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

Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear. To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event. Retrospective. Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years). 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event. Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure. Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P < 0.05 (FWE-corrected). TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR. In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR. 3 TECHNICAL EFFICACY: Stage 2.

The diagnosis of narcolepsy type 1 (NT1) currently requires the multiple sleep latency test (MSLT), or a nocturnal sleep-onset REM period (SOREMP) combined with typical cataplexy, or alternatively the determination of CSF hypocretin-1 (CSF-hcrt-1) deficiency. We evaluated the 24-hour polysomnography (PSG) recordings in adult and pediatric patients as an alternative diagnostic tool. Patients of any age, referred to the narcolepsy center of a university hospital for suspected central disorder of hypersomnolence (CDH), were consecutively recruited between 2013 and 2022. Participants underwent 2 days (day1-night1-day2-night2) of continuous dynamic PSG followed by MSLT. When consent was given, CSF-hcrt-1 was measured. The accuracy of 24-hour PSG variables from night1 and day2 (index test) was assessed with receiver operating characteristic (ROC) curve analysis in identifying NT1 based on current criteria (applied to night2-PSG, MSLT, and CSF-hcrt1). The markers with area under the curve (AUC) ≥0.75 were then tested in adults and children, separately, and to diagnose NT1 and narcolepsy type 2 (NT2) in different scenarios. Eight hundred seven patients (30.1% pediatric, 52.4% male) were included, and 709 had CSF-hcrt-1 measured. According to the standard criteria, 322 were diagnosed with NT1 (mean age 26.7 ± 17.1 years, 40.4% pediatric, 54.0% male) and 484 with non-NT1 (mean age 32.7 ± 16.5 years, 23.3% pediatric, 51.3% male), encompassing 31 with NT2, 163 with idiopathic hypersomnia, and 281 with other diagnoses. Detecting SOREMP ≥1 during daytime resulted in AUC = 0.84 (95% CI 0.82-0.87), with 84.4% sensitivity and 84.5% specificity for NT1. Performance was superior to all nighttime-PSG measures (p < 0.001) including nighttime-SOREMP (AUC = 0.77, 95% CI 0.74-0.80; sensitivity = 62.1%, specificity = 91.7%) and did not differ from 24-hour SOREMP ≥1 (AUC = 0.85, 95% CI 0.82-0.87; sensitivity = 89.7%, specificity = 80.2%). The combination of daytime-SOREMP ≥1 with cataplexy showed AUC = 0.89 (95% CI 0.86-0.91) for NT1, superior to the combination of nighttime-SOREMP with cataplexy (AUC = 0.78, 95% CI 0.76-0.81, p < 0.001) and similar to MSLT criteria for narcolepsy (AUC = 0.90, 95% CI 0.88-0.92, p = 0.36). Performances were similar in adults and children. Daytime-SOREMP ≥1 identified NT1 and NT2 combined within all CDH with a sensitivity of 80.8% and specificity of 88.0%. The detection of daytime-SOREMP during dynamic 24-hour PSG is more accurate than nighttime-SOREMP for diagnosing narcolepsy and, combined with cataplexy, is comparable with MSLT criteria for the identification of NT1. These results offer the prospect of 24-hour PSG diagnostics for NT1 in the home setting. This study provides Class II evidence that daytime SOREMP during a 24-hour PSG accurately distinguishes NT1 in patients with a clinical history of possible cataplexy from those who do not have NT1.

Differential tractography identifies a distinct pattern of white matter alterations in essential tremor with or without resting tremor.

Autoantibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel (VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC-complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex-associated limbic encephalitis, primarily affecting mesiotemporal gray matter.

BackgroundIsolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF).MethodWe included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests.ResultCompared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance (T = 2.0, p < 0.05, Figure 2).ConclusionOur study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

