Journal of psychiatry & neuroscience : JPN, Jan 23, 2015
Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MD... more Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MDD). However, findings regarding negative feedback are ambiguous, with both exaggerated and blunted responses being reported. The ventral striatum (VS) plays a major role in processing valenced feedback, and previous imaging studies have shown that the locus of controls (self agency v. external agency) over the outcome influences VS response to feedback. We investigated whether attributing the outcome to one's own action or to an external agent influences feedback processing in patients with MDD. We hypothesized that depressed participants would be less sensitive to the feedback attribution reflected by an altered VS response to self-attributed gains and losses. Using functional MRI and a motion prediction task, we investigated the neural responses to self-attributed (SA) and externally attributed (EA) monetary gains and losses in unmedicated patients with MDD and healthy controls. We...
Journal of psychiatry & neuroscience : JPN, Jan 22, 2015
Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expressi... more Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expression. Increasing evidence suggests that negative symptoms are associated with altered neural activity of subcortical and cortical regions in the brain reward system. However, the neurobiological basis of the distinct symptom dimensions within negative symptoms is still poorly understood. The primary aim of our study was to examine the neural correlates of the negative symptom dimensions apathy and diminished expression during a reward processing task. Patients with schizophrenia and healthy controls underwent event-related fMRI while performing a variant of the Monetary Incentive Delay Task. We assessed negative symptom dimensions using the Brief Negative Symptom Scale. We included 27 patients and 25 controls in our study. Both groups showed neural activation indicated by blood oxygen-level dependent signal in the ventral striatum during reward anticipation. Ventral striatal activation dur...
Temporally unpredictable stimuli influence murine and human behaviour, as previously demonstrated... more Temporally unpredictable stimuli influence murine and human behaviour, as previously demonstrated for sequences of simple sounds with regular or irregular onset. It is unknown whether this influence is mediated by an evaluation of the unpredictable sound sequences themselves, or by an interaction with task context. Here, we find that humans evaluate unrelated neutral pictures as more negative when these are presented together with a temporally unpredictable sound sequence, compared to a predictable sequence. The same is observed for evaluation of neutral, angry and fearful face photographs. Control experiments suggest this effect is specific to interspersed presentation of negative and neutral visual stimuli. Unpredictable sounds presented on their own were evaluated as more activating, but not more aversive, and were preferred over predictable sounds. When presented alone, these sound sequences also did not elicit tonic autonomic arousal or negative mood change. We discuss how these findings might account for previous data on the effects of unpredictable sounds, in humans and rodents.
The negative symptoms of schizophrenia have been associated with altered neural activity during b... more The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward-cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior.
In most individuals suffering from chronic low back pain, psychosocial factors, specifically fear... more In most individuals suffering from chronic low back pain, psychosocial factors, specifically fear avoidance beliefs (FABs), play central roles in the absence of identifiable organic pathology. On a neurobiological level, encouraging research has shown brain system correlates of somatic and psychological factors during the transition from (sub) acute to chronic low back pain. The characterization of brain imaging signatures in pain-free individuals before any injury will be of high importance regarding the identification of relevant networks for low back pain (LBP) vulnerability. Fear-avoidance beliefs serve as strong predictors of disability and chronification in LBP and current research indicates that back pain related FABs already exist in the general and pain-free population. Therefore, we aimed at investigating possible differential neural functioning between high- and low fear-avoidant individuals in the general population using functional magnetic resonance imaging. Results re...
The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and... more The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects ...
Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate e... more Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate euphoric, prosocial, and empathogenic effects of the drug. We measured the effects of GHB on mood, prosocial behavior, social and non-social cognition and assessed potential underlying neuroendocrine mechanisms. GHB (20mg/kg) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual-analogue-scales and the GHB-Specific-Questionnaire. Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. Reaction time, memory, empathy, and theory-of-mind were also tested. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic-hormone (ACTH) were determined. GHB showed stimulating and sedating effects, and elicited euphoria, disinhibition, and enhanced vitality. In participants with low prosociality, the drug increased donations and prosocial money distributions. In contrast, social cognitive abilities such as emotion recognition, empathy, and theory-of-mind, and basal cognitive functions were not affected. GHB increased plasma progesterone, while oxytocin and testosterone, cortisol, aldosterone, DHEA, and ACTH levels remained unaffected. GHB has mood-enhancing and prosocial effects without affecting social hormones such as oxytocin and testosterone. These data suggest a potential involvement of GHB-/GABAB-receptors and progesterone in mood and prosocial behavior.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1995
Hemmeter, Ulrich, Erich Seifritz, Martin Hatzinger, Matthias J. Müller and Edith Holsboer-Trachsl... more Hemmeter, Ulrich, Erich Seifritz, Martin Hatzinger, Matthias J. Müller and Edith Holsboer-Trachsler: Serial Partial Sleep Deprivation as Adjuvant Treatment of Depressive Insomnia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995, 19(4): 593–602. 1.1. Sleep disturbance is a prominent symptom of major depression. Despite specific treatment with antidepressants, there is a substantial number of patients who improve in depressed mood but remain sleep
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 27, 2015
Cocaine users consistently develop working memory (WM) impairments but the mediating molecular me... more Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant-naïve controls. Two-hundred-twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single nucleotide polymorphisms (rs4570625, rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole blood samples. Several significant gene*environment interactions betw...
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 17, 2015
Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT... more Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT) receptor agonists impair emotional face processing. However, the specific contribution of the 5-HT1A receptor remains poorly understood. Here we investigated the spatiotemporal brain mechanisms underpinning the modulation of emotional face processing induced by buspirone, a partial 5-HT1A receptor agonist. In a psychophysical discrimination of emotional faces task, we observed that the discrimination fearful versus neutral faces were reduced, but not happy versus neutral faces. Electrical neuroimaging analyses were applied to visual evoked potentials elicited by emotional face images, after placebo and buspirone administration. Buspirone modulated response strength (i.e., global field power) in the interval 230-248ms after stimulus onset. Distributed source estimation over this time interval revealed that buspirone decreased the neural activity in the right dorsolateral prefrontal cort...
Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished ... more Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished expression, which might be caused by separable pathophysiological mechanisms. Recently, it has been proposed that apathy could be due to dysfunctional integration of reward and effort during decision making. We asked whether apathy in particular is associated with stronger devaluation ("discounting") of monetary rewards that require physical effort. Thirty-one patients with schizophrenia and 20 healthy control participants performed a computerized effort discounting task in which they could choose to exert physical effort on a handgrip to obtain monetary rewards. This procedure yields an individual measure for the strength of effort discounting. The degree of effort discounting was strongly correlated with apathy, but not with diminished expression. Importantly, the association between apathy and effort discounting was not driven by cognitive ability, antipsychotic medication, ...
In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations re... more In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Social...
Real-time functional magnetic resonance imaging (fMRI) enables one to monitor a subject's bra... more Real-time functional magnetic resonance imaging (fMRI) enables one to monitor a subject's brain activity during an ongoing session. The availability of online information about brain activity is essential for developing and refining interactive fMRI paradigms in research and clinical trials and for neurofeedback applications. Data analysis for real-time fMRI has traditionally been based on hypothesis-driven processing methods. Off-line data analysis, conversely, may be usefully complemented by data-driven approaches, such as independent component analysis (ICA), which can identify brain activity without a priori temporal assumptions on brain activity. However, ICA is commonly considered a time-consuming procedure and thus unsuitable to process the high flux of fMRI data while they are acquired. Here, by specific choices regarding the implementation, we exported the ICA framework and implemented it into real-time fMRI data analysis. We show that, reducing the ICA input to a few p...
The aim of the present study was to investigate whether healthy first-degree relatives of schizop... more The aim of the present study was to investigate whether healthy first-degree relatives of schizophrenia patients show reduced sensitivity performance, higher intra-individual variability (IIV) in reaction time (RT), and a steeper decline in sensitivity over time in a sustained attention task. Healthy first-degree relatives of schizophrenia patients (n = 23) and healthy control subjects (n = 46) without a family history of schizophrenia performed a demanding version of the Rapid Visual Information Processing task (RVIP). RTs, hits, false alarms, and the sensitivity index A′ were assessed. The relatives were significantly less sensitive, tended to have higher IIV in RT, but sustained the impaired level of sensitivity over time. Impaired performance on the RVIP is a possible endophenotype for schizophrenia. Higher IIV in RT, apparently caused by impaired context representations, might result in fluctuations in control and lead to more frequent attentional lapses.
