Organización de las redes cerebrales / Organization of brain networks

El procesamiento de información por el cerebro se basa en sistemas de redes (networks) que poseen propiedades estructurales y funcionales derivadas de su extrema complejidad. Al tratarse de sistemas complejos con propiedades dinámicos no lineares, las redes se auto organizan permanentemente para adecuarse tanto a los procesamientos rápidos, como en el caso de las funciones cognitivas o ejecutivas, como a las más lentas, derivadas de la capacidad de generar cambios plásticos para adaptarse a las situaciones cambiantes de los entornos externos e internos. El estudio de la conectividad en el SNC se ha sistematizado por teorías de gráficas, modelos simples de un sistema, basados en conjuntos de nodos y márgenes o bordes que poseen propiedades de pequeño mundo (ni azarística, ni regular) de modo tal que el conectoma se organiza en los pequeños volúmenes relativos del cerebro permietiendo una alta eficiencia a bajo costo dada la corta distancia ente nodos centrales que procesan gran cantidad de información. Las proyecciones largas entre regiones distantes del SNC si bien eficaces en las funciones integradoras son costosas en estructura y metabolismo, y por ello vulnerables tanto en el desarrollo como en patologías, como la enfermedad de Alzheimer, la esquizofreia, la epilepsia, el ADHD la esclerosis múltiple, etc. Se conceptualiza al conectoma como fenotipo intermedio o endofenotipo con características heredables modificables en las distintas etapas de la vida, desde el desarrollo pre y perinatal hasta el envejecimiento.

The processing of information by the brain is based on systems of networks that have both structural and functional properties, given their extreme complexity. Because they consist in complex systems with nonlinear dynamic properties, the networks organize themselves permanently to adjust either to quick processings, as is the case with cognitive or executive functions and to the slowest processings which result from the capability of generating plastic changes to adapt to the changing contexts of the external and internal environments. The study of connectivity in the CNS has been systematized by graphics theories, which consist in simple models of a system based on sets of nodes and margins or borders that have properties of a small-world network (neither at random nor regular), so that the connectome is organized in the small relative volumes of the brain, enabling a high efficiency at a low cost, given the short distance between central nodes that process a large amount of information. Although the long projections between the regions that are far from the CNS are efficacious in the integrative functions, they are costly in structure and metabolism, and therefore, vulnerable both in development as well as in pathologies such as Alzheimer's Disease, schizophrenia, epilepsy and ADHD in multiple sclerosis, etc. The author conceptualizes the connectome as an intermediate phenotype or endophenotype with modifying inheritable characteristics in the different stages of life, from the pre- and perinatal development until ageing.

Mecanismos neuronales en el modelo cognitivo de depresión de Beck / Neural Mechanisms in Beck's Cognitive Model of Depression

El modelo cognitivo de la depresión que fuera formulado por Beck hace más de 40 años se fundamentaba en procesamientos sesgados de la atención, memoria y el pensamiento, con rumiación y desvíos hacia los llamados “pensamientos negativos repetitivos”, como jugando roles primarios en el desarrollo y mantenimiento de la depresión. En 2011, el propio Beck y sus colaboradores hacen un resumen de los hallazgos referentes a los mecanismos neurales que subyacen a los aspectos cognitivos de la depresión. Sin embargo, sólo se consideran aquellos aspectos referentes al procesamiento cognitivo sin hacer lo mismo con el procesamiento emocional que es el endofenotipo nuclear del trastorno depresivo y se refleja en la lectura de las emociones por el cerebro emocional y la corteza de la ínsula según el esquema de Damasio actualizado por Craig (14), que deberá tenerse en cuenta como la base fundamental de las terapias cognitivo/conductuales y las cognitivo/emocionales junto al necesario tratamiento farmacológico, adecuadamente complementados en tiempo y forma

The cognitive model of depression, which was formulated by Beck more than 40 years ago, was grounded on biased processings of attention, memory and thought, with rumination and deviations towards the so-called "negative repetitive thoughts", as playing primry roles in the development and maintenance of depression. In 2011, Beck himself, as well as his collaborators, summarized the findings concerning the neural mechanisms underlying the cognitive aspects of depression. However, only those aspects relating to the cognitive processing are considered and not the emotional processing that is the nuclear endophenotype of depressive disorder and is reflected in the reading of emotions by the brain and the insular cortex, according to Damasio's scheme updated by Craig (14), which should be considered the fundamental basis of cognitive/behavioral therapies and cognitive/emotional therapies together with the necessary pharmacological treatment, adequately complimented in due time and forma

Mecanismos neuronales en el modelo cognitivo de depresión de Beck / Neural Mechanisms in Becks Cognitive Model of Depression

