Clinical features of nine cases of leucine-rich glioma inactivated 1 protein antibody-associated encephalitis.

To investigate clinical features of leucine-rich glioma inactivated 1 protein (LGI1) antibody-associated autoimmune encephalitis (AE). The clinical data were collected and analyzed in nine patients with LGI1 AE. All nine patients (100%) presented acute/subacute onset, had seizures, cognitive impairment, mental/behavioral abnormalities, six had sleep disorders and seven showed hyponatremia. Seizures manifested in three types: faciobranchial dystonia seizure (FBDS) (44%), mesial temporal lobe epilepsy (MTLE)-like seizure (66%), and focal to bilateral tonic-clonic seizure (FBTCS) (77%). Six of nine cases (66%) showed abnormalities in brain MRI, among them four showed high T2/flair signal on unilateral/bilateral hippocampus, two showed high T1/T2 signal on unilateral basal ganglia. All nine patients (100%) showed abnormalities in EEG, among them 1 (11%) showed diffuse slow waves, 8 (88%) showed focal slow waves; 6 (66%) revealed interictal epileptic discharges; ictal EEG was recorded in five patients, two were FBDS, three were MTLE-like seizure.LGI1 antibodies in serum and cerebrospinal fluid were both positive. No signs of tumor were found in all patients. Eight of nine patients received immunotherapy and antiepileptic drug (AED) treatment, one only treated with AED without immunotherapy. Eight patients improved significantly with seizure-free after immunotherapy, only one still had FBDS after immunotherapy and AED treatment. In LGI1 AE hippocampus and basal ganglia were two main targets, the corresponding seizure type was MTLE-like seizure and FBDS respectively. Diagnosis depended on detection of LGI1 antibodies in CSF. The incidence of tumor was low. The effect of immunotherapy was good and AEDs should be considered as add-on symptomatic treatment.

Association of CSF orexin-A levels and nocturnal sleep stability in patients with hypersomnolence.

OBJECTIVE: To evaluate the associations between CSF orexin-A (ORX) levels and markers of nocturnal sleep stability, assessed by polysomnography. METHODS: Nocturnal polysomnography data and ORX levels of 300 drug-free participants (55% men, 29.9±15.5 years, ORX level 155.1±153.7 pg/mL) with hypersomnolence were collected. Several markers of nocturnal sleep stability were analyzed: sleep and wake bouts and sleep/wake transitions. Groups were categorized according to ORX levels, in 2 categories (deficient ≤110; >110), in tertiles (≤26, 26-254, >254), and compared using logistic regression models. Results were adjusted for age, sex, and body mass index. RESULTS: We found higher number of wake bouts (43 vs 25, p < 0.0001), sleep bouts (43 vs 25.5, p < 0.0001), and index of sleep bouts/hour of sleep time, but lower index of wake bouts/hour of wake time (41.4 vs 50.6, p < 0.0001), in patients with ORX deficiency. The percentage of wake bouts <30 seconds was lower (51.3% vs 60.8%, p < 0.001) and of wake bouts ≥1 minutes 30 seconds higher (7.7% vs 6.7%, p = 0.02) when ORX deficient. The percentage of sleep bouts ≤14 minutes was higher (2-5 minutes: 23.7% vs 16.1%, p < 0.0001), and of long sleep bouts lower (>32 minutes 30 seconds: 7.3% vs 18.3%, p < 0.0001), when ORX deficient. These findings were confirmed when groups were categorized according to ORX tertiles, with a dose-response effect of ORX levels in post hoc comparisons, and in adjusted models. INTERPRETATION: This study shows an association between ORX levels and nocturnal sleep stabilization in patients with hypersomnolence. Sleep and wake bouts are reliable markers of nighttime sleep stability that correlate with CSF ORX levels in a dose-dependent manner.

Novel method for evaluation of eye movements in patients with narcolepsy.

