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Evidence for cognitive resource imbalance in adolescents with narcolepsy
Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).ORCID iD: 0000-0002-7809-2481
Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. (Linnaeus Center HEAD)
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2018 (English)In: Brain Imaging and Behavior, ISSN 1931-7557, E-ISSN 1931-7565, Vol. 12, no 2, p. 411-424Article in journal (Refereed) Published
Abstract [en]

The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2018. Vol. 12, no 2, p. 411-424
Keywords [en]
EEG, GABA, MRS, Narcolepsy, Working memory, fMRI
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:liu:diva-145535DOI: 10.1007/s11682-017-9706-yISI: 000429029000011PubMedID: 28321606Scopus ID: 2-s2.0-85015625386OAI: oai:DiVA.org:liu-145535DiVA, id: diva2:1187615
Available from: 2018-03-05 Created: 2018-03-05 Last updated: 2019-03-04Bibliographically approved
In thesis
1. Brain Networks and Dynamics in Narcolepsy
Open this publication in new window or tab >>Brain Networks and Dynamics in Narcolepsy
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Narcolepsy is a chronic sleep disorder, characterised by excessive daytime sleepiness with frequent uncontrollable sleep attacks. In addition to sleeprelated problems, changes in cognition have also been observed in patients with narcolepsy and has been linked to the loss of Orexin-A in a number of studies. Results from previous functional and structural neuroimaging studies would suggest that the loss of Orexin-A has numerous downstream effects in terms of both resting state glucose metabolism and perfusion and reduction in cortical grey matter.

Specifically, studies investigating narcolepsy with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have observed aberrant perfusion and glucose metabolism in the hypothalamus and thalamus, as well as in prefrontal cortex. A very recent PET study in a large cohort of adolescents with type 1 narcolepsy further observed that the hypoand hypermetabolism in many of these cortico-frontal and subcortical brain regions also exhibited significant correlations with performance on a number of neurocognitive tests. These findings parallel those found in structural neuroimaging studies, where a reduction of cortical grey matter in frontotemporal areas has been observed.

The Aim of this thesis was to investigate mechanisms and aetiology behind the symptoms in narcolepsy through the application of different neuroimaging techniques. I present in this thesis evidence supporting that the complaints about subjective memory deficits in narcolepsy are related to a misallocation of resources.

I further describe how this has its seat in defective default mode network activation, possibly involving alterations to GABA and Glutamate signaling. In addition to this, I present our findings of a structural deviation in an area of the brainstem previously not described in the aetiology of narcolepsy.

This finding may have implications for further understanding the aetiology of the disease and the specific neuronal populations involved.

In addition to this, I show evidence from adipose tissue measurements in specific compartments, confirming that weight gain in narcolepsy is characterized by centrally located weight gain and may be specifically related to OX changes, but maybe not brown adipose tissue volume.

The findings presented in this thesis provides new insights to the pathophysiology of narcolepsy beyond the well-known depletion of OX producing neurons in the hypothalamus.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 54
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1651
National Category
Neurosciences Radiology, Nuclear Medicine and Medical Imaging Neurology Physiology
Identifiers
urn:nbn:se:liu:diva-153629 (URN)10.3384/diss.diva-153629 (DOI)9789176851814 (ISBN)
Public defence
2019-01-25, Hugo Theorells sal, Campus US, Linköping, 09:15 (English)
Opponent
Supervisors
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2019-01-07Bibliographically approved
2. Neurotransmitter Imaging of the Human Brain: Detecting γ-Aminobutyric Acid (GABA) Using Magnetic Resonance Spectroscopy
Open this publication in new window or tab >>Neurotransmitter Imaging of the Human Brain: Detecting γ-Aminobutyric Acid (GABA) Using Magnetic Resonance Spectroscopy
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: In this thesis, MEGA-edited Magnetic Resonance Spectroscopy (MRS) has been used for the purpose of non-invasive detection of !- aminobutyric acid (GABA) within the brain. GABA is the main inhibitory neurotransmitter in the human central nervous system, and glutamate is the corresponding main excitatory neurotransmitter. A balance between GABA and glutamate is crucial for healthy neurotransmission within the brain, and regional altered concentrations have been linked to certain neurological disorders. However, it is challenging to measure GABA, and special editing approaches are needed in order to allow reliable quantification. In addition, the GABA measurement is further complicated due to disturbances such as movements during the acquisition that may lead to artifacts in the resulting spectrum. This thesis can be divided into two sections, where the first section focuses on three clinical applications (narcolepsy, irritable bowel syndrome (IBS), and essential tremor (ET)), which were all investigated using MEGA-edited single- voxel spectroscopy (SVS). The second section focuses on method development, where two statistical retrospective approaches were investigated for the purpose of improving MEGA-edited data. In addition, a new MRS imaging (MRSI) pulse sequence with the purpose of GABA detection using a high spatial resolution, short acquisition time, and full brain coverage was also investigated.

