Visualization-Based Mapping of Language Function in the Brain

Cortical language maps, obtained through intraoperative electrical stimulation studies, provide a rich source of information for research on language organization. Previous studies have shown interesting correlations between the distribution of essential language sites and such behavioral indicators as verbal IQ and have provided suggestive evidence for regarding human language cortex as an organization of multiple distributed systems. Noninvasive studies using ECoG, PET, and functional MR lend support to this model; however, there as yet are no studies that integrate these two forms of information. In this paper we describe a method for mapping the stimulation data onto a 3-D MRI-based neuroanatomic model of the individual patient. The mapping is done by comparing an intraoperative photograph of the exposed cortical surface with a computer-based MR visualization of the surface, interactively indicating corresponding stimulation sites, and recording 3-D MR machine coordinates of the indicated sites. Repeatability studies were performed to validate the accuracy of the mapping technique. Six observers—a neurosurgeon, a radiologist, and four computer scientists, independently mapped 218 stimulation sites from 12 patients. The mean distance of a mapping from the mean location of each site was 2.07 mm, with a standard deviation of 1.5 mm, or within 5.07 mm with 95% confidence. Since the surgical sites are accurate within approximately 1 cm, these results show that the visualization-based approach is accurate within the limits of the stimulation maps. When incorporated within the kind of information system envisioned by the Human Brain Project, this anatomically based method will not only provide a key link between noninvasive and invasive approaches to understanding language organization, but will also provide the basis for studying the relationship between language function and anatomical variability

Fuzzy knowledge-based recognition of internal structures of the head

Nous proposons une méthode basée sur la connaissance a priori pour la segmentation et la reconnaissance des formes des structures internes du cerveau en IRM. Les connaissances sur les formes des structures et les distances entre elles, provenant de l'atlas de Talairach, sont modélisées par un champ flou en utilisant une analogie avec la distribution du potentiel d'électrostatique. Une sur-segmentation est d'abord effectuée sur le cerveau pour obtenir des régions homogènes. La reconnaissance des structures est ensuite obtenue par la classification des régions utilisant un algorithme génétique, suivie par un affinement au niveau du pixel. Les connaissances floues modélisées sont utilisées dans ces deux étapes. La performance de la méthode proposée est validée par référence aux résultats manuels en utilisant 4 indices de quantification

Morphometric reorganization induced by working memory training: perspective from vertex and network levels

