Dissertations / Theses on the topic 'Voxel-based morphometry'

The importance of brain structure is indisputable. It forms the framework on which functional parameters can be mapped and referenced. The classical region of interest based morphometric methods that have hitherto formed the mainstay of structural neuroimaging have a number of drawbacks not least because they are spatially constrained and operator dependent. In light of substantial advances in magnetic resonance imaging techniques and concomitant computational post processing innovations, new insights into brain structure are now possible. A new generation of whole brain imaging techniques can now inform about brain structure in a more holistic way with enhanced precision. Computational neuroanatomy is a new method employing the versatile framework of statistic parametric mapping and volumetric high-resolution magnetic resonance images of the brain. It consists of a triad of interactive techniques: voxel-based morphometry (VBM) which provides voxel-wise inferences about regional grey and white matter, deformation-based morphometry (DBM) which characterises global brain shape differences and tensor-based morphometry (TBM) which characterises local shape differences with high precision. This thesis examines the application and usefulness of voxel-based morphometry with particular reference to its practicality, reproducibility, validity and sensitivity to characterise brain structure. VBM is first applied to a large normative catabase to characterise physiological variations in normal brain structure in order to create a canonical framework against which pathology can be measured. VBM is then rigorously compared with classical morphometrics in patients with two distinct forms of dementia and in patients with mesial temporal sclerosis in order to establish validity and sensitivity. VBM is then applied to a variety of disease groups where classical morphometrics have failed to reveal consistent brain structural phenotypes in order to reveal morphological changes in functionally implicated regions. Finally VBM is used is a tool to allow genotype-phenotype mapping. The strengths and weaknesses of this new technique are discussed with reference to its applicability and usefulness for neurologists and neuroradiologists.

Vestibular-related problems (dizziness, vertigo, and imbalance) are common sequelae following concussion and blast exposures that result in mild traumatic brain injury (mTBI). However, the anatomical substrate connected to these dysfunctions is not well understood. To provide a better understanding of this area, we used voxel-based morphometry (VBM) as a platform for studying vestibular-related mTBI in the human brain. Briefly, VBM is a group comparison study which evaluates structural differences in magnetic resonance (MR) images between agematched groups of individuals (11 vestibular TBI patients and 10 controls). Using the VBM-8 Toolbox and statistical probability mapping (SPM), MRI images were segmented into gray matter, white matter, and cerebrospinal fluid, normalized into a standardized anatomical space, and then analyzed statistically for significant anatomical differences between groups. Based on the VBM analysis, most notable differences in brain anatomy were characterized by reductions in gray matter volume observed in the middle frontal gyrus, mesial frontal lobe, and in the insular area in the left mesial temporal lobe. These findings provide a preliminary analysis of distributed gray matter changes in key frontal and temporal areas of the brain associated with mTBI related vestibular dysfunction.

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno del neurodesarrollo caracterizado por síntomas de inatención, hiperactividad e impulsividad. Los modelos clásicos acerca de la neuroanatomía del trastorno apuntan a alteraciones en los circuitos fronto-estriado-cerebelares. Los estudios de neuroimagen estructural apoyan parcialmente estos modelos. Sin embargo, casi todos estos estudios se basan en el análisis de regiones seleccionadas a priori (procedimiento que se conoce como ROI, acrónimo inglés de regiones de interés: "region of interest"). Estudios más recientes basados en aproximaciones globales apuntan a que las alteraciones estructurales no se limitan a los circuitos fronto-estriado-cerebelares, sino que también afectan las regiones temporales, parietales y cinguladas.
El objetivo de la presente tesis es el de redefinir y aplicar dos métodos de análisis estructural complementarios para identificar los circuitos cerebrales alterados en el TDAH así como para relacionar dichos circuitos con los diferentes subtipos clínicos. Para tal fin, presentaremos y discutiremos dos estudios de resonancia magnética estructural (Carmona et al. 2005; Tremols et al. 2008). Estos dos estudios representan una novedad y mejora de estudios de TDAH previos, por dos razones principales: a) la aplicación por primera vez un estudios basado en la morfometría de vóxeles para comparar el cerebro de niños con TDAH con el cerebro de niños controles no relacionados familiarmente; b) el diseño e implementación de un nuevo método, fácil de aplicar, de segmentación manual del núcleo caudado.
Los resultados confirman los datos obtenidos en estudios previos acerca de menor volumen cerebral en niños con TDAH, y localizan esta reducción en determinadas regiones de sustancia gris. A parte de confirmar las alteraciones fronto-estriado-cerebelares hayamos reducciones en áreas parietales, cingulares y temporales. En concreto observamos decrementos volumétricos de sustancia gris en la corteza frontal inferior, el estriado dorsal, la corteza parietal inferior y la corteza cingulada posterior, regiones clásicamente relacionadas con problemas de inhibición, deficits de memoria de trabajo y alteraciones en tareas de atención visuoespacial, respectivamente. También observamos reducciones volumétricas en áreas típicamente emocionales, como la corteza orbitofrontal, el estriado ventral y las estructurales temporales mediales deficits que podrían explicar las disfunciones motivacionales así como las alteraciones en el procesamiento del refuerzo. Curiosamente, las reducciones de sustancia gris en áreas relacionadas con el procesamiento emocional son más pronunciadas en el subtipo hiperactivo-impulsivo, algo menos en el subtipo combinado y casi inexistentes en el subtipo inatento. Esta diferente afectación en función de los subtipos va en la línea de teorías neuroanatómicas actuales acerca del TDAH (Castellanos and Tannock 2002). También observamos déficits de sustancia gris en áreas sensorio-motoras (específicamente en la corteza perirrolándica y el área motora suplementaria), y en el cerebelo. Por un lado, los déficits en áreas sensorio-motoras probablemente reflejan los problemas de psicomotricidad fina que presentan muchos de los niños con TDAH. Sin embargo, el hecho de que estas reducciones sean especialmente prominentes en los subtipos combinado e inatento, sugieren la posibilidad de que estas alteraciones estén especialmente relacionadas con los déficits atencionales. En base a esto, hipotetizamos que las alteraciones en estas regiones producirían un déficit para integrar y actualizar la información procedente del mundo exterior y, a su vez darían lugar a un sesgo a favor del procesamiento de los estados internos resultando en inatención. Por otro lado, las reducciones cerebelares (extensamente observadas en la literatura del TDAH) parecen están relacionadas con los déficits cognitivos, los afectivos y los emocionales. Creemos que la implicación del cerebelo en estas disfunciones estaría vehiculada por el papel de esta estructural como moduladora del flujo de información entre los circuitos fronto-estriatales. Finalmente nuestros hallazgos son los primeros en demostrar alteraciones diferenciales en la cabeza y el cuerpo del núcleo caudado en el TDAH. Esta desigual implicación de las diferentes partes del núcleo caudado explicaría en parte la heterogeneidad de los estudios previos.
Como conclusión, las reducciones volumétricas de sustancia gris en áreas cognitivas y emocionales apoyan la implicación de disfunciones en los circuitos fronto-estriatales llamados cool (cognitivos) y hot (emocionales) respectivamente. Hasta la fecha este es el primer estudio neuroanatómico que apoya la existencia de disfunciones tanto cognitvas como emocionales en niños con TDAH. Nuestros hallazgos constituyen la primera evidencia neuroanatómica a favor de los modelos de doble ruta porpuestos por Sonuga-Barke (Sonuga- Barke 2002; Sonuga-Barke 2003).
REFERENCIAS:
1. Tremols V, Bielsa A, Soliva JC, Raheb C, Carmona S, Tomas J, et al. (2008): Differential abnormalities of the head and body of the caudate nucleus in attention deficit-hyperactivity disorder. Psychiatry Res. 163:270-278.
2. Carmona S, Vilarroya O, Bielsa A, Tremols V, Soliva JC, Rovira M, et al. (2005): Global and regional gray matter reductions in ADHD: a voxel-based morphometric study. Neurosci Lett. 389:88-93.
3. Castellanos FX, Tannock R (2002): Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 3:617-628.
4. Sonuga-Barke EJ (2003): The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 27:593-604.
5. Sonuga-Barke EJ (2002): Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition. Behav Brain Res. 130:29-36.
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease characterized by symptoms of inattention, hyperactivity and impulsivity. Data from different studies point to ADHD abnormalities in fronto-striatal circuits. Structural neuroimaging studies partially support fronto-striatal abnormalities and suggest an important role of the cerebellum. However, nearly all these studies are based on the analysis of apriori selected regions of interest (known as ROI approaches). Recent studies, using more global approaches, found that ADHD structural abnormalities were not limited to fronto-striatal-cerebellar circuits, but also affect temporal, parietal and cingulate regions.
The aim of the present dissertation is to refine and apply two complementary methods of structural neuroimaging, in order to identify the brain circuits altered in
ADHD and relate them to different clinical ADHD subtypes and to known ADHD neuropsychological deficits. For that purpose, two structural MRI studies will be presented and discussed (Carmona et al. 2005; Tremols et al. 2008). The differential contributions of these studies, which represent a novelty and an improvement of previous ADHD studies, are: a) the application for the first time of
voxel-based morphometry analysis to compare ADHD children with non family related control children; b) the design and application of a new, easy to apply, manual method of caudate nucleus segmentation.
The results confirm previous findings about smaller brain volume in ADHD children, and refine this reduction by attributing it to grey matter (GM) volume. We also confirm abnormalities in fronto-striatal-cerebellar circuits as well as in parietal, cingulate and temporal regions. Specifically, we observed reductions in inferior frontal cortex, dorsal striatum, inferior parietal cortex and posterior cingulate cortex; thus explaining inhibition problems, spatial working memory deficits and visuospatial attentional alterations. We also observed GM volume reductions in emotionally driven areas such as orbitofrontal cortex, ventral striatum and middle temporal structures; thus accounting for dysfunctional delayed reward and motivational deficits. Interestingly, GM volume reductions, related to emotional processes are more prominent in H-I subtype, more preserved in combined subtypes, and relatively undisrupted in inattentive subtypes, which is in agreement with previous ADHD theories (Castellanos and Tannock 2002). We have also found GM deficits in "sensori-motor" areas (specifically in perirolandic cortex and supplementary motor area), and in the cerebellum. On the one hand, deficits in sensori-motor areas probably reflect problems in fine motor coordination. However, the fact that these reductions are especially prominent in combined and inattentive subtypes brings up the possibility that they may be related to attentional dysfunctions.
I hypothesized that deficits in these regions may produce a deficit when integrating and updating information from the external world and, in turn, produce a bias toward internal world focusing, thus, resulting in inattention. On the other hand, cerebellar reductions (which are extensively reported in ADHD literature) seem to be related to all cognitive, affective and sensorimotor deficits. The implication of cerebellum in all these dysfunctions may arise from its role as a modulator of the flow of information between fronto-strital circuits. Finally, our findings are also the first to show caudate head and body differential abnormalities in ADHD, which explain previous heterogeneous results, providing a new and reliable method to study striatal structures.
As a conclusion, GM volume reductions in emotional and cognitive areas support the implication of both hot (emotional) and cool (cognitive) functions, which agrees with most neuropsychological accounts of ADHD. To our knowledge this is the first time that a neuroanatomical study provides support for the existence of both cognitive and emotional dysfunctions in ADHD children. If these findings are replicated, they will constitute critical evidence for Sonuga-Barke's theory (Sonuga- Barke 2002; Sonuga-Barke 2003) about the dual route model.
REFERENCIAS:
1. Tremols V, Bielsa A, Soliva JC, Raheb C, Carmona S, Tomas J, et al. (2008): Differential abnormalities of the head and body of the caudate nucleus in attention deficit-hyperactivity disorder. Psychiatry Res. 163:270-278.
2. Carmona S, Vilarroya O, Bielsa A, Tremols V, Soliva JC, Rovira M, et al. (2005): Global and regional gray matter reductions in ADHD: a voxel-based morphometric study. Neurosci Lett. 389:88-93.
3. Castellanos FX, Tannock R (2002): Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 3:617-628.
5. Sonuga-Barke EJ (2003): The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 27:593-604.
6. Sonuga-Barke EJ (2002): Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition. Behav Brain Res. 130:29-36.

Early language experience is thought to be essential to develop a high level of linguistic proficiency in adulthood. Impoverished language input during childhood has been found to lead to functional changes in the brain. In this study, we explored if delayed exposure to a first language modulates the neuroanatomical development of the brain. To do so, voxel-based morphometry (VBM) was carried out in a group of congenitally deaf individuals varying in the age of first exposure to American Sign Language (ASL). To explore a secondary question about the effect of auditory deprivation on structural brain development, a second VBM analysis compared deaf individuals to matched hearing controls. The results show that delayed exposure to sign language is associated with a decrease in grey-matter concentration in the visual cortex close to an area found to show functional reorganization related to delayed exposure to language, while auditory deprivation is associated with a decrease in white matter in the right primary auditory cortex. These findings suggest that a lack of early language experience alters the anatomical organization of the brain.

Primary Progressive aphasia (PPA) is a disorder characterized by gradual decline in language functions, with relative sparing of other cognitive abilities. This behavioral profile results from neurodegenerative disease that preferentially affects language cortex. As is the case in aphasia resulting from stroke, any of several critical language processing domains may be affected in PPA, including syntax, semantics, phonology, and orthography. In stroke-induced aphasia, traditional lesion mapping approaches have provided important insight into the localization of cortical regions supporting these domains. Specifically, left perisylvian cortex has been implicated in syntactic and phonological aspects of language, whereas left extrasylvian cortical regions are associated with lexical-semantic and orthographic functions. The goal of the present study was to seek converging evidence for the role of left hemisphere cortical regions in language using a voxel-based imaging technique in individuals with PPA. Fifteen individuals with progressive aphasia and fifteen normal controls were given a comprehensive language battery comprising tasks in the domains of syntax, semantics, phonology, and orthography. A subset of patients and all normal controls underwent high-resolution structural MRI scanning. Voxel-based morphometry (VBM) was used to characterize patterns of regional cortical atrophy in the patients relative to controls and to correlate language tasks with gray matter volumes. Results confirm a key role for left perisylvian cortex in phonological and syntactic processes, and indicate that left temporal regions are critically involved in semantic processes. Findings shed light on the veracity of the "primary systems" hypothesis of written language, which posits that written language impairments arise from core cognitive deficits affecting semantic and phonological systems.

Prior research has suggested that any cortical volume (CV) abnormalities in Autism Spectrum Disorder (ASD) need to be further explored by examination of the two determinants of CV, that being cortical thickness (CT) and pial surface area (PSA; Murphy, Beecham, Craig, & Ecker, 2011). The current study suggests that the two determinants of CV should be explored even in the presence of null CV findings, if structure-function analyses are significant (i.e., bi-lateral precentral gyrus and neuropsychological motor test) as demonstrated in the current sample (see Duffield et al., 2013). The only significant anatomic finding was reduced CT in the left frontal motor regions (primarily left precentral gyrus), which also corresponded to the only significant relationship between a motor variable (i.e., grooved pegboard test) and motor region-of-interest (ROI) where ASD had a stronger relationship than typically developing controls (TDC; ASD > TDC). Left hemisphere biased CT group differences has been shown to have the highest classification accuracy (i.e., designation of ASD versus TDC) of morphological parameters (Ecker et al., 2010), yet PSA has been shown to have far greater modulation of CV abnormalities. This is particularly true for subthreshold PSA (Ecker et al., 2013). These prior findings are not only consistent with the current motor ROI findings, but also provide an explanatory framework for the functional neuroanatomy of a generally worse left handed performance (i.e., non-dominant hand) for ASD compared to controls in a generally right handed dominant sample (no significant group differences on handedness). The only significant motor ROI finding was in the left hemisphere (i.e., ipsilateral to worse left handed performance), but subthreshold PSA findings in the right precentral were found and likely provide explanatory power of motor performances in the aggregate, despite a lack of significant statistical differences in a specific motor ROI individually.

