stinekhe

• Follin, Louise Frøstrup; Viste, Rannveig; Vevelstad, Janita; Langdalen, Kristin; Hansen, Berit M Hjelde & Grande, Ragnhild Kristine Berling [Show all 12 contributors for this article] (2026). High-resolution sleep fragmentation assessment in narcolepsy type 1 and their non-narcoleptic siblings: a 5-s mini-epoch study. Sleep. ISSN 0161-8105. doi: 10.1093/sleep/zsag015. Full text in Research Archive Show summary

  Study Objectives Narcolepsy type 1 (NT1) is characterized by fragmented sleep, yet brief transitions may be concealed in traditional 30-s epochs. We therefore aimed to assess sleep fragmentation in NT1 patients and their non-narcoleptic siblings using 5-s mini-epochs. Methods We analyzed sleep stages from human-scored 30-s epochs and automatically (U-Sleep) scored 5-s mini-epochs in polysomnographies from 125 NT1 patients and their 100 non-narcoleptic siblings. Sleep fragmentation was quantified using transition indices and probabilities in epochs and mini-epochs, furthermore, stratified by 1st and 2nd night-half. Predictors (H1N1-vaccination, CSF hypocretin-1 deficiency severity (low [40–150 pg/mL]; undetectable [<40 pg/mL]), HLA-DQB1*06:02-positivity, narcolepsy core symptom severity) for sleep transitions were explored. Results NT1 patients had significantly higher all-stages and sleep–wake transition indices compared to siblings in epochs and mini-epochs. Both epoch and mini-epoch transition indices varied significantly from 1st to 2nd night-half. Only in mini-epochs, sleep–wake fragmentation was (a) higher in patients with severe core symptoms, and (b) increased in the 2nd night-half in NT1 patients with severe hypocretin-1 deficiency (<40 pg/mL) and/or severe core symptoms. Conclusions Our findings suggest that sleep fragmentation, a core feature of NT1, is associated with disease severity and hypocretin deficiency severity when high-resolution sleep stages are analyzed. Five-second sleep staging and split-night analyses enhance detection of sleep instability and reveal new specific patterns and clinical associations. Automated mini-epoch analyses may improve future NT1 phenotyping and possibly its borderland by supplementing with clinically relevant high-resolution features otherwise hidden in traditional full-night 30-s epoch analyses.

• Follin, Louise Frøstrup; Christensen, Julie Anja Engelhard; Vevelstad, Janita; Juvodden, Hilde Therese; Viste, Rannveig & Hansen, Berit M Hjelde [Show all 10 contributors for this article] (2025). Optimizing automated sleep stage scoring of 5-s mini-epochs: a transfer learning study. Sleep. ISSN 0161-8105. p. 1–14. doi: 10.1093/sleep/zsaf393. Full text in Research Archive Show summary

  Study Objectives Conventional sleep staging relies on 30-s epochs, potentially concealing transient sleep stage intrusion and reducing precision. Building on our previous study of mini-epochs, we investigated whether U-Sleep, an existing automatic deep learning-based sleep staging model with high performance in epochs, could be optimized to similar performance level in 5-s mini-epoch scoring, thereby enabling more detailed sleep characterization. Methods We created a dataset of 48 000 human-scored 5-s mini-epochs from 100 polysomnographies. We compared mini-epochs to human-scored epochs before U-Sleep was optimized using transfer learning and evaluated on a test set. Model performance was assessed using F1-scores, confusion matrices, stage distributions and transition rates comparing scorings of the original U-Sleep before, and the optimized U-Sleep after transfer learning to human-scored mini-epochs. Results Compared to human-scored epochs, human-scored mini-epochs captured significantly more transitions (1.70/min vs. 0.21/min, p < .001), and significantly more wake (8.4 per cent vs. 5.4 per cent), N1 (7.2 per cent vs. 5.4 per cent), and N2 (51.8 per cent vs. 40.9 per cent), less N3 (15.4 per cent vs. 25.2 per cent), and REM sleep (16.7 per cent vs. 23.0 per cent) (all p < .001). Optimizing U-Sleep improved its performance significantly from F1 = 0.74 to F1 = 0.81 (p < .05) and gave increased transition rates in the test set (original U-Sleep: 1.06/min, optimized U-Sleep: 1.34/min, human-scored mini-epochs: 1.70/min). Stage distributions did not differ between optimized U-Sleep’s scorings and human-scored mini-epochs. Conclusion After optimization, U-Sleep performance in mini-epochs matched the high performance levels previously reported in both human and automated 30-s epoch scoring. This demonstrates the feasibility of precise, automated high-resolution sleep staging. Future work should include external validation and application to full-night recordings.