Der sich beschleunigende globale Alterungsprozess und die Tatsache, dass sich die kog-nitiven Fähigkeiten mit dem Alter verschlechtern, was sich erheblich auf die Lebensquali-tät älterer Erwachsener auswirkt, insbesondere bei altersbedingten Störungen (z. B. kogni-tiver Beeinträchtigung, Demenz), weisen auf einen dringenden Bedarf an Ansätzen zum Schutz und zur Verbesserung der kognitiven Fähigkeiten sowie an Untersuchungen der neuronalen Substrate altersbedingter Veränderungen und der Neuroplastizität hin. Da man davon ausgeht, dass das Arbeitsgedächtnis (WM) die grundlegende Ursache für altersbe-dingte kognitive Beeinträchtigungen bei einer Vielzahl von kognitiven Fähigkeiten dar-stellt, ist das Arbeitsgedächtnistraining (WMT) zu einem aktuellen Thema und einem be-liebten Ansatz geworden. Frühere Studien haben gezeigt, dass das Arbeitsgedächtnistrai-ning (WMT) die kognitive Leistung verbessert. Die spezifischen Auswirkungen sowie die zugrunde liegenden neurobiologischen Mechanismen sind jedoch nach wie vor um-stritten. Ziel dieser Arbeit ist es, die durch das WMT induzierte neuronale strukturelle Plastizität auf mehreren Ebenen sowie die Verhaltenseffekte des WMT zu untersuchen. In der ers-ten Studie untersuchten wir die topographischen Veränderungen der Morphologie der grauen Substanz durch WMT, indem wir vier strukturelle Metriken (d.h. die kortikale Dicke, das kortikale Volumen, die kortikale Oberfläche und den lokalen Gyrifikationsin-dex, LGI) sowie die subkortikalen Volumina explorierten. Konkret wurden 59 gesunde Probanden mittleren Alters nach dem Zufallsprinzip entweder einem adaptiven WMT oder einer nicht-adaptiven Intervention zugewiesen. Alle Teilnehmer unterzogen sich vor und nach der 8-wöchigen WMT-Phase einer Neurobildgebung sowie kognitiven Tests. Vor und nach dem WMT wurden vier kortikale Metriken auf Scheitelpunktniveau und sieben subkortikale Volumina sowie die globale mittlere kortikale Dicke berechnet. Das wich-tigste Ergebnis war, dass die WMT-Gruppe im Vergleich zur aktiven Kontrollgruppe eine größere Zunahme der kortikalen Faltung in den bilateralen parietalen Regionen zeigte. Die Ergebnisse deuten darauf hin, dass strukturelle Veränderungen durch WMT in WM-bezogenen Regionen, insbesondere in parietalen Regionen, die Verarbeitung einer höhe-ren WM-Belastung erleichtern können. Darüber hinaus könnte die kortikale Faltung das relevanteste und plastischste Merkmal von WM und Lernen sein und WMT-Effekte stär-ker widerspiegeln als andere Metriken. Basierend auf den Ergebnissen der ersten Studie haben wir darüber hinaus untersucht, ob die trainingsinduzierten Effekte des WMT in der kortikalen Faltung auf Vertex-Ebene von topologischen Veränderungen begleitet werden. Zu diesem Zweck untersuchten wir in Studie zwei die durch WMT verursachte Plastizität auf Netzwerkebene mit Hilfe eines strukturellen Kovarianzansatzes (SC), der auf denselben Stichproben basiert. Es wurden gyrifikationsbasierte SC-Matrizen für jede Gruppe vor und nach dem Training sowie lon-gitudinale gyrifikationsbasierte SC-Matrizen erstellt. Innerhalb jeder Gruppe ergab die LGI-basierte SC-Analyse keine Hinweise auf WMT-induzierte Veränderungen der kor-tiko-kortikalen Verbindungen, weder in der WMT- noch in der aktiven Kontrollgruppe. Die Ergebnisse der longitudinalen SC-Analyse (unkorrigiert p < 0,005) zeigten, dass die trainingsinduzierten Veränderungen der kortikalen Faltungsintensität signifikante Unter-schiede zwischen Paaren von parietalen Regionen sowie Paaren von frontalen Regionen aufwiesen. Insgesamt deuten die kombinierten Ergebnisse dieser beiden Studien darauf hin, dass ers-tens WMT neuronale strukturelle Plastizität hervorrufen kann; zweitens die kortikale Fal-tung das relevanteste und plastischste Merkmal von WM und Lernen sein könnte, das die Auswirkungen von WMT besser widerspiegelt als andere Indikatoren auf Vertex-Ebene; und drittens die trainingsinduzierten lokalisierten Veränderungen der kortikalen Faltung von einem ähnlichen Muster vergleichbarer struktureller Veränderungen zwischen ROIs innerhalb der Regionen begleitet wurden. In Zukunft sind weitere Forschungen erforder-lich, um diese Ergebnisse zu wiederholen und zu validieren sowie um trainingsinduzierte topologische und topografische Veränderungen anhand einer breiteren Palette von Metri-ken und Eigenschaften zu untersuchen.The accelerating global aging process and the fact that cognitive abilities deteriorate with age, which has a significant impact on the quality of life of older adults, particularly those with age-related disorders (e.g., cognitive impairment, dementia), all point to an urgent need for approaches to protect and enhance cognitive abilities, as well as studies of the neural substrates of aging-related changes and neuroplasticity. Since working memory (WM) has been assumed to be the fundamental source of age-related cognitive impair-ments in a variety of cognitive abilities, working memory training (WMT) has become a hot topic as well as a popular approach. Previous studies have established that working memory training (WMT) improves cognitive performance. However, the specific effects, as well as the underlying neurobiological mechanisms, remain a matter of controversy. The purpose of this thesis is to investigate WMT-induced neural structural plasticity at multiple levels together with the behavioral effects of WMT. In study one, we investigated the topographic changes of grey matter morphology due to WMT by combining four structural metrics (i.e., cortical thickness (CT), cortical volume (CV), cortical surface area (CSA), and local gyrification index (LGI)) as well as subcortical volumes. Specifically, 59 healthy volunteers between the ages of 50 and 65 were randomly assigned to either an adaptive or a non-adaptive intervention. All participants underwent neuroimaging as well as cognitive testing before and after the 8-week intervention. Four cortical metrics at ver-tex level and seven subcortical volumes, as well as global mean cortical thickness, were calculated before and after the intervention. The most important finding was that the adap-tive WMT group showed greater increases in cortical folding in bilateral parietal regions in comparison to the active control group who performed the non-adaptive intervention. The results indicate that structural changes due to adaptive WMT in WM related regions, particularly parietal regions, may facilitate the processing of a higher WM load. In addi-tion, the cortical folding might be the most relevant and plastic feature of WM and learn-ing, reflecting WMT effects more than other metrics. Based on the findings of study one, we further asked whether the training-induced effects of WMT in cortical folding at vertex-level are accompanied by topological changes. To this end, study two investigated network-level plasticity due to WMT by using the struc-tural covariance (SC) approach based on the same samples. Gyrification based SC matri-ces for each group before and after training, together with longitudinal gyrification SC matrices, were constructed. Within each group, the LGI-based SC analysis revealed no evidence of WMT-induced changes in cortical-cortical connections, either in the WMT or the active control groups. The results of the longitudinal SC analysis (uncorrected p < 0.005) revealed that the training induced changes of cortical folding intensity showed sig-nificant difference between pairs of parietal regions as well as pairs of frontal regions. Overall, the combined findings of these two studies indicate that: firstly, WMT can pro-duce neural structural plasticity; secondly, cortical folding might be the most relevant and plastic feature of WM and learning, better reflecting the effects of WMT than other vertex-level indicators; and thirdly, the training induced localized changes in cortical folding were accompanied by the pattern of similar structural changes between ROIs within the regions. In the future, more research is required to replicate and validate these findings, as well as to investigate training-induced topological and topographic changes using a broader set of metrics and properties

