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Author: Gregor Hasler (83)


Jan
2018

Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability.

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Mar
2018

With advances in technology, artificial agents such as humanoid robots will soon become a part of our daily lives. For safe and intuitive collaboration, it is important to understand the goals behind their motor actions. In humans, this process is mediated by changes in activity in fronto-parietal brain areas.

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Mar
2018

The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa.

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Dec
1969

Deep brain stimulation (DBS) for refractory psychiatric disorders shows promising effects on symptom-reduction, however, little is known regarding the effects of DBS on social outcome.
A PubMed search based on original studies of DBS for psychiatric disorders [treatment resistant depression (TRD), Gilles de la Tourette's syndrome (GTS), and obsessive compulsive disorder (OCD)] was conducted. Data on social outcome following surgery were extracted and analyzed.

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Dec
1969

Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion.

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Feb
2017

To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive-compulsive disorder (OCD) resistant to SSRI treatment.
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on.

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May
2017

The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status.

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Dec
1969

There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD.

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Mar
2016

Price's social competition hypothesis interprets the depressive state as an unconscious, involuntary losing strategy, which enables individuals to yield and accept defeat in competitive situations.
We investigated whether patients who suffer from major depressive disorder (MDD) would avoid competition more often than either patients suffering from borderline personality disorder (BPD) or healthy controls.
In a simple paper-folding task healthy participants and patiens with MDD and BPD were matched with two opponents, one with an unknown diagnosis and one who shared their clinical diagnosis, and they had to choose either a competitive or cooperative payment scheme for task completion.

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Dec
1969

Well-Being: An Important Concept for Psychotherapy and Psychiatric Neuroscience.

Psychother Psychosom 2016 11;85(5):255-61. Epub 2016 Aug 11.
Gregor Hasler

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Dec
1969

Social functioning in major depressive disorder.

Neurosci Biobehav Rev 2016 10 6;69:313-32. Epub 2016 Jul 6.
Aleksandra Kupferberg, Lucy Bicks, Gregor Hasler
Depression is associated with social risk factors, social impairments and poor social functioning. This paper gives an overview of these social aspects using the NIMH Research and Domain Criteria 'Systems for Social Processes' as a framework. In particular, it describes the bio-psycho-social interplay regarding impaired affiliation and attachment (social anhedonia, hyper-sensitivity to social rejection, competition avoidance, increased altruistic punishment), impaired social communication (impaired emotion recognition, diminished cooperativeness), impaired social perception (reduced empathy, theory-of-mind deficits) and their impact on social networks and the use of social media.

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Sep
2016

Inconsistent social behavior is a core psychopathological feature of borderline personality disorder. The goal of the present study was to examine inconsistency in social decision-making using simple economic social experiments. We investigated the decisions of 17 female patients with BPD, 24 patients with major depressive disorder (MDD), and 36 healthy controls in three single shot economic experiments measuring trust, cooperation, and punishment.

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Dec
1969

Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic.

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Dec
1969

Schizophrenia is a complex disorder, characterized by the interplay between genetic and environmental factors. Human endogenous retroviruses (HERVs), genetic elements that originated from infections by exogenous retroviruses millions of years ago, comprise ~8% of the human genome. Here, we provide a comprehensive review of accumulating evidence, detailing HERV aberrancies associated with schizophrenia.

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Mar
2016

Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.

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Dec
1969

In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches-from basic neurobiological approaches to human studies-might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone.

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Jan
2016

Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years.

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Mar
2015

Toward stratified treatments for bipolar disorders.

Eur Neuropsychopharmacol 2015 Mar 2;25(3):283-94. Epub 2015 Jan 2.
Gregor Hasler, Andreas Wolf
In bipolar disorders, there are unclear diagnostic boundaries with unipolar depression and schizophrenia, inconsistency of treatment guidelines, relatively long trial-and-error phases of treatment optimization, and increasing use of complex combination therapies lacking empirical evidence. These suggest that the current definition of bipolar disorders based on clinical symptoms reflects a clinically and etiologically heterogeneous entity. Stratification of treatments for bipolar disorders based on biomarkers and improved clinical markers are greatly needed to increase the efficacy of currently available treatments and improve the chances of developing novel therapeutic approaches.

