| 1. |
- Frykholm, Erik, 1985-
(författare)
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The relevance and assessment of limb muscle function in individuals with chronic obstructive pulmonary disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic obstructive pulmonary disease (COPD) is a disease that is characterised by persistent respiratory symptoms and airflow limitation. Consequences beyond the airways and lungs are common, and include limb muscle dysfunction. Limb muscle dysfunction is treated with exercise training, and should be preceded by assessments to individualise prescriptions. Guidelines recommend assessment of quadriceps strength, but limb muscle dysfunction affects more than strength. Other less investigated assessments may be of interest. During training, direct physiological (cardiorespiratory, metabolic, and biomechanical) and symptomatic responses are important, since they can affect training effectivity, and they may differ depending on whether arms or legs are used. The main aims of this thesis were to investigate the relevance of assessments of quadriceps function, feasibility and reliability of methods to assess quadriceps endurance, and to compare the direct physiological and symptomatic responses during arm and leg activities in people with COPD.Method: This thesis is based on four papers. These include one systematic review with a meta-analysis of studies comparing direct physiological and symptomatic responses to activities performed with the arms versus the legs, and three papers based on an international cross-sectional multicentre study investigating reliability, feasibility, and relevance of three leg extension assessments of quadriceps endurance. Relative and absolute reliability were determined via interclass correlation coefficient (ICC), coefficient of variation (CV %), and limits of agreement (LoA %) for measures of isokinetic total work, isokinetic fatigue index, isometric time to exhaustion, and isotonic repetitions to exhaustion. The relevance of the measures of quadriceps endurance and other quadriceps functions were determined by the association to functional capacity and physical activity with Pearson correlation analyses (r) and multiple linear regression models (R2, adjusted R2, Δ R2, and Δ adjusted R2).Results: Results from the meta-analyses show that leg-cycle ergometer resulted in greater tidal volume (137 mL), minute ventilation (4.8 L/min), and oxygen consumption (164 mL/min) compared to arm cycle ergometer, while symptomatic responses were similar. Physiological responses (e.g., minute ventilation and oxygen consumption) during arm compared to leg resistance training exercises were similar. Results from studies on functional activities depend on the type and intensity of the activity performed. Isokinetic total work was the measurement with the highest relative reliability (ICC = 0.98) and the smallest absolute reliability (e.g., CV% = 6.5). Isokinetic fatigue index, isometric, and isotonic measures demonstrated low-to-high relative reliability (ICC = 0.64, 0.88, 0.91), and absolute reliability was larger (e.g., CV% = 20.3, 14.9, and 15.8%). Participants performed better on the retest for isokinetic total work and isometric measurements (4.8 and 10%, p < 0.001). The feasibility was similar across protocols, with an average time consumption of< 7.5 minutes, limited perceived dyspnoea compared to leg fatigue, and no major adverse advents. The measures of quadriceps function had mostly similar (r = +/- 0.07–0.45) levels of correlations to the functional capacity and physical activity. In multiple regression analyses improved quadriceps power the models to predict functional capacity the most (Δ adjusted R2= 0.10, 0.15, adjusted R2 = 0.60, 0.39). Isotonic endurance was the only muscle function that improved all physical activity models (ΔR2 = 0.04–0.07, p < 0.05, R2 = 0.38–0.49).Conclusions: The results indicate that if the goal of an activity is to maximise physiological responses such as minute ventilation and oxygen consumption, activities involving the legs should be preferred. Symptomatic responses seems task and intensity dependent, which suggest that strategies used to reduce symptoms should be based on relative intensity. In the assessment of quadriceps endurance, isokinetic, isometric and isotonic protocols present low to very high relative reliability. Differences in reliability and the better performance at retest might reflect differences in ability to detect true change. Quadriceps power seems to be more relevant to functional capacity, and isotonic quadriceps endurance seems to be more relevant to physical activity.
