BDNF Val66Met polymorphism moderates the association between sleep spindles and overnight visual recognition

A common single nucleotide polymorphism (SNP) of the brain-derived neurotrophic factor (BDNF) gene, Val66Met, has been reported to impair BDNF secretion and memory function. However, few studies have investigated the interaction of BDNF genotype and sleep characteristics, such as sleep spindles, that promote long-term potentiation during sleep. In this study we compared overnight visual memory between the carriers of BDNF Met and non-carriers (Val homozygotes), and examined how sleep spindle density associated with memory performance. The sample constituted of 151 adolescents (mean age 16.9 years; 69% Val homozygotes, 31% Met carriers). The learning task contained high and low arousal pictures from Interactive Affective Picture System. The learning task and all-night polysomnography were conducted at the homes of the adolescents. Slow (10–13 Hz) and fast (13–16 Hz) spindles were detected with automated algorithm. Neither post-sleep recognition accuracy nor spindle density differed between Val homozygotes and Met carriers. While frontal slow and fast spindle densities associated with better recognition accuracy in the entire sample, examining the allelic groups separately indicated paralleling associations in Val homozygotes only. Interaction analyses revealed a significant genotype-moderated difference in the associations between frontal fast sleep spindles and high arousal pictures. In sum, sleep spindles promote or indicate visual learning in Val homozygote adolescents but not in Met carriers. The result suggests that the role of sleep spindles in visual recognition memory is not equal across individuals but moderated by a common gene variant.Peer reviewe

Sleep and its oscillatory characteristics in overnight learning : what is the role of plasticity genes BDNF and COMT?