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Dec
2014

A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin.
Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT).

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Dec
2014

Although posttraumatic stress disorder (PTSD) is associated with a variety of structural and functional brain changes, the molecular pathophysiological mechanisms underlying these macroscopic alterations are unknown. Recent studies support the existence of an altered excitation-inhibition balance in PTSD. Further, there is preliminary evidence from blood-sample studies suggesting heightened oxidative stress in PTSD, potentially leading to neural damage through excessive brain levels of free radicals.

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Jun
2014

Patient-reported outcome (PRO) refers to measures that emphasize the subjective view of patients about their health-related conditions and behaviors. Typically, PROs include self-report questionnaires and clinical interviews. Defining PROs for borderline personality disorder (BPD) is particularly challenging given the disorder's high symptomatic heterogeneity, high comorbidity with other psychiatric conditions, highly fluctuating symptoms, weak correlations between symptoms and functional outcomes, and lack of valid and reliable experimental measures to complement self-report data.

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Dec
1969

Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signaling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical, and experimental accounts of phasic dopamine signaling, with implications for the role of learning-related dopamine signaling in addiction and related disorders. We describe the theoretical and behavioral characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations.

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Dec
2014

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls.

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Dec
1969

Current diagnostic definitions of psychiatric disorders based on collections of symptoms encompass very heterogeneous populations and are thus likely to yield spurious results when exploring biological correlates of mental disturbances. It has been suggested that large studies of biomarkers across diagnostic entities may yield improved clinical information. Such a view is based on the concept of assessment as a collection of symptoms devoid of any clinical judgment and interpretation.

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Sep
2014

Recent evidence suggests that increased psychophysiological response to negatively valenced emotional stimuli found in major depressive disorder (MDD) may be associated with reduced catecholaminergic neurotransmission. Fourteen unmedicated, remitted subjects with MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral α-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover trial. Subjects were exposed to fearful (FF) and neutral faces (NF) during a scan with [15O]H2O positron emission tomography to assess the brain-catecholamine interaction in brain regions previously associated with emotional face processing.

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Dec
1969

Purchases are driven by consumers' product preferences and price considerations. Using caloric vestibular stimulation (CVS), we investigated the role of vestibular-affective circuits in purchase decision-making. CVS is an effective noninvasive brain stimulation method, which activates vestibular and overlapping emotional circuits (e.

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Dec
1969

Many patients with Posttraumatic Stress Disorder (PTSD) feel overwhelmed in situations with high levels of sensory input, as in crowded situations with complex sensory characteristics. These difficulties might be related to subtle sensory processing deficits similar to those that have been found for sounds in electrophysiological studies.
Visual processing was investigated with functional magnetic resonance imaging in trauma-exposed participants with (N = 18) and without PTSD (N = 21) employing a picture-viewing task.

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Apr
2015

Bulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa.

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Apr
2015

Clinical evidence suggests a link between vestibular dysfunctions and mood disorders. No study has yet investigated mood and affective control during vestibular stimulation in healthy participants.
We predicted a modulating effect of caloric vestibular stimulation (CVS) on affective control measured in an affective Go/NoGo task (AGN).

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Dec
2013

The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0mg, 150mg and 300mg GBP.

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Nov
2013

The brain reward circuitry innervated by dopamine is critically disturbed in schizophrenia. This study aims to investigate the role of dopamine-related brain activity during prediction of monetary reward and loss in first episode schizophrenia patients.
We measured blood-oxygen-level dependent (BOLD) activity in 10 patients with schizophrenia (SCH) and 12 healthy controls during dopamine depletion with α-methylparatyrosine (AMPT) and during a placebo condition (PLA).

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Oct
2013

We investigated whether the human growth hormone (HGH) response to catecholamine depletion differs between fully remitted patients with major depressive disorder and healthy control subjects. Fourteen unmedicated subjects with remitted major depressive disorder (RMDD) and 11 healthy control subjects underwent catecholamine depletion with oral α-methylparatyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the serum level of HGH.