El modelo cognitivo de la depresión que fuera formulado por Beck hace más de 40 años se fundamentaba en procesamientos sesgados de la atención, memoria y el pensamiento, con rumiación y desvíos hacia los llamados ôpensamientos negativos repetitivosö, como jugando roles primarios en el desarrollo y mantenimiento de la depresión. En 2011, el propio Beck y sus colaboradores hacen un resumen de los hallazgos referentes a los mecanismos neurales que subyacen a los aspectos cognitivos de la depresión. Sin embargo, sólo se consideran aquellos aspectos referentes al procesamiento cognitivo sin hacer lo mismo con el procesamiento emocional que es el endofenotipo nuclear del trastorno depresivo y se refleja en la lectura de las emociones por el cerebro emocional y la corteza de la ínsula según el esquema de Damasio actualizado por Craig (14), que deberá tenerse en cuenta como la base fundamental de las terapias cognitivo/conductuales y las cognitivo/emocionales junto al necesario tratamiento farmacológico, adecuadamente complementados en tiempo y forma (AU)

The cognitive model of depression, which was formulated by Beck more than 40 years ago, was grounded on biased processings of attention, memory and thought, with rumination and deviations towards the so-called "negative repetitive thoughts", as playing primry roles in the development and maintenance of depression. In 2011, Beck himself, as well as his collaborators, summarized the findings concerning the neural mechanisms underlying the cognitive aspects of depression. However, only those aspects relating to the cognitive processing are considered and not the emotional processing that is the nuclear endophenotype of depressive disorder and is reflected in the reading of emotions by the brain and the insular cortex, according to Damasios scheme updated by Craig (14), which should be considered the fundamental basis of cognitive/behavioral therapies and cognitive/emotional therapies together with the necessary pharmacological treatment, adequately complimented in due time and forma (AU)

Neurobiología de las adicciones y procesos de plasticidad involucrados / The Neurobiology of Addiction and the Plasticity Processes Involved

Las evidencias acumuladas en los últimos diez años, indican que las drogas de abuso pueden cooptar los mecanismos de plasticidad en circuitos cerebrales involucrados en las recompensas a reforzadores naturales (comida, bebida, sexo, etc.), resultando en una forma patológica pero poderosa, de memoria y aprendizaje. El circuito involucra esencialmente, el sistema dopaminérgico mesolímbico (area tegmental ventral (VTA), nucleus accumbens (NAcc) y estructuras límbicas asociadas). La plasticidad sináptica en las íreas involucradas incide particularmente en la abstinencia, la recurrencia, la reincidencia y la pérdida del autocontrol. La ínsula y en particular, la ínsula anterior derecha, participa en las percepciones de los estados emocionales corporales que generan las urgencias de consumo y las saliencias de incentivos corporales. Esto se refleja en los estudios imagenológicos funcionales y se confirma por la pérdida del hábito al consumo de tabaco en los casos de lesiones cerebrales en éstas áreas específicas.

Evidence gathered during the past ten years demonstrates that drugs of abuse may co-opt plasticity mechanisms in brain circuits involved in the rewards to natural reinforcements (food, drink, sex, etc.) which results in a pathological but powerful form of memory and learning. The circuit basically involves the mesolimbic dopamine system (ventral tegmental area (VTA), the nucleus accumbens (NAcc) and associated limbic structures). The synaptic plasticity in the areas involved particularly impacts on abstinence, recurrence, recidivism and the loss of self-control. The insula, and the right anterior insula in particular, plays a role in the perceptions of the emotional states of the body that trigger the craving for consumption and the salience of body incentives. This is depicted in functional imaging studies and is demonstrated by the break of the habit of smoking in cases of brain injuries in these specific areas.

Actualización en la patofisiología de la esquizofrenia desde la perspectiva de la neurociencia de sistemas / Update on the pathophysiology of schizophrenia from the systems neuroscience point of view

La patofisiología de la esquizofrenia (EQZ) sólo podrá entenderse en una aproximación integrativa, basada en la neurociencia de sistemas, para tratar de explicar cómo múltiples genes y neurotransmisores pueden actuar de manera sinérgica para producir el trastorno. En este trabajo se analizarán por separado los diversos endofenotipos de esta enfermedad para tratar de explicar, sobre la base de aproximaciones sistémicas, cómo ocurren los cambios en las interneuronas GABAérgicas en la EQZ, comenzando con la hipofunción GABAérgica y sus consecuencias sobre las neuronas piramidales corticales y la disfunción dopaminérgica a punto de origen hipocampal, lo que permite conciliar eventos neurobiológicos con sus consecuencias conductuales (consilience). Los circuitos involucrados por Lisman, Grace, Coyle, Green y otros autores en esta revisión integran las neurotransmisiones glutamatérgica, GABAérgica, dopaminérgica y colinérgica en un marco sistémico en que también se involucran factores de riesgo genético, para intentar demostrar sus acciones sinérgicas dentro del circuito y generar una aproximación desde la neurociencia de sistemas. Se intentará desarrollar estrategias de distinto orden para comprender la EQZ como enfermedad que produce sus consecuencias devastadoras a través de la acción sinérgica de genes y diversos neurotransmisores integrados en circuitos de procesamiento que operan en complejas dinámicas de tipo no-lineal.

Understanding the pathophysiology of schizophrenia (SZ) entails adopting a holistic approach based on systems neuroscience that allows to explain how multiple genes and neurotransmitters can act synergistically to trigger the disorder. In this article, the different endophenotypes of schizophrenia are analysed separaately, with the aim of explaining, by means of systemic approaches, how changes take place in GABAergic interneurons in SZ, starting from the GABAergic hypofunction and ists effects on cortical pyramidal neurons, as well as on the dopaminergic dysfunction at he pont of origin of the hippocampus, which enables to reconcile neurobiological events with their behavioural consequences ("consilience"). The circuits proposed by Lisman, Grace, Coyle, Green and other authors, that make up glutamatergic, GABAerci, dopaminergic and cholinergic neurotransmissions embedded in a systemic framework in whic genetic risk factors are also involved, are included in this review to demonstrate their synergistic actions within the circuit, as well as to develop an approach based on systems neuroscience. The present article will also provide different types of strategies intended to understand SZ as a disease that causes its devastating effects through the synergistic action of genes and the different neurotransmitters organized in processing circuits that operte in complex non-linear dynamics.

Actualización en la patofisiología de la esquizofrenia desde la perspectiva de la neurociencia de sistemas / Update on the pathophysiology of schizophrenia from the systems neuroscience point of view

La patofisiología de la esquizofrenia (EQZ) sólo podrá entenderse en una aproximación integrativa, basada en la neurociencia de sistemas, para tratar de explicar cómo múltiples genes y neurotransmisores pueden actuar de manera sinérgica para producir el trastorno. En este trabajo se analizarán por separado los diversos endofenotipos de esta enfermedad para tratar de explicar, sobre la base de aproximaciones sistémicas, cómo ocurren los cambios en las interneuronas GABAérgicas en la EQZ, comenzando con la hipofunción GABAérgica y sus consecuencias sobre las neuronas piramidales corticales y la disfunción dopaminérgica a punto de origen hipocampal, lo que permite conciliar eventos neurobiológicos con sus consecuencias conductuales (consilience). Los circuitos involucrados por Lisman, Grace, Coyle, Green y otros autores en esta revisión integran las neurotransmisiones glutamatérgica, GABAérgica, dopaminérgica y colinérgica en un marco sistémico en que también se involucran factores de riesgo genético, para intentar demostrar sus acciones sinérgicas dentro del circuito y generar una aproximación desde la neurociencia de sistemas. Se intentará desarrollar estrategias de distinto orden para comprender la EQZ como enfermedad que produce sus consecuencias devastadoras a través de la acción sinérgica de genes y diversos neurotransmisores integrados en circuitos de procesamiento que operan en complejas dinámicas de tipo no-lineal.(AU)

Understanding the pathophysiology of schizophrenia (SZ) entails adopting a holistic approach based on systems neuroscience that allows to explain how multiple genes and neurotransmitters can act synergistically to trigger the disorder. In this article, the different endophenotypes of schizophrenia are analysed separaately, with the aim of explaining, by means of systemic approaches, how changes take place in GABAergic interneurons in SZ, starting from the GABAergic hypofunction and ists effects on cortical pyramidal neurons, as well as on the dopaminergic dysfunction at he pont of origin of the hippocampus, which enables to reconcile neurobiological events with their behavioural consequences ("consilience"). The circuits proposed by Lisman, Grace, Coyle, Green and other authors, that make up glutamatergic, GABAerci, dopaminergic and cholinergic neurotransmissions embedded in a systemic framework in whic genetic risk factors are also involved, are included in this review to demonstrate their synergistic actions within the circuit, as well as to develop an approach based on systems neuroscience. The present article will also provide different types of strategies intended to understand SZ as a disease that causes its devastating effects through the synergistic action of genes and the different neurotransmitters organized in processing circuits that operte in complex non-linear dynamics.(AU)

Psychotic disorders in Argentine patients with refractory temporal lobe epilepsy: a case-control study.

