Selective attention and speech processing in the cortex

In noisy and complex environments, human listeners must segregate the mixture of sound sources arriving at their ears and selectively attend a single source, thereby solving a computationally difficult problem called the cocktail party problem. However, the neural mechanisms underlying these computations are still largely a mystery. Oscillatory synchronization of neuronal activity between cortical areas is thought to provide a crucial role in facilitating information transmission between spatially separated populations of neurons, enabling the formation of functional networks. In this thesis, we seek to analyze and model the functional neuronal networks underlying attention to speech stimuli and find that the Frontal Eye Fields play a central 'hub' role in the auditory spatial attention network in a cocktail party experiment. We use magnetoencephalography (MEG) to measure neural signals with high temporal precision, while sampling from the whole cortex. However, several methodological issues arise when undertaking functional connectivity analysis with MEG data. Specifically, volume conduction of electrical and magnetic fields in the brain complicates interpretation of results. We compare several approaches through simulations, and analyze the trade-offs among various measures of neural phase-locking in the presence of volume conduction. We use these insights to study functional networks in a cocktail party experiment. We then construct a linear dynamical system model of neural responses to ongoing speech. Using this model, we are able to correctly predict which of two speakers is being attended by a listener. We then apply this model to data from a task where people were attending to stories with synchronous and scrambled videos of the speakers' faces to explore how the presence of visual information modifies the underlying neuronal mechanisms of speech perception. This model allows us to probe neural processes as subjects listen to long stimuli, without the need for a trial-based experimental design. We model the neural activity with latent states, and model the neural noise spectrum and functional connectivity with multivariate autoregressive dynamics, along with impulse responses for external stimulus processing. We also develop a new regularized Expectation-Maximization (EM) algorithm to fit this model to electroencephalography (EEG) data

An fMRI investigation on empathy: physical and social pain, prosocial behavior and the role of the opioid system

The work presented in this thesis collects three fMRI studies mainly focusing on empathy, i.e. the capacity to understand and/or share the emotional state of others. Empathy is central to human sociality, as it allows us to resonate with others\u2019 positive and negative feeling, and consequently adjust our behavior. Despite recent research has shed light on many feature of empathic responses, we still ignore many other aspects: for instance, which kind of computational processes are executed by empathy \u301s neural substrates, how empathic responses vary according to the type of observed experience, which neurochemical mechanisms are at the core of empathic responses, or also what is the link between empathic responses and the tendency to behave altruistically (usually referred to as \u2018prosocial behavior\u2019). The purpose of the work presented in this thesis is providing answers to some of the open questions. In Study 1 we aimed at understanding what are the neural substrates of empathy for social pain, a kind of pain that is constantly grabbing increasingly attention among social neuroscientists, and to which extent they overlap with the ones coding for physical pain. In Study 2 we investigated brain correlates of prosocial behavior by exploring functional connectivity within brain networks of participants who exhibited either a self-benefit behavior or an altruistic one in a life-threatening situation simulated in a virtual environment. In Study 3 we used a placebo manipulation on a group of participants undergoing first- hand and vicarious painful stimulations in order to observe how the supposed enhancement of endogenous opioids release would affect their behavioral and neurophysiological responses to the painful experience. Overall, the work presented in this thesis advances the knowledge on both empathy and prosociality mechanisms and opens the way for new investigations aiming at clarifying key aspects of social behavior

Longitudinal change in executive function is associated with impaired top-down frontolimbic regulation during reappraisal in older adults

Networks in the prefrontal cortex (PFC) that are important for executive function are also engaged in adaptive responding to negative events. These networks are particularly vulnerable to age-related structural atrophy and an associated loss of executive function, yet existing evidence suggests preserved emotion processing ability in ageing. Using longitudinally acquired data from a battery of cognitive tasks, we defined a metric for the rate of decline of executive function. With this metric, we investigated relationships between changes in executive function and emotion reappraisal ability and brain structure, in 34 older adults, using functional and structural MRI. During task-based fMRI, participants were asked to cognitively reappraise negatively valenced images. We hypothesised one of two associations with decreasing executive function over time: 1) a decreased ability to reappraise reflected in decreased PFC and increased amygdala activation, or 2) a neural compensation mechanism characterised by increased PFC activation but no differential amygdala activation. Structurally, for a decreased reappraisal ability, we predicted a decrease in grey matter in PFC and/or a decrease of white matter integrity in amygdala-PFC pathways. Neither of the two hypotheses relating to brain function were completely supported, with the findings indicating a steeper decline in executive function associated with both increased PFC and increased left amygdala activity when reappraising negative stimuli. In addition, white matter integrity of the uncinate fasciculus, a primary white matter tract connecting the amygdala and ventromedial areas of PFC, was lower in those individuals who demonstrated a greater decrease in executive function. These findings highlight the association of diminishing cognitive ability with brain structure and function linked to emotion regulation

