주요 우울 장애의 음성 기반 분석: 연속적인 발화의 음향적 변화를 중심으로

학위논문(박사) -- 서울대학교대학원 : 융합과학기술대학원 융합과학부(디지털정보융합전공), 2023. 2. 이교구.Major depressive disorder (commonly referred to as depression) is a common disorder that affects 3.8% of the world's population. Depression stems from various causes, such as genetics, aging, social factors, and abnormalities in the neurotransmitter system; thus, early detection and monitoring are essential. The human voice is considered a representative biomarker for observing depression; accordingly, several studies have developed an automatic depression diagnosis system based on speech. However, constructing a speech corpus is a challenge, studies focus on adults under 60 years of age, and there are insufficient medical hypotheses based on the clinical findings of psychiatrists, limiting the evolution of the medical diagnostic tool. Moreover, the effect of taking antipsychotic drugs on speech characteristics during the treatment phase is overlooked. Thus, this thesis studies a speech-based automatic depression diagnosis system at the semantic level (sentence). First, to analyze depression among the elderly whose emotional changes do not adequately reflect speech characteristics, it developed the mood-induced sentence to build the elderly depression speech corpus and designed an automatic depression diagnosis system for the elderly. Second, it constructed an extrapyramidal symptom speech corpus to investigate the extrapyramidal symptoms, a typical side effect that can appear from an antipsychotic drug overdose. Accordingly, there is a strong correlation between the antipsychotic dose and speech characteristics. The study paved the way for a comprehensive examination of the automatic diagnosis system for depression.주요 우울 장애 즉 흔히 우울증이라고 일컬어지는 기분 장애는 전 세계인 중 3.8%에 달하는 사람들이 겪은바 있는 매우 흔한 질병이다. 유전, 노화, 사회적 요인, 신경전달물질 체계의 이상등 다양한 원인으로 발생하는 우울증은 조기 발견 및 일상 생활에서의 관리가 매우 중요하다고 할 수 있다. 인간의 음성은 우울증을 관찰하기에 대표적인 바이오마커로 여겨져 왔으며, 음성 데이터를 기반으로한 자동 우울증 진단 시스템 개발을 위한 여러 연구들이 진행되어 왔다. 그러나 음성 말뭉치 구축의 어려움과 60세 이하의 성인들에게 초점이 맞추어진 연구, 정신과 의사들의 임상 소견을 바탕으로한 의학적 가설 설정의 미흡등의 한계점을 가지고 있으며, 이는 의료 진단 기구로 발전하는데 한계점이라고 할 수 있다. 또한, 항정신성 약물의 복용이 음성 특징에 미칠 수 있는 영향 또한 간과되고 있다. 본 논문에서는 위의 한계점들을 보완하기 위한 의미론적 수준 (문장 단위)에서의 음성 기반 자동 우울증 진단에 대한 연구를 시행하고자 한다. 우선적으로 감정의 변화가 음성 특징을 잘 반영되지 않는 노인층의 우울증 분석을 위해 감정 발화 문장을 개발하여 노인 우울증 음성 말뭉치를 구축하고, 문장 단위에서의 관찰을 통해 노인 우울증 군에서 감정 문장 발화가 미치는 영향과 감정 전이를 확인할 수 있었으며, 노인층의 자동 우울증 진단 시스템을 설계하였다. 최종적으로 항정신병 약물의 과복용으로 나타날 수 있는 대표적인 부작용인 추체외로 증상을 조사하기 위해 추체외로 증상 음성 말뭉치를 구축하였고, 항정신병 약물의 복용량과 음성 특징간의 상관관계를 분석하여 우울증의 치료 과정에서 항정신병 약물이 음성에 미칠 수 있는 영향에 대해서 조사하였다. 이를 통해 주요 우울 장애의 영역에 대한 포괄적인 연구를 진행하였다.Chapter 1 Introduction 1 1.1 Research Motivations 3 1.1.1 Bridging the Gap Between Clinical View and Engineering 3 1.1.2 Limitations of Conventional Depressed Speech Corpora 4 1.1.3 Lack of Studies on Depression Among the Elderly 4 1.1.4 Depression Analysis on Semantic Level 6 1.1.5 How Antipsychotic Drug Affects the Human Voice? 7 1.2 Thesis objectives 9 1.3 Outline of the thesis 10 Chapter 2 Theoretical Background 13 2.1 Clinical View of Major Depressive Disorder 13 2.1.1 Types of Depression 14 2.1.2 Major Causes of Depression 15 2.1.3 Symptoms of Depression 17 2.1.4 Diagnosis of Depression 17 2.2 Objective Diagnostic Markers of Depression 19 2.3 Speech in Mental Disorder 19 2.4 Speech Production and Depression 21 2.5 Automatic Depression Diagnostic System 23 2.5.1 Acoustic Feature Representation 24 2.5.2 Classification / Prediction 27 Chapter 3 Developing Sentences for New Depressed Speech Corpus 31 3.1 Introduction 31 3.2 Building Depressed Speech Corpus 32 3.2.1 Elements of Speech Corpus Production 32 3.2.2 Conventional Depressed Speech Corpora 35 3.2.3 Factors Affecting Depressed Speech Characteristics 39 3.3 Motivations 40 3.3.1 Limitations of Conventional Depressed Speech Corpora 40 3.3.2 Attitude of Subjects to Depression: Masked Depression 43 3.3.3 Emotions in Reading 45 3.3.4 Objectives of this Chapter 45 3.4 Proposed Methods 46 3.4.1 Selection of Words 46 3.4.2 Structure of Sentence 47 3.5 Results 49 3.5.1 Mood-Inducing Sentences (MIS) 49 3.5.2 Neutral Sentences for Extrapyramidal Symptom Analysis 49 3.6 Summary 51 Chapter 4 Screening Depression in The Elderly 52 4.1 Introduction 52 4.2 Korean Elderly Depressive Speech Corpus 55 4.2.1 Participants 55 4.2.2 Recording Procedure 57 4.2.3 Recording Specification 58 4.3 Proposed Methods 59 4.3.1 Voice-based Screening Algorithm for Depression 59 4.3.2 Extraction of Acoustic Features 59 4.3.3 Feature Selection System and Distance Computation 62 4.3.4 Classification and Statistical Analyses 63 4.4 Results 65 4.5 Discussion 69 4.6 Summary 74 Chapter 5 Correlation Analysis of Antipsychotic Dose and Speech Characteristics 75 5.1 Introduction 75 5.2 Korean Extrapyramidal Symptoms Speech Corpus 78 5.2.1 Participants 78 5.2.2 Recording Process 79 5.2.3 Extrapyramidal Symptoms Annotation and Equivalent Dose Calculations 80 5.3 Proposed Methods 81 5.3.1 Acoustic Feature Extraction 81 5.3.2 Speech Characteristics Analysis recording to Eq.dose 83 5.4 Results 83 5.5 Discussion 87 5.6 Summary 90 Chapter 6 Conclusions and Future Work 91 6.1 Conclusions 91 6.2 Future work 95 Bibliography 97 초 록 121박

