Clinical applications of magnetic resonance imaging based functional and structural connectivity

Advances in computational neuroimaging techniques have expanded the armamentarium of imaging tools available for clinical applications in clinical neuroscience. Non-invasive, in vivo brain MRI structural and functional network mapping has been used to identify therapeutic targets, define eloquent brain regions to preserve, and gain insight into pathological processes and treatments as well as prognostic biomarkers. These tools have the real potential to inform patient-specific treatment strategies. Nevertheless, a realistic appraisal of clinical utility is needed that balances the growing excitement and interest in the field with important limitations associated with these techniques. Quality of the raw data, minutiae of the processing methodology, and the statistical models applied can all impact on the results and their interpretation. A lack of standardization in data acquisition and processing has also resulted in issues with reproducibility. This limitation has had a direct impact on the reliability of these tools and ultimately, confidence in their clinical use. Advances in MRI technology and computational power as well as automation and standardization of processing methods, including machine learning approaches, may help address some of these issues and make these tools more reliable in clinical use. In this review, we will highlight the current clinical uses of MRI connectomics in the diagnosis and treatment of neurological disorders; balancing emerging applications and technologies with limitations of connectivity analytic approaches to present an encompassing and appropriate perspective

Combined brain language connectivity and intraoperative neurophysiologic techniques in awake craniotomy for eloquent-area brain tumor resection

Speech processing can be disturbed by primary brain tumors (PBT). Improvement of presurgical planning techniques decrease neurological morbidity associated to tumor resection during awake craniotomy. The aims of this work were: 1. To perform Diffusion Kurtosis Imaging based tractography (DKI-tract) in the detection of brain tracts involved in language; 2. To investigate which factors contribute to functional magnetic resonance imaging (fMRI) maps in predicting eloquent language regional reorganization; 3. To determine the technical aspects of accelerometric (ACC) recording of speech during surgery. DKI-tracts were streamlined using a 1.5T magnetic resonance scanner. Number of tracts and fiber pathways were compared between DKI and standard Diffusion Tensor Imaging (DTI) in healthy subjects (HS) and PBT patients. fMRI data were acquired using task-specific and resting-state paradigms during language and motor tasks. After testing intraoperative fMRI’s influence on direct cortical stimulation (DCS) number of stimuli, graph-theory measures were extracted and analyzed. Regarding speech recording, ACC signals were recorded after evaluating neck positions and filter bandwidths. To test this method, language disturbances were recorded in patients with dysphonia and after applying DCS in the inferior frontal gyrus. In contrast, HS reaction time was recorded during speech execution. DKI-tract showed increased number of arcuate fascicle tracts in PBT patients. Lower spurious tracts were identified with DKI-tract. Intraoperative fMRI and DCS showed similar stimuli in comparison with DCS alone. Increased local centrality accompanied language ipsilateral and contralateral reorganization. ACC recordings showed minor artifact contamination when placed at the suprasternal notch using a 20-200 Hz filter bandwidth. Patients with dysphonia showed decreased amplitude and frequency in comparison with HS. ACC detected an additional 11% disturbances after DCS, and a shortening of latency within the presence of a loud stimuli during speech execution. This work improved current knowledge on presurgical planning techniques based on brain structural and functional neuroimaging connectivity, and speech recordingA função linguística do ser humano pode ser afetada pela presença de tumores cerebrais (TC) A melhoria de técnicas de planeamento pré-cirurgico diminui a morbilidade neurológica iatrogénica associada ao seu tratamento cirúrgico. O objetivo deste trabalho é: 1. Testar a fiabilidade da tractografia estimada por difusor de kurtose (tract-DKI), dos feixes cerebrais envolvidos na linguagem 2. Identificar os fatores que contribuem para o mapeamento linguagem por ressonância magnética funcional (RMf) na predição da neuroplasticidade. 3. Identificar aspetos técnicos do registo da linguagem por accelerometria (ACC). A DKI-tract foi estimada após realização de RM cerebral com 1.5T. O número e percurso das fibras foi avaliado. A RMf foi adquirida durante realização de tarefas linguísticas, motoras, e em repouso. Foi testada influência dos mapas de ativação calculados por RMf, no número de estímulos realizados durante a estimulação direta cortical (EDC) intraoperatória. Medidas de conectividade foram extraídas de regiões cerebrais. A posição e filtragem de sinal ACC foram estudadas após vocalização de palavras. O sinal ACC obtido em voluntários foi comparado com doentes disfónicos, após estimulação do giro inferior frontal, e após a adição de um estímulo sonoro perturbador durante vocalização. A tract-DKI estimou um elevado número de fascículos do feixe arcuato com menos falsos negativos. Os mapas linguísticos de RMf intraoperatória, não influenciou a EDC. Medidas de centralidade aumentaram após neuroplasticidade ipsilateral e contralateral. A posição supraesternal e a filtragem de sinal ACC entre 20-200Hz demonstrou menor ruido de contaminação. Este método identificou diminuição de frequência e amplitude em doentes com disfonia, 11% de erros linguísticos adicionais após estimulação e diminuição do tempo de latência quando presente o sinal sonoro perturbador. Este trabalho promoveu a utilização de novas técnicas no planeamento pré-cirúrgico do doente com tumor cerebral e alterações da linguagem através do estudo de conectividade estrutural, funcional e registo da linguagem