In humans, exposure to stress during development is associated with structural and functional alt... more In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype × developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HTT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HTT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression.
Recent evidence has shown that a single maintenance dose of heroin attenuates psychophysiological... more Recent evidence has shown that a single maintenance dose of heroin attenuates psychophysiological stress responses in heroin-dependent patients, probably reflecting the effectiveness of heroin-assisted therapies for the treatment of severe heroin addiction. However, the underlying neural circuitry of these effects has not yet been investigated. Using a cross-over, double-blind, vehicle-controlled design, 22 heroin-dependent and heroin-maintained outpatients from the Centre of Substance Use Disorders at the University Hospital of Psychiatry in Basel were studied after heroin and placebo administration, while 17 healthy controls from the general population were included for placebo administration only. Functional magnetic resonance imaging was used to detect brain responses to fearful faces and dynamic causal modelling was applied to compute fear-induced modulation of connectivity within the emotional face network. Stress responses were assessed by hormone releases and subjective rati...
Temporal integration is a fundamental process that the brain carries out to construct coherent pe... more Temporal integration is a fundamental process that the brain carries out to construct coherent percepts from serial sensory events. This process critically depends on the formation of memory traces reconciling past with present events and is particularly important in the auditory domain where sensory information is received both serially and in parallel. It has been suggested that buffers for transient auditory memory traces reside in the auditory cortex. However, previous studies investigating "echoic memory" did not distinguish between brain response to novel auditory stimulus characteristics on the level of basic sound processing and a higher level involving matching of present with stored information. Here we used functional magnetic resonance imaging in combination with a regular pattern of sounds repeated every 100 ms and deviant interspersed stimuli of 100-ms duration, which were either brief presentations of louder sounds or brief periods of silence, to probe the formation of auditory memory traces. To avoid interaction with scanner noise, the auditory stimulation sequence was implemented into the image acquisition scheme. Compared to increased loudness events, silent periods produced specific neural activation in the right planum temporale and temporoparietal junction. Our findings suggest that this area posterior to the auditory cortex plays a critical role in integrating sequential auditory events and is involved in the formation of short-term auditory memory traces. This function of the planum temporale appears to be fundamental in the segregation of simultaneous sound sources.
The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathome... more The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathomechanism of the disorder further we recorded a surface electromyogram (EMG) of the anterior tibial muscle during functional magnetic resonance imaging (fMRI) in patients with idiopathic RLS. Seven subjects with moderate to severe RLS were investigated in the present pilot study. Patients were lying supine in the scanner for over 50 min and were instructed not to move voluntarily. Sensory leg discomfort (SLD) was evaluated on a 10-point Likert scale. For brain image analysis, an algorithm for the calculation of tonic EMG values was developed. We found a negative correlation of tonic EMG and SLD (p <0.01). This finding provides evidence for the clinical experience that RLS-related subjective leg discomfort increases during muscle relaxation at rest. In the fMRI analysis, the tonic EMG was associated with activation in motor and somatosensory pathways and also in some regions that are not...
Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GAB... more Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GABA B receptor) agonist baclofen modulates reinforcement learning and reduces craving in patients with addiction spectrum disorders. However, in contrast to the well established role of dopamine in reinforcement learning, the mechanisms by which the GABA B receptor influences reinforcement learning in humans remain completely unknown. To further elucidate this issue, a cross-over, double-blind, placebo-controlled study was performed in healthy human subjects (N =15) to test the effects of baclofen (20 and 50 mg p.o.) on probabilistic reinforcement learning. Outcomes were the feedback-induced P2 component of the event-related potential, the feedback-related negativity, and the P300 component of the event-related potential. Baclofen produced a reduction of P2 amplitude over the course of the experiment, but did not modulate the feedback-related negativity. Furthermore, there was a trend towards increased learning after baclofen administration relative to placebo over the course of the experiment. The present results extend previous theories of reinforcement learning, which focus on the importance of mesolimbic dopamine signaling, and indicate that stimulation of cortical GABA B receptors in a fronto-parietal network leads to better attentional allocation in reinforcement learning. This observation is a first step in our understanding of how baclofen may improve www.elsevier.com/locate/euroneuro http://dx.
