2,770 research outputs found
Addiction in context
The dissertation provides a comprehensive exploration of the interplay between social and cultural factors in substance use, specifically focusing on alcohol use disorder (AUD) and cannabis use disorder (CUD). It begins by introducing the concept of social plasticity, which posits that adolescents' susceptibility to AUD is influenced by their heightened sensitivity to their social environment, but this sensitivity increases the potential for recovery in the transition to adulthood.A series of studies delves into how social cues impact alcohol craving and consumption. One study using functional magnetic resonance imaging (fMRI) investigated social alcohol cue reactivity and its relationship to social drinking behavior, revealing increased craving but no significant change in brain activity in response to alcohol cues. Another fMRI study compared social processes in alcohol cue reactivity between adults and adolescents, showing age-related differences in how social attunement affects drinking behavior. Shifting focus to cannabis, this dissertation discusses how cultural factors, including norms, legal policies, and attitudes, influence cannabis use and processes underlying CUD. The research presented examined various facets of cannabis use, including how cannabinoid concentrations in hair correlate with self-reported use, the effects of cannabis and cigarette co-use on brain reactivity, and cross-cultural differences in CUD between Amsterdam and Texas. Furthermore, the evidence for the relationship between cannabis use, CUD, and mood disorders is reviewed, suggesting a bidirectional relationship, with cannabis use potentially preceding the onset of bipolar disorder and contributing to the development and worse prognosis of mood disorders and mood disorders leading to more cannabis use
Space, time and item coding in the lateral entorhinal cortex and the hippocampus
Episodic memory formation involves encoding information about space, items and time of an experience. In
humans and animals, episodic memory formation depends on the interaction of associative areas with the
hippocampus (HC) and its surrounding parahippocampal areas, in particular the entorhinal cortex (EC). The EC
medial and lateral subdivisions (MEC and LEC), harbour a plethora of spatially and item modulated cell types,
respectively. Thus, MEC and LEC were long considered specialised spatial and item coding centres, respectively,
that conveyed this information to the HC, where it was integrated into one episodic memory. In agreement
with this hypothesis, the firing of neurons in the HC is spatially modulated but is also modified by changes in
contextual and item components of an environment. However, recent studies suggest that both the MEC and
LEC carry out spatial and item coding, albeit the way these elements are encoded may differ. In addition,
temporal coding in the hippocampus requires an intact MEC, however, the specific functional MEC cell types
involved in this process are unknown. Thus, it is currently unclear how space, items and time are encoded in
each of the entorhinal-hippocampal areas, and how the different entorhinal-hippocampal circuits contribute to
the transmission and association of episodic memory components. In this thesis, I explored this question from
three different angles: firstly, I characterized mechanisms of spatial and item coding in the LEC and in the CA1
hippocampal area; secondly, I studied the contribution of a specific MEC-to-LEC pathway to spatial and item
coding in the LEC; thirdly, I evaluated whether the temporal coding process of phase precession in hippocampal
neurons is dependent on a specific MEC functional cell type, namely grid cells. For this purpose, I performed
and analysed in vivo electrophysiological recordings in freely moving mice subjected to a variety of experimental
settings, and combined this with optogenetic tagging of neurons for circuit characterisation. The findings
reported in this thesis fundamentally advance our understanding of the processes underlying episodic memory
encoding in several ways. First, I found that spatial selectivity in the LEC decreases along the anteroposterior
axis, and that spatially modulated neurons remap when the spatial framework changes. In addition, I describe
distinct functional cell types in the LEC encoding for different object features. Importantly, spatial and object
coding neurons appear to be distinct non-overlapping neuronal populations, arguing for a separate processing
of items and space in the LEC. Interestingly, object coding neurons are selectively avoided by long-range
GABAergic projections from MEC to LEC. In the HC, in turn, a subset of spatially modulated neurons also encode
object-related information, suggesting that these two components of episodic memory are integrated, at least
to some extent, in this region. These findings give experimental evidence to the episodic memory encoding
process proposed by the cognitive map theory. Finally, in respect to temporal coding, I demonstrated that phase
precession is intact in the HC when grid cell firing is disrupted in the MEC, indicating that this mechanism may
be dependent on other MEC neurons and/or pathways. Together, these findings uncover new mechanisms of
encoding and transmission of the three episodic memory components in the entorhinal-hippocampal circuits
Analysis of the impact of synaptic plasticity genes and Human Accelerated Regions on brain function and structure: from the healthy brain to schizophrenia
[eng] Schizophrenia is a severe psychiatric disorder affecting around 24 million people worldwide. While we begin to disentangle the biological actors implicated in the origin of the disorder, the precise aetiological mechanisms remain largely unknown. Therefore, psychiatry research efforts still need to focus on a better understanding of the complex biological foundations of the disorder to achieve more precise diagnoses and the development of novel therapeutic strategies improving the patients’ quality of life.
