Neurobiologische Korrelate der Belohnungs- und Suchtreizverarbeitung im Rahmen der Alkoholabhängigkeit und deren pharmakologische Modifikation mit Baclofen

Hintergrund: In der Erforschung alkoholbezogener psychischer Störungen konnte festgestellt werden, dass eine veränderte neurobiologische Verarbeitung des mesokortikolimbischen dopaminergen Systems, des sogenannten Belohnungssystems, vorliegt. In den letzten Jahren rückten vermehrt pharmakologische Behandlungsansätze der Alkoholabhängigkeit in den Fokus, mit überwiegend moderaten Effekten. Einen derzeit diskutierten Therapieansatz stellt die Off-Label Behandlung mit dem GABAB-Rezeptor Agonisten Baclofen zur Abstinenzerhaltung als auch zur Trinkmengenreduktion dar. Methodik: In dieser publikationsbasierten Dissertationsschrift wurden zunächst die pharmakologischen Effekte von individuell titriertem Hochdosis-Baclofen bezüglich der assoziierten Abstinenzraten bei alkoholabhängigen Patient*innen in einer klinischen Studie analysiert (Publikation 1). Diese Patient*innen wurden in Publikation 2 mittels sogenannten pharmako-fMRT-Ansatzes untersucht. Dieser Ansatz umfasst die Kombination aus der Behandlung mit Baclofen und der neurobiologischen Untersuchung mittels funktioneller Magnetresonanztomografie (fMRT) zu zwei Messzeitpunkten; vor und nach zweiwöchiger Behandlung mit Baclofen oder Placebo. Gegenstand von Publikation 2 war demnach die zusätzliche Aussage über die assoziierte neuronale Sucht-Reiz-Verarbeitung dieser Patient*innen mittels Cue-Reactivity Paradigma, welches die Reaktion auf alkoholbezogene Reize abbildet. Im Gegensatz dazu wurde in Publikation 3 die nicht-sucht-relatierte neuronale Belohnungsverarbeitung während der Belohnungsantizipation von Geldgewinnen im MRT bei gesunden Jugendlichen mit dem Slot Machine Paradigma untersucht, einem herkömmlich als „einarmigen Banditen“ bezeichneten Spielautomaten. Ergebnisse: Bei der Behandlung mit individuellem Hochdosis-Baclofen konnten signifikant höhere Abstinenzraten in der Baclofen- als in der Placebo-Gruppe berichtet werden (Publikation 1). Mittels Pharmako-fMRT-Ansatzes konnte eine Reduktion der neuronalen Aktivierung bei der Verarbeitung alkohol-relatierter Reize in der Baclofen- im Vergleich zur Placebo-Gruppe beobachtet werden (Publikation 2). Gesunde Jugendliche wiesen eine veränderte Belohnungsantizipation auf, wenn sie eine irrtümliche Kontrollüberzeugung, den Spielautomaten beeinflussen zu können („Illusion of Control; IOC“), innehatten (Publikation 3). Diskussion: Die genannten Studienergebnisse leisten einen wichtigen Beitrag in der Evaluierung der Behandlung mit Baclofen bei alkoholabhängigen Patient*innen und geben zudem Hinweise auf die zugrundeliegenden neurobiologischen Mechanismen, im Speziellen auf die Verarbeitung belohnungsanzeigender, alkohol-relatierter Reize. Bei gesunden Jugendlichen führte der Faktor einer irrtümlichen Kontrollüberzeugung („IOC“) zu einer veränderten Belohnungsverarbeitung und könnte eine mögliche Prädisposition für eine spätere Suchtentwicklung (z. B. Spielsucht) darstellen. Zusammenfassend trägt die publikationsbasierte Arbeit zum weiteren Verständnis der Alkoholabhängigkeit bei und gibt wichtige Hinweise auf die neurobiologische Funktionsweise eines vielversprechenden pharmakologischen Behandlungsansatzes mit Baclofen.Background: In the course of alcohol dependence, an altered neurobiological processing in the mesocorticolimbic dopaminergic system – the so-called reward system – has been shown. The current pharmacological treatment options for alcohol-dependent patients showed only modest effects. Newsworthy, baclofen a GABAB-receptor agonist has been investigated to prevent relapse behavior or to support alcohol reduction in alcohol-dependent patients. Methods: In this publication-based dissertation, the pharmacological effects of baclofen on abstinence rates in alcohol-dependent patients have been investigated in a clinical trial (publication 1). These patients were also enrolled with a so-called pharmaco-fMRI approach in publication 2. Pharmaco-fMRI is described as a combination of pharmacological treatment with baclofen or placebo and the neurobiological investigation using functional magnetic resonance imaging (fMRI) at baseline and after two weeks of individual titrated high-dose intake. During fMRI, a cue-reactivity paradigm comprising the presentation of alcohol- and non-alcohol-related stimuli, has been conducted twice. In publication 3, the processing of non-drug-related stimuli has been investigated via a slot machine paradigm with a focus on the anticipation phase of monetary gains. Results: Pharmacological treatment with individual high-dose baclofen revealed superiority over placebo in terms of abstinence rates (publication 1). Using pharmaco-fMRI, a reduced activation was observed during an alcohol-associated cue-reactivity paradigm in the baclofen compared to placebo group (study 2). FMRI investigation during non-drug-related gain anticipation revealed higher fronto-striatal activation in adolescents who misconceived an “illusion of control” (IOC group) compared to the noIOC group (adolescents who had no illusion of control). Discussion: The results significantly contribute to the evaluation of the treatment with individual high-dose baclofen in alcohol-dependent patients sustaining abstinence behavior. Furthermore, the associated neurobiological findings might indicate a rehabilitation effect. Illusion of control during neural gain anticipation might further predispose adolescents to a development of addiction-related problems like gambling disorders. In summary, the present publication-based dissertation contributes to the understanding of alcohol dependence and provides important new insights into the neurobiological mode of action during a new promising pharmacological treatment with baclofen