Journal of psychiatry & neuroscience : JPN, Jan 23, 2015
Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MD... more Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MDD). However, findings regarding negative feedback are ambiguous, with both exaggerated and blunted responses being reported. The ventral striatum (VS) plays a major role in processing valenced feedback, and previous imaging studies have shown that the locus of controls (self agency v. external agency) over the outcome influences VS response to feedback. We investigated whether attributing the outcome to one's own action or to an external agent influences feedback processing in patients with MDD. We hypothesized that depressed participants would be less sensitive to the feedback attribution reflected by an altered VS response to self-attributed gains and losses. Using functional MRI and a motion prediction task, we investigated the neural responses to self-attributed (SA) and externally attributed (EA) monetary gains and losses in unmedicated patients with MDD and healthy controls. We...
Journal of psychiatry & neuroscience : JPN, Jan 22, 2015
Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expressi... more Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expression. Increasing evidence suggests that negative symptoms are associated with altered neural activity of subcortical and cortical regions in the brain reward system. However, the neurobiological basis of the distinct symptom dimensions within negative symptoms is still poorly understood. The primary aim of our study was to examine the neural correlates of the negative symptom dimensions apathy and diminished expression during a reward processing task. Patients with schizophrenia and healthy controls underwent event-related fMRI while performing a variant of the Monetary Incentive Delay Task. We assessed negative symptom dimensions using the Brief Negative Symptom Scale. We included 27 patients and 25 controls in our study. Both groups showed neural activation indicated by blood oxygen-level dependent signal in the ventral striatum during reward anticipation. Ventral striatal activation dur...
Temporally unpredictable stimuli influence murine and human behaviour, as previously demonstrated... more Temporally unpredictable stimuli influence murine and human behaviour, as previously demonstrated for sequences of simple sounds with regular or irregular onset. It is unknown whether this influence is mediated by an evaluation of the unpredictable sound sequences themselves, or by an interaction with task context. Here, we find that humans evaluate unrelated neutral pictures as more negative when these are presented together with a temporally unpredictable sound sequence, compared to a predictable sequence. The same is observed for evaluation of neutral, angry and fearful face photographs. Control experiments suggest this effect is specific to interspersed presentation of negative and neutral visual stimuli. Unpredictable sounds presented on their own were evaluated as more activating, but not more aversive, and were preferred over predictable sounds. When presented alone, these sound sequences also did not elicit tonic autonomic arousal or negative mood change. We discuss how these findings might account for previous data on the effects of unpredictable sounds, in humans and rodents.
The negative symptoms of schizophrenia have been associated with altered neural activity during b... more The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward-cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior.
In most individuals suffering from chronic low back pain, psychosocial factors, specifically fear... more In most individuals suffering from chronic low back pain, psychosocial factors, specifically fear avoidance beliefs (FABs), play central roles in the absence of identifiable organic pathology. On a neurobiological level, encouraging research has shown brain system correlates of somatic and psychological factors during the transition from (sub) acute to chronic low back pain. The characterization of brain imaging signatures in pain-free individuals before any injury will be of high importance regarding the identification of relevant networks for low back pain (LBP) vulnerability. Fear-avoidance beliefs serve as strong predictors of disability and chronification in LBP and current research indicates that back pain related FABs already exist in the general and pain-free population. Therefore, we aimed at investigating possible differential neural functioning between high- and low fear-avoidant individuals in the general population using functional magnetic resonance imaging. Results re...
The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and... more The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects ...
Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate e... more Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate euphoric, prosocial, and empathogenic effects of the drug. We measured the effects of GHB on mood, prosocial behavior, social and non-social cognition and assessed potential underlying neuroendocrine mechanisms. GHB (20mg/kg) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual-analogue-scales and the GHB-Specific-Questionnaire. Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. Reaction time, memory, empathy, and theory-of-mind were also tested. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic-hormone (ACTH) were determined. GHB showed stimulating and sedating effects, and elicited euphoria, disinhibition, and enhanced vitality. In participants with low prosociality, the drug increased donations and prosocial money distributions. In contrast, social cognitive abilities such as emotion recognition, empathy, and theory-of-mind, and basal cognitive functions were not affected. GHB increased plasma progesterone, while oxytocin and testosterone, cortisol, aldosterone, DHEA, and ACTH levels remained unaffected. GHB has mood-enhancing and prosocial effects without affecting social hormones such as oxytocin and testosterone. These data suggest a potential involvement of GHB-/GABAB-receptors and progesterone in mood and prosocial behavior.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1995
Hemmeter, Ulrich, Erich Seifritz, Martin Hatzinger, Matthias J. Müller and Edith Holsboer-Trachsl... more Hemmeter, Ulrich, Erich Seifritz, Martin Hatzinger, Matthias J. Müller and Edith Holsboer-Trachsler: Serial Partial Sleep Deprivation as Adjuvant Treatment of Depressive Insomnia. Prog. Neuro-Psychopharmacol. &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Biol. Psychiat. 1995, 19(4): 593–602. 1.1. Sleep disturbance is a prominent symptom of major depression. Despite specific treatment with antidepressants, there is a substantial number of patients who improve in depressed mood but remain sleep
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 27, 2015
Cocaine users consistently develop working memory (WM) impairments but the mediating molecular me... more Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant-naïve controls. Two-hundred-twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single nucleotide polymorphisms (rs4570625, rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole blood samples. Several significant gene*environment interactions betw...
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 17, 2015
Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT... more Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT) receptor agonists impair emotional face processing. However, the specific contribution of the 5-HT1A receptor remains poorly understood. Here we investigated the spatiotemporal brain mechanisms underpinning the modulation of emotional face processing induced by buspirone, a partial 5-HT1A receptor agonist. In a psychophysical discrimination of emotional faces task, we observed that the discrimination fearful versus neutral faces were reduced, but not happy versus neutral faces. Electrical neuroimaging analyses were applied to visual evoked potentials elicited by emotional face images, after placebo and buspirone administration. Buspirone modulated response strength (i.e., global field power) in the interval 230-248ms after stimulus onset. Distributed source estimation over this time interval revealed that buspirone decreased the neural activity in the right dorsolateral prefrontal cort...
Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished ... more Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished expression, which might be caused by separable pathophysiological mechanisms. Recently, it has been proposed that apathy could be due to dysfunctional integration of reward and effort during decision making. We asked whether apathy in particular is associated with stronger devaluation ("discounting") of monetary rewards that require physical effort. Thirty-one patients with schizophrenia and 20 healthy control participants performed a computerized effort discounting task in which they could choose to exert physical effort on a handgrip to obtain monetary rewards. This procedure yields an individual measure for the strength of effort discounting. The degree of effort discounting was strongly correlated with apathy, but not with diminished expression. Importantly, the association between apathy and effort discounting was not driven by cognitive ability, antipsychotic medication, ...
In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations re... more In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Social...
Real-time functional magnetic resonance imaging (fMRI) enables one to monitor a subject's bra... more Real-time functional magnetic resonance imaging (fMRI) enables one to monitor a subject's brain activity during an ongoing session. The availability of online information about brain activity is essential for developing and refining interactive fMRI paradigms in research and clinical trials and for neurofeedback applications. Data analysis for real-time fMRI has traditionally been based on hypothesis-driven processing methods. Off-line data analysis, conversely, may be usefully complemented by data-driven approaches, such as independent component analysis (ICA), which can identify brain activity without a priori temporal assumptions on brain activity. However, ICA is commonly considered a time-consuming procedure and thus unsuitable to process the high flux of fMRI data while they are acquired. Here, by specific choices regarding the implementation, we exported the ICA framework and implemented it into real-time fMRI data analysis. We show that, reducing the ICA input to a few p...
The aim of the present study was to investigate whether healthy first-degree relatives of schizop... more The aim of the present study was to investigate whether healthy first-degree relatives of schizophrenia patients show reduced sensitivity performance, higher intra-individual variability (IIV) in reaction time (RT), and a steeper decline in sensitivity over time in a sustained attention task. Healthy first-degree relatives of schizophrenia patients (n = 23) and healthy control subjects (n = 46) without a family history of schizophrenia performed a demanding version of the Rapid Visual Information Processing task (RVIP). RTs, hits, false alarms, and the sensitivity index A′ were assessed. The relatives were significantly less sensitive, tended to have higher IIV in RT, but sustained the impaired level of sensitivity over time. Impaired performance on the RVIP is a possible endophenotype for schizophrenia. Higher IIV in RT, apparently caused by impaired context representations, might result in fluctuations in control and lead to more frequent attentional lapses.