Sleep is crucial for memory function. Sleep not only protects memories from wake-time interference, but it also actively transfers them from temporal storage to more permanent representations in the neocortex. This consolidation process of declarative memories is believed to be facilitated by certain oscillations during non-rapid eye movement (NREM) sleep, that is, sleep spindles, slow oscillations (SO) and sharp-wave ripples. Recent experiments in humans have demonstrated the importance of inter-oscillation synchrony on memory retention. Do all individuals equally share the memory benefits of sleep? Certain gene polymorphisms, such as BDNF Val66Met and COMT Val158Met, have been attributed with implications on synaptic plasticity, neuroanatomy and functional brain activation within memory-related brain networks. Behavioral studies have found relative mnemonic advantages to associate with the alleles that reportedly promote brain plasticity, i.e. ValBDNF and MetCOMT. Moreover, homeostatic sleep drive is moderated by BDNF Val66Met and COMT Val158Met. However, the role of these polymorphisms in memory retention over sleep has been scarcely studied. In this thesis, overnight memory for verbal and visual material was studied. Specific focus was put on how sleep spindles and their phasic synchrony with slow oscillations associate with memory performance. Importantly, it was questioned whether genetic predisposition for neural plasticity (BDNF Val66Met and COMT Val158Met) interacts with overnight memory and the related consolidation mechanisms. The studies in this thesis were conducted either on an adolescent (~17 y) cohort or on a sample consisting of young adults. Sleep was recorded with an ambulatory polysomnography in all studies. It was found that memory outcome – both verbal cued recall and picture recognition – was strongly associated with fast sleep spindles and their accurate coupling with the depolarized ‘upstate’ of SOs. BDNF Val66Met moderated the associations between sleep oscillations and visual recognition memory: memory outcome was robustly predicted by fast sleep spindles and their SO-coupling only in ValBDNF homozygotes but not MetBDNF carriers. In addition, memory performance in the ValBDNF homozygote group was seen more vulnerable to extended wake during the retention period. COMT Val158Met did not moderate the associations between sleep variables and recognition accuracy. In conclusion, the relation between sleep and memory may depend on inheritance. Genetic propensity for synaptic plasticity possibly enhances the effect of events that promote sleep-dependent consolidation. The findings question whether the benefits of sleep on memory are constant and equal across individuals.Uni on välttämätöntä muistin toiminnalle. Uni ei ainoastaan suojaa muistoja valveajan sekoittumiselta, vaan se myös aktiivisesti siirtää niitä väliaikaisesta muistivarastosta pysyviksi edustuksiksi aivokuorelle. Tiettyjen NREM-unen (non-rapid eye movement) aikaisten aivoaaltojen, eli unisukkuloiden, hitaiden aaltojen sekä hippokampusväreiden, uskotaan aktiivisesti edistävän tätä muistojen konsolidoitumista. Tutkimukset ihmisillä ovat osoittaneet, että aaltojen välinen synkronia on oleellista muistojen säilymiselle. Ovatko unen muistihyödyt yhtäläiset yksilöiden välillä? Tietyt geenipolymorfismit, kuten BDNF Val66Met ja COMT Val158Met, on aiemmassa tutkimuksessa yhdistetty aivoyhteyksien muovautuvuuteen, aivoanatomiaan sekä -toimintaan niissä rakenteissa, jotka tukevat muistitoimintoja. Alleelien, joiden oletetaan edistävän aivojen plastisuutta (ValBDNF ja MetCOMT), on käyttäytymisen tasolla havaittu assosioituvan suhteelliseen etuun muistisuoriutumisessa. Tämän lisäksi on raportoitu, että BDNF Val66Met sekä COMT Val158Met vaikuttavat unipaineen säätelyyn. Tästä huolimatta näiden polymorfismien roolia unen ja muistamisen yhteydessä on tutkittu vain vähän. Tämä väitöskirja tutki kielellistä ja näönvaraista muistamista yön yli. Erityisesti keskityttiin siihen, kuinka unisukkulat sekä niiden vaihesynkronia hitaiden aaltojen kanssa assosioituvat muistisuoriutumiseen. Lisäksi tarkasteltiin, onko perinnöllinen taipumus aivojen plastisuuteen (BDNF Val66Met ja COMT Val158Met) yhteydessä yön yli muistamiseen (näönvarainen tunnistus) ja unen aikaisiin konsolidaatiomekanismeihin. Väitöskirjan tutkimukset toteutettiin joko nuorista (~17 v) koostuvassa kohortissa tai nuorten aikuisten otoksessa. Genotyyppiin liittyvät tutkimukset koskivat nuorten otosta. Kaikissa tutkimuksissa unta mitattiin polysomnografialla. Muistitulos – sekä kielellinen, vihjeenvarainen muistaminen että kuvien tunnistus – oli selvästi yhteydessä unisukkuloihin sekä siihen, kuinka tarkasti unisukkulat ajoittuivat hitaisiin aaltoihin. BDNF Val66Met vaikutti aivoaaltojen ja näönvaraisen tunnistusmuistin yhteyksiin: yhteys ilmeni ainoastaan ValBDNF-homotsygooteilla, mutta ei MetBDNF-alleelin kantajilla. Lisäksi ValBDNF-homotsygooteilla runsas valve näytti haittaavan muistisuoriutumista. COMT Val158Met ei vaikuttanut unimuuttujien ja tunnistustarkkuuden yhteyksiin. Tulokset viittaavat siihen, että unen ja muistin yhteys saattaa jossain määrin riippua perimästä. Geneettinen taipumus aivoplastisuuteen saattaa voimistaa unen aikaisten konsolidaatiomekanismien vaikutusta. Tämä kyseenalaistaa ajatuksen siitä, että unen hyödyt olisivat muuttumattomat sekä jokaiselle yhtäläiset

Study of evoked responses and brain connectivity during human cognitive activity through direct intracranial recordings