• Zhang, Lisan; Cai, Shuo; Teng, Ashton; Lin, Ling; Han, Fang & Yan, Han [Show all 30 contributors for this article] (2025). HLA-DQB1*03:01 strongly affects age of onset of type 1 narcolepsy independently of DQA1 and ethnicity. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 122(50), p. 1–8. doi: 10.1073/pnas.2513989122. Full text in Research Archive
• Follin, Louise Frøstrup; Zahid, Alexander Neergaard; Viste, Rannveig; Vevelstad, Janita; Kaufmann, Tobias Herbert & Ramm-Pettersen, Anette [Show all 10 contributors for this article] (2025). An inter-rater variability study between human and automatic scorers in 5-s mini-epochs of sleep. Sleep Medicine. ISSN 1389-9457. 128, p. 139–150. doi: 10.1016/j.sleep.2025.02.005. Full text in Research Archive Show summary

  Study objective Sleep is traditionally scored using 30-s epochs of polysomnographies. As sleep is physiologically dynamic and 30-s epochs may conceal important characteristics, we aim to challenge this standard by scoring sleep in 5-s mini-epochs and analyzing inter-rater variability between human and automatic scorers. Methods In 40 polysomnography recordings, 120 mini-epochs per polysomnography were scored manually by three human experts (expert1_5s, expert2_5s and expert3_5s) and automatically by a validated sleep classifier (USleep_5s). Additionally, 5-s mini-epochs (clinical_5s) extracted from conventional human-scored 30-s epochs were considered. We assessed inter-rater variability and stage shifting in epochs and mini-epochs and further in narcolepsy type 1 (NT1) patients and siblings. Results Agreement for mini-epochs was κ = 0.50 ± 0.11 (expert1_5s vs clinical_5s) and κ = 0.51 ± 0.12, (expert1_5s vs USleep_5s). Between human experts, agreement was κ = 0.51 ± 0.16 (expert1_5s vs expert2_5s), and κ = 0.57 ± 0.11 (expert1_5s vs expert3_5s). Stage shift percentages were significantly higher in mini-epochs scored by expert1_5s (27.75 %) and USleep_5s (22.88 %) than corresponding conventional epochs (5.12 %), with no significant difference between NT1 patients and siblings. Conclusion While mini-epoch scoring agreement was generally high, it was still lower than within epochs, likely due to a lack of standard mini-epoch scoring procedure and the automatic classifier being trained on epochs. However, stage discrepancies between epochs and mini-epochs and increased stage shifting in mini-epochs support that epochs can contain several stages, and that mini-epochs could supplement more detailed sleep characterization potentially enabling more precise diagnosis and finding new polysomnographic biomarkers. Future studies should include larger datasets to refine mini-epoch scoring rules and exploit automatic classifiers e.g. via transfer learning.

• Juvodden, Hilde Therese; Alnæs, Dag; Agartz, Ingrid; Andreassen, Ole A.; Server, Andrés & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2024). Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study. Sleep Medicine. ISSN 1389-9457. 116, p. 81–89. doi: 10.1016/j.sleep.2024.02.031. Full text in Research Archive Show summary

  There was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. Methods We included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. Results Patients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. Conclusions Post-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Agartz, Ingrid; Andreassen, Ole & Server, Andrés [Show all 9 contributors for this article] (2023). Larger hypothalamic volume in narcolepsy type 1. Sleep. ISSN 0161-8105. 46(11). doi: 10.1093/sleep/zsad173. Full text in Research Archive Show summary

  Study Objectives: Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%–90% loss of the 50 000–70 000 hypocretin-producing neurons and 64%–94% increase in the 64 000–120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. Methods: We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. Results: The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen’s d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. Conclusions: In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.

• Viste, Rannveig; Follin, Louise Frøstrup; Kornum, Birgitte R.; Lie, Benedicte Alexandra; Viken, Marte Kathrine & Thorsby, Per Medbøe [Show all 9 contributors for this article] (2023). Increased muscle activity during sleep and more RBD symptoms in H1N1-(Pandemrix)-vaccinated narcolepsy type 1 patients compared with their non-narcoleptic siblings. Sleep. ISSN 0161-8105. 46(3), p. 1–14. doi: 10.1093/sleep/zsac316. Full text in Research Archive Show summary

  Abstract Study Objectives Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity. Methods RBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5–15 s); short (0.1–0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed. Results RBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p &amp;lt; 0.001). Patients with undetectable CSF hypocretin-1 levels (&amp;lt;40 pg/ml) had significantly more NREM periodic long muscle activity than patients with low but detectable levels (40–150 pg/ml) (p = 0.047). In siblings, REM and NREM sleep muscle activity indices were not associated with RBD symptoms, other narcolepsy symptoms, or HLA-DQB1*06:02-positivity. H1N1-(Pandemrix)-vaccination status did not predict muscle activity indices in patients or siblings. Conclusion Increased REM and NREM muscle activity and more RBD symptoms is characteristic of NT1, and muscle activity severity is predicted by hypocretin deficiency severity but not by H1N1-(Pandemrix)-vaccination status. In the patients’ non-narcoleptic siblings, neither RBD symptoms, core narcoleptic symptoms, nor the major NT1 risk factors is associated with muscle activity during sleep, hence not indicative of a phenotypic continuum.