Magnetic resonance imaging (MRI) is conventionally used for macroscopic qualitative observations. However, increasingly there is a need for quantitative MRI measures, which may lead to enhanced detection sensitivity. Two quantitative techniques that may be used to make neuroanatomical inferences about a population or between different populations are magnetization transfer ratio (MTR) and voxel-based morphometry (VBM).
VBM involves the statistical analysis of smoothed segmented white or gray matter maps to reflect increases or decreases in the probability of classifying a voxel as either white or gray matter. MTR provides a measure of the interaction of water and semi-solids within tissue, and thus is indicative of its macromolecular density and microstructural integrity. An MTR group analysis may detect variations of these semi-solid tissue characteristics within or between populations.
This thesis investigates the relationship between information attained from VBM and MTR population studies carried out in the context of the Saguenay Youth Study. Additionally, through this study, the effects of age and gender on brain neuroanatomy are explored using the above techniques. The observed age and gender VBM and MTR effects were consistent with existing literature, but also offered new findings. Overall, applying MTR in conjunction with VBM allows for further insight into the origins of specific anatomical changes, and the discovery of areas that undergo within-tissue development without corresponding white or gray matter volume changes.

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.

El balance del cerebro se altera a nivel estructural y funcional por el consumo de alcohol y puede causar trastornos por consumo de alcohol (TCA). El objetivo de esta Tesis Doctoral fue investigar los efectos del consumo crónico y excesivo de alcohol en el cerebro desde una perspectiva funcional y estructural, mediante análisis de imágenes multimodales de resonancia magnética (RM). Realizamos tres estudios con objetivos específicos: i) Para entender cómo las neuroadaptaciones desencadenadas por el consumo de alcohol se ven reflejadas en la conectividad cerebral funcional entre redes cerebrales, así como en la actividad cerebral, realizamos estudios en ratas msP en condiciones de control y tras un mes con acceso a alcohol. Para cada sujeto se obtuvieron las señales específicas de sus redes cerebrales tras aplicar análisis probabilístico de componentes independientes y regresión espacial a las imágenes funcionales de RM en estado de reposo (RMf-er). Después, estimamos la conectividad cerebral en estado de reposo mediante correlación parcial regularizada. Para una lectura de la actividad neuronal realizamos un experimento con imágenes de RM realzadas con manganeso. En la condición de alcohol encontramos hipoconectividades entre la red visual y las redes estriatal y sensorial; todas con incrementos en actividad. Por el contrario, hubo hiperconectividades entre tres pares de redes cerebrales: 1) red prefrontal cingulada media y red estriatal, 2) red sensorial y red parietal de asociación y 3) red motora-retroesplenial y red sensorial, siendo la red parietal de asociación la única red sin incremento de actividad. Estos resultados indican que las redes cerebrales ya se alteran desde una fase temprana de consumo continuo y prolongado de alcohol, disminuyendo el control ejecutivo y la flexibilidad comportamental. ii) Para comparar el volumen de materia gris (MG) cortical entre 34 controles sanos y 35 pacientes con dependencia al alcohol, desintoxicados y en abstinencia de 1 a 5 semanas, realizamos un análisis de morfometría basado en vóxel. Las principales estructuras cuyo volumen de MG disminuyó en los sujetos en abstinencia fueron el giro precentral (GPreC), el giro postcentral (GPostC), la corteza motora suplementaria (CMS), el giro frontal medio (GFM), el precúneo (PCUN) y el lóbulo parietal superior (LPS). Disminuciones de MG en el volumen de esas áreas pueden dar lugar a cambios en el control de los movimientos (GPreC y CMS), en el procesamiento de información táctil y propioceptiva (GPostC), personalidad, previsión (GFM), reconocimiento sensorial, entendimiento del lenguaje, orientación (PCUN) y reconocimiento de objetos a través de su forma (LPS). iii) Caracterizar estados cerebrales dinámicos en señales de RMf mediante una metodología basada en un modelo oculto de Markov (HMM en inglés)-Gaussiano en un paradigma con diseño de bloques, junto con distintas señales temporales de múltiples redes: componentes independientes y modos funcionales probabilísticos (PFMs en inglés) en 14 sujetos sanos. Cuatro condiciones experimentales formaron el paradigma de bloques: reposo, visual, motora y visual-motora. Mediante la aplicación de HMM-Gaussiano a los PFMs pudimos caracterizar cuatro estados cerebrales a partir de la actividad media de cada PFM. Los cuatro mapas espaciales obtenidos fueron llamados HMM-reposo, HMM-visual, HMM-motor y HMM-RND (red neuronal por defecto). HMM-RND apareció una vez el estado de tarea se había estabilizado. En un futuro cercano se espera obtener estados cerebrales en nuestros datos de RMf-er en ratas, para comparar dinámicamente el comportamiento de las redes cerebrales como un biomarcador de TCA. En conclusión, las técnicas de neuroimagen aplicadas en imagen de RM multimodal para estimar la conectividad cerebral en estado de reposo, la actividad cerebral y el volumen de materia gris han permitido avanzar en el entendimiento de los mecanismos homeostático
La ingesta d'alcohol altera el balanç del cervell a nivell estructural i funcional i pot causar trastorns per consum d' alcohol (TCA). L'objectiu d'aquesta Tesi Doctoral fou estudiar els efectes en el cervell del consum crònic i excessiu d'alcohol, des d'un punt de vista funcional i estructural i per mitjà d'anàlisi d'imatges de ressonància magnètica (RM). Vam realitzar tres anàlisis amb objectius específics: i) Per a entendre com les neuroadaptacions desencadenades pel consum d'alcohol es veuen reflectides en la connectivitat cerebral funcional entre xarxes cerebrals, així com en l'activitat cerebral, vam realitzar estudis en rates msP en les condicions de control i després d'un mes amb accés a alcohol. Per a cada subjecte vam obtindre els senyals de les xarxes cerebrals tras aplicar a les imatges funcionals de RM en estat de repòs una anàlisi probabilística de components independents i regressió espacial. Després, estimàrem la connectivitat cerebral en estat de repòs per mitjà de correlació parcial regularitzada. Per a una lectura de l'activitat cerebral vam adquirir imatges de RM realçades amb manganés. En la condició d'alcohol vam trobar hipoconnectivitats entre la xarxa visual i les xarxes estriatal i sensorial, totes amb increments en activitat. Al contrari, va haver-hi hiperconnectivitats entre tres parells de xarxes cerebrals: 1) xarxa prefrontal cingulada mitja i xarxa estriatal, 2) xarxa sensorial i xarxa parietal d'associació i 3) xarxa motora-retroesplenial i xarxa sensorial, sent la xarxa parietal d'associació l'única xarxa sense increment d'activitat. Aquests resultats indiquen que les xarxes cerebrals ja s'alteren des d'una fase primerenca caracteritzada per consum continu i prolongat d'alcohol, disminuint el control executiu i la flexibilitat comportamental. ii) Per a comparar el volum de MG cortical entre 34 controls sans i 35 pacients amb dependència a l'alcohol, desintoxicats i en abstinència de 1 a 5 setmanes vam emprar anàlisi de morfometria basada en vòxel. Les principals estructures on el volum de MG va disminuir en els subjectes en abstinència van ser el gir precentral (GPreC), el gir postcentral (GPostC), la corteça motora suplementària (CMS), el gir frontal mig (GFM), el precuni (PCUN) i el lòbul parietal superior (LPS). Les disminucions de MG en eixes àrees poden donar lloc a canvis en el control dels moviments (GPreC i CMS), en el processament d'informació tàctil i propioceptiva (GPostC), personalitat, previsió (GFM), reconeixement sensorial, enteniment del llenguatge, orientació (PCUN) i reconeixement d'objectes a través de la seua forma (LPS). iii) Caracterització de les dinàmiques temporals del cervell com a diferents estats cerebrals, en senyals de RMf mitjançant una metodologia basada en un model ocult de Markov (HMM en anglès)-Gaussià en imatges de RMf, junt amb dos tipus de senyals temporals de múltiples xarxes cerebrals: components independents i modes funcionals probabilístics (PFMs en anglès) en 14 subjectes sans. Quatre condicions experimentals van formar el paradigma de blocs: repòs, visual, motora i visual-motora. HMM-Gaussià aplicat als PFMs (senyals de RM funcional de xarxes cerebrals) va permetre la millor caracterització dels quatre estats cerebrals a partir de l'activitat mitjana de cada PFM. Els quatre mapes espacials obtinguts van ser anomenats HMM-repòs, HMM-visual, HMM-motor i HMM-XND (xarxa neuronal per defecte). HMM-XND va aparèixer una vegada una tasca estava estabilitzada. En un futur pròxim s'espera obtindre estats cerebrals en les nostres dades de RMf-er en rates, per a comparar dinàmicament el comportament de les xarxes cerebrals com a biomarcador de TCA. En conclusió, s'han aplicat tècniques de neuroimatge per a estimar la connectivitat cerebral en estat de repòs, l'activitat cerebral i el volum de MG, aplicades a imatges multimodals de RM i s'han obtés resultats que han permés avançar en l'enteniment dels m
Alcohol intake alters brain balance, affecting its structure and function, and it may cause Alcohol Use Disorders (AUDs). We aimed to study the effects of chronic, excessive alcohol consumption on the brain from a functional and structural point of view, via analysis of multimodal magnetic resonance (MR) images. We conducted three studies with specific aims: i) To understand how the neuroadaptations triggered by alcohol intake are reflected in between-network resting-state functional connectivity (rs-FC) and brain activity in the onset of alcohol dependence, we performed studies in msP rats in control and alcohol conditions. Group probabilistic independent component analysis (group-PICA) and spatial regression were applied to resting-state functional magnetic resonance imaging (rs-fMRI) images to obtain subject-specific time courses of seven resting-state networks (RSNs). Then, we estimated rs-FC via L2-regularized partial correlation. We performed a manganese-enhanced (MEMRI) experiment as a readout of neuronal activity. In alcohol condition, we found hypoconnectivities between the visual network (VN), and striatal (StrN) and sensory-cortex (SCN) networks, all with increased brain activity. On the contrary, hyperconnectivities were found between three pairs of RSNs: 1) medial prefrontal-cingulate (mPRN) and StrN, 2) SCN and parietal association (PAN) and 3) motor-retrosplenial (MRN) and SCN networks, being PAN the only network without brain activity rise. Interestingly, the hypoconnectivities could be explained as control to alcohol transitions from direct to indirect connectivity, whereas the hyperconnectivities reflected an indirect to an even more indirect connection. These findings indicate that RSNs are early altered by prolonged and moderate alcohol exposure, diminishing the executive control and behavioral flexibility. ii) To compare cortical gray matter (GM) volume between 34 healthy controls and 35 alcohol-dependent patients who were detoxified and remained abstinent for 1-5 weeks before MRI acquisition, we performed a voxel-based morphometry analysis. The main structures whose GM volume decreased in abstinent subjects compared to controls were precentral gyrus (PreCG), postcentral gyrus (PostCG), supplementary motor cortex (SMC), middle frontal gyrus (MFG), precuneus (PCUN) and superior parietal lobule (SPL). Decreases in GM volume in these areas may lead to changes in control of movement (PreCG and SMC), in processing tactile and proprioceptive information (PostCG), personality, insight, prevision (MFG), sensory appreciation, language understanding, orientation (PCUN) and the recognition of objects by touch and shapes (SPL). iii) To characterize dynamic brain states in functional MRI (fMRI) signals by means of an approach based on the Hidden Markov model (HMM). Several parameter configurations of HMM-Gaussian in a block-design paradigm were considered, together with different time series: independent components (ICs) and probabilistic functional modes (PFMs) on 14 healthy subjects. The block-design fMRI paradigm consisted of four experimental conditions: rest, visual, motor and visual-motor. Characterizing brain states' dynamics in fMRI data was possible applying the HMM-Gaussian approach to PFMs, with mean activity driving the states. The four spatial maps obtained were named HMM-rest, HMM-visual, HMM-motor and HMM-DMN (default mode network). HMM-DMN appeared once a task state had stabilized. The ultimate goal will be to obtain brain states in our rs-fMRI rat data, to dynamically compare the behavior of brain RSNs as a biomarker of AUD. In conclusion, neuroimaging techniques to estimate rs-FC, brain activity and GM volume can be successfully applied to multimodal MRI in the advance of the understanding of brain homeostasis in AUDs. These functional and structural alterations are a biomarker of chronic alcoholism to explain impairments in executive control, reward evaluation and visuospatial processing.
Pérez Ramírez, MÚ. (2018). Characterizing functional and structural brain alterations driven by chronic alcohol drinking: a resting-state fMRI connectivity and voxel-based morphometry analysis [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/113164
TESIS

Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

Doctor of Philosophy (PhD)
Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

La dystonie est une pathologie du mouvement dont la physiopathologie est mal connue. Jusqu'à présent, les données de l'imagerie IRM classique étaient décevantes, en particulier dans les dystonies primaires. Le développement de nouvelles techniques d'imagerie offre la possibilité d'explorer cette pathologie de façon plus précise avec les techniques d'analyse morphométrique voxel à voxel (VBM) et d'imagerie du tenseur de diffusion (DTI). Dans ce travail, nous avons utilisé une approche IRM multimodale pour étudier la physiopathologie de la dystonie. A l'aide de l'imagerie par résonance magnétique fonctionnelle, nous avons étudié la sélectivité des représentations neuronales dans le striatum des patients atteints de crampe des écrivains avant et après rééducation fonctionnelle. Nous avons recherché des anomalies structurelles à l'aide de la VBM et utilisé la tractographie pour rechercher une atteinte spécifique des fibres cortico - striatales sensorimotrices chez ces patients. Nous avons combiné une approche anatomique et par tractographie pour localiser le territoire fonctionnel des ganglions de la base lésé dans les dystonies secondaires à des lésions ischémiques. L'ensemble de nos travaux souligne le rôle du circuit sensorimoteur cortex - ganglions de la base - cervelet dans la physiopathologie de la dystonie
Dystonia is a movement disorder whose pathophysiology is not fully understood. To date, conventional MR imaging was unsuccessful in showing structural abnormality in primary dystonia. New recent imaging techniques, such as voxel based morphometry (VBM) and diffusion tensor imaging (DTI), can be utilized to explore more precisely the pathophysiology of dystonia. In this work, we used several MRI methods to investigate the pathophysiology of dystonia. We used fMRI to determine whether the selectivity of neuronal representation of basal ganglia neurons was altered in the putamen of patients with focal hand dystonia before and after rehabilitation. Using voxel-based morphometry and DTI, we tested the hypothesis that structural or microstructural changes occur in the sensorimotor basal ganglia - cortical circuit in primary focal hand dystonia. Lastly, we combined structural imaging and fiber tracking to determine the functionnal territory of the basal ganglia that is damaged in post stroke dystonia. Overall, our results show that cortico striatal thalamo cerebellar sensorimotor circuit is likely to play a fundamental role in the pathophysiology of the dystonia

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

Background: Adolescence and young adulthood are particularly vulnerable periods for the development of mental health disorders, including bipolar disorder (BD). Mental health screening at universities could aid in the early identification of particularly at- risk individuals, with the long-term aim of providing early treatment interventions to improve clinical outcomes. However, further research into the identification of appropriate behavioral and biological markers for vulnerability to psychiatric disorders – as well as into the acceptability and efficacy of mental health screening - is warranted. Methods: Young adults were recruited via an already existing Internet-based mental health screening survey of undergraduate students at the University of Oxford. In Study 1, qualitative interviews of young adults with and without previous mental health problems were conducted to assess the acceptability and efficacy of mental health screening within a university setting. In Studies 2-5 we explored the hypotheses of altered emotional decision-making, reward processing and neurostructural integrity as behavioral and neurobiological markers for vulnerability to bipolar disorder via the study of young adults with a common bipolar phenotype (BPP) - some of whom meet diagnostic criteria for bipolar II or not-otherwise-specified disorder (BD II/NOS). To that end, we employed a diverse range of methodologies: alcohol challenge (Study 2); neuropsychological task performance (Study 3); functional magnetic resonance imaging (fMRI; Study 4); diffusion tensor imaging (DTI) and voxel-based morphometry (VBM; Study 5). Results: Findings from Study 1 suggest that young adults are willing to participate in mental health screening within a university setting, and that such screening may be used to offer subsequent treatment interventions. Taken together, findings from Studies 2 and 4 suggest a general blunted reward response among unmedicated young adults at increased risk for BD during euthymia, and additionally suggest pathophysiological similarities between BD and alcohol use disorders (AUDs) that may provide a causal link between the elevated co-occurrence rates of the two disorders. Finally, findings from Study 5 suggest widespread white matter microstructural alterations – which are likely to be neurodevelopmental in origin – among antipsychotic- and mood-stabilizer naïve young adults with BD II/NOS. Conclusions: These data support the hypothesis of neurodevelopmental alterations identifiable prior to significant clinical impairment among young adults at increased risk of – or already meeting DSM-IV criteria for – bipolar disorder. They also suggest that young adults in higher education are willing to participate in mental health screening. Future studies should aim to identify more specific markers for individual disorders such as BD.