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| 2. |
- Persson Pavlović, Erik, 1985-
(författare)
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The weakest link : Governing the risk of floods and dam failure in Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The effects of climate change are already being felt today, and future effects, which will be determined by the readiness and resolve of today’s world leaders, are fraught with high levels of complexity, uncertainty, ambiguity, and transboundary effects – characteristics of systemic risk. Since climate change is seen as a threat multiplier, the risks that might be impacted by climate change, such as floods and dam failure, will be affected by systemic risk characteristics as well. Recent literature on risk governance calls for a more inclusive approach to address the challenges of systemic risks. Sweden has adopted the Sendai Framework, which aims to reduce disaster risk and strengthen societal resilience through a more people-centered approach. Sweden can be expected to have the resources and institutional structures needed to be able to implement the framework at a high level. However, evaluations of recent crises have shown a discrepancy between what can be expected and actual performance. This thesis aims to increase the understanding of contextual barriers to and drivers of inclusive risk governance, with a focus on responsibilities, (mandated) collaboration, and stakeholder participation, as an approach to increase societal resilience against disaster and systemic risk. The aim is reached by studying flood-related systemic risks and their governance. Three distinct, qualitative case studies focusing on different aspects of the Swedish disaster risk reduction and risk governance systems in relation to the risk of floods and dam failure are the empirical foundation for the four papers that are appended in the thesis. The thesis concludes that there is a need for a change in how resilience is framed, as part of a paradigm shift to a discourse that views resilience as a measure of adaptive capacity, and a change in how systemic risks should be understood and governed, as part of a paradigm shift to an inclusive risk governance framework.
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| 3. |
- Awad, Amar, 1988-
(författare)
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Functional brain imaging of sensorimotor dysfunction and restoration : investigations of discomplete spinal cord injury and deep brain stimulation for essential tremor
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nervous system exists to generate adaptive behaviour by processing sensory input from the body and the environment in order to produce appropriate motor output, and vice versa. Consequently, sensorimotor dysfunction is the basis of disability in most neurological pathologies. In the current thesis, I explore two conditions with different types and degrees of sensorimotor dysfunction by means of functional magnetic resonance imaging (fMRI). In part 1, I assess residual sensory connections to the brain in clinically complete spinal cord injury (SCI) with seemingly complete loss of sensorimotor function below the injury level. In part 2, fMRI is combined with deep brain stimulation (DBS) to investigate interventional mechanisms of restoring dysfunctional sensorimotor control in essential tremor (ET).Part 1: SCI disrupts the communication between the brain and below-injury body parts, but rarely results in complete anatomical transection of the spinal cord. In studies I and II, we demonstrate somatosensory cortex activation due to somatosensory (tactile and nociceptive) stimulation on below-level insensate body parts in clinically complete SCI. The results from studies I and II indicate preserved somatosensory conduction across the spinal lesion in some cases of clinically complete SCI, as classified according to international standards. This subgroup is referred to as sensory discomplete SCI, which represents a distinct injury phenotype with an intermediate degree of injury severity between clinically complete and incomplete SCI.Part 2: ET is effectively treated with DBS in the caudal zona incerta, but the neural mechanisms underlying the treatment effect are poorly understood. By exploring DBS mechanisms with fMRI, DBS was shown to cause modulation in the activity of the sensorimotor cerebello-cerebral regions during motor tasks (study III), but did not modulate the functional connectivity during resting-state (study IV).fMRI is a valuable tool to investigate sensorimotor dysfunction and restoration in SCI and DBS-treated ET. There is evidence for sensory discomplete SCI in about half of the patients with clinically complete SCI. DBS modulates DBS modulation of the activity in the sensorimotor cerebello-cerebral circuit during motor tasks, but not during resting-state, is action-dependent.