En las últimas décadas, diversos estudios en neurociencias cognitivas han mostrado que los procesos cognitivos dependen de la coordinación dinámica de diversas áreas cerebrales que se acoplan de forma flexible a corta y larga distancia. Desde esta perspectiva, el acto cognitivo ya no depende únicamente de un área cerebral específica, sino que requiere de integración a gran escala de un conjunto de regiones cerebrales. La mayor parte de la evidencia neurocientífica en humanos proviene de estudios que utilizan técnicas de resonancia magnética funcional o electromagnéticas que presentan limitaciones en su resolución temporal y espacial, respectivamente. En este contexto, los registros intracraneales invasivos en humanos presentan una oportunidad única para el estudio de la cognición. Esta técnica posee una resolución espacial del orden de los milímetros y temporal del orden de los milisegundos, tiene una de las mejores relaciones señal/ruido en humanos, y permite evaluar modelos neuroanatómicos y dinámicas temporales precisas de procesos cognitivos fundamentales, como la emoción, el juicio moral, o el lenguaje, entre otros. Asimismo, debido a la robustez de la relación señal/ruido de la técnica, es posible realizar estudios a nivel individual con gran precisión temporoespacial. Es por ello que su aporte a las neurociencias es fundamental. La presente Tesis recurre a esta técnica para combinar métodos clásicos de actividad evocada con el estudio de la conectividad cerebral a gran escala y algoritmos de aprendizaje para estudiar el acoplamiento de redes neuronales en procesos cognitivos clave de la vida cotidiana. Se abordan tres estudios basados en registros invasivos en humanos. En el primero, se investigaron los correlatos cerebrales de una tarea que evalúa el reconocimiento de la 3 intención de daño, un elemento decisivo en la cognición moral. Se encontró que el daño intencional induce actividad temprana (< 200 ms) en la amígdala, con modulaciones que discriminan sistemáticamente entre tipos de situaciones: daño intencional, daño no intencional e interacción no dañina (neutral). Además, los análisis de conectividad mostraron una rápida conexión con regiones prefrontales. Los resultados reflejan la relevancia de la amígdala en la codificación rápida de la intención de dañar, una habilidad crítica para la supervivencia y fundamental en la cognición moral. El segundo estudio se basó en una tarea de reconocimiento de emociones en caras y palabras, dos fenómenos centrales en la interacción social cotidiana. Se analizaron series temporales y métodos de conectividad con el uso de aprendizaje de máquinas estadístico para estudiar cómo el desempeño individual se refleja en la actividad neuronal en una muestra de sujetos con perfiles de desempeño contrastivos. Se mostró que los diferentes perfiles de desempeño se vieron reflejados en su conectividad entre regiones. Este trabajo es una contribución al enfoque de diferencias individuales, una tendencia reciente en el ámbito neurocientífico, que se concentra en estudiar la variabilidad del procesamiento neural a nivel individual. Por último, en el tercer estudio, se utilizaron registros intracraneales y electroencefalográficos para evaluar en qué medida la construcción del sentido semántico está asociada con regiones vinculadas con sistemas multimodales (áreas relacionadas con conceptos abstractos que integran diferentes vías sensoriales) y/o mecanismos corporizados (redes sensoriomotoras específicas para cada modalidad perceptual) involucrados a este proceso. A través de análisis clásicos de oscilaciones junto con aprendizaje automático, se estudió la dinámica de la modulación de estímulos lingüísticos relacionados con partes del rostro (sustantivos como ‘nariz’ y ‘boca’), y la interacción entre los sistemas multimodales y corporizados mediante métodos de conectividad. Se mostró por primera vez que estos estímulos rápidamente modulan marcadores tempranos en regiones de procesamiento de caras (regiones corporizadas), con contribuciones de regiones multimodales, lo cual sugiere que el significado lingüístico depende, en parte, de la reactivación de experiencias sensoriales pertinentes. En su conjunto, los tres estudios de la Tesis brindan aportes directos mediante registros invasivos en humanos para la construcción de modelos de neurociencias cognitivas. Finalmente, los métodos implementados en estos y otros trabajos realizados fueron incluidos en un toolbox propio de análisis de datos. Esta herramienta sirve como un repositorio de métodos con el fin de organizar, reutilizar, compartir y capacitar estudiantes e investigadores de un laboratorio. Si bien está construido con las funciones de los análisis presentados aquí, la principal 4 bondad del toolbox es que es fácilmente extensible y cada laboratorio o grupo de trabajo puede probarlo con sus propios métodos de análisis. Así, la presente Tesis brinda aportes en temáticas relevantes de las neurociencias de registros intracraneales a través de estudios en los que se aplicaron metodologías novedosas, como la conectividad y el aprendizaje automático, contribuyendo además a futuros estudios mediante la creación de una herramienta que facilita y potencia la tarea científica.In recent decades, cognitive neuroscience has shown that cognitive processes rely on dynamic couplings between brain areas over short and long distances. Cognitive events are thus no longer taken to depend solely on a specific region, but rather on the largescale integration of many regions. In human research, most relevant evidence stems from functional magnetic resonance or electromagnetic techniques, marked by limitations in their temporal and spatial resolution, respectively. In this context, invasive intracranial recordings represent a unique opportunity for studying cognition. This technique has a spatial resolution in the order of millimetres and a temporal resolution in the order of milliseconds, alongside one of the best signal-to-noise ratios. Therefore, it is very well suited to evaluating neuroanatomical models and complex temporal dynamics of elemental cognitive domains (e.g., emotion, moral judgement, and language) at the single-subject level. Building on such assets, this thesis relies on intracranial recordings combined with classical evoked activity methods, measures of large-scale brain connectivity, and machine learning approaches to study the coupling of neural networks in key cognitive processes of everyday life. The dissertation comprises three studies. The first one examines neural correlates of the recognition of harmful intentions, a decisive element of moral cognition. Intentional harm induced early amygdalar activity (< 200 ms), with modulations that discriminate among intentional harm, unintentional harm, and neutral actions. Furthermore, connectivity analyses showed a fast coupling with prefrontal regions. These results highlight the key role of the amygdala in the rapid encoding of intentional harm, a critical ability for survival and to moral cognition. The second study assessed emotion recognition in faces and words, two pillars of social interaction. Machine learning algorithms were applied to temporal series data and connectivity coefficients to examine individual signatures of neural activity in subjects with contrastive behavioural performance. The participant’s differential performance profiles were captured by connectivity coefficients. This work represents a contribution to the individual differences approach, a recent neuroscientific trend that focuses on individual neural variability. Lastly, through a combination of intracranial and scalp-level recordings, the third study focused on semantic processing to examine the temporal organization of multimodal systems (areas related to abstract concepts that integrate different sensory pathways) and/or embodied mechanisms (specific sensorimotor 6 networks for each perceptual modality) in the construal of meaning. We studied the dynamics of the modulations of linguistic stimuli denoting to facial body parts (nouns such as ‘nose’ and ‘mouth’) through classical oscillatory analysis together with machine learning, and the interaction between multimodal and embodied systems using connectivity methods. We showed, for the first time, that these stimuli rapidly modulate early markers in facial processing areas (embodied regions), with multimodal contributions, suggesting that linguistic meaning partly relies on fast reactivations of relevant sensory experiences. Together, the three studies provide direct contributions for the construction of models in cognitive neuroscience through invasive recordings in humans. Finally, the methods implemented for these and other works were included in a data analysis toolbox. This tool serves as a repository to ease the organization, reuse, and sharing of scripts, thus supporting student and researcher training. Already equipped with the functions used for present analyses, the toolbox is easily extensible and each laboratory or work group can populate it with their own methods. In sum, building on the uniqueness of intracranial human recordings, the present thesis affords methodological and theoretical contributions in hot topics of cognitive neuroscience, combining novel connectivity and machine learning methods and providing a tool that assists future studies and enhances other potential investigations.Fil: Hesse Rizzi, Eugenia Fátima. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt. Laboratorio de Psicología Experimental y Neurociencias; Argentin