Attention shapes our expectations and perceptions: The neural mechanisms of top-down attention during adulthood and development

Top-down attention is the focusing of attention at one\u27s will through knowledge regarding a current task. There is evidence that top-down attention involves the modulation of sensory cortices by higher order regions. However, the mechanisms of top-down attention across sensory modalities, its influence on early sensory inputs, as well as interactions with motivational systems remain unclear. We performed the following set of electrophysiological experiments in typically developed adults and adolescents to examine these areas. 1) The supramodal attentional theory holds that parietally-based attentional mechanisms are shared across sensory modalities. We tested the supramodal theory by examining if lateralized parieto-occipital alpha-band activity, an established metric of top-down spatial attention, was observed in an audiospatial and visuospatial task. In support of the supramodal theory, we observed similar anticipatory alpha-band processes across auditory and visual tasks, but we also found an interaction of supramodal and sensory-specific attentional control processes. 2) There is evidence that top-down attention influences information immediately upon its arrival to sensory cortices, although there is debate in this area. In the current work, volitionally-driven top-down attention was engaged toward one of several overlapping surfaces in an illusion, in which the perceived brightness of the attended surface was enhanced. We observed the attentional enhancement of early visual evoked potentials, indicating that top-down attention shapes the earliest activations in visual cortices. 3) It is well known that motivation impacts attention, but the neural bases of these interactions remain unclear. We examined how level of interest in stimuli influenced top-down spatial attention mechanisms in typically-developing adolescents. Motivation enhanced established attentional processes during the anticipation of high vs. low interest stimuli, but also independently influenced frontal and parieto-occipital activations. These findings provide potential implications to inform clinical measures to improve impaired attentional processes in clinical populations (e.g. individuals with autism spectrum disorders). In sum, these studies revealed the powerful influence of top-down attentional control and its interacting systems on neural activations through several stages of anticipatory and post-stimulus processing during development and adulthood

