Hintergrund: Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) umfasst die klinischen Symptome Hyperaktivität, Impulsivität und Unaufmerksamkeit und besitzt eine große erbliche Komponente. Veränderungen des Dopaminstoffwechsels und des präfrontalen Kortex scheinen mit der Erkrankung assoziiert zu sein. Bekannt sind auch Defizite in exekutiven Funktionen wie Arbeitsgedächtnis und Antworthemmung, welche gemeinsam als ein Endophänotyp der ADHS betrachtet werden. Solche sogenannten intermediären Phänotypen bilden möglicherweise ätiopathogenetisch sinnvollere Untergruppen von Krankheitsbildern als die Unterteilung nach den klassischen Diagnosesystemen. Zahlreiche Untersuchungen zu Arbeitsgedächtnis und Antworthemmung bei ADHS finden Mittelwertsunterschiede im Vergleich zu gesunden Stichproben in behavioralen und hirnphysiologischen Maßen. Ein genetischer Polymorphismus (Val158Met) mit Einfluss auf die Synthese der Catechol-O-Methyltransferase (COMT) moduliert Arbeitsgedächtnis und Antworthemmung bei Gesunden und Patienten mit ADHS. COMT ist ein Enzym, das den Abbau von präfrontalem Dopamin katalysiert. Das Valin(Val)-Allel ist mit einer geringeren, das Methionin(Met)-Allel mit einer höheren Verfügbarkeit von Dopamin in kortikalen Arealen assoziiert. Letzteres scheint die Funktion präfrontaler Hirnareale zu optimieren. Ziel: Es ist unklar, ob die beiden Prozesse Arbeitsgedächtnis und Antworthemmung miteinander in Verbindung stehen, also einen gemeinsamen Endophänotypen bezeichnen, und ob ein möglicher Zusammenhang dieser beiden Funktionen durch Dopamin moduliert wird. Gegenstand der vorliegenden Arbeit ist, (1) die bekannten Mittelwertsunterschiede zwischen Patienten mit ADHS und gesunden Kontrollpersonen zu replizieren, (2) den Zusammenhang von Arbeitsgedächtnis und Antworthemmung mit Korrelationsanalysen zu überprüfen, (3) den Einfluss des COMT-Polymorphismus auf Arbeitsgedächtnis und Antworthemmung zu untersuchen und (4) festzustellen, ob der COMT-Polymorphismus die Stärke der Korrelationen beeinflusst. Die Fragestellungen 3 und 4 sind aufgrund der kleinen Stichproben als explorativ zu bewerten. Methoden: In die Auswertung aufgenommen wurden 45 erwachsene Patienten mit ADHS und 41 nach Alter, Geschlecht, Händigkeit, Intelligenz, Bildungsniveau und Kopfumfang vergleichbare Kontrollen. Arbeitsgedächtnis und Antworthemmung wurden durch eine N-Back- bzw. eine Stoppsignal-Aufgabe operationalisiert. Als abhängige Variablen dienten als behaviorale Maße die Anzahl richtiger Antworten, Reaktionszeiten und Effizienz und als hirnphysiologische Parameter Konzentrationsveränderungen von oxygeniertem (O2Hb) und deoxygeniertem Hämoglobin (HHb) in präfrontalen Arealen, die mittels funktioneller Nah-Infrarot Spektroskopie gemessen wurden. Korrelationen wurden zwischen den Kontrollbedingungen (1-Back und Go-Trials) und zwischen den eigentlichen Bedingungen der Arbeitsgedächtnis- und Stoppsignal-Aufgabe (2-Back und Stopperfolge) berechnet. Ergebnisse: Kontrollen und Patienten zeigten hirnphysiologisch aufgabentypische signifikante Aktivierungsmuster, für das Arbeitsgedächtnis mehr ausgeprägt über dem dorso-lateralen präfrontalen Kortex (DLPFC), für die Antworthemmung mehr über dem inferioren frontalen Kortex (IFC). Fragestellung 1: Patienten zeigten im Vergleich zu den gesunden Kontrollpersonen signifikante Defizite in allen erhobenen behavioralen Maßen. Sie zeigten auch signifikant reduzierte Anstiege von O2Hb über dem linken und rechten IFC für Stopperfolge und eine statistisch tendenziell verringerte O2Hb-Konzentration im linken DLPFC für die 2-Back-Bedingung. Es fanden sich jedoch auch Defizite in den einfachen Kontrollaufgaben (behaviorale Maße und O2Hb während 1-Back). Nach einer Anpassung der Gruppen für die Unterschiede in den Kontrollaufgaben blieben die Gruppenunterschiede in den Aufgaben für Arbeitsgedächtnis und Antworthemmung bestehen. Fragestellung 2: Nur bei den Patienten und nur für die behavioralen Maße zeigten sich signifikante positive Assoziationen. Die Effizienz während 1-Back korrelierte mit der Reaktionszeit während der Go-Trials, und die Effizienz während 2-Back korrelierte mit der Stoppsignal-Reaktionszeit. Diese beiden Korrelationen unterschieden sich statistisch nicht in ihrer Stärke. In den für die Unterschiede in den Kontrollaufgaben angepassten Gruppen blieb nur die Korrelation der Kontrollaufgaben tendenziell signifikant, die Korrelation von Effizienz während 2-Back und Stoppsignal-Reaktionszeit verschwand. Die Patienten zeigten erhöhte Impulsivität (erhoben mit einem Fragebogen), die positiv mit behavioralen Maßen der beiden untersuchten Prozesse korrelierte. Fragestellung 3: Für 1-Back (O2Hb in rechter Hemisphäre) und 2-Back (O2Hb in linker Hemisphäre) wurden statistisch tendenzielle COMT x Gruppe Interaktionen gefunden. Für 1-Back zeigten die Kontrollen mit dem Val/Val-Genoytp sowohl im Vergleich zu Kontrollen mit dem Met/Met-Genotyp als auch im Vergleich zu Patienten mit zwei Val-Allelen eine signifikant höhere O2Hb-Konzentration. Gleichzeitig wies die Analyse der Verhaltensdaten auf eine höhere Effizienz der Kontrollen mit Met-Allelen im Vergleich zu Patienten mit Met-Allelen hin. Für 2-Back zeigte der Val/Val-Genotyp der Kontrollen eine höhere O2Hb-Konzentration als der Val/Val-Genotyp der Patienten. Zusätzlich wies der Met/Met-Genotyp in der ADHS-Gruppe einen stärkeren Anstieg von O2Hb im Vergleich zu dem Val/Val-Genotyp in der ADHS-Gruppe auf. Die Analyse der Verhaltensdaten zeigte eine höhere Effizienz der Kontrollen im Vergleich zu den Patienten für die Gruppen mit einem oder zwei Val-Allelen. Für Stopperfolge zeigten sich signifikante COMT x Gruppe Interaktionen für O2Hb in beiden Hemisphären. Die Kontrollen mit Val/Met-Genotyp hatten höhere O2Hb-Konzentrationen als Kontrollen mit Val/Val- oder Met/Met-Genotyp und als Patienten mit Val/Met-Genotyp. Patienten mit