• Ollila, Hanna M.; Sharon, Eilon; Lin, Ling; Sinnott-Armstrong, Nasa; Ambati, Aditya & Yogeshwar, Selina M. [Show all 411 contributors for this article] (2023). Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature Communications. 14. doi: 10.1038/s41467-023-36120-z. Full text in Research Archive Show summary

  Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

• Hansen, Berit M Hjelde; Andresen, Hilde Norsted; Gjesvik, Jonas; Thorsby, Per Medbøe; Nærland, Terje & Knudsen, Stine (2023). Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type1. Sleep Medicine. ISSN 1389-9457. 109, p. 149–157. doi: 10.1016/j.sleep.2023.06.021. Full text in Research Archive Show summary

  Objective/Background Psychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of this study was to evaluate the prevalence of psychiatric disorders and executive dysfunctions, secondly to explore the association between psychiatric comorbidity, executive dysfunctions, subjective and objective sleep measures, and severity of cerebrospinal fluid (CSF) hypocretin-1 deficiency in pediatric narcolepsy type 1 (PNT1). Patients/Methods Cross-sectional study of 59 consecutively included PNT1 patients (age: 6-20 years; 34:25 girls: boys; 54/59 H1N1 (Pandemrix®)-vaccinated). Core narcolepsy symptoms including subjective sleepiness, polysomnography and multiple sleep latency test results, CSF hypocretin-1 levels, psychiatric disorders (by semistructured diagnostic interview Kaufmann Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS)), and executive dysfunction (by Behavior Rating of Executive Function (BRIEF)) were assessed. Results 52.5% of the patients had one or more psychiatric comorbid disorder, and 64.7% had executive dysfunction in a clinically relevant range, with no sex difference in prevalence, while older age was associated with poorer executive function (p=0.013). Having any psychiatric comorbid disorder was associated with poorer executive functions (p=0.001). CSF hypocretin-1 deficiency severity was significantly associated with presence of psychiatric comorbidity (p=0.022) and poorer executive functions (p=0.030), and poorer executive functions was associated with subjective sleepiness (p=0.009). Conclusions The high occurrence of, and association between, psychiatric comorbidity and executive dysfunction underlines the importance of close attention to both these comorbidities in clinical care of NT1.

• Cesari, Matteo; Heidbreder, Anna; Louis, Erik K. St; Sixel-Döring, Friederike; Bliwise, Donald L. & Baldelli, Luca [Show all 22 contributors for this article] (2022). Video-polysomnography procedures for diagnosis of rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages: guidelines from the International RBD Study Group. Sleep. ISSN 0161-8105. 45(3). doi: 10.1093/sleep/zsab257. Full text in Research Archive
• Viste, Rannveig; Lie, Benedicte Alexandra; Viken, Marte Kathrine; Rootwelt, Terje; Knudsen-Heier, Stine & Kornum, Birgitte Rahbek (2021). Narcolepsy type 1 patients have lower levels of effector memory CD4+ T cells compared to their siblings when controlling for H1N1-(Pandemrix™)-vaccination and HLA DQB1∗06:02 status. Sleep Medicine. ISSN 1389-9457. 85, p. 271–279. doi: 10.1016/j.sleep.2021.07.024. Full text in Research Archive Show summary

  Study objectives Evidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings. Methods Peripheral blood mononuclear cells were collected in parallel and analysed with flow cytometry in 31 NT1 patients with disease onset after the 2009 influenza A (H1N1) pandemic and/or Pandemrix™ vaccination and 45 of their non-narcoleptic siblings (29/31 and 34/45 vaccinated, respectively). Results We observed significantly lower effector memory CD4+ T cell levels in NT1 patients compared to their siblings, when controlling for HLA DQB1∗06:02 and vaccination status. Further, within the sibling group, vaccination status significantly affected frequencies of central memory and CD8+CD25+ T cells, and HLA DQB1∗06:02 status significantly affected frequencies of CD4+CD25+ T cells. Conclusion We confirm that NT1 is associated with lower levels of effector memory CD4+ T cells in peripheral blood. Importantly, this finding was only significant when controlling for vaccination and HLA status in both patients and controls. We thus demonstrate the importance of characterizing such factors (eg HLA and vaccination) when studying T cell subsets in NT1. This might explain earlier conflicting results.

