135 White Matter Connectivity in Narcolepsy Type 1 3rd edition of the International Classification of Sleep Disorders [8] and had to be treatment-naïve or off medication for ≥14 days prior to the study. Exclusion criteria consisted of current use of psychotropic drugs; current diagnosis of any other serious medical conditions; contraindications for MRI studies and macroscopic structural brain abnormalities (tumour, ventricle enlargement, cortical atrophy or vascular lesions). In line with diagnostic criteria, the three patients without clear-cut cataplexy had hypocretin-1 levels determined in their cerebrospinal fluid (CSF). One patient had a concentration slightly higher (138 pg/mL) than the according to international standards assessed 110 pg/mL diagnostic threshold for narcolepsy type 1 [46]. This patient was still included because of the typical clinical phenotype and the still deficient hypocretin-1 level. All demographic and DTI analyses were repeated excluding this subject to verify that this person was no outlier. In total, CSF hypocretin-1 levels were available in nine patients as part of regular clinical care, of which all were hypocretin deficient. All patients had positive HLA-typing for DQB1*0602. Seven patients were drug naïve, and five discontinued their stimulants (4× methylphenidate and 1× modafinil) at least 2 weeks prior to study start. The five subjects had been using medication for 1–5 months prior to discontinuation. Following subject screening to assess study eligibility, written informed consent was obtained from all subjects. The study protocol was approved by the Medical Ethical Committee of LUMC. Data acquisition All subjects completed a survey on general characteristics (e.g. age and previous medication use). In addition, the Dutch Adult Reading Test [216] was completed to assess intelligence (IQ) and the Epworth Sleepiness Scale (ESS) [217] was administered as a measure of daytime sleepiness. All data collection was performed during the afternoon and subjects were asked to refrain from caffeine containing substances for at least 24 h prior to examination. MRI data were acquired with a high-field 3 T Philips Achieva MRI scanner (Philips Healthcare, Best, the Netherlands) and a 32-channel head coil with sponge cushions to minimize head movements. Three-dimensional T1weighted images (220 slices; TR 8.2 ms; TE 3.8 ms; inversion time 670.4 ms; FOV 240 × 240 × 220 mm; matrix size 240 × 240; flip angle 8°; 1 × 1 × 1 mm3 voxel size) and single-shot, gradient-echo, echo-planar imaging (EPI) sequences for DTI (60 slices; TR = 6700 ms; TE = 72 ms; FOV 224 × 224 × 120 mm; matrix size 112 × 112; flip angle = 90°; 2 × 2 × 2 mm3 voxel size) were obtained. DTI was carried out twice with reversed k-space readout along 46 non-collinear 5
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