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Fatigue after traumatic brain injury: exploring novel methods for diagnosis and treatment
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Trötthet efter traumatisk skallskada : utforskande av nya metoder för diagnostik och behandling (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-155409ISBN: 978-91-7601-979-5 (print)OAI: oai:DiVA.org:umu-155409DiVA, id: diva2:1278847
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
List of papers
1. The effects of (-)-OSU6162 on chronic fatigue in patients with traumatic brain injury: a randomized controlled trial
Open this publication in new window or tab >>The effects of (-)-OSU6162 on chronic fatigue in patients with traumatic brain injury: a randomized controlled trial
2017 (English)In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 32, no 2, p. E46-E54Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To examine the effects of the monoaminergic stabilizer (-)-OSU6162 on mental fatigue in patients with traumatic brain injury.

SETTING: Single-center Neurorehabilitation Clinic.

DESIGN: Randomized, double-blind, placebo-controlled trial.

PARTICIPANTS: Sixty-four subjects with traumatic brain injury were randomized to treatment (n = 33) and placebo (n = 31).

MAIN MEASURES: The effects of (-)-OSU6162 at a dose of 15 mg twice a day were evaluated using self-assessment scales and neuropsychological tests measuring mental fatigue.

RESULTS: No difference between groups was observed on any scale at baseline. At follow-up, both groups showed significant improvement on the Fatigue Severity Scale and the Mental Fatigue Scale (both Ps < .01). Similarly, the performance of both groups increased significantly on many neuropsychological tests. However, no significant between-group difference in changes on these scales was observed before or after adjustment for confounders except for one neuropsychological test favoring the control group. Sensitivity analyses showed significantly greater changes in levels of prolactin and folic acid and heart rate (all Ps < .05) in the treatment group. The mean plasma concentration after 4 weeks of treatment was 0.14 (range, 0.01-0.32) μM, which was lower than expected.

INTERPRETATION: Treatment with (-)-OSU6162 had no significant effect on mental fatigue in patients with traumatic brain injury compared with placebo.

Keywords
clinical trials, fatigue, mental, randomized, traumatic brain injury
National Category
Neurology
Research subject
Rehabilitation Medicine
Identifiers
urn:nbn:se:umu:diva-128140 (URN)10.1097/HTR.0000000000000236 (DOI)000395944700006 ()27120292 (PubMedID)
Available from: 2016-11-24 Created: 2016-11-24 Last updated: 2019-01-15Bibliographically approved
2. Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: changes linked to altered Striato-Thalamic-Cortical Functioning
Open this publication in new window or tab >>Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: changes linked to altered Striato-Thalamic-Cortical Functioning
Show others...
2018 (English)In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 33, no 4, p. 266-274Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI).

Setting: Neurorehabilitation clinic.

Participants: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27).

Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task.

Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001).The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%.

Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

Place, publisher, year, edition, pages
Wolters Kluwer, 2018
Keywords
fatigue, functional magnetic resonance imaging, neuropsychology, traumatic brain injury
National Category
Neurology
Research subject
Rehabilitation Medicine
Identifiers
urn:nbn:se:umu:diva-140021 (URN)10.1097/HTR.0000000000000340 (DOI)000442745900013 ()
Funder
Västerbotten County CouncilTorsten Söderbergs stiftelse
Available from: 2017-09-29 Created: 2017-09-29 Last updated: 2019-01-15Bibliographically approved
3. Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162
Open this publication in new window or tab >>Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162
Show others...
2018 (English)In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509XArticle in journal (Refereed) Epub ahead of print
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, 2018
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-152090 (URN)10.1097/HTR.0000000000000440 (DOI)30234850 (PubMedID)
Funder
Ragnar Söderbergs stiftelseTorsten Söderbergs stiftelseKnut and Alice Wallenberg FoundationVästerbotten County Council
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2019-04-05
4. White matter hyperintensities increases with traumatic brain injuryseverity: associations to neuropsychological performance and fatigue
Open this publication in new window or tab >>White matter hyperintensities increases with traumatic brain injuryseverity: associations to neuropsychological performance and fatigue
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: To examine the prevalence of white matter hyperintensities (WMHs) in patients with traumatic brain injury (TBI) as compared to healthy controls, and to investigate whether there is an association between WMH lesion burden and performance on neuropsychological tests in patients with TBI.

Methods: A total of 59 patients with TBI and 27 age- and gender- matched healthy controls underwent thorough neuropsychological testing and magnetic resonance imaging. The quantification of WMH lesions was performed using the fully automated Lesion Segmentation Tool.

Results: WMH lesions were more common in patients with TBI than in healthy controls (p = 0.032), and increased with higher TBI severity (p = 0.025). Linear regressions showed that WMH lesions in patients with TBI were not related to performance on any neuropsychological tests (p > 0.05 for all). However, a negative relationship between number of WMH lesions in patients with TBI and self-assessed fatigue was found (r = –0.33, p = 0.026).

Conclusion: WMH lesions are more common in patients with TBI than in healthy controls, and WMH lesions burden increases with TBI severity. However, these lesions do not seem to explain the decreased cognitive functioning or the increased fatigue in patients with TBI.

National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-155406 (URN)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-16

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