• Viste, Rannveig; Viken, Marte Kathrine; Lie, Benedicte Alexandra; Juvodden, Hilde Therese; Nordstrand, Sebjørg E. H. & Thorsby, Per M. [Show all 9 contributors for this article] (2021). High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y<inf>11</inf>protein levels in narcolepsy type 1. Sleep. ISSN 0161-8105. 44(8), p. 1–12. doi: 10.1093/sleep/zsab062. Full text in Research Archive Show summary

  Abstract Study Objectives Narcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls. Methods The P2RY11 SNP was genotyped in 100 patients (90/100 H1N1-(Pandemrix)-vaccinated), 119 related and 123 non-related controls. CD4 and CD8 T lymphocyte P2Y11 protein levels were quantified using flow cytometry in 167 patients and relatives. Symptoms and sleep recording parameters were also collected. Results We found an association between NT1 and the rs2305795 A allele (OR = 2, 95% CI (1.3, 3.0), p = 0.001). T lymphocyte P2Y11 protein levels were significantly lower in patients and relatives homozygous for the rs2305795 risk A allele (CD4: p = 0.012; CD8: p = 0.007). The nocturnal sleep fragmentation index was significantly negatively correlated with patients’ P2Y11 protein levels (CD4: p = 0.004; CD8: p = 0.006). Mean MSLT sleep latency, REM-sleep latency, and core clinical symptoms were not associated with P2Y11 protein levels. Conclusions We confirmed that the P2RY11 polymorphism rs2305795 is associated with NT1 also in a mainly H1N1-(Pandemrix)-vaccinated cohort. We demonstrated that homozygosity for the A risk allele is associated with lower P2Y11 protein levels. A high level of nocturnal sleep fragmentation was associated with low P2Y11 levels in patients. This suggests that P2Y11 has a previously unknown function in sleep-wake stabilization that affects the severity of NT1.

• Nordstrand, Sebjørg Elizabeth Hesla; Juvodden, Hilde Therese; Viste, Rannveig; Rootwelt-Revheim, Terje; Karlsen, Tor-Ivar & Thorsby, Per Medbøe [Show all 10 contributors for this article] (2020). Obesity and other medical comorbidities among NT1 patients after the Norwegian H1N1 influenza epidemic and vaccination campaign. Sleep. ISSN 0161-8105. 43(5). doi: 10.1093/sleep/zsz277. Full text in Research Archive
• Hansen, Berit M Hjelde; Juvodden, Hilde Therese; Nordstrand, Sebjørg Elizabeth Hesla; Viste, Rannveig; Thorsby, Per Medbøe & Swanson, David [Show all 9 contributors for this article] (2020). High prevalence of ADHD symptoms in unmedicated youths with post-H1N1 narcolepsy type 1. Sleep Medicine. ISSN 1389-9457. 75, p. 171–180. doi: 10.1016/j.sleep.2020.06.014. Full text in Research Archive Show summary

  Objectives To characterize attention deficit-hyperactivity disorder (ADHD) symptoms in unmedicated post-H1N1 narcolepsy type 1 (NT1) youths, and explore associations between ADHD symptoms and the narcolepsy phenotype. Methods A total of 50 consecutively enrolled post-H1N1 NT1 youths (7–20 years, 62% females, 98% HLA-DQB1∗06:02-positive, 98% CSF hypocretin-1 deficient, 88% vaccinated) were assessed after two weeks off medication for ADHD (ADHD diagnosis pre/post-narcolepsy, parent-rated ADHD symptoms) and narcolepsy-phenotyped (semi-structured interview, Stanford Sleep Questionnaire, Epworth Sleepiness Scale, polysomnography (PSG), Multiple Sleep Latency Test (MSLT)). Results In sum, 26 (52%) and 15 (30%) of participants had ADHD symptoms above and below the clinical significant cut-off, respectively, while 9 (18%) had no ADHD symptoms. High values were found for ADHD total score (mean (SD), 17.9 (9.5)) and ADHD subscores (inattentive score, 11.0 (6.3); hyperactive/impulsivity score, 6.9 (4.7)). These were significantly higher than previously reported in a mainly medicated narcolepsy cohort (p < 0.0001). Age, gender and disease duration did not influence scores. Two participants (4%) had ADHD diagnosis prior to narcolepsy onset. ADHD symptoms were correlated with parent-rated, but not with patient rated ESS scores, objective sleepiness (mean sleep latency), sleep fragmentation (sleep stage shift index, awakening index), or CSF hypocretin-1 level. Conclusion Comorbid ADHD symptoms were more prevalent in unmedicated post-H1N1 NT1 youths than previously reported in mainly medicated pediatric narcolepsy cohorts. The high prevalence was not due to pre-existing ADHD and generally not correlated with core narcolepsy sleep/wake phenotype characteristics, indicating that the ADHD symptoms were not a direct consequence of disturbed sleep or daytime sleepiness.