This thesis aimed to investigate the feasibility of two diffusion imaging techniques, Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), on detecting subtle physiological or pathological microstructural changes in normal-appearing neural tissues of human central nervous system. &#13;\n At first, ten patients with neuromyelitis optica (NMO) and twelve age- and gender-matched healthy subjects were recruited. DTI-derived indices including fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivities were quantified in the lateral and dorsal columns of cervical spinal cord. Based on the regions of interest (ROIs) measurement, NMO patients showed reduced FA, increased MD and radial diffusivity compared to control subjects, while axial diffusivity did not show any significant difference. The three former DTI metrics also showed significant correlations with disability scores, and especially FA was found to be sensitive to mild NMO. Our results show that DTI-derived indices can quantitatively assess the white matter (WM) abnormalities with seemingly normal appearance in conventional MRI, and are associated with the level of clinical disability, suggesting that DTI may have great potential as a useful diagnostic tool in the clinical setting.&#13;\n DKI is an extension of conventional DTI to probe the non-Gaussian diffusion property in biological tissues. Besides the four conventional DTI-derived metrics, DKI also provide three additional kurtosis metrics (mean kurtosis (MK), axial and radial kurtosis). In the second study, ROI-based analysis was used to characterize age-related microstructural changes in WM, cortical and subcortical gray matter (GM) of 27 healthy adults (21~59 yrs). Though the volumes of GM and WM were still preserved, DTI-derived metrics can detect the subtle changes in WM and GM. Meanwhile, MK and radial kurtosis significantly increased in both caudate nucleus and putamen while Thalamus showed little aging effect in the diffusivity and kurtosis metrics but significantly decreased only in FA. Our results demonstrated that DKI is sensitive to detect the age-related alterations in neural microstructures at the stage of early aging.&#13;\n In addition, DKI has been applied to detect the pathological changes in the normal-appearing neural tissues of 18 patients with multiple sclerosis (MS), compared to 22 healthy controls. Diffuse WM abnormalities have been observed extensively in the brain, revealed by DKI-derived metrics. Though the volumetric and voxel-wise analysis revealed no significant changes in the volume of cortical GM, decreased FA and kurtoses with increased diffusivities in MS group were sensitive to disclose the subtle alterations in global and regional cortical GM tissues. Significant correlations have been found between FA in the global, frontal and temporal cortical GM in relapsing-remitting MS patients and their disability scores, suggesting FA as an important biomarker to monitor the disease progress in cortical GM. Moreover, elevated kurtosis indices in MS patients did not correlate with diffusivities in caudate nucleus, putamen and thalamus, suggesting these metrics may be vulnerable to different pathologic aspects of the disease.&#13;\n In conclusion, DKI is sensitive to neural alterations during normal aging and in MS pathologies, and can provide complementary information to conventional MRI and DTI.

Introduction Decreased attention is common in pediatric Narcolepsy Type 1 (NT1). However, objective data assessing attention dysfunction in this population are limited. The psychomotor vigilance task (PVT) has been used to measure attention in adults with central disorders of hypersomnolence but understudied in pediatric NT1. In this study, we compare PVT metrics between pediatric NT1 patients and healthy controls (HC) in the evening and morning with a between interval of nocturnal sleep measured by in-lab polysomnography (PSG). We hypothesized that attention dysfunction would be worse in NT1 vs HC in evening and morning and both sessions would be associated with self-reported sleepiness. Methods 28 pediatric NT1 participants (mean age 15.9) and 27 healthy controls (mean age 13.6) completed 3-minute PVT testing in the evening before PSG and upon awakening in the morning. Before each PVT, participants rated their sleepiness on 3-item visual analog scale. We compared PVT metrics between NT1 and HC, adjusting for age (including non-linear effects) and gender. Outcomes included mean 1/reaction time (RT), lapses (RT ≥ 500 ms), lapses355 (RT ≥ 355 ms), and slowest 10% 1/RT. Results NT1 participants showed reduced attention across various PVT metrics vs. HC. In the evening, mean 1/RT was significantly worse in NT1 participants (p =.008) but we found no significant group differences in lapses, lapses355, or slowest 10% 1/RT. In the morning, NT1 participants performed significantly worse than controls on mean 1/RT (p =.002), lapses355 (p &amp;lt;.001), and slowest 10% 1/RT (p =.004). Age but not gender significantly predicted all PVT measures (p &amp;lt;.01). Contrary to our hypothesis, none of the PVT measures were associated with self-reported sleepiness. Conclusion Pediatric NT1 participants exhibit objective and significantly impaired objective attention vs HC. Slower mean reactions times were evident in evening and morning but lapses and slowest reactions times were more evident in the morning. Given that self-reported sleepiness did not predict PVT outcomes, it is possible other narcolepsy features such as disrupted nighttime sleep play contributing roles. Overall, the PVT could be useful for assessing attention in children/adolescents with NT1 in clinical and school based settings. Support (if any) NIH K23 NS104267 (Maski)

Imaging biomarkers of disease progression are desirable in inherited ataxias. MRI has demonstrated brain damage in Friedreich ataxia (FRDA) in form of regional atrophy of the medulla, peridentate cerebellar white matter (WM) and superior cerebellar peduncles (visible in T1-weighted images) and of change of microstructural characteristics of WM tracts of the brainstem, cerebellar peduncles, cerebellum, and supratentorial structures (visible through diffusion-weighted imaging). We explored the potential of brain MR morphometry and diffusion tensor imaging (DTI) to track the progression of neurodegeneration in FRDA. Eight patients (5F, 3M; age 13.4-41.2 years) and 8 healthy controls (2F, 6M; age 26.2-48.3 years) underwent 2 MRI examinations (mean 3.9 and 4.1 years apart, respectively) on the same 1.5T scanner. The protocol included 3D T1-weighted images and axial diffusion-weighted images (b-value 1,000 s/mm(2)) for calculating maps of fractional anisotropy, mean, axial and radial diffusivity, and mode of anisotropy. Tensor-based morphometry was used to investigate regional volume changes and tract-based spatial statistics was used to investigate microstructural changes in WM tracts. Longitudinal analyses showed no differences in regional volume changes but a significant difference in axial diffusivity changes in cerebral and corpus callosum WM of patients as compared to controls (mean longitudinal rate of change for axial diffusivity: -.02 × 10(-3) mm(2)/s/year in patients vs. .01 × 10(-3) mm(2)/s/year in controls). No correlation with number of triplets, disease duration, and worsening of the clinical deficit was observed. DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression.