The prevailing etiopathological hypothesis considers that schizophrenia originates from the interplay between subtle genetic and environmental insults that disrupt the perfectly orchestrated mechanisms guiding neurodevelopment. Additionally, from an evolutionary perspective, it is suggested that schizophrenia represents a costly trade-off in the evolution of human-specific ontogenic neurodevelopmental processes sustaining the inherent complexity and variability of brain functioning, cognition, and behaviour. Along the neurodevelopmental process, the synapse formation and the organisation and maturation of neural circuits anchor the emergence of distinctive human cortical brain functions. In turn, multidisciplinary evidence indicates that synaptic alterations participate in brain dysfunctions, eventually leading to the emergence of the symptoms and cognitive deficits of schizophrenia. Accordingly, it is suggested that synaptic plasticity impairments play a critical role in the pathophysiology of the disorder.
Among genes converging in neurodevelopmental and synaptic plasticity pathways, there are genes mediating signalling pathways involved in neural homeostasis, dendritic spine development and neural excitability, such as KCNH2, DISC1, CACNA1C and ZNF804A, all of them previously associated with the risk for schizophrenia. Moreover, evolutionary approaches have identified regions that accumulated human-specific changes since the divergence from chimpanzees, like Human Accelerated Regions (HARs). These regions act as transcriptional regulatory elements that endow human neurodevelopment with unique characteristics and harbour schizophrenia genetic susceptibility variants. To facilitate the identification of the genetic and biological mechanisms involved in schizophrenia aetiology, the use of brain-based intermediate phenotypes is a valuable strategy.
Following two approaches centred on the genetic-phenotypic correlates of synaptic plasticity candidate genes and HARs sequences in the brain-based alterations in schizophrenia, this thesis includes four original articles and one systematic review. In these articles, we report the effect of common polymorphisms in KCNH2, DISC1, CACNA1C and ZNF804A genes and the polygenic load of HARs-informative sets on the differences observed between healthy brains and brains with schizophrenia.
Overall, the results validate the efficacy of neuroimaging phenotypes to identify the genetic determinants of schizophrenia and point out the complementarity of candidate genes and genome-wide approaches in the study of the genetic architecture of the disorder. First, we describe the role of KCNH2 and DISC1 genetic variability in modulating the attentional and working memory-related functional responses in a diagnosis- dependent manner. Furthermore, we identify that the epistasis between two schizophrenia GWAS-associated genes, CACNAC1C and ZNF804A, influence the functional ability to adapt to increased working memory difficulty euqally in healthy controls and patients with schizophrenia. Second, we present a review of how HARs underlie human neurodevelopmental signatures, brain configuration, functioning and susceptibility behind psychiatric disorders. Likewise, we report the modulatory effect of HARs polygenicity on brain cortical architectural differences in schizophrenia and provide evidence on the importance of foetal-active regulatory HARs in patients' cortical surface area variability.