Val/Met-Genotyp hatten langsamere Stoppsignal-Reaktionszeiten im Vergleich zu den Kontrollen mit Val/Met-Genotyp. Fragestellung 4: Die Korrelationen in Abhängigkeit der Stichproben und COMT-Gruppen zeigten unterschiedlich hohe und unterschiedlich gerichtete Korrelationskoeffizienten. Nur in der Gruppe der Patienten und nur für die Verhaltensdaten wurden positive Assoziationen für alle COMT-Gruppen gefunden, vergleichbar mit den Ergebnissen aus Fragestellung 2. Diskussion: Die behavioralen und hirnphysiologischen Unterschiede in den Aufgaben zum Arbeitsgedächtnis und zur Antworthemmung zwischen Patienten mit ADHS und Kontrollen replizieren gut die Ergebnisse früherer Arbeiten. Ausgehend von den Gruppenunterschieden in den einfachen Kontrollaufgaben muss aber überlegt werden, inwieweit Patienten mit ADHS auch in einfachen psychomotorischen Aufgaben bereits Defizite zeigen. Die Korrelation behavioraler Maße der eigentlichen Arbeitsgedächtnis- und Inhibitionsaufgabe in der Gruppe der Patienten, die allerdings die Assoziation der Kontrollaufgaben nicht überschritt, und die mit dem Anpassen für Unterschiede in den Kontrollenaufgaben verschwand, lässt Zweifel an dem spezifischen Zusammenhang der beiden Prozesse bei ADHS aufkommen. Zudem werfen die positiven Assoziationen dieser Prozesse (behaviorale Maße) mit der Impulsivität (Fragebogen) die Frage auf, ob es sich um die Operationalisierung des gleichen Konstrukts handelt bzw. ob Impulsivität in Form behavioraler Tests das Gleiche misst wie Impulsivität auf symptomatischer Ebene. Ein Faktor, der möglicherweise Einfluss auf die Korrelationen zwischen den Aufgaben hat, könnte der Dopamingehalt sein, wie er in der vorliegenden Arbeit durch den COMT Polymorphismus operationalisiert wurde. Die Ergebnisse der COMT x Gruppe Interaktionen zeigten eine erhöhte O2Hb-Konzentration der Val-Allelträger der Kontrollen für die N-Back-Aufgaben bei teilweise besserer Effizienz und eine erhöhte O2Hb-Konzentration und teilweise schnellere Stoppsignal-Reaktionszeit der Val/Met-Allelträger der Kontrollen bei Stopperfolgen. Unsere Ergebnisse entsprechen nicht unbedingt den Annahmen aus der Literatur, dass das Met-Allel das günstige Allel in Bezug auf gute präfrontale Hirnfunktion sei. Diese Unterschiede in den COMT x Gruppe Interaktionen legen eine Abhängigkeit präfrontaler Hirnfunktionen vom allgemeinen dopaminergen Gehalt (Patienten vs. Kontrollen), vom präfrontalen dopaminergen Niveau (COMT-Genotyp) und von der Aufgabenart (Arbeitsgedächtnis vs. Antworthemmung) nahe. Diese Hypothese wird unterstützt durch die Unterschiede in den Korrelationskoeffizienten der beiden Prozesse in Abhängigkeit der Stichproben und Genotyp-Gruppen. Schlussfolgerung: Die Befunde stützen nicht die Annahme, dass es sich bei Arbeitsgedächtnis und Antworthemmung um zusammenhängende Funktionen bei ADHS oder Gesunden handelt, oder dass der exekutive Endophänotyp einen einheitlichen Subtyp der ADHS darstellt. Zudem scheint eine mögliche Assoziation der beiden Prozesse von mehreren Faktoren wie z. B. der Dopamin-Konzentration moduliert zu werden. Zukünftige Arbeiten sollten die Fragestellungen bearbeiten, welche Faktoren den Zusammenhang dieser Prozesse beeinflussen und welche Kombination solcher Faktoren eine Subgruppe von Patienten mit ADHS mit einem gemeinsamen exekutiven Endophänotyp darstellen könnten. / Objective: The highly heritable psychiatric disease Attention Deficit-/Hyperactivity Disorder (ADHD) is characterized by symptoms of hyperactivity, impulsivity, and inattention. The pathophysiology seems to involve alterations in the dopaminergic neurotransmitter system as well as changes in the prefrontal cortex. Working memory and response inhibition are two executive functions that have repeatedly been found to be deficient in ADHD patients, and have therefore been proposed as potential endophenotypes of the disease. Such so called intermediate phenotypes are thought to be more closely related to aetiopathogenetic factors than subtypes defined according to the classical diagnostic systems. Many studies have shown mean group differences for working memory and response inhibition in ADHD samples as compared to healthy control groups, both with respect to behavioural and brain imaging variables. A genetic polymorphism (Val158Met) in the gene coding for the enzyme catechol O methyltransferase (COMT) modulates working memory and response inhibition functions in controls and patients with ADHD. COMT catalyzes the degradation of prefrontal dopamine. The valine(val-)allele is associated with a low, the methionine(met-)allele with a high level of dopamine in cortical areas. The met-allele seems to be beneficial for prefrontal functions. Aim: It is an open question, if the two processes of working memory and response inhibition are associated, i. e. if they characterize the same endophenotype, and if a possible association of these processes is modulated by dopamine. The present work aims at (1) replicating previously shown mean group differences, (2) analyzing the association of working memory and response inhibition in a correlational analyses, (3) investigating the influence of COMT on working memory and response inhibition, and (4) measuring the influence of COMT on the strength of the correlations between the two processes of working memory and response inhibition. Questions 3 and 4 are indicated as exploratory analyses due to small sample sizes. Methods: 45 adult patients with ADHD und 41 healthy controls were included in the analyses. The two groups were comparable for age, gender, handedness, intelligence, education level, and head perimeter. Working memory and response inhibition were operationalized by an n-back and a stop signal task. Behavioural dependent variables were the number of correct answers, reaction times, and efficiency. Dependent physiological parameters were concentration changes of