Charles Bonnet syndrome (CBS) is defined as complex persistent visual hallucinations in the absence of mental disorder. It is associated with advanced age and poor vision. It is common, with prevalence estimates of up to 63% among older people with significant visual impairment. CBS would not be diagnosed in the presence of dementia, but its relationship to milder cognitive impairment is unclear. The few studies that have examined this are underpowered and provide contradictory results. There are 16 case reports of dementia emerging in people with a diagnosis of CBS. These cases raise the possibility of an association between impaired insight at diagnosis of CBS and the subsequent development of dementia. This thesis reports the findings of a prospective cohort study which describes changes in cognitive functioning over one year in patients with CBS and age-matched controls. Participants were recruited from low vision and glaucoma assessment clinics. A clinical assessment was carried out by an old age psychiatrist, and participants had a detailed assessment of visual functioning. This thesis also describes the findings of the first study to use voxel-based morphometry (VBM) to investigate changes in volume of grey and white matter in CBS. Participants were recruited from the same clinics as the cohort study, and underwent MRI scanning on a 1.5T scanner, to a protocol designed to produce 1mm3 voxels. Twelve participants with CBS and ten controls were followed up. Two people in the CBS group developed dementia, while none did in the control group. The CBS group showed a mean change in the score on the Addenbrooke’s cognitive examination (ACE-R) of -3.7 points, compared to a change of +1.4 in the control group. This difference was not statistically significant. The CBS participants performed worse on the verbal fluency item of the ACE-R, a difference which was statistically significant. The VBM analysis was conducted on 11 CBS participants and 11 controls. The CBS group showed an increase in grey matter volume in the right cerebellar hemisphere. This difference retained significance after family-wise error correction, non-stationary correction, and ANCOVA to control for the effects of possible confounders. As far as the author is aware, these are the most methodologically robust studies to date to have investigated cognition and morphological brain changes in CBS. The findings of the cohort study were inconclusive. However, the two cases of dementia in CBS patients add weight to the suspicion that this is a clinically important outcome in the condition, and the finding of abnormalities in frontal lobe testing in participants with CBS fits with a theoretical model of visual hallucination generation. Moreover, this type of research appears to be acceptable to a frail and visually disabled population, and studies powered to investigate this issue more fully would be feasible. The VBM findings report the presence of underlying structural brain abnormalities in CBS, in a region not usually associated with visual hallucinations. Possible links with Lewy body dementia, and implications for theories of visual hallucinations, are discussed.

Despite humans are known to embody a unique ability to self-regulate, sometimes they act impulsively (Hofmann et al., 2009). Generally, impulsive behaviors may derive from the co-occurrence of dysfunctional inhibitory processes and strong urges to act (Bari and Robbins, 2013). In more detail, our impulses, if not appropriate to the situation, are usually kept under control by inhibitory mechanisms; however, when inhibition fails, impulsive acts may stem (Bari and Robbins, 2013). Researchers and mental health experts agree that impulsivity can boost the risk for a range of maladaptive behaviors, such as substance abuse (Kale et al., 2018; Loxton, 2018). Recently, drawing upon the surmised similarities between addiction and overeating (Gearhardt et al., 2009), some authors have hypothesized that the same impulsivity aspects that lead people to abuse alcohol or drugs may also lead to dysregulated eating. In support of this theory, recent studies have shown that individuals with eating disorders and obesity are more impulsive than healthy people, especially when binge eating behavior is present (Waxman, 2008). However, given that most of these investigations focused on people with full-blown eating or weight disorders, it is still unclear whether high impulsivity characterized these individuals also before the dysregulated eating began or if it developed as a result of it. Thus, little is known about the role of impulsivity as a potential risk and predisposing factor for binge eating within the general population. Based on these premises, the aim of the present thesis is to shed some new light on the role of impulsivity at the roots of binge eating behavior. Starting from the contemporary state of the art, Chapter 1 provides an overview of the definitions of the various facets of impulsivity and their neural correlates. Subsequently, Chapter 2 reviews some of the behavioral and neuroimaging studies exploring the relationship between impulsivity and eating behavior. From the existing state of knowledge, I emphasize the need for an in-depth exploration of the role of different impulsivity-related aspects in normal-weight individuals with binge eating. Hence, I outline the primary purposes of this project. First, given the well-established impact of eating and weight disorders on cognitive and neurobiological processes (Horstmann et al., 2015; Smith et al., 2011; van den Akker et al., 2014), I decided to focus on a non-clinical population of normal-weight individuals with binge eating, to provide a clearer account of the role of impulsivity as a hallmark of this behavior, regardless of weight status. Second, given that impulsivity comprises several related forms that depend on distinct neuropsychological processes and neural systems (Dalley and Robbins, 2017), I chose to assess this construct multi-modally, with self-reported, behavioral and neuroimaging measures, in the same study population, to disentangle the relative contribution of each component in the characterization of binge eating (Filbey and Yezhuvath, 2017). The second part of the thesis cover four experiments, in which, by comparing two groups of normal-weight individuals with and without binge eating, I aimed to explore: • General trait impulsivity, as assessed by self-reported questionnaires (Chapter 3); • Response inhibition abilities toward food, measured with food-specific Go/No-Go, GNG (Chapter 4) and Stop Signal Task, SST (Chapter 5); • Task-related brain activity during the execution of both tasks (Task-based functional MRI studies; Chapters 4 - 5); • Functional brain connectivity at rest (Resting-state functional MRI study; Chapter 6); • Brain morphometry (Voxel-based morphometry study; Chapter 7). In conclusion, the last chapter (Chapter 8) will draw upon the entire thesis, tying up the various theoretical and empirical strands in order to discuss the main findings of the experiments and their implication to future studies into this area.
Nonostante una nostra caratteristica intrinseca sia quella di poter controllare e regolare il proprio comportamento, a volte agiamo in modo impulsivo (Hofmann et al., 2009). Un’azione impulsiva può derivare da processi inibitori deficitari uniti a forti impulsi ad agire: infatti, se di solito gli impulsi vengono tenuti a bada da un’efficiente capacità inibitoria, quando questa fallisce, il risultato può essere la messa in atto di comportamenti impulsivi (Bari e Robbins, 2013). Ad oggi, numerose evidenze riportano una chiara associazione tra impulsività e sviluppo di comportamenti maladattivi, come l’abuso di sostanze (Kale et al., 2018; Hogart, 2011). Recentemente, sulla base dell’ipotesi che dipendenze da sostanze e iperalimentazione condividano un substrato comune (Dawe and Loxton, 2004), alcuni ricercatori hanno ipotizzato che i tratti impulsivi che predispongono alle dipendenze, siano anche coinvolti nel discontrollo nei confronti del cibo (binge eating). Diverse ricerche hanno fornito un preliminare supporto a questa ipotesi, riportando una maggiore impulsività in individui affetti da obesità o disturbi alimentari, soprattutto quando presenti episodi di abbuffate (Waxman, 2009). Purtroppo però lo studio di persone con disturbi conclamati del peso o dell’alimentazione può fornire limitate informazioni sul motivo per cui alcune persone tendono a perdere il controllo nei confronti del cibo. Non si chiarisce cioè il ruolo dell’impulsività: è un tratto pre-estistente e di rischio per lo sviluppo delle abbuffate o è invece la risultante del perpetuarsi di questi comportamenti? Il presente elaborato intende mettere in luce il ruolo dell’impulsività alla base del binge eating. Nella prima parte, partendo dallo stato dell’arte, il Capitolo 1 si concentra sulla definizione delle diverse componenti dell’impulsività e sulle loro basi neurobiologiche. Seguendo la stessa struttura, il Capitolo 2 presenta alcuni studi che indagano l’impulsività e i suoi correlati in relazione al comportamento alimentare. Grazie all’analisi della letteratura, ho evidenziato la necessità di un’indagine del ruolo di diverse componenti dell’impulsività in individui sani, con episodi di binge eating. In particolare, visto l’impatto di disturbi alimentari e del peso sui processi cognitivi e neurobiologici (Horstmann et al., 2015; Smith et al., 2011; van den Akker et al., 2014), ho deciso di condurre lo studio considerando persone normopeso con episodi di binge eating, per comprendere il ruolo dell’impulsività come caratteristica alla base di questo comportamento, indipendentemente dalla presenza di disturbi alimentari o del peso. Inoltre, considerato che il termine impulsività racchiude in sé varie componenti, sottese da diversi substrati neurobiologici (Dalley e Robbins, 2017), ho scelto di indagare questo costrutto usando molteplici misure (questionari, compiti comportamentali, e tecniche di neuroimmagine), nella stessa popolazione, al fine di comprende il contributo di ogni dimensione nella caratterizzazione del binge eating. La parte sperimentale della tesi si compone di quattro studi, nei quali, confrontando due gruppi di persone con e senza episodi di binge eating, ho esplorato i seguenti aspetti: • Impulsività di tratto, tramite questionari autosomministrati (Cap. 3) • Capacità di inibizione della risposta motoria nei confronti del cibo, attraverso: Go/No-Go, GNG (Cap. 4) e Stop Signal Task, SST (Cap. 5) • Attività cerebrale durante l’esecuzione di GNG e SST (task-based fMRI study; Cap. 4-5) • Connettività funzionale a riposo (resting-state fMRI study; Cap. 6) • Morfometria cerebrale (Voxel-based Morphometry study; Cap. 7) In conclusione, il Capitolo 8, sulla base del cappello teorico introduttivo e dei risultati degli esperimenti, propone una discussione generale dei risultati e le loro implicazioni per future ricerche in questo campo.

Cognitive impairment strongly affects people with multiple sclerosis (MS). It comprises multifactorial symptoms and no consistent treatments are available to date. Although cognitive impairment has been observed in all stages of the disease, the majority of studies mainly focused on a specific clinical phenotype (primarily relapsing-remitting MS) or did not differentiate between MS subtypes. Advanced magnetic resonance imaging (MRI) techniques are providing useful measures of functional and structural abnormalities in patients with MS, allowing to overcome the limits of conventional MRI. This thesis wished to improve the understanding of the mechanisms responsible for the accumulation of cognitive dysfunction in patients with relapse-onset MS by combining different advanced structural and functional MRI techniques. First, we applied functional MRI (fMRI) to assess brain functional reorganization in relation to different cognitive tasks (face encoding and N-back) in patients with the main relapse-onset clinical phenotypes. We also explored the relationship between functional network alterations and clinical, cognitive, behavioural and structural MRI measures of disease-related damage. Our results provide new evidence for the debate about adaptive/maladaptive functional reorganization in MS, specifically in relation to the clinical and cognitive characteristics of MS phenotypes. Second, the investigation of resting state default mode network (DMN) functional connectivity enabled us to highlight that different modulations of DMN recruitment lead to different clinical profiles and manifestations. Moreover, functional connectivity of specific DMN areas (hippocampi) was found to be central for the assessment of important cognition-related aspects, such as depression. Finally, by applying voxel-wise MRI methods (VBM and TBSS) we explored the extent and distribution of brain GM atrophy and WM microstructural alterations in adult MS patients according to their age of disease onset, and we made some assumptions about the possible presence of pathophysiological mechanisms related to age of MS onset, that suggests a preserved reserve for structural plasticity that could modulate the structural and functional brain organization, in order to preserve or slow-down MS-related dysfunction. To conclude, the application of advanced MRI techniques allowed us to improve our knowledge on neuropsychological features in patients with relapse-onset MS.

Avec le vieillissement de la population, les pathologies liées à l’âge ont pris une dimension importante en médecine. Nous nous intéressons ici à deux pathologies fréquentes chez le sujet et reliées à des troubles cognitifs : l’apnée du sommeil et la syndrome des jambes sans repos. L’apnée du sommeil est une perturbation de la respiration nocturne se manifestant par des pauses respiratoires cause une hypoxie. Cette hypoxie devrait avoir un retentissement important sur le cerveau. Le cerveau est, de plus, un élément important dans le contrôle de la respiration. Il semble donc essentiel d’étudier les relations entre le volume cérébral et l’apnée du sommeil. De la même façon, le syndrome des jambes sans repos, qui se traduit par un besoin urgent de bouger les jambes, est une pathologie fréquente chez le sujet âgé. L’influence du cerveau, et notamment des structures thalamiques dans cette pathologie semble prédominante. Pour étudier les relations entre ces deux pathologies et la structure cérébrale, nous utilisons une technique de morphométrie automatique, la Voxel Based Morphometry. Cette technique permet de comparer différentes images du cerveau , voxel par voxel, après les avoir normalisées par rapport à une référence et les avoir segmentées en substance grise et substance blanche. Nous avons observé une diminution locale de substance grise associée avec l’apnée du sommeil dans le tronc cérébral, semblant indiquer soit un défaut de la commande respiratoire, soit une sensibilité à l’hypoxie de cette région du cerveau. Nous n’avons pas observé de différence significative de volume de substance grise dans le cadre du syndrome des jambes sans repos.

Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Succédant à une théorisation centrée sur le rôle des déficits des fonctions exécutives, les modèles contemporains du trouble déficit de l'attention / hyperactivité (TDAH) mettent en avant l’hétérogénéité d’une catégorie diagnostique impliquant des déficits neuropsychologiques, voies cérébrales et mécanismes étiopathogéniques multiples. En dépit de cette évolution, la majorité des études d'imagerie cérébrale des corrélats structurels du trouble menées à ce jour ont été conduites au niveau de la catégorie diagnostique, sans spécification supplémentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH à un groupe de sujets sains a donné des résultats très variables d'une étude à l'autre, la comparaison inter-étude étant toutefois rendue difficile par la présence de facteurs confondants, tels que des différences en terme de régions d’intérêt examinées, de comorbidités acceptées chez les patients, de pourcentages de sujets masculins et féminins, de fenêtre d’âge sélectionnée, de méthodologie d'analyse ou encore de pourcentage de patients traités par méthylphénidate. Dans ce doctorat, nous nous sommes appuyés sur la morphométrie voxel-à-voxel pour isoler l’influence sur les volumes de matière grise de deux facteurs d’hétérogénéité intra-catégorielle dans le TDAH : le genre d’une part, et un polymorphisme génétique (Val158Met du gène Catéchol-O-méthyltransferase (COMT)) d’autre part ; ces deux facteurs présentant l’intérêt de moduler le risque associé de développer un trouble de type externalisé. Nous avons également comparé les volumes de matière grise d’enfants avec TDAH ayant reçu un traitement par méthylphénidate, de patients n'ayant jamais été exposé à la médication, et de sujet sains. Ces recherches expérimentales ont été inscrites dans une discussion plus générale de l’hétérogénéité des résultats de la littérature structurelle consacrée au TDAH et des sources neuropsychologiques de cette hétérogénéité. Dans notre étude des effets du genre sur les volumes de matière grise dans le TDAH, nous reportons pour la première fois une interaction entre genre et diagnostic, avec des corrélats structurels du trouble différents chez les garçons et les filles avec TDAH dans des régions de la ligne médiane du cerveau, impliquées à la fois dans la régulation émotionnelle et dans le fonctionnement du mode de réseau par défaut. Nous suggérons que ces différences structurelles pourraient contribuer aux différences de risque associé pour les troubles internalisés et externalisés présentées par les garçons et filles avec TDAH. Dans notre étude explorant l'influence du polymorphisme Val158Met sur les volumes de matière grise, nous mettons en évidence une modulation génétique des corrélats structurels du trouble : les sujets homozygotes pour l'allèle Val158, identifiés dans la littérature comme à risque pour le développement d'un trouble des conduites, présentent des volumes de matière grise supérieurs dans le noyau caudé comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allèle Met158 présentent des volumes de matière grise plus faibles dans le cortex préfrontal inférieur droit, une région cruciale pour les processus de contrôle attentionnel. Enfin, dans notre étude des corrélats structurels de l'exposition au méthylphénidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matière grise de l'insula et du pole temporal, des volumes de matière grise plus faibles chez les patients traités comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus précentral, et une association entre volume de matière grise dans le nucleus accumbens gauche et durée d'exposition au méthylphénidate chez les sujets traités. (...)
Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkley’s or Brown’s conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD

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Fundação de Amparo à Pesquisa do Estado de Mato Grosso (FAPEMAT)
Fundamento: Evidências experimentais de modelos animais de crises de ausência sugerem focalidades no início das descargas generalizadas. Estudos clínicos indicam que pacientes com o diagnóstico de epilepsia generalizada idiopática (EGI) exibem anormalidades focais que envolvem o circuito tálamo-cortical no eletroencefalograma (EEG) e na neuroimagem. Objetivos: Investigar a presença de características focais nas descargas generalizadas interictais usando análise quantitativa do EEG (EEGq) e avaliar o córtex do giro do cíngulo usando múltiplas abordagens quantitativas de neuroimagem. Métodos: 75 EEGs de 64 pacientes foram analisados. A primeira espícula generalizada inequívoca foi marcada para cada descarga. Três métodos de análise de fonte geradora da atividade observada foram aplicados: transformação do dipolo em imagem (dipole source imaging-DSI), abordagem LORETA aplicada iterativamente (CLARA), e análise de dipolo equivalente de componentes independentes com análise de agrupamentos. Após processamento do EEG, 32 pacientes (18 mulheres, 32 ± 11) fizeram ressonância magnética. Foram utilizados três métodos para comparar o giro do cíngulo de pacientes e controles: morfometria baseada em voxel (VBM), análise cortical e análise de formato. Resultados: 753 descargas generalizadas foram analisadas. Usando as três técnicas, o lobo frontal foi a principal fonte das descargas (70%), seguido pelos lobos parietal e occipital (14%) e, por fim, os núcleos da base (12%). As principais fontes anatômicas das descargas generalizadas foram o córtex da porção anterior do giro do cíngulo (36%) e giro frontal medial (23%). A VBM mostrou atrofia de substância cinzenta na porção anterior do giro do cíngulo (972 mm3) e no istmo (168 mm3). Análises individuais do córtex do giro do cíngulo mostraram resultados semelhantes. Comparações de superfície mostraram anormalidades principalmente na porção posterior do giro do cíngulo (718.12 mm2). A análise de formato demonstrou uma predominância de anormalidades nas porções anterior e posterior do giro do cíngulo. Discussão: A análise de fonte não mostrou uma fonte única comum a todas as descargas generalizadas mas indicou predominância do giro do cíngulo e lobo frontal. Além disso, o estudo sugere a existência de anormalidades estruturais sutis no giro do cíngulo, principalmente nas porções anterior e posterior.
Background: Experimental evidence from animal models of absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic and subtle structural abnormalities, which involve the thalamo-cortical circuitry. Aims: The objectives of the current investigation were to investigate whether interictal generalized discharges exhibit focal characteristics using qEEG analysis and to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. Methods: 75 EEG recordings from 64 patients were analyzed. The first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. After EEG analysis, 32 patients (18 women, 30± 10 years) and 36 controls (18 women, 32 ±11 years) were imaged by 3 Tesla magnetic resonance (MRI). We used three models to compare cingulate gyrus of patients and the control group: voxel-based morphometry (VBM), cortical analyses and shape analyses. Results: A total of 753 GSW discharges were spatiotemporally analyzed. Source analysis using all three techniques revealed that the frontal lobe was the principal source of GSW discharges (70%), followed by the parietal and occipital lobes (14%), and the basal ganglia (12%). The main anatomical sources of the generalized discharges were the anterior cingulate cortex (36%) and the medial frontal gyrus (23%). VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm3) and the isthmus (168 mm3). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface- based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm2). Shape analyses demonstrated a predominance of abnormalities in the anterior and posterior portions of cingulate gyrus abnormalities. Discussion: Source analysis did not reveal a common focal source of generalized discharges. However, there was a predominance of GSW discharges originating from the cingulate gyrus and the frontal lobe. Furthermore, this study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients.
FAPEMAT: 11/16452-2

Orientador: Luiz Eduardo Gomes Garcia Betting
Resumo: Fundamento: Evidências experimentais de modelos animais de crises de ausência sugerem focalidades no início das descargas generalizadas. Estudos clínicos indicam que pacientes com o diagnóstico de epilepsia generalizada idiopática (EGI) exibem anormalidades focais que envolvem o circuito tálamo-cortical no eletroencefalograma (EEG) e na neuroimagem. Objetivos: Investigar a presença de características focais nas descargas generalizadas interictais usando análise quantitativa do EEG (EEGq) e avaliar o córtex do giro do cíngulo usando múltiplas abordagens quantitativas de neuroimagem. Métodos: 75 EEGs de 64 pacientes foram analisados. A primeira espícula generalizada inequívoca foi marcada para cada descarga. Três métodos de análise de fonte geradora da atividade observada foram aplicados: transformação do dipolo em imagem (dipole source imaging-DSI), abordagem LORETA aplicada iterativamente (CLARA), e análise de dipolo equivalente de componentes independentes com análise de agrupamentos. Após processamento do EEG, 32 pacientes (18 mulheres, 32 ± 11) fizeram ressonância magnética. Foram utilizados três métodos para comparar o giro do cíngulo de pacientes e controles: morfometria baseada em voxel (VBM), análise cortical e análise de formato. Resultados: 753 descargas generalizadas foram analisadas. Usando as três técnicas, o lobo frontal foi a principal fonte das descargas (70%), seguido pelos lobos parietal e occipital (14%) e, por fim, os núcleos da base (12%... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Background: Experimental evidence from animal models of absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic and subtle structural abnormalities, which involve the thalamo-cortical circuitry. Aims: The objectives of the current investigation were to investigate whether interictal generalized discharges exhibit focal characteristics using qEEG analysis and to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. Methods: 75 EEG recordings from 64 patients were analyzed. The first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. After EEG analysis, 32 patients (18 women, 30± 10 years) and 36 controls (18 women, 32 ±11 years) were imaged by 3 Tesla magnetic resonance (MRI). We used three models to compare cingulate gyrus of patients and the control group: voxel-based morphometry (VBM), cortical analyses and shape analyses. Results: A total of 753 GSW discharges were spatiotemporally analyzed. Source analysis using all three techniques revealed that the frontal lobe was the principal ... (Complete abstract click electronic access below)
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Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Written and oral text comprehension abilities are indispensable for human experiences. Strokes causing left hemisphere (LH) damage may impact comprehension and textual production. However, little is known about this influence at the textual/discursive level, including the comparison between oral and written modalities in this kind of lesion. This research aimed at investigating text comprehension in two modalities of presentation (read and heard) by left brain damaged individuals (LBD) and healthy controls, comparing their performance in the micro- and macro-structural levels of text comprehension to neuropsychological data and to density of the brain areas involved. In order to do that, we performed two researches, Study 1, with 18 LBD and 10 controls, and Study 2, with 10 LBD and 10 controls, with matched age and education. In both studies, neuropsychological tests assessed working memory, verbal fluency and naming abilities. Comprehension of macro- and microstructural levels was verified by means of six short narratives, presented in oral or written modality. The participants were asked to retell the stories and answer to five interpretation questions. In Study 2, the same method was used, but it included structural magnetic resonance imaging indicating the density of brain regions by voxel-based morphometry (VBM). The results of Study 1 indicated significant differences in narrative comprehension between LBD and controls. The lower performance observed at the macrostructural level of LBD compared to the micro- suggest individuals who had a stroke may face difficulties in the application of macrorules of deletion, construction and generalization, which underlie overall comprehension of a text. The data from Study 2, with a lower number of participants, indicated a tendency to confirm results found in Study 1, with statistical significant differences in benefit of controls at the macrostructural level of oral narratives. We found significant differences between groups regarding the modality of text presentation. In both Study 1 and Study 2, differences were observed between the groups in auditory word span and in naming, with an advantage to controls. The morphometry data of brain regions, related to the participants of Study 2, indicated an integration of areas from left and right hemispheres to process text comprehension in oral and written modalities. In the left hemisphere, precuneus, cerebellum white matter, superior frontal region and medial orbitofrontal region and from the right hemisphere, accumbens and superior temporal sulcus were observed. The right superior temporal sulcus, left precuneus, left cerebellar white matter and superior frontal region are positively correlated among the participants, presenting better performance as the density increases. The left medial orbitofrontal region shows a negative correlation with comprehension. The right accumbens seems to compensate LH demands, showing increased density in the LBD and reduced volume in the controls. The present study intends to contribute to deepen our understanding of the comprehension of texts presented in the oral compared to written modality in the LH lesion, related to neuropsychological and brain data.
Compreender um texto, seja ele ouvido ou lido, ? indispens?vel para as experi?ncias humanas. Acidentes vasculares cerebrais (AVCs) ocorridos em especial no hemisf?rio esquerdo (HE) podem impactar na compreens?o e na produ??o textual. No entanto, pouco ainda se sabe sobre essa influ?ncia no n?vel textual/discursivo, incluindo, por exemplo, a compara??o entre a modalidade oral e escrita na compreens?o textual/discursiva nesse tipo de les?o. Esta pesquisa teve por objetivo investigar a compreens?o de narrativas em duas modalidades de apresenta??o (lidas e ouvidas) por indiv?duos com les?o no hemisf?rio esquerdo (LHE) e controles saud?veis, comparando-se seu desempenho nos n?veis micro- e macroestruturais da compreens?o de narrativas a dados neuropsicol?gicos e ? densidade das ?reas cerebrais implicadas. Para tal, realizamos dois estudos, o Estudo 1, com 18 LHE e 10 controles, e o Estudo 2, que contemplou exames de neuroimagem, com 10 LHE e 10 controles (os mesmos do Estudo 1), com idade e escolaridade equiparadas. Em ambos os estudos, testes neuropsicol?gicos avaliaram a mem?ria de trabalho, a flu?ncia verbal e a nomea??o. A compreens?o dos n?veis macro- e microestrutural foi verificada por meio de seis narrativas curtas, divididas na modalidade oral ou escrita. Os participantes realizavam um reconto e respondiam a cinco perguntas de interpreta??o. No Estudo 2 empregou-se o mesmo m?todo, por?m com inclus?o de exame de resson?ncia magn?tica estrutural indicando a densidade das regi?es cerebrais pela morfometria baseada em voxels (VBM). Os resultados do Estudo 1 apontaram diferen?as significativas na compreens?o de narrativas entre LHE e controles. Os preju?zos observados no n?vel macroestrutural dos LHE em detrimento do micro- sugerem falhas na aplica??o das macrorregras de dele??o, constru??o e generaliza??o, subjacentes ? compreens?o global de um texto. Os dados do Estudo 2, com menor n?mero de participantes, indicaram uma tend?ncia a corroborar os resultados encontrados no Estudo 1, observando-se diferen?a significativa em benef?cio dos controles no n?vel macroestrutural das narrativas apresentadas oralmente. Foram encontradas diferen?as entre os grupos quanto ? modalidade de apresenta??o dos textos. Tanto no Estudo 1 quanto no Estudo 2 observou-se diferen?as no span auditivo de palavras e na nomea??o, com vantagem para os controles. Os dados da morfometria das regi?es cerebrais, atinentes aos participantes do segundo estudo, apontam uma integra??o de regi?es do hemisf?rio esquerdo e do direito. Do esquerdo, prec?neus, subst?ncia branca do cerebelo, regi?o frontal superior e regi?o orbitofrontal medial e do direito, accumbens e sulco temporal superior foram observadas. O sulco temporal superior direito, o prec?neus esquerdo, a subst?ncia branca cerebelar esquerda e a regi?o frontal superior correlacionam-se positivamente entre os participantes, apresentando desempenho superior ? medida que a densidade aumenta. A regi?o orbitofrontal medial esquerda apresenta correla??o negativa com a compreens?o. A regi?o do accumbens direito parece compensar as demandas do HE, apresentando sua densidade aumentada nos LHE e reduzida nos controles. O presente estudo pretende contribuir para aprofundarmos nossa compreens?o sobre a compreens?o de narrativas apresentadas na modalidade oral versus escrita na les?o de HE, relacionados a dados neuropsicol?gicos e cerebrais.

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

L'instabilité posturale est souvent observée chez les patients atteints de la sclérose latérale amyotrophique (SLA). Cependant, les mécanismes neuronaux impliqués dans cette instabilité posturale demeurent largement inconnus. Comparés aux patients SLA sans instabilité postural, les patients atteints de SLA avec instabilité posturale présentent des APA altérés avec un déplacement postérieur du centre de pression du pied diminué (CP) et une durée des APA augmentée, la longueur et la vitesse du premier pas sont réduites, enfin, le contrôle postural dynamique est déficitaire avec une diminution spectaculaire de l'indice de freinage. A l'inverse, nous n’observons aucune modification des phases d’anticipation et d’exécution du pas chez les patients SLA sans instabilité posturale comparés aux sujets témoins. Le faible recul du CP au cours de la phase d’anticipation est corrélé positivement de façon significative à l’atrophie de la substance grise du PCC, SPL, PPN et le CN ; et la durée augmentée de la phase d’anticipation est corrélée négativement de façon significative à l’atrophie de la matière grise du AMS et du cervelet. Les réductions de la vitesse et de la longueur du premier pas sont liées de façon significative à l’atrophie de la matière grise dans le PMC, le PPN et le vermis cérébelleux, enfin, l’absence de freinage actif est corrélée à une diminution du volume de la matière grise du CUN. Ces résultats suggèrent que l'instabilité posturale des patients atteints de SLA est causée, au moins en partie, par le dysfonctionnement des régions et des réseaux connus pour être impliqués dans l'initiation de la marche et dans le contrôle de l’équilibre
Postural instability is frequently reported in Amyotrophic Lateral Sclerosis (SLA) patients. However, the neural mechanisms that contribute to postural instability in SLA patients remain largely unknown. In comparison to both SLA patients without postural instability and controls, SLA patients with postural instability presented an altered anticipatory postural adjustment (APA) phase with a decreased posterior displacement of the center of foot pressure (CP) and a increased APA duration, decreased length and velocity of the first step and deficit of the dynamic postural control with a dramatic decreased braking index. Conversely, the gait initiation was not significantly modified in SLA patients without postural instability in comparison to controls. The reduced posterior CP displacement during the APA was significantly related to reduced grey matter volume of the left PCC, left SPL, right PPN and caudate nucleus, and the increased APA duration to the reduced grey matter volume of the left AMS and right cerebellum. The reduced velocity of the first step was significantly related to a decreased grey matter volume within the left PMC, right PPN and cerebellar vermis and the reduced braking index to decreased grey matter volume of the right CUN. These results suggest that postural instability of SLA patients result, at least partly, from dysfunction of brain regions and networks known to be involved in gait initiation and balance controls in human