Feature selection in detection of adverse drug reactions from the Health Improvement Network (THIN) database

Adverse drug reaction (ADR) is widely concerned for public health issue. ADRs are one of most common causes to withdraw some drugs from market. Prescription event monitoring (PEM) is an important approach to detect the adverse drug reactions. The main problem to deal with this method is how to automatically extract the medical events or side effects from high-throughput medical events, which are collected from day to day clinical practice. In this study we propose a novel concept of feature matrix to detect the ADRs. Feature matrix, which is extracted from big medical data from The Health Improvement Network (THIN) database, is created to characterize the medical events for the patients who take drugs. Feature matrix builds the foundation for the irregular and big medical data. Then feature selection methods are performed on feature matrix to detect the significant features. Finally the ADRs can be located based on the significant features. The experiments are carried out on three drugs: Atorvastatin, Alendronate, and Metoclopramide. Major side effects for each drug are detected and better performance is achieved compared to other computerized methods. The detected ADRs are based on computerized methods, further investigation is needed.Comment: International Journal of Information Technology and Computer Science (IJITCS), in print, 201

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification

3D Pharmacophoric Similarity improves Multi Adverse Drug Event Identification in Pharmacovigilance

Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining

Mathematical Modelling and Machine Learning Methods for Bioinformatics and Data Science Applications