oxygenated (O2Hb) and deoxygenated haemoglobin (HHb) in prefrontal cortical areas as assessed by functional near-infrared spectroscopy. Correlations were calculated between control conditions (1-back und go-trials) and between the active conditions of the working memory and response inhibition tasks (2-back und successful stop signals). Results: Controls and patients showed task-specific significant activation patterns, for working memory over dorso-lateral prefrontal cortex (DLPFC) and for response inhibition over inferior frontal cortex (IFC). Question 1: Compared to the control sample, patients had deficits in all behavioural parameters. They also showed significantly reduced increases in O2Hb in bilateral IFC for successful stop trials, and a statistical trend for a reduced increase in the left DLPFC for the 2-back condition. Furthermore, deficits were found in the simple control tasks (behavioural parameters and O2Hb during 1-back). After matching of the groups for differences in control tasks, group differences remained significant for tasks of working memory and response inhibition. Question 2: Significant positive associations were found only for the patients and only for behavioural variables. Efficiency during 1-back correlated with reaction time during go-trials, and efficiency during 2-back correlated with stop signal reaction time, with no statistical difference between the strength of these correlations. Only the correlation of the control tasks remained significant as a trend after matching of the groups for differences in the control tasks. The significant correlation of efficiency during 2-back und stop signal reaction time disappeared. Patients showed an elevated impulsivity (assessed by a questionnaire) correlating positively with behavioural measures of both tasks. Question 3: For the 1-back (O2Hb and right hemisphere) and 2-back condition (O2Hb and left hemisphere) COMT x group interactions were found as a statistical trend. For 1-back, controls with the val/val-genotype had higher oxygenation levels than controls with the met/met-genotype. Controls with val-alleles had higher O2Hb concentration changes than patients with val-alleles. Analysis of the behavioural data revealed higher efficiency for controls with met-alleles in contrast to patients with met-alleles. For 2-back, controls with the val/val-genotype showed higher oxygenation than val/val-allele carriers within the group of patients. Additionally, the met/met-genotype in the ADHD group had higher O2Hb changes than the val/val-genotype in the ADHD group. Behavioural analyses indicated higher efficiency in controls compared to patients for the groups with one or two val-alleles. For successful stop signals, significant COMT x group interactions were found for O2Hb in both hemispheres. Controls with the val/met-genotype had higher oxygenation than controls with the val/val- or met/met-genotype, and than patients with the val/met-genotype. Patients with the val/met-genotype had slower stop signal reaction times as compared to controls with the val/met-genotype. Question 4: Correlations showed differences in strength and direction depending on samples and COMT groups. Only for the patients and only for behavioral variables significant positive associations were found for all COMT groups, comparable to the results of question 2. Discussion: The behavioural and physiological differences observed between patients with ADHD and controls replicate previous findings. Considering differences in control tasks, it is an important issue for future research to investigate group differences in simple psychomotor tasks. The correlation for behavioural measures of working memory and response inhibition in the group of patients, which did not exceed the association of behavioural measures for the control tasks, and which disappeared after matching of groups for differences in control tasks, raises doubts regarding the hypothesis of a specific association of these two processes in ADHD. Considering the correlation of these processes (behavioural measures) with impulsivity (questionnaire), the question arises, whether impulsivity in terms of behavioural task measures reflects the same construct as impulsivity at a symptomatic level. One factor that might potentially influence correlations between tasks could be the level of extracellular prefrontal dopamine, as indicated by the COMT polymorphism in the present investigation. Results of the COMT x group interactions revealed an increased oxygenation and to some extent increased efficiency of the controls with val-allels for the n-back tasks and an increased oxygenation and to some extent a fastened stop signal reaction time of the controls with val/met-genotype. Our results do not correspond to the assumptions from literature indicating an association of the met allele with beneficial prefrontal functions. Differences in COMT x group interactions suggest that prefrontal functions depend on general dopaminergic level (patients vs. controls), on prefrontal dopaminergic level (COMT genotype), and on task type (working memory vs. response inhibition). This hypothesis is supported by the differences in correlations of both processes in dependence of sample and genotype group. Conclusion: Our findings do not directly support the assumption, that working memory and response inhibition are associated functions in patients with ADHD or controls, or that the executive phenotype is one integrative subtype of ADHD. Furthermore, a possible association of both functions seems to depend on several factors, e. g. dopaminergic level as shown in the current investigation. Future investigations should address the open questions as to which factors influence this association and what combinations of such factors might constitute a subgroup of patients with ADHD with an integrative executive endophenotype.