BACKGROUND: Narcolepsy causes abnormalities in the control of wake-sleep, non-rapid-eye-movement (non-REM) sleep and REM sleep, which includes specific eye movements (EMs). In this study, we aim to evaluate EM characteristics in narcolepsy as compared to controls using an automated detector. METHODS: We developed a data-driven method to detect EMs during sleep based on two EOG signals recorded as part of a polysomnography (PSG). The method was optimized using the manually scored hypnograms from 36 control subjects. The detector was applied on a clinical sample with subjects suspected for central hypersomnias. Based on PSG, multiple sleep latency test and cerebrospinal fluid hypocretin-1 measures, they were divided into clinical controls (N = 20), narcolepsy type 2 (NT2, N = 19), and narcolepsy type 1 (NT1, N = 28). We investigated the distribution of EMs across sleep stages and cycles. RESULTS: NT1 patients had significantly less EMs during wake, N1, and N2 sleep and more EMs during REM sleep compared to clinical controls, and significantly less EMs during wake and N1 sleep compared to NT2 patients. Furthermore, NT1 patients showed less EMs during NREM sleep in the first sleep cycle and more EMs during NREM sleep in the second sleep cycle compared to clinical controls and NT2 patients. CONCLUSIONS: NT1 patients show an altered distribution of EMs across sleep stages and cycles compared to NT2 patients and clinical controls, suggesting that EMs are directly or indirectly controlled by the hypocretinergic system. A data-driven EM detector may contribute to the evaluation of narcolepsy and other disorders involving the control of EMs.

[Moebius syndrome and narcolepsy]. / Möbius-Syndrom und Narkolepsie.

BACKGROUND: Moebius syndrome is a rare neurological disease that has a frequent association with parasomnia. CASE REPORT: We report on a patient with Moebius syndrome and the clinical presentation of a narcolepsy cataplexy syndrome. With the hypoplasia of the brainstem in the cranial magnetic resonance imaging, we were able to show the morphological correlate of Moebius syndrome. Comorbidity was detected by cognitive tests, polysomnography and detection of hypocretin in the cerebrospinal fluid. Despite normal sleep onset latency and only one episode of sleep onset rapid eye movement (REM) in the multiple sleep latency test, where expressiveness is significantly reduced in cases of paralysis of horizontal eye movement, the diagnosis of parasomnia with narcolepsy cataplexy symptoms could be made. DISCUSSION: The hypocretin level of 132 pg/ml measured in the cerebro spinal fluid is compatible with this diagnosis and shows the relevance of a detailed diagnostic of parasomnia in patients with Moebius syndrome.

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease.

IMPORTANCE: Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. OBJECTIVES: To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and ß-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex. EXPOSURE: Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and ß-amyloid 1-42 and polysomnographic assessment of sleep variables. MAIN OUTCOMES AND MEASURES: Levels of orexin, tau proteins, and ß-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. RESULTS: Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration. CONCLUSIONS AND RELEVANCE: Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.

HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency.

STUDY OBJECTIVES: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. SETTINGS: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). DESIGN: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. MEASUREMENTS AND RESULTS: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. CONCLUSIONS: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

Cerebrospinal-fluid orexin levels and daytime somnolence in frontotemporal dementia.

Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the cerebrospinal-fluid (CSF) orexin levels in a population of FTD patients and evaluated whether there is a relationship between daytime somnolence and CSF orexin concentrations. CSF orexin levels were measured in a sample of FTD patients (n = 11) compared to a population of non-demented controls (n = 13) similar for age and sex. Moreover, CSF orexin concentrations were correlated with daytime somnolence investigated by means of the Epworth Sleepiness Scale (ESS) in both FTD patients and controls. FTD patients showed CSF orexin concentrations (164.3 ± 66.45 vs 170.81 ± 42.73 pg/mL) and ESS scores (7.45 ± 4.36 vs 3.84 ± 1.82) not different from controls. However, three FTD patients showed pathological daytime sleepiness (ESS > 10) coupled with the lowest CSF orexin levels. In addition, we found a significant negative correlation between CSF orexin levels and ESS scores in the FTD population (R = -0.91; p < 0.0001), which was not evident in the control group (R = 0.16; p > 0.05). This is the first study investigating CSF orexin concentrations in FTD. We did not find differences in CSF orexin concentrations between FTD patients and controls. However, a significant negative correlation between daytime somnolence and CSF orexin levels was evident in FTD patients. Moreover, we have found that pathological daytime somnolence was evident in those FTD patients with the lowest CSF orexin levels. Based on these findings, we argued that lower orexin levels may be permissive for increased daytime somnolence in FTD.

[A 39 years old woman responding to modafinil with bilateral hypothalamic lesion associated with hyperthermia and hypersomnia: a case report].

A 39 years old woman was admitted to our hospital with a status epilepticus, with high fever of 41°C. Magnetic resonance Imaging (MRI) revealed high signal intensities of both sides of thalami and hypothalami in T2 weighted and fluid attenuated inversion recovery (FLAIR) images. A needle biopsy of the thalamic lesion was consistent with neuromyelitis optica spectrum disorder although her serum antibody to aquaporin-4 was negative. The level of orexin in celebrospinal fluid (CSF) was reduced. She presented hypersomnia, which didn't improve even after intravenous methylprednisolone 1 g daily for 3 days. Administration of oral modafinil extended her waking time. There is a number of reports about neuromyelitis optica (NMO) with hypothalamic lesions. We report this case as important suggestion of treatment of these cases.

Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy.

OBJECTIVE: Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness. METHODS: We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. RESULTS: Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. CONCLUSIONS: (1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

Challenges in diagnosing narcolepsy without cataplexy: a consensus statement.

BACKGROUND: Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy. METHODS: A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy. RECOMMENDATIONS: To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without cataplexy patients.

[Positivity analysis of human leukocyte histocompatibility antigen-DQB1*0602 allele in Chinese patients with narcolepsy].

OBJECTIVE: To explore the association of narcolepsy with human leukocyte histocompatibility antigen (HLA)-DQB1*0602 allele in Chinese narcoleptic patients and examine its relationship with different phenotypes. METHODS: A total of 1 223 narcoleptic patients (NC, narcolepsy with typical cataplexy, n = 1 132; NWC, narcolepsy without cataplexy, n = 91) diagnosed at Sleep Center of Peking University People's Hospital from August 1998 to July 2011 were recruited into this retrospective study. According to the onset age, they were divided into early-onset group (onset age ≤ 15 y, n = 1 037) and late-onset group (onset age >15 y, n = 181). All of them underwent a polymerase chain reaction with specific sequence primer (PCR-SSP) HLA-DQB1*0602 typing. And the cerebrospinal fluid levels of hypocretin-1 (hcrt-1) were measured in 156 narcoleptic patients and they were divided into hcrt deficiency group (hcrt-1<138 ng/L, n = 115) and hcrt normal group (hcrt-1 ≥ 138 ng/L, n = 41). And 728 healthy volunteers were selected as control group. The expression positivity of HLA-DQB1*0602 gene was analyzed for each group. RESULTS: There were 1 223 narcoleptic patients including 825 males (67.5%) and 398 females (32.5%) with an average age of (16.6 ± 12.6) years on visiting. There were 728 normal controls including 443 males (60.9%) and 285 females (39.1%) with an average age of (26.6 ± 11.4) years on blood sampling. The positive rate of HLA-DQB1*0602 in narcoleptic, NC and NWC groups was 94.7% (1 158/1 223), 97.0% (1 098/1 132) and 65.9% (60/91) respectively.NC group had a higher rate of HLA-DQB1*0602 positivity (χ² = 155.4, P = 0.000). Both groups were higher than that in control group of 19.5% (142/728). The positive rate of HLA-DQB1*0602 in early-onset group was 95.5% (990/1 037) versus 90.1% (163/181) in late-onset group (χ² = 9.25, P = 0.010). Among those with hcrt-1 measurement, 98.3% (113/115) were HLA-DQB1*0602 positive in hcrt deficiency narcolepsy group versus 25.6% (11/43) in hcrt non-deficiency group (χ² = 94.6, P = 0.001). CONCLUSIONS: HLA-DQB1* 0602 is an important marker in this large sample of Chinese patients with narcolepsy.Its frequency is much higher in patients with cataplexy, early-onset age and hcrt-1 deficiency.

Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy.

BACKGROUND: The association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75-90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy. METHODS: Two patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aß42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF. RESULTS: The concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups. CONCLUSION: The findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.

[Case of herpes simplex encephalitis with hypersomnia and low orexin level in the cerebrospinal fluid].

A 60-year-old woman suffered from high fever (38°C) and abnormal behavior, was admitted to our hospital on the seventh day of the fever. At admission, she was stuporous, and a cerebrospinal fluid (CSF) analysis revealed pleocytosis (55/µl, monocytes). Fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images showed high-intensity signals in the medial temporal lobe, inferior surface of the frontal cortex, right cerebellar vermis, and left thalamus. We diagnosed herpes simplex encephalitis, based on the finding of an elevated titer of herpes simplex virus antibody in the CSF (2.90). She was started on treatment with acyclovir and steroid pulse therapy, which was followed by rapid clinical improvement. After recovering from the stupor, the patient exhibited the symptoms of hypersomnia with low orexin level in the CSF. Thus, we should bear in mind that other than consciousness disturbance, patients with herpes simplex encephalitis can also present with rare complications due to the extent of the lesions.

The influence of preanalytical conditions on the DJ-1 concentration in human cerebrospinal fluid.

AIM: The purpose of this study was to establish the influence of centrifugation and protease activity on the cerebrospinal fluid (CSF) concentrations of DJ-1 and hemoglobin. MATERIALS & METHODS: The concentrations of DJ-1 and hemoglobin were determined in 12 (DJ-1) and six (hemoglobin) pairs of CSF samples, with one sample being stored without centrifugation and the other being centrifuged at 2000 × g before storage. The DJ-1 concentration was also determined in centrifuged and uncentrifuged CSF containing protease inhibitors and compared with values determined in centrifuged and uncentrifuged CSF samples without protease inhibitors. Furthermore, specific protein concentrations were determined in CSF from two groups, each comprising 23 patients with Parkinson's disease. In one group the CSF was centrifuged at 1300-1800 × g, 4°C, 10 min, and in the other at 2000 × g, 4°C, 10 min. RESULTS: Centrifugation at 2000 × g resulted in significantly lower CSF DJ-1 concentrations compared with no centrifugation and centrifugation at a lower g-force. There was a significant difference in the hemoglobin concentration between centrifuged and uncentrifuged CSF. In all centrifuged samples the hemoglobin concentration was <200 ng/ml including blood contaminated samples centrifuged at 2000 × g. When a protease inhibitor cocktail was added to the CSF prior to centrifugation, the DJ-1 concentration was significantly higher. CONCLUSION: Preanalytical factors such as centrifugation and protease inhibition must be carefully controlled when handling CSF for analysis of DJ-1 and other biomarkers, as DJ-1 was influenced by blood contamination, centrifugation and protease activity.

Cataplectic facies: clinical marker in the diagnosis of childhood narcolepsy-report of two cases.

BACKGROUND: Narcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition. PATIENTS: We present two children who presented with "cataplectic facies," an unusual facial feature only recently described in children with narcolepsy with cataplexy. RESULT: The diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay. CONCLUSION: The diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies.

Humor as a reward mechanism: event-related potentials in the healthy and diseased brain.

Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine-deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease.