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Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193301 Year: Pages: 219 DOI: 10.3389/978-2-88919-330-1 Language: English
Publisher: Frontiers Media SA
Subject: Psychiatry --- Therapeutics --- Neurology --- Medicine (General) --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia.

The Philosophy of Psychiatry and Biologism

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193547 Year: Pages: 99 DOI: 10.3389/978-2-88919-354-7 Language: English
Publisher: Frontiers Media SA
Subject: Psychology --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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There has been an ongoing debate about the capabilities and limits of the bio-natural sciences as sources and the methodological measure in the philosophy of psychiatry for quite some time now. Still, many problems remain unsolved, at least partly for the following reasons: The opposing parties do not tend to speak with each other, exchange their arguments and try to increase mutual understanding. Rather, one gets the impression that they often remain in their “trenches”, busy with confirming each others' opinions and developing their positions in isolation. This leads to several shortcomings: (1) Good arguments and insights from both sides of the debate get less attention they deserve. (2) The further improvement of each position becomes harder without criticism, genuinely motivated by the opposing standpoint. (3) The debate is not going to stop, at least not in the way it would finish after a suggested solution finds broad support; (4) Related to this, insisting on the ultimate aptnessof one side is just plainly wrong in almost every case. Since undeniably, most philosophical positions usually have a grain of truth hidden in them. In sum, many controversies persist with regard to the appropriate methodological, epistemological, and even ontological level for psychiatric explanation and therapies. In a conference which took place in December last year, we tried to contribute to a better understanding about what really is at issue in the philosophy of psychiatry. We asked for a common basis for several sides, for points of divergence and for the practical impact of different solutions on everyday work in psychiatry. Since psychiatry as a whole is a subject that is to wide to be covered in a single meeting, we focused on the following four core topics: 1.Competing accounts of psychiatric biologism, reductionism, and physicalism. 2.Mental disease and brain disease in the light of current neuroscientific and epigenetic findings. 3.Normative suppositions for different accounts of mental disease. 4.Normative implications of different accounts of mental disease. These topics, which have been vigorously as well as fruitfully discussed at our conference, will (ideally) be, too, in the center of our contribution to Frontiers. More precisely, we think of arranging a “research topic” which assembles the issues of the conference. At this point, it seems promising to us to group three or four Target Articles (TA) and let them get criticized by a couple of commentaries from different angles to give the issue a much broader and detailed perspective.

The Neural Underpinnings of Vicarious Experience

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192649 Year: Pages: 169 DOI: 10.3389/978-2-88919-264-9 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-12-03 13:02:24
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Everyday we vicariously experience a range of states that we observe in other people: we may "feel" embarrassed when witnessing another making a social faux pas, or we may feel sadness when we see a loved one upset. In some cases this process appears to be implicit. For instance, observing pain in others may activate pain-related neural processes but without generating an overt feeling of pain. In other cases, people report a more literal, conscious sharing of affective or somatic states and this has sometimes been described as representing an extreme form of empathy. By contrast, there appear to be some people who are limited in their ability to vicariously experience the states of others. This may be the case in several psychiatric, neurodevelopmental, and personality disorders where deficits in interpersonal understanding are observed, such as schizophrenia, autism, and psychopathy. In recent decades, neuroscientists have paid significant attention to the understanding of the “social brain,” and the way in which neural processes govern our understanding of other people. In this Research Topic, we wish to contribute towards this understanding and ask for the submission of manuscripts focusing broadly on the neural underpinnings of vicarious experience. This may include theoretical discussion, case studies, and empirical investigation using behavioural techniques, electrophysiology, brain stimulation, and neuroimaging in both healthy and clinical populations. Of specific interest will be the neural correlates of individual differences in traits such as empathy, how we distinguish between ourselves and other people, and the sensorimotor resonant mechanisms that may allow us to put ourselves in another's shoes.

