Complex network models of functional connectivity have emerged as a paradigm shift in brain mapping over the past decade. Despite significant attention within the neuroimaging and cognitive neuroscience communities, these approaches have hitherto not been extensively explored in neurosurgery. The aim of this thesis is to investigate how the field of connectomics can contribute to understanding the effects of focal brain lesions and to functional brain mapping in neurosurgery. This datasets for this thesis include a clinical population with focal brain tumours and a cohort focused on healthy adolescent brain development. Multiple network analyses of increasing complexity are performed based upon resting state functional MRI. In patients with focal brain tumours, the full complement of resting state networks were apparent, while also suggesting putative patterns of network plasticity. Connectome analysis was able to identify potential signatures of node robustness and connections at risk that could be used to individually plan surgery. Focal lesions induced the formation of new hubs while down regulating previously established hubs. Overall these data are consistent with a dynamic rather than a static response to the presence of focal lesions. Adolescent brain development demonstrated discrete dynamics with distinct gender specific and age-gender interactions. Network architecture also became more robust, particularly to random removal of nodes and edges. Overall these data provide evidence for the early vulnerability rather than enhanced plasticity of brain networks. In summary, this thesis presents a combined analysis of pathological and healthy development datasets focused on understanding the functional effects of focal brain lesions at a network level. The coda serves as an introduction to a forthcoming study, known as Connectomics and Electrical Stimulation for Augmenting Resection (CAESAR), which is an evolution of the results and methods herein.

The aim of this study was to determine and evaluate resting energy expenditure (REE) and the utilization of nutritional substrates in 14 polytrauma patients in the ICU. Was also assessed level of impact Overhydration (OH) on the accuracy of the determination. Diagnostic investigations using indirect calorimetry (IC) was performed in 9 men and 5 women (age 30 ± 15 years, BMI 27.5 ± 9.4 kg·m-2) with polytrauma (ISS 41 ± 16). For more accurate sizing of REE and extent of utilization of nutritional substrates were used equations derived from the equation of Weir, not Softwear calorimeter. Using IC volumes were determined only inspired an expired oxygen and carbon dioxide. To determine the rate of OH was used bioimpedance analysis methods using BCM. Almost 86% (8 men and 4 women) examined patients showed hypermetabolism. Average REE value was 2241.38 ± 854.27 kcal·day-1, which represented an average increase of prediction of 38.09 ± 49.09% due to the physiological condition. A statistically significant relationship was demonstrated between REE determined using the Weir equation according and the Harris-Bennedict equation without (P = 0,01) with deduction of OH (P = 0,007) only in men. In clinical practice, significant correlations were established between the REE-IC and BSA (P < 0,01), LTM (P < 0,05),...

