Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Despite evidence indicating negative consequences of repetitive head impacts (RHIs) on the brain, the long-term effects remain largely unknown. Contact sports, such as football, expose players to multiple collisions. Professional sports players have undergone thousands of concussive and sub-concussive RHIs over their careers. In this study we used structural 3T MRI to evaluate cortical thickness of 86 former NFL players (mean age ± SD = 54.9 ± 7.9 years old) and 24 former professional non-contact sport athletes as controls (mean age ± SD =57.2 ± 6.9 years old). Cortical thickness was compared between groups using FreeSurfer. The NFL players displayed decreased cortical thickness in the right temporal lobe and fusiform gyrus (cluster-wise p-value=0.0003, 90% CI=0.0001-0.0005) and the left pre- and postcentral gyrus (cluster-wise p-value=0.0096, 90% CI=0.0084-0.0109). When looking only at NFL subjects impaired in measurements of mood and behavior (n=36) compared to controls, NFL players displayed a similar but more extensive cluster of decreased cortical thickness in the right temporal lobe and fusiform gyrus (cluster-wise p-value=0.0001, 90% CI=0.0000-0.0002) and in the left supramarginal gyrus and pre- and postcentral gyrus, (cluster-wise p-value=0.0002, 90% CI=0.0000-0.0004). Reduced cortical thickness in NFL players is suggestive of the long-term effects of RHIs. Still, future studies are necessary for examining the time-course of damage and the implications of regional cortical thinning.

O transtorno de identidade de gênero (TIG) carateriza-se pela persistente convicção de pertencer ao sexo oposto. Apesar das diferentes abordagens metodológicas e de inúmeros estudos, sua etiologia ainda permanece desconhecida. Sabe-se da influência de fatores ambientais, hormonais, genéticos e de alterações neuroanatômicas. A literatura em neuroimagem ainda é extremamente restrita, e estudos com foco em espessura cortical inexistem. Achados neuroanatômicos de morfometria baseada em voxels com maior volume de massa cinzenta já foram relatados em regiões ligadas ao circuito neural da senso-percepção. Hipotetizamos que diferenças de espessura cortical estariam localizadas nas regiões desse circuito. Estudamos um par de gêmeos monozigóticos masculinos discordantes para TIG (masculino-para-feminino) aplicando VBM e SBM (FreeSurfer). Evidenciamos maior volume de substância cinzenta e maior espessura cortical na junção tempo-parietal direita, córtex frontal inferior direito e córtex da insula direito no gêmeo TIG-MTF em relação ao seu irmão. O presente estudo agrega o achado de espessura cortical na caracterização das alterações neuroanatômicas do TIG. / Gender Identity Disorder (GID) is characterized by the persistent conviction of belonging to the opposite sex. Despite all the different technical approaches and the several studies performed, its etiology still remains unknown. There is knowledge about the influence of environmental hormonal, genetic and neuroanatomic factors involved. The literature about GID neuroimaging is extremely restrict and there are no studies focusing on cortical thickness. The neuroanatomical findings from Voxel-Based Morphometry (VBM) have reported regions within the sense-perception network with increased grey matter volume. We hypothesized that differences of cortical thickness would be found in the cortical areas of this network. Thus we studied a male monozigotic twin pair discordant for GID (male-to-female) using VBM and SBM (FreeSurfer). We found increased grey matter volume and thicker cortex in the right temporo-parietal junction, right inferior frontal cortex and right insular cortex in the affected twin in comparison to his brother. The present study adds the findings on cortical thickness to the characterization of the neuroanatomic alterations in Gender Identity Disorder.

O transtorno de identidade de gênero (TIG) carateriza-se pela persistente convicção de pertencer ao sexo oposto. Apesar das diferentes abordagens metodológicas e de inúmeros estudos, sua etiologia ainda permanece desconhecida. Sabe-se da influência de fatores ambientais, hormonais, genéticos e de alterações neuroanatômicas. A literatura em neuroimagem ainda é extremamente restrita, e estudos com foco em espessura cortical inexistem. Achados neuroanatômicos de morfometria baseada em voxels com maior volume de massa cinzenta já foram relatados em regiões ligadas ao circuito neural da senso-percepção. Hipotetizamos que diferenças de espessura cortical estariam localizadas nas regiões desse circuito. Estudamos um par de gêmeos monozigóticos masculinos discordantes para TIG (masculino-para-feminino) aplicando VBM e SBM (FreeSurfer). Evidenciamos maior volume de substância cinzenta e maior espessura cortical na junção tempo-parietal direita, córtex frontal inferior direito e córtex da insula direito no gêmeo TIG-MTF em relação ao seu irmão. O presente estudo agrega o achado de espessura cortical na caracterização das alterações neuroanatômicas do TIG. / Gender Identity Disorder (GID) is characterized by the persistent conviction of belonging to the opposite sex. Despite all the different technical approaches and the several studies performed, its etiology still remains unknown. There is knowledge about the influence of environmental hormonal, genetic and neuroanatomic factors involved. The literature about GID neuroimaging is extremely restrict and there are no studies focusing on cortical thickness. The neuroanatomical findings from Voxel-Based Morphometry (VBM) have reported regions within the sense-perception network with increased grey matter volume. We hypothesized that differences of cortical thickness would be found in the cortical areas of this network. Thus we studied a male monozigotic twin pair discordant for GID (male-to-female) using VBM and SBM (FreeSurfer). We found increased grey matter volume and thicker cortex in the right temporo-parietal junction, right inferior frontal cortex and right insular cortex in the affected twin in comparison to his brother. The present study adds the findings on cortical thickness to the characterization of the neuroanatomic alterations in Gender Identity Disorder.

