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Global cerebral ischemia (GCI) in rats has been shown to promote exploration of anxiogenic zones of the Elevated-Plus Maze (EPM) and Open Field Test (OFT). This study investigated changes in impulsive choice and/or defensive responses as possible contributors of heightened anxiogenic exploration observed after ischemia. Impulsivity was assessed using delay discounting (DD) paradigms, while the Predator Odour Test (PO) served to assess changes in defensive responses towards a naturally aversive stimulus. Male Long Evans rats underwent 9 days of autoshaping training and 24 days of DD training prior to GCI or sham surgery (n= 9/group). Post-surgery, rats completed the OFT, EPM, and PO, followed by 6 days of DD sessions. Blood droplets served to evaluate corticosterone secretion associated with PO exposure. With impulsivity being regulated through mesocorticolimbic monoaminergic pathways, we also characterized post-ischemic changes in the expression of dopamine D2 receptors (DRD2), dopamine transporters (DAT), and ΔFosB in the basolateral amygdala (BLA), nucleus accumbens core (NAcC) and shell (NAcS), and ventromedial prefrontal cortex (vmPFC) using immunohistofluorescence. Our findings revealed no impact of GCI on delay discounting rates, while PO approach behaviours were minimally affected. Nonetheless, GCI significantly reduced DRD2 and ΔFosB-ir in the NAcS and NAcC, respectively, while DAT-ir was diminished in both NAc subregions. Collectively, our findings refine the understanding of cognitive-behavioural and biochemical responses following stroke or cardiac arrest. They support significant alterations to the dopaminergic mesocorticolimbic pathway after ischemia, which are not associated with altered impulsive choice in a DD task but may influence locomotor exploration of the OFT and EPM.

Prior research suggests that adolescents are drawn to the temptations of immediate rewards to a greater degree than adults, particularly when making decisions in the company of their peers. Dual-systems models of adolescent decision making posit that this immediate reward bias derives from a developmentally normative imbalance in the neural dynamics characterizing the adolescent brain. At a time when the brain's "top-down" cognitive control system is still developing the processing efficiency and functional integration thought to support mature self-regulation in adulthood, changes in "bottom-up" dopaminergic functioning imbue adolescents with heightened sensitivity to environmentally salient rewards. The resulting bias toward under-controlled, reward-driven behavior may be further accentuated by the presence of peers, who are hypothesized to prime incentive processing circuitry to respond to opportunities for immediate rewards. The present study utilized functional magnetic resonance imaging (fMRI) to examine age- and context-related differences between adolescents and adults in neural activity and choice behavior corresponding to the comparative evaluation of sooner-smaller and larger-later rewards in an intertemporal choice task. Half of the participants were scanned in a standard "alone" condition, and half were scanned in a "peer" condition, wherein two same-sex, same-age peers informed the participant that they would be observing task performance from the scanner control room. Although behavioral results did not support the hypothesis that peer presence would accentuate adolescents' bias toward immediate rewards, they confirm that, even when making decisions alone, adolescents are more inclined than adults to sacrifice the added value of a larger future reward in order to receive a smaller reward immediately. Furthermore, fMRI results demonstrate at least three important differences between adolescents and adults in neural activity corresponding to the comparative evaluation of rewards. First, adolescents evince stronger activation than adults in regions implicated in incentive processing (including bilateral caudate), consistent with a bias toward reward-driven behavior. Second, adolescents show stronger functional connectivity between a region in the orbitofrontal cortex (OFC) whose activity is correlated with impulsive choice and a region in the ventromedial prefrontal cortex (vmPFC) shown by prior research to represent the value of decision options. This stronger OFC-vmPFC connectivity among adolescents is consistent with greater affective (OFC) influence on choice valuation and behavior (vmPFC). Finally, adolescents show stronger deactivation of regions implicated in cognitive control (including anterior cingulate and dorsolateral prefrontal cortex) when evaluating rewards with relatively longer delays, consistent with a failure to carefully consider the value of future rewards. Together, results suggest that neurodevelopmental theories of adolescent decision making would be improved by more explicit modeling of age differences in the neural processes underlying evaluation of the temporal properties of rewards. / Psychology

