Spatio-temporal Principles of Infra-slow Brain Activity

In the study of systems where basic laws have eluded us, as is largely the case in neuroscience, the simplest approach to progress might be to ask: what are the biggest, most noticeable things the system does when left alone? Without any perturbations or fine dissections, can regularities be found in the basic operations of the system as a whole? In the case of the brain, it turns out that there is an amazing amount of activity even in the absence of explicit environmental inputs or outputs. We call this spontaneous, or resting state, brain activity. Prior work has shown that spontaneous brain activity is dominated by very low frequencies: the biggest changes in brain activity happen relatively slowly, over 10’s-100’s of seconds. Moreover, this very slow activity of the brain is quite metabolically expensive. The brain accounts for 2% of body mass in an adult, but requires 20% of basal metabolic expenditure. Remarkably, the energy required to sustain brain function is nearly constant whether one is engaged in a demanding mental task or simply out to lunch. Furthermore, work over the past three decades has established that the spontaneous activities of the brain are not random, but instead organized into specific patterns, most often characterized by correlations within large brain systems. Yet, how do these correlations arise, and does spontaneous activity support slow signaling within and between neural systems? In this thesis, we approach these questions by providing a comprehensive analysis of the temporal structure of very low frequency spontaneous activity. Specifically, we focus on the direction of travel in low frequency activity, measured using resting state fMRI in humans, but also using electrophysiological techniques in humans and mice, and optical calcium imaging in mice. Our temporal analyses reveal heretofore unknown regularities in the way slow signals move through the brain. We further find that very low frequency activity behaves differently than faster frequencies, that it travels through distinct layers of the cortex, and that its travel patterns give rise to correlations within networks. We also demonstrate that the travel patterns of very low frequency activity are highly dependent on the state of the brain, especially the difference between wake and sleep states. Taken together, the findings in this thesis offer a glimpse into the principles that govern brain activity

The role of multi-scale phase synchronization and cross-frequency interactions in cognitive integration