The present thesis comprises three main parts: one theoretical and two experimental. The first part, composed of two chapters, will introduce the clinical and neuropathological features underlying parkinsonian disorders, namely in Parkinson’s disease (PD) as well as in atypical parkinsonisms — multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) (Chapter 1). In this regard, PD and MSA are defined as synucleinopathies due to the presence of synuclein aggregates; while PSP that is characterized by tau protein accumulations, is part of tauopathies. Further, Chapter 2 will provide an overview of the cognitive dysfunctions characterizing these disorders, as well as evidence on the biological mechanisms and structural changes underlying cognitive alterations. The second and third parts are composed by studies I conducted during my doctoral research. Namely, in Chapter 3, I report results of my studies on cognitive screening instruments most sensitive in detecting cognitive alterations in atypical parkinsonisms compared to PD. In the following study, I characterized the progression of cognitive decline in these disorders (Chapter 4). Finally, I investigated with magnetic resonance imaging the structural changes underlying cognitive alterations in PD (Chapter 5), and MSA (Chapter 6). I conclude this thesis by discussing the clinical consequences of these cognitive and imaging findings (Chapter 7). PART I - Theoretical background Chapter 1: Parkinsonian disorders Parkinsonian disorders are characterized by different underlying pathologies. In PD and MSA there are synuclein aggregates respectively in dopamine neurons or in glial cells, while PSP patients present pathological aggregation of the tau-protein, resulting in neurofibrillary tangles formation (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Clinical manifestations depend by the characteristics of protein aggregation and by the extent of disease spread to cortical and subcortical regions (Halliday, Holton, Revesz, & Dickson, 2011). Thus, the present chapter will overview the underlying pathology of PD, MSA and PSP; and it will describe the different clinical features; and lastly review the most recent diagnostic criteria (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Chapter 2: Cognitive features and their underlying mechanisms in parkinsonian disorders Non-motor symptoms represent a crucial part of the parkinsonian disorders spectrum; and cognitive dysfunctions, including dementia, are probably the most relevant, since they affect functional independence of patients, increase caregiver burden as well as wield a considerable socioeconomic impact (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). The first part of this chapter will provide an overview on cognitive dysfunctions in PD, MSA, and PSP. Moreover, the clinical criteria for the diagnosis of mild cognitive impairment and dementia in PD will be reported (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), while so far there are no available criteria to assess cognitive syndromes in PSP and MSA. Lastly, the second and third parts of this chapter will review the evidence on biological mechanisms and structural changes underlying cognitive alterations in these disorders. PART II - Studies on cognitive manifestations in parkinsonian disorders Chapter 3: Montreal Cognitive Assessment and Mini-Mental State Examination performance in progressive supranuclear palsy, multiple system atrophy and Parkinson’s disease There is general agreement that cognitive dysfunctions are common in PD as well as in other parkinsonian disorders (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Brief screening cognitive scales can be adopted in routine care, to support the clinician in the diagnostic process (Marras, Troster, Kulisevsky, & Stebbins, 2014). The Mini-Mental State Examination (MMSE) is the most widely used (Folstein, Folstein, & McHugh, 1975) although MMSE is relatively insensitive in detecting cognitive deficits in parkinsonian disorders mainly because it does not investigate the fronto-executive domain (Hoops et al., 2009). Conversely, the Montreal Cognitive Assessment (MoCA), another brief cognitive screening tool widely used with PD patients (Nasreddine et al., 2005), showed high sensitivity and specificity in the assessment of cognitive dysfunctions in PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), as well as also in several neurodegenerative conditions such as Alzheimer’s disease, dementia with Lewy bodies (DLB) and Huntington’s disease (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). However, MoCA has been poorly investigated in atypical parkinsonisms — especially in PSP and MSA (Kawahara et al., 2015). Thus, this study’s main aim was to determine if MoCA is more sensitive than the commonly used MMSE in detecting cognitive abnormalities in patients with probable PSP and MSA, compared to PD. In this multicenter study across three European institutions, MMSE and MoCA were administered to 130 patients: 35 MSA, 30 PSP and 65 age, and education and sex matched-PD. We assessed between-group differences for MMSE, MoCA, and their subitems and calculated receiver operating characteristic (ROC) curves. Our results show that the mean MMSE is higher than the mean MoCA score in each patient group: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), and PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Furthermore, MoCA total score as well as its letter fluency subitem differentiates PSP from MSA and PD with high specificity and moderate sensitivity. Namely, a cut-off score of seven words or less per minute would support a diagnosis of PSP (PSP vs. PD: 86% specificity, 70% sensitivity; PSP vs. MSA: 71% specificity, 70% sensitivity). On the contrary, MMSE presented a ceiling effect for most subitems, except for the ‘bisecting pentagons’, with PSP performing worse than MSA and PD patients. These findings suggest that PSP and MSA, similar to PD patients, may present normal performance on MMSE, but reduced performance on MoCA. To conclude, MoCA is more sensitive than MMSE in detecting cognitive dysfunctions in atypical parkinsonisms, and together with its verbal fluency subitem can be a valuable test to support PSP diagnosis. Chapter 4: Prospective assessment of cognitive dysfunctions in parkinsonian disorders Clinical and research evidence suggests cognitive impairments in parkinsonian disorders are progressive. However, there are only a few longitudinal studies in the literature that investigated cognitive progression in PSP and MSA compared to PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In addition, previous studies are based on brief cognitive screening scales or on neuropsychological assessments that do not extensively investigate the full spectrum of cognitive abilities across the five cognitive domains (i.e., attention/working-memory, executive, memory, visuospatial and language). Furthermore, even though clinical criteria for mild cognitive impairment (MCI) and dementia in PD have been formulated (Dubois et al., 2007; Litvan et al., 2012), it remains to be investigated whether similar criteria might be applied also for atypical parkinsonisms (Marras et al., 2014). Based on these observations, the aims of the present study were to: i) assess the severity of cognitive dysfunctions in PSP and MSA patients using PD-criteria for cognitive statuses (i.e., MCI or dementia); ii) investigate the sensitivity of two widely used cognitive screening instruments, the MMSE and MoCA, in differentiating MSA, PSP and PD global cognitive profile; iii) characterize the progression of cognitive decline on the five cognitive domains and behavioral features; and to compare the 15-month follow-up profile across the parkinsonian diseases. Our sample included 18 patients with PSP, 12 MSA; and 30 PD patients, matched for age, education and sex. They were evaluated at baseline and at a mean of 15-month follow-up. Demographic and clinical variables were collected. From the cognitive standpoint, I selected a comprehensive neuropsychological battery specifically designed to target cognitive deficits in PD, according to Level II criteria (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Thus, I applied these criteria also to MSA and PSP since there are no published criteria for atypical parkinsonisms. Statistical non-parametric analyses were used. I found PSP patients had more severe cognitive decline compared to PD and MSA. Namely, after 15-month follow-up, we noted a marked decline in the executive and language domains in the PSP group. Baseline and follow-up evaluations agreed, showing that PSP had a worse performance than PD and MSA patients: especially, in the Stroop test, verbal fluencies (semantic and phonemic) and MoCA. Assessing the severity of cognitive deficits, I found different percentages of cognitive status (i.e., normal cognition vs. MCI vs. dementia) among the three groups. In particular, the percentage of patients with dementia was higher in PSP compared to MSA (33% vs. no patients with dementia) even if disease duration was similar. Among MSA and PSP patients with multidomain MCI at baseline only PSP converted to dementia at follow-up. Then, although the disease duration was longer for PD patients compared with PSP, the proportion of patients who converted to dementia was lower in the PD group compared to PSP (7% vs. 16%), despite both groups having had similar baseline severity of MCI. Overall, these results suggest more rapid and severe cognitive decline in PSP while MSA patients generally have milder deficits. MoCA showed higher sensitivity than MMSE in detecting cognitive changes, especially in PSP. But MoCA was less sensitive than MMSE in detecting cognitive decline at 15-month in PD, suggesting that MMSE is better if one wants to track cognitive changes in PD. Neuropsychiatric features are more common in PSP than PD patients, especially apathy with accompanying low levels of anxiety and depression. Lastly, analysis of subitems revealed that PSP patients had a ‘clinically significant’ worsening after 15-month in the attentive/executive subitems (Trial Making Test part B and Clock drawing). But it has been observed that some patients also improved in specific subtasks at the follow-up. This improvement could be related to their higher medication dose (although the dopaminergic treatment was not significantly different between the baseline and follow-up). However, noteworthy alterations in performance have been seen for subitems sensitive to motor conditions (such as drawing figures and linking circles with a pen), which could affect cognitive outcome, leading to higher performance at follow-up. These limits of MoCA and MMSE scale have already been reported in PD patients (Biundo et al., 2016b; Hu et al., 2014), and maybe are more pronounced in atypical parkinsonisms. Taken together, these findings show that PSP patients were markedly impaired in comparison to the other parkinsonian disorders (MSA and PD) and six years after first symptoms, 33 percent of patients have dementia. This severe progression is possibly associated with the distribution of tau pathology that involves also cortical structures. On the contrary, the pattern of cognitive impairment in MSA is less severe, possibly due to the predominance of subcortical pathology with cortical involvement occurring only secondary to these abnormalities. Thus, these findings recommend using cognitive assessment to help differential diagnosis in atypical parkinsonisms, and to monitor disease progression. PART III - Neuroimaging studies of synucleinopathies Chapter 5: Amyloid depositions affect cognitive and motor manifestations in Parkinson’s disease Cognitive deficits, particularly executive problems, can be observed early in PD (Aarsland, Bronnick, Larsen, Tysnes, & Alves, 2009). Dysfunction of the frontostriatal dopaminergic system may influence the presence of executive and attention problems (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), but so far, evidence from dopamine transporter (DAT) imaging are inconsistent (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). In this regard, the neuropathology underlying cognitive impairment in PD is heterogeneous (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker, & Robbins, 2010) and amyloid deposit involvement with synuclein pathology remains poorly defined, particularly in the disease’s early stages. Thus, this study’s aims were to investigate the interplay between amyloid depositions in frontostriatal pathways, striatal dopaminergic deficit and brain atrophy rates; and their contribution to cognitive defects (i.e., fronto-executive functions) in early-PD. A multicenter cohort of 33 PD patients from the Parkinson's Progression Markers Initiative underwent [18F]florbetaben positron emission tomography (PET) amyloid, [123I]FP-CIT (see Abbreviations List) single-photon emission computed tomography (SPECT), structural magnetic resonance imaging (MRI), clinical and selective cognitive evaluations. Our results showed that high amyloid levels were associated with reduced dopaminergic deficits in the dorsal striatum (as compared to low amyloid levels), increased brain atrophy in frontal and occipital regions and a tendency to show more frequent cognitive impairment in global cognition (as assessed by MoCA) and fronto-executive tests. Of note, amyloid depositions in frontostriatal regions were inversely correlated with cognitive performance. Overall, our findings suggest that early-PD patients with amyloid burden have higher brain atrophy rates and may experience more cognitive dysfunctions (i.e., executive) and motor impairment as compared to amyloid negative subjects. In this regard, our results seem to be aligned with a recent neuropathological hypothesis that considers synaptic axonal damage and dysfunction as the PD key feature (Tagliaferro & Burke, 2016). Indeed, dopaminergic system neurons are particularly vulnerable to synuclein pathology due to their axonal characteristics — long, thin and unmyelinated. This is also confirmed by imaging studies with DAT-binding PET (Caminiti et al., 2017), suggesting that synuclein aggregations in PD can affect synaptic function, and thus signal transmission from the disease’s very early stages. Our findings suggested a possible interaction between synuclein and the coincident amyloid pathology, wherein amyloid burden may facilitate the spread of synuclein (i.e., Lewy bodies) (Toledo et al., 2016), and we speculate that this interaction can further contribute to axonal vulnerability. Thus, consistently with this hypothesis, we conclude that possibly amyloid depositions act synergistically with synuclein pathology and affect PD clinical manifestations. Chapter 6: Brain structural profile of multiple system atrophy patients with cognitive impairment In contrast to other synucleinopathies (e.g., PD and DLB), presence of dementia is considered a non-supporting feature for MSA diagnosis (Gilman et al., 2008), however there is growing evidence that MSA patients can experience cognitive impairment ranging from executive dysfunctions to multiple-domain cognitive deficits, and in a few cases, also dementia (Gerstenecker, 2017). MMSE is a commonly used global cognitive scale and recently a large multicenter study has suggested using a cutoff score below 27 to increase the MMSE sensitivity in identifying cognitive dysfunctions in MSA (Auzou et al., 2015). Underlying mechanisms of cognitive impairment in MSA are still not understood, and in this regard evidence from MRI studies suggested a discrete cortical and subcortical contribution to explain cognitive deficits (Kim et al., 2015; Lee et al., 2016a), even though these findings were based on a relatively small number of patients at various disease stages as well as being single-center. Thus, the aim of our multicenter study was to better characterize the anatomical changes associated with cognitive impairment in MSA and to further investigate the cortical and subcortical structural differences in comparison to a sample of healthy subjects. We examined retrospectively 72 probable MSA patients and based on the MMSE threshold below 27, we defined 50 MSA as cognitively normal (MSA-NC) and 22 with cognitive impairment (MSA-CI). We directly compared the MSA subgroup, and further compared them to 36 healthy subjects using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to healthy subjects, MSA patients showed widespread cortical (i.e., bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white matter alterations. However, the direct comparison MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These findings suggest only a marginal contribution of cortical pathology to cognitive deficits in MSA. Hence, we suggest that cognitive alterations are driven by focal frontostriatal degeneration that is in line with the concept of ‘subcortical cognitive impairment’.
La presente tesi è formata da tre parti principali: la prima teorica mentre le due seguenti sono sperimentali. La prima parte, composta di due capitoli, introdurrà le caratteristiche cliniche e neuropatologiche sottostanti ai disturbi parkinsoniani, in particolare nella malattia di Parkinson (PD) e nei parkinsonismi atipici — atrofia multisistemica (MSA) e paralisi progressiva sopranucleare (PSP) (Capitolo 1). Nello specifico, PD ed MSA sono definite come sinucleinopatie per la presenza di aggregati di sinucleina, mentre la PSP che è caratterizzata dall’accumulo di proteina tau rientra a far parte delle tauopatie. Invece, il Capitolo 2 fornirà una panoramica delle disfunzioni cognitive che caratterizzano questi disturbi e fornirà inoltre evidenze circa i meccanismi biologici e i cambiamenti strutturali che sono alla base delle alterazioni cognitive. Nella seconda e la terza parte sono riportati alcuni studi che ho condotto durante il dottorato di ricerca. In particolare, nel Capitolo 3 riporto i risultati dei miei studi sugli strumenti di screening cognitivo più sensibili nel rilevare alterazioni cognitive nei parkinsonismi atipici rispetto ai pazienti con PD. Nel successivo studio invece ho investigato la progressione del declino cognitivo in questi disturbi (Capitolo 4). Infine, ho investigato con studi di risonanza magnetica i cambiamenti strutturali che sottendono le alterazioni cognitive nel PD (Capitolo 5) e nella MSA (Capitolo 6). Seguiranno le conclusioni generali, in cui discuto le conseguenze cliniche dei risultati ottenuti negli studi cognitivi e di imaging (Capitolo 7). PARTE I – Background teorico Capitolo 1: I disturbi parkinsoniani I disturbi parkinsoniani sono caratterizzati da una diversa patologia sottostante. Nel PD ed MSA ci sono aggregati di sinucleina rispettivamente nei neuroni dopaminergici o nelle cellule gliali, mentre i pazienti con PSP presentano delle aggregazioni di proteina tau che determina la formazione di ammassi neurofibrillari (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Le manifestazioni cliniche dipendono dalle caratteristiche di aggregati proteici e dall’entità di diffusione della malattia nelle regioni corticali e sottocorticali (Halliday, Holton, Revesz, & Dickson, 2011). Quindi, il presente capitolo illustrerà la patologia sottostante nel PD, MSA e PSP, saranno poi descritte le diverse caratteristiche cliniche ed infine, saranno presentati i più recenti criteri diagnostici di questi disturbi (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Capitolo 2: Caratteristiche cognitive e i sottostanti meccanismi nei disturbi parkinsoniani I sintomi non-motori rappresentano una parte cruciale dello spettro dei disturbi parkinsoniani, in particolare le disfunzioni cognitive, inclusa la demenza, sono probabilmente tra i sintomi non-motori più rilevanti, in quanto influenzano l'autonomia funzionale dei pazienti, incrementano il carico di gestione del caregiver ed hanno un notevole impatto socioeconomico (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). La prima parte di questo capitolo fornirà una panoramica sulle disfunzioni cognitive nel PD, MSA e PSP. Saranno inoltre riportati i criteri clinici per la diagnosi di declino cognitivo lieve e di demenza nel PD (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), al contrario invece non esistono al momento criteri disponibili per valutare le sindromi cognitive in PSP e MSA. Infine, la seconda e la terza parte di questo capitolo forniranno evidenze sui meccanismi biologici e sui cambiamenti strutturali sottostanti alle alterazioni cognitive in questi disturbi. PARTE II - Studi sulle manifestazioni cognitive nei disturbi parkinsoniani Capitolo 3: Performance al Montreal Cognitive Assessment e Mini-Mental State Examination nella paralisi sopranucleare progresiva, atrofia multisistemica e malattia di Parkinson Vi è un generale consenso nel riconoscere che le alterazioni cognitive siano frequenti nei PD e negli altri disturbi parkinsoniani (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Pertanto, nella pratica clinica possono essere adottate delle scale brevi di screening cognitivo, per supportare il clinico nel processo diagnostico (Marras, Troster, Kulisevsky, & Stebbins, 2014). Il Mini-Mental State Examination (MMSE) è la scala più utilizzata (Folstein, Folstein, & McHugh, 1975), anche se MMSE è relativamente insensibile nell’identificare rilevare disfunzioni cognitive nei disturbi parkinsoniani principalmente perché non indaga il dominio fronto-esecutivo (Hoops et al., 2009). Al contrario, il Montreal Cognitive Assessment (MoCA), un altro strumento di screening cognitivo ampiamente utilizzato nei pazienti con PD (Nasreddine et al., 2005), ha mostrato un’elevata sensibilità e specificità nell’identificazione di alterazioni cognitive nei PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), come anche in altre malattie neurodegenerative come l’Alzheimer, la demenza da corpi di Lewy (DLB) e la malattia di Huntington (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). Tuttavia, vi sono poche evidenze sull’uso del MoCA nei parkinsonismi atipici, in particolare nella PSP ed MSA (Kawahara et al., 2015). Pertanto, lo scopo del presente studio era di determinare se il MoCA fosse più sensibile del comunemente utilizzato MMSE nel rilevare alterazioni cognitive nei pazienti con probabile PSP e MSA, rispetto al PD. In questo studio multicentrico, che ha coinvolto altri tre centri europei, sono state somministrate le scale MMSE e MoCA a 130 pazienti: 35 MSA, 30 PSP e 65 pazienti PD appaiati per età, scolarità e sesso. Sono state valutate le differenze tra i gruppi per MMSE, MoCA, e i loro subitem; infine sono state calcolate le curve ROC (Receiver-Operating Characteristic). Dai risultati emerge che la media del MMSE è superiore al punteggio medio del MoCA in ogni gruppo di pazienti: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), e PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Inoltre, il punteggio totale MoCA così come il suo subitem di fluenza fonemica è in grado di differenziare la PSP da MSA e PD con un’alta specificità e moderata sensibilità. Specificamente, un punteggio uguale o inferiore a sette parole al minuto sembra supportare una diagnosi di PSP (PSP vs PD: 86% specificità, sensibilità al 70%, PSP vs MSA: 71% specificità, sensibilità al 70%). Al contrario, nel MMSE è stato possibile osservare un ‘effetto-soffitto’ per la maggior parte dei subitem, ad eccezione del subitem dei ‘due pentagoni’, in cui i pazienti con PSP hanno una prestazione peggiore rispetto a MSA e PD. I nostri risultati suggeriscono che PSP ed MSA, similmente al PD, possono presentare una prestazione normale al MMSE ma deficitaria al MoCA. In conclusione, il MoCA è più sensibile del MMSE nel rilevare disfunzioni cognitive nei parkinsonismi atipici ed insieme al suo subitem di fluenza verbale sembra essere un valido test per supportare una diagnosi di PSP. Capitolo 4: Valutazione prospettica delle disfunzioni cognitive nei disturbi parkinsoniani Evidenze in ambito clinico e di ricerca suggeriscono che le disfunzioni cognitive nei disturbi parkinsoniani siano progressive. Tuttavia, in letteratura vi sono pochi studi longitudinali che indagano la progressione cognitiva in pazienti con PSP ed MSA rispetto a pazienti PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In particolare, i precedenti studi si basano solo su scale globali di screening cognitivo, oppure su valutazioni neuropsicologiche parziali che non esaminano l'intero spettro delle abilità cognitive nei cinque domini (i.e., attenzione/memoria di lavoro, esecutivo, mnesico, visuospaziale e del linguaggio). Inoltre, sebbene siano stati formulati criteri clinici per la diagnosi di declino cognitivo lieve (MCI) e di demenza in pazienti PD (Dubois et al., 2007; Litvan et al., 2012), rimane ancora da investigare se tali criteri possano essere applicati anche nei parkinsonismi atipici (Marras et al., 2014). Date tali premesse, gli obiettivi del presente studio sono stati: i) valutare la severità delle alterazioni cognitive in pazienti PSP ed MSA utilizzando i criteri validati nei pazienti PD, per identificare gli stati cognitivi (i.e., MCI o demenza); ii) esaminare la sensibilità di due strumenti di screening cognitivo ampiamente utilizzati, (i.e., MMSE e MoCA), nel differenziare il profilo cognitivo globale di pazienti MSA, PSP e PD; iii) caratterizzare la progressione del declino cognitivo nei cinque domini, il profilo comportamentale e infine confrontare il profilo cognitivo al follow-up tra i vari disturbi parkinsoniani. Il nostro campione includeva 18 pazienti con PSP, 12 MSA e 30 pazienti con PD appaiati per età, scolarità e sesso, che sono stati valutati alla baseline e al follow-up a 15 mesi. Sono stati raccolti dati demografici e clinici; inoltre dal punto di vista cognitivo è stata selezionata una batteria di test neuropsicologici completa, specifica per l’identificazione di deficit cognitivi in pazienti PD, secondo i criteri pubblicati di ‘Livello II’ (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Abbiamo quindi applicato tali criteri anche a pazienti MSA e PSP, dato che non esistono criteri pubblicati per i parkinsonismi atipici. Infine, sono state utilizzate analisi statistiche di tipo non-parametrico. Dai nostri risultati emerge che i pazienti con PSP hanno un declino cognitivo più severo rispetto a pazienti PD ed MSA. Nello specifico, al follow-up è stato possibile osservare un marcato declino a carico del dominio esecutivo e del linguaggio nel gruppo con PSP. Le valutazioni cognitive alla baseline e al follow-up erano concordanti, ed entrambe confermano che i pazienti PSP hanno una prestazione peggiore rispetto ai pazienti PD ed MSA: in particolare, nello Stroop test, nelle fluenze verbali (semantica e fonematica) e nel MoCA. Valutando la severità dei deficit cognitivi, abbiamo inoltre trovato diverse percentuali di diagnosi cognitive (i.e., profilo nella norma, MCI vs. demenza) tra i tre gruppi. In particolare, la percentuale più elevata di pazienti con demenza era nel gruppo con PSP rispetto ai pazienti MSA (i.e., 33% vs. nessun paziente con demenza), anche se la durata di malattia era simile. Inoltre, tra i pazienti MSA e PSP con un profilo MCI-multidominio alla baseline, solo pazienti con PSP passano ad una diagnosi di demenza al follow-up. Infine nel gruppo di pazienti PD, nonostante avessero una durata di malattia più lunga, la percentuale di soggetti che passano ad una diagnosi di demenza era inferiore rispetto al gruppo con PSP (7% vs. 16%), nonostante entrambi i gruppi avessero una gravità di MCI simile alla baseline. Complessivamente questi risultati suggeriscono un più rapido e severo declino cognitivo in soggetti PSP, mentre i pazienti MSA mostrano generalmente deficit più limitati. La scala globale MoCA sembra essere maggiormente sensibile, rispetto al MMSE, nel rilevare cambiamenti cognitivi, in particolare nella PSP. Tuttavia il MoCA mostra una sensibilità inferiore rispetto al MMSE nell’identificare un declino cognitivo al follow-up in pazienti PD; quindi il MMSE sembra essere uno strumento migliore per monitorare longitudinalmente cambiamenti cognitivi in pazienti PD. Riguardo al profilo comportamentale, i pazienti PSP riportano più comunemente rispetto ai pazienti PD: apatia, ansia e depressione. Infine, l'analisi dei subitem rivela che i pazienti PSP mostrano un peggioramento ‘clinicamente significativo’ dopo 15 mesi soprattutto nei subitem attentivo-esecutivi (Trial Making Test parte B e il disegno di un orologio). Tuttavia è stato possibile osservare che alcuni pazienti hanno anche un miglioramento in specifici subitem al follow-up. Questo miglioramento potrebbe essere attribuibile ad una più elevata dose farmacologica (nonostante il trattamento dopaminergico alla baseline non fosse significativamente diverso al follow-up). Tuttavia, è importante notare che tali alterazioni erano presenti soprattutto in subitem sensibili alle problematiche motorie (i.e., disegno di figure e collegamento di cerchi con una penna) che quindi potrebbero aver alterato la performance. Questi limiti della scala MoCA e MMSE sono già stati osservati in precedenza nei pazienti con PD (Biundo et al., 2016b; Hu et al., 2014), e possibilmente sono ancora più pronunciati nei parkinsonismi atipici. In conclusione i nostri risultati rivelano che i pazienti PSP hanno una performance notevolmente alterata rispetto agli altri disturbi parkinsoniani (MSA e PD), e dopo circa 6 anni di durata di malattia, il 33% dei pazienti PSP ha una diagnosi di demenza. Questa severa progressione è probabilmente associata ad una diffusione di aggregati tau che coinvolge anche strutture corticali. Al contrario, il pattern di compromissione cognitiva in pazienti con MSA è meno severo, e probabilmente è associato ad una predominanza sottocorticale della patologia, con un coinvolgimento corticale solo secondario alle alterazioni sottocorticali. Pertanto, i nostri risultati suggeriscono che la valutazione neuropsicologica può essere utile nella differenziazione dei profili cognitivi nei parkinsonismi atipici e per monitorare la progressione della malattia. PARTE III – Studi di neuroimmagine sulle sinucleinopatie Capitolo 5: Effetti dei depositi di amiloide sulle manifestazioni cognitive e motorie nella malattia di Parkinson Alterazioni cognitive, in particolare deficit esecutivi, possono essere osservati anche nelle prime fasi del PD (Aarsland, Bronnick, Larsen, Tysnes & Alves, 2009). La disfunzione frontostriatale del sistema dopaminergico può influenzare la presenza di problemi esecutivi ed attentivi (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), tuttavia al momento le evidenze relative al trasportatore striatale di dopamina (DAT) sono inconsistenti (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). I meccanismi neuropatologici che stanno alla base delle alterazioni cognitive nei PD sono eterogenei (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker & Robbins, 2010), ed il contributo del deposito di amiloide in aggiunta alla sinucleinopatia rimane ancora poco definito, soprattutto nelle prime fasi della malattia. Pertanto, lo scopo del presente studio è stato quello di indagare l'interazione tra depositi di amiloide nel circuito frontostriatale, deficit dopaminergico striatale, grado di atrofia cerebrale ed il loro contributo nelle alterazioni cognitive (i.e., funzioni fronto-esecutive) nelle prime fasi del PD. Una coorte multicentrica di 33 pazienti con PD ricavata dal ‘Parkinson's Progression Markers Initiative’ è stata sottoposta a una tomografia ad emissione di positroni (PET) con radiofarmaco [18F]florbetaben, tomografia ad emissione di fotone singolo (SPECT) con radiofarmaco [123I]FP-CIT, risonanza magnetica (MRI) strutturale, valutazione clinica e cognitiva. Dai nostri risultati emerge che elevati livelli di depositi di amiloide erano associati ad una riduzione del deficit dopaminergico nello striato dorsale (rispetto ai bassi livelli di depositi di amiloide), ad un aumento dell’atrofia cerebrale in regioni frontali ed occipitali, e ad una tendenza a manifestare più frequentemente alterazioni cognitive globali (come valutato dal MoCA), ed in test fronto-esecutivi. Inoltre, le deposizioni di amiloide nelle regioni frontostriatali erano inversamente correlate alla performance cognitiva. Nel complesso i nostri risultati suggeriscono che pazienti con PD in fase iniziale di malattia e amiloidosi hanno un più elevato grado di atrofia cerebrale e possono esperire maggiori deficit cognitivi (i.e., disfunzioni esecutive) e alterazioni motorie rispetto a soggetti negativi all’amiloide. I nostri risultati sembrano essere in linea con una recente ipotesi neuropatologica che considera il danno e disfunzione assonale a livello sinaptico come un elemento caratteristico del PD (Tagliaferro & Burke, 2016). Infatti, i neuroni del sistema dopaminergico sono particolarmente vulnerabili alla sinucleinopatia a causa delle loro caratteristiche assonali: gli assoni sono lunghi, sottili e non mielinizzati. Questa ipotesi è confermata anche da studi di neuroimmagine PET con traccianti che si legano al DAT (Caminiti et al., 2017), suggerendo che le aggregazioni di sinucleina nel PD possono influenzare la funzione sinaptica e la trasmissione di segnale sin dalle prime fasi della malattia. I nostri risultati suggeriscono quindi una possibile interazione tra depositi di amiloide e sinucleinopatia, in cui la presenza di amiloide può facilitare la diffusione di sinucleina (i.e., corpi di Lewy) (Toledo et al., 2016), pertanto questa interazione può contribuire ulteriormente alla vulnerabilità assonale. In linea con questa ipotesi, i nostri risultati sembrano confermare che le deposizioni di amiloide agiscono sinergicamente con la sinucleinopatia, influenzando le manifestazioni cliniche del PD. Capitolo 6: Profilo neurostrutturale dell’atrofia multisistemica con alterazioni cognitive A differenza di altre sinucleinopatie (e.g., PD e DLB), la presenza di demenza è considerata un criterio di esclusione nella diagnosi di MSA (Gilman et al., 2008), tuttavia vi è una crescente evidenza che pazienti affetti da MSA possano manifestare alterazioni cognitive, che includono disfunzioni esecutive ma anche deficit cognitivi multidominio, e in alcuni casi anche demenza (Gerstenecker, 2017). Il MMSE è una scala cognitiva globale comunemente utilizzata nella pratica clinica, e recentemente uno studio multicentrico ha suggerito l’utilizzo di un cutoff <27 per aumentare la sensibilità di tale scala nell'identificare alterazioni cognitive in pazienti MSA (Auzou et al., 2015). I meccanismi che sottendono le disfunzioni cognitive in soggetti MSA non sono ancora stati identificati ed evidenze da studi di MRI suggeriscono un discreto contributo corticale e sottocorticale per spiegare tali alterazioni cognitive (Kim et al., 2015; Lee et al., 2016a). Tuttavia questi risultati sono basati su un numero relativamente piccolo di pazienti e in vari stadi di malattia, inoltre sono studi basati su singoli centri. Pertanto, lo scopo del nostro studio multicentrico è stato quello caratterizzare i cambiamenti anatomici associati ad alterazioni cognitive in pazienti MSA e di investigare le differenze strutturali corticali e sottocorticali rispetto ad un campione di soggetti sani. Abbiamo quindi esaminato retrospettivamente 72 pazienti MSA, e definito 50 MSA come cognitivamente normali (MSA-NC) e 22 con alterazioni cognitive (MSA-CI) utilizzando il cutoff del MMSE <27. Abbiamo inoltre confrontato direttamente i due sottogruppi di MSA, e comparato l’intero gruppo di MSA ad un campione di 36 controlli sani (HC) utilizzando un’analisi di ‘morfometria basata sui voxel’ che analizzava la sostanza grigia e bianca. Inoltre, abbiamo applicato anche una segmentazione automatizzata dei volumi sottocorticali. Dai nostri risultati emerge che i pazienti MSA, rispetto a soggetti sani, hanno una diffusa atrofia corticale (i.e., che coinvolge bilateralmente aree frontali, occipito-temporali e parietali), sottocorticale ed alterazioni alla sostanza bianca. Tuttavia, nel confronto diretto, i soggetti MSA-CI mostrano solo una focale riduzione del volume a carico della corteccia prefrontale dorsolaterale sinistra rispetto a pazienti MSA-NC. Tali risultati suggeriscono che la patologia corticale abbia un effetto marginale sulle alterazioni cognitive nei pazienti MSA. Suggeriamo quindi che le alterazioni cognitive siano piuttosto determinate da una degenerazione frontostriatale focale, che sembra essere in linea con il concetto di ‘alterazioni cognitive sottocorticali’.