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| 4. |
- Berginström, Nils, 1984-
(författare)
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Fatigue after traumatic brain injury : exploring novel methods for diagnosis and treatment
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Traumatic brain injury (TBI) is one of the most common causes of disability and mortality. While some patients recover quickly, especially at the mild side of the injury severity continuum, many will experience symptoms for years to come. In this chronic phase, patients report a wide array of symptoms, where fatigue is one the most common. This fatigue makes huge impact in several areas of these patients’ lives. Despite the prevalence of fatigue after TBI, the underlying mechanisms are unclear. Further, there are no standardized way for assessment and diagnosis, and there are no treatments with satisfying empirical support. The aim of this thesis was to examine the effects of the novel compound OSU6162 on fatigue in patients with TBI, and to explore functional and structural brain imaging correlates of fatigue after TBI.Methods: Studies I and III were based on a placebo-controlled, double-blinded clinical trial examining the effects of the monoaminergic stabilizer OSU6162 on fatigue in patients in the chronic phase of traumatic brain injury. In study I, self-assessment scales of fatigue and neuropsychological tests were used as outcomes, while functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) signal was the primary outcome in study III. Studies II and IV used cross-sectional designs, comparing patients with TBI with age- and gender matched healthy controls. Study II examined whether fMRI BOLD signal could be used to detect and diagnose fatigue in patients with TBI, and study IV whether white matter hyperintensities (WMH) contribute to lower cognitive functioning and presence of fatigue after TBI.Results: Study I revealed no effects of OSU6162 during 28 days of treatment at maximum doses of 15 mg twice daily on measures of fatigue or any other outcome. The results from study II indicated that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and suggested that fMRI could be a promising technique to use in the diagnosis of fatigue after TBI. In study III the results revealed effects of treatment in the right occipitotemporal and orbitofrontal cortex. In these areas, the BOLD response was normalized in the OSU6162 group as compared to healthy controls, while the placebo group showed a steady low activity in these areas. The regional effects were located outside the network shown to be linked to fatigue in study II, which might explain why there were no effects on fatigue after treatment with OSU6162 in study I. Study IV showed that WMH lesions increased with increased TBI severity, but the presence and extent of lesions did not explain lower neuropsychological functioning or fatigue in subjects with previous TBI.Conclusions: In summary, although no effects on fatigue after treatment with OSU6162 were seen, the results provide support to the theory that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and on how fatigue after TBI could be assessed or diagnosed using fMRI. Structural damage within white matter was however not related to fatigue.
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| 5. |
- Ekman, Urban, 1968-
(författare)
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Functional brain imaging of cognitive status in Parkinson's disease
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.
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| 6. |
- Vikner, Tomas, 1990-
(författare)
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Cerebral arterial pulsatility imaging using 4D flow MRI : methodological development and applications in brain aging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 4D flow magnetic resonance imaging (MRI) is increasingly recognizedas a versatile tool to assess arterial and venous hemodynamics. Cerebral arterial pulsatility is typically assessed by analyzing flow waveforms over the cardiac cycle, where flow amplitude is a function of cardiac output, central arterial stiffness, and cerebrovascular resistance and compliance. Excessive pulsatility may propagate to the cerebral microcirculation, and constitute a harmful mechanism for the brain. Indeed, imaging studies have linked arterial pulsatility to hippocampus volume, cerebral small vessel disease (SVD), and Alzheimer’s disease (AD). In animal models, elevated pulsatility leads to blood-brain barrier (BBB) leakage, capillary loss, and cognitive decline. However, associations to cerebrovascular lesions and brain function in the spectrum of normal aging are less investigated. Further, previous 4D flow studies have mainly assessed pulsatility in relatively large cerebral arteries. When exploring links to microvascular damage and brain function, more distal measurements, closer to the microcirculation, are desired. This thesis aimed to develop 4D flow MRI post-processing methods to obtain pulsatile waveforms in small, distal cerebral arteries with noisy velocity data and a complex vascular anatomy, and to evaluate pulsatility (primarily assessed by the pulsatility index) in relation to aging, brain function, and other imaging biomarkers of cerebrovascular damage, with particular dedication towards the hippocampus and cerebral SVD. To assess pulsatility in distal cerebral arteries, a post-processing method that automatically samples waveforms from numerous small arteries, to obtain a whole-brain representation of the distal arterial waveform, was developed (Paper I). We demonstrated the importance of averaging flow waveforms along multiple vessel segments to