Neuronal processing is distributed into anatomically distinct, largely specialized, neuronal populations. These populations undergo rhythmic fluctuations in excitability, which are commonly known as neuronal oscillations. Electrophysiological studies of neuronal activity have shown that phase synchronization of oscillations within frequencies characterizes both resting state and task execution and that its strength is correlated with task performance. Therefore phase-synchronization within frequencies is thought to support communication between oscillating neuronal populations and thereby integration and coordination of anatomically distributed processing in cognitive functions. However, it has remained open if and how phase synchronization is associated with directional flow of information. Furthermore, oscillations and synchronization are observed concurrently in multiple frequencies, which are thought to underlie distinct computational functions. Little is known how oscillations and synchronized networks of different frequencies in the human brain are integrated and enable unified cognitive function and experience. In the first study of this thesis, we developed a measure of directed connectivity in networks of coupled oscillators, called Phase Transfer Entropy (Phase TE) and tested if Phase TE could detect directional flow in simulated data in the presence of noise and signal mixing. Results showed that Phase TE indeed reliably detected information flow under these conditions and was computationally efficient. In the other three studies, we investigated if two different forms of inter-areal cross-frequency coupling (CFC), namely cross-frequency phase synchrony (CFS) and phase-amplitude coupling (PAC), could support integration and coordination of neuronal processing distributed across frequency bands in the human brain. In the second study, we analyzed source-reconstructed magneto- and electroencephalographic (M/EEG) data to investigate whether inter-areal CFS could be observed between within-frequency synchronized networks and thereby support the coordination of spectrally distributed processing in visual working memory (VWM). The results showed that CFS was increased during VWM maintenance among theta to gamma frequency bands and the strength of CFS networks predicted individual VWM capacity. Spectral patterns of CFS were found to be different from PAC, indicating complementary roles for both mechanisms. In the third study, we analyzed source-reconstructed M/EEG data to investigate whether inter-areal CFS and PAC could be observed during two multi-object visual tracking tasks and thereby support visual attention. PAC was found to be significantly correlated with object load in both tasks, and CFS in one task. Further, patterns of CFS and PAC differed significantly between subjects with high and low capacity for visual attention. In the fourth study, we analyzed intracerebral stereo-electroencephalographic data (SEEG) and source-reconstructed MEG data to investigate whether CFS and PAC are present also in resting state. Further, in order to address concerns about observations of CFC being spurious and caused by non-sinusoidal or non-zero mean signal waveforms, we introduced a new approach to identify true inter-areal CFC connections and discard potentially spurious ones. We observed both inter-areal CFS and PAC, and showed that a significant part of connections was unambiguously true and non-spurious. Spatial profiles differed between CFS and PAC, but were consistent across datasets. Together, the results from studies II-IV provide evidence that inter-areal CFS and PAC, in complementary ways, connect frequency-specific phase-synchronized networks that involve functionally specialized regions across the cortex to support complex functions such as VWM and attention, and also characterize the resting state. Inter-areal CFC thus may be crucial for the coordination and integration of spectrally distributed processing and the emergence of introspectively coherent cognitive function.Keskeinen kysymys aivotutkimuksessa on, kuinka ajattelu ja kognitio syntyvät ihmisaivojen 10^15 hermosolussa. Informaation käsittely aivoissa tapahtuu suurissa hermosolupopulaatioissa, jotka ovat toiminnallisesti erikoistuneita ja anatomisesti eroteltuja eri aivoalueille. Niiden aktivaatiorakenteiden jaksollisia muutoksia kutsutaan aivorytmeiksi eli oskillaatioiksi. Hermosolupopulaatioiden välistä viestintää edesauttaa niiden toiminnan samantahtisuus eli synkronoituminen. Sähköfysiologisissa tutkimuksissa on havaittu aivorytmien synkronoituvan sekä lepomittausten että tehtävien suorituksen aikana siten että tämä synkronoituminen ennustaa kognitiivissa tehtävissä suoriutumista. Oskillaatioiden vaihesynkronia ei kuitenkaan kerro niiden välisen vuorovaikutuksen suunnasta. Tämän lisäksi oskillaatioita ja niiden välistä synkroniaa havaitaan yhtäaikaisesti lukuisilla eri taajuuksilla, joiden ajatellaan olevan vastuussa erillisistä laskennallisista ja kognitiivisista toiminnoista. Toistaiseksi on kuitenkin jäänyt kartoittamatta, miten informaation käsittely eri taajuuksilla yhdistetään yhtenäisiksi kognitiivisiksi toiminnoiksi, ja havaitaanko myös eri taajuisten oskillaatioverkkojen välillä synkroniaa. Väitöskirjan ensimmäisessä osatyössä on kehitetty uusi tapata mitata oskillaattoriverkkojen vuorovaikutusten suuntia, jonka toimivuus todennettiin simuloimalla synkronoituneita hermosolupopulaatioita. Väitöskirjan muissa osatöissä on tutkittu havaitaanko ihmisaivoissa eri taajuisten oskillaatioiden välistä synkronoitumista. Erityisesti tutkittiin kahta erilaista synkronian muotoa, joista ensimmäinen (’cross- frequency phase synchrony’,CFS) mittaa kahden oskillaation välistä vaihesuhdetta ja toinen (’phase-amplitude coupling’, PAC) vaiheen ja amplitudin suhdetta. Väitöskirjan toisessa osassa tutkittiin, selittääkö CFS koehenkilöiden suoriutumista näkötyömuistitehtävässä. Tutkimukseen osallistuneilta koehenkilöiltä mitattiin aivosähkökäyrä (EEG) ja aivomagneettikäyrä (MEG), joiden avulla selvitettiin havaitaanko aivoalueiden välistä synkroniaa (CFS). Tutkimustulokset osoittivat, että koehenkilöiden CFS oli korkeampi näkötyömuistitehtävän mielessä pitämisen aikana theta-taajuuksista gamma-taajuuksiin asti ja että CFS-verkkojen vahvuus ennusti yksilöllistä työmuistikapasiteettia. Kolmannessa tutkimuksessa analysoitiin MEG- ja EEG-aivokuvantamislaitteita käyttäen onko aivoalueiden välillä CFS:ä ja PAC:a kahdessa näkötarkkaavaisuustehtävässä. PAC lisääntyi tilastollisesti merkitsevästi tehtävän vaikeuden mukaan kummassakin tehtävässä, kun taas CFS lisääntyi yhdessä tehtävässä. Lisäksi CFS ja PAC taajuusparit olivat erilaisia hyvin suoriutuvien koehenkilöiden sekä heikosti suoriutuvien koehenkilöiden välillä. Neljännessä tutkimuksessa tutkittiin havaitaanko CFS:ä ja PAC:a aivojen lepotilassa. Aivokuoren aktiivisuutta mitattiin MEG:llä sekä epilepsiapotilailta aivoihin kirurgisesti asetetuilla elektrodeilla. CFS:ä sekä PAC:a havaittiin kummallakin menetelmällä. Lisäksi kehitimme menetelmän joka vähentää väärien havaintojen todennäköisyyttä ja lisää aitojen CFS ja PAC yhteyksien havaitsemista. Tulokset osoittavat, että merkittävä osuus yhteyksistä aivoalueiden välillä on aitoja. CFS- ja PAC-profiilit erosivat toisistaan, mutta olivat samanlaisia eri menetelmillä tutkittaessa. Yhdistettynä tulokset tutkimuksista II–IV viittaavat siihen, että CFS ja PAC yhdistävät eri taajuuksille ja aivoalueille hajautettua informaation käsittelyä. CFS:sää ja PAC:ia havaittiin aivojen lepotilassa mutta myös tarkkaavaisuus- ja näkötyömuistitehtävän aikana. CFS ja PAC saattavat mahdollistaa eri taajuisten aivorytmien ja hajautettujen prosessien koordinaation ja yhdistämisen

