| 1. |
- Trolle, Carl, 1985-
(författare)
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Stem Cell Transplantation in Dorsal Root Injury
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- After traumatic injuries to the brachial plexus there is a risk that one or more of the spinal roots are torn from the spinal cord, known as avulsion injury. This often leads to paralysis and chronic pain, notoriously difficult to treat with current pharmacotherapy. Surgical treatment may improve motor function but sensory recovery is usually poor as sensory axons fail to establish functional connections inside the spinal cord. The aims of this thesis were to develop a model for dorsal root avulsion in rodents in order to investigate the potentials of stem cell therapy for enhancing sensory regeneration after spinal root avulsion. Two different types of stem cells, embryonic and neural crest stem cells, have been transplanted to the avulsion model and analysed using immunohistochemical methods. The results indicate that stem cells survive after transplantation to the avulsed dorsal root and associate with regenerating axons. Furthermore, the different stem cells display different phenotypes after transplantation where embryonic stem cells give rise to neurons located outside the spinal cord that could serve as projection neurons whereas the neural crest stem cells form elongated tubes outlining the avulsed dorsal root and are associated with regenerating neuronal fibers. We have also discovered that the neural crest stem cells migrate into the damaged spinal cord as single cells. The neural crest stem cells also display a diversity in generating both neuronal and glial cells that may have different beneficial effects in neural repair following dorsal root avulsion. To improve the survival of stem cell transplants, the potentials of co-transplanting embryonic stem cells together with nanoparticle delivered growth factor mimetics has been investigated. The results indicate that nanoparticle delivered growth factors improve both transplant survival and maturation in comparison to untreated controls and may be a promising strategy in stem cell transplantation.
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| 2. |
- Ekmark Lewén, Sara, 1978-
(författare)
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Cellular Reactions and Behavioral Changes in Focal and Diffuse Traumatic Brain Injury : A Study in the Rat and Mouse
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traumatic brain injury (TBI) is a severe condition and a major cause of death and disability. There is no pharmacological treatment available in clinical practice today and knowledge of brain injury mechanisms is of importance for development of neuroprotective drugs. The aims of the thesis were to get a better understanding of astrocyte reactions and immune responses, as well as behavioral changes after focal unilateral cortical contusion injury and diffuse bilateral central fluid percussion injury in rats and mice.In the focal injury models, the astrocyte reactions were generally restricted to the ipsilateral hemisphere. After diffuse TBI, vimentin and glial fibrillary acidic protein (GFAP) positive reactive astrocytes were bilaterally expressed in brain regions even distant from the injury site, including regions where axonal injury was seen. Early after diffuse TBI, there was a robust immune response, including activation of macrophages/microglia (Mac-2+) and infiltration of neutrophils (GR-1+) and T-cells (CD3+).In order to measure functional outcome, the recently established Multivariate Concentric Square Field™ (MCSF) test for complex behaviors, including risk taking and explorative strategies was used. The Morris water maze (MWM) was applied for testing learning and memory. The MCSF test revealed alterations in risk taking, risk assessment and exploratory behavior, in the mice subjected to focal injury whereas mice subjected to the diffuse injury showed a deviant stereotyped behavior. After focal injury mice showed a decreased ability to adapt to the arena in the second trial, when tested repeatedly in the MCSF test. Mice subjected to diffuse injury had an impaired memory but not learning, in the MWM test. Post-injury treatment with the anti-inflammatory anti-interleukin-1β (IgG2 a/k) antibody showed a positive effect on functional outcome in the diffuse injury model. Altogether, the results demonstrate that focal and diffuse TBI models produce differences in cellular reactions and behavioral outcome and that the immune response plays a key role in the pathology after brain injury.
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| 3. |
- Ozen, Ilknur, et al.
(författare)
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Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:2
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.