右前頭葉機能の高次脳機能ネットワーク

　従来，右前頭葉は損傷されたとしても，ヒトが生きる上での致命的な障害を残す可能性が低いことから，脳損傷後に生じる右前頭葉機能の障害にはあまり注意が払われてこなかった。しかし，実際には右前頭葉の損傷後，麻痺や言語障害がないとしても上手く社会復帰できない患者が少なからず存在したことも事実である。近年，脳画像解析の技術が進歩し，脳機能およびそのネットワークに関する理解は飛躍的に進歩した。これらの進歩と共に，右前頭葉はヒトが社会生活を営む上で欠かすことができない種々の機能を司っていることが明らかになってきた。本項では，種々の右前頭葉機能のうち，作業記憶，視空間認知，メンタライジング，注意に焦点を絞ってその症状と関連するネットワークについて最新の知見をまとめた。さらに，近年注目されている脳腫瘍の手術法，覚醒下手術における右前頭葉機能の温存についても言及した。Disorders of right frontal lobe function have attracted relatively little attention as theygenerally do not have major adverse effects on activities of daily living. However, somepatients have difficulty in returning to their professional lives after right frontal lobedamage, even though they do not have language or motor deficits. Recent developmentsin neuroimaging methodologies have increased our understanding of neuropsychologicalfunctions and networks, and have shown that the right frontal lobe plays critical roles insocial life, including working memory, visuospatial cognition, mentalizing, and attention.This review presents a summary of recent findings regarding right frontal lobe functionsand their neural networks focusing on the above four functions

Inference of Language Functional Network in Healthy, Cancerous and Bilingual Brains by fMRI and Network Modeling

We study the underlying mechanism by which language processing occurs in the human brain using inference methods on functional magnetic resonance imaging data. The data analyzed stems from several cohorts of subjects; a monolingual group, a bilingual group, a healthy control group and one diseased case. We applied a complex statistical inference pipeline to determine the network structure of brain components involved with language. This healthy network reveals a fully connected triangular relationship between the pre-Supplementary Motor Area (pre-SMA), the Broca\u27s Area (BA), and the ventral Pre-Motor Area (PreMA) in the left hemisphere. This triangle\u27\u27 shows consistently in all the healthy subjects (100%) we analyzed regardless of their mono- or multi-lingual status. In addition, we found that Wernicke\u27s Area (WA) on the left hemisphere connects with BA and PreMA to form a V\u27\u27 shape connectivity across 75% of the monolinguals, 50% of the bilinguals speaking a second language and 100% of the bilinguals speaking their native language. By comparing the quantified link weights, we found that the strongest link is between BA and PreMA, followed by pre-SMA and PreMA, and then pre-SMA and BA. This is consistent for all healthy subjects (p \u3c 0.05). Furthermore, we conducted a k-core analysis testing the resiliency of subnetworks in the three groups. Our results show that nodes in the three triangle areas belong mostly to the maximum shell, whereas WA populates mostly in the lower shell, consistently across the data. In a separate study, we describe frontal language reorganization in a 57-year-old right-handed patient with a low-grade left frontotemporal insular glioma. Pre-operative fMRI revealed robust activation in left WA and in the right BA. Intra-operative cortical stimulation of the left inferior frontal gyrus and adjacent cortices elicited no speech deficits, and gross total resection including the expected location of BA resulted in no speech impairment. Our network model found that the right homologue of the BA in this patient functionally connected to the same areas as the left BA in a typical healthy control. As opposed to the functional connection of the left BA in a healthy brain, the right BA did not connect directly with the left WA, but connected indirectly, mediated by the pre-SMA and preMA. In addition, the trans-located BA and WA moves from the lower k shell to the maximum shell during the recovery of the surgery. This case illustrates that pre-surgical fMRI can be used to identify atypical hemispheric language reorganization in the presence of a brain tumor and that network theory can help understand the underlying structure behind functional reorganization

