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Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162
Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik. School of Sport Sciences, The Arctic University of Norway, Tromsø, Norway Medicine.
Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
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2019 (Engelska)Ingår i: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 34, nr 3, s. 189-198Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Wolters Kluwer, 2019. Vol. 34, nr 3, s. 189-198
Nyckelord [en]
dopaminergic agents, functional magnetic resonance imaging, randomized controlled trial, traumatic brain injury
Nationell ämneskategori
Neurologi Neurovetenskaper
Identifikatorer
URN: urn:nbn:se:umu:diva-152090DOI: 10.1097/HTR.0000000000000440ISI: 000474249100015PubMedID: 30234850OAI: oai:DiVA.org:umu-152090DiVA, id: diva2:1251230
Forskningsfinansiär
Ragnar Söderbergs stiftelseTorsten Söderbergs stiftelseKnut och Alice Wallenbergs StiftelseVästerbottens läns landstingTillgänglig från: 2018-09-26 Skapad: 2018-09-26 Senast uppdaterad: 2019-08-06Bibliografiskt granskad
Ingår i avhandling
1. Fatigue after traumatic brain injury: exploring novel methods for diagnosis and treatment
Öppna denna publikation i ny flik eller fönster >>Fatigue after traumatic brain injury: exploring novel methods for diagnosis and treatment
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2019. s. 59
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2000
Nyckelord
Traumatic brain injury, fatigue, OSU6162, randomized clinical trials, functional magnetic resonance imaging, neuropsychology, structural magnetic resonance imaging, white matter hyperintensities
Nationell ämneskategori
Övrig annan medicin och hälsovetenskap
Forskningsämne
rehabiliteringsmedicin
Identifikatorer
urn:nbn:se:umu:diva-155409 (URN)978-91-7601-979-5 (ISBN)
Disputation
2019-02-08, Aulan, Vårdvetarhuset, Umeå, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2019-01-18 Skapad: 2019-01-15 Senast uppdaterad: 2019-01-17Bibliografiskt granskad

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