Lorenz Deserno

Otto-von-Guericke-Universität Magdeburg, Magdeburg, Saxony-Anhalt, Germany

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Publications (28)137 Total impact

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    ABSTRACT: A dysfunctional differentiation between self-relevant and irrelevant information may affect the perception of environmental stimuli as abnormally salient. The aberrant salience hypothesis assumes that positive symptoms arise from an attribution of salience to irrelevant stimuli accompanied by the feeling of self-relevance. Self-referential processing relies on the activation of cortical midline structures which was demonstrated to be impaired in psychosis. We investigated the neural correlates of self-referential processing, aberrant salience attribution, and the relationship between these 2 measures across the psychosis continuum. Twenty-nine schizophrenia patients, 24 healthy individuals with subclinical delusional ideation, and 50 healthy individuals participated in this study. Aberrant salience was assessed behaviorally in terms of reaction times to task irrelevant cues. Participants performed a self-reference task during fMRI in which they had to apply neutral trait words to them or to a public figure. The correlation between self-referential processing and aberrant salience attribution was tested. Schizophrenia patients displayed increased aberrant salience attribution compared with healthy controls and individuals with subclinical delusional ideation, while the latter exhibited intermediate aberrant salience scores. In the self-reference task, schizophrenia patients showed reduced activation in the ventromedial prefrontal cortex (vmPFC), but individuals with subclinical delusional ideation did not differ from healthy controls. In schizophrenia patients, vmPFC activation correlated negatively with implicit aberrant salience attribution. Higher aberrant salience attribution in schizophrenia patients is related to reduced vmPFC activation during self-referential judgments suggesting that aberrant relevance coding is reflected in decreased neural self-referential processing as well as in aberrant salience attribution. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Schizophrenia Bulletin 07/2015; DOI:10.1093/schbul/sbv098 · 8.61 Impact Factor
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    ABSTRACT: The striatum is known to play a key role in reinforcement learning, specifically in the encoding of teaching signals such as reward prediction errors (RPEs). It has been proposed that aberrant salience attribution is associated with impaired coding of RPE and heightened dopamine turnover in the striatum, and might be linked to the development of psychotic symptoms. However, the relationship of aberrant salience attribution, RPE coding, and dopamine synthesis capacity has not been directly investigated. Here we assessed the association between a behavioral measure of aberrant salience attribution, the salience attribution test, to neural correlates of RPEs measured via functional magnetic resonance imaging while healthy participants (n = 58) performed an instrumental learning task. A subset of participants (n = 27) also underwent positron emission tomography with the radiotracer [(18)F]fluoro-l-DOPA to quantify striatal presynaptic dopamine synthesis capacity. Individual variability in aberrant salience measures related negatively to ventral striatal and prefrontal RPE signals and in an exploratory analysis was found to be positively associated with ventral striatal presynaptic dopamine levels. These data provide the first evidence for a specific link between the constructs of aberrant salience attribution, reduced RPE processing, and potentially increased presynaptic dopamine function. Copyright © 2015 the authors 0270-6474/15/3510103-09$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2015; 35(28):10103-10111. DOI:10.1523/JNEUROSCI.0805-15.2015 · 6.75 Impact Factor
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    ABSTRACT: Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role of prefrontal and striatal glutamate for ventral striatal presynaptic dopamine levels. Such glutamate-dopamine relationships improve our understanding of neurochemical interactions in prefrontostriatal circuits and have implications for the neurobiology of mental disease. Copyright © 2015 the authors 0270-6474/15/359615-07$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2015; 35(26):9615-9621. DOI:10.1523/JNEUROSCI.0329-15.2015 · 6.75 Impact Factor
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    ABSTRACT: Background: Current models of obsessive-compulsive disorder (OCD) link symptomatology to alterations in cortico-striatal circuits. OCD patients show difficulties in tasks probing a balance of habitual/model-free versus goal-directed/model-based control. Gray matter volume (GMV) in cortico-striatal regions is associated with model-based control. Here we investigated structural alterations in OCD versus controls and its relation to model-based control as measured using a sequential decision-making task. Methods: GMV of 27 OCD patients and 27 matched controls was compared and associated with OCD severity (Y-BOCS) within the patient group using VBM-DARTEL. Sequential decision-making was analyzed using computational modeling to explore the degree of model-based vs. model-free control which was associated with GMV in both groups. Results: OCD patients showed reduced GMV in left medial OFC (t=3.85,p(FWE-SVC)<0.05) compared with controls. Within patients GMV was reduced with increasing OCD severity in the right insula (t=7.27,p(FWE_whole-brain)<0.05). We observed no behavioral group differences in omega, the relative weight of model-free vs. model-based control, and no association with disease severity. GMV in ventral striatum correlated with omega in controls (t=3.60,p(uncorr.)