Materials and Methods: In total, 164 participants were included and 272 MRS measurements were performed with the voxel placed in the medial prefrontal cortex (mPFC, 136), thalamus (32), and cerebellum (104) using two different but “identical” MR systems. Nineteen narcolepsy patients and 21 matched healthy controls performed an fMRI working memory task using a simultaneous EEG followed by an mPFC GABA-edited MRS measurement. Sixty-four IBS patients and 32 matched healthy controls underwent an mPFC GABA-edited MRS measurement followed by resting state fMRI. In addition, psychological symptoms were assessed using questionnaires. Ten ET patients and six matched healthy controls underwent four GABA-edited MRS measurements with the voxels placed in the thalamus and cerebellum. In this study, the symptom severity was investigated using the essential tremor rating scale (ETRS). All clinical MRS datasets were analyzed using conventional methods for post-processing and quantification. Furthermore, 12 volunteers were recruited for the purpose of investigating statistical retrospective approaches for artifact detection and elimination of MRS data. Each participant underwent three reference measurements and three measurements with induced head movements conducted according to a movement paradigm. Order statistic filtering (OSF) and jackknife correlation (JKC) were investigated as regards to the elimination of artifact-influenced spectra and reliability of the resulting concentrations. Finally, phantom measurements were performed for the purpose of investigating MEGA-edited MRSI.

Results: In narcolepsy, a trend-level association was observed between the mPFC MRS concentrations and increased deactivation within the default mode network during the working memory task. A significantly higher mPFC GABA+ concentration was observed in IBS patients with a high severity of comorbid anxiety. In ET, a positive correlation was observed between cerebellar GABA+/Glx ratios and tremor severity. Moreover, movements during the measurement decreased the concentration estimates due to signal loss in the spectra. Both OSF and JKC resulted in trend-level improvement of the signal- intense metabolites in spectrum when artifacts were present in the data, while performing equally as well as conventional analysis methodology when no intentional movements were present in the data. Finally, using the fast MEGA- edited multi-voxel sequence developed for a conventional clinical scanner, our phantom measurements showed that GABA was detectable using a 1:45 min acquisition time and an MRSI voxel size of 1 mL.

Discussion: Several challenges such as time constraints, large voxel sizes, and protocol design were encountered when performing SVS MEGA-PRESS in the clinical research settings. In addition, artifacts in the MRS data originating for example, from motions, negatively impacted the resulting averaged spectra, which was evident in both data from clinical populations and healthy controls. In the presence of artifacts in the data, both OSF and JKC improved the SVS MEGA-edited spectra. In addition, the implemented JKC method can be used not only for artifact detection, but also as a generally applicable retrospective technique for the quality control of a dataset, or as an indication of whether a shift in voxel placement occurred during the measurement. Using the MEGA-edited MRSI pulse sequence, there are many technical challenges, including detrimental effects from eddy currents, spurious echoes, and field inhomogeneities. Even though there are many technical challenges when using MEGA-edited MRSI, an optimized version of the MRSI sequence would be extremely valuable in clinical research applications where high spatial resolution and short acquisition times are highly desired.

Conclusions: OSF and JKC improved the metabolite quantification when artifacts were present in the data, and JKC was preferable. Although there are many technical challenges, MEGA-edited MRSI with full brain coverage in combination with a minimal voxel size for the purpose of GABA detection, would be extremely useful in clinical research applications where disorders such as narcolepsy, IBS, or ET, are investigated.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2019
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1667
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-154904 (URN)978-91-7685-119-7 (ISBN)
Public defence
2019-04-12, Hugo Theorell, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-03-04Bibliographically approved

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Drissi, Natasha MoralesTapper, SofieWretman, AnnaLandtblom, Anne-MarieKarlsson, ThomasLundberg, PeterEngström, Maria

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