By monitoring ongoing actions and performance outcomes, we are able to detect errors or mismatches between our intentions or predictions. Disturbances in such performance-monitoring processes may... Show moreBy monitoring ongoing actions and performance outcomes, we are able to detect errors or mismatches between our intentions or predictions. Disturbances in such performance-monitoring processes may importantly contribute to impaired adaptive behavior in clinical disorders, such as excessively impulsive behavior in externalizing disorders or excessively rigid or careful behavior in anxiety- and obsessive-compulsive disorders. In daily life, performance monitoring often takes place in a social context, where our actions have consequences not only for ourselves, but also for others. The investigation of (alterations in) such (pro)social performance-monitoring processes may help explain functional and social impairments across a wide range of clinical disorders. In this dissertation, we used various neuroimaging paradigms to examine subclinical and neurochemical influences on performance monitoring when errors had consequences for oneself or others. The studies in this dissertation indicate that neural performance-monitoring correlates are modulated by social, subclinical, and neurochemical factors, including social (responsibility) context, obsessive-compulsive symptoms, ovarian hormones, and pharmacological manipulations of dopamine and oxytocin. These findings have implications for the potential and utility of error-related brain activity as a clinical biomarker or endophenotype, our insight into social symptoms and impairments in obsessive-compulsive disorder, and for our understanding of the neurochemical mechanisms underlying performance monitoring. Show less
The aim of the present study was to gain insight into the neurobiological processes, particularly the dopaminergic processes, underlying attentional control during reading and reading comprehension... Show moreThe aim of the present study was to gain insight into the neurobiological processes, particularly the dopaminergic processes, underlying attentional control during reading and reading comprehension. In order to test the effects of increased levels of dopamine (DA) in the brain, female university students (N = 80), half of them being carriers of the DRD4-7R allele and half of them not, participated in a double-blind placebo-controlled within-subjects experiment in which they were orally administered levodopa or a placebo before reading a text. After reading the text, participants reported on their attentional control during reading and completed comprehension questions. Pharmacologically increasing DA levels in the brain negatively influenced reading comprehension. This effect was moderate (ηp2 = .13). No interaction effects of condition and DRD4 genotype were found, for either attentional control or reading comprehension. Exploratory analyses showed that increased DA levels in the brain positively influenced fluctuations in attentional control, but only in a group of slow readers. No effects of increased DA were found for the two other attentional control measures used in the present study and no effects of increased DA on attentional control were found for fast readers. Results are discussed from the perspective of the inverted U-shape theory and the possible dopamine-related mechanisms. Show less
The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
Adaptive behavioral control involves a balance between top-down persistence and flexible updating of goals under changing demands. According to the metacontrol state model (MSM), this balance... Show moreAdaptive behavioral control involves a balance between top-down persistence and flexible updating of goals under changing demands. According to the metacontrol state model (MSM), this balance emerges from the interaction between the frontal and the striatal dopaminergic system. The attentional blink (AB) task has been argued to tap into the interaction between persistence and flexibility, as it reflects overpersistence—the too-exclusive allocation of attentional resources to the processing of the first of two consecutive targets. Notably, previous studies are inconclusive about the association between the AB and noninvasive proxies of dopamine including the spontaneous eye blink rate (sEBR), which allegedly assesses striatal dopamine levels. We aimed to substantiate and extend previous attempts to predict individual sizes of the AB in two separate experiments with larger sample sizes (N = 71 & N = 65) by means of noninvasive behavioral and physiological proxies of dopamine (DA), such as sEBR and mood measures, which are likely to reflect striatal dopamine levels, and color discrimination, which has been argued to tap into the frontal dopamine levels. Our findings did not confirm the prediction that AB size covaries with sEBR, mood, or color discrimination. The implications of this inconsistency with previous observations are discussed. Show less