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| 4. |
- Skoglund, Karin, 1964-
(författare)
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The Neurological Wake-up Test in Neurocritical Care
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neurological wake-up test, NWT, is a clinical monitoring tool that can be used to evaluate the level of consciousness in patients with traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) during neurocritical care (NCC). Since patients with severe TBI or SAH are often treated with mechanical ventilation and sedation, the NWT requires that the continuous sedation is interrupted. However, interruption of continuous sedation may induce a stress response and the use of the NWT in NCC is controversial.The effects of the NWT on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were evaluated in 21 patients with TBI or SAH. Compared to baseline when the patients were sedated with continuous propofol sedation, the NWT resulted in increased ICP and CPP (p<0.05). Next, the effects of the NWT on the stress hormones adrenocorticotrophic hormone (ACTH), cortisol, epinephrine and norepinephrine were evaluated in 24 patients. Compared to baseline, the NWT caused a mild stress response resulting in increased levels of all evaluated stress hormones (p<0.05). To compare the use of routine NCC monitoring tools, the choice of sedation and analgesia and the frequency of NWT in Scandinavian NCC units, a questionnaire was used. The results showed that all 16 Scandinavian NCC units routinely use ICP and CPP monitoring and propofol and midazolam were primary choices for patient sedation in an equal number of NCC units. In 2009, the NWT was not routinely used in eight NCC units whereas others used the test up to six times daily.Finally, intracerebral microdialysis (MD), brain tissue oxygenation (PbtiO2) and jugular bulb oxygenation (SjvO2) were used in 17 TBI patients to evaluate the effect of the NWT procedure on focal neurochemistry and cerebral oxygenation. The NWT did not negatively alter interstitial markers of energy metabolism or cerebral oxygenation.In conclusion, the NWT induced a mild stress response in patients with TBI or SAH that did not result in a detectable, significant secondary insult to the injured brain. These results suggest that the NWT may safely be used as a clinical monitoring tool in the NCC of severe TBI and SAH in a majority of patients.
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| 5. |
- Vedung, Fredrik
(författare)
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Short- and long-term consequences of sport-related concussion
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Concussions are common in contact sports. Symptoms such as confusion and/or loss of consciousness following an impact to the head indicate that a sport-related concussion (SRC) has occurred. The symptoms normally resolve within 10-14 days following an SRC in adults although at least 10 % of athletes suffer from prolonged symptoms. Repeated SRCs have been linked to increased incidence of neurodegenerative disorders including tau aggregation, attributed to axonal injury and neuroinflammation. This thesis investigates the epidemiology and management of SRC in Swedish elite soccer, and pathophysiologic aspects of concussed athletes.In questionnaire-based studies, paper I (retrospective) and II (prospective), >1000 Swedish elite soccer players were evaluated. One third of players continued to play at time of SRC, in opposition to current guidelines. In addition, the concussion incidence (ca 1.19 /1000 game hours) was similar in males and females. However, females had a higher symptoms load at baseline, at time of SRC, and had a longer duration of symptoms than male players. In Papers III and IV, pathophysiological aspects were evaluated in young athletes with ≥ 3 previous SRCs, diagnosed with post-concussion syndrome, and moderate to severe traumatic brain injury (TBI) patients ≥6 month post-injury. We used 3T PET/MR in addition to blood and cerebrospinal fluid biomarkers, and cognitive evaluation. MR imaging (arterial spin labelling; ASL) was used to estimate cerebral blood flow (CBF) in Paper III. Here, increased TBI severity was associated with decreased total grey matter CBF, and female athletes had globally decreased CBF. In Paper IV, tau aggregations were investigated by the PET tracer THK5317, and microglial neuroinflammation by the PK11195 tracer. SRC athletes had increased tau in the corpus callosum, and increased neuroinflammation medially in the medial temporal lobes. In TBI patients, tau was increased in thalami, temporal white matter and midbrain, with widespread neuroinflammation in white matter tracts. The alterations of CBF, and increased tau and neuroinflammation, in persistently symptomatic SRC athletes may contribute to the pathophysiology of SRC and the risk of long-term consequences. However, to determine whether these changes are persistent, exacerbate with time or may resolve spontaneously longitudinal studies are required.