Globally, the findings exposed in this thesis point towards the fact that the aetiological foundations of schizophrenia are related to the individual genetic differences altering neurodevelopment and synaptic plasticity trajectories but also to the genomic make-up that defines us as a species. This thesis provides a drop in the ocean of knowledge on disorders inherently linked to the human condition and has sought to comprehend the unique characteristics of our brain to help unravel what it means to be human.[cat] L’esquizofrènia Ă©s un trastorn neuropsiquiĂ tric greu que afecta a 24 milions de persones a tot el mĂłn. Tot i que comencem a conèixer els mecanismes biològics implicats en l’origen del trastorn, els processos etiològics precisos continuen essent en gran part desconeguts. Per tant, els esforços en la recerca encara necessiten dirigir-se en millorar el coneixement dels fonaments biològics del trastorn, per tal d’aconseguir un diagnòstic mĂ©s precĂs i el desenvolupament de noves estratègies terapèutiques que millorin la qualitat de vida dels pacients.
La hipòtesi etiopatogènica predominant considera que el trastorn s’origina a partir de la interacciĂł entre factors genètics i ambientals que pertorben els mecanismes perfectament orquestrats que guien el neurodesenvolupament. A mĂ©s, des d’una perspectiva evolutiva, s’ha suggerit que l’esquizofrènia representaria el “preu a pagar” per evoluciĂł dels processos ontogènics especĂficament humans que sustenten la complexitat i la variabilitat inherent al funcionament del cervell, la cogniciĂł i el comportament de la nostra espècie. Al llarg del neurodevenvolupament, la formaciĂł de sinapsis i l’organitzaciĂł i maduraciĂł dels circuits neurals ancoren l’apariciĂł de funcions cerebrals corticals distintivament humanes. Al seu torn, evidències multidisciplinĂ ries indiquen que les alteracions sinĂ ptiques participen en disfuncions cerebrals que tenen com a resultat l’apariciĂł dels sĂmptomes cognitius i clĂnics de l’esquizofrènia. En conseqüència, s’ha proposat que les alteracions de la plasticitat sinĂ ptica tenen un paper crĂtic en la fisiopatologia del trastorn.
Entre els gens que conflueixen en vies del neurodesenvolupament i de plasticitat sinĂ ptica, hi ha gens que participen en vies de senyalitzaciĂł implicades en l’homeòstasi neuronal, el desenvolupament de les espines dendrĂtiques i l’excitabilitat neuronal, com els gens KCNH2, el DISC1, el CACNA1C i el ZNF804A, tots prèviament associats amb el risc per a l’esquizofrènia. A mĂ©s, aproximacions evolutives han identificat regions que han acumulat canvis especĂficament en humans des de la divergència amb els ximpanzĂ©s, com les Regions Humanes Accelerades (o Human Accelerated Regions, HARs en anglès). Aquestes regions actuen com a elements reguladors de la transcripciĂł atorgant caracterĂstiques Ăşniques al neurodesenvolupament humĂ , i contenen variants genètiques de susceptibilitat per a l’esquizofrènia. Per tal de facilitar l’identificar els mecanismes genètics i biològics implicats en l’etiologia de l’esquizofrènia, la utilitzaciĂł de fenotips cerebrals intermedis, com mesures de neuroimatge funcional i estructural, representa una estratègia molt Ăştil.
Seguint dues aproximacions centrades en l’anĂ lisi dels correlats genètics-fenotĂpics entre gens candidats relacionats amb la plasticitat sinĂ ptica i regions HARs i les alteracions cerebrals de l’esquizofrènia, aquesta tesi inclou quatre articles originals i una revisiĂł sistemĂ tica. En aquests articles, exposem l’efecte de polimorfismes en els gens
KCNH2, DISC1, CACNA1C i ZNF804A i la cà rrega poligènica en conjunts informatius de HARs sobre les diferències observades entre cervells de persones sanes i persones amb esquizofrènia.