Optimized Targeting in Deep Brain Stimulation for Movement Disorders.

Deep brain stimulation (DBS) is the dominant surgical therapy for medically-refractory Parkinson’s Disease (PD) and Essential Tremor (ET). Despite its success in treating the physical symptoms of many movement disorders, optimal targeting protocols are unknown. The success of the surgery is highly dependent upon proper placement of the electrode in the brain. However, the anatomical targets for PD and ET DBS—the subthalamic nucleus (STN) and ventral intermediate (Vim) nucleus of the thalamus, respectively—are not distinguishable on conventional magnetic resonance imaging. Neurosurgeons typically locate these structures using imprecise atlas-based indirect targeting methods requiring several attempts, increasing the risk of intracranial hemorrhage. The purpose of this work was to optimize targeting in DBS for PD and ET. First, we evaluated the most common indirect STN targeting methods with our validated 3-Tesla MRI protocol optimized for STN visualization. We calculated indirect targets as prescribed by midcommissural point (MCP) -based and red nucleus-based (RN) methods, and compared those coordinates to the position of the STN. We found that RN-based targeting is statistically superior to MCP-based targeting and should be routinely used in the absence of direct STN visualization. In our next study, we investigated the volume of tissue activated (VTA) in thalamic DBS. First, we developed a k-means clustering algorithm that operates on diffusion tensor imaging data to segment the thalamus into its functionally-distinct nuclei. We segmented individual patient thalami and an atlas thalamus in an existing VTA model, and created an individualized VTA model by utilizing each patient’s own anatomy and tissue conductivity. We measured stimulation overlaps with relevant nuclei for clinically efficacious stimulation settings. Our preliminary results indicated that individualized VTA modeling may provide more precise modeling results than existing atlas-based VTA modeling. Next, we investigated the ability of atlas-based and individualized VTA modeling methods to explain common side effects from thalamic DBS. We found that individualized VTA modeling is superior to atlas-based modeling in the prediction of side effects. The results of this work advance the understanding of proper DBS targeting for movement disorders, and our VTA modeling system represents the most individualized approach for ET DBS surgical planning.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111402/1/hlayla_1.pd