Every day to we make decisions that require us to reconcile our desire to be satisfied immediately with our desire to improve upon our current situation, which often requires waiting. People tend to devalue future rewards as a function of the time they must wait receive them, a phenomenon known as a delay discounting. Nearly all species exhibit delay discounting, yet there is a striking level of inter-individual variability in discounting severity. In humans, discounting rate predicts a wide array of outcomes such as academic achievement, drug addiction, salary, and obesity. Such correlational relationships have led some to argue that discounting is a stable trait. Contrary to this perspective, several studies have shown that discounting rates may gradually decrease with age. There is also evidence that contextual factors can more immediately alter an individual's discounting rate. One such factor is how information is presented, or "framed". The way in which options are framed-even if they are logically equivalent-can influence choice. Framing a choice as a loss often leads to avoidance that option, i.e. to loss aversion. Delay discounting and susceptibility to loss framing have thus far only been studied in isolation, yet in day to day life we regularly must consider both temporal and loss information, particularly as we become older. This study seeks to the bridge delay discounting, framing, and normative aging literatures to examine (1) whether reframing choices can reduce delay discounting; (2) what factors drive individual differences in discounting and framing susceptibility; (3) to what extent these phenomena interact with age; and (4) a potential application of these findings in the context of Social Security claiming. / Psychology

Maltreatment is a pervasive global problem known to have cascading consequences that persist long after exposure subsides (Masten and Cicchetti, 2010). Maltreatment is often co-occurring, involving exposure to multiple types. Cumulative maltreatment, or exposure to multiple types of neglect and abuse, is proposed to be of critical importance for developmental psychopathology. However, a cumulative approach to studying maltreatment provides little insight into the developmental processes whereby it exerts its effects on health. Thus, we employed both a cumulative approach and a multidimensional approach to facilitate our comprehensive understanding of maltreatment experiences related to behavioral development. Given the high prevalence of maltreatment, it is important to cultivate a greater understanding of the processes linking maltreatment and health and to identify developmental periods of vulnerability to its deleterious effects. The present study uses a longitudinal design and a multidimensional approach to examine the effects of maltreatment on delay discounting and health-promoting and health-demoting behaviors during adolescence and across the transition from adolescence to young adulthood. The study sample includes 167 adolescents (aged 13–14 at Time 1; 53% male) who participated across 5 time points over 6 years. At Time 5, adolescents provided retrospective reports of their exposure to maltreatment during adolescence across ages 13–18. Delay discounting, substance use, and body mass index (BMI) were assessed at each time point. We used a developmental cascade model with autoregressive, cross-lagged, and cross-sectional associations to examine the longitudinal multivariate change processes and indirect effects from maltreatment exposure during adolescence to delay discounting and health-promoting and health-demoting behaviors during adolescence and across the transition to young adulthood. Our results indicate that cumulative maltreatment affects health-demoting behavior via its effects on delay discounting and that maltreatment of omission but not commission drives this effect. Furthermore, the findings identify adolescents exposed to maltreatment of omission as being especially vulnerable to marijuana use via elevated delay discounting. Identifying mediating processes linking maltreatment exposure to health-promoting and health-demoting behaviors may be instrumental for preventing deleterious developmental cascades and interrupting related health problems during adolescence and across the transition from adolescence to young adulthood. / Doctor of Philosophy / Maltreatment is a pervasive global problem that casts a long shadow, often involving exposure to multiple types of abuse or neglect. Cumulative maltreatment involves exposure to different types of neglect and abuse and is especially problematic for adjustment and health. However, a cumulative approach to studying maltreatment provides little insight into the developmental processes whereby it exerts its effects on health. We took a cumulative approach and a multidimensional approach to improve our understanding of how maltreatment experiences relate to health in adolescence and young adulthood. Given the high prevalence of maltreatment, it is important to understand how maltreatment and health are related and to identify developmental periods of vulnerability to maltreatment. The present study includes 167 adolescents (aged 13–14 at the study outset; 53% male) who participated across 6 years. At ages 17–18, adolescents provided reports of their exposure to maltreatment during adolescence (across ages 13–18). Delay discounting, substance use, and body mass index (BMI) were gathered at each assessment. We examined the cascading effects of cumulative maltreatment, abuse, and neglect on delay discounting and health behaviors over time. Our results indicate that cumulative maltreatment affects health-demoting behavior via delay discounting and that maltreatment of omission but not commission drives this effect. Furthermore, the findings identify adolescents exposed to maltreatment of omission as being especially vulnerable to marijuana use via elevated delay discounting. These findings may inform prevention and intervention efforts aimed at mitigating risks for adolescents exposed to neglect during adolescence and across the transition from adolescence to young adulthood.