En conjunt, els resultats validen l’efectivitat dels fenotips de neuroimatge per identificar els determinants genètics de l’esquizofrènia i posen de manifest la complementarietat de les aproximacions centrades tant en gens candidats com en la variabilitat global del genoma per a l’estudi de l’arquitectura genètica del trastorn. Primer, descrivim el paper de la variabilitat genètica dels genes KCNH2 i DISC1 en la modulaciĂł de la resposta funcional a l’atenciĂł i la memòria de treball de manera condicionada al diagnòstic. TambĂ©, identifiquem que l’epistasi entre dos gens associats amb l’esquizofrènia a nivell de GWAS, el CACNAC1C i el ZNF804A, influeix en la capacitat funcionalde cervell per adaptar-se a l’increment de requeriments cognitius en memòria de treball en controls sans i pacients amb esquizofrènia. En segon lloc, oferim una revisiĂł sobre com les HARs sustenten les caracterĂstiques del neurodesenvolupament humĂ , la configuraciĂł cerebral, el funcionament i la susceptibilitat per als trastorns psiquiĂ trics AixĂ mateix, informem de l'efecte modulador de la poligenicitat de les HARs sobre les diferències en l’arquitectura cortical en l'esquizofrènia i proporcionem evidències sobre l’especial rellevĂ ncia de les HARs associades amb elements reguladors de la transcripciĂł actius durant l’etapa fetal.
De manera global, els resultats d’aquesta tesi indiquen que els fonaments etiològics de l’esquizofrènia estan relacionats amb diferències genètiques individuals que impacten en les trajectòries del neurodesenvolupament i les vies de plasticitat sinĂ ptica, aixĂ com amb la composiciĂł genòmica que ens defineix com a espècie. Aquesta tesi aporta una gota en l’oceĂ del coneixement sobre els trastorns intrĂnsecament vinculats a la condiciĂł humana i ha pretès contribuir en la comprensiĂł de les caracterĂstiques Ăşniques del nostre cervell per ajudar a entendre què vol dir ser humĂ .[spa] La esquizofrenia es un trastorno psiquiátrico que afecta a 24 millones de personas en todo el mundo. A pesar de que empezamos a conocer los mecanismos biolĂłgicos implicados en el origen del trastorno, los procesos etiolĂłgicos precisos continĂşan siendo en gran parte desconocidos. Por ello, los esfuerzos investigadores todavĂa necesitan dirigirse en mejorar el conocimiento de los fundamentos biolĂłgicos del trastorno, para asĂ conseguir una mayor precisiĂłn en el diagnĂłstico y desarrollar nuevas estrategias terapĂ©uticas que mejoren la calidad de vida de los pacientes.
La hipĂłtesis etiopatogĂ©nica predominante considera que el trastorno se origina de la interacciĂłn entre factores genĂ©ticos y ambientales que modifican los mecanismos perfectamente orquestados que guĂan el neurodesarrollo. Además, desde una perspectiva evolutiva, se sostiene que la esquizofrenia representa “el precio a pagar” por la evoluciĂłn de los procesos ontogĂ©nicos especĂficamente humanos que sustentan la complejidad y la variabilidad inherente al funcionamiento del cerebro, asĂ como la cogniciĂłn y comportamiento de nuestra especie. A lo largo del neurodesarrollo, la formaciĂłn de sinapsis y la organizaciĂłn y maduraciĂłn de los circuitos neurales anclan la apariciĂłn de funciones cerebrales corticales distintivamente humanas. Por su parte, evidencias multidisciplinares indican que las alteraciones sinápticas participan en disfunciones cerebrales asociadas a la apariciĂłn de los sĂntomas cognitivos y clĂnicos de la esquizofrenia. En consecuencia, se ha propuesto que las alteraciones de la plasticidad sináptica tienen un papel crĂtico en la fisiopatologĂa del trastorno.
Entre los genes que confluyen en vĂas del neurodesarrollo y de plasticidad sináptica, hay genes que participan en vĂas de señalizaciĂłn implicadas en la homeostasis neuronal, el desarrollo de las espinas dendrĂticas y la excitabilidad neural, como el KCNH2, el DISC1, el CACNA1C y el ZNF804A, todos ellos previamente asociados con el riesgo para la esquizofrenia. Además, aproximaciones evolutivas han identificado regiones que han acumulado cambios especĂficamente humanos desde la divergencia con los chimpancĂ©s, como las Regiones Humanas Aceleradas (o Human Accelerated Regions, HARs en inglĂ©s). Estas regiones actĂşan como elementos reguladores de la transcripciĂłn otorgando caracterĂsticas Ăşnicas al neurodesarrollo humano, y albergan variantes genĂ©ticas de susceptibilidad para la esquizofrenia. Para facilitar la identificaciĂłn de los mecanismo genĂ©ticos y biolĂłgicos implicados en la etiologĂa del trastorno, el uso de fenotipos cerebrales intermedios, como medidas de neuroimagen funcional y estructural, es una herramienta de gran valor.
