Aus dem Zentralinstitut für Seelische Gesundheit der Medizinischen Fakultät Mannheim (Direktor: Prof. Dr. med. Andreas Meyer-Lindenberg) Exploration of the biological mechanisms in neuropsychiatric disorders using multimodal imaging Inauguraldissertation zur Erlangung des Doctor scientiarum humanarum (Dr. sc. hum.) der Medizinischen Fakultät Mannheim der Ruprecht-Karls-Universität zu Heidelberg vorgelegt von Guo-Ying Wang aus Shanxi 2017 Dekan: Herr Prof. Dr. rer. nat. Dr. med. Sergij Goerdt Referentin: Frau apl. Prof. Dr.Gabriele Ende Table of contents ABBREVIATIONS ............................................................................................. III CHAPTER I. GENERAL INTRODUCTION .................................................... 1 1 OUTLINE .......................................................................................................... 2 2 STUDY BACKGROUND AND IMAGING IMPLICATION ......................... 4 2.1 Alcohol addiction ....................................................................................................... 4 2.1.1 Alcohol dependence, abstinence, withdrawal ................................................... 4 2.1.2 Underlying neurochemical mechanisms ........................................................... 6 2.1.3 MRS neurometabolite level changes in withdrawal and abstinence ................ 7 2.1.4 Partial recovery of brain volumes with abstinence ........................................... 8 2.1.5 The potential link between neurometabolites and brain volume recovery ....... 9 2.2 Borderline Personality Disorder .............................................................................. 9 2.2.1 Clinical picture .................................................................................................. 9 2.2.2 Impulsivity and its measurement .................................................................... 10 2.2.3 Neurochemical basis of impulsivity ............................................................... 11 2.2.4 Neural correlates of impulsivity ..................................................................... 11 2.2.5 Associations of regional GABA with BOLD ................................................. 13 3 NEUROIMAGING TECHNICAL BACKGROUND .................................... 14 3.1 Structural MRI (sMRI) ........................................................................................... 14 3.1.1 The physical basis of sMRI ............................................................................ 14 3.1.2 Voxel-based analysis ...................................................................................... 15 3.1.3 Surface-based analysis .................................................................................... 17 3.2 1H MRS ..................................................................................................................... 19 3.2.1 The physical basis of 1H MRS ........................................................................ 20 3.2.2 1H MRS of Glu, Gln, GABA .......................................................................... 22 3.2.3 Quantification of metabolites ......................................................................... 23 3.3 Functional MRI ........................................................................................................ 25 3.3.1 The physical basis of functional MRI ............................................................. 25 3.3.2 The physiological basis of fMRI .................................................................... 26 3.3.3 The neural signalling basis of fMRI ............................................................... 27 3.3.4 Data analysis ................................................................................................... 28 4 AIMS OF THE THESIS ................................................................................. 30 i CHAPTER II. EMPIRICAL STUDIES ............................................................ 33 5 Longitudinal mapping of gyral and sulcal patterns of cortical thickness and brain volume regain during early alcohol abstinence .............................................................. 34 6 Negative association between MR-spectroscopic glutamate markers and grey matter volume after alcohol withdrawal in the hippocampus: a translational study in humans and rats ............................................................................................................................... 58 7 ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder ........................................................................................................... 91 CHAPTER III. GENERAL DISCUSSION .................................................... 126 8 GENERAL DISCUSSION ............................................................................ 127 8.1 Brain recovery during early alcohol abstinence ................................................. 127 8.1.1 Summary of the findings .............................................................................. 127 8.1.2 Limitation ..................................................................................................... 129 8.1.3 Outlook ......................................................................................................... 130 8.2 Biological mechanisms underlying impulsivity in BPD ..................................... 130 8.2.1 Summary of the findings .............................................................................. 130 8.2.2 Limitations .................................................................................................... 132 8.2.3 Future directions ........................................................................................... 133 9 SUMMARY .................................................................................................. 134 10 REFERENCE ................................................................................................ 136 CURRICULUM VITAE ................................................................................... 146 PUBLICATIONS .............................................................................................. 147 ACKNOWLEDGEMENT ................................................................................. 148 ii Abbreviations ADS Alcohol Dependence Scale ADP Alcohol Dependent Patients ADHD Attention-Deficit/Hyperactivity Disorder BIS Barratt Impulsiveness Scale CMRO2 Blood Oxygen Consumption BOLD Blood Oxygen Level Dependent BPD Borderline Personality Disorder CBF Cerebral Blood Flow CSF Cerebrospinal Fluid CIE Chronic Intermittent Exposure CTh Cortical Thickness Cr Creatine DTI Diffusion Tensor Imaging EPI Echo Planar Imaging FDR False Discovery Rate FWE Family Wise Error Rates FISP Fast Imaging with Steady Precession FWHM Full Width at Half Maximum fMRI Functional Magnetic Resonance Imaging GABA γ-aminobutyric acid GCA Gaussian Classifier Array GLM General Linear Model Glu Glutamate Gln Glutamine GM Gray Matter HCs Healthy Controls HRF Hemodynamic Response Function IFC Inferior Frontal Cortex MRSI Magnetic Resonance Spectroscopic Imaging MRS Magnetic Resonance Spectroscopy MEGA-PRESS MEscher-GArwood Point REsolved Spectroscopy MNI Montreal Neurological Institute MANCOVA Multivariate Analysis with Covariates NAA N-acetylaspartate Acid NMDA N-methyl-D-aspartate OCDS Obsessive Compulsive Drinking Scale PRESS Point-RESolved Spectroscopy PFC Prefrontal Cortex RF Radio Frequency ROIs Regions of Interest sMRI Structural Magnetic Resonance Imaging SMA Supplementary Motor Area SA Surface Area SBM Surface-based morphometry eTIV Estimated Total Intracranial Volume VBM Voxel-based morphometry iii TP Time Point WM White Matter iv CHAPTER I. GENERAL INTRODUCTION 1 GENERAL INTRODUCTION 1 Outline It has been increasingly recognized that combining multimodal brain imaging data promotes a more comprehensive understanding of biological processes in the brain and pathologies in mental disorders, which can also uncover hidden features in unimodal imaging (Calhoun & Sui, 2016). Moreover, the joint information across these modalities reveals crucial information, such as the impact of brain neurochemistry on brain structures and functions, the effect of psychopathology, and the relationship between those alterations and cognitive deficits. Thus, the present doctoral thesis focused on the multimodal imaging investigation of brain mechanisms in alcohol addiction (project I) and borderline personality disorder (BPD) (project II). In brief, the emphasis of thesis was on the association of brain neurochemistry with: 1) the brain volume recovery within the first two weeks of abstinence in alcohol dependent patients (ADP) and the rat model. 2) brain functions related to impulsivity in patients with BPD. Three imaging measures of particular interest were applied in the frame of the thesis: Magnetic Resonance Spectroscopy (MRS) to measure the neurochemical levels in the brain tissues; structural Magnetic Resonance Imaging (sMRI) to estimate brain volumes and cortical thickness; functional Magnetic Resonance Imaging (fMRI) to examine hemodynamic response related to neural activity and functional connectivity during impulse control. The general introduction part (chapter I) consists of the following points: 1) the clinical background knowledge and literature review of imaging findings related to those two