The 21st century world is characterized by globalization, optimization, high performance demands, and continuous acceleration of processes. Not surprisingly, stress has steadily become more prevalent over the past years and has become a permanent challenge for many of us. Still we are always expected to perform at our best, and an impairment of cognitive performance can be devastating, particularly in the professional world. This ubiquity in daily life of chronic stress, cognitive demands, and their potential interactions was the motivation for this dissertation. Among cognitive processes executive functioning (EF) are of particular interest, as they represent set of fundamental cognitive abilities for mastering daily life. More precisely, EF is described as higher-order cognitive processes that control and coordinate complex cognitive tasks (Diamond, 2013; Miyake et al., 2000). The primary aim of this dissertation was to investigate the interplay between chronic stress and EF in detail. A three-year longitudinal cohort, the StressCog cohort, was established for this purpose. In order to understand the longitudinal interplay between chronic stress and EF, methodological foundations and cross-sectional matters had to be investigated first. As a result, this dissertation encompasses the following three studies: With classical laboratory designs, the estimation of generalizable and robust effects on the relationship between chronic stress and EF is impaired. Therefore, the StressCog study was set up to make use of internet-based data assessment within domestic environments. Study 1 addressed the feasibility of internet-based response time data, including the common concern that internet-based response time data collected in domestic environments is subject to increased data variability (Chetverikov & Upravitelev, 2016; Reips, 2002). To this end, performance measures collected in the laboratory were compared with measures collected in domestic environments. We found that a setting-related difference in the variability of conventional performance measures (i.e., response times and error rates), as well as diffusion model-based measures is only of small size. An overall increase of variance of approximately 5% was visible in domestic environments. However, as internet-based assessments allow for the recruitment of larger sample sizes (Reips, 2002) the loss of static power can be easily compensated. Therefore, the findings of Study 1 support the use of internet-based cognitive data collection in domestic environments. This formed a valuable basis regarding the collection and interpretation of the StressCog data used in Study 2 and Study 3. In order to get a broad picture of chronic stress the StressCog study aimed for multimethod assessment. The subjective (i.e., perceived) extent of chronic stress and conceptually related constructs were assessed by multiple self-reported measures. The objective (i.e., physiological) extent of chronic stress was assessed via hair cortisol concentration, which has been established as a widely accepted biological marker of chronic stress (E. Russell et al., 2012; Stalder & Kirschbaum, 2012). Surprisingly, however, multiple studies have shown that hair cortisol concentration is, at best, only weakly correlated with subjective chronic stress (Stalder et al., 2017; Staufenbiel et al., 2013; Weckesser et al., 2019). This lack of psychoendocrine covariance was addressed in Study 2 by investigating the construct validity of commonly used chronic stress instruments. A multidimensional item response theory approach was applied in order to display the overlap between items of commonly used measures of chronic stress, depressiveness, and neuroticism. A common latent scale covered the major amount of variance (40% to 48%). It appeared that the overlap of content is mainly based on fatigue, which is a core symptom of depressiveness. Similar to previously reported findings, the common latent scale displayed only a weak association with hair cortisol concentration. It can therefore be argued that items of self-reported chronic stress do not reflect the physiological (i.e., endocrine) aspect of chronic stress to a satisfactory extent. Thus, the results of Study 2 were a valuable basis for the interpretation of chronic stress data in Study 3. In Study 3, we investigated the cross-sectional association between chronic stress and EF. The study made use of data from the baseline assessment of the StressCog cohort (N = 514). Using structural equation modelling, we found no evidence for a meaningful association between chronic stress (i.e., self-reported measures and hair cortisol concentration) and a common latent EF factor. The results found in Study 3 were further supported by unpublished longitudinal StressCog data and analyses making use of diffusion model performance measures. Considering the mainstream of existing findings, which suggests chronic stress to be negatively associated with EF (e.g., Deligkaris et al., 2014; Sandi, 2013), an absence of an association between chronic stress and EF seems surprising. However, other existing findings support this perspective (Castaneda et al., 2011a; McLennan et al., 2016). Beyond this, the results of Study 1 and 2 help to explain why a lack of an association between chronic stress and EF is quite plausible. As within traditional, laboratory-based settings a recruitment of larger samples sizes is difficult and costly, most existing studies lack large, representative samples. In consequence, many findings are based on narrow sample characteristics. Supported by the findings of Study 1, the StressCog study made use of internet-based data collection, which led to the establishment of one the largest, population-based cohorts in the field. Thus, the results presented in this dissertation can be seen as much more robust and representative than many other studies that suggest opposing results. The findings of Study 2 allow for the assumption that many studies in the field make use of questionable self-report instruments and that subjective (i.e., self-reported) measures of chronic stress are only weakly related to objective (i.e., HCC) measures. In consequence, results always depend on the operationalization of the chronic stress measures being used. Caution is advised when comparing opposing results of different measures. With regard to our daily life demands, it may appear quite promising that no association between chronic stress and EF was found in this dissertation. However, these results should not be misunderstood. It has been demonstrated countless times that chronic stress can severely affect the human organism, causing various negative effects that go far beyond a possible impairment of cognitive abilities. Knowing that chronic stress can impair EF under certain circumstances leads to the central question of what conditions make stress toxic. In order to answer this question further systematic research is needed, in which representative samples and experimental study designs will be of crucial help. As long as these questions are not satisfactorily clarified, it seems best to deal with the challenges of chronic stress in a conscious and responsible manner.