avoid overestimations in the pulsatility index, showed agreement with reference methods, and linked distal arterial pulsatility to age. To explore links to hippocampal function, we evaluated pulsatility in relation to cognition, hemodynamic low-frequency oscillations (LFOs), perfusion, and hippocampus volume (Paper II). We found that higher pulsatility was linked to worse hippocampus-sensitive episodic memory, weaker hippocampal LFOs, and lower whole-brain perfusion. These findings aligned with models suggesting that hippocampal microvessels could be particularly susceptible to pulsatile stress.To inform on SVD pathophysiology, we evaluated 5-year associations among pulsatility, white matter lesions (WMLs) and perivascular space (PVS) dilation, using mixed models, factor analysis, and change score models (Paper III). Lead-lag analyses indicated that, while pulsatility at baseline could not predict WML nor PVS progression, WML and PVS volumes at baseline predicted 5-year pulsatility-increases. These findings indicate that individuals with a higher load of cerebrovascular damage are more prone to see increased pulsatility over time, and suggest that high pulsatility is a manifestation, rather a risk factor, for cerebral SVD. To shed light on the potential role of BBB leakage in aging and SVD, we used dynamic contrast enhanced (DCE) MRI and intravenous gadolinium injections to quantify BBB permeability (Paper IV). We found stepwise increases in permeability from healthy white matter to WMLs, supporting that BBB leakages are implicated in SVD. However, hippocampal BBB permeability was unrelated to age, indicating that this capillary property is maintained in aging. Finally, arterial pulsatility was unrelated to BBB permeability in WMLs and in the hippocampus, providing no evidence of excessive pulsatility as a trigger of BBB leakage. In conclusion, distal arterial pulsatility measurements are reliable when averaging 4D flow waveforms over a large number of vessels. Pulsatility increases with age, and individuals with more cerebrovascular lesions are prone to see larger increases over time. Pulsatility is negatively related to perfusion and hippocampal function. However, the temporal dynamics among the SVD biomarkers, and the absence of pulsatility–permeability associations, challenge the concept of excessive pulsatility as a trigger of microvascular damage. Future studies are needed to understand whether altered cerebral hemodynamics play a causal role in cognitive decline and dementia. Meanwhile, 4D flow hemodynamic parameters could be useful as biomarkers related to vessel properties and cerebrovascular health.
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| 7. |
- Andin, Josefine
(författare)
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Dealing with Digits : Arithmetic, Memory and Phonology in Deaf Signers
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Deafness has been associated with poor abilities to deal with digits in the context of arithmetic and memory, and language modality-specific differences in the phonological similarity of digits have been shown to influence short-term memory (STM). Therefore, the overall aim of the present thesis was to find out whether language modality-specific differences in phonological processing between sign and speech can explain why deaf signers perform at lower levels than hearing peers when dealing with digits. To explore this aim, the role of phonological processing in digit-based arithmetic and memory tasks was investigated, using both behavioural and neuroimaging methods, in adult deaf signers and hearing non-signers, carefully matched on age, sex, education and non-verbal intelligence. To make task demands as equal as possible for both groups, and to control for material effects, arithmetic, phonological processing, STM and working memory (WM) were all assessed using the same presentation and response mode for both groups. The results suggested that in digit-based STM, phonological similarity of manual numerals causes deaf signers to perform more poorly than hearing non-signers. However, for digit-based WM there was no difference between the groups, possibly due to differences in allocation of resources during WM. This indicates that similar WM for the two groups can be generalized from lexical items to digits. Further, we found that in the present work deaf signers performed better than expected and on a par with hearing peers on all arithmetic tasks, except for multiplication, possibly because the groups studied here were very carefully matched. However, the neural networks recruited for arithmetic and phonology differed between groups. During multiplication tasks, deaf signers showed an increased reliance on cortex of the right parietal lobe complemented by the left inferior frontal gyrus. In contrast, hearing non-signers relied on cortex of the left frontal and parietal lobes during multiplication. This suggests that while hearing non-signers recruit phonology-dependent arithmetic fact retrieval processes for multiplication, deaf signers recruit non-verbal magnitude manipulation processes. For phonology, the hearing non-signers engaged left lateralized frontal and parietal areas within the classical perisylvian language network. In deaf signers, however, phonological processing was limited to cortex of the left occipital lobe, suggesting that sign-based phonological processing does not necessarily activate the classical language network. In conclusion, the findings of the present thesis suggest that language modality-specific differences between sign and speech in different ways can explain why deaf signers perform at lower levels than hearing non-signers on tasks that include dealing with digits.