Pathologisches Glücksspiel (PG) ist eine psychiatrische Erkrankung, die gerade erst im DSM-5 der gleichen Kategorie wie substanzgebundene Suchterkrankungen zugeordnet wurde. Bildgebungsstudien zu Substanzabhängigkeit beobachteten funktionelle und strukturelle Veränderungen im präfrontalen Kortex (PFC) und mesolimbischen Belohnungssystem (d.h. Striatum). Für PG wurden ähnliche Veränderungen berichtet; jedoch gibt es kaum Studien, die sich mit verschiedenen Aspekten funktioneller und struktureller Korrelate in diesen Regionen beschäftigen. Diese Arbeit untersuchte PG Patienten, alkoholabhängige (AD) Patienten und Kontrollpersonen (HC) mit Magnetresonanztomografie. In Analyse I wurden funktionelle Gehirndaten während der Belohnungsaufgabe zwischen den drei Gruppen verglichen. In Analyse II wurde das Volumen grauer Substanz mit voxelbasierter Morphometrie und in Analyse III die intrinsische Gehirnaktivität mit einer seedbasierten funktionellen Konnektivitätsanalyse von PG Patienten und HC ausgewertet. Die Analysen ergaben veränderte Aktivierungen in frontostriatalen Arealen während der Verarbeitung von Verlustvermeidung für PG Patienten im Vergleich zu HC. PG Patienten unterschieden sich dabei in ihrer Aktivierung von AD Patienten während der Antizipation von Geldverlust. Weiterhin zeigten PG Patienten erhöhte Volumina grauer Substanz und eine erhöhte funktionelle Konnektivität in frontostriatalen Arealen im Vergleich zu HC. Die Ergebnisse liefern weitere Hinweise für eine veränderte Belohnungsverarbeitung in PG und betonen die Bedeutung der Verlustvermeidungsverarbeitung. Die Volumenveränderungen im und die erhöhte Konnektivität zwischen dem PFC and Belohnungssystem deuten auf eine veränderte Interaktion zwischen diesen Regionen hin. Da solche Veränderungen in kortikostriatalen Systemen Ähnlichkeiten zu denen in Substanzabhängigkeiten aufweisen, unterstützen die Ergebnisse die neue Klassifikation des PG im DSM-5.
Pathological gambling (PG) is a psychiatric disorder newly classified under the same category as substance use disorders in the DSM-5. Neuroimaging studies on substance-related addictions reported functional and structural changes in the prefrontal cortex (PFC) and the mesolimbic reward system (i.e., striatum). For PG, findings are not that extensive, but also demonstrate altered reward processing and prefrontal function. However, there is a lack of studies focusing on different aspects of functional and structural correlates within these areas in PG. This thesis investigated PG patients, alcohol dependent (AD) patients and healthy controls with magnetic resonance imaging (MRI). In analysis I, functional brain data of a reward paradigm was compared between the three groups. In analysis II, local gray matter volume of PG patients and controls was processed via voxel-based morphometry. Resting-state data of PG patients and controls was analyzed via seed-based functional connectivity in analysis III. Results revealed altered brain responses in fronto-striatal areas during loss avoidance processing in PG patients as compared to controls. Importantly, PG patients differed in their brain responses from AD patients during the prospect of monetary loss. Moreover, PG patients showed an increase in local gray matter volume and functional connectivity in frontal-striatal areas as compared to controls. Our results add further evidence for an altered reward processing in PG and underline the importance of loss avoidance processing. Moreover, our findings of volumetric alterations within and increased connectivity between PFC and reward system, suggest an altered interaction between these brain regions. Since such alterations in cortico-striatal circuits resemble those reported for substance-related addictions, our findings support the new classification of PG in the DSM-5.