인지 노쇠에서 FDG PET과 휴지상태 fMRI를 이용한 뇌 신경 활동과 기능적 연결성 패턴의 동적 변화 연구

학위논문(박사)--서울대학교 대학원 :의과대학 의과학과,2019. 8. 이재성.Cognitive frailty is a recently defined clinical condition characterized by concurrent appearance of physical frailty and mild cognitive impairments (MCI). Literature suggests common neuropathophysiological processes underlying physical and cognitive deficits, and physical dysfunction promotes cognitive decline, eventually leading to the emergence of Alzheimers disease dementia. It remains to be discovered how neural activities and brain network reconfigurations are altered in the presence of physical frailty in MCI. In the present study, [18F]FDG PET and resting state fMRI scans were examined in 21 MCI patients without physical frailty (robust group: mean age = 74.7 ± 5.8 years) and 27 MCI with physical frailty (at-risk group: mean age = 75.5 ± 7.3 years). The first part of the study aimed to investigate changes in glucose metabolism and regional homogeneity in cognitive frailty. Regional cerebral hypometabolism was observed in right frontal cortex, anterior cingulate, and bilateral superior parietal cortex in at-risk group, and the metabolic changes in left superior parietal cortex were associated with poorer performances in handgrip strength and executive function. Brain regional homogeneity was reduced in bilateral caudate, right medial and lateral frontal cortex, right superior temporal cortex, and cerebellum, and was increased in right precuneus and cerebellum. Decreased regional homogeneity in bilateral caudate and right superior temporal cortex showed correlations with weaker grip strength, slower gait speed, and lower physical activity, and the regional changes were also linked to cognitive performances in language and visuospatial function. The results demonstrated that the metabolic and functional alterations in cognitive frailty resembled Alzheimer's disease related pattern. The second part of the study aimed to explore alterations in dynamic functional connectivity states and the temporal properties. Dynamic functional connectivity was measured using a sliding-window approach, and certain connectivity configurations (states) were estimated using k-means clustering method. Four distinguishing patterns of functional connectivity were found during the resting state scan time in our MCI cohorts. The most frequently occurring state (State 1) displayed mostly within-network connections, and the less occurring states (States 2, 3 and 4) displayed stronger between-network connections in both positive and negative fashions. The alterations in the temporal properties of dynamic states such as the number of transition, fractional windows, and mean dwell time of states did not reach the significance level, however, at-risk group appeared to have less reoccurrence of within-network State 1 and more reoccurrences of between-network States 2 and 3. Reduced reoccurrence and shorter dwell time of within-network State 1 were significantly correlated with weaker handgrip strength, and the abnormally reduced within-network State 1 may reflect reduced functional network segregation coupled with physical deficits. On the other hand, higher reoccurrence and longer dwell time of State 2, which was characterized by heightened default mode network within-connectivity and increased interactions between default mode network and sensorimotor networks were associated with poorer MMSE-K score. The overexpression of interactions between default mode and sensorimotor networks may interfere with network functional specializations, leading to poor cognitive function. Furthermore, the functional connectivity strengths between sensorimotor and cognitive networks and within cognitive control network were altered in at-risk individuals. The neuroimaging outcomes present that aberrant functional changes in frontal, temporal and parietal cortex may indicate advanced pathological process in the presence of physical frailty in MCI. The time-varying network reconfigurations indicating decreased functional segregation of brain networks may also serve as a potential biomarker in cognitive frailty.인지 노쇠는 신체적 노쇠와 경도 인지 장애가 동시에 존재하는 것이 특징적인 최근 정의된 임상적 질환이다. 기존 연구에 의하면 신체적 노쇠와 인지 기능 저하는 공통적인 신경 병리적 기전을 가지는 것으로 알려져 있다. 또한, 신체적 기능 장애는 인지 기능 감소를 촉진하고, 나아가 알츠하이머병 치매 발병까지 연결된다. 