O transtorno de identidade de gênero (TIG) carateriza-se pela persistente convicção de pertencer ao sexo oposto. Apesar das diferentes abordagens metodológicas e de inúmeros estudos, sua etiologia ainda permanece desconhecida. Sabe-se da influência de fatores ambientais, hormonais, genéticos e de alterações neuroanatômicas. A literatura em neuroimagem ainda é extremamente restrita, e estudos com foco em espessura cortical inexistem. Achados neuroanatômicos de morfometria baseada em voxels com maior volume de massa cinzenta já foram relatados em regiões ligadas ao circuito neural da senso-percepção. Hipotetizamos que diferenças de espessura cortical estariam localizadas nas regiões desse circuito. Estudamos um par de gêmeos monozigóticos masculinos discordantes para TIG (masculino-para-feminino) aplicando VBM e SBM (FreeSurfer). Evidenciamos maior volume de substância cinzenta e maior espessura cortical na junção tempo-parietal direita, córtex frontal inferior direito e córtex da insula direito no gêmeo TIG-MTF em relação ao seu irmão. O presente estudo agrega o achado de espessura cortical na caracterização das alterações neuroanatômicas do TIG. / Gender Identity Disorder (GID) is characterized by the persistent conviction of belonging to the opposite sex. Despite all the different technical approaches and the several studies performed, its etiology still remains unknown. There is knowledge about the influence of environmental hormonal, genetic and neuroanatomic factors involved. The literature about GID neuroimaging is extremely restrict and there are no studies focusing on cortical thickness. The neuroanatomical findings from Voxel-Based Morphometry (VBM) have reported regions within the sense-perception network with increased grey matter volume. We hypothesized that differences of cortical thickness would be found in the cortical areas of this network. Thus we studied a male monozigotic twin pair discordant for GID (male-to-female) using VBM and SBM (FreeSurfer). We found increased grey matter volume and thicker cortex in the right temporo-parietal junction, right inferior frontal cortex and right insular cortex in the affected twin in comparison to his brother. The present study adds the findings on cortical thickness to the characterization of the neuroanatomic alterations in Gender Identity Disorder.

The doctoral dissertation: Searching for pathomechanisms of late-life minor depression – a combined MRI, biomarker and meta-analytic study was one of the first studies investigating the underlying pathophysiology of minor depression. The dissertation comprises a systematic review of the prevalence rates of minor depression, two meta-analyses of peripheral BDNF changes in major depressive disorder, as well as two original studies investigating serum BDNF, S100B and NSE levels and gray matter changes in minor depression. The limitations of studies and proposed improvements to the study design are discussed extensively.:1. INTRODUCTION 1.1 Motivation 1.1.1 Minor depression in the spectrum of psychiatric disorders 1.1.2 Minor depression is prevalent but unrecognized. 1.2 Theoretical background 1.2.1 Overview of depression hypotheses 1.2.2 Neurotrophic hypothesis of depressive disorders 1.2.3 Glial hypothesis of depressive disorders 1.2.4 Structural neuroimaging changes in major depression 1.3. Rationale and hypotheses of the empirical studies 1.3.1 Research questions 1.3.2 Research hypotheses 2. EMPIRICAL STUDIES 2.1 The prevalence of minor depression in the late life 2.2 The meta-analysis of BDNF changes in mood disorders 2.3 The meta-analysis of BDNF changes following ECT in depression 2.4 Serum biomarkers in minor depression 2.5 Structural brain imaging in minor depression 3. GENERAL DISCUSSION 3.1 Summary of results 3.2 Implications for research 3.3 Implications for clinical studies SUMMARY REFERENCES APPENDIX A: DECLARATION OF CONTRIBUTION APPENDIX B: STATEMENT OF AUTHORSHIP APPENDIX C: CURRICULUM VITAEAPPENDIX D: ACADEMIC CONTRIBUTIONS APPENDIX E: ACKNOWLEDGMENT