Without even realizing, human beings perform extraordinary feats on a daily basis. We navigate an increasingly complicated and demanding world by using our sophisticated ability to override... Show moreWithout even realizing, human beings perform extraordinary feats on a daily basis. We navigate an increasingly complicated and demanding world by using our sophisticated ability to override habitual tendencies. Furthermore, we can meticulously plan, carry out and adapt actions in order to achieve goals that we set for ourselves. This capacity for goal-directed behavior—often considered a hallmark of human excellence over other animals—is commonly referred to as ‘cognitive control’ or ‘executive function’. These are rather vague, typically synonymous concepts that serve more as an umbrella term for many different processes rather than referring to a single, unitary function. Decades of neuropsychological research have been devoted to understanding cognitive control and its component processes, the way it is implemented in the brain, and how we can alter—and possibly improve—its efficacy. These issues have driven the work included in this dissertation. In particular, the research presented in this dissertation concerns itself with the overarching questions of how chemical processes in the brain (dopamine, glutamate, and GABA) enable and affect cognitive control, and how we might non-invasively measure and manipulate these biological underpinnings of goal-directed behavior. Show less
Discovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between... Show moreDiscovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between the drug and the neurological systems of interest. Here we present a systems-pharmacology approach that combines a multi-biomarker approach (e.g. metabolomics) with pharmacokinetic/pharmacodynamic (PK/PD) modeling to reveal quantitative pharmacological characteristics that are relevant to dopaminergic drug action. Moreover, we set out to identify biomarkers that can be obtained from the blood as non-invasive sampling site. In the first section of this thesis the methodology is introduced in the context of translational CNS drug development. Moreover, a systematic search is performed to available biomarkers of dopaminergic drug action. Then, in the second part, the multi-biomarker PK/PD approach is applied to biomarkers from the neuroendocrine system as connection between brain and blood. In the third section, the methodology is developed using the simultaneous, time-resolved metabolomics response in brain extracellular fluid and plasma. By applying multi-biomarker PK/PD modeling we revealed quantitative pharmacological characteristics of dopaminergic drugs with regard to multiple biological processes. Moreover, we identified potential blood-based biomarkers of dopaminergic effect in the brain. Show less
The locus coeruleus (LC) is a nucleus in the brainstem, and projects widely to the forebrain where it releases norepinephrine (NE). Catecholamines such as NE do not have a unitary effect on their... Show moreThe locus coeruleus (LC) is a nucleus in the brainstem, and projects widely to the forebrain where it releases norepinephrine (NE). Catecholamines such as NE do not have a unitary effect on their target neurons, but instead influence the function of other neurotransmitters, a process that is known known as neuromodulation. By virtue of the LC’s wide projection profile and the neuromodulatory properties of NE, the LC-NE system profoundly influences neural firing characteristics and associated cognitive processes. The work presented in this thesis addresses the role of the LC-NE system in various aspects of human cognition, and the modulation of brain state. Show less
The research presented in this thesis focused on the effects of cannabis on mental functions and the brain. Specifically, the investigation aimed at exploring how cannabis affects creative... Show moreThe research presented in this thesis focused on the effects of cannabis on mental functions and the brain. Specifically, the investigation aimed at exploring how cannabis affects creative thinking, awareness of errors, and the neurotransmitter dopamine among regular cannabis users. It was discovered that cannabis does not improve creativity and that it can decrease error awareness and impair dopaminergic functioning. Consequently, these findings allow for a better understanding of the nature of subtle mental impairments among chronic cannabis users. Show less