A Longitudinal Study of Closed Head Injury: Neuropsychological Outcome and Structural Analysis using Region of Interest Measurements and Voxel-Based Morphometry

Background: The hippocampus and corpus callosum have been shown to be vulnerable in head injury. Various neuroimaging modalities and quantitative measurement techniques have been employed to investigate pathological changes in these structures. Cognitive and behavioural deficiencies have also been well documented in head injury. Aims: The aim of this research project was to investigate structural changes in the hippocampus and corpus callosum. Two different quantitative methods were used to measure physical changes and neuropsychological assessment was performed to determine cognitive and behavioural deficit. It was also intended to investigate the relationship between structural change and neuropsychology at 1 and 6 months post injury. Method: Forty-seven patients with head injury (ranging from mild to severe) had undergone a battery of neuropsychological tests and an MRI scan at 1 and 6 months post injury. T1-weighted MRI scans were obtained and analysis of hippocampus and corpus callosum was performed using region-of-interest techniques and voxel-based morphometry which also included comparison to 18 healthy volunteers. The patients completed neuropsychological assessment at 1 and 6 months post injury and data obtained was analysed with respect to each assessment and with structural data to determine cognitive decline and correlation with neuroanatomy. Results: Voxel-based morphometry illustrated reduced whole scan signal differences between patients and controls and changes in patients between 1 and 6 months post injury. Reduced grey matter concentration was also found using voxel-based morphometry and segmented images between patients and controls. A number of neuropsychological aspects were related to injury severity and correlations with neuroanatomy were present. Voxel-based morphometry provided a greater number of associations than region-of-interest analysis. No longitudinal changes were found in the hippocampus or corpus callosum using region-of-interest methodology or voxel-based morphometry. Conclusions: Decreased grey matter concentration identified with voxel-based morphometry illustrated that structural deficit was present in the head injured patients and does not change between 1 and 6 months. Voxel-based morphometry appears more sensitive for detecting structural changes after head injury than region- of-interest methods. Although the majority of patients had suffered mild head injury, cognitive and neurobehavioural deficits were evidenced by a substantial number of patients reporting increased anxiety and depression levels. Also, the findings of relationships between reduced grey matter concentration and cognitive test scores are indicative of the effects of diffuse brain damage in the patient group

Differences in callosal and subcortical volumes and associated neurobehavioural deficits in children with prenatal alcohol exposure