Alcohol use disorder (AUD) remains a major public health concern globally with substantially increased mortality and a significant economic burden. The low rates of treatment and the high rates of relapse mean that excessive alcohol consumption detrimentally affects many aspects of the user's life and the lives of those around them. One reason for the low efficacy of treatments for AUD could be an unclear understanding of the neural correlates of the disease. As such, the studies in this dissertation aim at elucidating the neural mechanisms undergirding AUD, which could lead to more efficacious treatment and rehabilitation strategies. The propensity for impulsive decision making (choosing smaller, sooner rewards over larger, later ones) also known as delay discounting (DD), is an established risk-factor for a variety of substance abuse disorders, including AUD. Brain mapping of DD routinely uses modalities such as blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI). However, the extent to which these brain activation maps reflect the characteristics of impulsive behavior has not been directly studied. To examine this, we used multi-voxel pattern analysis (MVPA) methods such as multivariate classification using Support Vector Machine (SVM) algorithms and trained accurate classifiers of high vs. low impulsivity with individual fMRI brain maps. Our results demonstrate that brain regions in the prefrontal cortex encode neuroeconomic decision making characterizing DD behavior and help classify individuals with low impulsivity from individuals with high impulsivity. Individuals suffering from addictive afflictions such as AUD are often unable to plan for the future and are trapped in a narrow temporal window, resulting in short-term, impulsive decision making. Episodic future thinking (EFT) or the ability to project oneself into the future and pre-experience an event, is a rapidly growing area of addiction research and individuals suffering from addictive disorders are often poor at it. However, it has been shown across healthy individuals and disease populations (addiction, obesity) that practicing EFT reduces impulsive decision making. We provided real-time fMRI neurofeedback to alcohol users while they performed EFT inside the MR scanner to aid them in successfully modulating their thoughts between the present and the future. After the scanning session, participants made more restrained choices when performing a behavioral task outside the scanner, demonstrating an improvement in impulsivity. These two neuroimaging studies interrogate the brain mechanisms of delay discounting and episodic future thinking in alcohol use disorder. Successful classification of impulsive behavior as demonstrated in the first study could lead to accurate prediction of treatment outcomes in AUD. The second study suggests that rtfMRI provides direct access to brain mechanisms regulating EFT and highlights its potential as an intervention for impulsivity in the context of AUD. The work in this dissertation thus investigates important cognitive process for the treatment of alcohol use disorder that could pave the way for novel therapeutic interventions not only for AUD, but also for a wide spectrum of other addictive disorders. / Doctor of Philosophy / Alcohol use disorder (AUD) remains a major public health concern globally with substantially increased mortality and a significant economic burden. The low rates of treatment and the high rates of relapse mean that excessive alcohol consumption detrimentally affects many aspects of the user’s life and the lives of those around them. One reason for the low efficacy of treatments for AUD could be an unclear understanding of the brain regions affected by it. As such, the studies in this dissertation aim at elucidating the neural mechanisms undergirding AUD, which could lead to more efficacious treatment and rehabilitation strategies. The propensity for impulsive decision making (choosing smaller, sooner rewards over larger, later ones) also known as delay discounting (DD), is an established risk-factor for a variety of substance abuse disorders, including AUD. Brain mapping of DD routinely uses modalities such as blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI). However, the extent to which these brain activation maps reflect the characteristics of impulsive behavior has not been directly studied. To examine this, we searched for highly reproducible spatial patterns of brain activation that differ across experimental conditions (multi-voxel pattern analysis) and trained accurate classifiers of high vs. low impulsivity with individual fMRI brain maps. Our results demonstrate that brain regions in the prefrontal cortex encode neuroeconomic decision making and help classify individuals with low impulsivity from individuals with high impulsivity. Individuals suffering from addictive afflictions such as AUD are often unable to plan for the future and are trapped in a narrow temporal window, resulting in short-term, impulsive decision making. Episodic future thinking (EFT) or the ability to project oneself into the future and pre-experience an event, is a rapidly growing area of addiction research. However, it has been shown across healthy individuals and disease populations (addiction, obesity) that practicing EFT reduces impulsive decision making. We provided v real-time fMRI neurofeedback to alcohol users while they performed EFT inside the MR scanner to aid them in successfully modulating their thoughts between the present and the future. After the scanning session, participants made more restrained choices when performing a behavioral task outside the scanner, demonstrating an improvement in impulsivity. These two neuroimaging studies interrogate the brain mechanisms of delay discounting and episodic future thinking in alcohol use disorder. Successful classification of impulsive behavior as demonstrated in the first study could lead to accurate prediction of treatment outcomes in AUD. The second study suggests that rtfMRI provides direct access to brain mechanisms regulating EFT and highlights its potential as an intervention for impulsivity in the context of AUD. The work in this dissertation thus investigates important cognitive process for the treatment of alcohol use disorder that could pave the way for novel therapeutic interventions not only for AUD, but also for a wide spectrum of other addictive disorders.