BackgroundEarly changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.MethodParticipants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.ResultAll MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p&lt;0.001; Figure 1).ConclusionWe found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.

This study aimed to characterize age-related white matter changes by evaluating patterns of overlap between the linear association of age with fractional anisotropy (FA) with mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Specifically, we assessed patterns of overlap between diffusion measures of normal appearing white matter by covarying for white matter hyperintensity (WMH) load, as WMHs are thought to increase with age and impact diffusion measures. Seventy-nine healthy adults aged between 18 and 75 years took part in the study. Diffusion tensor imaging (DTI) data were based on 61 directions acquired with a b-value of 2,000. We found five main patterns of overlap: FA alone (15.95%); FA and RD (31.90%); FA and AD (12.99%); FA, RD, and AD (27.93%); and FA, RD, and MD (8.79%). We showed that cognitively healthy aging adults had low WMH load, which subsequently had minimal effect on diffusion measures. We discuss how patterns of overlap may reflect underlying biological changes observed with aging such as loss of myelination, axonal damage, as well as mild microstructural and chronic white matter impairments. This study contributes to understanding the underlying causes of degeneration in specific regions of the brain and highlights the importance of considering the impact of WMHs in aging studies of white matter.

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD.

Microstructural changes and atrophy in brain white matter tracts with aging

Patients with classic trigeminal neuralgia (CTN) have abnormalities in white matter integrity of the corpus callosum (CC). However, in CTN patients, it is unclear whether the CC substructure region is affected to varying degrees. A total of 22 patients with CTN and 22 healthy controls (HC) with matching age, gender, and education were selected. All subjects underwent 3.0 T magnetic resonance diffusion tensor imaging and high resolution T1-weighted imaging. The CC was reconstructed by DTI technology, which was divided into three substructure regions: genu, body, and splenium. Group differences in multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), were compared between CTN patients and HC, and correlations between the white matter change and disease duration and VAS in CTN patients were assessed. Compared with HC group, CTN patients had extensive damage to the CC white matter. The FA of the genu (P = 0.04) and body (P = 001) parts decreased, while RD (P = 0.003; P = 0.02) and MD (P = 0.002; P = 0.04) increased. In addition, the authors observed that the disease duration and VAS of CTN patients were negatively correlated with FA. The corpus callosum substructure region has extensive damage in chronic pain, and the selective microstructural integrity damage was particularly manifested by changes in axons and myelin sheath in the genu and body of corpus callosum.

Symptoms of central disorders of hypersomnolence (CDH) extend beyond excessive daytime sleepiness (EDS) to include non-restorative sleep, fatigue and cognitive dysfunction. Thus, they share much in common with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), recently renamed systemic exertion intolerance disease (SEID), whose additional discriminating features include post-exertional malaise and orthostatic intolerance. Clarifying the distinction and overlap between these disorders will help guide patient management. Patients evaluated for hypersomnolence completed a questionnaire battery about EDS and fatigue; questionnaires and clinical records were used for SEID assessment. PSG/MSLT, CSF hypocretin, and cataplexy status were additionally used to assign ICSD-3 diagnoses of CDH or sleep apnea. Patients reporting problematic hypersomnolence but not meeting any ICSD-3 criteria (i.e., with MSL > 8 min) were labelled subjective EDS (sEDS). Final sample was 205 patients, with mean age 35.6 years (+/-14.9; 63% women) and diagnoses of idiopathic hypersomnia (n=68), narcolepsy type 1 (n=6), narcolepsy type 2 (n=25), persistent sleepiness after OSA treatment (n=25), insufficient sleep (n=41), psychiatric hypersomnolence (n=7), and sEDS (n=33). Nineteen percent met SEID criteria, and frequency of SEID was not different across ICSD-3 diagnoses (p=0.33). MSLT mean sleep latency was not different between those with and without SEID (6.58 vs 6.63, p=0.95). Patients with SEID were more likely than those without to have failed standard hypersomnolence treatments (88.6% vs 67.8%, p=0.02), but had similar response rates to clarithromycin (37.5% vs 42.9%, p=0.59) and flumazenil (64.0% vs 59.2%, p=0.67). SEID patients were no different from those without SEID by gender, age, chronotype, sleep duration, Epworth, depressive symptoms, family history, or PSG/MSLT parameters. Nearly one-in-five patients evaluated for hypersomnolence meet SEID criteria, but this diagnosis is independent of ICSD-3 diagnoses and PSG/MSLT findings. Patients with comorbid SEID may be more refractory to standard hypersomnolence treatments, but appear no less likely to benefit from GABA-A antagonists. K23 NS083748 (LMT), R01 NS089719 and the Mind Science Foundation (DBR), and UL1 TR000424.