<0.001), but not in OCD patients resulting in a significant group by covariate interaction (t=4.50,p(FWE-SVC)<0.05). Conclusions: Structural orbitofrontal alterations in OCD patients confirm previous meta-analyses. No difference in the balance between model-free vs. model-based control was observed in OCD patients compared with controls, although we confirm a positive association between ventral striatal GMV and model-based actions only in controls. This absent association in OCD patients suggests that behavioral control in OCD is differently related to fronto-striatal integrity. Keywords: Obsessive-Compulsive Disorder, Gray Matter Volume, Decision Making, Computational Modeling Supported by: DFG SCHL1969/2-1
    Society for Biological Psychiatry, Annual Meeting, Toronto; 05/2015
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    ABSTRACT: In the present study, we explored possible alterations in the default mode network (DMN) and its functional connectivity in 41 schizophrenia patients and 42 age-matched healthy controls. Schizophrenia patients displayed reduced activation in the ventromedial prefrontal cortex, left superior temporal gyrus including auditory cortex and temporal pole. Psychophysiological interaction analysis revealed reduced connectivity between left superior temporal gyrus including auditory cortex and the left temporal pole in schizophrenia patients compared to healthy subjects. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 04/2015; 165(1). DOI:10.1016/j.schres.2015.03.027 · 4.43 Impact Factor
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    ABSTRACT: Dual system theories suggest that behavioral control is parsed between a deliberative "model-based" and a more reflexive "model-free" system. A balance of control exerted by these systems is thought to be related to dopamine neurotransmission. However, in the absence of direct measures of human dopamine, it remains unknown whether this reflects a quantitative relation with dopamine either in the striatum or other brain areas. Using a sequential decision task performed during functional magnetic resonance imaging, combined with striatal measures of dopamine using [(18)F]DOPA positron emission tomography, we show that higher presynaptic ventral striatal dopamine levels were associated with a behavioral bias toward more model-based control. Higher presynaptic dopamine in ventral striatum was associated with greater coding of model-based signatures in lateral prefrontal cortex and diminished coding of model-free prediction errors in ventral striatum. Thus, interindividual variability in ventral striatal presynaptic dopamine reflects a balance in the behavioral expression and the neural signatures of model-free and model-based control. Our data provide a novel perspective on how alterations in presynaptic dopamine levels might be accompanied by a disruption of behavioral control as observed in aging or neuropsychiatric diseases such as schizophrenia and addiction.
    Proceedings of the National Academy of Sciences 01/2015; 112(5). DOI:10.1073/pnas.1417219112 · 9.81 Impact Factor
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    ABSTRACT: Online: http://www.sciencedirect.com/science/article/pii/S0306453014004715 It is suggested that acute stress shifts behavioral control from goal-directed, model-based towards habitual, model-free strategies. Recent findings indicate that interindividual differences in cortisol stress response influence model-based decision-making. Although not yet investigated in humans, animal studies show that chronic stress also shifts decision-making towards more habitual behavior. Here, we ask whether acute stress and individual vulnerability factors, such as stress reactivity and previous exposure to stressful life events, impact the balance between the model-free and the model-based control systems. To test this, 39 male participants (21–30 years old) were exposed to a potent psychosocial stressor (Trier Social Stress Test) and a control condition in a within-subjects design before they performed a sequential decision-making task which evaluates the balance between the two systems. Physiological and subjective stress reactivity was assessed before, during, and after acute stress exposure. By means of computational modeling, we demonstrate that interindividual variability in stress reactivity predicts impairments in model-based decision-making. Whereas acute psychosocial stress did not alter model-based behavioral control, we found chronic and acute stress to interact in their detrimental effect on decision-making: subjects with high but not low chronic stress levels as indicated by stressful life events exhibited reduced model-based control in response to acute psychosocial stress. These findings emphasize that stress reactivity and chronic stress play an important role in mediating the relationship between stress and decision-making. Our results might stimulate new insights into the interplay between chronic and acute stress, attenuated model-based control, and the pathogenesis of various psychiatric diseases.
    Psychoneuroendocrinology 01/2015; DOI:10.1016/j.psyneuen.2014.12.017 · 5.59 Impact Factor
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    ABSTRACT: Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non-drug-related stimuli towards drug-related stimuli. Such ‘hijacked’ dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N = 27). All participants also underwent 6-[18F]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs nor striatal dopamine synthesis capacity differed between groups. However, ventral striatal coding of RPEs correlated inversely with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between dopamine synthesis capacity and RPE coding depended on the amount of chronic, habitual alcohol intake. Despite the relatively small sample size, a power analysis supports the reported results. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence in proportion to long-term alcohol intake of patients. Alcohol intake may perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake.
    European Journal of Neuroscience 12/2014; 41(4). DOI:10.1111/ejn.12802 · 3.67 Impact Factor
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    ABSTRACT: [(11)C]P943 is a novel, highly selective 5-HT1B PET radioligand. The aim of this study was to determine the test-retest reliability of [(11)C]P943 using two different modeling methods and to perform a power analysis with each quantification technique. Seven healthy volunteers underwent two PET scans on the same day. Regions of interest (ROIs) were the amygdala, hippocampus, pallidum, putamen, insula, frontal, anterior cingulate, parietal, temporal and occipital cortices, and cerebellum. Two multilinear radioligand quantification techniques were used to estimate binding potential: MA1, using arterial input function data, and the second version of the multilinear reference tissue model analysis (MRTM2), using the cerebellum as the reference region. Between-scan percent variability and intraclass correlation coefficients (ICC) were used to assess test-retest reliability. We also performed power analyses to determine the method that would allow the least number of subjects using within-subject or between-subject study designs. A voxel-wise ICC analysis for MRTM2 BPND was performed for the whole brain and all the ROIs studied. Mean percent variability between two scans across regions ranged between 0.4 % and 12.4 % for MA1 BPND, 0.5 % and 11.5 % for MA1 BPP, 16.7 % and 28.3 % for MA1 BPF, and between 0.2 % and 5.4 % for MRTM2 BPND. The power analyses showed a greater number of subjects were required using MA1 BPF compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BPND and the lowest with MA1 BPF in ten ROIs. Small regions and regions with low binding had lower ICC values than large regions and regions with high binding. Reliable measures of 5-HT1B receptor binding can be obtained using the novel PET radioligand [(11)C]P943. Quantification of 5-HT1B receptor binding with MRTM2 BPND and with MA1 BPP provided the least variability and optimal power for within-subject and between-subject designs.
    European journal of nuclear medicine and molecular imaging 11/2014; 42(3). DOI:10.1007/s00259-014-2958-5 · 5.22 Impact Factor
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    ABSTRACT: Impulsivity is a multidimensional construct that has been suggested as a vulnerability factor for several psychiatric disorders, especially addiction disorders. Poor response inhibition may constitute one facet of impulsivity. Trait impulsivity can be assessed by self-report questionnaires such as the widely used Barratt Impulsiveness Scale (BIS-11). However, regarding the multidimensionality of impulsivity different concepts have been proposed, in particular the UPPS self-report questionnaire (‘Urgency’, ‘Lack of Premeditation’, ‘Lack of Perseverance’, ‘Sensation Seeking’) that is based on a factor analytic approach. The question as to which aspects of trait impulsivity map on individual differences of the behavioral and neural correlates of response inhibition so far remains unclear.
    NeuroImage 09/2014; 103. DOI:10.1016/j.neuroimage.2014.09.021 · 6.36 Impact Factor
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    ABSTRACT: In experimental psychology different experiments have been developed to assess goal-directed as compared to habitual control over instrumental decisions. Similar to animal studies selective devaluation procedures have been used. More recently sequential decision-making tasks have been designed to assess the degree of goal-directed vs. habitual choice behavior in terms of an influential computational theory of model-based compared to model-free behavioral control. As recently suggested, different measurements are thought to reflect the same construct. Yet, there has been no attempt to directly assess the construct validity of these different measurements. In the present study, we used a devaluation paradigm and a sequential decision-making task to address this question of construct validity in a sample of 18 healthy male human participants. Correlational analysis revealed a positive association between model-based choices during sequential decisions and goal-directed behavior after devaluation suggesting a single framework underlying both operationalizations and speaking in favor of construct validity of both measurement approaches. Up to now, this has been merely assumed but never been directly tested in humans.
    Frontiers in Human Neuroscience 08/2014; 8:587. DOI:10.3389/fnhum.2014.00587 · 2.90 Impact Factor
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    ABSTRACT: The fronto-limbic network interaction, driven by glutamatergic and dopaminergic neurotransmission, represents a core mechanism of motivated behavior and personality traits. Reward seeking behavior undergoes tremendous changes in adolescence paralleled by neurobiological changes of this network including the prefrontal cortex, striatum and amygdala. Since fronto-limbic dysfunctions also underlie major psychiatric diseases beginning in adolescence, this investigation focuses on network characteristics separating adolescents from adults. To investigate differences in network interactions, the brain reward system activity (slot machine task) together with frontal glutamate concentration (anterior cingulate cortex, ACC) was measured in 28 adolescents and 26 adults employing functional magnetic resonance imaging and magnetic resonance spectroscopy, respectively. An inverse coupling of glutamate concentrations in the ACC and activation of the ventral striatum was observed in adolescents. Further, amygdala response in adolescents was negatively correlated with the personality trait impulsivity. For adults, no significant associations of network components or correlations with impulsivity were found. The inverse association between frontal glutamate concentration and striatal activation in adolescents is in line with the triadic model of motivated behavior stressing the important role of frontal top-down inhibition on limbic structures. Our data identified glutamate as the mediating neurotransmitter of this inhibitory process and demonstrates the relevance of glutamate on the reward system and related behavioral traits like impulsivity. This fronto-limbic coupling may represent a vulnerability factor for psychiatric disorders starting in adolescence but not in adulthood.
    Brain Structure and Function 07/2014; DOI:10.1007/s00429-014-0844-3 · 4.57 Impact Factor
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    ABSTRACT: Although neural signals of reward anticipation have been studied extensively, the functional relationship between reward and attention has remained unclear: Neural signals implicated in reward processing could either reflect attentional biases towards motivationally salient stimuli, or proceed independently of attentional processes. Here, we sought to disentangle reward and attention-related neural processes by independently modulating reward value and attentional task demands in a functional magnetic resonance imaging study in healthy human participants. During presentation of a visual reward cue that indicated whether monetary reward could be obtained in a subsequent reaction time task, participants either attended to the reward cue or performed an unrelated attention-demanding task at two different levels of difficulty. In ventral striatum and ventral tegmental area, neural responses were modulated by reward anticipation irrespective of attentional demands, thus indicating attention-independent processing of reward cues. By contrast, additive effects of reward and attention were observed in visual cortex. Critically, reward-related activations in right anterior insula strongly depended on attention to the reward cue. Dynamic causal modelling revealed that the attentional modulation of reward processing in insular cortex was mediated by enhanced effective connectivity from ventral striatum to anterior insula. Our results provide evidence for distinct functional roles of the brain regions involved in the processing of reward-indicating information: While subcortical structures signal the motivational salience of reward cues even when attention is fully engaged elsewhere, reward-related responses in anterior insula depend on available attentional resources, likely reflecting the conscious evaluation of sensory information with respect to motivational value. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
    Human Brain Mapping 07/2014; 35(7). DOI:10.1002/hbm.22383 · 6.92 Impact Factor