Der vorliegende Arbeit systematisiert Befunde aus dem Gebiet der exekutiven Funktionen und ihren Modulationen durch verschiedene Parameter (d.h. Shifting, Inhibition, Updating, Dual tasking). Diese Parameter werden in einer entsprechenden Rahmenkonzeption illustriert und umfassen die Parameter Kontext, Training, Alter und ihre Kombinationen. Die vorliegende Arbeit zeigt Beispiele, wie diese Parameter in Bezug auf exekutive Funktionen realisiert werden können. Im Rahmen des Kontext-Parameters wird beispielsweise gezeigt, wie die Vorhersagbarkeit von Aufgaben und Aufgabenreihenfolgen Dual tasking (Heinrich et al., 2012) und wie aktuelle Anforderungen an das Arbeitsgedächtnis Inhibition (Soutschek et al., 2013) modulieren kann. Allerdings zeigen Töllner et al. (2012) auch Grenzen des Kontext-Parameters bei der Modulation der erstgenannten exekutiven Funktion. Der Parameter Training wurde realisiert mit Fokus auf (1) Shifting (Strobach et al., 2012a) und (2) Updating (Salminen et al., 2011, 2012). Schubert and Strobach (2012) sowie Strobach et al. (2012b) untersuchten den Transfereffekt von Video-game- und Arbeitsgedächtnistraining auf Dual tasking und Shifting. Schließlich zeigen Strobach et al. (2012c, 2012d) Modulationseffekte bei der Kombination des Alters- und Trainingsparameters auf die exekutive Funktion Dual tasking. Abschließend systematisiert die vorgestellte Rahmenkonzeption die Lücken und Ziele zukünftiger Forschung zur Modulation von exekutiven Funktionen. / The present review aims at a systematization of findings in the field of executive functions and their modulation due to different operational parameters (i.e., dimensions). This systematization is realized in the form of the Framework on modulations of executive functions. Basically, this framework illustrates how different types of executive functions (i.e., Shifting, Inhibition, Updating, Dual tasking) are modulated by their context (Context dimension), training (Training dimension), age (Age dimension), and combinations of these dimensions. The present review includes examples of studies that demonstrate a realization of each of these dimensions and their effects on executive function types. In detail, the Context dimension modulates the executive function type Dual tasking (i.e., due to task order predictability in dual tasks; Hendrich et al., 2012 ) and Inhibition (i.e., due to the level of concurrent working memory demand in a Stroop task; Soutschek et al., 2013); however, Töllner et al. (2012) demonstrated that Context also affects processes that are not related with executive functioning (i.e., perception and motor processes) in a dual-task situation. The framework’s Training dimension was realized when (1) Strobach et al. (2012a) investigated effects of training on the executive function Shifting in a task switching situation and (2) Salminen et al. (2011, 2012), Schubert and Strobach (2012), as well as Strobach et al. (2012b) investigated transfer effects on executive functioning of Dual tasking and Shifting after video game and working memory training. Finally, Strobach et al. (2012c, 2012d) illustrated modulation effects of age and training (i.e., the combination of Age and Training dimension) on the executive function type Dual tasking. In sum, this framework helps to systematize research gaps and future studies in this field (i.e., executive functions).

Background: Old-old age (80+ years) is associated with substantial cognitive decline. In this population, training-induced cognitive plasticity has rarely been studied. While earlier findings on strategy trainings suggested reduced training gains in old-old age, recent results of an extensive process-based working memory (WM) training have been more positive. Objective: Following up on previous research, the present study aimed at examining the effects of a short WM training in old-old adults and the influence of baseline WM capacity on training gains. Methods: A training group (mean age: 86.8 years) and a matched control group (mean age: 87.1 years) participated in the study. The WM training consisted of five tasks that were trained in each of 10 sessions. To evaluate possible transfer effects, executive functions were assessed with two tests before and after training. The training group was divided via median split in high- and low-capacity individuals to determine the influence of baseline WM capacity on training gains. Results: The training group improved in four of the trained tasks (medium-to-large effects). Training gains were significantly larger in the training group than in the control group in only two of those tasks. The training effects were mainly driven by the low-capacity individuals who improved in all trained tasks. No transfer effects were observed. Conclusions: These positive effects of a short WM training, particularly for low-capacity individuals, emphasize the potential for cognitive plasticity in old-old age. The absence of transfer effects may also point to its limits. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Old-old age (80+ years) is associated with substantial cognitive decline. In this population, training-induced cognitive plasticity has rarely been studied. While earlier findings on strategy trainings suggested reduced training gains in old-old age, recent results of an extensive process-based working memory (WM) training have been more positive. Objective: Following up on previous research, the present study aimed at examining the effects of a short WM training in old-old adults and the influence of baseline WM capacity on training gains. Methods: A training group (mean age: 86.8 years) and a matched control group (mean age: 87.1 years) participated in the study. The WM training consisted of five tasks that were trained in each of 10 sessions. To evaluate possible transfer effects, executive functions were assessed with two tests before and after training. The training group was divided via median split in high- and low-capacity individuals to determine the influence of baseline WM capacity on training gains. Results: The training group improved in four of the trained tasks (medium-to-large effects). Training gains were significantly larger in the training group than in the control group in only two of those tasks. The training effects were mainly driven by the low-capacity individuals who improved in all trained tasks. No transfer effects were observed. Conclusions: These positive effects of a short WM training, particularly for low-capacity individuals, emphasize the potential for cognitive plasticity in old-old age. The absence of transfer effects may also point to its limits. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