Mathematical modeling is routinely used in physical and engineering sciences to help understand complex systems and optimize industrial processes. Mathematical modeling differs from Artificial Intelligence because it does not exclusively use the collected data to describe an industrial phenomenon or process, but it is based on fundamental laws of physics or engineering that lead to systems of equations able to represent all the variables that characterize the process. Conversely, Machine Learning methods require a large amount of data to find solutions, remaining detached from the problem that generated them and trying to infer the behavior of the object, material or process to be examined from observed samples. Mathematics allows us to formulate complex models with effectiveness and creativity, describing nature and physics. Together with the potential of Artificial Intelligence and data collection techniques, a new way of dealing with practical problems is possible. The insertion of the equations deriving from the physical world in the data-driven models can in fact greatly enrich the information content of the sampled data, allowing to simulate very complex phenomena, with drastically reduced calculation times. Combined approaches will constitute a breakthrough in cutting-edge applications, providing precise and reliable tools for the prediction of phenomena in biological macro/microsystems, for biotechnological applications and for medical diagnostics, particularly in the field of precision medicine

Characterizing cognitive deficits and dementia in an aging urban population in India.

Rapid rise in the population of older adults in India will lead to the need for increased health care services related to diagnosis, management, and long-term care for those with dementia and cognitive impairment. A direct approach for service provision through memory clinics can be an effective, successful, and sustaining means of delivering specialized health care services. We have established a memory clinic in Mumbai, India by employing the diverse clinical skills available in Indian academic institutions, diagnostic and research expertise of clinicians and psychologists, and the support of the U.S. National Institutes of Health. Our project involved recruitment of patients, clinical and neuropsychological assessment, and standardized diagnostic procedures, demonstrating the feasibility of using research methods to develop a memory clinic. In this paper, we describe the development of a community-based memory clinic in urban India, including linguistic and cultural factors and present detailed results, including diagnostic characterization, on 194 subjects with various stages of cognitive deficits. Our findings support the feasibility of developing a memory clinic in a public hospital and successful use of research diagnostic criteria to categorize cognitive deficits observed in this population, which may be used to inform the development of other such clinics

The Application of Unsupervised Clustering Methods to Alzheimer’s Disease

Clustering is a powerful machine learning tool for detecting structures in datasets. In the medical field, clustering has been proven to be a powerful tool for discovering patterns and structure in labeled and unlabeled datasets. Unlike supervised methods, clustering is an unsupervised method that works on datasets in which there is no outcome (target) variable nor is anything known about the relationship between the observations, that is, unlabeled data. In this paper, we focus on studying and reviewing clustering methods that have been applied to datasets of neurological diseases, especially Alzheimer’s disease (AD). The aim is to provide insights into which clustering technique is more suitable for partitioning patients of AD based on their similarity. This is important as clustering algorithms can find patterns across patients that are difficult for medical practitioners to find. We further discuss the implications of the use of clustering algorithms in the treatment of AD. We found that clustering analysis can point to several features that underlie the conversion from early-stage AD to advanced AD. Furthermore, future work can apply semi-clustering algorithms on AD datasets, which will enhance clusters by including additional information

Electrophysiological Investigation of Auditory Mismatch Negativity: A Brain-Based Biomarker of N-Methyl-D-Aspartate Signalling

Inconsistent reports on the therapeutic efficacy of increasing synaptic glycine concentration have raised doubt as to the benefit of N-methyl-D-aspartate receptor (NMDAr) mediated treatments for schizophrenia. Categorising individuals based on broad diagnostic criteria does not appear to adequately identify individuals who will benefit from such treatments. Mismatch negativity (MMN) may be a suitable biomarker of NMDAr function, to help clarify the neurobiological relationship between pharmacological intervention and clinical treatment efficacy. MMN is an auditory event-related potential elicited following the presentation of a deviant stimulus, when it violates an established sequence stored in echoic memory. MMN is a robust deficit in schizophrenia and is categorised as a physiological element in the Cognitive Systems domain of the Research Domain Criteria framework. However, few studies have examined direct pharmacological modulation of MMN in schizophrenia patients. The aim of this thesis was to determine the nature of the relationship between MMN and NMDAr function, to inform the relative utility of MMN as a biomarker of NMDAr-mediated improvements in clinical symptoms in schizophrenia. To achieve this aim, three separate empirical studies were performed..