Hyperconnectivity is a fundamental response to neurological disruption

In the cognitive and clinical neurosciences, the past decade has been marked by dramatic growth in a literature examining brain "connectivity" using noninvasive methods. We offer a critical review of the blood oxygen level dependent functional MRI (BOLD fMRI) literature examining neural connectivity changes in neurological disorders with focus on brain injury and dementia. The goal is to demonstrate that there are identifiable shifts in local and large-scale network connectivity that can be predicted by the degree of pathology. We anticipate that the most common network response to neurological insult is hyperconnectivity but that this response depends upon demand and resource availability

Moderating Effects of Harm Avoidance on Resting-State Functional Connectivity of the Anterior Insula

As an index of behavioral inhibition and an individual’s propensity to avoid, rather than seek, potentially dangerous situations, harm avoidance has been linked to internalizing psychopathology. Altered connectivity within intrinsic functional neural networks has been linked to internalizing psychopathology; however, less is known about the effects of harm avoidance on functional connectivity within and between these networks. Importantly, harm avoidance may be distinguishable from trait anxiety and have clinical relevance as a risk factor for psychopathology. To this end, the current study aimed to examine associations between harm avoidance and resting state functional connectivity. A sample of undergraduate students (n=92) completed a resting state functional magnetic resonance imaging (fMRI) scan and self-report measures of harm avoidance and trait anxiety. Results indicated a main effect of harm avoidance on functional connectivity, such that higher harm avoidance was associated with decreased connectivity between the right anterior insula and clusters in the precuneus/PCC, left lateral parietal lobe, and left superior/middle frontal gyrus. Higher harm avoidance was also associated with decreased connectivity between the left anterior insula and precuneus/PCC. There were no effects of trait anxiety on functional connectivity of the anterior insula. Overall, the results indicate that individual differences in harm avoidance relate to disruptions in internetwork connectivity that may contribute to deficits in appropriately modulating attentional focus

The interaction between 5-HTTLPR and stress exposure influences connectivity of the executive control and default mode brain networks

We recently reported that the serotonin transporter polymorphism 5-HTTLPR moderates the relation between stress exposure and attention-deficit/hyperactivity disorder (ADHD) severity. This gene-environment interaction (GxE) has been previously tied to the processing of emotional stimuli, which is increasingly recognized to be a key factor in ADHD-related impairment. The executive control and default mode brain networks play an important role in the regulation of emotion processing, and altered connectivity of these networks has also been associated with ADHD. We therefore investigated whether resting-state connectivity of either of these networks mediates the relation of 5-HTTLPR and stress exposure with ADHD severity. Resting-state functional magnetic resonance imaging, genetic, and stress exposure questionnaire data was available for 425 adolescents and young adults (average age 17.2 years). We found that 5-HTTLPR S-allele carriers showed a more negative relation between stress exposure and connectivity of the executive control network than L-allele homozygotes, specifically in the pre/postcentral gyrus, striatum, and frontal pole. In the default mode network, we found a positive association between the GxE and supramarginal gyrus connectivity. Connectivity of either network did not significantly mediate the effect of this GxE on ADHD. Opposite effects of stress exposure on connectivity in the executive and default mode networks may contribute to findings that stress exposure is associated with lowered cognitive control and heightened levels of rumination and worrying, for S-allele carriers but not L-allele homozygotes. When combined, these effects on connectivity of both networks may relate to the emotional problems seen in individuals with ADHD