A pervasive real-world memory task is remembering to carry out intended activities at appropriate moments in the future, such as remembering to call one’s mother after returning from work or to hand a message to a colleague when seeing him in the office on the next morning. Such types of tasks are termed prospective memory (PM) tasks (Einstein & McDaniel, 1996). PM has been identified as one of the most frequent everyday memory challenges (e.g., Maylor, 1990), particularly in old age (McDaniel, Einstein, & Rendell, 2008) and an intact PM is considered to be crucial for the maintenance of independent living (Kliegel & Martin, 2003). Therefore, many researchers have focused on the exploration of possible age differences in PM. While age-related deficits were found in standard lab-based PM tasks, age-related benefits occured in naturalistic tasks that are carried out in participants’ everyday lives. This surprising pattern has been called the age-PM-paradox (Rendell & Craik, 2000). It has been supported by a meta-analysis comparing PM age effects found in studies that focused either on lab-based or on naturalistic PM tasks (Henry, MacLeod, Phillips, & Crawford, 2004). However, the mechanisms which are critical in determining the direction of age effects remain poorly delineated. Thus, the overall aim of the research programme presented in the present thesis was to investigate the age-PM-paradox as well as potential cognitive, motivational and emotional mechanisms and processes associated with age-related PM performance. For that purpose, three experimental studies were conducted testing adult age effects in different PM task settings with different task material. Furthermore, several possible underlying mechanisms suggested by the literature on age effects in PM were measured and/ or varied experimentally. The first aim of Study 1 was to cross-validate the age-PM-paradox within a single sample. The second aim was to empirically explore the relative importance of four recently proposed factors (motivation, metacognitive awareness, activity absorption, and control over the task) that may be associated with the direction of age effects inside and outside of the laboratory. For that purpose, 20 young and 20 older adults performed a lab-based and a naturalistic PM task, which were similar in structure and demand. The level of control was experimentally manipulated in both task settings. The remaining possibly influencing factors (motivation, metacognitive awareness, and activity absorption) were assessed via questionnaires in the laboratory and with a daily diary in the field. First, analysing mean level age differences, the paradox was confirmed. Second, exploring possible correlates of the paradox revealed that the level of daily activity absorption (i.e., everyday stress) was the most important mechanism in naturalistic PM performance. Further, high motivation and good metacognitive awareness were associated with age benefits in PM performance in the naturalistic task, while high ongoing activity absorption and low control over the PM cue were related to deficits in lab-based tasks. Thus, Study 1 confirmed the age-PM-paradox within one sample and with carefully matched lab-based and naturalistic tasks. In addition, the results indicate that the relative importance of the suggested factors may vary as a function of setting. While cognitive factors were most influential in the laboratory, motivational and knowledge-based factors were associated with high PM performance in the naturalistic task. The strong association between PM performance in the field and everyday stress highlights the need for future studies exploring the mechanisms underlying this effect. Results from Study 1 suggest that cognitive resources are most influential for PM age effects in the laboratory. Yet, it is not clear, which specific cognitive resources are needed for successful PM performance and if these processes differ between young and older adults. Thus, Study 2 explored the role of executive functions (i.e. shifting, updating and inhibition) as possible developmental mechanisms associated with PM age effects. 170 young and 110 older adults performed a battery of cognitive tests including measures of PM, shifting, updating, inhibition, working memory and speed. A comprehensive set of statistical approaches (e.g. median analyses, structural equation modelling) was used to analyze the possible cognitive correlates in predicting PM performance. First, age effects were confirmed in PM and also obtained in measures of executive control. Moreover, the facets of executive control differently predicted PM performance. Specifically, shifting was the strongest predictor of PM performance in young and older adults as well as for explaining age differences in PM. Thus, Study 2 clarified the role of different facets of controlled attention in age effects in PM and bears important conceptual implications: The results suggest that executive functions are important developmental mechanisms of PM across adulthood beyond working memory and speed. Specifically, shifting appeared to be an essential aspect of cognitive control involved in age-related PM performance. Moreover, examining PM as a latent construct confirmed the convergent and discriminant validity of PM. This demonstrates PM as a separate cognitive construct and suggests that PM is related to, but not identical with, executive control. Study 3 was set out to explore if the amount of cognitive resources needed to successfully perform a PM task in the laboratory can be influenced by the emotionality of the task material. First studies suggested that emotional task material may enhance PM performance in young and older adults by heightening the salience of the task and thereby reducing the need for controlled attention. However, the extent and mechanisms of this effect are still under debate. Therefore, Study 3 explored possible differential effects of PM target cue valence on PM age effects. For that purpose, 45 young and 41 older adults performed a PM task in which emotional valence of the PM cue was manipulated (positive, negative, neutral). Results revealed an interaction indicating that age differences were smaller in both emotional valence conditions compared to the neutral condition. This finding supports an emotionally enhanced memory effect in PM, but only for the older adults as PM performance in young adults was not affected by cue valence. From a conceptual perspective, the results from Study 3 may also contribute to the explanation of the age-PM-paradox, as they suggest that the neutral material usually applied in lab-based studies might overestimate PM age effects. In summary, the present thesis makes an important contribution to the ongoing conceptual debate concerning adult age effects in PM performance assessed in the laboratory versus participants’ everyday lives. Results strongly suggest that mostly different variables may be crucial for understanding PM age deficits in the laboratory and age benefits in naturalistic PM tasks. Successful PM performance in the laboratory seems to require high levels of cognitive resources. The present results suggest that shifting ability is especially relevant in this respect. On a task level the emotionality of the material seems to influence the required amount of cognitive resources as it reduced PM age effects. Everyday stress seems to be particularly important for successful PM performance in the field. Thus, possible future studies should specify the relation between stress and PM as outlined in the general discussion.

Background. In everyday life it is often required to integrate multisensory input to successfully conduct response inhibition (RI) and thus major executive control processes. Both RI and multisensory processes have been suggested to be altered in autism spectrum disorder (ASD). It is, however, unclear which neurophysiological processes relate to changes in RI in ASD and in how far these processes are affected by possible multisensory integration deficits in ASD. Method. Combining high-density EEG recordings with source localization analyses, we examined a group of adolescent ASD patients (n = 20) and healthy controls (n = 20) using a novel RI task. Results. Compared to controls, RI processes are generally compromised in adolescent ASD. This aggravation of RI processes is modulated by the content of multisensory information. The neurophysiological data suggest that deficits in ASD emerge in attentional selection and resource allocation processes related to occipito-parietal and middle frontal regions. Most importantly, conflict monitoring subprocesses during RI were specifically modulated by content of multisensory information in the superior frontal gyrus. Conclusions. RI processes are overstrained in adolescent ASD, especially when conflicting multisensory information has to be integrated to perform RI. It seems that the content of multisensory input is important to consider in ASD and its effects on cognitive control processes.

