A Review on the Cognitive Neuroscience of Autism

With increased recognition in the media, heightened prevalence, and advances in research technologies, investigation into the causes of autism has broadened in recent years. Studies at the molecular, structural, and behavioral levels have resulted in significant findings, linking autism to qualitative differences in neurological function and an alteration of early development. Familial aggregation of autism demonstrate a strong genetic factor, although genetics can not completely account for its pathogenesis. Studies show autism having one of the most complex pathologies among neurodevelopmental disorders. Future studies applying sophisticated methodologies in new areas may shed light on current mysteries surrounding the disorder

REGISTRATION AND SEGMENTATION OF BRAIN MR IMAGES FROM ELDERLY INDIVIDUALS

Quantitative analysis of the MRI structural and functional images is a fundamental component in the assessment of brain anatomical abnormalities, in mapping functional activation onto human anatomy, in longitudinal evaluation of disease progression, and in computer-assisted neurosurgery or surgical planning. Image registration and segmentation is central in analyzing structural and functional MR brain images. However, due to increased variability in brain morphology and age-related atrophy, traditional methods for image registration and segmentation are not suitable for analyzing MR brain images from elderly individuals. The overall goal of this dissertation is to develop algorithms to improve the registration and segmentation accuracy in the geriatric population. The specific aims of this work includes 1) to implement a fully deformable registration pipeline to allow a higher degree of spatial deformation and produce more accurate deformation field, 2) to propose and validate an optimum template selection method for atlas-based segmentation, 3) to propose and validate a multi-template strategy for image normalization, which characterizes brain structural variations in the elderly, 4) to develop an automated segmentation and localization method to access white matter integrity (WMH) in the elderly population, and finally 5) to study the default-mode network (DMN) connectivity and white matter hyperintensity in late-life depression (LLD) with the developed registration and segmentation methods. Through a series of experiments, we have shown that the deformable registration pipeline and the template selection strategies lead to improved accuracy in the brain MR image registration and segmentation, and the automated WMH segmentation and localization method provides more specific and more accurate information about volume and spatial distribution of WMH than traditional visual grading methods. Using the developed methods, our clinical study provides evidence for altered DMN connectivity in LLD. The correlation between WMH volume and DMN connectivity emphasizes the role of vascular changes in LLD's etiopathogenesis

Ventral striatal fMRI in affective and psychotic disorders: a transdiagnostic approach using resting state and task functional resonance imaging, clinical and genetic data

The effective clinical management of psychotic and affective disorders still represents a major challenge in psychiatry. Due to the high prevalence of these disorders and the subjective suffering, they cause a massive burden for the health system and society, and improvement in diagnostic and treatment strategies is urgently sought. In consideration of the literature, there are two promising avenues for this endeavour: On the one hand, particularly regarding schizophrenia (SCZ), early detection of high risk states or disease manifestation is crucial for the eventual treatment success. On the other hand, the heterogeneity of psychotic and affective disorders as well as blurry boundaries between the associated clinical syndromes often leave the diagnosis, which is the foundation of an evidence based treatment selection, on shaky ground. At the neurobiological level, several lines of evidence underline the role of the ventral striatum, particularly the nucleus accumbens (NAcc), for the pathophysiology of psychosis and more generally reward processing. Disturbed reward processing in turn is related to anhedonia, a core symptom of major depressive disorder (MDD), bipolar disorder (BD) and also SCZ. Against this background, this thesis aimed to unravel the potential of ventral striatal brain circuits as a source of biomarkers of psychotic and affective disorders. For this purpose, two sub-studies were performed: Firstly, we studied the impact of a validated polygenic risk score (PGRS) for SCZ, childhood adversity (CA) as widespread environmental factor and their interaction on resting state (RS) fMRI measures and NAcc seed connectivity in 253 healthy controls (HC) and compared these patterns with fully expressed disease in 23 patients with SCZ. Consistent with previous reports, SCZ patients showed strong regional functional connectivity density (FCD) increases in subcortical nuclei, particularly in the NAcc, compared with HC. Furthermore, in the HC sample, a a positive association between the FCD of the NAcc and both the PGRS and the interaction between PGRS and CA was found. Fine-mapping exhibited increased connectivity between the NAcc and visual association cortices for high levels of both PGRS and the PGRS-by-CA interaction. Taken together, this study showed that in HC, high PGRS for SCZ affects both global and regionally specific connectivity of the NAcc in a similar pattern as observed in SCZ patients, and that this effect was already amplified even by a history of very mild CA. This latter observation strengthened the notion that environmental factors need consideration in imaging genetics studies. Secondly, we examined the neural underpinnings of reward anticipation (RA) in MDD, BD and SCZ as studied by fMRI. This study revealed that aberrantly low striatal activation during RA is typical of SCZ, whereas the response of this network appeared to be preserved in MDD and BD. Interestingly, two further large-scale brain networks involved in RA – the salience network and the default mode network showed both transdiagnostic and further disease-specific alterations: While the salience network was found to be impaired primarily in SCZ patients, all patient groups revealed deficits in the suppression of the default mode network. Among hub regions of all three networks that were further differentiated in an early and a late response period, levels of anhedonia were correlated with the extent of the (early) hippocampal deactivation failure across diagnostic boundaries. In sum, both investigations confirm the possibility to use fMRI to probe the functional status of the ventral striatum. The first study underlines the centrality of striatal regions in the pahophysiology of psychosis as these alterations already emerged in healthy individuals at high genetic risk for developing SCZ, particularly when including unspecific environmental risk to the model. Hyperconnectivity of this region in SCZ during the resting state matched with a blunted response during the RA task. The latter studyshowed that at least two further large-scale brain networks are impaired in both psychotic and affective disorders during RA, indicating a potential of reward processing as a source of imaging phenotypes or biomarkers to characterize patients of the respective disease spectrum

