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Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. School of Sport Sciences, The Arctic University of Norway, Tromsø, Norway Medicine.
Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
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2019 (English)In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 34, no 3, p. 189-198Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To examine the effects of monoaminergic stabilizer (-)-OSU6162 on brain activity, as measured by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients in the chronic phase of traumatic brain injury suffering from fatigue.

SETTING: Neurorehabilitation clinic.

PARTICIPANTS: Patients with traumatic brain injury received either placebo (n = 24) or active treatment (n = 28). Healthy controls (n = 27) went through fMRI examination at one point and were used in sensitivity analysis on normalization of BOLD response.

DESIGN: Randomized, double-blinded, placebo-controlled design.

MAIN MEASURES: Effects on BOLD signal changes from before to after treatment during performance of a fatiguing attention task.

RESULTS: The fMRI results revealed treatment effects within the right occipitotemporal cortex and the right orbitofrontal cortex. In these regions, the BOLD response was normalized relative to healthy controls at the postintervention fMRI session. No effects were seen in regions in which we previously observed activity differences between patients and healthy controls while performing this fMRI task, such as the striatum.

CONCLUSION: (-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue.

Place, publisher, year, edition, pages
Wolters Kluwer, 2019. Vol. 34, no 3, p. 189-198
Keywords [en]
dopaminergic agents, functional magnetic resonance imaging, randomized controlled trial, traumatic brain injury
National Category
Neurology Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-152090DOI: 10.1097/HTR.0000000000000440ISI: 000474249100015PubMedID: 30234850OAI: oai:DiVA.org:umu-152090DiVA, id: diva2:1251230
Funder
Ragnar Söderbergs stiftelseTorsten Söderbergs stiftelseKnut and Alice Wallenberg FoundationVästerbotten County CouncilAvailable from: 2018-09-26 Created: 2018-09-26 Last updated: 2019-08-06Bibliographically approved
In thesis
1. Fatigue after traumatic brain injury: exploring novel methods for diagnosis and treatment
Open this publication in new window or tab >>Fatigue after traumatic brain injury: exploring novel methods for diagnosis and treatment
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Trötthet efter traumatisk skallskada : utforskande av nya metoder för diagnostik och behandling
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2019. p. 59
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2000
Keywords
Traumatic brain injury, fatigue, OSU6162, randomized clinical trials, functional magnetic resonance imaging, neuropsychology, structural magnetic resonance imaging, white matter hyperintensities
National Category
Other Medical Sciences not elsewhere specified
Research subject
Rehabilitation Medicine
Identifiers
urn:nbn:se:umu:diva-155409 (URN)978-91-7601-979-5 (ISBN)
Public defence
2019-02-08, Aulan, Vårdvetarhuset, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-01-18 Created: 2019-01-15 Last updated: 2019-01-17Bibliographically approved

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Berginström, NilsNordström, PeterEkman, UrbanEriksson, JohanNyberg, LarsNordström, Anna

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