Lateral prefrontal model-based signatures are reduced in healthy individuals with high trait impulsivity

High impulsivity is an important risk factor for addiction with evidence from endophenotype studies. In addiction, behavioral control is shifted toward the habitual end. Habitual control can be described by retrospective updating of reward expectations in ‘model-free’ temporal-difference algorithms. Goal- directed control relies on the prospective consideration of actions and their outcomes, which can be captured by forward-planning ‘model-based’ algorithms. So far, no studies have examined behavioral and neural signatures of model- free and model-based control in healthy high-impulsive individuals. Fifty healthy participants were drawn from the upper and lower ends of 452 individuals, completing the Barratt Impulsiveness Scale. All participants performed a sequential decision-making task during functional magnetic resonance imaging (fMRI) and underwent structural MRI. Behavioral and fMRI data were analyzed by means of computational algorithms reflecting model-free and model-based control. Both groups did not differ regarding the balance of model-free and model-based control, but high-impulsive individuals showed a subtle but significant accentuation of model-free control alone. Right lateral prefrontal model-based signatures were reduced in high-impulsive individuals. Effects of smoking, drinking, general cognition or gray matter density did not account for the findings. Irrespectively of impulsivity, gray matter density in the left dorsolateral prefrontal cortex was positively associated with model-based control. The present study supports the idea that high levels of impulsivity are accompanied by behavioral and neural signatures in favor of model-free behavioral control. Behavioral results in healthy high-impulsive individuals were qualitatively different to findings in patients with the same task. The predictive relevance of these results remains an important target for future longitudinal studies

Behavioural addiction-A rising tide?

The term 'addiction' was traditionally used in relation to centrally active substances, such as cocaine, alcohol, or nicotine. Addiction is not a unitary construct but rather incorporates a number of features, such as repetitive engagement in behaviours that are rewarding (at least initially), loss of control (spiralling engagement over time), persistence despite untoward functional consequences, and physical dependence (evidenced by withdrawal symptoms when intake of the substance diminishes). It has been suggested that certain psychiatric disorders characterized by maladaptive, repetitive behaviours share parallels with substance addiction and therefore represent 'behavioural addictions'. This perspective has influenced the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which now has a category 'Substance Related and Addictive Disorders', including gambling disorder. Could other disorders characterised by repetitive behaviours, besides gambling disorder, also be considered 'addictions'? Potential examples include kleptomania, compulsive sexual behaviour, 'Internet addiction', trichotillomania (hair pulling disorder), and skin-picking disorder. This paper seeks to define what is meant by 'behavioural addiction', and critically considers the evidence for and against this conceptualisation in respect of the above conditions, from perspectives of aetiology, phenomenology, co-morbidity, neurobiology, and treatment. Research in this area has important implications for future diagnostic classification systems, neurobiological models, and novel treatment directions.This research was supported by a Grant from the Academy of Medical Sciences (UK) to Dr Chamberlain. Dr Chamberlain consults for Cambridge Cognition. Dr Grant has received research Grants from the National Center for Responsible Gaming, and Forest and Roche Pharmaceuticals. Dr Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies and has received royalties from Oxford University Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill. Dr. Goudriaan was supported by an innovative scheme Grant of the Dutch Scientific Association (ZonMw VIDI Grant no. 016.136.354) and received support from the European Association for Alcohol Research, the National Center for Responsible Gaming and has consulted for TüV Germany. The other authors report no potential conflicts of interest or funding declarationsThis is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.08.01