신체적 노쇠를 보이는 경도 인지 장애 환자에서의 신경 활동 변화와 동적 뇌 네트워크 재구성 변화에 대한 연구는 아직까지 보고된 바가 없으며, 본 연구 결과를 통하여 뇌 영상 데이터가 인지 노쇠의 중요한 바이오마커의 역할을 할 것으로 기대된다. 본 연구에서는 [18F]FDG PET과 rs-fMRI 뇌 영상 검사를 총 48명의 경도 인지 기능 장애 환자 (신체적 노쇠가 없는 대조군: 21명, 평균 연령 = 74.7 ± 5.8세; 신체적 노쇠가 있는 위험군: 27명, 평균 연령 = 75.5 ± 7.3세)를 대상으로 진행하였다. 본 연구의 첫번째 부분에서는 위험군에서의 뇌 영역의 포도당 대사의 변화와 regional homogeneity를 이용한 뇌 활동 변화를 조사하였다. 위험군에서는 우측 전두피질, 전대상피질, 양측 상두정소엽에서 뇌 대사 감소가 나타났고, 상두정소엽에서의 대사 변화와 악력, 집행 기능과 양의 상관 관계를 보였다. 뇌 영역의 regional homogeneity 변화는 양측 꼬리핵, 우측 내측과 가측 전두피질, 우측 상측두피질, 소뇌에서 감소하는 것으로 보였고, 꼬리핵과 상측두피질에서의 regional homogeneity 감소는 악력, 보행 속도, 신체 활동 감소 수치와 높은 상관성을 보였다. 또한, 언어 및 시공간 기능의 인지 수행 능력과 높은 상관 관계를 보이는 것을 관찰하였다. 본 연구의 두번째 부분은 위험군에서의 뇌 네트워크의 동적 기능적 연결성과 특징 변화를 살펴보았다. 동적 기능적 연결 분석은 sliding-window 방법과 k-means clustering 방법을 사용하여 뇌 네트워크 연결 구성 상태 (State)를 추정하였다. 휴지기 상태의 영상 촬영 시간 동안 총 4개의 기능적 연결성 패턴이 발견되었고, 가장 자주 발생하는 State 1은 주로 뇌 네트워크 내부 연결성을 보이고, 네트워크 간의 연결성은 약한 것이 특징으로 나타났다. 그 다음으로 자주 나타난 State 2, 3, 4는 네트워크 간의 양과 음의 연결성 모두 강하게 나타났다. State의 전환 수, fractional windows, mean dwell time과 같은 시간적 속성의 그룹 비교 결과는 유의한 수준에 도달하지 못했지만, 위험군에서 State1의 재발현이 감소되고 State 2, State 3의 발현 증가가 나타나는 것으로 확인되었다. State 1의 속성 (fractional windows, mean dwell time)이 악력 및 신체 활동량과 양의 상관 관계를 나타냈고, 반면에, 디폴트 모드 네트워크 기능 연결성 증가가 특징적이었던 State 2의 발현 증가 및 dwell time 증가는 낮은 MMSE-K 점수 저하와 상관이 있는 것을 관찰하였다. 네트워크 변화는 노화현상에서 관측되는 네트워크 기능적 분리 (functional segregation)의 감소를 나타내는 것으로 생각되며, 신체적 기능 저하가 이러한 현상을 촉진하는 것으로 보여진다. 뿐만 아니라, 위험군에서 감각운동 네트워크와 인지 기능 네트워크 간의 기능적 연결성과 인지 조절 네트워크 내부 연결성 세기에도 변화가 나타나는 것을 발견하였다. 결론으로는, 뇌 영상 분석 결과에서 인지 노쇠 위험군 환자에서 전두엽, 측두엽 그리고 두정엽에서 기능적 활동 변화가 나타나는 것을 관찰하였고, 이는 신체적 노쇠가 존재할 경우 병리학적 과정이 가속화되는 것으로 추정된다. 뇌 네트워크의 동적 기능적 연결성 분석을 통해 악력 감소와 함께 네트워크 기능적 분리 감소 현상이 두드러지는 것을 확인하였으며, 따라서, 뇌 영상 데이터가 인지 노쇠의 생체 표지자 역할을 할 수 있는 것으로 기대된다.Chapter 1. Introduction 1 1.1 Frailty and cognition 1 1.2 Purpose of the study 3 Chapter 2. Methodological Background 5 2.1 Measurement of cerebral glucose metabolism using [18F]FDG PET. 5 2.2 Measurements of brain functional activity and intrinsic network using rsfMRI 6 2.2.1 Regional homogeneity using rs-fMRI 6 2.2.2 Group independent component analysis . 7 2.3 Dynamic functional connectivity analysis 10 Chapter 3. Subjects and Methods. 13 3.1 Participants . 13 3.1.1 Criteria of participants 13 3.1.2 Neuropsychological tests 14 3.1.3 Physical frailty definition . 14 3.1.4 Acquisition of [18F]FDG PET and rs-fMR images 19 3.1.5 Statistical analysis . 19 3.2 [18F]FDG PET image analysis . 20 3.2.1 Preprocessing steps of [18F]FDG PET . 20 3.2.2 Statistical analysis . 22 3.3 Resting state functional MRI analysis 22 3.3.1 Preprocessing steps of rs-fMRI 22 3.3.2 Calculations of regional homogeneity 23 3.3.3 Statistical analysis . 23 3.4 Functional connectivity analysis using rs-fMRI. 23 3.4.1 Group independent component analysis . 23 3.4.2 Dynamic functional network connectivity analysis 24 3.4.3 Reproducibility analyses of dynamic functional connectivity states. 26 3.4.4 Graph theory-based topological analysis: network efficiency . 27 3.4.5 Statistical analysis . 28 Chapter 4. Results. 30 4.1 Demographic and clinical characteristics of robust and at-risk groups 30 4.2 Glucose metabolism using [18F]FDG PET . 32 4.2.1 Group comparison in glucose metabolism 32 4.2.2 Relationships between cerebral glucose metabolism and physical and cognitive performances. 35 4.3 Resting-state functional activity using regional homogeneity. 38 4.3.1 Group comparison in regional homogeneity. 38 4.3.2 Relationships between regional homogeneity and physical and cognitive performances 41 4.4 Dynamic functional connectivity of brain networks . 45 4.4.1 Functional connectivity networks . 45 4.4.2 Dynamic functional connectivity states. 53 4.4.3 Validation results of dynamic functional connectivity states 57 4.4.4 Temporal properties of dynamic functional connectivity states . 62 4.4.5 Relationships between dynamic functional connectivity measures and physical and cognitive performances 66 4.4.6 Functional connectivity strengths in states . 70 4.4.7 Dynamic changes of global and local network efficiency 72 Chapter 5. Discussion 75 5.1 Metabolic and functional abnormalities in cognitive frailty 75 5.2 Alterations of dynamic functional connectivity states in cognitive frailty. 79 5.3 Conclusion and limitations of the study . 84 References . 88 국문 초록. 102Docto