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| 6. |
- Watanabe, Hiroyuki, et al.
(författare)
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Ipsilesional versus contralesional postural deficits induced by unilateral brain trauma : a side reversal by opioid mechanism
- 2020
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Ingår i: Brain Communications. - : Oxford University Press. - 2632-1297. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Unilateral traumatic brain injury and stroke result in asymmetric postural and motor deficits including contralateral hemiplegia and hemiparesis. In animals, a localized unilateral brain injury recapitulates the human upper motor neuron syndrome in formation of hindlimb postural asymmetry with contralesional limb flexion and the asymmetry of hindlimb nociceptive withdrawal reflexes. The current view is that these effects are developed due to aberrant activity of motor pathways that descend from the brain into the spinal cord. These pathways and their target spinal circuits may be regulated by local neurohormonal systems that may also mediate effects of brain injury. Here we evaluate if a unilateral traumatic brain injury induces hindlimb postural asymmetry, a model of postural deficits, and if this asymmetry is spinally encoded and mediated by the endogenous opioid system in rats. A unilateral right-sided controlled cortical impact, a model of clinical focal traumatic brain injury was centered over the sensorimotor cortex and was observed to induce hindlimb postural asymmetry with contralateral limb flexion. The asymmetry persisted after complete spinal cord transection, implicating local neurocircuitry in the development of the deficits. Administration of the general opioid antagonist naloxone and µ-antagonist β-funaltrexamine blocked formation of postural asymmetry. Surprisingly, κ-antagonists nor-binaltorphimine and LY2444296 did not affect the asymmetry magnitude but reversed the flexion side; instead of contralesional (left) hindlimb flexion the ipsilesional (right) limb was flexed. The postural effects of the right-side cortical injury were mimicked in animals with intact brain via intrathecal administration of the opioid κ-agonist U50,488 that induced hindlimb postural asymmetry with left limb flexion. The δ-antagonist naltrindole produced no effect on the contralesional (left) flexion but inhibited formation of the ipsilesional (right) limb flexion in brain-injured rats that were treated with κ-antagonist. The effects of the antagonists were evident before and after spinal cord transection. We concluded that the focal traumatic brain injury-induced postural asymmetry was encoded at the spinal level, and was blocked or its side was reversed by administration of opioid antagonists. The findings suggest that the balance in activity of the mirror symmetric spinal neural circuits regulating contraction of the left and right hindlimb muscles is controlled by receptors; and that this equilibrium is impaired after unilateral brain trauma through side-specific opioid mechanism.
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| 7. |
- Özen, Ilknur, et al.
(författare)
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Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits
- 2022
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Ingår i: Acta neuropathologica communications. - : Springer Nature. - 2051-5960. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Cerebellar dysfunction is commonly observed following traumatic brain injury (TBI). While direct impact to the cerebellum by TBI is rare, cerebellar pathology may be caused by indirect injury via cortico-cerebellar pathways. To address the hypothesis that degeneration of Purkinje cells (PCs), which constitute the sole output from the cerebellum, is linked to long-range axonal injury and demyelination, we used the central fluid percussion injury (cFPI) model of widespread traumatic axonal injury in mice. Compared to controls, TBI resulted in early PC loss accompanied by alterations in the size of pinceau synapses and levels of non-phosphorylated neurofilament in PCs. A combination of vDISCO tissue clearing technique and immunohistochemistry for vesicular glutamate transporter type 2 show that diffuse TBI decreased mossy and climbing fiber synapses on PCs. At 2 days post-injury, numerous axonal varicosities were found in the cerebellum supported by fractional anisotropy measurements using 9.4 T MRI. The disruption and demyelination of the cortico-cerebellar circuits was associated with poor performance of brain-injured mice in the beam-walk test. Despite a lack of direct input from the injury site to the cerebellum, these findings argue for novel long-range mechanisms causing Purkinje cell injury that likely contribute to cerebellar dysfunction after TBI.
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