Ziel: Das Ziel der vorliegenden Studie war einen Zusammenhang zwischen posttraumatischen Riechstörungen und Frontalhirnläsionen zu beweisen. Methode: Dafür wurden 51 Patienten mit posttraumatischen Riechstörungen und 50 Patienten mit Riechstörungen anderer Ätiologie untersucht. Der Grad der Riechstörungen wurde mit dem orthonasalen Testverfahren der Sniffin‘ Sticks sowie dem retronasalem Schmeckpulvertest eingestuft. Zusätzlich wurden neuropsychologische Tests (TMT-A, COWA, WCST, d2-R) durchgeführt, um Funktionen, die als typisch für die Frontallappen angesehen werden, zu überprüfen. Außerdem sollte jeder Patient den Fragebogen des Beck Depressions Inventars für eine Einschätzung seiner depressiven Tendenz beantworten. Ergebnisse: Es konnte in beiden untersuchten Patientengruppen kein Zusammenhang zwischen dem Riechvermögen und der neuropsychologischen Leistung festgestellt werden. Allerdings wurde in der posttraumatischen Patientengruppe eine signifikante, inverse Korrelation zwischen der Punktzahl des BDI und der Punktzahl im Diskriminationstest beobachtet. In der Kontrollgruppe bestand zwischen diesen Faktoren kein Zusammenhang. Schlussfolgerungen: Trotz der Ergebnisse dieser Studie kann ein Zusammenhang zwischen posttraumatischen Riechstörungen und Frontalhirnläsionen nicht ausgeschlossen werden, da u.a. die Funktionen der Frontallappen aufgrund ihrer Komplexität und Unspezifität schwierig zu messen sind. Außerdem waren die Traumata der Patienten sowie der klinische Verlauf sehr variabel und individuell. Frontalhirnläsionen können allerdings dramatische Einschnitte bedeuten, auf die klinisch besonders geachtet werden sollte. Olfaktorische Probleme können darüber hinaus zusätzlich die Lebensqualität stark beeinträchtigen und sollten daher ebenfalls Bestandteil der posttraumatischen Diagnostik sein.:Inhaltsverzeichnis 1 ABKÜRZUNGSVERZEICHNIS IV 2 EINLEITUNG 1 2.1 POSTTRAUMATISCHER RIECHVERLUST 1 2.2 FRONTALHIRN 3 3 ZIELSETZUNG DER STUDIE 9 3.1 HYPOTHESE 9 3.2 ERWARTETE ERGEBNISSE 10 4 MATERIAL UND METHODEN 10 4.1 PATIENTEN 10 4.2 METHODEN 10 4.2.1 RIECHTESTS 10 4.2.2 NEUROPSYCHOLOGISCHE TESTS 17 4.3 STATISTISCHE AUSWERTUNG 24 5 ERGEBNISSE 25 5.1 DESKRIPTIVE STATISTIK 25 5.1.1 PATIENTENKOLLEKTIV 25 5.1.2 POSTTRAUMATISCHE PATIENTEN 27 5.1.3 KONTROLLGRUPPE 28 5.2 KORRELATIONSPRÜFUNGEN 29 5.2.1 KORRELATION DER ERGEBNISSE DER RIECHTESTS MIT DEN ERGEBNISSEN DER NEUROPSYCHOLOGISCHEN TESTS 29 5.2.2 KORRELATION DER NEUROPSYCHOLOGISCHEN TESTS UNTEREINANDER 35 5.2.3 KORRELATION DER ERGEBNISSE DER RIECHTESTS MIT DER PUNKTZAHL DES BDI 36 6 DISKUSSION 39 6.1 METHODEN 40 6.1.1 RIECHTESTS 40 6.1.2 NEUROPSYCHOLOGISCHE TESTS 41 6.1.3 BECK DEPRESSIONS INVENTAR 43 6.2 ERGEBNISSE 43 6.2.1 ZUSAMMENHANG RIECHLEISTUNG MIT ERGEBNISSEN DER NEUROPSYCHOLOGISCHEN TESTS 43 6.2.2 ZUSAMMENHANG DISKRIMINATIONSLEISTUNG MIT PUNKTZAHL DES BECK DEPRESSIONS INVENTARS 48 7 AUSBLICK 50 8 ZUSAMMENFASSUNG 52 9 SUMMARY 53 10 ABBILDUNGSVERZEICHNIS V 11 TABELLENVERZEICHNIS VII 12 LITERATURVERZEICHNIS VIII 13 ERKLÄRUNG ZUR ERÖFFNUNG DES PROMOTIONSVERFAHRENS XXI 14 EINHALTUNG DER AKTUELLEN GESETZLICHEN VORGABE XXII 15 DANKSAGUNG XXIII 16 CURRICULUM VITAE XXIV 17 PUBLIKATIONEN XXVI

A pervasive real-world memory task is remembering to carry out intended activities at appropriate moments in the future, such as remembering to call one’s mother after returning from work or to hand a message to a colleague when seeing him in the office on the next morning. Such types of tasks are termed prospective memory (PM) tasks (Einstein & McDaniel, 1996). PM has been identified as one of the most frequent everyday memory challenges (e.g., Maylor, 1990), particularly in old age (McDaniel, Einstein, & Rendell, 2008) and an intact PM is considered to be crucial for the maintenance of independent living (Kliegel & Martin, 2003). Therefore, many researchers have focused on the exploration of possible age differences in PM. While age-related deficits were found in standard lab-based PM tasks, age-related benefits occured in naturalistic tasks that are carried out in participants’ everyday lives. This surprising pattern has been called the age-PM-paradox (Rendell & Craik, 2000). It has been supported by a meta-analysis comparing PM age effects found in studies that focused either on lab-based or on naturalistic PM tasks (Henry, MacLeod, Phillips, & Crawford, 2004). However, the mechanisms which are critical in determining the direction of age effects remain poorly delineated. Thus, the overall aim of the research programme presented in the present thesis was to investigate the age-PM-paradox as well as potential cognitive, motivational and emotional mechanisms and processes associated with age-related PM performance. For that purpose, three experimental studies were conducted testing adult age effects in different PM task settings with different task material. Furthermore, several possible underlying mechanisms suggested by the literature on age effects in PM were measured and/ or varied experimentally. The first aim of Study 1 was to cross-validate the age-PM-paradox within a single sample. The second aim was to empirically explore the relative importance of four recently proposed factors (motivation, metacognitive awareness, activity absorption, and control over the task) that may be associated with the direction of age effects inside and outside of the laboratory. For that purpose, 20 young and 20 older adults performed a lab-based and a naturalistic PM task, which were similar in structure and demand. The level of control was experimentally manipulated in both task settings. The remaining possibly influencing factors (motivation, metacognitive awareness, and activity absorption) were assessed via questionnaires in the laboratory and with a daily diary in the field. First, analysing mean level age differences, the paradox was confirmed. Second, exploring possible correlates of the paradox revealed that the level of daily activity absorption (i.e., everyday stress) was the most important mechanism in naturalistic PM performance. Further, high motivation and good metacognitive awareness were associated with age benefits in PM performance in the naturalistic task, while high ongoing activity absorption and low control