Background: Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder with currently no known cure. PD has a significant impact on quality of life of the patients, as well as, the caregivers and family members. It is the second most common cause of chronic neurological disability in US and Europe. According to National Parkinson's Foundation, there are almost 1 million patients in the Unites States and 50,000 to 60,000 new cases of PD are diagnosed each year. The total number of cases of PD is predicted to double by 2030. The annual cost associated with this disease is estimated to be $10.8 billion in the United States, including the cost of treatment and the cost of the disability. Although it is primarily thought of as a movement-disorder and is clinically diagnosed based on motor symptoms, non-motor symptoms such as cognitive and emotional deficits are thought to precede the clinical diagnosis by almost 20 years. By the time of clinical diagnosis, there is 80% loss in the dopamine content in the striatum and 50% degeneration of the substantia nigra dopamine cells. The research presented in this thesis was an attempt to develop an animal model of PD in its pre-motor stages. Such a model would allow us to develop pre-clinical markers for PD, and facilitate the development and testing of potential treatment strategies for the non-motor symptoms of the disorder. Specific Aims: There were five specific aims for this research: * The first specific aim dealt with development of a rat model of PD with slow, progressive onset of motor deficits, determination of timeline for future studies, and quantification the dopamine depletion in this model at a pre-motor stage. * The second and the third specific aims focused on testing for emotional (aversion) deficits and cognitive (executive functioning) deficits in this rat model at the 3 week timepoint determined during specific aim 1. * The fourth specific aim was to determine the brain network changes associated with the behavioral changes observed our rat model using resting state connectivity as a measure. * The fifth and the final specific aim was to test sodium butyrate, a drug from the histone deacetylase inhibitor family, as a potential treatment option for cognitive deficits in PD. Results: The 6-hydroxy dopamine based stepwise striatal lesion model of pre-motor PD, developed during this research, exhibits delayed onset of Parkinsonian gait like symptoms by week 4 after the lesions. At 3 weeks post lesion (3WKPD), the rats exhibit 27% reduction in striatal dopamine and 23%reduction in substantia nigra dopamine cells, with lack of any apparent motor deficits. The 3WKPD rats also exhibited changes in aversion. The fMRI study with the aversive scent pointed towards possible amygdala dysfunction sub-serving the aversion deficits. The executive function deficits tested using a rat analog of the Wisconsin card sorting test, divulged an extra-dimensional set shifting deficit in the 3WKPD rats similar to those reported in PD patients. The resting state connectivity study indicated significant changes in the 3WKPD rats compared to age matched controls. We observed increased overall connectivity of the motor cortex and increased CPu connectivity with prefrontal cortex, cingulate cortex, and hypothalamus in the 3WKPD rats compared to the controls. These observations parallel the observations in unmedicated early-stage PD patients. We also observed negative correlation between amygdala and prefrontal cortex as reported in humans. This negative correlation was lost in 3WKPD rats. Sodium butyrate treatment, tested in the cognitive deficit study, was able to ameliorate the extra-dimensional set shifting deficit observed in this model. This treatment also improved the attentional set formation. Conclusion: Taken together, our observations indicate that, the model of pre-motor stage PD developed during this research is a very high face validity rat model of late Braak stage 2 or early Braak stage 3 PD. Sodium butyrate was able to alleviate the cognitive deficits observed in our rat model. Hence, along with the prior reports of anti-depressant and neuroprotective effects of this drug, our results point towards a possible treatment strategy for the non-motor deficits of PD.

Older bilingual adults typically perform better than monolinguals in tasks of executive control, and are diagnosed later with dementia. Studies have also shown structural and functional brain differences between bilinguals and monolinguals. However, it remains poorly understood how language history influences the functional organization of the aging brain. The current study investigated; 1) differences in resting-state functional connectivity between monolinguals and bilinguals in the Default Mode Network (DMN), Frontoparietal Network (FPN), Executive Control Network (ECN), Language Network (LANG), and a network consisting of structures associated with tasks of executive control coined the Bilingual Control Network (BCN); 2) the relationship of cognitive performance with functional connectivity of the BCN; and 3) whether proficiency, age of second language acquisition, degree of second language exposure, and frequency of language use predicts the network’s functional connectivity. Healthy older bilinguals (N=10) were matched pairwise for age, sex and education to healthy older monolinguals (N=10). All participants completed a battery of cognitive tests, a language history questionnaire, and a 6-minute functional scan during rest. Results showed that groups did not differ in cognitive performance, or in the functional connectivity of the FPN, ECN, LANG, or BCN. However, monolinguals had significantly stronger functional connectivity in the DMN compared to bilinguals. Later age of second language acquisition and lower proficiency were also associated with greater DMN functional connectivity. None of these variables predicted BCN’s functional connectivity. However, bilinguals showed stronger functional connectivity with other structures outside of the canonical networks compared to monolinguals. Finally, vocabulary scores, local switch cost accuracy and reaction time were negatively correlated with BCN’s functional connectivity. Overall, these findings illustrate differences in functional brain organization associated with language experience in the DMN, while challenging the “bilingual advantage” hypothesis. The results also suggest a possible neural mechanism by which bilingualism might mediate cognitive reserve.

Leptin acts within the brain to increase resting metabolic rate (RMR) and blood pressure (BP). The renin-angiotensin system (RAS) elicits similar effects in the brain, as reviewed in chapter 1, and it has previously been shown that central angiotensin II type 1 (AT1) receptors are required for leptin-mediated inductions in sympathetic nerve activity to the brown adipose tissue. Thus, we hypothesize that the brain RAS mediates the metabolic effects of leptin. To investigate the interaction between the RAS and leptin, we generated the AT1ALepR-KO mouse which lacks the AT1A receptor in leptin-sensitive cells. In chapter 2, we demonstrated that stimulation of RMR by DOCA-salt and high fat diet requires AT1A receptors in leptin receptor-expressing cells and that these cells expressing both AT1A and the leptin receptor appear to be agouti related-peptide (AgRP) neurons. In chapter 3, we investigated the role of AT1A specifically in AgRP neurons by utilizing AT1AAgRP-KO mice. Similar to AT1ALepR-KO mice, AT1AAgRP-KO mice exhibited deficits in BAT SNA responses to leptin and induction of RMR by alpha melanocyte stimulating hormone. In chapter 4, we utilized a novel transgenic mouse model to demonstrate that microglia do not express the AT1A receptor under chow or high fat diet fed conditions. Taken together, we conclude that a subset of AgRP neurons, which express both the leptin receptor and the AT1A receptor, are critical for the control of sympathetic nerve activity and ultimately RMR.

This thesis gives an overview on how to estimate changes in functional brain networks using graph theoretical measures. It explains the assessment and definition of functional brain networks derived from fMRI data. More explicitly, this thesis provides examples and newly developed methods on the measurement and visualization of changes due to pathology, external electrical stimulation or ongoing internal thought processes. These changes can occur on long as well as on short time scales and might be a key to understanding brain pathologies and their development. Furthermore, this thesis describes new methods to investigate and visualize these changes on both time scales and provides a more complete picture of the brain as a dynamic and constantly changing network.

In this study, we used resting-state functional magnetic resonance imaging (fMRI) scans from subjects with early mild cognitive impairment (EMCI) and control subjects to study functional network connectivity. The scans were acquired by the Alzheimer's Disease Neuroscience Initiative (ADNI). We used genetic data from the ADNI database to further subdivide the EMCI and control groups into genotype groups with or without the ApoE4 allele. ROI-to-ROI resting-state functional connectivity was measured using Freesurfer and the Functional Connectivity Toolbox for Matlab (CONN). In our analysis, we compared whole-brain ROI connectivity strength and ROI-to-ROI functional network connectivity strength between EMCI, control and genotype subject groups. We found that the ROI network properties were disrupted in EMCI and ApoE4-containing groups. Notably, we show that (1) EMCI disrupts functional connectivity strength in many areas; (2) the ApoE4 allele disrupts functional connectivity strength in similar areas to EMCI; and (3) the differences in functional connectivity between groups shows a multifactor contribution to functional network dysfunction along the trajectory leading to dementia.

The aim of this study was to analyze the amount and the species composition of Daphnia gr. longispina resting egg bank in reservoirs. Studied reservoirs (Brno, Seč, Vír, Vranov a Žlutice) were sampled in July 2004 and 2005 at three sites {--} tributary, deep tributary and dam area. It was confirmed that there are more resting eggs at dam area than at tributary one and species composition differs for studied sites.

Resting frontal alpha asymmetry was measured with an electroencephalogram in 28 volunteers to predict the evaluation of emotions in music. Sixteen music excerpts either expressing happiness, sadness, anger or fear were rated by the participants with regard to conveyed mood, pleasantness and arousal. In addition, various variables of music background were collected. The experiment started with the assessment of current mood, followed by the evaluation of the music excerpts, and finished with the assessment of the participants’ approach and withdrawal behaviour. The results showed that each music excerpt was specic for the intended mood except for music of the category anger which obtained also high ratings for fear. These music excerpts were also the only ones for which a difference in ratings between relatively more left-active and right-active participants could be observed. Partly against expectations, left-dominant volunteers perceived music excerpts of the category anger to express more fear and anger than right-active participants. Results are interpreted within the behavioural inhibitionand approach model of anterior brain asymmetry.

Emotional intelligence (EI) is defined as an individual's capacity to accurately perceive, understand, reason about, and regulate emotions, and to apply that information to facilitate thought and achieve goals. Although EI plays an important role in mental health and success in academic, professional and social realms, the neurocircuitry underlying this capacity remains poorly characterized, and no study to date has yet examined the relationship between EI and intrinsic neural network function. Here, in a sample of 54 healthy individuals (28 women, 26 men), we apply independent components analysis (ICA) with dual regression to functional magnetic resonance imaging (fMRI) data acquired while subjects were resting in the scanner to investigate brain circuits (intrinsic resting state networks) whose activity is associated with greater self-reported (i.e. Trait) and objectively measured (i.e. Ability) EI. We show that higher Ability EI, but not Trait EI, is associated with stronger negatively correlated spontaneous fMRI signals between the basal ganglia/limbic network (BGN) and posterior default mode network (DMN), and regions involved in emotional processing and regulation. Importantly, these findings suggest that the functional connectivity within and between intrinsic networks associated with mentation, affective regulation, emotion processing, and reward are strongly related to ability EI.