Finding neural correlates of intelligence and cognitive abilities in the developing brain during childhood may be important in many ways, such as predicting and understanding educational abilities or making clinical evaluations of patients. Even if substantial contemporary research has established relationships between brain structures and general intelligence, little is known about the lingual gyri and their links to IQ. In this thesis it is examined (1) whether cortical thickness in the right and left lingual gyri is associated with different levels of IQ in childrenand (2) if the rate of change in cortical thickness located in the lingual gyri is associated with change in Performance IQ (PIQ). Neuroimaging data originated from a study by Solé-Casals and colleagues (2019) as well as a dataset from a study by Suárez-Pellicioni and colleagues(2019). Both datasets were downloaded from the OpenNeuro library of brain imaging data. Neuroimaging metrics of twenty-nine boys of approximately twelve years of age were utilizedto test the hypothesis that higher IQ is related to thinner cortical thickness in lingual gyri. Neuroimaging metrics of twenty-one girls and fifteen boys under fourteen years of age utilized to examine if the rate of change in cortical thickness is related to a change in Performance IQ.Results revealed that high IQ was related to thinner cortical thickness at the age of twelve. Further results indicated that rate of thinning of the cortex in the lingual gyri is correlated to change in Performance IQ. The present thesis adds to the growing evidence that regional cortical thickness and change of cortical thickness are relevant biomarkers for intelligence. Future research with larger sample sizes and longitudinal design with additional points in timemight be needed to confirm the results of the present thesis.

Identification of human or nonhuman skeletal remains is important in assisting the police and law enforcement officers for the investigation of forensic cases. Identification of bone can be difficult, especially in fragmented remains. It has been reported that 25 to 30% of medicolegal cases, which involved nonhuman skeletal remains have been mistaken for human. In such cases, histomorphometric method was used to identify human and nonhuman skeletal remains. However, literature has shown that histomorphometric data for human and nonhuman bone were insufficient. Additionally, age estimation in bone may help in the identification of human individual, which can be done by using a histomorphometric method. Age estimation is based on bone remodeling process, where microstructural parameters have strong correlations with age. Literature showed that age estimation has been done on the American and European populations. However, little work has been done in the Asian population. The aims of this project were thus, to identify human and nonhuman bone, and to estimate age in human bones by using histomorphometric analysis. In this project, 64 human bones and 65 animal bones were collected from the mortuary of the Universiti Kebangsaan Malaysia Medical Centre and the Zoos in Malaysia, respectively. A standard bone preparation was used to prepare human and nonhuman bone thin sections for histomorphometric assessment. Assessments were made on the microstructural parameters such as cortical thickness, medullary cavity diameter, osteon count, osteon diameter, osteon area, osteon perimeter, Haversian canal diameter, Haversian canal area, Haversian canal perimeter, and Haversian lamella count per osteon by using image analysis, and viewed under a transmitted light microscope. The microstructural measurements showed significant differences between human and nonhuman samples. The discriminant functions showed correct classification rates for 81.4% of cases, and the accuracy of identification was 96.9% for human and 66.2% for animal. Human age estimation showed a standard error of estimate of 10.41 years, comparable with those in the literature. This study project offers distinct advantages over currently available histomorphometric methods for human and nonhuman identification and human age estimation. This will have significant implications in the assessment of fragmentary skeletal and forensic population samples for identification purposes.

Temporomandibular disorders (TMD) are a family of prevalent chronic pain disorders affecting masticatory muscles and/or the temporomandibular joint. There is no unequivocally recognized peripheral aetiology for idiopathic TMD. The central nervous system (CNS) may initiate and/or maintain the pain in idiopathic TMD due to sustained or long-term nociceptive input that induces maladaptive brain plasticity, and/or to inherent personality-related factors that may reduce the brain's capacity to modulate nociceptive activity. The main aim of this thesis is to determine whether there are structural neural abnormalities in patients with TMD, and whether these abnormalities are related to TMD pain characteristics, or to neuroticism. The specific aims are to delineate in TMD: (1) gray matter (GM) brain abnormalities and the contribution of pain and neuroticism to abnormalities; (2) the contribution of abnormal brain GM aging in focal cortical regions associated with nociceptive processes; and (3) abnormalities in brain white matter and trigeminal nerve and the contribution of pain. In groups of 17 female patients with TMD and 17 age- and sex- matched controls, magnetic resonance imaging revealed that patients with TMD had: (1) thicker cortex in the somatosensory, ventrolateral prefrontal and frontal polar cortices than controls, (2) cortical thickness in motor and cognitive areas that was negatively related to pain intensity, orbitofrontal cortical thickness that was negatively correlated to pain unpleasantness, and thalamic GM volume correlated to TMD duration, (3) an abnormal relationship between neuroticism and orbitofrontal cortical thickness, (4) abnormal GM aging in nociceptive, modulatory and motor areas, (5) widespread abnormalities in white matter tracts in the brain related to sensory, motor and cognitive functions, (6) reduced trigeminal nerve integrity related to pain duration, and (7) abnormal connectivity in cognitive and modulatory brain regions. In sum, this thesis demonstrates for the first time abnormalities in both peripheral nerve and CNS in patients with TMD.