Interactions between emotions and social context: Basic, clinical and non-human evidence

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193196 Year: Pages: 217 DOI: 10.3389/978-2-88919-319-6 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-02-05 17:24:33
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The emotions that we feel and also those that we perceive in others are crucial to the social functioning of both humans and non-human animals. Although the role of context has been extensively studied in basic sensory processing, its relevance for social cognition and emotional processing is little understood. In recent years, several lines of research at the behavioral and neural levels have highlighted the bidirectional interactions that take place between emotions and social context. Experienced emotions, even when incidental, bias decision-making. Remarkably, even basic emotions can be strongly influenced by situational contexts. In addition, both humans and non-human animals can use emotional expressions strategically as a means of influencing and managing the behavioral response of others in relation to specific environmental situations. Moreover, social emotions (e.g., engaged in moral judgment, empathic concern and social norms) seem to be context-dependent, which also questions a purely abstract account of emotion understanding and expression, as well as other social cognition domains. The present Research Topic of Frontiers in Human Neuroscience highlights the need for a situated approach to emotion and social cognition. We presented theoretical and empirical work at the behavioral and neural levels that contribute to our understanding of emotion within a highly contextualized social realm, and vice-versa. Relevant contributions are presented from diverse fields, including ethology, neurology, biology, cognitive and social neuroscience, and as well as psychology and neuropsychiatry. This integrated approach that entails the interaction between emotion and social context provide important new insights into the growing field of social neuroscience.

Towards a New Cognitive Neuroscience: Modeling Natural Brain Dynamics

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192717 Year: Pages: 166 DOI: 10.3389/978-2-88919-271-7 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2015-12-03 13:02:24
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Decades of brain imaging experiments have revealed important insights into the architecture of the human brain and the detailed anatomic basis for the neural dynamics supporting human cognition. However, technical restrictions of traditional brain imaging approaches including functional magnetic resonance tomography (fMRI), positron emission tomography (PET), and magnetoencephalography (MEG) severely limit participants' movements during experiments. As a consequence, our knowledge of the neural basis of human cognition is rooted in a dissociation of human cognition from what is arguably its foremost, and certainly its evolutionarily most determinant function, organizing our behavior so as to optimize its consequences in our complex, multi-scale, and ever-changing environment. The concept of natural cognition, therefore, should not be separated from our fundamental experience and role as embodied agents acting in a complex, partly unpredictable world. To gain new insights into the brain dynamics supporting natural cognition, we must overcome restrictions of traditional brain imaging technology. First, the sensors used must be lightweight and mobile to allow monitoring of brain activity during free participant movements. New hardware technology for electroencephalography (EEG) and near infrared spectroscopy (NIRS) allows recording electrical and hemodynamic brain activity while participants are freely moving. New data-driven analysis approaches must allow separation of signals arriving at the sensors from the brain and from non-brain sources (neck muscles, eyes, heart, the electrical environment, etc.). Independent component analysis (ICA) and related blind source separation methods allow separation of brain activity from non-brain activity from data recorded during experimental paradigms that stimulate natural cognition. Imaging the precisely timed, distributed brain dynamics that support all forms of our motivated actions and interactions in both laboratory and real-world settings requires new modes of data capture and of data processing. Synchronously recording participants’ motor behavior, brain activity, and other physiology, as well as their physical environment and external events may be termed mobile brain/body imaging ('MoBI'). Joint multi-stream analysis of recorded MoBI data is a major conceptual, mathematical, and data processing challenge. This Research Topic is one result of the first international MoBI meeting in Delmenhorst Germany in September 2013. During an intense workshop researchers from all over the world presented their projects and discussed new technological developments and challenges of this new imaging approach. Several of the presentations are compiled in this Research Topic that we hope may inspire new research using the MoBI paradigm to investigate natural cognition by recording and analyzing the brain dynamics and behavior of participants performing a wide range of naturally motivated actions and interactions.

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