• Juvodden, Hilde Therese; Viken, Marte Kathrine; Nordstrand, Sebjørg Elizabeth Hesla; Viste, Rannveig; Westlye, Lars Tjelta & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2020). HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives. Sleep. ISSN 0161-8105. 43(3), p. 1–11. doi: 10.1093/sleep/zsz239. Full text in Research Archive Show summary

  Abstract Study Objectives To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives. Methods Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semistructured interviews, Stanford Sleep Questionnaire, polysomnography, and multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls). A subsample (74 patients, 114 relatives) was investigated for associations between HLA-loci and continuous sleep variables using logistic regression. Identified candidate HLA-loci were explored for HLA allele associations with hypnagogic hallucinations and sleep paralysis in 90 patients, and patient allele findings were checked for similar associations in 202 relatives. Results DQB1*06:02 heterozygous post-H1N1 NT1 patients (84.4% H1N1-vaccinated) showed several significant HLA associations similar to those reported previously in samples of mainly sporadic NT1, i.e. DQB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:07, DRB1*11:04, A*25:01, B*35:03, and B*51:01, and novel associations, i.e. B*14:02, C*01:02, and C*07:01. Parents HLA alleles did not deviate significantly from controls. The HLA-C locus was associated with sleep parameters in patients and relatives. In patients C*02:02 seems to be associated with protective effects against sleep paralysis and hypnagogic hallucinations. Conclusions Our findings of similar risk/protective HLA-alleles in post-H1N1 as in previous studies of mainly sporadic narcolepsy support similar disease mechanisms. We also report novel allelic associations. Associations between HLA-C and sleep parameters were seen independent of NT1 diagnosis, supporting involvement of HLA-C in sleep subphenotypes.

• Pedersen, Natasja Wulff; Holm, Anja; Kristensen, Nikolaj Pagh; Bjerregaard, Anne-Mette; Bentzen, Amalie Kai & Marquard, Andrea Marion [Show all 13 contributors for this article] (2019). CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nature Communications. 10(837), p. 1–12. doi: 10.1038/s41467-019-08774-1. Full text in Research Archive
• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Dietrichs, Espen; Thorsby, Per Medbøe & Westlye, Lars Tjelta [Show all 7 contributors for this article] (2019). Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing. Sleep. ISSN 0161-8105. 42:zsz082(7), p. 1–12. doi: 10.1093/sleep/zsz082. Full text in Research Archive Show summary

  Study Objectives To assess brain activation patterns in response to fun-rated and neutral-rated movies we performed functional magnetic resonance imaging (fMRI) during a humor-paradigm in narcolepsy type 1 (NT1) patients with cataplexy (muscle atonia triggered by emotions) and controls. The fMRI-humor-paradigm consisted of short movies (25/30 with a humorous punchline; 5/30 without a humorous punchline [but with similar build-up/anticipation]) rated by participants based on their humor experience. We included 41 NT1 patients and 44 controls. Group-level inferences were made using permutation testing. Permutation testing revealed no group differences in average movie ratings. fMRI analysis found no group differences in brain activations to fun-rated movies. Patients showed significantly higher activations compared to controls during neutral-rated movies; including bilaterally in the thalamus, pallidum, putamen, amygdala, hippocampus, middle temporal gyrus, cerebellum, brainstem and in the left precuneus, supramarginal gyrus, and caudate. We found no brain overactivation for patients during movies without a humorous punchline (89.0% neutral-rated). Group analyses revealed significantly stronger differentiation between fun-rated and neutral-rated movies in controls compared with patients (patients showed no significant differentiation), including bilaterally in the inferior frontal gyrus, thalamus, putamen, precentral gyrus, lingual gyrus, supramarginal gyrus, occipital areas, temporal areas, cerebellum and in the right hippocampus, postcentral gyrus, pallidum, and insula. Patients showed significantly higher activations in several cortical and subcortical regions during neutral-rated movies, with no differentiation from activations during fun-rated movies. This lower threshold for activating the humor response (even during neutral-rated movies), might represent insight into the mechanisms associated with cataplexy.

• Nordstrand, Sebjørg Elizabeth Hesla; Hansen, Berit M Hjelde; Rootwelt-Revheim, Terje; Karlsen, Tor-Ivar; Swanson, David & Nilsen, Kristian Bernhard [Show all 7 contributors for this article] (2019). Psychiatric symptoms in patients with post-H1N1 narcolepsy type 1 in Norway. Sleep. ISSN 0161-8105. 42(4), p. 1–9. doi: 10.1093/sleep/zsz008. Full text in Research Archive Show summary