The issue of psychotic disorders in epilepsy has given rise to great controversy among professionals; however, there are not many studies in this area and the physiopathological mechanisms remain unknown. The aim of this study was to describe the spectrum of psychotic disorders in an Argentine population with refractory temporal lobe epilepsy (RTLE) and to determine the risk factors associated with psychotic disorders. Clinical variables of the epileptic syndrome were compared among a selected population with RTLE with and without psychotic disorders (DSM-IV/Ictal Classification of psychoses). Logistic regression was performed. Sixty-three patients with psychotic disorders (Psychotic Group, PG) and 60 controls (Control Group, CG) were included. The most frequent psychotic disorders were brief psychotic episodes (35%) (DSM-IV) and interictal psychosis (50%) (Ictal Classification). Risk factors for psychotic disorders were bilateral hippocampal sclerosis, history of status epilepticus, and duration of epilepsy greater than 20 years.

NADPH diaphorase reactive neurons in temporal lobe cortex of patients with intractable epilepsy and hippocampal sclerosis.

Several studies have demonstrated a controversial involvement of NO in epileptogenesis. The aim of this study is to compare the NADPH diaphorase (NADPH-d) reactivity in the temporal cortex between surgical specimens of patients with intractable epilepsy and hippocampal sclerosis and autopsy controls. Brain samples of patients and postmortem controls were stained with the NADPH-d technique. Sprouting and larger areas of NADPH-d reactive neurons were found in the temporal cortex of epileptic patients.

Altered nitric oxide synthase and PKC activities in cerebellum of gamma-irradiated neonatal rats.

In this study, we show that one single dose of gamma-irradiation at birth induces an inhibition of the cerebellar calcium dependent nitric oxide synthase (NOS) activity, probably correlated to the motor abnormalities and the disarrangement in the cerebellar cytoarchitecture observed in adult rats. This decrease in calcium dependent NOS activity could be associated with an increased protein kinase C (PKC) activity. PKC inhibition partially restores calcium dependent NOS activity, indicating that PKC activity could be negatively modulating the catalytic activity of calcium dependent NOS. These findings suggest that a decrease in nitric oxide (NO) production and the related increase in PKC activity could be intracellular events that participate in the onset of motor and cerebellar abnormalities induced by postnatal gamma-irradiation at early stages of life.

Ionizing radiation-induced damage on developing cerebellar granule cells cultures can be prevented by an early amifostine post-treatment.

Developing central nervous system (CNS) is highly sensitive to ionizing radiation due, in part, to reactive oxygen species (ROS) damage. A variety of compounds able to protect brain cells essentially by decreasing ROS production have been widely used to confirm ROS participation in different mechanisms of brain injury, as well as to evaluate them as therapeutic tools. To test if ionizing radiation-induced damage on immature cerebellar granule cells is mainly mediated by ROS accumulation, a free radical scavenger--amifostine (amf)--was used in an in vitro model. Moreover, the amf therapeutic effect was investigated. Results show that only an early (20-30 min) post-treatment with amf, acting through an antioxidant mechanism, has been effective in preventing cerebellar granule cell loss observed after ionizing radiation exposure in vitro. These data suggest that immature cerebellar granule cells grown in vitro are highly vulnerable to ROS damage and that a therapeutic intervention could be effective in a narrow temporal window. Moreover, radiation-induced cell death can be partially prevented by a complete limitation of ROS generation, suggesting that other mechanisms besides oxidative stress would also be responsible for the cellular damage found in this model.

Deferoxamine antioxidant activity on cerebellar granule cells gamma-irradiated in vitro.

Oxidative stress has been implicated in the pathogenesis of many neurodegenerative and neurological disorders, with reactive oxygen species (ROS) as part of the intracellular effectors of damage formed in the presence of an excess of iron. Ionizing radiation induces tissue damage on developing CNS through different simultaneous mechanisms, including ROS-induced oxidative damage; therefore, exogenously added iron chelators might contribute to protect cells from free-radical injury. Cerebellar granule cells grown in vitro were exposed to 0.3 Gy of gamma radiation, and 30-60 min before irradiation, deferoxamine (Dfx), an iron chelator, was added at different nontoxic concentrations. When cell viability and ROS levels were evaluated in Dfx-treated cultures, a partial prevention of radiation-induced cell death and ROS increase were found, being this prevention concentration independent. These data support the involvement of an iron-driven hydroxyl radical formation pathway in the acute toxic mechanism of radiation in cultures of cerebellar granule cells, being ROS-induced oxidative damage one of the mechanisms through which radiation might induce cell death. Therefore, blocking ROS production through the use of a chelating agent, such as Dfx, would be a useful therapeutic tool in different experimental models.