Siguiendo dos aproximaciones centradas en el análisis de los correlatos genĂ©tico- fenotĂpicos entre genes candidatos relacionados con la plasticidad sináptica y secuencias HARs y las alteraciones cerebrales en la esquizofrenia, esta tesis incluye cuatro artĂculos originales y una revisiĂłn sistemática. En estos artĂculos, exponemos el
efecto de polimorfismos en los genes KCNH2, DISC1, CACNA1C y ZNF804A y la carga poligénica en conjuntos informativos de HARs sobre las diferencias observadas entre cerebros sanos y cerebros con esquizofrenia.
En su conjunto, los resultados validan la efectividad de los fenotipos de neuroimagen para identificar los mecanismos genĂ©ticos de la esquizofrenia y ponen de manifiesto la complementariedad de las aproximaciones centradas tanto en genes candidatos como en la variabilidad global del genoma para estudiar la arquitectura genĂ©tica del trastorno. Primero describimos el papel de la variabilidad genĂ©tica de los genes KCNH2 y DISC1 en la modulaciĂłn de la respuesta funcional a la atenciĂłn y la memoria de trabajo de manera condicional al diagnĂłstico. Además, identificamos que la epistasis entre dos genes asociados con la esquizofrenia a nivel de GWAS, el CACNAC1C y el ZNF804A, influye en la capacidad funcional de cerebro para adaptarse al incremento de requerimientos cognitivos en memoria de trabajo tanto en controles sanos como en pacientes con esquizofrenia. En segundo lugar, ofrecemos una revisiĂłn sobre cĂłmo las HARs sustentan las caracterĂsticas del neurodesarrollo humano, la configuraciĂłn y el funcionamiento cerebral y la susceptibilidad para trastornos psiquiátricos. AsĂ mismo, informamos del efecto modulador de la poligenicidad de las HARs sobre las diferencias en la arquitectura cortical en la esquizofrenia y proporcionamos evidencias sobre la especial relevancia de las HARs asociadas con elementos reguladores de la transcripciĂłn activos durante la etapa fetal.
De manera global, los resultados de esta tesis indican que los fundamentos etiolĂłgicos de la esquizofrenia están relacionados con diferencias genĂ©ticas individuales que impactan en las trayectorias del neurodesarrollo y en las vĂas de plasticidad sináptica, asĂ como en la composiciĂłn genĂ©tica que nos define como especie. Esta tesis aporta una gota en el ocĂ©ano del conocimiento sobre los trastornos intrĂnsicamente vinculados a la condiciĂłn humana y ha pretendido contribuir en la comprensiĂłn de las caracterĂsticas Ăşnicas de nuestro cerebro para ayudar a entender quĂ© quiere decir ser humano
Expression and localization of the endocannabinoid system in area V2 of the vervet monkey
La présence du système endocannabinoïde (eCB), en particulier le récepteur CB1 (CB1R), dans la rétine, le corps genouillé latéral, et l’aire visuelle primaire (V1) du singe a récemment été mise en évidence. Cependant, aucune étude n’a démontré la présence de ce système dans l’aire visuelle secondaire V2, une région qui reçoit la plupart des efférences de V1. Comme V1 exprime ce récepteur, nous faisons l’hypothèse que l’aire V2 l’exprime également. Le but de notre étude est donc de caractériser l’expression et la localisation cellulaire de ce système dans l’aire V2 du singe vervet. Des cerveaux de cinq singes vervets (Chlorocebus sabeus) adultes ont été utilisés. Les marqueurs cellulaires NeuN, SMI-32, et PV ont été employés pour caractériser et identifier les différentes couches de V2. En localisant ces derniers, nous déterminons la distribution de CB1R et des enzymes de synthèse (NAPE-PLD) et de dégradation (FAAH) du système eCB en utilisant des techniques d’immunofluorescence. De plus, l’organisation laminaire en six couches de V2 a été mise en évidence par nos marqueurs cellulaires. Nos résultats démontrent la présence de CB1R dans les fibres axonales aux extrémités de V2, c’est-à -dire dans les couches superficielles (1-3) et profondes (5-6). CB1R est peu ou pas exprimé dans la couche 4. CB1R entoure, mais n’est pas exprimé par les cellules positives- NeuN, SMI-32 et PV. Cependant, les enzymes NAPE-PLD et FAAH sont présentes dans les cellules pyramidales SMI-32 et les cellules interneurones PV -positives. Ces données indiquent que CB1R, NAPE-PLD et FAAH sont présentes dans V2 et pourraient moduler l’information visuelle provenant