Conjoint and dissociated structural and functional abnormalities in first-episode drug-naive patients with major depressive disorder: a multimodal meta-analysis

Published MRI evidence of structural and resting-state functional brain abnormalities in MDD has been inconsistent. To eliminate interference by repeated disease episodes and antidepressant treatment, we conducted the first multimodal voxel-wise meta-analysis of studies of voxel-based morphometry (VBM) and the amplitude of low-frequency fluctuation (ALFF) in first-episode drug-naive MDD patients, using the Seed-based d Mapping method (SDM). Fifteen VBM data sets and 11 ALFF data sets were included. SDM-based multimodal meta-analysis was used to highlight brain regions with both structural and functional abnormalities. This identified conjoint structural and functional abnormalities in left lateral orbitofrontal cortex and right supplementary motor area, and also dissociated abnormalities of structure (decreased grey matter in right dorsolateral prefrontal cortex and right inferior temporal gyrus; increased grey matter in right insula, right putamen, left temporal pole, and bilateral thalamus) and function (increased brain activity in left supplementary motor area, left parahippocampal gyrus, and hippocampus; decreased brain activity in right lateral orbitofrontal cortex). This study reveals a complex pattern of conjoint and dissociated structural and functional abnormalities, supporting the involvement of basal ganglia-thalamocortical circuits, representing emotional, cognitive and psychomotor abnormalities, in the pathophysiology of early-stage MDD. Specifically, this study adds to Psychoradiology, an emerging subspecialty of radiology, which seems primed to play a major clinical role in guiding diagnostic and treatment planning decisions in patients with mental disorder

A Perspective on the Potential Role of Neuroscience in the Court

This Article presents some lessons learned while offering expert testimony on neuroscience in courts. As a biomedical investigator participating in cutting-edge research with clinical and mentoring responsibilities, Dr. Ruben Gur, Ph.D., became involved in court proceedings rather late in his career. Based on the success of Dr. Gur and other research investigators of his generation, who developed and validated advanced methods for linking brain structure and function to behavior, neuroscience findings and procedures became relevant to multiple legal issues, especially related to culpability and mitigation. Dr. Gur found himself being asked to opine in cases where he could contribute expertise on neuropsychological testing and structural and functional neuroimaging. Most of his medical-legal consulting experience has been in capital cases because of the elevated legal requirement for thorough mitigation investigations in such cases, and his limited availability due to his busy schedule as a full-time professor and research investigator who runs the Brain and Behavior Lab at the University of Pennsylvania (“Penn”). Courtroom testimony, however, has not been a topic of his research and so he has not published extensively on the issues in peer-reviewed literature

Early Life Stress Enhancement of Limbic Epileptogenesis in Adult Rats: Mechanistic Insights