Certain high-risk communities in the Western Cape Province of South Africa where heavy maternal prenatal alcohol consumption is perpetuated by historical and societal challenges, have some of the highest prevalence rates of fetal alcohol syndrome (FAS) in the world. FAS has lifelong behavioural and cognitive consequences. Neuroimaging research aims to link deficits in brain structure and function to behavioural outcomes. Manual tracing is considered the gold standard of neuroanatomical volumetric analysis. Combined with neurobehavioural testing it can provide links between structure and function, but is time consuming and labour intensive. Automated segmentation programmes, such as FreeSurfer, are a faster alternative. The challenge is creating automated programmes that can provide results that are comparable to manual tracing, especially in a clinical sample. The aims of this thesis were to investigate (1) the effects of prenatal alcohol exposure (PAE) on the sizes of the caudate nucleus, nucleus accumbens, hippocampus and corpus callosum (CC) and potential relations of regional volumes with IQ and verbal learning, (2) to compare the performance of manual and automated segmentation methods in identifying alcohol-related changes in brain morphometry, and (3) to examine the effects of PAE on inter-hemispheric transfer during adolescence and potential relations of CC size with inter-hemispheric transfer deficits. Participants for this project were recruited from the Cape Town Longitudinal Cohort for whom alcohol exposure data were gathered prospectively from the mothers during pregnancy using the timeline follow-back approach. Participants had been diagnosed previously by two expert dysmorphologists as either control, non-syndromal heavily exposed (HE), partial FAS (PFAS) or FAS. High-resolution T1-weighted images were acquired using a sequence optimized for morphometric neuroanatomical analysis on a Siemens 3T Allegra MRI scanner for 71 right-handed children (9 FAS, 19 PFAS, 24 HE and 19 non-exposed controls) from this cohort at ages 9-11 years. Bilateral caudate nuclei, nucleus accumbens and hippocampi and the CC were manually traced using Multitracer. FreeSurfer was used for automated segmentation. All structures were segmented with both FreeSurfer versions 5.1 and 6.0 to compare progress within development of automated segmentation algorithms. Associations of volumes from manual tracing with IQ and performance on the California Verbal Learning Test-Children’s Version (CVLT-C) were also examined. Inter-hemispheric transfer was assessed using a finger localization task (FLT) administered to 74 participants (12 FAS, 16 PFAS, 14 HE, and 32 controls) from the same cohort at ages 16-17 years. Of these, 34 participants had completed MRI at 9-11 years. Higher levels of PAE were associated with reductions in CC area, as well as bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after controlling for alcohol-related reductions in TIV (total intracranial volume). Amongst dysmorphic children (FAS/PFAS), poorer performance on the CVLT-C was related to larger hippocampi and smaller CC. Smaller CC was also associated with lower IQ and partially mediated the effect of PAE on IQ. Manual and automated comparisons showed good agreement in the caudate nuclei, which are simpler to segment, moderate to good agreement in the smaller, more complex nucleus accumbens and hippocampi, and poor agreement in the CC. The latter is not surprising, however, in view of the fact that manual tracing measured the average area of the CC on a mid-sagittal slice, while FreeSurfer measures CC volume over a number of contiguous slices. After controlling for confounders and adjustment for smaller TIV, the latest FreeSurfer version 6.0 provided evidence of alcohol-related volumetric brain reductions comparable to manual segmentation. Only the most severely affected children with FAS demonstrated inter-hemispheric transfer deficits, with the number of transfer-related errors tending to increase with decreasing CC volume among children with PAE. This study confirms and extends evidence of PAE-related decreases in subcortical and CC size and that callosal volume partially mediates alcohol-related impairment in IQ. Although FreeSurfer v 6.0 achieves automated segmentations that are comparable to manual tracing, even in a paediatric clinical sample, performance is more reliable in some structures than others. Improvement and standardization of CC segmentation is especially important given the vulnerability of the CC and its critical role in domains affected by PAE, including verbal learning, IQ and inter-hemispheric transfer of information

Inherited Obsession: The Role of Genetics and Serotonin in the Etiology of Obsessive-Compulsive Disorder

We still do not understand why some individuals are more likely to develop OCD than others. Research has implicated the serotonin system specifically the serotonin transporter and the 5-HT2A receptor as potential neurochemical underpinnings of OCD. Innovations in genetics have allowed research to hone in on the specific genes which code for the neurochemical dysfunction implicated in OCD. In this literature review, I gathered data in the form of research which addresses the neurochemical and genetic underpinnings of OCD in order to gain a better understanding of the etiology of the disorder. The findings presented represent my analysis of current research in the field in the hopes of drawing conclusions about the etiology of OCD. My conclusions implicate the specific genes which code for the serotonin transporter and the 5-HT2A receptor as the potential neurochemical and genetic underpinnings of OCD