de V1 et se dirigeant vers les aires V4 et V5, et probablement, influencer la perception visuelle.The presence of the endocannabinoid system in the retina, the lateral geniculate body, and the primary visual area (V1) of the monkey has recently been established. However, no study has demonstrated the presence of this system in area V2, a region that receives most of the afferents from V1. As V1 expresses this system, we assume that the area V2 also expresses it. The aim of our study is to characterize the expression and cellular localization of this system in the visual cortex V2 of the vervet monkey. The brains of 5 adult monkeys were used in this project. Cellular markers NeuN, SMI-32, and PV were used to characterize and identify the layers of V2. Using immunofluorescence, these markers were also localized in order to study the distribution of CB1R, the enzyme of synthesis (NAPE-PLD) and of degradation (FAAH) of eCB ligands. The six-layer organization of V2 was also identified by our cellular markers. Our results show the presence of the eCB system in area V2. Furthermore, we found that CB1R immunoreactivity is present in the axonal fibers at the ends of V2; in the superficial (L1-3) and deep (L5-6) layers. CB1R expression was low to non-existence in layer 4. CB1R surrounds but does not co-localize with NeuN-, SMI-32-, and PV- positive cells. On the other hand, NAPE-PLD and FAAH enzymes were co-localized with SMI-32-positive pyramidal cells and PV-positive interneuron cells. These data, therefore, indicate that CB1R, NAPE-PLD and FAAH are present in V2 and their presence can modulate visual information coming from V1 and going to V4 and V5, and probably, influence visual perception
Effekte pathogener Anti-NMDAR-Antikörper auf die Funktionalität von Synapsen und neuronalen Netzwerken
N-methyl-D-aspartate (NMDA) receptors lay at the core of excitatory glutamatergic transmission and their dysfunction has been implicated in a number of neurological and psychiatric disorders. One such recently described disease is anti-NMDAR encephalitis, characterized by prominent psychiatric, cognitive and autonomic symptoms, which are linked to presence of autoantibodies targeting the NMDARs. To date, the majority of mechanistic studies have focused on antibodies’ action in the hippocampus, where they cause receptor cross-linking and internalization. However, little is known what is the specific contribution of individual antibodies and what are their effects in other brain regions such as cortex, which could help explain dysfunction on higher cognitive level. Here, we employed recently developed monoclonal anti-NMDAR autoantibodies and studied their effects on in vitro rodent neuronal cultures, using electrophysiological and imaging techniques. We report that both affinity-matured and germline, “naïve” NMDAR autoantibodies can pose pathogenic effects and impair NMDAR transmission. Moreover, these autoantibodies show brain regional specificity, exerting different effects in hippocampal versus cortical neurons. While in hippocampus they impair NMDAR currents of excitatory neurons, in cultures from cortex they selectively decrease NMDA currents and synaptic output of inhibitory, but not excitatory, neurons. Consequently, decreased inhibitory drive leads to disinhibition of networks from cortical neurons, bringing them into a hyper-excitable state. This is further associated with lowered levels of crucial pre-synaptic inhibitory proteins, specifically in inhibitory-to-excitatory neuron synapses. Together, these findings deepen our understanding of the pathology of autoimmune encephalitis by showing pathogenic potential of both matured and naïve autoantibodies and providing a novel, cortex specific mechanism of antibody-induced network hyper-excitability. Of note, similar mechanisms of NMDA-mediated cortical disinhibition have been suggested to underlie the etiology of schizophrenia, therefore there is an emerging framework for common mechanisms across neuropsychiatric disorders.N-Methyl-D-Aspartat-Rezeptoren (NMDA-Rezeptoren) sind das Herzstück der exzitatorischen glutamatergen Signalübertragung, und ihre Fehlfunktion wird mit einer Reihe von neurologischen und psychiatrischen Erkrankungen in Verbindung gebracht. Eine solche