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Interactions of dopamine and hypocretin in sleep-wake functions: Vigilance, emotional processing, and learning in patients with narcolepsy, restless legs syndrome, Parkinson’s disease and healthy controls

English title Interactions of dopamine and hypocretin in sleep-wake functions: Vigilance, emotional processing, and learning in patients with narcolepsy, restless legs syndrome, Parkinson’s disease and healthy controls
Applicant Khatami Ramin
Number 124763
Funding scheme Project funding (Div. I-III)
Research institution Klinik Barmelweid
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.08.2009 - 31.01.2013
Approved amount 399'202.88
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Keywords (16)

hypocretin; dopamine; narcolepsy; restless legs syndrom; Parkinson's disease; arousal; sleep; motor performance; reward; learning; emotions; high density EEG; functional MRI; vigilance; emotional processing; motor behavior

Lay Summary (English)

Lead
Lay summary
In the human brain multiple neurotransmitters mediate different behavioral states. The dopaminergic and hypocretinergic systems are implicated in the regulation of various arousal states (including vigilance, emotional/reward processing, learning) as well as motor behaviors. Neuroanatomically the two systems are densely interconnected and experimental data suggests the existence of a link between sleep-wake functions and emotional processing, cognitive and motor performances. The goals of this project are to investigate the interaction of hypocretins and dopamine in emotional processing and reward-related learning, as well as their relationship to sleep-wake functions. To this aim we will study and compare patients with distinct patterns of hypocretinergic and/or dopaminergic dysfunction: patients with narcolepsy (NC), restless legs syndrome (RLS), Parkinson's disease (PD), and healthy controls using functional neuroimaging and various electrophysiological methods. We hypothesize that the degree of vigilance influences emotional processing, reward related learning and motor performance. We also assume that emotional processing is disturbed in NC patients and untreated PD patients and possibly in RLS patients. We predict that patients with combined dopamine and hypocretin deficiency (PD) will have a more profound dysfunction in all stages of processing as compared to hypocretin deficient patients (NC) or patients with dopaminergic dysfunction (RLS)). These complementary results will thus improve our understanding of mechanisms responsible for some major neurological disorders and may thus have important implications for future pharmacological treatment strategies.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Advanced EEG analysis using threshold-free cluster enhancement and non-parametric statistics
Mensen A, Khatami R (2013), Advanced EEG analysis using threshold-free cluster enhancement and non-parametric statistics, in Neuroimage , 67, 111-118.
Humor as a Reward Mechanism: Event-Related Potentials in the Healthy and Diseased Brain
Mensen Armand, Poryazova Rositsa, Schwartz Sophie, Khatami Ramin, Humor as a Reward Mechanism: Event-Related Potentials in the Healthy and Diseased Brain, in PLOS one.
Time perception in narcolepsy in comparison to patients with Parkinson’s disease and healthy controls - an explorative study
Neumann Rosita, Mensen Armand, Bislimi Fatime, Eberle Tania, Hügli Gordana, Badel Line, Baumann Christian, Khatami Ramin, Time perception in narcolepsy in comparison to patients with Parkinson’s disease and healthy controls - an explorative study, in Journal of sleep research.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Sleep Research Society 2012 21st Congress Poster 04.09.2012 Paris, Frankreich, France Badel Line; Poriazova Neumann Rositsa Galabova; Baumann Christian Rainer; Schwartz Sophie; Khatami Ramin; Hügli Gordana; Mensen Armand;
European Sleep Research Society 2012 21st Congress Talk given at a conference 04.09.2012 Paris, France Badel Line; Poriazova Neumann Rositsa Galabova; Baumann Christian Rainer; Schwartz Sophie; Mensen Armand; Khatami Ramin; Hügli Gordana; Zhong Zhongxing;
26th Annual Meeting of the Associated Professional Sleep Societies (APSS) 2012 Poster 09.06.2012 Boston, United States of America Hügli Gordana; Schwartz Sophie; Poriazova Neumann Rositsa Galabova; Badel Line; Zhong Zhongxing; Mensen Armand; Khatami Ramin; Baumann Christian Rainer;
26th Annual Meeting of the Associated Professional Sleep Societies (APSS) 2012 Poster 09.06.2012 Boston USA, United States of America Khatami Ramin; Baumann Christian Rainer; Schwartz Sophie; Badel Line; Hügli Gordana; Poriazova Neumann Rositsa Galabova; Mensen Armand;
World Sleep Meeting (WASM) 2011 Poster 10.09.2011 Quebec, Canada Mensen Armand; Baumann-Vogel Heide; Baumann Christian Rainer; Hügli Gordana; Poriazova Neumann Rositsa Galabova; Khatami Ramin;
ZIHP Symposium 2011 Poster 26.08.2011 Zurich, Switzerland Mensen Armand; Khatami Ramin;
Swiss Society of Neuroscience 2011 Poster 26.03.2011 Basel, Switzerland Khatami Ramin; Mensen Armand;