  Study Objectives Several studies have reported psychiatric comorbidity in patients with narcolepsy type 1 (NC1). The primary aim of this study was to explore the extent of psychiatric symptoms in a cohort of Norwegian NC1 patients, most of whom were H1N1-vaccinated. We also wanted to explore possible causes of the psychiatric symptoms seen in NC1. Methods Cross-sectional study. Psychiatric symptoms were assessed by the Achenbach System of Empirically Based Assessment (ASEBA) Child Behavior Check List (CBCL) in children and by Adult Self Report (ASR) in adults. Results The mean (SD) total T-scores were 58.6 (9.2) for children and 57.0 (9.8) for adults, these being mainly driven by internalizing problems. Internalizing symptom T-scores showed that 37.5% of the children and 33.3% of the adults were in the clinical range of concern. T-scores were lower when the questionnaire’s sleep-related items were excluded. However, 27.5% of children and 22.2% of adults still remained within the total psychiatric symptoms clinical range. Psychiatric symptoms and excessive daytime sleepiness were not associated. However, in children fragmented sleep, measured by sleep-stage shift index was significantly negatively associated with all the psychiatric summary scores (all p ≤ 0.020), and awakening index was negatively associated with externalizing (p = 0.042) and total summary scores (p = 0.042). In adults, awakening index, but not sleep-stage shift index, was positively associated with internalizing score (p = 0.015). Hypocretin-1 levels showed no association with psychiatric symptoms. Conclusions We found a high prevalence of psychiatric symptoms in NC1 patients. Fragmented sleep was significantly associated with psychiatric symptoms. Keywords: narcolepsy type 1, narcolepsy with cataplexy, psychiatric symptoms, Pandemrix, H1N1

• Nordstrand, Sebjørg Elizabeth Hesla; Hansen, Berit M Hjelde; Kamaleri, Yusman; Nilsen, Kristian Bernhard; Rootwelt-Revheim, Terje & Karlsen, Tor-Ivar [Show all 7 contributors for this article] (2018). Changes in quality of life in individuals with narcolepsy type 1 after the H1N1-influenza epidemic and vaccination campaign in Norway: a two-year prospective cohort study. Sleep Medicine. ISSN 1389-9457. 50, p. 175–180. doi: 10.1016/j.sleep.2018.05.037. Full text in Research Archive Show summary

  Objective Cross-sectional studies show a lower health-related quality of life (HRQoL) in individuals with narcolepsy. We aimed to describe changes in HRQoL after two years of multidisciplinary follow-up in a cohort of mainly post-H1N1 vaccination narcolepsy type-1 (NT1) patients in Norway. Methods Prospective-cohort study. Narcolepsy diagnosis was based on the International Classification of Sleep Disorders (third edition). Psychiatric comorbidity was assessed using the Achenbach System of Empirically Based Assessment (ASEBA). HRQoL was evaluated with the Pediatric Quality of Life Inventory (PedsQL™ Generic Core Scales 4.0) at baseline and follow-up. Mean follow-up time was 20.7 (2.7) months. Results Thirty one patients (18 females) with NT1, mean age 14.6 (SD = 4.8) years answered questionnaires at baseline and follow-up. On a group level, the PedsQL Total Health Summary score significantly improved by a mean of 5.9 (95%CI = 0.4, 11.9), p = 0.038; this was mainly driven by improvements in the Physical Health Summary score by 9.8 (3.0, 16.5) points, p = 0.006 and the School Functioning Scale score by 7.5 (1.0, 13.9) points p = 0.025. The Total ASEBA score was correlated with PedsQL Total Health Summary score at baseline, but not with changes in HRQoL. Sodium oxybate (Xyrem®) treatment at follow up was positively associated with changes in PedsQL Total Health Summary score, after adjusting for age and gender, p = 0.027. Conclusion HRQoL in NT1 patients improved after two years of follow-up. The use of sodium oxybate (Xyrem®) at follow-up was associated with increases in HRQoL. Psychiatric comorbidity was correlated with HRQoL at baseline but did not predict changes in HRQoL at follow-up.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Agartz, Ingrid; Andreassen, Ole Andreas & Dietrichs, Espen [Show all 9 contributors for this article] (2018). Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives. Sleep. ISSN 0161-8105. 41(10). doi: 10.1093/sleep/zsy145. Full text in Research Archive Show summary

  Study Objectives To assess white matter involvement in H1N1-vaccinated hypocretin deficient patients with narcolepsy type 1 (NT1) compared with first-degree relatives (a potential risk group) and healthy controls. Methods We compared four diffusion tensor imaging–based microstructural indices (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) in 57 patients with NT1 (39 females, mean age 21.8 years, 51/57 H1N1-vaccinated, 57/57 HLA-DQB1*06:02-positive, 54/54 hypocretin-deficient), 54 first-degree relatives (29 females, mean age 19.1 years, 37/54 H1N1-vaccinated, 32/54 HLA-DQB1*06:02-positive), and 55 healthy controls (38 females, mean age 22.3 years). We tested for differences between these groups, for parametric effects (controls > first-degree relatives > patients) and associations in patients (cerebrospinal fluid [CSF] hypocretin-1 and disease duration) and first-degree relatives (HLA-DQB1*06:02 and H1N1-vaccination). We employed tract-based spatial statistics and used permutation testing and threshold-free cluster enhancement for inference. Results Patients with NT1 had a widespread, bilateral pattern of significantly lower FA compared with first-degree relatives and healthy controls. Additionally, patients with NT1 also exhibited significantly higher RD and lower AD in several focal white matter clusters. The parametric model showed that first-degree relatives had intermediate values. Full sample of patients with NT1 showed no significant associations with disease duration or CSF hypocretin-1. Conclusions Our study suggests widespread abnormal white matter involvement far beyond the already known focal hypothalamic pathology in NT1, possibly reflecting the combined effects of the loss of the widely projecting hypothalamic hypocretin neurons, and/or secondary effects of wake/sleep dysregulation. These findings demonstrate the importance of white matter pathology in NT1.

