my commitment to complementary therapies, my little grain of sand in the development of a noninvasive therapeutic approach and very low cost, well and can be used in a preventive manner resulting in a society with less sick. The purpose of this thesis is to outline a methodology that can then be applied to neurological diseases, here we lay the groundwork. New researchers are needed to continue this path for a sufficiently extensive records database of subjects who have undergone binaural therapy, and so to draw firm conclusions. The contribution of this thesis includes: the application, selection, signal processing and algorithm development, indicated cognitive tests for the specific case at hand, calculation of system uncertainty of the system and development of a specific psychoacoustic test. The use of sound in medicine, such as music therapy or sound therapy has experienced a great diffusion in recent years, more than 100,000 new citations have appeared over the previous year but very few are those referring to acoustic physical characteristics of sound employee, we have only found a couple of them that physical sound characteristics are correlated with the therapeutic response. We found no specific citations posing a scientific experimental model capable of reproducing the same answers to the same parameters and stimuli. In this thesis we propose the use of binaural sound stimulation which involves the use of two identical but slightly different in frequency pure tones presented separately each in one ear, as a result the subject perceives a third tone, called binaural tone, formed by the difference in frequency with amplitude variations Studies suggest that these binaural frequencies can modify the electrical patterns of brain activity and arousal levels, being known in the literature under the name of “entrainment”. After the literature review of the state of the art, we conclude, it is necessary to develop well-designed double-blind studies, in order to establish a solid foundation on the effects of such stimulation, since most of the documented benefits relate to very small samples and unscientific may be obtained positive results due to the placebo effect. The binaural technology is cheap being any progress in this direction in the public interest. The specific objective of the research is to study the potential of binaural waves in a particular area: tasks requiring attention and concentration also we want to get any change in brain waves that can correlate with improvements. In view of the results of this research we seek to apply this methodology in neuropathology presenting any deficiency in the area of attention such as Autism Spectrum Disorder. In this thesis we present the results of two independent studies, the first to lay the foundation of the method (times, stimulation design, processing) in a sample of 78 healthy adults, the second from the results obtained in the first, refine the methodology for a group of 20 children between 8 and 12 years, the results of the second study used to justify its use in children with ASD that present attention deficit.

Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease

Evidence from postmortem studies suggest an involvement of oxidative stress in the degeneration of dopaminergic neurons in Parkinson disease (PD) that have recently been shown to die by apoptosis, but the relationship between oxidative stress and apoptosis has not yet been elucidated. Activation of the transcription factor NF-κB is associated with oxidative stress-induced apoptosis in several nonneuronal in vitro models. To investigate whether it may play a role in PD, we looked for the translocation of NF-κB from the cytoplasm to the nucleus, evidence of its activation, in melanized neurons in the mesencephalon of postmortem human brain from five patients with idiopathic PD and seven matched control subjects. In PD patients, the proportion of dopaminergic neurons with immunoreactive NF-κB in their nuclei was more than 70-fold that in control subjects. A possible relationship between the nuclear localization of NF-κB in mesencephalic neurons of PD patients and oxidative stress in such neurons has been shown in vitro with primary cultures of rat mesencephalon, where translocation of NF-κB is preceded by a transient production of free radicals during apoptosis induced by activation of the sphingomyelin-dependent signaling pathway with C2-ceramide. The data suggest that this oxidant-mediated apoptogenic transduction pathway may play a role in the mechanism of neuronal death in PD.

A hierarchical neuronal network for planning behavior

Planning a goal-directed sequence of behavior is a higher function of the human brain that relies on the integrity of prefrontal cortical areas. In the Tower of London test, a puzzle in which beads sliding on pegs must be moved to match a designated goal configuration, patients with lesioned prefrontal cortex show deficits in planning a goal-directed sequence of moves. We propose a neuronal network model of sequence planning that passes this test and, when lesioned, fails in a way that mimics prefrontal patients’ behavior. Our model comprises a descending planning system with hierarchically organized plan, operation, and gesture levels, and an ascending evaluative system that analyzes the problem and computes internal reward signals that index the correct/erroneous status of the plan. Multiple parallel pathways connecting the evaluative and planning systems amend the plan and adapt it to the current problem. The model illustrates how specialized hierarchically organized neuronal assemblies may collectively emulate central executive or supervisory functions of the human brain.

A widely expressed βIII spectrin associated with Golgi and cytoplasmic vesicles

Spectrin is an important structural component of the plasma membrane skeleton. Heretofore-unidentified isoforms of spectrin also associate with Golgi and other organelles. We have discovered another member of the β-spectrin gene family by homology searches of the GenBank databases and by 5′ rapid amplification of cDNA ends of human brain cDNAs. Collectively, 7,938 nucleotides of contiguous clones are predicted to encode a 271,294-Da protein, called βIII spectrin, with conserved actin-, protein 4.1-, and ankyrin-binding domains, membrane association domains 1 and 2, a spectrin dimer self-association site, and a pleckstrin-homology domain. βIII spectrin transcripts are concentrated in the brain and present in the kidneys, liver, and testes and the prostate, pituitary, adrenal, and salivary glands. All of the tested tissues contain major 9.0-kb and minor 11.3-kb transcripts. The human βIII spectrin gene (SPTBN2) maps to chromosome 11q13 and the mouse gene (Spnb3) maps to a syntenic region close to the centromere on chromosome 19. Indirect immunofluorescence studies of cultured cells using antisera specific to human βIII spectrin reveal a Golgi-associated and punctate cytoplasmic vesicle-like distribution, suggesting that βIII spectrin associates with intracellular organelles. This distribution overlaps that of several Golgi and vesicle markers, including mannosidase II, p58, trans-Golgi network (TGN)38, and β-COP and is distinct from the endoplasmic reticulum markers calnexin and Bip. Liver Golgi membranes and other vesicular compartment markers cosediment in vitro with βIII spectrin. βIII spectrin thus constitutes a major component of the Golgi and vesicular membrane skeletons.

Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias

The cortex of the brain is organized into clear horizontal layers, laminae, which subserve much of the connectional anatomy of the brain. We hypothesize that there is also a vertical anatomical organization that might subserve local interactions of neuronal functional units, in accord with longstanding electrophysiological observations. We develop and apply a general quantitative method, inspired by analogous methods in condensed matter physics, to examine the anatomical organization of the cortex in human brain. We find, in addition to obvious laminae, anatomical evidence for tightly packed microcolumnar ensembles containing approximately 11 neurons, with a periodicity of about 80 μm. We examine the structural integrity of this new architectural feature in two common dementing illnesses, Alzheimer disease and dementia with Lewy bodies. In Alzheimer disease, there is a dramatic, nearly complete loss of microcolumnar ensemble organization. The relative degree of loss of microcolumnar ensembles is directly proportional to the number of neurofibrillary tangles, but not related to the amount of amyloid-β deposition. In dementia with Lewy bodies, a similar disruption of microcolumnar ensemble architecture occurs despite minimal neuronal loss. These observations show that quantitative analysis of complex cortical architecture can be applied to analyze the anatomical basis of brain disorders.

Retinotopic mapping of lateral geniculate nucleus in humans using functional magnetic resonance imaging

Subcortical nuclei in the thalamus, which play an important role in many functions of the human brain, provide challenging targets for functional mapping with neuroimaging techniques because of their small sizes and deep locations. In this study, we explore the capability of high-resolution functional magnetic resonance imaging at 4 Tesla for mapping the retinotopic organization in the lateral geniculate nucleus (LGN). Our results show that the hemifield visual stimulation only activates LGN in the contralateral hemisphere, and the lower-field and upper-field visual stimulations activate the superior and inferior portion of LGN, respectively. These results reveal a similar retinotopic organization between the human and nonhuman primate LGN and between LGN and the primary visual cortex. We conclude that high-resolution functional magnetic resonance imaging is capable of functional mapping of suborganizations in small nuclei together with cortical activation. This will have an impact for studying the thalamocortical networks in the human brain.

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

Catecholamines, thought to derive from the extrinsic innervation of the ovary, participate in the regulation of ovarian development and mature gonadal function. Recently, intraovarian neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, were described in the ovary of nonhuman primates. We now show that the primate ovary expresses both the genes encoding TH and dopamine β-hydroxylase (DBH), the key enzymes in norepinephrine (NE) biosynthesis. Ovarian neurons were identified as a site of TH and DBH gene expression, and surprisingly, oocytes were identified as an exclusive site of DBH synthesis. Oocytes contain neither TH mRNA nor protein, indicating that they are unable to synthesize dopamine (DA). They did, however, express a DA transporter gene identical to that found in human brain. The physiological relevance of this transporter system and DBH in oocytes was indicated by the ability of isolated oocytes to metabolize exogenous DA into NE. Isolated follicles containing oocytes—but not those from which the oocytes had been removed—responded to DA with an elevation in cAMP levels; this elevation was prevented by propranolol, a β-adrenoreceptor antagonist. The results suggest that oocytes and somatic cells are linked by a neuroendocrine loop consisting of NE synthesized in oocytes from actively transported DA and cAMP produced by somatic follicular cells in response to NE-induced β-adrenoreceptor activation.

Verb generation in patients with focal frontal lesions: A neuropsychological test of neuroimaging findings

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.

The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)38 tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.

Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A

We have used a yeast two-hybrid approach to uncover protein interactions involving the D2-like subfamily of dopamine receptors. Using the third intracellular loop of the D2S and D3 dopamine receptors as bait to screen a human brain cDNA library, we identified filamin A (FLN-A) as a protein that interacts with both the D2 and D3 subtypes. The interaction with FLN-A was specific for the D2 and D3 receptors and was independently confirmed in pull-down and coimmunoprecipitation experiments. Deletion mapping localized the dopamine receptor–FLN-A interaction to the N-terminal segment of the D2 and D3 dopamine receptors and to repeat 19 of FLN-A. In cultures of dissociated rat striatum, FLN-A and D2 receptors colocalized throughout neuronal somata and processes as well as in astrocytes. Expression of D2 dopamine receptors in FLN-A-deficient M2 melanoma cells resulted in predominant intracellular localization of the D2 receptors, whereas in FLN-A-reconstituted cells, the D2 receptor was predominantly localized at the plasma membrane. These results suggest that FLN-A may be required for proper cell surface expression of the D2 dopamine receptors. Association of D2 and D3 dopamine receptors with FLN-A provides a mechanism whereby specific dopamine receptor subtypes may be functionally linked to downstream signaling components via the actin cytoskeleton.