Self-organised

Title Date Place
Annual Meetig of Swiss Society for Sleep Research, Sleep Medicine and Chronibiology 2013 23.05.2013 Aarau, Switzerland, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Gut geschlafen ist halb gelernt Berner Zeitung German-speaking Switzerland 2013
Media relations: print media, online media Licht kann nicht alles Korrigieren Aargauer Zeitung German-speaking Switzerland 2013
Media relations: print media, online media Narkolepsie Tagesanzeiger/Mediaplant German-speaking Switzerland 2011
Media relations: radio, television Schlafen ist lernbar PULS Schweizer Fernsehen German-speaking Switzerland 2011
Media relations: radio, television Schlafwandeln TAgesanzeiger/Mediaplant German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
135653 Emotional relevance and sleep shape neural plasticity: A multimodal neuroimaging investigation in humans 01.09.2011 Project funding (Div. I-III)
185362 Swiss Primary Hypersomnolence and Narcolepsy Cohort Study 01.09.2019 Project funding (Div. I-III)

Abstract

Background: Hypocretins (orexins) are excitatory neuropeptides, produced in lateral hypothalamus. Dopamine is a monoaminergic neurotransmitter produced in several areas of the brain, including the substantia nigra, the ventral tegmental area and the arcuate nucleus of the hypothalamus. Hypocretins and dopamine have been both implicated in a variety of functions including the regulation of different arousal states (including vigilance, emotional/reward processing, learning) as well as motor behaviors. Neuroanatomically the two systems are densely interconnected and experimental data suggests the existence of a link between sleep-wake functions and emotional processing, cognitive and motor performances. Consistent with these findings, patients with hypocretin and/or dopamine deficiency/dysfunction were found to exhibit several sleep-wake, emotional, cognitive and motor disturbances. In addition, drug treatment (e.g. dopamine, dopamine agonists, hypocretin antagonists, amphetamine analogs, antidepressants) may modulate and sometimes aggravate these disturbances.Aims/hypotheses: Our main goal is to investigate the interaction of hypocretins and dopamine in emotional processing and (reward-related) learning, as well as their relationship to sleep-wake functions. To this aim we will study and compare patients with distinct patterns of hypocretinergic and/or dopaminergic dysfunction: patients with narcolepsy (NC), restless legs syndrome (RLS), Parkinson‘s disease (PD), and healthy controls. Our hypotheses: 1) The degree of vigilance influences emotional processing, reward related learning and motor performance in both patients and controls; 2) Emotional processing is disturbed in NC patients and untreated PD patients and possibly in RLS patients as assessed with evoked response potentials (ERPs); 3) Reward anticipation and reward feedback are disturbed in NC patients and untreated PD patients and possibly in RLS patients as assessed with ERPs and functional magnetic resonance imaging (fMRI). 4) A reward-related implicit sequence learning task would induce localized increase of slow wave activity (SWA) and/or theta-waves in REM-sleep as a marker of reward related learning over specific brain areas (e.g. inferior parietal cortex, premotor cortex, orbitofrontal cortex) using high-density(hd-) EEG in sleep in healthy controls and RLS patients. As dopamine and hypocretins contribute differently to sleep-wake regulation and across distinct stages of learning we expect differences in reward and implicit motor learning between the groups. More specifically, we predict that patients with combined dopamine and hypocretin deficiency (PD) will have a more profound dysfunction in all stages of processing as compared to hypocretin deficient patients (NC) or patients with dopaminergic dysfunction (RLS)). Patients and methods: Drug-free, HLA-positive, hypocretin deficient patients with NC, untreated RLS patients and untreated PD patients (in early and late stages) will be compared to age-matched healthy controls. Vigilance will be assessed using subjective (Epworth sleepiness scale (ESS), Stanford (SSS) and Karolinska sleepiness scale (KSS)) and objective (psychomotor vigilance task, PVT and sustained attention to response task, SART) measures. Emotional processing will be studied with ERPs using hd-EEG with 128 electrodes to assess the early posterior negativity (EPN) and the late positive potential (LPP). Reward anticipation and reward feedback will be examined in different tests using hd EEG (to assess stimulus preceding negativity (SPN) and feedback related negativity (FRN)) and fMRI (with a focus on the striatum-nucleus accumbens (NACC) and ventral tegmental area (VTA)). The role of sleep in reward related learning will be studied by means of hd-EEG during 2 consecutive nights: before and after an implicit motor sequence learning task. Behavior will be assessed using a semi-structured interview specifically designed to assess hypo- and hyperdopaminergic states, including disorders of impulse control.Potential value of the project: This project offers a unique way to study the role of dopamine and hypocretins in different behavioral states. A multimodal approach-combining functional neuroimaging and various electrophysiological methods (hd-EEG, fMRI) is most promising to assess the complex interaction between arousal, emotions, learning and motor performance at a system level. While hd-EEG and evoked potentials allow assessing brain states and cortical electrical activities with high temporal resolution, fMRI is able to localize subcortical (and cortical) brain activities. These complementary results will thus improve our understanding of mechanisms responsible for some major neurological disorders and may thus have important implications for future pharmacological treatment strategies.
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