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    ABSTRACT: Background: Substance addiction (e.g. Alcohol addiction) and other psychiatric conditions (e.g. Binge Eating Disorder, BED) might be characterized by the loss of behavioral control particularly when behavioral adaptation is required. It has been hypothesized that Alcohol addiction and BED share as a common ground a failure of behavioral adaptation, which potentially results from aberrant Reinforcement Learning and its neural teaching signals. However, studies including both patient groups are scarce which renders direct comparisons difficult and speculative. Methods: We present behavioral and fMRI data from 18 alcohol dependent patients, 10 patients diagnosed with BED and 20 healthy, matched controls. Participants performed an operant volatility task designed to assess behavioral adaptation in changing environmental conditions. We use computational modeling of Reinforcement Learning to describe changes in learning dynamically and to derive quantitative parameters for behavioral and fMRI analyses. Results: We found significantly (p <.05) impaired task performance shown by less correct choices for both patient groups compared to controls indicating impaired behavioral adaptation over the course of the experiment. In all participants, fMRI revealed activation of a fronto-striatal network (ventral and dorsal striatum, anterior cingulate cortex, medial and lateral prefrontal cortices) during prediction error (PE) modulated feedback. However, coding of PEs appeared to be reduced in the patient groups which might underlie the observed behavioral impairment. Conclusions: Impaired behavioral adaptation seems to be a common pathway in nosologically different psychiatric conditions both characterized by the loss of behavioral control. Preliminary analyses indicate that a disrupted neural coding of RL-signals like PEs might be the neural basis of this impairment. Keywords: Transdiagnostic approach, Reinforcement Learning, Addiction/ Addiction-like Disorders, Computional Modeling, fMRI Supported By: SCHL1969/1-1
    Society for Biological Psychiatry, 69th Annual Meeting, New York City, NY, USA; 05/2014
  • Schizophrenia Research 04/2014; 153:S200. DOI:10.1016/S0920-9964(14)70580-8 · 4.43 Impact Factor
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    ABSTRACT: Background: Human and animal work suggests a shift from goal-directed to habitual decision-making in addiction. However, the evidence for this in human alcohol dependence is as yet inconclusive. Methods: Twenty-six healthy controls and 26 recently detoxified alcohol-dependent patients underwent behavioral testing with a 2-step task designed to disentangle goal-directed and habitual response patterns. Results: Alcohol-dependent patients showed less evidence of goal-directed choices than healthy controls, particularly after losses. There was no difference in the strength of the habitual component. The group differences did not survive controlling for performance on the Digit Symbol Substitution Task. Conclusion: Chronic alcohol use appears to selectively impair goal-directed function, rather than promoting habitual responding. It appears to do so particularly after nonrewards, and this may be mediated by the effects of alcohol on more general cognitive functions subserved by the prefrontal cortex. (C) 2014 S. Karger AG, Basel
    Neuropsychobiology 01/2014; 70(2):122-31. DOI:10.1159/000362840 · 2.30 Impact Factor
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    ABSTRACT: Abnormalities in reinforcement learning are a key finding in schizophrenia and have been proposed to be linked to elevated levels of dopamine neurotransmission. Behavioral deficits in reinforcement learning and their neural correlates may contribute to the formation of clinical characteristics of schizophrenia. The ability to form predictions about future outcomes is fundamental for environmental interactions and depends on neuronal teaching signals, like reward prediction errors. While aberrant prediction errors, that encode non-salient events as surprising, have been proposed to contribute to the formation of positive symptoms, a failure to build neural representations of decision values may result in negative symptoms. Here, we review behavioral and neuroimaging research in schizophrenia and focus on studies that implemented reinforcement learning models. In addition, we discuss studies that combined reinforcement learning with measures of dopamine. Thereby, we suggest how reinforcement learning abnormalities in schizophrenia may contribute to the formation of psychotic symptoms and may interact with cognitive deficits. These ideas point toward an interplay of more rigid versus flexible control over reinforcement learning. Pronounced deficits in the flexible or model-based domain may allow for a detailed characterization of well-established cognitive deficits in schizophrenia patients based on computational models of learning. Finally, we propose a framework based on the potentially crucial contribution of dopamine to dysfunctional reinforcement learning on the level of neural networks. Future research may strongly benefit from computational modeling but also requires further methodological improvement for clinical group studies. These research tools may help to improve our understanding of disease-specific mechanisms and may help to identify clinically relevant subgroups of the heterogeneous entity schizophrenia.
    Frontiers in Psychiatry 12/2013; 4:172. DOI:10.3389/fpsyt.2013.00172
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    ABSTRACT: While watching movies, the brain integrates the visual information and the musical soundtrack into a coherent percept. Multisensory integration can lead to emotion elicitation on which soundtrack valences may have a modulatory impact. Here, dynamic kissing scenes from romantic comedies were presented to 22 participants (13 females) during fMRI scanning. The kissing scenes were either accompanied by happy music, sad music or no music. Evidence from cross-modal studies motivated a predefined three-region network for multisensory integration of emotion, consisting of the fusiform gyrus (FG), the amygdala (AMY) and the anterior superior temporal gyrus (aSTG). The interactions in this network were investigated using dynamic causal models of effective connectivity. This revealed bilinear modulations by happy and sad music with suppression effects on the connectivity from FG and AMY to aSTG. Nonlinear dynamic causal modeling showed a suppressive gating effect of aSTG on fusiform-amygdalar connectivity. In conclusion, fusiform to amygdala coupling strength is modulated via feedback through aSTG as region for multisensory integration of emotional material. This mechanism was emotion-specific and more pronounced for sad music. Therefore, soundtrack valences may modulate emotion elicitation in movies by differentially changing preprocessed visual information to the amygdala.
    Social Cognitive and Affective Neuroscience 12/2013; DOI:10.1093/scan/nst169 · 5.88 Impact Factor
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    ABSTRACT: Subjects with schizophrenia are impaired at reinforcement-driven reversal learning from as early as their first episode. The neurobiological basis of this deficit is unknown. We obtained behavioral and fMRI data in 24 unmedicated, primarily first episode, schizophrenia patients and 24 age-, IQ- and gender-matched healthy controls during a reversal learning task. We supplemented our fMRI analysis, focusing on learning from prediction errors, with detailed computational modeling to probe task solving strategy including an ability to deploy an internal goal directed model of the task. Patients displayed reduced functional activation in the ventral striatum (VS) elicited by prediction errors. However, modeling task performance revealed that a subgroup did not adjust their behavior according to an accurate internal model of the task structure, and these were also the more severely psychotic patients. In patients who could adapt their behavior, as well as in controls, task solving was best described by cognitive strategies according to a Hidden Markov Model. When we compared patients and controls who acted according to this strategy, patients still displayed a significant reduction in VS activation elicited by informative errors that precede salient changes of behavior (reversals). Thus, our study shows that VS dysfunction in schizophrenia patients during reward-related reversal learning remains a core deficit even when controlling for task solving strategies. This result highlights VS dysfunction is tightly linked to a reward-related reversal learning deficit in early, unmedicated schizophrenia patients.
    NeuroImage 11/2013; 89(100). DOI:10.1016/j.neuroimage.2013.11.034 · 6.36 Impact Factor
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    ABSTRACT: This proof-of-concept study examines the feasibility of defining subgroups in psychiatric spectrum disorders by generative embedding, using dynamical system models which infer neuronal circuit mechanisms from neuroimaging data. To this end, we re-analysed an fMRI dataset of 41 patients diagnosed with schizophrenia and 42 healthy controls performing a numerical n-back working-memory task. In our generative-embedding approach, we used parameter estimates from a dynamic causal model (DCM) of a visual–parietal–prefrontal network to define a model-based feature space for the subsequent application of supervised and unsupervised learning techniques. First, using a linear support vector machine for classification, we were able to predict individual diagnostic labels significantly more accurately (78%) from DCM-based effective connectivity estimates than from functional connectivity between (62%) or local activity within the same regions (55%). Second, an unsupervised approach based on variational Bayesian Gaussian mixture modelling provided evidence for two clusters which mapped onto patients and controls with nearly the same accuracy (71%) as the supervised approach. Finally, when restricting the analysis only to the patients, Gaussian mixture modelling suggested the existence of three patient subgroups, each of which was characterised by a different architecture of the visual–parietal–prefrontal working-memory network. Critically, even though this analysis did not have access to information about the patients' clinical symptoms, the three neurophysiologically defined subgroups mapped onto three clinically distinct subgroups, distinguished by significant differences in negative symptom severity, as assessed on the Positive and Negative Syndrome Scale (PANSS). In summary, this study provides a concrete example of how psychiatric spectrum diseases may be split into subgroups that are defined in terms of neurophysiological mechanisms specified by a generative model of network dynamics such as DCM. The results corroborate our previous findings in stroke patients that generative embedding, compared to analyses of more conventional measures such as functional connectivity or regional activity, can significantly enhance both the interpretability and performance of computational approaches to clinical classification.
    11/2013; 4. DOI:10.1016/j.nicl.2013.11.002