A polineuropatia inflamatória desmielinizante crônica (PIDC) é uma síndrome caracterizada fundamentalmente pela disfunção do Sistema Nervoso Periférico e que afeta muito a qualidade de vida dos pacientes. O envolvimento da PIDC com o Sistema Nervoso Central tem sido descrito, maiormente como sendo subclínico, porém não há estudos sobre a caracterização deste envolvimento de uma forma ampla e quantitativa. Avaliamos 11 pacientes com PIDC, todos tratados e sem sinais clínicos de alterações centrais, e 11 controles, pareados em gênero e faixa etária de 19 a 69 anos. Foram adquiridas neuroimagens em uma máquina de Ressonância Magnética de alto campo (3T) usando diferentes técnicas de imagens; volumétricas ponderadas em T1, volumétricas de inversão e recuperação com atenuação de fluidos e ponderadas em T2, relaxométricas de cinco ecos para mapas de T2, de transferência de magnetização e por tensor de difusão. As imagens foram processadas em diferentes ferramentas computacionais e foram obtidos resultados para estudos da difusibilidade, volumetria, morfometria, tratometria e conectividade cerebral, além de achados radiológicos para os pacientes. As análises de grupos foram executadas por; 1) testes paramétricos monocaudais de duas amostras pareadas para os resultados da volumetria, da tratometria e conectividade cerebral; 2) mapeamento estatístico paramétrico para os resultados da morfometria baseada em voxel e; 3) estatística espacial baseada em tratos para os resultados da difusibilidade. Foram detectas alterações em todas as comparações. Os principais achados indicam um envolvimento possivelmente caracterizado por uma perda volumétrica encefálica generalizada, sobretudo nas regiões periventriculares associadas a ventrículos proeminentes acrescido de, um aumento da difusibilidade transversa e oblíqua nos maiores tratos de substância branca e, também há uma perda de densidade na substância branca periventricular e um aumento na substância cinzenta em uma região que sinaliza para o espessamento trigeminal bilateral e, uma redução geral da conectividade cerebral estrutural.
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a severe disease fundamentally characterized by dysfunction of the Peripheral Nervous System and affects greatly the quality of life of patients. The Central Nervous System (CNS) involvement in CIDP has not been described using recent quantitative neuroimaging techniques. We evaluated 11 patients with CIDP, all treated and without clinical signs of central alterations and 11 controls matched for gender and age group of 19 to 69 years. Magnetic Resonance Imaging were performed on a 3T scanner using different imaging techniques; structural 3D T1-weighted, fluid-attenuated inversion recovery, relaxometry with 5 echoes pulse sequence for T2 maps, magnetization transfer weighted and diffusion tensor imaging. The images were processed on different tools and were obtained results for the studies of diffusivity, volumetry, morphometry, tractometry, brain connectivity, and radiological findings of patients. Different statistical group analyses were performed in the quantitative results: 1) Parametric test for volumetry, tractometry and brain connectivity; 2) Parametric mapping for voxel morphometry; 3) Tract-based spatial statistics (TBSS) for diffusion coefficients. Changes were detected in all comparisons. In the patients, our main findings are: generalized loss brain volume more pronounced in periventricular regions associated with prominent ventricles, increased simultaneously perpendiculars and parallel diffusivity in the major tracts of the TBSS analyze, white matter density loss in the periventricular area, some bilateral trigeminal thickening, and general reduction of the brain connectivity. The CIDP affects the global brain and represents a demyelination in the CNS.

In this study, we examined the regional grey matter density in 35 spider phobic patients and 33 age, gender and education matched healthy controls. We used a method called Voxel-Based Morphometry, which allowed us to conduct a voxel- by-voxel analysis of the entire brain. We also tried to determine if there was any relationship between the severity of fear (expressed in BAT and SPQ score) and grey matter density. Based on previous findings, we expected to find structural changes in the following brain regions: - prefrontal cortex; - orbitofrontal cortex; - anterior cingulate cortex; - insula; - visual and associative cortices. Between-group comparison of spider phobic patients and healthy controls yielded no significant results. Additionally, and as expected, we did not find a between- group difference in TIV. Surprisingly, however, we found several brain regions whose GMD was significantly correlated with severity of spider phobia. The score that correlated with several regions GMD and yielded the largest cluster was the SPQ. SPQ was positively correlated with dorsal anterior cingulate, right insula and left inferior parietal lobule. Final distance in centimetres was correlated with left superior frontal gyrus and right paracentral lobule densities. All correlations were observed at a cluster level and no significant results at peak level were found. Interestingly, out of all BAT fear values, only BAT when the spider was taken away had a positive correlation with GMD (vermis). There were no indications of reduced GMD in spider phobic patients. Overall, our regions of significance were in line of those of other structural and functional neuroimaging studies in the field of specific phobia. As expected, we found GMD changes in the prefrontal cortex, ACC, insula and the associative 60 cortices. The functions of these regions such as processing of disgust, attention, autonomous responses, consolidation of memory and regulation of affect support the possible involvement of these structures in SP. We did, however, also yield some unexpected results (vermis, right paracentral lobule). Interestingly and in contrast to other studies, our results were only limited to the phobic group itself- we found no regions of significance in the SP-HC between-group analysis. In the future, more VBM studies with larger size of spider phobic subjects should be conducted, further investigating both the between-group differences and the correlation between spider phobia severity and GMD. Additionally, studies should investigate the relationship between structural changes and activation patterns observed in fMRI, find out whether brain changes precede the clinical symptoms or vice versa and see, if structural changes normalize in response to CBT the same way functional changes do
In dieser Studie wurde mittels auf MRT-Datensätzen basierender VBM der Frage nachgegangen, ob Patienten mit einer Spinnenphobie Veränderungen der grauen oder weißen Substanz des Gehirns aufweisen. Bei VBM werden regionale Volumenveränderungen der grauen und der weißen Substanz auf dem Boden struktureller MRT-Bilder bestimmt. Wir haben veränderungen in folgenden Regionen erwartet: - präfrontalem Kortex - orbitofrontalem Kortex - anteriorem cingulärem Kortex - Inselkortex - Sehrinde. Der Spinnenphobie-Fragebogen (SPQ) ergab eine positive Korrelation mit dorsalem cingulärem Kortex, rechtem Inselkortex und dem linkem Lobulus parietalis inferior. Auch Vermis, rechter Lobulus paracentralis und der linke Gyrus frontalis superior Dichte zeigte eine positive Korrelation mit Schwergrad der Spinnenphobie. Zusammenfassend sind unsere Ergebnisse übereinstimmend mit den Ergebnissen von anderen Studien. Wie erwartet, haben wir Veränderungen im präfrontalen Kortex, anteriorem cingulärem Kortex und Inselkortex gefunden. Diese Regionen sind für Ekel, Aufmerksamkeit, autonome Reaktionen und Gedächtnis verantwortlich, alle diese Funktionen spielen eine Rolle in spezifischen Phobien. In Zukunft, mehr und größeren VBM-Studien sind notwendig, um die Ergebnisse von unserer Studie zu überprüfen

BACKGROUND: Migraine is a primary headache disorder that has a high prevalence and burden of disease throughout the world. Migraine symptoms include throbbing head pain, nausea, hypersensitivity to light, sound, and smell, and autonomic, cognitive, emotional, and motor disturbances. About a third of migraineurs have aura symptoms which are transient neurological symptoms with gradual onset before the migraine attack, visual disturbances, sensory loss, and/or communication impairment. The trigeminovascular system, central descending modulation, and brainstem descending modulation have been implicated in the pathophysiology of migraine. However, the exact neurovascular mechanism for migraine has not been determined. Several imaging techniques have been used to find structural and functional brain changes in migraineurs. OBJECTIVE: In order to further existing knowledge of migraine pathophysiology, structural brain differences were investigated using imaging between migraineurs and healthy individuals and differences within migraineurs. METHODS: Thirty-two patients with migraine (25 females) and 32 healthy control subjects (25 females) age-, ethnicity-, and gender-matched participated in our study. Magnetic resonance imaging (MRI) scans were collected from each participant. Then, voxel-based morphometry (VBM) was utilized to find any gray matter (GM) volume differences between migraine patients and controls. Also, VBM was performed in specific regions-of-interest (ROIs) to compare 11 migraine patients with aura (MA) and 11 migraine patients without aura (MO). RESULTS: A significant increase in regional gray matter volume difference was observed for migraine patients compared to control subjects in the intracalcarine gyrus of the visual cortex (corrected, p<0.05). In the VBM analysis of ROIs, the similarities between the MO and MA subjects included increases in the anterior cingulate cortex (ACC), hippocampus, insula, and intracalcarine cortex, along with decreases in the ACC and insula (uncorrected, p<0.05). MO subjects had decreases in the amygdala, hippocampus, intracalcarine cortex, and thalamus, but not in the MA subjects (uncorrected, p<0.05). The MA patients had increases in the amygdala and thalamus, but not in the MO patients (uncorrected, p<0.05). DISCUSSION: It can be concluded that the visual cortex is involved in the migraine mechanism since a large increase in GM volume difference was found in migraine, MO, and MA cohorts, as well as results from previous studies. Numerous GM volume changes in MO and MA cohorts reinforce evidence that particular brain regions are a part of migraine pathophysiology, but there were some regions that do not. Further research using imaging analysis and with larger study populations should be conducted to enhance our understanding of the migraine mechanism and differences that arise between migraine groups, so that diagnosis and treatment administration can be improved.

碩士
國立陽明大學
腦科學研究所
101
Background: Conventional voxel-based morphometry (VBM) protocols rely on T1-weighted image (T1WI) for analyses with proposed major limitation in (1) inaccurate tissue segmentation, (2) signal inhomogeneities and (3) field dependence. Patients with focal cortical dysplasia (FCD) have involved in several VBM studies because FCD may be very subtle in appearance and might be not clearly visible by conventional clinical diagnosis. The comparison between single patient and normal database was used to detect the potential lesion of FCD. Hypothesis: The VBM algorithms with multi-modal approach provide (1) improved segmentation of sublobar gray-matter (GM) in comparison with single-modal approach, and (2) the potential applications in detecting FCD with the abnormal tissue of sublobar GM. Materials and Methods: With brain image data of 24 normal subjects using both 1.5T and 3T magnetic resonance imaging (MRI), GM segmentation was obtained with single- and multi-modal approaches using customized VBM. After de-scalping and bias-field correction, the images were segmented with single-modal [that using T1WI only, we called them as FAST-1 (FMRIB’s Automated Segmentation Tool-1) and SPM8-1 (Statistical Parametric Mapping 8-1)] and multi-modal [that combing the information of T1WI, proton-density weighted image (PDWI) and T2-weighted image (T2WI), we called them as FAST-3 and SPM8-3] approaches by FSL (FMRIB Software Library) and SPM8 algorithms. Group comparison of GM probabilities was made after the images normalized to the customized template of GM. Additionally, two patients of FCD were compared with the normal database which was created from 24 normal subjects, and were evaluated for the potential detection of brain lesions by single- or multi-modal VBM approaches. Results: (1) Based on optimized and customized VBM protocol, our results demonstrated the order of GM probability as FAST-3 > SPM8-3 > SPM8-1 > FAST-1 by statistical inferences using paired t-test with false discovery rate (FDR), p < 1×10-5. By validation using BrainWeb (simulated brain MRI data) and expert-based (real brain data) as ground truth, multi-modal approach (FAST-3) showed higher sensitivity and similar indices of GM segmentation (GM probability > 50%) in the basal ganglia with expert-based validataion. (2) The results of two FCD patients with z value > 3 showed focal lesions (based on the post-operation T1WI) was detected by both single-modal and multi-modal approaches, but multi-modal approach showed more regional differences as compared with single-modal approach. Conclusion: VBM protocol was optimized by comparing the sensitivity and similarity of GM segmented by single- and multi-modal approaches. FAST-3 demonstrated improved segmentation of sublobar GM using multiple image modalities. VBM approaches may be used to assist or remind neuroradiologists to detect the subtle lesions, e.g. FCD.