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Jan
2014

Thyroid hormones and their interactions with catecholamines play a potentially important role in alterations of mood and cognition.
This study aimed to examine the neurobiological effects of catecholamine depletion on thyroid hormones by measuring endocrine and cerebral metabolic function in unmedicated subjects with remitted major depressive disorder (RMDD) and in healthy controls.
This was a randomized, placebo-controlled, and double-blind crossover trial that included 15 unmedicated RMDD subjects and 13 healthy control subjects.

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Sep
2013

Associations between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (-703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder.

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Sep
2013

There is increasing preclinical and clinical evidence of the important role played by the gastric peptide hormone ghrelin in the pathogenesis of symptoms of depression and eating disorders. To investigate the role of ghrelin and its considered counterpart, peptide tyrosine tyrosine (PYY), in the development of bulimic and depressive symptoms induced by catecholamine depletion, we administered the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine (AMPT) in a randomized, double-blind, placebo-controlled crossover, single-site experimental trial to 29 healthy controls and 20 subjects with fully recovered bulimia nervosa (rBN). We found a decrease between preprandial and postprandial plasma ghrelin levels (p<0.

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Jul
2013

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly.

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Jan
2013

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction.

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Nov
2012

Previous studies have suggested that polymorphism in the serotonin transporter gene (5-HTTLPR) influences responses to serotonergic manipulation, with opposite effects in patients recovered from depression (rMDD) and controls. Here we sought to clarify the neurocognitive mechanisms underpinning these surprising results. Twenty controls and 23 rMDD subjects completed the study; functional magnetic resonance imaging (fMRI) and genotype data were available for 17 rMDD subjects and 16 controls.

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Jul
2012

Disturbances in reward processing have been implicated in bulimia nervosa (BN). Abnormalities in processing reward-related stimuli might be linked to dysfunctions of the catecholaminergic neurotransmitter system, but findings have been inconclusive. A powerful way to investigate the relationship between catecholaminergic function and behavior is to examine behavioral changes in response to experimental catecholamine depletion (CD).

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Oct
2011

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration.

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Jan
2012

Can the neuroeconomics revolution revolutionize psychiatry?

Neurosci Biobehav Rev 2012 Jan 29;36(1):64-78. Epub 2011 Apr 29.
Gregor Hasler
Neuroeconomics is a rapidly growing new research discipline aimed at describing the neural substrate of decision-making using incentivized decisions introduced in experimental economics. The novel combination of economic decision theory and neuroscience has the potential to better examine the interactions of social, psychological and neural factors with regard to motivational forces that may underlie psychiatric problems. Game theory will provide psychiatry with computationally principled measures of cognitive dysfunction.

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Jul
2011

Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.

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Oct
2010

Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology. Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophic factors, and circadian rhythms.

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Oct
2010

(11)C-ABP-688 is a selective tracer for the mGluR5 receptor. Its kinetics is fast and thus favourable for an equilibrium approach to determine receptor-related parameters. The purpose of this study was to test the hypothesis that the pattern of the (11)C-ABP688 uptake using a bolus-plus-infusion (B/I) protocol at early time points corresponds to the perfusion and at a later time point to the total distribution volume.

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Oct
2010

Impaired function of the central gamma-aminobutyric acid (GABA) system, which provides the brain's major inhibitory pathways, is thought to play an important role in the pathophysiology of anxiety disorders. The effect of acute psychological stress on the human GABA-ergic system is still unknown, however. The purpose of this study was to determine the effect of acute stress on prefrontal GABA levels.

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Apr
2011

Reward related behaviour is linked to dopaminergic neurotransmission. Our aim was to gain insight into dopaminergic involvement in the human reward system. Combining functional magnetic resonance imaging with dopaminergic depletion by α-methylparatyrosine we measured dopamine-related brain activity in 10 healthy volunteers.

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Mar
2010

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects.

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