Os fatores de risco cardiovascular (FRCV) podem estar associados com pior funcionamento cognitivo em idosos e afetar a estrutura cerebral. Usando ressonância magnética (RM) e morfometria baseada em voxel (voxel-based morphometry; VBM), foram avaliados neste estudo volumes regionais de substância branca (SB) cerebral em uma amostra de base populacional de indivíduos saudáveis com idades entre 65-75 anos (n = 156). Usando o escore de risco de Framingham (ERF) como índice de risco cardiovascular, subdividimos a amostra total em três subgrupos de acordo com a gravidade de FRCV. Comparamos os volumes regionais cerebrais de SB entre estes grupos, e investigamos a relação entre volume de SB e desempenho cognitivo. Por fim, dada a possível influência de variações no gene que codifica a apoliproteína E (APOE) sobre cognição, anatomia cerebral e FRCV, avaliamos possíveis mudanças nos resultados das análises volumétricas cerebrais dependendo da presença do alelo APOE?4. No subgrupo de alto risco, detectamos clusteres com volume significativamente menor de SB na região pré-frontal direita dorsolateral juxtacortical em comparação com ambos os subgrupos de baixo e médio risco cardiovascular. Estes achados permaneceram os mesmos quando a análise estatística levou em conta a presença do alelo APOE?4 como covariável de confusão. O desempenho em tarefa cognitiva de controle inibitório foi inversamente correlacionado com o volume de SB pré-frontal direita, em proporção direta com o grau de risco cardiovascular. Redução significativa na SB parietal profunda também foi detectada bilateralmente no subgrupo de alto RCV em comparação com os outros dois subgrupos. Este é o primeiro estudo de VBM usando amostra grande de idosos a documentar a topografia de déficits volumétricos de SB associados com alto ERF em todo o cérebro. A associação significativa entre menor volume de SB e pior desempenho cognitivo em termos de resposta inibitória indica que as mudanças de volume de SB pré-frontal relacionadas com FRCV são clinicamente significativas, uma vez que o controle inibitório é uma operação cognitiva amplamente reconhecida por depender da integridade cortical pré-frontal / Cardiovascular risk factors (CVRF) may be associated with poor cognitive functioning in elderlies and affect brain structure. Using magnetic resonance imaging (MRI) and voxel-based morphometry (VBM), we assessed regional white matter (WM) volumes in a population-based sample of healthy individuals aged 65-75 years (n=156). Using the Framingham Risk Score (FRS) to assess the severity of CVRF, we subdivided the sample in three subgroups. We compared regional WM volumes in the brain between these subgroups, and investigated the relationship between WM volumes and cognitive performance. Also, given the possible influence of variations in the gene that code the apoliprotein E (APOE) on cognition, brain anatomy and CVRF, we evaluate changes in the results of our volumetric analysis depending on the presence of the APOE?4 allele. In the high-risk subgroup, we detected one cluster of significantly reduced WM volume in the right juxtacortical dorsolateral prefrontal region compared to both low- and intermediate-risk subgroups. This finding remained unchanged when the analysis was repeated taking into account the presence of the APOE?4 allele as a confounding covariate. Inhibitory control performance was negatively related to right prefrontal WM volume, in direct proportion to the degree of CVRF. Significantly reduced deep parietal WM was also detected bilaterally in the high-risk CVRF subgroup. This is the first large VBM study documenting the topography of WM volume deficits associated with high FRS across the whole brain. The significant association regarding poor response inhibition indicates that prefrontal WM volume changes related to CVR are clinically meaningful, since inhibitory control is a cognitive operation widely known to rely on prefrontal cortical integrity

A neuroimaging feature extraction model is designed to extract region-based image features whose values are predicted by base learners trained on raw neuroimaging morphological variables. The main objectives are to identify Alzheimer’s disease (AD) in its earliest manifestations, and be able to predict and gauge progression of the disease through the stages of mild cognitive impairment (EMCI), late MCI (LMCI) and AD. The model was evaluated on the ADNI database and showed 75.26% accuracy for the challenging EMCI diagnosis based on the 10-fold cross-validation. Our approach also performed well for the other binary classifications: EMCI vs. LMCI (72.3%), EMCI vs. AD (95%), LMCI vs. AD (84.3%), CN vs. LMCI (77.5%), and CN vs. AD (96.5%). By applying the model to the Genome-wide Association Study, along with the sparse Partial Least Squares regression method, we successfully detected risk genes such as the APOE, TOMM40, RVRL2 and APOC1 along with the new finding of rs917100. Moreover, the research aimed to investigate the relationship of different biomarkers; especially the imaging biomarkers to better understand the precise biologic changes that characterize Alzheimer’s disease. The unique and independent contribution of APOE4 allele status (E4+\E4-), amyloid (Aβ) load status (Amy+\Amy-) and combined APOE4 and Aβ status on regional cortical thickness (CTh) and cognition were evaluated via a series of two-way ANCOVAs with post-hoc Tukey HSD tests. Results showed that decreased CTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4+ status is associated with increased CTh, in medial and inferior temporal regions. Diverging association patterns of global and regional Aβ load with cortical volume were found in the entorhinal, temporal pole and parahippocampal regions, which were positively associated with regional Aβ load, but with a negative correlation for global Aβ load in MCI stages. In addition, strong positive correlations were shown between baseline regional CTh and the difference of CTh in each region between the CN and AD, even after adjusting for the regional Aβ and APOE genotype (E4+: r = 0.521 and E4-: r = 0.694).