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Informática Médica)
Os estudos relacionados com a neuroimagem têm assumido nos últimos anos grande importância por parte da comunidade médica e científica. O aumento da esperança média de vida faz com que se registem cada vez mais doenças do cérebro, das quais as demências e as doenças degenerativas têm assumido especial importância. Na tentativa de perceber quais as alterações anatómicas registadas no cérebro com a idade e aquando do surgimento destas patologias começaram a ser realizados estudos estruturais a este onde a Ressonância Magnética tem-se demonstrado como principal ferramenta para este estudo. Atualmente existem diversas técnicas que possibilitam o estudo estrutural e anatómico do cérebro todavia ainda não existe nenhuma técnica que possibilite o estudo integral de todas as características estruturais do cérebro; no entanto a medição da espessura cortical, volumetria e morfometria baseada em vóxel têm assumido especial preponderância no estudo destas características. O objetivo principal do presente trabalho consistiu em efetuar uma análise por regiões e por vóxeis de forma a perceber quais as regiões cerebrais que eram mais afetadas com a idade no estudo da volumetria, espessura cortical e da área, para isto foram utilizados um método convencional, e o GLMfit para a análise por regiões e o QDEC e o SPM8 para o estudo por vóxeis. Para se poder efetuar os estudos referidos anteriormente foi necessário pré-processar todos os dados em estudo através da utilização da aplicação Freesurfer que possibilitou a correção de pequenos erros originados durante a aquisição das imagens. Com esta dissertação conclui-se que os métodos utilizados para a deteção do comportamento das variáveis em estudo nas análises por regiões se demonstram coerentes entre si e entre os dados bibliográficos consultados, todavia na análise por vóxeis as conclusões não foram tão lineares sendo mesmo impossível efetuar uma comparação entre esses métodos, pois os resultados obtidos foram totalmente distintos.
Studies of neuroimaging have assumed great importance in recent years by the medical and scientific community. The increase in life expectancy increases also the number of brain desease, including dementia and degenerative diseases with particular importance. In order to understand the anatomical alterations caused by aging and these diseases, structural Magnetic Resonance Imaging has proven to be a valuable tool for . Currently there are several techniques that enable structural and anatomical study of the brain However there is still no technique that enables the comprehensive study of all the structural features of the brain, however cortical thickness, volumetric and voxel-based morphometry measurements have assumed particular preponderance in study of these topics. The main objective of this study was to perform an analysis by region and voxel in order to understand which brain regions were affected with aging in term of volumes, cortical thickness and area, so for that were used for a conventional method, and GLMfit for analysis by regions and QDEC and SPM8 for study by voxels. In order to make the studies described above, it was necessary to pre-process all the data in the study by using the FreeSurfer application that enabled the correction of minor errors originated during image acquisition. With this thesis it is possible to conclude that the methods used for the detection of the variables behavior under study are coherent among them and according to the literature, however in the analysis by voxels the findings were not as linear as expected and it was even impossible to performe a comparison between these methods once the results were completely different.

Dissertação de mestrado em Psicologia Aplicada
Creativity is a complex construct since there isn´t a consensual definition among the authors in the field. Numerous instruments have been used to evaluate this construct, one of them was used for Portuguese population properly validated, to study creative personality, that is, the Creative Personality Scale (CPS). Numerous studies have tried to understand neural correlates of creative personality. This specific study intends to explore the association between creative personality scale score and gray matter (GM) density using Voxel-Based Morphometry (VBM), through volumetrical alterations of gray matter (GM). In order to achieve this, the Creative Personality Scale was administered in adolescents and young adults and GM densities were measured through VBM, analyzing the volumetrical alterations of GMV. The results observed confirmed that there is a negative association between GM densities and scores of CPS. This means that a decreased on the GM was found in Superior Frontal Gyrus (SFG), Middle Frontal Gyrus (MFG), Inferior Frontal Gyrus (IFG) and Left Caudate(LC) which was related to an increase of creative personality. We concluded that the smaller the density of GM, the greater were the scores of creative personalities.
A criatividade é um constructo complexo visto que, não existe uma definição consensual entre os autores deste campo. Inúmeros instrumentos têm vindo a avaliar este constructo, sendo que, um deles foi usado na população portuguesa, devidamente validado para estudar a personalidade criativa, a Escala da Personalidade Criativa. Vários estudos têm tentado perceber os correlatos neurais da personalidade criativa. Este estudo em específico visa explorar a associação entre a personalidade criativa e a densidade da substância cinzenta avaliada através da Voxel-Based Morphometry (VBM), analisando as alterações volumétricas na substância cinzenta. Assim, foi administrada a Escala de Personalidade Criativa a adolescentes e jovens adultos e recolhidas imagens de ressonância magnética estrutural para estudar a possível associação entre os scores da personalidade criativa e as alterações volumétricas da substância cinzenta. Os resultados observados confirmam que existe uma associação negativa entre o volume de substância cinzenta e os scores da escala da personalidade criativa, o que significa que foi encontrado um decréscimo de substância cinzenta no Giro Frontal Superior, Giro Frontal Médio, Giro Frontal Inferior e Caudado Esquerdo, associada a um aumento da personalidade criativa. Concluímos que quanto menor o volume de substância cinzenta maiores os scores de personalidade criativa.
Apoio disponibilizado através do financiamento prestado oriundo do anterior projeto com a referência POCI-01-0145-FEDER-028228

The human brain is a complex and powerful organ, directing every aspect of life from somatosensory and motor function to visceral responses to higher order cognition. Neurological and psychiatric disorders often disrupt normal functioning. While the clinical symptoms of such disorders are known, their biological underpinnings are not as clearly characterized. Structural neuroimaging is a powerful, non-invasive tool that can play a critical role in finding biomarkers of these illnesses. Currently, variations in pre-processing techniques yield inconsistent and conflicting results. As neuroimaging is a nascent branch of medical research, gold standards in imaging methodologies have not yet been established. Quantitatively validating and optimizing the way these images are preprocessed is the first step towards standardization. Voxel-based morphometry (VBM) is one technique that is commonly used to compare whole-brain structural differences between groups. Statistical tests are used to compare intensities of voxels throughout all brain scans in each group. In order to ensure that comparable voxels are being tested, the images must be fitted into a common space, which is done through image preprocessing. Spatial normalization to templates is an early pre-processing step that is executed unreliably as many options for both templates and normalization algorithms exist. To determine the effect variations in template usage may cause, we utilized a VBM approach to detect simulated lesions. Template performance was analyzed by comparing the accuracy with which the lesion was detected.

Negli ultimi 15 anni si è sviluppato un notevole interesse attorno all'analisi statistica di immagini MRI alla ricerca di alterazioni nei tessuti cerebrali. A tutt'oggi si hanno a disposizione diverse metodologie che permettono di studiare le differenze tra gruppi sia nella materia grigia che nella materia bianca. In particolare, per individuare atrofia nella materia grigia, è stata sviluppata una tecnica chiamata Voxel Based Morphometry (VBM). Questa tecnica è stata ampiamente utilizzata sia per caratterizzare diverse malattie di ordine neurodegenerativo, quali, ad esempio, Alzheimer e Parkinson sia per sottolineare sottili differenze strutturali tra pazienti sani raggruppati per differenti caratteristiche, quali sesso, destrorsi o mancini o più semplicemente per età. La tecnica VBM è stata applicata anche allo studio delle variazioni nelle mappe derivate da imaging di tipo DTI (VBM-DTI). Tuttavia, sono state sollevate obiezioni sulla reale precisione ed efficacia dei risultati ottenuti con l'analisi effettuata su questo tipo di dati. Sono state allora proposte diverse tecniche che tentassero di ovviare ai problemi sollevati dai ricercatori. Una tecnica in particolare, presentata nel 2006, Tract-based Spatial Statistics (TBSS), punta a dare una risposta precisa a tutte le obiezioni fino ad allora sollevate sull'analisi VBM applicata a dati DTI. A tutt'oggi è una tecnica ampiamente utilizzata e riconosciuta efficace nella caratterizzazione delle alterazioni cerebrali individuabili con lo studio delle metriche derivate da immagini DTI, quali Fractional Anisotropy (FA), Axial Diffusivity (AD), Radial Diffusivity (RD) e Apparent Diffusion Coefficient (ADC). In questo lavoro sono state mostrate le potenzialità dell'analisi VBM di immagini MR strutturali acquisite in topi, ratti e umani. Ci siamo concentrati sia su modelli traslazionali di multiple sclerosis (MS) e amyotrophic lateral sclerosis (ALS) sia su dati clinici provenienti da pazienti che hanno subito mild traumatic brain injuries (mTBI) derivanti da incidenti automobilistici, cadute o traumi derivanti da attività sportive. Abbiamo utilizzato il modello sperimentale Experimental Autoimmune Encephalomyelitis (EAE) come modello traslazionale per la MS e il modello murino SOD1(G93A) come modello traslazionale per la ALS. Nel modello sperimentale di Multiple Sclerosis ci siamo concentrati sull'identificazione, con tecnica VBM, di atrofia nella materia grigia corticale di ratti malati. Lo scopo finale era di correlarne i risultati con le analisi istologiche e i dati derivanti da MRI funzionale. Nella seconda parte di questa tesi abbiamo riportato i risultati di uno studio concentrato sulla definizione di biomarcatori in un modello sperimentale murino di amyotrophic lateral sclerosis. Il nostro scopo era di definire tramite MRI, utilizzando sia il VBM che tipi di imaging più tradizionali (basati su analisi di tipo region-based), diversi biomarcatori della malattia col fine ultimo di seguirne l'evoluzione per valutare l'efficacia di una terapia basata su cellule staminali. Nella terza e ultima parte, utilizzando la tecnica TBSS (e VBM-DTI), si è cercato di individuare biomarcatori specifici per gli eventi mTBI, per tentare di risolvere il problema del ritardato recupero delle capacità neurocognitive in pazienti mTBI. In questo lavoro si è cercato di correlare i risultati ottenuti con i dati derivanti dai test neurofisiologici, con lo scopo ultimo di meglio delineare la prognosi in pazienti che hanno subito traumi di tipo mTBI.

Trabalho de revisão do 6º ano médico com vista à atribuição do grau de mestre (área científica de neurociências) no âmbito do ciclo de estudos de Mestrado Integrado em Medicina.
Retinitis Pigmentosa is a group of hereditary retinal dystrophy disorders associated with progressive visual field loss. In the typical form, retinal degeneration starting at photoreceptors rods in the mid-periphery of the retina causes peripheral visual field defects. Twenty-seven patients and forty healthy controls were examined to determine whether progressive peripheral vision loss in Retinitis Pigmentosa patients with partially preserved vision leads to structural cortical changes. Retinal thickness and retinal nerve fiber layer (RNFL) thickness were assessed with optical coherence tomography (OCT). T1 high-resolution brain anatomical magnetic resonance images from each subject were obtained on a 3-T scanner and processed using SPM8. A whole brain voxel-wise statistical comparison of grey matter volume between the two groups was performed using two different contrasts (controls > patients and patients > controls). Significant statistical difference was found for retinal thickness (P < 0.05), but not for RNFL thickness (p > 0.05) between groups. Grey matter atrophy was observed in the left pericalcarine cortex, cuneus gyrus, posterior cingulate gyrus, right pericalcarine cortex and lingual gyrus (p < 0.001, uncorrected for multiple comparisons, at the whole brain level) of Retinitis Pigmentosa patients. Further analysis with a family-wise error (FWE) correction for multiple comparisons revealed grey matter atrophy in the left pericalcarine cortex, cuneus gyrus and lingual gyrus (p < 0.05). Grey matter hypertrophy was not observed. While the retinal thinning observed is consistent with photoreceptor degeneration, no evidence of structural alteration of RNFL was found. The locations of the grey matter atrophy in visual primary and association cortices are coincident with the profile of peripheral visual field deficit seen in Retinitis Pigmentosa. The cortical atrophy registered is likely to be a result of disuse-driven neuronal atrophy and/or transneuronal degeneration of the visual pathway. These findings may have clinical implications for disease management. A Retinopatia Pigmentar é um grupo de distúrbios hereditários de distrofia da retina associado a perda progressiva de campo visual. Na forma típica, a degeneração da retina que se inicia pelos fotoreceptores bastonetes na médio-periferia da retina causa defeitos periféricos de campo visual. Vinte e sete doentes e quarenta controlos saudáveis foram examinados para determinar se a perda progressiva de visão periférica nos doentes com Retinopatia Pigmentar com visão parcialmente preservada conduz a alterações estruturais corticais. As espessuras da retina e da camada de fibras nervosas da retina (CFNR) foram avaliadas com tomografia de coerência óptica (TCO). As imagens cerebrais anatómicas de ressonância magnética de cada participante foram obtidas num scanner 3-T utilizando a sequência T1 de alta resolução e processadas usando o SPM8. Foi realizada uma comparação estatística voxel-a-voxel do volume de matéria cinzenta entre os dois grupos, examinando todo o cérebro, usando dois contrastes simétricos (controlos > doentes e doentes > controlos). Foi encontrada uma diferença estatística significativa para a espessura da retina entre os grupos (p < 0.05) , mas não para a espessura da CFNR (p > 0.05). Na análise exploratória inicial, foi observada atrofia de matéria cinzenta no córtex pericalcarino esquerdo, giro cúneos, giro cingulado posterior, córtex pericalcarino direito e giro lingual (p < 0.001, com correção apenas para clusters de 100 vóxeis) dos doentes com Retinopatia Pigmentar. Uma análise confirmatória subsequente com correção para comparações múltiplas “family-wise error” (FWE) demonstrou atrofia de matéria cinzenta no córtex pericalcarino esquerdo, giro cúneos e giro lingual (p < 0.05). Não foi observada hipertrofia de matéria cinzenta. Enquanto que a redução da espessura da retina observada é consistente com a degeneração de fotoreceptores, não foi encontrada evidência de alteração estrutural da CFNR. A localização das áreas de atrofia de matéria cinzenta nos córtex visuais primário e de associação coincidem com o perfil de défice periférico de campo visual observado na Retinopatia Pigmentar. A atrofia cortical observada é provavelmente um resultado de atrofia neuronal induzida pelo desuso e/ou degeneração transneuronal da via visual. Estes achados podem ter implicações clínicas no controlo da patologia.

碩士
國立陽明大學
腦科學研究所
100
Background: Graphic visualization with an effective interface of integrated anatomical and functional information is helpful for multimodal neuroimaging brain research. Specific aims: (1) To build up an interactive graphic user interface platform with four-dimensional data (3D visualization and time) as well as anatomical information for multiple modalities; (2) To construct a database which includes neuroimage data and anatomical/functional information. Methods and Materials: We employed IDL package to build up graphic visualization and interactive interface. The kernel of visualization platform was constructed based on graphic object class library and the interactive interface was developed using widget I/O control class library provided in IDL environment. The MySQL package was used to construct and to assess both anatomical and functional databases. The platform consisted of four kernel functions, including (1) three-dimension visualization (2) anatomical ontologe (3) structural and functional volume data presentation (4) Four-dimension video presentation Results: The proposed system can read ANALYZE neuroimage data and display two-dimensional graphical section and three-dimensional graphical rendering. The requested anatomical and functional information could be extracted from the database and then be displayed on the screen. The VBM result for mood disorders patients in comparison with normal subjects was directly imported in the platform. The MEG experiment was used to demonstrate the display of time serious data. Conclusions: We developed a flexible, effective, and interactive platform for multimodal neuroimages data visualization. The system could provide the integrated anatomical and functional information to facilitate brain research. Key Words: Interactive visualization software, multimodal neuroimage database, IDL