Neural Network Dynamics of Visual Processing in the Higher-Order Visual System

Vision is one of the most important human senses that facilitate rich interaction with the external environment. For example, optimal spatial localization and subsequent motor contact with a specific physical object amongst others requires a combination of visual attention, discrimination, and sensory-motor coordination. The mammalian brain has evolved to elegantly solve this problem of transforming visual input into an efficient motor output to interact with an object of interest. The frontal and parietal cortices are two higher-order (i.e. processes information beyond simple sensory transformations) brain areas that are intimately involved in assessing how an animal’s internal state or prior experiences should influence cognitive-behavioral output. It is well known that activity within each region and functional interactions between both regions are correlated with visual attention, decision-making, and memory performance. Therefore, it is not surprising that impairment in the fronto-parietal circuit is often observed in many psychiatric disorders. Network- and circuit-level fronto-parietal involvement in sensory-based behavior is well studied; however, comparatively less is known about how single neuron activity in each of these areas can give rise to such macroscopic activity. The goal of the studies in this dissertation is to address this gap in knowledge through simultaneous recordings of cellular and population activity during sensory processing and behavioral paradigms. Together, the combined narrative builds on several themes in neuroscience: variability of single cell function, population-level encoding of stimulus properties, and state and context-dependent neural dynamics.Doctor of Philosoph

In vitro neuronal cultures on MEA: an engineering approach to study physiological and pathological brain networks

Reti neuronali accoppiate a matrici di microelettrodi: un metodo ingegneristico per studiare reti cerebrali in situazioni fisiologiche e patologich

Identifying the Neurocognitive bases of creativity to increase human and computational creativity

En esta Tesis Doctoral se ha identificado la estructura neurocognitiva que sustenta la creatividad humana a partir del análisis conjunto de más de 800 referencias bibliográficas que muestran las investigaciones más importantes realizadas hasta la fecha. Sobre la base de esta estructura, se ha identificado un paradigma neurocognitivo de la creatividad humana y se ha propuesto un modelo neurocognitivo del proceso creativo. Finalmente, también se ha propuesto un paradigma creativo neurocognitivo computacional y se ha diseñado la estructura de un sistema computacional creativo, basado en una estructura multiagente. La investigación que se ha realizado sobre el tema hasta la fecha es muy especializada y se centra en aspectos muy concretos de la creatividad, y en muchos casos tienen poca relación entre sí. Por ello, y para tener una idea conjunta y holística de los procesos neurocognitivos de la creatividad humana, es necesario estudiar todas estas investigaciones de forma interconectada. Esta idea conjunta permitiría dirigir investigaciones más específicas para ser más efectivos. Por ello, lo primero que se ha hecho ha sido clasificar, agrupar, analizar, entrelazar y estructurar, de forma ordenada, las investigaciones más importantes que se han realizado hasta la fecha. Sin embargo, el trabajo realizado va mucho más allá, ya que estructurando y entrelazando las investigaciones existentes ha sido posible identificar ciertos patrones, correlaciones y paralelismos, y realizar ciertas deducciones, que en su conjunto, han permitido identificar los procesos neurocognitivos fundamentales. bases de la creatividad humana. La Tesis se estructura en los siguientes capítulos: Capitulo 2 Análisis de los principales métodos para estimular la creatividad Se analizan las principales definiciones de creatividad, y se ha decidido que el mejor enfoque para su análisis es estructurarla taxonómicamente, bajo el modelo 4P. Se ha realizado una recopilación y análisis de los métodos más efectivos que estimulan la creatividad humana, mostrando las ventajas y desventajas de cada uno. Capítulo 3 Estructura funcional del cerebro humano y su relación con el proceso creativo Se identifica la estructura neurocognitiva general del cerebro humano que permite generar los procesos fundamentales y básicos de su actividad creativa. Capítulo 4 El papel fundamental de la DMN en el proceso creativo Se ha observado que la red de modo predeterminado (DMN) tiene un papel principal en la creatividad. Por ello, se ha dedicado un capítulo a su estudio, y se han identificado varios factores que la involucran directamente en la actividad creativa del cerebro humano. Capítulo 5 Identificación y análisis de las bases neurocognitivas de la creatividad humana Se ha identificado el conjunto general de factores neurocognitivos que sustentan los procesos creativos en el cerebro humano. Capítulo 6 Paradigma neurocognitivo de la creatividad humana Se ha propuesto un modelo neurocognitivo del proceso creativo que reestructura, completa y detalla todos los modelos conceptuales propuestos hasta el momento. Capítulo 7 Paradigma computacional de la creatividad basado en la estructura neurocognitiva humana Analizando las diferentes bases neurocognitivas que sustentan la creatividad humana, se han establecido paralelismos computacionales y se han realizado diferentes sugerencias para el diseño de un sistema computacional creativo.In this Doctoral Thesis, the neurocognitive structure that supports human creativity has been identified based on the joint analysis of more than 800 bibliographical references that show the most important investigations carried out to date. Based on this structure, a neurocognitive paradigm of human creativity has been described, and a neurocognitive model of creative process has been proposed. Finally, a computational neurocognitive creative paradigm has been also proposed, and the structure of a creative computational multi-agent system has been designed. The research that has been carried out on the subject is very specialized and focuses on very specific aspects of creativity, and in many cases they have little relationship with each other. For this reason, and in order to have a joint and holistic idea of the neurocognitive processes of human creativity, it is necessary to study all these investigations in an interconnected way. This joint idea would allow directing more specific investigations in order to be more effective. For this reason, the first thing that has been done has been to classify, group, analyze, intertwine and structure, in an orderly manner, the most important investigations that have been carried out to date. However, the work carried out goes much further, since by structuring and intertwining the existing research it has been possible to identify certain patterns, correlations and parallelisms, and make certain deductions, which as a whole, have made it possible to identify the fundamental neurocognitive bases of human creativity. Chapter 2 Analysis of the main methods to stimulate creativity The main definitions of creativity are analyzed, and it has been decided that the best approach for its analysis is to structure it taxonomically, under the 4P model. A compilation and analysis of the most effective methods that stimulate human creativity has been carried out, showing the advantages and disadvantages of each one. Chapter 3 Functional structure of the human brain and its relationship with the creative process The general neurocognitive structure of the human brain that allows the generation of the fundamental and basic processes of its creative activity are identified. Chapter 4 The fundamental role of the DMN in the creative process It has been observed that the Default mode network (DMN) has a main role in creativity. For this reason, a chapter has been dedicated to its study, and several factors have been identified that directly involve it in the creative activity of the human brain. Chapter 5 Identification and analysis of the neurocognitive bases of human creativity The general set of neurocognitive factors that underpin creative processes in the human brain has been identified. Chapter 6 Neurocognitive paradigm of human creativity A neurocognitive model of the creative process has been proposed, which restructures, completes and details all the conceptual models proposed so far. Chapter 7 Computational paradigm of creativity based on the human neurocognitive structure Analyzing the different neurocognitive bases that support human creativity, computational parallels have been established and different suggestions have been made for the design of a creative computational system

기능적 뇌네트워크 간 연결성의 차이를 통한 임상적 고위험군에서 정신증 발병 예측

학위논문 (박사)-- 서울대학교 대학원 자연과학대학 뇌인지과학과, 2017. 8. 권준수.Among individuals at clinical high risk for psychosis (CHR) who show prodromal symptoms of psychosis, some progress to full-blown psychosis. There have been attempts to find markers predicting the onset of psychosis, and brain structures related to onset of psychosis have been reported. However, no studies have examined wide-range interactions at the functional network level that can adequately account for the schizophrenia, a dysconnectivity disorder. To discover predicting markers for psychosis, I conducted a longitudinal study for a follow-up period of a minimum of 12 months. At the baseline, the resting-state functional magnetic resonance imaging was acquired from individuals at CHR (N = 69), individuals with first-episode psychosis (FEP) (N = 35), and healthy controls (HC) (N = 70). Eight psychosis-related functional networks were extracted, and interactions between paired functional networks were measured, resulting in estimations of 28 possible combinations. After the group comparison, correlation analyses between the altered network interactions and symptom severity were conducted to reveal clinical associations. Seven of 69 (10%) individuals at CHR proceeded to full-blown psychosis (CHR-C). There were no significant difference in age, gender, and handedness among FEP, CHR-C, CHR-NC, and HC. Of the 28 combinations, there were significant group differences in four functional network connectivity. The FEP group showed the most severe degree of decrement in functional network connectivity compared to HC. Among all four significantly different functional network interactions, CHR-C showed no significant difference from FEP, while the nonconverters (CHR-NC) had significantly higher functional network connectivity compared to FEP. Among the altered combinations, the interaction between the anterior default mode network and salience network of the FEP group was associated with the overall negative psychotic symptom severity. This is the first study to suggest that large network interactions can serve as potential markers of the psychosis onset by showing that the CHR-C is similar to FEP, while CHR-NC is comparable to HC. The degree of functional network connectivity in CHR may have prognostic implications regarding the risk of conversion to full-blown psychosis.Chapter 1. Introduction 1 Chapter 2. Methods 12 Chapter 3. Results 20 Chapter 4. Discussion 22 Chapter 5. Conclusion 31 References 32 Tables 44 Figures 57 Abstract in Korean 67Docto