BACKGROUND: Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life 'programming' of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week old Wistar rats, previously exposed on postnatal days 2-14 to either maternal separation stress (MS) or control brief early handling (EH), underwent rapid amygdala kindling. We measured seizure-induced serum CORT levels and post-kindling neurogenesis (using BrdU). Three weeks post-kindling, rats were euthanized for histology of the hippocampal CA3c region (pyramidal cell counts) and dentate gyrus (DG) (to count BrdU-labelled cells and measure mossy fibre sprouting). As in our previous studies, rats exposed to MS had accelerated kindling rates in adulthood. Female MS rats had heightened CORT responses during and after kindling (p<0.05), with a similar trend in males. In both sexes total CA3c pyramidal cell numbers were reduced in MS vs. EH rats post-kindling (p = 0.002). Dentate granule cell neurogenesis in female rats was significantly increased post-kindling in MS vs. EH rats. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that early life stress results in enduring enhancement of HPA axis responses to limbic seizures, with increased hippocampal CA3c cell loss and augmented neurogenesis, in a sex-dependent pattern. This implicates important candidate mechanisms through which early life stress may promote vulnerability to limbic epileptogenesis in rats as well as to human MTLE and its associated psychiatric disorders

Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology

Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders

Urban green is more than the absence of city: Structural and functional neural basis of urbanicity and green space in the neighbourhood of older adults

The relationship between urbanization, the brain, and human mental health is subject to intensive debate in the current scientific literature. Particularly, since mood and anxiety disorders as well as schizophrenia are known to be more frequent in urban compared to rural regions. Here, we investigated the association between cerebral signatures, mental health and land use indicators (Urban Fabric and Urban Green) within a 1 km radius around the home address of 207 well-characterized older adults. We observed a negative association between Urban Fabric coverage and a positive association between Urban Green coverage and grey matter volume in perigenual/subgenual anterior cingulate cortex (p/sACC). Although p/sACC has repeatedly been associated with depressive symptoms, neither brain structure nor land use categories were related to measures of mental health. However, resting-state measure in p/sACC showed a negative association with Urban Fabric in our healthy sample, reminiscent of previous reports on major depression where p/sACC is often found to be reduced in activation. Interestingly, hierarchical regression analyses showed that Urban Green accounted for additional variance in brain structure beyond Urban Fabric. We take this finding as an exploratory result that hints at potentially salutogenic elements of green spaces (e.g. terpenes, nature sounds) that go beyond the absence of the detrimental elements of urban contexts (e.g. traffic noise, air pollution), which may inform the future search of environmental factors affecting mental health and disease

Fusion analysis of first episode depression: where brain shape deformations meet local composition of tissue.

Computational neuroanatomical techniques that are used to evaluate the structural correlates of disorders in the brain typically measure regional differences in gray matter or white matter, or measure regional differences in the deformation fields required to warp individual datasets to a standard space. Our aim in this study was to combine measurements of regional tissue composition and of deformations in order to characterize a particular brain disorder (here, major depressive disorder). We use structural Magnetic Resonance Imaging (MRI) data from young adults in a first episode of depression, and from an age- and sex-matched group of non-depressed individuals, and create population gray matter (GM) and white matter (WM) tissue average templates using DARTEL groupwise registration. We obtained GM and WM tissue maps in the template space, along with the deformation fields required to co-register the DARTEL template and the GM and WM maps in the population. These three features, reflecting tissue composition and shape of the brain, were used within a joint independent-components analysis (jICA) to extract spatially independent joint sources and their corresponding modulation profiles. Coefficients of the modulation profiles were used to capture differences between depressed and non-depressed groups. The combination of hippocampal shape deformations and local composition of tissue (but neither shape nor local composition of tissue alone) was shown to discriminate reliably between individuals in a first episode of depression and healthy controls, suggesting that brain structural differences between depressed and non-depressed individuals do not simply reflect chronicity of the disorder but are there from the very outset

Exploring Emotions Using Invasive Methods: Review of 60 Years of Human Intracranial Electrophysiology

Over the past 60 years, human intracranial electrophysiology (HIE) has been used to characterize seizures in patients with epilepsy. Secondary to the clinical objectives, electrodes implanted intracranially have been used to investigate mechanisms of human cognition. In addition to studies of memory and language, HIE methods have been used to investigate emotions. The aim of this review is to outline the contribution of HIE (electrocorticography, single-unit recording and electrical brain stimulation) to our understanding of the neural representations of emotions. We identified 64 papers dating back to the mid-1950s which used HIE techniques to study emotional states. Evidence from HIE studies supports the existence of widely distributed networks in the neocortex, limbic/paralimbic regions and subcortical nuclei which contribute to the representation of emotional states. In addition, evidence from HIE supports hemispheric dominance for emotional valence. Furthermore, evidence from HIE supports the existence of overlapping neural areas for emotion perception, experience and expression. Lastly, HIE provides unique insights into the temporal dynamics of neural activation during perception, experience and expression of emotional states. In conclusion, we propose that HIE techniques offer important evidence which must be incorporated into our current models of emotion representation in the human brain