Atypical Cortical Connectivity in Autism Spectrum Disorder (ASD) as Measured by Magnetoencephalography (MEG)

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition, characterised by impairments in social interaction and communication, the presence of repetitive behaviours, and multisensory hyper- and hypo-sensitives. This thesis utilised magnetoencephalography, in combination with robust analysis techniques, to investigate the neural basis of ASD. Based on previous research, it was hypothesised that cortical activity in ASD would be associated with disruptions to oscillatory synchronisation during sensory processing, as well as during high-level perspective-taking. More specifically, a novel framework was introduced, based on local gamma-band dysregulation, global hypoconnectivity and deficient predictive-coding. To test this framework, data were collected from adolescents diagnosed with ASD and age-matched controls. Using a visual grating stimulus, it was found that in primary visual cortex, ASD participants had reduced coupling between the phase of alpha oscillations and the amplitude of gamma oscillations (i.e. phase amplitude coupling), suggesting dysregulated visual gamma in ASD. These findings were based on a robust analysis pipeline outlined in Chapter 2. Next, directed connectivity in the visual system was quantified using Granger causality. Compared with controls, ASD participants showed reductions in feedback connectivity, mediated by alpha oscillations, but no differences in inter-regional feedforward connectivity, mediated by gamma oscillations. In the auditory domain, it was found that ASD participants had reduced steady-state responses at 40Hz, in terms of oscillatory power and inter-trial coherence, again suggesting dysregulated gamma. Investigating predictive-coding theories of ASD using an auditory oddball paradigm, it was found that evoked responses to the omission of an expected tone were reduced for ASD participants. Finally, we found reductions in theta-band oscillatory power and connectivity for ASD participants, during embodied perspective-taking. Overall, these findings fit the proposed framework, and demonstrate that cortical activity in ASD is characterised by disruptions to oscillatory synchronisation, at the local and global scales, during both sensory processing and higher-level perspective-taking