<p>The central theme of the present thesis revolves around the exploration of similarities and differences in brain activity patterns invoked by the component processes underlying mnemonic, executive and attentional functions. The primary aim was to identify and functionally characterize commonly recruited brain regions in terms of shared component processes, which has been a largely neglected area of research in cognitive neuroscience. The vast majority of functional brain imaging investigations of cognition has focused on delineating differences between cognitive functions or processes, with the purpose of isolating the unique functional neuroanatomy that underlies specific cognitive domains. By contrast, the present thesis builds on the results from three imaging studies that focused primarily on detecting commonalities in functional brain activity across different forms of memory processes. In study I, the imaging data from two positron emission tomography (PET) experiments were re-analyzed to identify common activation patterns associated with nine different memory tasks incorporated across the experiments, three each separately indexing working memory, episodic memory, and semantic memory. A generic prefrontal cortex (PFC) network involving discrete subregions of the left hemisphere located in ventrolateral (BA 45/47), dorsolateral (BA 9/44/46), and frontopolar (BA 10) sectors of PFC, as well as a midline portion of the frontal lobes, encompassing the dorsal part of the anterior cingulate cortex (ACC) (BA 24/32), was conjointly recruited across all tasks. In study II, we used a novel mixed blocked/event-related functional magnetic resonance imaging (fMRI) design, which enables separation of brain responses associated with different temporal dynamics to further investigate commonalities of neural activation across working memory, episodic memory, semantic memory, and attention/vigilance. A similar set of common PFC regions, as that discovered in Study I, was found to elicit overlapping brain activity across all memory tasks, with a subset of regions also activated in the attention/vigilance task. Furthermore, the task-induced brain activity was dissociated in terms of the temporal profiles of the evoked neural responses. A common pattern of sustained activity seen across all memory tasks and the attention task involved bilateral (predominantly right-lateralized) ventrolateral PFC (BA 45/47), and the dorsal ACC (BA 24/32), which was assumed to reflect general processes of attention/vigilance. A pattern of sustained activity elicited in all memory tasks, in the absence of attention-related activity, involved the right frontopolar cortex (BA 10), which was assumed to reflect control processes underlying task set maintenance. In addition, common transient activation evoked in the memory tasks relative to the attention task was found in the dorsolateral (BA 9/44) and ventrolateral (BA 47) PFC, the superior parietal cortex (BA 7), and cerebellum. In study III, a mixed fMRI design was used to assess the degree of common brain activity associated with increased executive demand, which was independently manipulated within episodic and working memory. Unitary control modulations involved a shared tonic executive component subserved by fronto-striatal-cerebellar circuitry, assumed to govern top-down context processing throughout task periods, and a stimulus-synchronous phasic component mediated by the intraparietal sulcus (BA 7), assumed to support dynamic shifting of the ‘focus of attention’ among internal representations. Collectively, the theoretical implications of shared neural mechanisms are discussed, with a special focus on human memory and its multifaceted relationships with attention and executive control functions. Finally, the presented imaging data are used to outline a tentative hierarchical neurocognitive model that attempts to give an account of how different unitary component processes might work together during cognitive task performance.</p>

<p>The present thesis investigated family history and neurobiology of social phobia. Social phobia is a disabling disorder characterized by a marked fear of scrutiny in a variety of social situations. By using a validated questionnaire, study I related family history of excessive social anxiety to social phobia and avoidant personality disorder in epidemiologically identified probands in the Swedish general population. A two- to threefold increased relative risk of social anxiety was observed for both diagnostic groups. Thus, having an affected family member is associated with approximately a doubled risk for both social phobia and avoidant personality disorder.</p><p>The neurobiological studies explored situational and anticipatory elicited anxiety by means of positron emission tomography and 15O-water. Study II examined the functional neuroanatomy of social anxiety provocation in social phobics and a healthy comparison group during a public speaking task. Social phobia symptomatology was associated with higher neural activity in the amygdaloid complex, i.e. "the alarm system" of the brain, and lower activity in the prefrontal cortex. Study III examined the neural correlates of anxiety elicited by the anticipation of public speaking in individuals with social phobia. Anticipatory anxiety was accompanied by enhanced regional cerebral blood flow in the dorsolateral prefrontal and inferior temporal cortices as well as in the amygdaloid-hippocampal region. Brain blood flow was lower in the temporal pole and in the cerebellum. These results suggest that social phobia has a neuroanatomical basis in a highly sensitive fear network centered in the amygdaloid-hippocampal region and encompassing the prefrontal cortex.</p>