over the PM cue were related to deficits in lab-based tasks. Thus, Study 1 confirmed the age-PM-paradox within one sample and with carefully matched lab-based and naturalistic tasks. In addition, the results indicate that the relative importance of the suggested factors may vary as a function of setting. While cognitive factors were most influential in the laboratory, motivational and knowledge-based factors were associated with high PM performance in the naturalistic task. The strong association between PM performance in the field and everyday stress highlights the need for future studies exploring the mechanisms underlying this effect. Results from Study 1 suggest that cognitive resources are most influential for PM age effects in the laboratory. Yet, it is not clear, which specific cognitive resources are needed for successful PM performance and if these processes differ between young and older adults. Thus, Study 2 explored the role of executive functions (i.e. shifting, updating and inhibition) as possible developmental mechanisms associated with PM age effects. 170 young and 110 older adults performed a battery of cognitive tests including measures of PM, shifting, updating, inhibition, working memory and speed. A comprehensive set of statistical approaches (e.g. median analyses, structural equation modelling) was used to analyze the possible cognitive correlates in predicting PM performance. First, age effects were confirmed in PM and also obtained in measures of executive control. Moreover, the facets of executive control differently predicted PM performance. Specifically, shifting was the strongest predictor of PM performance in young and older adults as well as for explaining age differences in PM. Thus, Study 2 clarified the role of different facets of controlled attention in age effects in PM and bears important conceptual implications: The results suggest that executive functions are important developmental mechanisms of PM across adulthood beyond working memory and speed. Specifically, shifting appeared to be an essential aspect of cognitive control involved in age-related PM performance. Moreover, examining PM as a latent construct confirmed the convergent and discriminant validity of PM. This demonstrates PM as a separate cognitive construct and suggests that PM is related to, but not identical with, executive control. Study 3 was set out to explore if the amount of cognitive resources needed to successfully perform a PM task in the laboratory can be influenced by the emotionality of the task material. First studies suggested that emotional task material may enhance PM performance in young and older adults by heightening the salience of the task and thereby reducing the need for controlled attention. However, the extent and mechanisms of this effect are still under debate. Therefore, Study 3 explored possible differential effects of PM target cue valence on PM age effects. For that purpose, 45 young and 41 older adults performed a PM task in which emotional valence of the PM cue was manipulated (positive, negative, neutral). Results revealed an interaction indicating that age differences were smaller in both emotional valence conditions compared to the neutral condition. This finding supports an emotionally enhanced memory effect in PM, but only for the older adults as PM performance in young adults was not affected by cue valence. From a conceptual perspective, the results from Study 3 may also contribute to the explanation of the age-PM-paradox, as they suggest that the neutral material usually applied in lab-based studies might overestimate PM age effects. In summary, the present thesis makes an important contribution to the ongoing conceptual debate concerning adult age effects in PM performance assessed in the laboratory versus participants’ everyday lives. Results strongly suggest that mostly different variables may be crucial for understanding PM age deficits in the laboratory and age benefits in naturalistic PM tasks. Successful PM performance in the laboratory seems to require high levels of cognitive resources. The present results suggest that shifting ability is especially relevant in this respect. On a task level the emotionality of the material seems to influence the required amount of cognitive resources as it reduced PM age effects. Everyday stress seems to be particularly important for successful PM performance in the field. Thus, possible future studies should specify the relation between stress and PM as outlined in the general discussion.

Neurofeedback (NF) is an important treatment for attention deficit/hyperactivity disorder (ADHD). In ADHD, cognitive control deficits pose considerable problems to patients. However, NF protocols are not yet optimized to enhance cognitive control alongside with clinical symptoms, partly because they are not driven by basic cognitive neuroscience. In this study, we evaluated different EEG theta and/or beta frequency band NF protocols designed to enhance cognitive control. Participants were n = 157 children and adolescents, n = 129 of them were patients with ADHD (n = 28 typically developing (TD) controls). Patients with ADHD were divided into five groups in the order of referral, with four of them taking part in different NF protocols systematically varying theta and beta power. The fifth ADHD group and the TD group did not undergo NF. All NF protocols resulted in reductions of ADHD symptoms. Importantly, only when beta frequencies were enhanced during NF (without any theta regulation or in combination with theta upregulation), consistent enhancing effects in both response inhibition and conflict control were achieved. The theta/beta NF protocol most widely used in clinical settings revealed comparatively limited effects. Enhancements in beta band activity are key when aiming to improve cognitive control functions in ADHD. This calls for a change in the use of theta/beta NF protocols and shows that protocols differing from the current clinical standard are effective in enhancing important facets of cognitive control in ADHD. Further studies need to examine regulation data within the neurofeedback sessions to provide more information about the mechanisms underlying the observed effects.