In humans, exposure to stress during development is associated with structural and functional alt... more In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype × developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HTT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HTT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression.
Recent evidence has shown that a single maintenance dose of heroin attenuates psychophysiological... more Recent evidence has shown that a single maintenance dose of heroin attenuates psychophysiological stress responses in heroin-dependent patients, probably reflecting the effectiveness of heroin-assisted therapies for the treatment of severe heroin addiction. However, the underlying neural circuitry of these effects has not yet been investigated. Using a cross-over, double-blind, vehicle-controlled design, 22 heroin-dependent and heroin-maintained outpatients from the Centre of Substance Use Disorders at the University Hospital of Psychiatry in Basel were studied after heroin and placebo administration, while 17 healthy controls from the general population were included for placebo administration only. Functional magnetic resonance imaging was used to detect brain responses to fearful faces and dynamic causal modelling was applied to compute fear-induced modulation of connectivity within the emotional face network. Stress responses were assessed by hormone releases and subjective rati...
Temporal integration is a fundamental process that the brain carries out to construct coherent pe... more Temporal integration is a fundamental process that the brain carries out to construct coherent percepts from serial sensory events. This process critically depends on the formation of memory traces reconciling past with present events and is particularly important in the auditory domain where sensory information is received both serially and in parallel. It has been suggested that buffers for transient auditory memory traces reside in the auditory cortex. However, previous studies investigating "echoic memory" did not distinguish between brain response to novel auditory stimulus characteristics on the level of basic sound processing and a higher level involving matching of present with stored information. Here we used functional magnetic resonance imaging in combination with a regular pattern of sounds repeated every 100 ms and deviant interspersed stimuli of 100-ms duration, which were either brief presentations of louder sounds or brief periods of silence, to probe the formation of auditory memory traces. To avoid interaction with scanner noise, the auditory stimulation sequence was implemented into the image acquisition scheme. Compared to increased loudness events, silent periods produced specific neural activation in the right planum temporale and temporoparietal junction. Our findings suggest that this area posterior to the auditory cortex plays a critical role in integrating sequential auditory events and is involved in the formation of short-term auditory memory traces. This function of the planum temporale appears to be fundamental in the segregation of simultaneous sound sources.
The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathome... more The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathomechanism of the disorder further we recorded a surface electromyogram (EMG) of the anterior tibial muscle during functional magnetic resonance imaging (fMRI) in patients with idiopathic RLS. Seven subjects with moderate to severe RLS were investigated in the present pilot study. Patients were lying supine in the scanner for over 50 min and were instructed not to move voluntarily. Sensory leg discomfort (SLD) was evaluated on a 10-point Likert scale. For brain image analysis, an algorithm for the calculation of tonic EMG values was developed. We found a negative correlation of tonic EMG and SLD (p <0.01). This finding provides evidence for the clinical experience that RLS-related subjective leg discomfort increases during muscle relaxation at rest. In the fMRI analysis, the tonic EMG was associated with activation in motor and somatosensory pathways and also in some regions that are not...
Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GAB... more Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GABA B receptor) agonist baclofen modulates reinforcement learning and reduces craving in patients with addiction spectrum disorders. However, in contrast to the well established role of dopamine in reinforcement learning, the mechanisms by which the GABA B receptor influences reinforcement learning in humans remain completely unknown. To further elucidate this issue, a cross-over, double-blind, placebo-controlled study was performed in healthy human subjects (N =15) to test the effects of baclofen (20 and 50 mg p.o.) on probabilistic reinforcement learning. Outcomes were the feedback-induced P2 component of the event-related potential, the feedback-related negativity, and the P300 component of the event-related potential. Baclofen produced a reduction of P2 amplitude over the course of the experiment, but did not modulate the feedback-related negativity. Furthermore, there was a trend towards increased learning after baclofen administration relative to placebo over the course of the experiment. The present results extend previous theories of reinforcement learning, which focus on the importance of mesolimbic dopamine signaling, and indicate that stimulation of cortical GABA B receptors in a fronto-parietal network leads to better attentional allocation in reinforcement learning. This observation is a first step in our understanding of how baclofen may improve www.elsevier.com/locate/euroneuro http://dx.
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Papers by Erich Seifritz