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| 8. |
- Bergström, Fredrik, 1983-
(författare)
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The neural substrates of non-conscious working memory
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite our distinct impression to the contrary, we are only conscious of a fraction of all the neural activity underlying our thoughts and behavior. Most neural processes occur non-consciously, and in parallel with our conscious experience. However, it is still unclear what the limits of non-conscious processes are in terms of higher cognitive functions. Many recent studies have shown that increasingly more advanced functions can operate non-consciously, but non-conscious information is still thought to be fleeting and undetectable within 500 milliseconds. Here we used various techniques to render information non-conscious, together with functional magnetic resonance imaging (fMRI), to investigate if non-consciously presented information can be retained for several seconds, what the neural substrates of such retention are, and if it is consistent with working memory maintenance.Results: In Study I we used an attentional blink paradigm to render stimuli (single letters) non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that non-conscious memory performance was above chance after all delay durations, and showed no signs of decline over time. Univariate fMRI analysis showed that the durable retention was associated with sustained BOLD signal change in the prefrontal cortex and cerebellum during the delay period. In Study II we used continuous flash suppression (CFS) to render stimuli (faces and tools) non-conscious, and a variable delay period (5 or 15 s) prior to memory test. The durable retention of up to 15 s was replicated, and it was found that stimuli identity and spatial position was retained until prospective use. In Study III we used CFS to render tools non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that memory performance was not better than chance. However, by using multi-voxel pattern analysis it was nonetheless possible to detect the presence vs. absence of non-conscious stimuli in the frontal cortex,and their spatial position (left vs. right) in the occipital cortex during the delay.Conclusions: Overall these findings suggest that non-consciously presented information (identity and/or position) can be retained for several seconds,and is associated with BOLD signal in frontal and posterior regions. These findings are consistent with working memory maintenance of non-consciously presented information, and thereby constrain models of working memory and theories of consciousness.
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| 9. |
- Holm, Linus, 1978-
(författare)
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Predictive eyes precede retrieval : visual recognition as hypothesis testing
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Does visual recognition entail verifying an idea about what is perceived? This question was addressed in the three studies of this thesis. The main hypothesis underlying the investigation was that visual recognition is an active process involving hypothesis testing. Recognition of faces (Study 1), scenes (Study 2) and objects (Study 3) was investigated using eye movement registration as a window on the recognition process. In Study 1, a functional relationship between eye movements and face recognition was established. Restricting the eye movements reduced recognition performance. In addition, perceptual reinstatement as indicated by eye movement consistency across study and test was related to recollective experience at test. Specifically, explicit recollection was related to higher eye movement consistency than familiarity-based recognition and false rejections (Studies 1-2). Furthermore, valid expectations about a forthcoming stimulus scene produced eye movements which were more similar to those of an earlier study episode, compared to invalid expectations (Study 2). In Study 3 participants recognized fragmented objects embedded in nonsense fragments. Around 8 seconds prior to explicit recognition, participants began to fixate the object region rather than a similar control region in the stimulus pictures. Before participants’ indicated awareness of the object, they fixated it with an average of 9 consecutive fixations. Hence, participants were looking at the object as if they had recognized it before they became aware of its identity. Furthermore, prior object information affected eye movement sampling of the stimulus, suggesting that semantic memory was involved in guiding the eyes during object recognition even before the participants were aware of its presence. Collectively, the studies support the view that gaze control is instrumental to visual recognition performance and that visual recognition is an interactive process between memory representation and information sampling.
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| 10. |
- Josefsson, Maria, 1979-
(författare)
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Attrition in Studies of Cognitive Aging
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Longitudinal studies of cognition are preferred to cross-sectional stud- ies, since they offer a direct assessment of age-related cognitive change (within-person change). Statistical methods for analyzing age-related change are widely available. There are, however, a number of challenges accompanying such analyzes, including cohort differences, ceiling- and floor effects, and attrition. These difficulties challenge the analyst and puts stringent requirements on the statistical method being used.The objective of Paper I is to develop a classifying method to study discrepancies in age-related cognitive change. The method needs to take into account the complex issues accompanying studies of cognitive aging, and specifically work out issues related to attrition. In a second step, we aim to identify predictors explaining stability or decline in cognitive performance in relation to demographic, life-style, health-related, and genetic factors.In the second paper, which is a continuation of Paper I, we investigate brain characteristics, structural and functional, that differ between suc- cessful aging elderly and elderly with an average cognitive performance over 15-20 years.In Paper III we develop a Bayesian model to estimate the causal effect of living arrangement (living alone versus living with someone) on cog- nitive decline. The model must balance confounding variables between the two living arrangement groups as well as account for non-ignorable attrition. This is achieved by combining propensity score matching with a pattern mixture model for longitudinal data.In paper IV, the objective is to adapt and implement available impu- tation methods to longitudinal fMRI data, where some subjects are lost to follow-up. We apply these missing data methods to a real dataset, and evaluate these methods in a simulation study.
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