• Kornum, Birgitte Rahbek; Burgdorf, Kristoffer Sølvsten; Holm, Anja; Ullum, Henrik; Jennum, Poul & Knudsen, Stine (2017). Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot. Journal of Neuroimmunology. ISSN 0165-5728. 309, p. 7–11. doi: 10.1016/j.jneuroim.2017.05.001. Full text in Research Archive
• Viste, Rannveig; Soosai, Joseph; Vikin, Truls; Thorsby, Per Medbøe; Nilsen, Kristian Bernhard & Knudsen, Stine (2017). Long-Term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy. Neurology: Neuroimmunology and neuroinflammation. 4(5). doi: 10.1212/NXI.0000000000000389. Full text in Research Archive Show summary

  We previously described the possible clinical effects of early monotherapeutic IV-immunomodulation (IVIg) treatment in sporadic1 but not in postH1N1 vaccination narcolepsy type 1 (NT1).2 We report here an early post-H1N1 vaccination NT1 case treated with combined immunomodulation of IVIg and methylprednisolone, and a comparable sporadic NT1 case.

• Schrolkamp, Maren; Jennum, Poul J.; Gammeltoft, Steen; Holm, Anja; Kornum, Birgitte Rahbek & Knudsen, Stine (2017). Normal morning melanin-concentrating hormone levels and no association with rapid eye movement or non-rapid eye movement sleep parameters in narcolepsy type 1 and type 2. Journal of Clinical Sleep Medicine (JCSM). ISSN 1550-9389. 13(2), p. 235–243. doi: 10.5664/jcsm.6454. Full text in Research Archive
• Kornum, Birgitte Rahbek; Knudsen, Stine; Ollila, Hanna Maria; Pizza, Fabio; Jennum, Poul Jørgen & Dauvilliers, Yves [Show all 7 contributors for this article] (2017). Narcolepsy. Nature Reviews Disease Primers. 3, p. 1–19. doi: 10.1038/nrdp.2016.100. Full text in Research Archive
• Jennum, Poul J.; Kornum, Birgitte Rahbek; Issa, Nadia M.; Gammeltoft, Steen; Tommerup, Niels & Morling, Niels [Show all 8 contributors for this article] (2016). Monozygotic twins discordant for narcolepsy type 1 and multiple sclerosis. Neurology: Neuroimmunology and neuroinflammation. 3. doi: 10.1212/NXI.0000000000000249. Full text in Research Archive
• Ollila, Hanna M.; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling & Zheng, Xiuwen [Show all 34 contributors for this article] (2015). HLA-DPB1 and HLA class i confer risk of and protection from narcolepsy. American Journal of Human Genetics. ISSN 0002-9297. 96(1), p. 136–146. doi: 10.1016/j.ajhg.2014.12.010. Full text in Research Archive
• Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine; Plazzi, Giuseppe; Jennum, Poul & Mignot, Emmanuel (2015). Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain, Behavior, and Immunity. ISSN 0889-1591. 49, p. 54–58. doi: 10.1016/j.bbi.2015.03.004. Full text in Research Archive
• Barloese, Mads; Jennum, Poul; Lund, Nunu; Knudsen, Stine; Gammeltoft, Steen & Jensen, Rigmor (2015). Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia. ISSN 0333-1024. 35(10), p. 869–876. doi: 10.1177/0333102414562971. Full text in Research Archive
• Holm, Anja; Bang-Berthelsen, Claus Heiner; Knudsen, Stine; Modvig, Signe; Kornum, Birgitte Rahbek & Gammeltoft, Steen [Show all 7 contributors for this article] (2014). MiRNA profiles in cerebrospinal fluid from patients with central hypersomnias. Journal of the Neurological Sciences. ISSN 0022-510X. 347(1-2), p. 199–204. doi: 10.1016/j.jns.2014.09.047. Full text in Research Archive
• Han, Fang; Lin, Ling; Schormair, Barbara; Pizza, Fabio; Plazzi, Giuseppe & Ollila, Hanna M. [Show all 17 contributors for this article] (2014). HLA DQB1∗06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep. ISSN 0161-8105. 37(10), p. 1601–1608. doi: 10.5665/sleep.4066. Full text in Research Archive
• Heier, Mona Frederikke Jayne Skard; Gjerstad, Michaela-Alexandra Dreetz & Knudsen, Stine (2013). Ny kunnskap om narkolepsi hos barn. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 133(12-13), p. 1326–1328. doi: 10.4045/tidsskr.13.0414. Full text in Research Archive

