Decision and Reward in Intertemporal Choice: The Roles of Brain Development, Inter-individual Differences and Pharmacological Influences

Human decision making is closely related to reward processing because many decisions rely to a certain degree on the evaluation of different outcome values. Reward-based decisions can be health-related, for example if someone has to compare the outcome value of the instant reward of smoking a cigarette to that of the long term goal of keeping well and fit. Such comparisons do not only rely on the nominal value of the alternatives but also on devaluation of rewards over time. The value of being healthy at older age might outweigh the value of smoking a cigarette but since the payoff of the health-outcome will be delayed, humans tend to decrease the value of this option. Therefore in this example one might choose the immediate reward of smoking a cigarette. The proclivity to devaluate the value of rewards over time has been widely investigated with experimental intertemporal choice tasks, in which subjects have to choose between smaller sooner rewards and larger later rewards. A stronger individual devaluation proclivity (i.e. discounting rate) has been reported to be related to addiction. Research in neuroeconomics has suggested the competing neurobehavioural decision systems (CNDS) theory, proposing that an imbalance between an executive (cortical prefrontal brain areas) and an impulsive (i.e. subcortical areas, such as ventral striatum (VS), amygdala) system in the brain leads to steeper discounting and a higher risk for addiction. Additionally, temporal discounting has been proposed as a transdisease process, i.e., “a process that occurs across a range of disorders, making findings from one disorder relevant to other disorders” (Bickel, Jarmolowicz, Mueller, Koffarnus, & Gatchalian, 2012, Abstract). Thus, the CNDS theory and temporal discounting might also have implications for other health-related behaviour than substance use. So far many factors have been shown to be associated with higher discount rates: for instance, adolescent age, lower intelligence and nicotine dependence. Further, it has been shown that adolescents are at highest risk to start smoking. On the other hand a higher education level has been shown to be associated to lower rates of smoking. Thus, it seems likely that a higher discount rate might be one reason why adolescents experiment with smoking, why lower education is associated to nicotine addiction and why dependent smokers are not successful in smoking cessation. But relatively little is known about the neural processes behind these variables, which could be also seen as exemplary risk- and protective factors regarding addiction. The 3 studies of the thesis at hand were conducted to extend the knowledge about neural processes associated to age, intelligence and smoking in their relation to intertemporal choice. The task was chosen because of its relevance for addiction and a variety of health-related behaviour. The first study was conducted to explore the neural correlates of age related differences between adolescents at age 14 and young adults during intertemporal choices. Additionally, the roles of discounting and choice consistency were investigated. Although adoles-cents discounted delayed rewards more steeply than adults, neural processing of reward value did not differ between groups, when controlling reward values for the individual discount rates. However, a higher discount rate was related to a lower responsivity in the ventral striatum to delayed rewards, independent of age. Concerning decision making, adolescents exhib-ited a lower consistency of choices and less brain activity in a parietal network than adults (i.e. posterior and inferior parietal regions). Thus, reward value processing might be more sensitive to the discount rate than to chronological age. Lower consistency of intertemporal choices might indicate ongoing maturation of parietal brain areas from adolescence to young adulthood. The second study was conducted to reveal the associations between neural processes of decision making and intelligence in adolescents. The results of study 2 revealed networks in the adolescent brain where brain activity was related to crystallised intelligence as well as to intertemporal choice behaviour. Specifically, during decision processing higher crystallised intelligence as well as more consistent decisions were associated with higher brain activity in the posterior parietal cortex. Processing of delayed rewards was also related to crystallised intelligence, i.e. more intelligent adolescents showed higher brain activation in the anterior cingulate cortex (ACC) and the inferior frontal gyrus (IFG), which was in turn related to a lower discount rate. Additionally, associations between the parental education level and crys-tallised intelligence of the adolescent participants of the study and their discount rate were found, indicating that parental education as an environmental factor could be related to a low-er risk for addiction. This protective effect might be mediated by the offspring’s crystallised intelligence and discount rate which are both related to brain activity in parts of the same brain networks (i.e. the IFG). The third study was done to investigate neural processes of intertemporal decisions in smokers and non-smokers. To test whether the effects of smoking on the discount rate are due to chronic or acute nicotine intake, non-smokers were additionally assessed under acute nico-tine administration. Study 3 revealed that the effects of nicotine on intertemporal choice behaviour were related to chronic intake of nicotine in smokers rather than to acute nicotine ad-ministration in non-smokers. Regarding the neural processes, smokers compared to non-smokers showed lower brain activity in the posterior parietal cortex. Comparable but weaker effects were found under acute nicotine in non-smokers. Although acute nicotine administra-tion altered neural processes, behavioural changes might only occur after repeated nicotine intake. However, the study did not preclude that the differences are predrug characteristics. Altogether the studies revealed overlapping neural correlates of intertemporal choices which are related to the individual age, the discount rate, the choice consistency, the individual intelligence as well as acute and chronic nicotine intake. This might provide an integrative view on how inter-individual differences and behaviour during intertemporal choices are based on common neural correlates which in turn might have implications for the development and the maintenance of addiction. Specifically, hyposensitivity towards delayed rewards in the adolescent ventral striatum, which has also been found in smokers compared to non-smokers, is associated with higher discount rates and higher risk for smoking initiation. In contrast, higher activation in the IFG and the ACC in more intelligent individuals during reward value processing might enhance behavioural inhibition and control and, hence, might prevent nicotine addiction. In line with the CNDS theory responsivity in subcortical brain areas (i.e. impulsive system), such as the VS was related to the risk factor of adolescent age, whereas activity in cortical areas (IFG and ACC) was related to the protective factors of high-er crystallised intelligence. Since there was only one study beside the studies of the current thesis reporting results regarding consistency, one can only speculate about implications for health-related behaviour, such as addiction. Consistency might play a role, especially for cessation success. Thus, the findings that adolescents as well as less intelligent individuals were less consistent might point to a higher risk for maintenance of nicotine addiction. The higher brain activity in a fronto-parietal network, which has been shown in studies 1 and 2 in adults as well as in more intelligent adolescents, was related to higher consistency of choices in both studies. Thus, the finding might be a possible neural correlate for the association between the risk factor of ado-lescent age, the protective factor of higher crystallised intelligence, and more consistent deci-sion making. In conclusion the findings of the current thesis contribute to a better understanding of how inter-individual differences and environmental factors might be accompanied by neural processes which in turn might be related to individual development of addiction. Further the results might extend the CNDS theory regarding neural correlates of exemplary risk and pro-tective factors regarding adolescents’ health behaviour and smoking in adults

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Background Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replicatio

Intranasal oxytocin administration impacts the acquisition and consolidation of trauma-associated memories: a double-blind randomized placebo-controlled experimental study in healthy women

Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD) and oxytocin has been implicated in the formation of intrusive memories. This study investigates how oxytocin influences the acquisition and consolidation of trauma-associated memories and whether these effects are influenced by individual neurobiological and genetic differences. In this randomized, double-blind, placebo-controlled study, 220 healthy women received either a single dose of intranasal 24IU oxytocin or a placebo before exposure to a trauma film paradigm that solicits intrusive memories. We used a "general random forest" machine learning approach to examine whether differences in the noradrenergic and hypothalamic-pituitary-adrenal axis activity, polygenic risk for psychiatric disorders, and genetic polymorphism of the oxytocin receptor influence the effect of oxytocin on the acquisition and consolidation of intrusive memories. Oxytocin induced significantly more intrusive memories than placebo did (t(188.33) = 2.12, p = 0.035, Cohen's d = 0.30, 95% CI 0.16-0.44). As hypothesized, we found that the effect of oxytocin on intrusive memories was influenced by biological covariates, such as salivary cortisol, heart rate variability, and PTSD polygenic risk scores. The five factors that were most relevant to the oxytocin effect on intrusive memories were included in a Poisson regression, which showed that, besides oxytocin administration, higher polygenic loadings for PTSD and major depressive disorder were directly associated with a higher number of reported intrusions after exposure to the trauma film stressor. These results suggest that intranasal oxytocin amplifies the acquisition and consolidation of intrusive memories and that this effect is modulated by neurobiological and genetic factors. Trial registration: NCT03031405

Genetic modifiers and subtypes in schizophrenia: Investigations of age at onset, severity, sex and family history

Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified. We performed genome-wide association studies (GWAS) examining genetic influences on age at onset (AAO) and illness severity as well as specific risk by sex or family history status using up to 2762 cases and 3187 controls from the International Schizophrenia Consortium (ISC)

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Background Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). Methods We conducted a large- scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10−6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a ‘neurodevelopmental hub’ on chromosome 8p11.23. Conclusions This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P\u3c1×10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p \u3c 5×10−8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD

Polygenetic risk scores and phenotypic constellations of obsessive–compulsive disorder in clozapine-treated schizophrenia

Obsessive–compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clo- zapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive–compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabo- lism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant cor- relation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment dura- tion in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development