kürzlich beschriebene Krankheit ist die Anti-NMDAR-Enzephalitis, die durch auffällige psychiatrische, kognitive und andere autonome Symptome gekennzeichnet ist, alle werden mit dem Vorhandensein von Autoantikörpern gegen NMDARs in Verbindung gebracht. Bisher haben sich die meisten mechanistischen Studien auf die Wirkung der Antikörper im Hippocampus konzentriert, wo sie eine Vernetzung und Internalisierung der Rezeptoren verursachen. Es ist jedoch nur wenig darüber bekannt, welchen spezifischen Beitrag einzelne Antikörper leisten und welche Auswirkungen sie in anderen Hirnregionen wie zum Beispiel dem Kortex haben. Effekte der Autoantikörper im Kortex könnten eine Erklärung für die beobachtete Dysfunktion auf höherer kognitiver Ebene liefern. In dieser Studie haben wir kürzlich entwickelte monoklonale Anti-NMDAR-Autoantikörper eingesetzt und ihre Auswirkungen auf neuronale In-vitro-Kulturen von Nagetieren mit Hilfe bildgebender und elektrophysiologischer Verfahren untersucht. Wir berichten, dass sowohl affinitätsgereifte als auch keimbahnspezifische, "naive" NMDAR-Autoantikörper pathogen wirken und die NMDAR-Signalübertragung beeinträchtigen können. Darüber hinaus weisen diese Autoantikörper eine hirnregionale Spezifität auf, indem sie in hippocampalen und kortikalen Neuronen unterschiedliche Wirkungen entfalten. Während sie im Hippocampus die NMDAR-Ströme exzitatorischer Neuronen beeinträchtigen, vermindern sie in kortikalen Kulturen selektiv die NMDA-Ströme und die synaptische Übertragung inhibitorischer, aber nicht exzitatorischer Neuronen. Infolgedessen führt die verringerte hemmende Wirkung zu einer generellen Enthemmung kortikaler neuronaler Netzwerke und was diese in einen übererregbaren Zustand versetzt. Dies geht zusätzlich einher mit einer Abnahme wichtiger präsynaptischer inhibitorischer Proteine, insbesondere in Synapsen zwischen inhibitorischen und erregenden Neuronen. Zusammengenommen vertiefen diese Ergebnisse unser Verständnis der Pathologie der Autoimmunenzephalitis, indem sie das pathogene Potenzial sowohl gereifter als auch naiver Autoantikörper aufzeigen und einen neuen, Kortex-spezifischen Mechanismus der antikörperinduzierten Hypererregbarkeit von neuronalen Netzwerken liefern. Es ist bemerkenswert, dass ähnliche Mechanismen der NMDA-vermittelten kortikalen Enthemmung auch für die Pathologie der Schizophrenie verantwortlich gemacht werden, so dass sich gemeinsame, grundlegende Mechanismen bei neuropsychiatrischen Störungen abzeichnen
Neuromotor and electrocortical activity characteristics of dynamic postural control
Subconcussive impacts to the head have become a growing area of research and concern in the athletic setting. While knowledge on the short- and long-term consequences of concussions has been identified, there is relatively less research on the effects of repetitive subconcussive impacts. Research has shown that neuromotor deficits (i.e., dynamic balance) can be detected acutely after repeatedly heading a soccer ball (a laboratory-based way to induce subconcussive head impacts), but this has typically been done with expensive and non-portable laboratory equipment. However, the AccWalker smartphone application may allow for an objective cost-effective test to examine the effective of repetitive subconcussive exposure. Nonetheless, while cost-effective and portable (e.g., a smartphone app), there is a need for examination of its reliability. Moreover, the extent to which cortical activity is related to dynamic balance control is not well understood. If an association between cortical activity is observed, an increase or decrease in the strength of the association after repeated subconcussive head impacts could be used as an indicator of nervous system impact. These gaps in the literature will be addressed through three specific aims in this dissertation 1) to investigate the reliability of the AccWalker app as a test for neuromotor performance before and after light athletic activity (e.g., kicking a soccer ball); 2) compare EEG spectral power characteristics of dynamic balance across three different AccWalker conditions, and 3) to examine correlations between EEG spectral power characteristics and temporal and spatial kinematic data during a stepping in place task (mTBI Assessment of