Identifying the Neurocognitive bases of creativity to increase human and computational creativity

En esta Tesis Doctoral se ha identificado la estructura neurocognitiva que sustenta la creatividad humana a partir del análisis conjunto de más de 800 referencias bibliográficas que muestran las investigaciones más importantes realizadas hasta la fecha. Sobre la base de esta estructura, se ha identificado un paradigma neurocognitivo de la creatividad humana y se ha propuesto un modelo neurocognitivo del proceso creativo. Finalmente, también se ha propuesto un paradigma creativo neurocognitivo computacional y se ha diseñado la estructura de un sistema computacional creativo, basado en una estructura multiagente. La investigación que se ha realizado sobre el tema hasta la fecha es muy especializada y se centra en aspectos muy concretos de la creatividad, y en muchos casos tienen poca relación entre sí. Por ello, y para tener una idea conjunta y holística de los procesos neurocognitivos de la creatividad humana, es necesario estudiar todas estas investigaciones de forma interconectada. Esta idea conjunta permitiría dirigir investigaciones más específicas para ser más efectivos. Por ello, lo primero que se ha hecho ha sido clasificar, agrupar, analizar, entrelazar y estructurar, de forma ordenada, las investigaciones más importantes que se han realizado hasta la fecha. Sin embargo, el trabajo realizado va mucho más allá, ya que estructurando y entrelazando las investigaciones existentes ha sido posible identificar ciertos patrones, correlaciones y paralelismos, y realizar ciertas deducciones, que en su conjunto, han permitido identificar los procesos neurocognitivos fundamentales. bases de la creatividad humana. La Tesis se estructura en los siguientes capítulos: Capitulo 2 Análisis de los principales métodos para estimular la creatividad Se analizan las principales definiciones de creatividad, y se ha decidido que el mejor enfoque para su análisis es estructurarla taxonómicamente, bajo el modelo 4P. Se ha realizado una recopilación y análisis de los métodos más efectivos que estimulan la creatividad humana, mostrando las ventajas y desventajas de cada uno. Capítulo 3 Estructura funcional del cerebro humano y su relación con el proceso creativo Se identifica la estructura neurocognitiva general del cerebro humano que permite generar los procesos fundamentales y básicos de su actividad creativa. Capítulo 4 El papel fundamental de la DMN en el proceso creativo Se ha observado que la red de modo predeterminado (DMN) tiene un papel principal en la creatividad. Por ello, se ha dedicado un capítulo a su estudio, y se han identificado varios factores que la involucran directamente en la actividad creativa del cerebro humano. Capítulo 5 Identificación y análisis de las bases neurocognitivas de la creatividad humana Se ha identificado el conjunto general de factores neurocognitivos que sustentan los procesos creativos en el cerebro humano. Capítulo 6 Paradigma neurocognitivo de la creatividad humana Se ha propuesto un modelo neurocognitivo del proceso creativo que reestructura, completa y detalla todos los modelos conceptuales propuestos hasta el momento. Capítulo 7 Paradigma computacional de la creatividad basado en la estructura neurocognitiva humana Analizando las diferentes bases neurocognitivas que sustentan la creatividad humana, se han establecido paralelismos computacionales y se han realizado diferentes sugerencias para el diseño de un sistema computacional creativo.In this Doctoral Thesis, the neurocognitive structure that supports human creativity has been identified based on the joint analysis of more than 800 bibliographical references that show the most important investigations carried out to date. Based on this structure, a neurocognitive paradigm of human creativity has been described, and a neurocognitive model of creative process has been proposed. Finally, a computational neurocognitive creative paradigm has been also proposed, and the structure of a creative computational multi-agent system has been designed. The research that has been carried out on the subject is very specialized and focuses on very specific aspects of creativity, and in many cases they have little relationship with each other. For this reason, and in order to have a joint and holistic idea of the neurocognitive processes of human creativity, it is necessary to study all these investigations in an interconnected way. This joint idea would allow directing more specific investigations in order to be more effective. For this reason, the first thing that has been done has been to classify, group, analyze, intertwine and structure, in an orderly manner, the most important investigations that have been carried out to date. However, the work carried out goes much further, since by structuring and intertwining the existing research it has been possible to identify certain patterns, correlations and parallelisms, and make certain deductions, which as a whole, have made it possible to identify the fundamental neurocognitive bases of human creativity. Chapter 2 Analysis of the main methods to stimulate creativity The main definitions of creativity are analyzed, and it has been decided that the best approach for its analysis is to structure it taxonomically, under the 4P model. A compilation and analysis of the most effective methods that stimulate human creativity has been carried out, showing the advantages and disadvantages of each one. Chapter 3 Functional structure of the human brain and its relationship with the creative process The general neurocognitive structure of the human brain that allows the generation of the fundamental and basic processes of its creative activity are identified. Chapter 4 The fundamental role of the DMN in the creative process It has been observed that the Default mode network (DMN) has a main role in creativity. For this reason, a chapter has been dedicated to its study, and several factors have been identified that directly involve it in the creative activity of the human brain. Chapter 5 Identification and analysis of the neurocognitive bases of human creativity The general set of neurocognitive factors that underpin creative processes in the human brain has been identified. Chapter 6 Neurocognitive paradigm of human creativity A neurocognitive model of the creative process has been proposed, which restructures, completes and details all the conceptual models proposed so far. Chapter 7 Computational paradigm of creativity based on the human neurocognitive structure Analyzing the different neurocognitive bases that support human creativity, computational parallels have been established and different suggestions have been made for the design of a creative computational system