Neurophysiological correlates underlying social behavioural adjustment of conformity

[eng] Conformity is the act of changing one’s behaviour to adjust to other human beings. It is a crucial social adaptation that happens when people cooperate, where one sacrifices their own perception, expectations, or beliefs to reach convergence with another person. The aim of the present study was to increase the understanding of the neurophysiological underpinnings regarding the social behavioural adjustment of conformity. We start by introducing cooperation and how it is ingrained in human behaviour. Then we explore the different processes that the brain requires for the social behavioural adjustment of conformity. To engage in this social adaptation, a person needs a self-referenced learning mechanism based on a predictive model that helps them track the prediction errors from unexpected events. Also, the brain uses its monitoring and control systems to encode different value functions used in action selection. The use of different learning models in neuroscience, such as reinforcement learning (RL) algorithms, has been a success story identifying learning systems by means of the mapped activity of different regions in the brain. Importantly, experimental paradigms which has been used to study conformity have not been based in a social interaction setting and, hence, the results, cannot be used to explain an inherently social phenomenon. The main goal of the present thesis is to study the neurophysiological mechanisms underlying the social behavioural adjustment of conformity and its modulation with repeated interaction. To reach this goal, we have first designed a new experimental task where conformity appears spontaneously between two persons and in a reiterative way. This design exposes learning acquisition processes, which require iterative loops, as well as other cognitive control mechanisms such as feedback processing, value-based decision making and attention. The first study shows that people who previously cooperate increase their level of convergence and report a significantly more satisfying overall experience. In addition, participants learning on their counterparts’ behaviour can be explained using a RL algorithm as opposed to when they do not have previously cooperated. In the second study, we have studied the event-related potentials (ERP) and oscillatory power underlying conformity. ERP results show different levels of cognitive engagement that are associated to distinct levels of conformity. Also, time-frequency analysis shows evidence in theta, alpha and beta related to different functions such as cognitive control, attention and, also, reward processing, supporting the idea that convergence between dyads acts as a social reward. Finally, in the third study, we explored the intra- and inter- oscillatory connectivity between electrodes related to behavioural convergence. In intra-brain oscillatory connectivity coherence, we have found two different dynamics related to attention and executive functions in alpha. Also, we have found that the learning about peer’s behaviour as computed using a RL is mediated by theta oscillatory connectivity. Consequently, combined evidence from Study 2 and Study 3 suggests that both cognitive control and learning computations happening in the social behavioural adaptation of conformity are signalled in theta frequency band. The present work is one of the first studies describing, with credible evidence, that conformity, when this occurs willingly and spontaneously rather than induced, engages different brain activity underlying reward-guided learning, cognitive control, and attention.