Information about objective probability of a lottery and the illusion of control

This paper investigates the effect of explicitly informing participants about the objective probability of winning a lottery on the illusion of control. In a procedure based on Experiment 3 from Langer's 1975 seminal paper, participants were faced with lotteries based on familiar vs. unfamiliar stimuli and either explicitly informed about the objective probability of winning or not (the probability could be derived from other data). Results indicated that stating the objective probability of winning the lottery reduced, but not eliminated the illusion of control. Moreover, Langer's effect of stimulus familiarity was not replicated. Experiment 2, which included a lottery based on the full set of Polish alphabet letters, confirmed the same effects. Results indicate that illusion of control may be explained by the control heuristic (Thompson et al., 1998) - in absence of explicitly stated probability, participants estimate their chances of winning based on perceived control, even though calculating the objective probability is possible

Approach Motivation, Goal Pursuit, and Reward-Related Neural Responses: A Combined Experience-Sampling and fMRI Approach.

This thesis examines potential associations between trait approach motivation and related measures, the everyday experience of affect and goal pursuit, and reward-related neural responses. The Behavioural Activation System (BAS) is a core motivational system, subserved by the neural reward circuitry, eliciting approach-type behaviour and positive emotion when activated by appetitive stimuli. Deficits in BAS sensitivity are thought to underlie the lack of motivation and positive affect (PA) that characterise anhedonia, whilst hyperactivation of the BAS has been linked to the increased goal-directed behaviour and positive affectivity associated with hypomania. In order to explore relationships between BAS sensitivity, goal pursuit, and reward processing, young participants, recruited from the student population (N = 65), and older participants, from the community (N = 63), underwent a 7-day period of experience sampling (ESM) to provide a naturalistic measure of momentary affect and goal-focused motivation. Functional Magnetic Resonance Imaging (fMRI; in a subset of n = 28 and n = 31 respectively) was then used to investigate individual differences in sensitivity of brain reward-related systems to various social and non-social rewards. Limited support was found for the relationship between BAS traits and the more motivational aspects of goal pursuit and reward processing, whilst anhedonia seemed to pertain more to reward consumption, with few links to everyday goal pursuit. This would indicate that anhedonia might not be as closely related to BAS sensitivity as was initially anticipated. Finally, in order to examine real-world correlates of neural activation, the data from the naturalistic measure were correlated with reward-related activation. Everyday PA correlated with striatal activation when viewing pleasant images, but no other associations emerged. This would suggest that the basic measures of brain function in relation to the particular reward-related stimuli used might be of limited relevance to everyday affective experience and goal pursuit.University of Exete

Interoception in anxiety and depression

We review the literature on interoception as it relates to depression and anxiety, with a focus on belief, and alliesthesia. The connection between increased but noisy afferent interoceptive input, self-referential and belief-based states, and top-down modulation of poorly predictive signals is integrated into a neuroanatomical and processing model for depression and anxiety. The advantage of this conceptualization is the ability to specifically examine the interface between basic interoception, self-referential belief-based states, and enhanced top-down modulation to attenuate poor predictability. We conclude that depression and anxiety are not simply interoceptive disorders but are altered interoceptive states as a consequence of noisily amplified self-referential interoceptive predictive belief states

Using Psycho-physiological Interaction Analysis with fMRI Data in IS Research: A Guideline

The integration of neuroscientific methods in Information Systems (IS) research to better understand how the brain interacts with IS-relevant context has gained in importance. Many papers that highlight the potential of neuroIS and that discuss methodological issues associated with using functional brain imaging already exist. However, neuroIS researchers have to keep in mind that the emergence of complex mental processes such as trust in IS contexts is based on activity in a network of brain regions rather than on activity in one area alone. Accordingly, we introduce psycho-physiological interaction (PPI) analysis, a technique that one can use to analyze fMRI data. Specifically, we review how one can conduct PPI analysis, provide a concrete research example, and show how this analysis can inform IS trust research. Thus, we introduce neuroIS researchers working in the domain of functional brain imaging to advanced fMRI analyses methods and show, based on the example of trust, how these methods can enhance our understanding of the nature of IS constructs