Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study.

OBJECTIVE: 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.

Larger hypothalamic volume in narcolepsy type 1.

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.

High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y11 protein levels in narcolepsy type 1.

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.

High prevalence of ADHD symptoms in unmedicated youths with post-H1N1 narcolepsy type 1.

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.

HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives.

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.

Obesity and other medical comorbidities among NT1 patients after the Norwegian H1N1 influenza epidemic and vaccination campaign.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) may be complicated by comorbidities. We aimed to study the extent of obesity and other medical comorbidities in a Norwegian population of NT1 patients with debut of symptoms after the 2009 H1N1 influenza epidemic and vaccination campaign. We also aimed to explore factors associated with obesity. METHODS: Ninety-one patients (48 children and 43 adults) were included in this cross-sectional study, 80 of whom were H1N1-vaccinated. All participants were hospitalized and underwent sleep investigation and physical examination, and completed a semi-structured clinical interview. RESULTS: In children, 16 females (70%) and 10 males (40%) were classified as overweight or obese. Twenty children (42%) had a co-existing medical disorder. Medical comorbidity was significantly positively associated with BMI in children (p = .032). In adults, 19 females (58%) and 7 males (70%) were classified as overweight or obese. Twenty-six adults (61%) had a co-existing medical disorder. We found no factors significantly associated with BMI in adults. On a fatigue scale from 0 to 100, lower scores indicating more fatigue, we found a mean (SD) total fatigue score of 50 (17) in children and 39 (16) in adults. CONCLUSION: In a cohort of predominantly H1N1-vaccinated NT1 patients, we found a high prevalence of overweight or obesity. Half of the cohort presented with one or more additional medical comorbidities, and patients reported a clinically relevant degree of fatigue. Our findings highlight the importance of carefully monitoring patients with NT1 with regard to the development of obesity, which is a significant risk factor for cardiovascular disorders.

Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing.

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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives.

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.

Error-preceding brain activity reflects (mal-)adaptive adjustments of cognitive control: a modeling study.

Errors in choice tasks are preceded by gradual changes in brain activity presumably related to fluctuations in cognitive control that promote the occurrence of errors. In the present paper, we use connectionist modeling to explore the hypothesis that these fluctuations reflect (mal-)adaptive adjustments of cognitive control. We considered ERP data from a study in which the probability of conflict in an Eriksen-flanker task was manipulated in sub-blocks of trials. Errors in these data were preceded by a gradual decline of N2 amplitude. After fitting a connectionist model of conflict adaptation to the data, we analyzed simulated N2 amplitude, simulated response times (RTs), and stimulus history preceding errors in the model, and found that the model produced the same pattern as obtained in the empirical data. Moreover, this pattern is not found in alternative models in which cognitive control varies randomly or in an oscillating manner. Our simulations suggest that the decline of N2 amplitude preceding errors reflects an increasing adaptation of cognitive control to specific task demands, which leads to an error when these task demands change. Taken together, these results provide evidence that error-preceding brain activity can reflect adaptive adjustments rather than unsystematic fluctuations of cognitive control, and therefore, that these errors are actually a consequence of the adaptiveness of human cognition.

A forced-attention dichotic listening fMRI study on 113 subjects.

We report fMRI and behavioral data from 113 subjects on attention and cognitive control using a variant of the classic dichotic listening paradigm with pairwise presentations of consonant-vowel syllables. The syllable stimuli were presented in a block-design while subjects were in the MR scanner. The subjects were instructed to pay attention to and report either the left or right ear stimulus. The hypothesis was that paying attention to the left ear stimulus (FL condition) induces a cognitive conflict, requiring cognitive control processes, not seen when paying attention to the right ear stimulus (FR condition), due to the perceptual salience of the right ear stimulus in a dichotic situation. The FL condition resulted in distinct activations in the left inferior prefrontal gyrus and caudate nucleus, while the right inferior frontal gyrus and caudate were activated in both the FL and FR conditions, and in a non-instructed (NF) baseline condition.

Mal-adaptation of event-related EEG responses preceding performance errors.

Recent EEG and fMRI evidence suggests that behavioral errors are foreshadowed by systematic changes in brain activity preceding the outcome by seconds. In order to further characterize this type of error precursor activity, we investigated single-trial event-related EEG activity from 70 participants performing a modified Eriksen flanker task, in particular focusing on the trial-by-trial dynamics of a fronto-central independent component that previously has been associated with error and feedback processing. The stimulus-locked peaks in the N2 and P3 latency range in the event-related averages showed expected compatibility and error-related modulations. In addition, a small pre-stimulus negative slow wave was present at erroneous trials. Significant error-preceding activity was found in local stimulus sequences with decreased conflict in the form of less negativity at the N2 latency (310-350 ms) accumulating across five trials before errors; concomitantly response times were speeding across trials. These results illustrate that error-preceding activity in event-related EEG is associated with the performance monitoring system and we conclude that the dynamics of performance monitoring contribute to the generation of error-prone states in addition to the more remote and indirect effects in ongoing activity such as posterior alpha power in EEG and default mode drifts in fMRI.