Purpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis... Show morePurpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis remains challenging. Neuroimaging techniques have provided valuable insights into the pathophysiology of narcolepsy and idiopathic hypersomnia. Here, we review current structural and functional brain imaging findings in central hypersomnolence disorders and discuss the future perspectives of neuroimaging in these sleep disorders.Recent FindingsMost studies have focused on narcolepsy type 1 (or narcolepsy with cataplexy), showing inconsistent but extensive structural differences in the hypothalamus and its normally widespread projections. Functional studies have mainly focused on resting-state or emotion regulation in narcolepsy type 1 and have revealed disturbed activity in limbic and mesolimbic structures in relation to cataplexy. Finally, recent studies suggest a disruption of the default-mode network in patients with idiopathic hypersomnia.SummaryMost neuroimaging studies to date have been conducted in small samples, while narcolepsy type 2 (or narcolepsy without cataplexy) and idiopathic hypersomnia remain relatively understudied. Larger studies with consistent clinical phenotyping should be the focus of future investigations. In addition, multi-modal imaging methods will be crucial to resolve previous inconsistencies and identify reliable objective biomarkers that could aid in understanding the pathophysiology and potentially support the diagnostic process. Show less
The premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors.... Show moreThe premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors. Clinical research strategies, experimental designs, neuroimaging techniques and biochemical methods have revealed clinical risk factors, biochemical modulators and pharmacological triggers. Furthermore, newly discovered hypothalamus-specific alterations in metabolism and perfusion in the early phases of the migraine attack were described. Taken together, these results suggest that each migraine attack starts well before the initiation of the headache phase. The hypothalamus is postulated to have a pivotal role in the early phases of the migraine attack, and possibly affects attack susceptibility interictally as well. Show less
Opstal, A.M. van; Kaal, I.; Berg-Huysmans, A.A. van den; Hoeksma, M.; Blonk, C.; Pijl, H.; ... ; Grond, J. van der 2019
The results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons ... Show moreThe results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons (hippocampus and olfactory forebrain), DCL expression was found in three novel brain areas namely hypothalamic tanycytes, suprachiasmatic nucleus and Islands of Calleja. A state of the art conditional shRNA expressing mouse model was used to target DCL mRNA. The analysis of these DCL knockdown animals using qPCR and Western blot revealed strong reduction of DCL protein expression. Subsequent stereological analysis using BrdU and several stem cell and neuronal markers revealed increased progenitor proliferation, but impaired neurogenesis in the hippocampus. This impaired neurogenesis was associated, however, with an apparent normal spatial and contextual fear memory formation in circular hole board and in a contextual fear conditioning paradigm. Therefore, DCL-regulated adult neurogenesis seems not crucial for hippocampus-dependent learning. However, more subtle functions like pattern separation and context distinction might be regulated by DCL. DCL knockdown also increased D2 activity within the hypothalamus. Altogether, the DCL-KD mouse seems a good working model to study adult neurogenesis and the role of DCL in this process. Show less
Het dagelijkse ritme van slapen en waken wordt gereguleerd door de suprachiasmatische nuclei, twee kleine kernen die diep in de hersenen liggen en functioneren als een interne biologische klok.... Show moreHet dagelijkse ritme van slapen en waken wordt gereguleerd door de suprachiasmatische nuclei, twee kleine kernen die diep in de hersenen liggen en functioneren als een interne biologische klok. Dankzij de werking van deze kernen vertonen allerlei hersenstructuren en fysiologische processen 24 uurs ritmen die het lichaam in staat stellen zich optimaal aan te passen aan het dagelijks ritme van dag en nacht. Het onderzoek in dit proefschrift bestaat uit twee experimentele delen. In het eerste deel worden de mechanismes onderzocht waarmee de suprachiasmatische nuclei de timing van gedragsactiviteit en rust reguleren. In het tweede deel is onderzocht hoe verstoringen van de biologische klok samenhangen met ziekteontwikkeling in de context van psychiatrische aandoeningen, metabole stoornissen en chronisch nierfalen. Show less
Snel, M.; Wijngaarden, M.A.; Bizino, M.B.; Grond, J. van der; Teeuwisse, W.M.; Buchem, M.A. van; ... ; Pijl, H. 2012
Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble... Show moreSleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th–75th percentiles]); AD 12,935 neurons (9972–19,051); controls 21,002 neurons (16,439–25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197–317]; controls: 320 pg/mL [262–363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels. Show less
Er zijn steeds meer aanwijzingen dat neuropeptiden in de hypothalamus en maagdarmhormonen die hun werking hebben op de hypothalamus en betrokken zijn bij de regulatie van voedselinname, ook... Show moreEr zijn steeds meer aanwijzingen dat neuropeptiden in de hypothalamus en maagdarmhormonen die hun werking hebben op de hypothalamus en betrokken zijn bij de regulatie van voedselinname, ook betrokken zouden kunnen zijn bij de regulatie van insuline gevoeligheid. Daarom hebben we eerst de effecten van voedselstatus zelf op insuline gevoeligheid gekarakteriseerd en vervolgens gekeken naar de effecten van een aantal signalen voor voedselstatus binnen de maagdarm-brein as op insuline gevoeligheid. Insuline gevoeligheid in lever, spier en vetweefsel hebben we in alle studies in wildtype muizen gemeten met een hyperinsulinemische euglycemische clamp in combinatie met radioisotopen. De studies die uitgevoerd zijn binnen dit proefschrift laten zien dat samenwerking tussen het maagdarmstelsel en het brein niet alleen een belangrijke rol speelt bij de regulatie van voedselinname reguleert, maar ook bij de regulatie van de insuline gevoeligheid van het glucose metabolisme in de lever en perifere weefsels, zoals spier en vetweefsel, afhankelijk en onafhankelijk van voedingsstatus. Op deze manier kan op ieder moment de weefsel-specifieke insuline gevoeligheid nauwkeurig worden gereguleerd, afhankelijk en onafhankelijk van voedingsstatus. Deze eigenschappen maken dat maagdarmhormonen mogelijk ideale nieuwe farmaceutische aangrijpingspunten zijn voor de behandeling van obesitas en type II diabetes mellitus. Show less