<p>The present thesis explored the neurobiological basis of three aspects of defense behaviors in humans. Positron emission tomography methodology was used, and changes in regional cerebral blood flow (rCBF) were measured as an index of neural activity. Firstly, brain function was studied in a group of patients suffering from combat-related posttraumatic stress disorder, using a symptom provocation paradigm with combat sounds in order to elicit fear. Exposure to auditory trauma reminders relative to neutral sounds was associated with increased rCBF in sensorimotor areas, the cerebellar vermis, the periaqueductal gray matter, and the right amygdala, whereas decreased activity was observed in the retrosplenial area of the posterior cingulate cortex. Secondly, the neural circuitry mediating the acoustic startle response and its habituation was studied in a group of healthy subjects. During acoustic startle stimulation as compared to a resting condition, increased rCBF was found in a medial posterior area of the pons corresponding to the nucleus reticularis pontis caudalis. As a result of startle repetition, altered activity was found in the cerebellum, pointing to its involvement in startle habituation. Thirdly, neural activity associated with startle modulation by phobic fear was studied in a group of subjects with specific animal phobias during exposure to pictures of their feared and non-feared objects, paired and unpaired with acoustic startle stimuli. As a result of startle potentiation, increased rCBF was found in the left amygdaloid-hippocampal region, and medially in the affective division of the anterior cingulate cortex. In conclusion, these results provide evidence for the involvement of limbic and paralimbic brain areas during fear provocation and fear-potentiated startle and for a similar neurocircuitry underlying startle in humans and animals.</p>

The present thesis investigated family history and neurobiology of social phobia. Social phobia is a disabling disorder characterized by a marked fear of scrutiny in a variety of social situations. By using a validated questionnaire, study I related family history of excessive social anxiety to social phobia and avoidant personality disorder in epidemiologically identified probands in the Swedish general population. A two- to threefold increased relative risk of social anxiety was observed for both diagnostic groups. Thus, having an affected family member is associated with approximately a doubled risk for both social phobia and avoidant personality disorder. The neurobiological studies explored situational and anticipatory elicited anxiety by means of positron emission tomography and 15O-water. Study II examined the functional neuroanatomy of social anxiety provocation in social phobics and a healthy comparison group during a public speaking task. Social phobia symptomatology was associated with higher neural activity in the amygdaloid complex, i.e. "the alarm system" of the brain, and lower activity in the prefrontal cortex. Study III examined the neural correlates of anxiety elicited by the anticipation of public speaking in individuals with social phobia. Anticipatory anxiety was accompanied by enhanced regional cerebral blood flow in the dorsolateral prefrontal and inferior temporal cortices as well as in the amygdaloid-hippocampal region. Brain blood flow was lower in the temporal pole and in the cerebellum. These results suggest that social phobia has a neuroanatomical basis in a highly sensitive fear network centered in the amygdaloid-hippocampal region and encompassing the prefrontal cortex.

The present thesis explored the neurobiological basis of three aspects of defense behaviors in humans. Positron emission tomography methodology was used, and changes in regional cerebral blood flow (rCBF) were measured as an index of neural activity. Firstly, brain function was studied in a group of patients suffering from combat-related posttraumatic stress disorder, using a symptom provocation paradigm with combat sounds in order to elicit fear. Exposure to auditory trauma reminders relative to neutral sounds was associated with increased rCBF in sensorimotor areas, the cerebellar vermis, the periaqueductal gray matter, and the right amygdala, whereas decreased activity was observed in the retrosplenial area of the posterior cingulate cortex. Secondly, the neural circuitry mediating the acoustic startle response and its habituation was studied in a group of healthy subjects. During acoustic startle stimulation as compared to a resting condition, increased rCBF was found in a medial posterior area of the pons corresponding to the nucleus reticularis pontis caudalis. As a result of startle repetition, altered activity was found in the cerebellum, pointing to its involvement in startle habituation. Thirdly, neural activity associated with startle modulation by phobic fear was studied in a group of subjects with specific animal phobias during exposure to pictures of their feared and non-feared objects, paired and unpaired with acoustic startle stimuli. As a result of startle potentiation, increased rCBF was found in the left amygdaloid-hippocampal region, and medially in the affective division of the anterior cingulate cortex. In conclusion, these results provide evidence for the involvement of limbic and paralimbic brain areas during fear provocation and fear-potentiated startle and for a similar neurocircuitry underlying startle in humans and animals.