People make food choices based upon the motivation to consume foods that are reinforcing compared to alternatives that may be available.1 Delay discounting (DD) is a measure used to assess impulsivity, quantifying how people make decisions based on time to receive and amount of the choice presented. The food purchase task (FPT) assesses the demand for a food and how reinforcing this item is at various prices. Using a controlled feeding study design, 10 males (n=7 sedentary, n=10 endurance trained) consumed an iso-caloric, standard diet (55% carbohydrate, 30% fat, and 15% protein) for 10 days, followed by a high-fat diet (55% fat, 30% carbohydrate, 15% protein) for 5 days. DD, FPT, and Three Factor Eating Questionnaire (TFEQ) were assessed at three time points: baseline, after the standard diet/before high-fat diet, and after the high-fat diet. Discounting rates were significantly different at baseline between sedentary and endurance trained males, with the sedentary males having higher discounting rates (mean difference 1.43, p=.037). Discounting rates for the whole sample significantly decreased between baseline (time 1) and post-STD diet/before HFD (time 2), between time 2 and after the HFD (time 3), and between time 1 and time 3 (all indicated by p<0.05). No group differences were noted over time for demand elasticity, intensity, or TFEQ measures (all indicated by p<0.05). Results could be used to advance the understanding of factors that influence impulsive and unhealthy eating behaviors and inform the development of interventions that use reinforcers to positively influence eating behaviors. / MS

Background: According to the Centers for Disease Control and Prevention (CDC), over one-third of US adults are obese. In order to assess causes of and treatments for obesity, researchers have evaluated a number of processes underlying health-related behaviors, one of which is delay discounting. Delay discounting is a cognitive process that describes the phenomenon by which individuals discount the value of a future reward compared to the value of an immediate reward. Researchers have associated delay discounting with drug addiction, alcoholism, and cigarette smoking. More recently, delay discounting has been studied with regards to health-related behaviors, such as body weight management, food intake, glucose control, and physical activity. While a number of studies have concluded that obese individuals tend to be greater discounters, the relationship between delay discounting and various health-related behaviors beyond smoking and drug use remains unclear. The purpose of this study is to evaluate the relationship between delay discounting and diet quality, glucose tolerance, physical activity, and fasting vs. non-fasting conditions. Methods: Sixty-five males (n=20) and females (n=45) were recruited for the present study. Participants completed two lab sessions: one under non-fasting conditions, and one under fasting conditions which involved measurements of body mass and composition, blood pressure, blood glucose, blood lipids, and health-related questionnaires. Delay discounting and food purchase tasks were completed at both visits. Participants were asked to complete a four-day food intake record and wear a physical activity monitor for four days. Results: Lower rates of discounting were found in those who consumed more total vegetables, and lower food reinforcement was observed in those who spent less time sedentary and more time physically active, had greater dietary Restraint, and had a lower resting heart rate. There were no significant differences between discounting rates and food reinforcement across fasting and non-fasting conditions. / Master of Science

Yes / Gambling research often refers to attitude and belief measurements to distinguish between problem and non-problem gamblers. Past studies also indicated that problem gamblers have a tendency to steeply discount rewards. We join both research streams and investigate the relationships between attitudes and beliefs on gambling addiction with the moderating effects of delay discounting using a novel methodological approach of double-hurdle model. We hereby differentiate the five subdimensions of the Gambling Attitude and Belief Scale (GABS): emotions, chasing, luck, attitudes and strategies. Findings show that emotional predispositions and chasing tendencies are positively related to the severity of online gambling addiction, independent of gamblers´ impulsivity. In contrast hereto, gambling attitudes act as inhibitor for gamblers willing to wait for some time to receive higher reward. Findings show that money-related impulsiveness influences the relationship between sub-dimensions of GABS and gambling addiction: Gambling attitudes and beliefs do not necessarily harm online gamblers but that their positive or negative relationship to addiction depends on online gamblers’ impulsivity.

