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Brain Networks and Dynamics in Narcolepsy
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).
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: urn:nbn:se:liu:diva-153629DOI: 10.3384/diss.diva-153629ISBN: 9789176851814 (print)OAI: oai:DiVA.org:liu-153629DiVA, id: diva2:1275113
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
List of papers
1. Altered Brain Microstate Dynamics in Adolescents with Narcolepsy
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2016 (English)In: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 10, no 369Article in journal (Refereed) Published
Abstract [en]

Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional fMRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2016
Keywords
narcolepsy; default mode network; functional magnetic resonance imaging (fMRI); electroencephalography (EEG); microstates; resting state networks; orexin; sleep
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-131167 (URN)10.3389/fnhum.2016.00369 (DOI)000380989900001 ()27536225 (PubMedID)
Note

Funding Agencies|Research Council of South East Sweden (FORSS); Knut and Alice Wallenberg foundation (KAW); strategic research area of systems neurobiology at Linkoping University; Country council of Ostergotland Sweden

Available from: 2016-09-20 Created: 2016-09-12 Last updated: 2019-01-04
2. Evidence for cognitive resource imbalance in adolescents with narcolepsy
Open this publication in new window or tab >>Evidence for cognitive resource imbalance in adolescents with narcolepsy
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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
Keywords
EEG, GABA, MRS, Narcolepsy, Working memory, fMRI
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-145535 (URN)10.1007/s11682-017-9706-y (DOI)000429029000011 ()28321606 (PubMedID)2-s2.0-85015625386 (Scopus ID)
Available from: 2018-03-05 Created: 2018-03-05 Last updated: 2019-03-04Bibliographically approved
3. Unexpected Fat Distribution in Adolescents With Narcolepsy
Open this publication in new window or tab >>Unexpected Fat Distribution in Adolescents With Narcolepsy
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2018 (English)In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 728Article in journal (Refereed) Published
Abstract [en]

Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
orexin; hypocretin; brown adipose tissue; visceral adipose tissue; subcutaneous adipose tissue; BMI; magnetic resonance imaging (MRI); obesity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-153502 (URN)10.3389/fendo.2018.00728 (DOI)000452268600001 ()
Note

Funding Agencies|Research Council of South East Sweden [FORSS-480551]; Knut and Alice Wallenberg foundation [KAW 2013.0076]

Available from: 2019-01-02 Created: 2019-01-02 Last updated: 2019-01-04

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Drissi, Natasha Morales

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