The central theme of the present thesis revolves around the exploration of similarities and differences in brain activity patterns invoked by the component processes underlying mnemonic, executive and attentional functions. The primary aim was to identify and functionally characterize commonly recruited brain regions in terms of shared component processes, which has been a largely neglected area of research in cognitive neuroscience. The vast majority of functional brain imaging investigations of cognition has focused on delineating differences between cognitive functions or processes, with the purpose of isolating the unique functional neuroanatomy that underlies specific cognitive domains. By contrast, the present thesis builds on the results from three imaging studies that focused primarily on detecting commonalities in functional brain activity across different forms of memory processes. In study I, the imaging data from two positron emission tomography (PET) experiments were re-analyzed to identify common activation patterns associated with nine different memory tasks incorporated across the experiments, three each separately indexing working memory, episodic memory, and semantic memory. A generic prefrontal cortex (PFC) network involving discrete subregions of the left hemisphere located in ventrolateral (BA 45/47), dorsolateral (BA 9/44/46), and frontopolar (BA 10) sectors of PFC, as well as a midline portion of the frontal lobes, encompassing the dorsal part of the anterior cingulate cortex (ACC) (BA 24/32), was conjointly recruited across all tasks. In study II, we used a novel mixed blocked/event-related functional magnetic resonance imaging (fMRI) design, which enables separation of brain responses associated with different temporal dynamics to further investigate commonalities of neural activation across working memory, episodic memory, semantic memory, and attention/vigilance. A similar set of common PFC regions, as that discovered in Study I, was found to elicit overlapping brain activity across all memory tasks, with a subset of regions also activated in the attention/vigilance task. Furthermore, the task-induced brain activity was dissociated in terms of the temporal profiles of the evoked neural responses. A common pattern of sustained activity seen across all memory tasks and the attention task involved bilateral (predominantly right-lateralized) ventrolateral PFC (BA 45/47), and the dorsal ACC (BA 24/32), which was assumed to reflect general processes of attention/vigilance. A pattern of sustained activity elicited in all memory tasks, in the absence of attention-related activity, involved the right frontopolar cortex (BA 10), which was assumed to reflect control processes underlying task set maintenance. In addition, common transient activation evoked in the memory tasks relative to the attention task was found in the dorsolateral (BA 9/44) and ventrolateral (BA 47) PFC, the superior parietal cortex (BA 7), and cerebellum. In study III, a mixed fMRI design was used to assess the degree of common brain activity associated with increased executive demand, which was independently manipulated within episodic and working memory. Unitary control modulations involved a shared tonic executive component subserved by fronto-striatal-cerebellar circuitry, assumed to govern top-down context processing throughout task periods, and a stimulus-synchronous phasic component mediated by the intraparietal sulcus (BA 7), assumed to support dynamic shifting of the ‘focus of attention’ among internal representations. Collectively, the theoretical implications of shared neural mechanisms are discussed, with a special focus on human memory and its multifaceted relationships with attention and executive control functions. Finally, the presented imaging data are used to outline a tentative hierarchical neurocognitive model that attempts to give an account of how different unitary component processes might work together during cognitive task performance.

Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n = 89 patients and n = 90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self-reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research.

This dissertation is composed of three studies that use statistical, behavioral, and neuroimaging methods to investigate Chinese and English speakers’ semantic interpretations of four types of visual information including icons, single Chinese characters, single English words, and pictures. The goal is to examine whether people cognitively process icons as logographical words. By collecting survey data from 211 participants, the first study investigated how differently these four types of visual information can express specific meanings without ambiguity on a quantitative scale. In the second study, 78 subjects participated in a behavioral experiment that measured how fast people could correctly interpret the meaning of these four types of visual information in order to estimate the differences in reaction times needed to process these stimuli. The third study employed functional magnetic resonance imaging (fMRI) with 20 participants selected from the second study to identify brain regions that were needed to process these four types of visual information in order to determine if the same or different neural networks were required to process these stimuli. Findings suggest that 1) similar to pictures, icons are statistically more ambiguous than English words and Chinese characters to convey the immediate semantics of objects and concepts; 2) English words and Chinese characters are more effective and efficient than icons and pictures to convey the immediate semantics of objects and concepts in terms of people’s behavioral responses, and 3) according to the neuroimaging data, icons and pictures require more resources of the brain than texts, and the pattern of neural correlates under the condition of reading icons is different from the condition of reading Chinese characters. In conclusion, icons are not cognitively processed as logographical words like Chinese characters although they both stimulate the semantic system in the brain that is needed for language processing. Chinese characters and English words are more evolved and advanced symbols that are less ambiguous, more efficient and easier for a literate brain to understand, whereas graphical representations of objects and concepts such as icons and pictures do not always provide immediate and unambiguous access to meanings and are prone to various interpretations. / text