Readiness Gait Evaluation Test (TARGET)). It was hypothesized that, 1) temporal and spatial characteristics of dynamic balance will not significantly change between pre- and post-soccer kicking activity, 2) EEG power spectral density (PSD) within the delta and theta frequency bands will increase across the three AccWalker conditions, and 3) EEG PSD within the delta and theta frequency bands will correlate with the temporal and spatial kinematic variables measured using the AccWalker TARGET protocol. Twenty-four participants were enrolled in this study. Aim 1 used a pre-test/post-test design. Both pre- and post-testing included using the TARGET protocol before and after kicking ten soccer balls. The findings for aim 1 indicated that that the AccWalker TARGET protocol displayed good test-retest reliability with similar data characteristics to previous work. Aim 2 results revealed that EEG PSD measures increased compared to the resting condition. Finally, for aim 3, several significant correlations between the AccWalker spatial metrics within the Delta and Theta frequencies were found. These findings suggest that postural control assessment can be measured reliably in a pre- to post-test design. This may be important as the AccWalker TARGET protocol may offer a reliable test for changes in neuromotor performance and the body’s ability to adapt to “real-life” (or more dynamic) situations. Additionally, this study has expanded on previous literature indicating increased involvement of the frontal-central and central regions of the brain during perturbed balance. Further, this study expands upon the simultaneous use of EEG and balance assessment; specifically, as it is the first study to use a truly dynamic balance task along with a 32-electrode mobile EEG system. This may be important for continued study of not only unaffected balance, but that study of neural changes due to injury or pathological processes
Oscillatory mechanisms of conscious perception and attention
Although the prominent role of neural oscillations in perception and cognition has been continuously investigated, some critical questions remain unanswered. My PhD thesis was aimed at addressing some of them.
First, can we dissociate oscillatory underpinnings of perceptual accuracy and subjective awareness? Current work would strongly suggest that this dissociation can be drawn. While the fluctuations in alpha-amplitude decide perceptual bias and metacognitive abilities, the speed of alpha activity (i.e., alpha-frequency) dictates sensory sampling, shaping perceptual accuracy.
Second, how are these oscillatory mechanisms integrated during attention? The obtained results indicate that a top-down visuospatial mechanism modulates neural assemblies in visual areas via oscillatory re-alignment and coherence in the alpha/beta range within the fronto-parietal brain network. These perceptual predictions are reflected in the retinotopically distributed posterior alpha-amplitude, while perceptual accuracy is explained by the higher alpha-frequency at the to-be-attended location. Finally, sensory input, elaborated via fast gamma oscillations, is linked to specific phases of this slower activity via oscillatory nesting, enabling integration of the feedback-modulated oscillatory activity with sensory information.
Third, how can we relate this oscillatory activity to other neural markers of behaviour (i.e., event-related potentials)? The obtained results favour the oscillatory model of ERP genesis, where alpha-frequency shapes the latency of early evoked-potentials, namely P1, with both neural indices being related to perceptual accuracy. On the other hand, alpha-amplitude dictates the amplitude of later P3 evoked-response, whereas both indices shape subjective awareness.
Crucially, by combining different methodological approaches, including neurostimulation (TMS) and neuroimaging (EEG), current work identified these oscillatory-behavior links as causal and not just as co-occurring events. Current work aimed at ameliorating the use of the TMS-EEG approach by explaining inter-individual differences in the stimulation outcomes, which could be proven crucial in the way we design entrainment experiments and interpret the results in both research and clinical settings
- …