A narrative review of the anatomy and function of the white matter tracts in language production and comprehension

Much is known about the role of cortical areas in language processing. The shift towards network approaches in recent years has highlighted the importance of uncovering the role of white matter in connecting these areas. However, despite a large body of research, many of these tracts’ functions are not well-understood. We present a comprehensive review of the empirical evidence on the role of eight major tracts that are hypothesized to be involved in language processing (inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, extreme capsule, middle longitudinal fasciculus, superior longitudinal fasciculus, arcuate fasciculus, and frontal aslant tract). For each tract, we hypothesize its role based on the function of the cortical regions it connects. We then evaluate these hypotheses with data from three sources: studies in neurotypical individuals, neuropsychological data, and intraoperative stimulation studies. Finally, we summarize the conclusions supported by the data and highlight the areas needing further investigation

Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons

Frontoparietal networks underlying saccadic eye movements in the common marmoset

Common marmosets (Callithrix jacchus) are small-bodied New World primates that are increasingly popular as model animals for neuroscience research. Their lissencephalic cortex provides substantial advantages for the application of high-density electrophysiological techniques to enhance our understanding of local cortical circuits and their cognitive and motor functions. The oculomotor circuitry underlying saccadic eye movements has been a popular system to study cognitive control. Most of what we know about this system, comes from electrophysiological studies on macaques, but most of their cortical oculomotor areas are buried within sulci and harder to access for high-density recordings. In contrast, marmosets provide greater advantages for studies of the oculomotor system, since critical areas of this network such as the frontal eye fields (FEF) and lateral intraparietal area (LIP) are easily accessible at the cortical surface. In contrast to the well-established macaques, little is known about functional connectivity patterns of common marmosets. In this thesis, we used resting-state ultra-high-field fMRI on anesthetized marmosets and macaques along with awake human subjects, to examine and compare the functional organization of the brain, with emphasis on the saccade system. Independent component analysis revealed homologous resting-state networks in marmoset to those in macaques and humans, including a distributed frontoparietal network. Seed-region analyses of the marmoset superior colliculus (SC) revealed the strongest frontal functional connectivity with area 8aD bordering area 6DR. This frontal region exhibited a similar functional connectivity pattern to the FEF in macaques and humans. The results supported an evolutionarily preserved frontoparietal system and provided a starting point for invasive neurophysiological studies in the marmoset saccade system. We started by investigating the function of the marmoset posterior parietal cortex with electrical microstimulation. We implanted 32-channel Utah arrays at the location of area LIP as identified from our resting-state fMRI study and applied microstimulation while animals watched videos. Similar to macaque studies, stimulation evoked fixed-vector and goal-directed saccades, staircase saccades, and eyeblinks in marmosets. These findings demonstrated that the marmoset area LIP plays a role in the regulation of eye movements and is potentially homologous to that of the macaque. Next, we recorded the neuronal activity in marmoset areas LIP and 8aD using linear electrode arrays while animals performed a pro/antisaccade task. The antisaccade task is a popular paradigm to probe executive control. In this task, participants suppress a prepotent stimulus-driven response in favor of a less potent response away from the stimulus. Our behavioral findings indicated that area 8aD neurons were significantly more active for correct than errorenous antisaccades in contralateral directions, with respect to the recording site. We found neurons with significant stimulus-related activity in area LIP and significant saccade-related neurons in both areas 8aD and LIP. These findings provided further evidence on the role of marmoset frontal and parietal oculomotor areas in oculomotor control, supporting marmosets as alternative primate models of the oculomotor system

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques