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- Tapper, Sofie, 1989-
(författare)
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Neurotransmitter Imaging of the Human Brain : Detecting γ-Aminobutyric Acid (GABA) Using Magnetic Resonance Spectroscopy
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: In this thesis, MEGA-edited Magnetic Resonance Spectroscopy (MRS) has been used for the purpose of non-invasive detection of !- aminobutyric acid (GABA) within the brain. GABA is the main inhibitory neurotransmitter in the human central nervous system, and glutamate is the corresponding main excitatory neurotransmitter. A balance between GABA and glutamate is crucial for healthy neurotransmission within the brain, and regional altered concentrations have been linked to certain neurological disorders. However, it is challenging to measure GABA, and special editing approaches are needed in order to allow reliable quantification. In addition, the GABA measurement is further complicated due to disturbances such as movements during the acquisition that may lead to artifacts in the resulting spectrum. This thesis can be divided into two sections, where the first section focuses on three clinical applications (narcolepsy, irritable bowel syndrome (IBS), and essential tremor (ET)), which were all investigated using MEGA-edited single- voxel spectroscopy (SVS). The second section focuses on method development, where two statistical retrospective approaches were investigated for the purpose of improving MEGA-edited data. In addition, a new MRS imaging (MRSI) pulse sequence with the purpose of GABA detection using a high spatial resolution, short acquisition time, and full brain coverage was also investigated.Materials and Methods: In total, 164 participants were included and 272 MRS measurements were performed with the voxel placed in the medial prefrontal cortex (mPFC, 136), thalamus (32), and cerebellum (104) using two different but “identical” MR systems. Nineteen narcolepsy patients and 21 matched healthy controls performed an fMRI working memory task using a simultaneous EEG followed by an mPFC GABA-edited MRS measurement. Sixty-four IBS patients and 32 matched healthy controls underwent an mPFC GABA-edited MRS measurement followed by resting state fMRI. In addition, psychological symptoms were assessed using questionnaires. Ten ET patients and six matched healthy controls underwent four GABA-edited MRS measurements with the voxels placed in the thalamus and cerebellum. In this study, the symptom severity was investigated using the essential tremor rating scale (ETRS). All clinical MRS datasets were analyzed using conventional methods for post-processing and quantification. Furthermore, 12 volunteers were recruited for the purpose of investigating statistical retrospective approaches for artifact detection and elimination of MRS data. Each participant underwent three reference measurements and three measurements with induced head movements conducted according to a movement paradigm. Order statistic filtering (OSF) and jackknife correlation (JKC) were investigated as regards to the elimination of artifact-influenced spectra and reliability of the resulting concentrations. Finally, phantom measurements were performed for the purpose of investigating MEGA-edited MRSI.Results: In narcolepsy, a trend-level association was observed between the mPFC MRS concentrations and increased deactivation within the default mode network during the working memory task. A significantly higher mPFC GABA+ concentration was observed in IBS patients with a high severity of comorbid anxiety. In ET, a positive correlation was observed between cerebellar GABA+/Glx ratios and tremor severity. Moreover, movements during the measurement decreased the concentration estimates due to signal loss in the spectra. Both OSF and JKC resulted in trend-level improvement of the signal- intense metabolites in spectrum when artifacts were present in the data, while performing equally as well as conventional analysis methodology when no intentional movements were present in the data. Finally, using the fast MEGA- edited multi-voxel sequence developed for a conventional clinical scanner, our phantom measurements showed that GABA was detectable using a 1:45 min acquisition time and an MRSI voxel size of 1 mL.Discussion: Several challenges such as time constraints, large voxel sizes, and protocol design were encountered when performing SVS MEGA-PRESS in the clinical research settings. In addition, artifacts in the MRS data originating for example, from motions, negatively impacted the resulting averaged spectra, which was evident in both data from clinical populations and healthy controls. In the presence of artifacts in the data, both OSF and JKC improved the SVS MEGA-edited spectra. In addition, the implemented JKC method can be used not only for artifact detection, but also as a generally applicable retrospective technique for the quality control of a dataset, or as an indication of whether a shift in voxel placement occurred during the measurement. Using the MEGA-edited MRSI pulse sequence, there are many technical challenges, including detrimental effects from eddy currents, spurious echoes, and field inhomogeneities. Even though there are many technical challenges when using MEGA-edited MRSI, an optimized version of the MRSI sequence would be extremely valuable in clinical research applications where high spatial resolution and short acquisition times are highly desired.Conclusions: OSF and JKC improved the metabolite quantification when artifacts were present in the data, and JKC was preferable. Although there are many technical challenges, MEGA-edited MRSI with full brain coverage in combination with a minimal voxel size for the purpose of GABA detection, would be extremely useful in clinical research applications where disorders such as narcolepsy, IBS, or ET, are investigated.
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| 2. |
- Alonso, Fabiola, 1980-, et al.
(författare)
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Influence of Virchow-Robin spaces in the Electric Field Distribution in Subthalamic Nucleus Deep Brain Stimulation
- 2019
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Konferensbidrag (refereegranskat)abstract
- Objectives: Previous investigations have shown the appearance of cysts i.e. Virchow-Robin spaces (VR) in the basal ganglia and their relationship with parkinsonian symptoms [1-3]. Simulations [4]using the finite element method (FEM) suggests that VR affects the electric field around deep brain stimulation (DBS) electrodes. The aim of the study was to evaluate how the electric field is modified by the presence of cysts in the STN. Methods: The effect of cysts on the electric field around the DBS lead placed in the STN was evaluated using FEM. 3D patient-specific brain models were built with COMSOL 5.2 (COMSOL AB, Sweden) and an in-house developed software [5] to convert a T2 weighted MRI of Parkinsonian patients (ethics approval no: 2012/434-3) into electrical conductivity matrix readable by FEM software. VR was classified as CSF [6]assigning a high electrical conductivity (2.0 S/m). The stimulation amplitudes were set to the clinically programmed values. Depending on the lead used, the stimulation was set to voltage control (3389) or current control (6180, ring mode). The coordinates corresponding to the lowest (first) electrode and the third higher up in the lead, taken from the postoperative CT electrode artefact, were used to localize the leads in the brain model [7]. The electric field was visualized with a 0.2V/mm isosurface. Results: Simulations showed that the electric field distribution is affected by the cysts. The higher conductivity at these regions in the vicinity of the electrode redistributes the electric field pushing it away from the cyst. The same effect occurs regardless of the operating mode or the lead design as long as the directional lead is configured in ring mode. Conclusions: The use of patient-specific models has shown the importance of considering nuances of the patients’ anatomy in the STN. This information can be used to determine the stimulation parameter and to support the analysis of side effects induced by the stimulation. The potential advantage of directional leads can also be assessed by including in the model patient-specific data.
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| 4. |
- Göransson, Nathanael, et al.
(författare)
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Postoperative lead movement after deep brain stimulation surgery and changes of stimulation area
- 2017
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionLead movement after deep brain stimulation (DBS) may occur and influence the area of stimulation. The cause of the displacement is not fully understood. The aim of the study was to investigate differences in lead position between the day after surgery and approximately one month postoperatively and also simulate the electric field (EF) around the active contacts.Methods23 patients with movement disorders underwent DBS surgery (37 leads). CT at the two time points were co-fused respectively with the stereotactic images in Surgiplan. The coordinates (x, y, z) of the lead tips were compared between the two dates (paired t-test). 8 of these patients were selected for the EF simulation in Comsol Multiphysics.ResultsThere was a significant discrepancy (mean ± s.d.) on the left lead: x (0.44 ± 0.72, p < 0.01), y (0.64 ± 0.54, p < 0.001), z (0.62 ± 0.71, p < 0.001). On the right lead, corresponding values were: x (-0.11 ± 0.61, n.s.), y (0.71 ± 0.54, p < 0.001), z (0.49 ± 0.81, p < 0.05). No correlation was found between bilateral (n =14) vs. unilateral DBS, gender (n = 17 male) and age < 60 years (n = 8). The lead movement affected the EF spread (Fig. 1).ConclusionThe left lead tip displayed a tendency to move lateral, anterior and inferior and the right a tendency to move anterior and inferior. Lead movement after DBS can be a factor to consider before starting the stimulation. The differences in the area of stimulation might affect clinical outcome.
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| 5. |
- Nord, Maria, et al.
(författare)
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Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
- 2017
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Ingår i: Advances in Parkinsons Disease. - : Scientific Research Publishing Inc. - 2169-9712 .- 2169-9720. ; 6:2, s. 52-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.
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| 7. |
- Nordin, Teresa, 1987-, et al.
(författare)
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White matter tracing combined with electric field simulation – A patient-specific approach for deep brain stimulation
- 2019
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Ingår i: NeuroImage. - : Elsevier. - 2213-1582. ; 24, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveDeep brain stimulation (DBS) in zona incerta (Zi) is used for symptom alleviation in essential tremor (ET). Zi is positioned along the dentato-rubro-thalamic tract (DRT). Electric field simulations with the finite element method (FEM) can be used for estimation of a volume where the stimulation affects the tissue by applying a fixed isolevel (VDBS). This work aims to develop a workflow for combined patient-specific electric field simulation and white matter tracing of the DRT, and to investigate the influence on the VDBS from different brain tissue models, lead design and stimulation modes. The novelty of this work lies in the combination of all these components.MethodPatients with ET were implanted in Zi (lead 3389, n = 3, voltage mode; directional lead 6172, n = 1, current mode). Probabilistic reconstruction from diffusion MRI (dMRI) of the DRT (n = 8) was computed with FSL Toolbox. Brain tissue models were created for each patient (two homogenous, one heterogenous isotropic, one heterogenous anisotropic) and the respective VDBS (n = 48) calculated from the Comsol Multiphysics FEM simulations. The DRT and VDBS were visualized with 3DSlicer and superimposed on the preoperative T2 MRI, and the common volumes calculated. Dice Coefficient (DC) and level of anisotropy were used to evaluate and compare the brain models.ResultCombined patient-specific tractography and electric field simulation was designed and evaluated, and all patients showed benefit from DBS. All VDBS overlapped the reconstructed DRT. Current stimulation showed prominent difference between the tissue models, where the homogenous grey matter deviated most (67 < DC < 69). Result from heterogenous isotropic and anisotropic models were similar (DC > 0.95), however the anisotropic model consistently generated larger volumes related to a greater extension of the electric field along the DBS lead. Independent of tissue model, the steering effect of the directional lead was evident and consistent.ConclusionA workflow for patient-specific electric field simulations in combination with reconstruction of DRT was successfully implemented. Accurate tissue classification is essential for electric field simulations, especially when using the current control stimulation. With an accurate targeting and tractography reconstruction, directional leads have the potential to tailor the electric field into the desired region.
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| 8. |
- Tobieson, Lovisa, et al.
(författare)
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Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood Flow Following Surgery for Intracerebral Hemorrhage
- 2019
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Ingår i: Neurosurgery. - : Ovid Technologies (Wolters Kluwer Health). - 0148-396X .- 1524-4040. ; 84:6, s. 1269-1279
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We hypothesized that reduced cerebral blood flow (CBF) and/or energy metabolic disturbances exist in the tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH). If present, such CBF and/or metabolic impairments may contribute to ongoing tissue injury and the modest clinical efficacy of ICH surgery.OBJECTIVE: To conduct an observational study of CBF and the energy metabolic state in the perihemorrhagic zone (PHZ) tissue and in seemingly normal cortex (SNX) by microdialysis (MD) following surgical ICH evacuation.METHODS: We evaluated 12 patients (median age 64; range 26-71 yr) for changes in CBF and energy metabolism following surgical ICH evacuation using Xenon-enhanced computed tomography (n = 10) or computed tomography perfusion (n = 2) for CBF and dual MD catheters, placed in the PHZ and the SNX at ICH surgery.RESULTS: CBF was evaluated at a mean of 21 and 58 h postsurgery. In the hemisphere ipsilateral to the ICH, CBF improved between the investigations (36.6 ± 20 vs 40.6 ± 20 mL/100 g/min; P < .05). In total, 1026 MD samples were analyzed for energy metabolic alterations including glucose and the lactate/pyruvate ratio (LPR). The LPR was persistently elevated in the PHZ compared to the SNX region (P < .05). LPR elevations in the PHZ were predominately type II (pyruvate normal-high; indicating mitochondrial dysfunction) as opposed to type I (pyruvate low; indicating ischemia) at 4 to 48 h (70% vs 30%) and at 49 to 84 h (79% vs 21%; P < .05) postsurgery.CONCLUSION: Despite normalization of CBF following ICH evacuation, an energy metabolic disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone.
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| 9. |
- Tobieson, Lovisa
(författare)
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Surgically Treated Intracerebral Haemorrhage : Pathophysiology and Clinical Aspects
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mortality and morbidity of intracerebral haemorrhage (ICH) is excessively high, and the case fatality rate has not improved in the last decades. Although surgery for ICH can be life-saving, no positive effect on functional outcome has been found in large cohorts of ICH patients. Increased understanding of the pathophysiology of ICH is needed to develop improved treatment strategies.In 17 ICH patients, paired cerebral microdialysis (CMD) catheters were inserted in the perihaemorrhagic zone (PHZ) and in normal uninjured cortex at time of surgery. Despite normalisation of cerebral blood flow, a persistent metabolic crisis indicative of mitochondrial dysfunction was detected in the PHZ. This metabolic pattern was not observed in the uninjured cortex.CMD was also used to sample proteins for proteomic analysis. A distinct proteome profile that changed over time was found in the PHZ when compared to the seemingly normal, uninjured cortex. However, protein adsorption to CMD membranes, which may interfere with concentration measurements, was substantial.Surgical treatment of 578 ICH patients was analysed in a nation-wide retrospective multi-centre study in Sweden over five years. Patients selected for surgery had similar age, pre-operative level of consciousness and co-morbidity profiles, but ICH volume and the proportion of deep-seated ICH differed among the six neurosurgical centres. Furthermore, there was variability in the post-operative care, including the use and duration of intracranial pressure monitoring, cerebrospinal fluid drainage and mechanical ventilation.In conclusion, the results of this thesis show that:(i) Despite surgical removal of an ICH a metabolic crisis caused by mitochondrial dysfunction, a potential future therapeutic target, persists in the perihaemorrhagic zone.(ii-iii) CMD is a valuable tool in ICH research for sampling novel biomarkers using proteomics, which may aid in the development of improved therapeutic interventions. However, caveats of the technique, such as protein adsorption to the CMD membrane, must be considered.(iv) The nation-wide study illustrates similar clinical features in patients selected for ICH surgery, but substantial variability in ICH volume and location as well as neurocritical care strategies among Swedish neurosurgical centres. Development of refined clinical guidelines may reduce such intercentre variability and lead to improved functional outcome for ICH patients.
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