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• Plazzi, Giuseppe; Pizza, Fabio; Lecendreux, Michel; Gringras, Paul; Barateau, Lucie & Bruni, Oliviero [Show all 22 contributors for this article] (2023). Letter to editor. Journal of Sleep Research. ISSN 0962-1105. doi: 10.1111/jsr.14055. Full text in Research Archive
• Cesari, Matteo; Heidbreder, Anna; Louis, Erik K. St; Sixel-Döring, Friederike; Bliwise, Donald L. & Baldelli, Luca [Show all 22 contributors for this article] (2023). Polysomnographic diagnosis of REM sleep behavior disorder: a change is needed. Sleep. ISSN 0161-8105. 46(1). doi: 10.1093/sleep/zsac276. Full text in Research Archive
• Hansen, Berit M Hjelde & Knudsen, Stine (2018). ADHD symptoms in H1N1-vaccinated youths with narcolepsy type 1. Full text in Research Archive
• Engstrøm, Morten; Aarrestad, Sigurd; Eldøen, Guttorm; Alme, Anders; Bjørge, Trond & Miljeteig, Harald [Show all 10 contributors for this article] (2018). Nye anbefalinger for objektiv undersøkelse av søvn og søvnforstyrrelser. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(19), p. 1805–1806. doi: 10.4045/tidsskr.18.0741. Full text in Research Archive
• Hansen, Berit M Hjelde & Knudsen, Stine (2017). ADHD SYMPTOMS IN UNMEDICATED YOUTHS WITH NARCOLEPSY TYPE 1.Poster ESCAP Geneve 2017. Hansen BH, Knudsen S. Full text in Research Archive
• Andresen, Hilde; Hansen, Berit M Hjelde; Bronder, Knut Halvard; Juvodden, Hilde Therese & Knudsen, Stine (2017). Psychiatric Comorbidity and Executive Function after onset of narcolepsy. Full text in Research Archive
• Nordstrand, Sebjørg Elizabeth Hesla; Hansen, Berit M Hjelde; Kamaleri, Yusman; Nilsen, Kristian Bernhard; Karlsen, Tor-Ivar & Knudsen, Stine (2017). Changes in Quality of Life in individuals with narcolepsy in Norway after H1N1-influensa epidemic in 2009- a 2-year prospective cohort study. Full text in Research Archive
• Hansen, Berit Marina Hjelde & Knudsen, Stine (2017). ADHD symptoms in unmedicated youths with Narcolepsy type 1. Full text in Research Archive
• Andresen, Hilde K; Hansen, Berit Marina Hjelde; Bronder, Knut Halvard; Juvodden, Hilde Therese & Knudsen, Stine (2016). Narcolepsy type 1 is associated with executive dysfunction. Full text in Research Archive
• Follin, Louise Frøstrup; Knudsen, Stine; Christensen, Julie Anja Engelhard; Juvodden, Hilde Therese & Kaufmann, Tobias Herbert (2026). Narcolepsy after H1N1 vaccination: A data-driven approach for understanding electrophysiological signals and disease risk in vaccinated individuals. Universitetet i Oslo. ISSN 9788234807893. Full text in Research Archive Show summary

  Narcolepsy type 1 (NT1) is a chronic neurological sleep disorder characterized by excessive daytime sleepiness, cataplexy, and disturbed nocturnal sleep. In Norway, a more than tenfold increase in new NT1 diagnoses occurred after the 2009/2010 H1N1 vaccination campaign. NT1 is caused by an autoimmune destruction of hypocretin-producing neurons in the hypothalamus, causing unstable sleep-wake regulation. Night-time sleep fragmentation is a core feature of NT1, assessed by investigating sleep stages in 30-second epochs from an over-night polysomnography (PSG). As sleep is though biologically dynamic, 30-second epochs may be too coarse to capture brief transitions and microstructural dynamics. In this PhD project, high-resolution sleep staging in 5-second mini-epochs was explored. Initial evaluation of existing automated sleep staging models showed that reliable mini-epoch scoring required model adaptation. By retraining the existing U-Sleep model using transfer learning on human-scored mini-epochs, performance comparable to human and automatic epoch scoring was achieved. Mini-epoch sleep staging with the optimized U-Sleep model was then applied to PSGs from NT1 patients and their non-narcoleptic siblings to assess sleep fragmentation. Analyses showed that NT1 patients had significantly increased sleep fragmentation compared to their siblings, both with epochs and mini-epochs. Mini-epoch analyses, however, captured substantially more stage transitions and revealed patterns of sleep instability not detectable with epoch scoring. With mini-epochs, but not epochs, sleep-wake fragmentation was significantly higher in patients with all core narcolepsy symptoms and increased significantly from the 1st to the 2nd night-half in patients with undetectable hypocretin-1 levels (<40 pg/ml) and/or all core narcolepsy symptoms. These findings highlight the clinical value of high-resolution, temporally sensitive sleep stage analyses for detailed phenotyping and detection of future disease biomarkers.

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