[spa] La conformidad es el acto de cambiar el comportamiento de uno a favor de ajustarnos a otros seres humanos. Se trata de una adaptación crucial que ocurre cuando la gente coopera, donde uno sacrifica su propia percepción, expectativas o creencias en aras de conseguir una convergencia con la otra persona. El objetivo del presente estudio ha sido tratar de aportar a la comprensión de las estructuras neurofisiológicas que soportan un ajuste social como el de la conformidad. En la primera parte de esta tesis comenzamos hablando de la cooperación y lo profundamente arraigada que está en nuestro comportamiento. Más tarde exploramos diferentes procesos que el cerebro requiere en el ajuste social de la conformidad. Así pues, para involucrarse en esta adaptación social, una persona requiere de un mecanismo de aprendizaje auto-referenciado basado en un modelo predictivo que le ayude a seguir el rastro de los errores de predicción que acompañan a los eventos inesperados. Además, el cerebro usa sus sistemas de control y predicción para codificar diferentes funciones de valor usadas en la selección de acción. El uso de diferentes modelos de aprendizaje en neurociencia, como los algoritmos de aprendizaje por refuerzo (RL), han sido una historia de éxito a la hora de identificar los sistemas de aprendizaje a través del mapeo de la actividad de diferentes regiones del cerebro. Es importante destacar que los paradigmas experimentales que se han usado para estudiar la conformidad no se han basado en entornos de interacción social y que, por lo tanto, sus resultados no pueden usarse para explicar un fenómeno inherentemente social. El objetivo principal de la presente tesis es el estudio de los mecanismos neurofisiológicos que fundamentan el comportamiento de ajuste social de la conformidad y su modulación con la interacción repetida. Para alcanzar este objetivo, primero hemos diseñado una nueva tarea experimental en la que la conformidad aparece de forma espontánea entre dos personas y, además, de forma reiterativa. Este diseño permite exponer tanto los procesos de adquisición del aprendizaje, que requieren de ciclos iterativos, así como otros mecanismos de control cognitivo tales como el procesamiento de la retroalimentación, las tomas de decisiones basadas en procesos valorativos y la atención. El primer estudio nos muestra que la gente que coopera previamente incrementa sus niveles de convergencia y reportan significativamente una experiencia generalmente más satisfactoria en el experimento. Adicionalmente, un modelo de RL nos explica que los participantes tratan de aprender del comportamiento de sus parejas en mayor medida si estos han cooperado previamente. En el segundo estudio, hemos estudiado los potenciales relacionados con eventos (ERP) y el poder de las oscilaciones que sustentan la conformidad. Los estudios de ERP muestran diferentes niveles de implicación cognitiva asociados con diferentes niveles de conformidad. Además, los análisis de tiempo-frecuencia muestran evidencia en theta, alfa y beta relacionados con diferentes funciones como el control cognitivo, la atención, y, también, el procesamiento de la recompensa, apoyando la idea de que la convergencia entre díadas actúa como una recompensa social. Finalmente, en el tercer estudio, exploramos la conectividad oscilatoria intra e inter entre electrodos que se pudieran relacionar con la conducta de convergencia. A propósito de la conectividad oscilatoria coherente intra, hemos hallado dos dinámicas relacionadas con la atención y las funciones ejecutivas en alfa. Asimismo, hemos encontrado que el aprendizaje de la conducta de la pareja computada a través de RL está mediada a través de la conectividad oscilatoria de theta. Consecuentemente, la evidencia combinada entre el estudio 2 y el estudio 3 sugiere que conjuntamente el control cognitivo y las computaciones de aprendizaje que ocurren en la conducta de adaptación social de la conformidad están relacionadas con la actividad de la banda de frecuencia theta. Este trabajo constituye uno de los primeros estudios que describen, con evidencia creíble, que la conformidad, cuando ocurre voluntaria y espontáneamente a diferencia cuando esta es inducida, involucra actividad del cerebro que se fundamenta en el aprendizaje guiado por reforzamiento, el control cognitivo y la atención