Delay Discounting im Sinne eines Abwertens zukünftiger Belohnungen ist ein weit verbreitetes Phänomen. Es zeigt sich z. B. in persönlichen Angelegenheiten, wie der Entscheidung für den kurzfristigen Genuss von Süßigkeiten und gegen die langfristigen, durchaus größeren Vorteile einer schlanken Figur. Auch internationale wirtschaftliche und politische Diskussionen zum Klimaschutz oder der Finanzkrise werden von der Präferenz für sofortige, kleinere Belohnungen über verzögerte, größere Belohnungen getrieben. In der Psychologie wird Delay Discounting als Maß für Impulsivität bzw. Selbstkontrolle mit dem Auftreten von Aufmerksamkeitsdefizit-Hyperaktivitäts-Syndromen und von Abhängigkeitserkrankungen in Verbindung gebracht. Bezüglich der neuronalen Grundlagen von Delay Discouting ist mithilfe von sogenannten Intertemporal Choice Tasks bereits herausgefunden worden, dass die Entscheidung für eine sofortige Belohnung stärkere neuronale Aktivierung in belohnungsspezifischen Gehirnregionen evoziert als die Entscheidung für eine verzögerte Belohnung. Außerdem wurden sowohl theoretisch wie auch empirisch ein impulsives und ein reflektives System als Grundlage des Delay Discounting beschrieben, deren Existenz jedoch von manchen Wissenschaftlern angezweifelt wird. Ebenso wird angezweifelt, ob Delay Discounting unabhängig vom Einsatz von Intertemporal Choice Tasks und der damit verbundenen Entscheidung zwischen zwei Alternativen überhaupt besteht. Da die neuronalen Grundlagen des Delay Discounting und des impulsiven und reflektiven Systems bisher nicht unabhängig von einer Entscheidungsaufgabe erfasst wurden, konnten diese Zweifel nicht ausgeräumt werden. Ebenso ist zurzeit unbekannt, ob sich die neuronalen Korrelate des Delay Discounting bei Personen mit unterschiedlichen Persönlichkeitseigenschaften, bei Männern und Frauen, bei Rauchern und Nichtrauchern und in Abhängigkeit von verschiedenen Genvarianten unterscheiden. Um diese Lücke zu schließen, ist im Rahmen der vorliegenden Arbeit ein neuartiges Delay Discounting Paradigma zum Einsatz im Magnetresonanztomographen entwickelt worden. Dieses Paradigma ähnelt einem Monetary Incentive Delay Task und ermöglicht es, neuronale Aktivierung bei der Antizipation und bei dem Erhalt einer einzelnen Belohnung zu einem Zeitpunkt zu erfassen. Außerdem kann nach der Antizipation einer Belohnung, die sich durch eine bestimmte Höhe (0,05 €, 0,50 €, 1,00 €) und eine bestimmte Auszahlungsverzögerung (0 Tage, 10 Tage, 100 Tage) auszeichnet, in einer einfachen visuellen Diskriminationsaufgabe eine Reaktionszeit erfasst werden, die als behaviorales Maß für die inzentive Motivation fungiert. Zusammen mit einer Erfassung verschiedener Persönlichkeitseigenschaften und einer Genotypisierung für den COMT Val 158 Met Polymorphismus, den DRD2 Taq 1 A Polymorphismus und den DAT 1 Polymorphismus ist das Delay Discounting Paradigma an insgesamt 90 Probanden im Magnetresonanztomographen eingesetzt worden, so dass 84 auswertbare Datensätze gewonnen werden konnten. Diese 84 Datensätze stammten insgesamt von 42 Frauen und 42 Männern bzw. von 43 strikten Nichtrauchern, 38 starken Rauchern und drei Gelegenheitsrauchern. Anhand der Auswertung der Gesamtstichprobe konnte bestätigt werden, dass das Delay Discounting Paradigma belohnungs- und verzögerungsspezifisch unterschiedliche Reaktionszeiten und unterschiedliche neuronale Aktivierung hervorruft. In belohnungsverarbeitenden Gehirnregionen wie dem ventralen Striatum zeigte sich sowohl stärkere Aktivierung für größere Belohnungen als auch für Belohnungen, die früher ausgezahlt wurden. Damit steht fest, dass Delay Discounting unabhängig von der Entscheidung zwischen zwei Alternativen auftritt. Außerdem konnte erstmalig ein Interaktionseffekt zwischen Belohnungshöhe und Belohnungsverzögerung aufgedeckt werden: Es zeigte sich eine Abnahme der Differenzen in der neuronalen Aktivierung zwischen größter und kleinster Belohnung über die Zeit, was auf eine Indifferenz gegenüber der Höhe verzögerter Belohnung hindeutet. Ein Einfluss der Belohnungsverzögerung wurde allerdings nur beim Erhalt von Belohnungen messbar, bei der Antizipation von Belohnungen zeigte sich kein Delay Discounting Effekt. Bezüglich der Kontroverse zur Existenz eines impulsiven und reflektiven Systems konnten Ergebnisse gewonnen werden, die beide Positionen integrieren. So wurde zwar die Beteiligung von zwei distinkten neuronalen Systemen beim Abwerten zukünftiger Belohnungen bestätigt, allerdings zeigte sich auch, dass beide Systeme – in einem unterschiedlichen Ausmaß – verzögerte Belohnungen abwerten. Trotzdem wird von den vorliegenden Ergebnissen die Annahme, dass sich aus der Interaktion von impulsivem und reflektivem System impulsives und selbstkontrolliertes Verhalten ergeben kann, gestützt. Im Hinblick auf die interindividuellen Unterschiede, die in der vorliegenden Arbeit aufgedeckt werden sollten, haben sich vor allem Zusammenhänge zwischen dem subjektiv berichteten allgemeinen Stress der Versuchspersonen (operationalisiert über das Selbststeuerungsinventar) und der neuronalen Aktivität von Gehirnregionen, die dem impulsiven und reflektiven System zugeordnet werden, gezeigt. So ist bei niedrigem Stress das impulsive System signifikant weniger aktiviert als das reflektive System, während sich bei hohem Stress dieser Zusammenhang umkehrt. Die relative Hyperaktivierung des impulsiven Systems bei Stress könnte erklären, warum unter Stress vermehrt Rückfälle bei abhängigkeitserkrankten Probanden beobachtet werden. Außerdem ging starkes neuronales Delay Discounting in medial präfrontalen Gehirnregionen mit hohem Stress, ebenso wie mit hoher nichtplanender Impulsivität (gemessen anhand der Barratt Impulsivitätsskala) und mit geringer Selbstkontrolle (gemäß des Selbststeuerungsinventars) einher. Dieses Ergebnis belegt unter anderem, dass das neu entwickelte Delay Discounting Paradigma neuronale Prozesse abbildet, die mit Impulsivität und Selbstkontrolle in Verbindung stehen. Darüber hinaus konnte kongruent mit entsprechenden Vorbefunden ein Einfluss des COMT Val 158 Met Polymorphismus auf das neuronale Delay Discounting im ventralen Striatum und erstmalig ein Zusammenhang zwischen dem DRD2 Taq 1 A A1-Allel und neuronalem Delay Discounting im posterioren Cingulum aufgedeckt werden. Damit ist die Bedeutung des Neurotransmitters Dopamin, der durch die untersuchten Polymorphismen beeinflusst wird, für die neuronalen Grundlagen des Delay Discounting bestätigt worden. Zusammengenommen deuten sowohl die beschriebenen Befunde als auch die sonstigen Ergebnisse der Arbeit darauf hin, dass sich neuronales Delay Discounting interindividuell unterscheidet. Im Hinblick auf Pathologien, die mit diesem Phänomen in Verbindung stehen, sollte daher weitere Forschung zu interindividuellen Unterschieden und zu spezifischen Behandlungsmethoden erfolgen.