Dexamphetamine (dAMPH) is not only used for the treatment of attention deficit hyperactivity disorder (ADHD), but also as a recreational drug. Acutely, dAMPH induces release of predominantly... Show moreDexamphetamine (dAMPH) is not only used for the treatment of attention deficit hyperactivity disorder (ADHD), but also as a recreational drug. Acutely, dAMPH induces release of predominantly dopamine (DA) in the striatum, and in the cortex both DA and noradrenaline. Recent animal studies have shown that chronic dAMPH administration can induce changes in the DA system following long-term exposure, as evidenced by reductions in DA transporters, D-2/3 receptors and endogenous DA levels. However, only a limited number of studies have investigated the effects of dAMPH in the human brain. We used a combination of resting-state functional magnetic resonance imaging (rs-fMRI) and [I-123] IBZM single-photon emission computed tomography (SPECT) (to assess baseline D-2/3 receptor binding and DA release) in 15 recreational AMPH users and 20 matched healthy controls to investigate the short-, and long-term effects of AMPH before and after an acute intravenous challenge with dAMPH. We found that acute dAMPH administration reduced functional connectivity in the cortico-striatal-thalamic network. dAMPH-induced DA release, but not DA D-2/3 receptor binding, was positively associated with connectivity changes in this network. In addition, acute dAMPH reduced connectivity in default mode networks and salience-executive-networks networks in both groups. In contrast to our hypothesis, no significant group differences were found in any of the rs-fMRI networks investigated, possibly due to lack of sensitivity or compensatory mechanisms. Our findings thus support the use of ICA-based resting-state functional connectivity as a tool to investigate acute, but not chronic, alterations induced by dAMPH on dopaminergic processing in the striatum. Show less
De neurotransmitter dopamine speelt een essenti_le rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de... Show moreDe neurotransmitter dopamine speelt een essenti_le rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de ziekte van Parkinson, schizofrenie, drugsverslaving en hyperprolactinemie. De huidige farmacotherapeutische methoden om dopaminerge neurotransmissie te be_nvloeden, hebben slechts een beperkt effect op de symptomen, terwijl hinderlijke bijwerkingen kunnen optreden. Derhalve heeft verbetering van de farmacotherapie van deze ziekten een hoge prioriteit. De bevindingen van studies in dit proefschrift en followup studies tonen aan dat verbetering van de kinetiek van het geneesmiddel ter plaatse van de receptor en verbetering van de selectiviteit van het geneesmiddel veelbelovende strategie_n zijn. De resultaten van be_nvloeding van de controle mechanismen door tachykinines en gaba lijken vooralsnog minder therapeutisch nut op te leveren, maar geven wel indicaties voor biologische effecten die verder onderzoek verdienen. Deze onderzoekslijnen geven aan dat, ondanks de grote verscheidenheid aan beschikbare dopamine agonisten en antagonisten, de therapeutische mogelijkheden om dopamine neurotransmissie te be_nvloeden nog lang niet verzadigd zijn Show less
Schizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate... Show moreSchizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate if a hyperactive dopaminergic genotype interacts with adverse life experiences that activate the stress system. To examine this gene-by-environment interaction, we exposed rats genetically-selected for enhanced apomorphine susceptibility to two stress-provoking life events, poor maternal care early-in-life, and isolation rearing later-in-life. This promoted the development of schizophrenia endophenotypes. Our experiments involved two complementary steps: First, we focused on the immediate endocrine adaptations to maternal separation in common rats. It is known that a single episode of prolonged maternal separation slowly increases corticosterone levels in the neonate rat. We discovered that if the pups had been previously exposed to maternal separation, this rise in corticosterone was abolished, suggesting that the pups had learned to predict the return of the dam. While readily adapting to repeated maternal absence, the pups, surprisingly, stayed alert and displayed a rapid response to an acute stressor. We then investigated whether pup__s stress responsiveness was influenced by the context of maternal separation. It appeared that the experience of being kept in isolation in a novel environment during repeated maternal separation, rather than the maternal absence per se, caused priming of the amygdala fear pathway, with lasting consequences for the responsiveness of the neuroendocrine and behavioral stress system. These endocrine and behavioral alterations, caused by early-life stress experience, consisted of schizophrenia-like phenotypes. Second, we sought to investigate the interplay of such early-life stress experience with schizophrenia genetic predisposition and/or later-life social stress experience. Thus, we were able to test the three-hit (cumulative stress) and the developmental mismatch hypotheses. The former states that exposure to earlylife adversity and later-life psychosocial stressors, superimposed on genetic susceptibility, result in a severe schizophrenia-like phenotype. The latter proposes that experiences early-in-life program the developing brain in preparation for the future. In the case of genetically-predisposed apomorphine susceptible rats (schizophrenia-susceptible), we provide strong evidence for the three-hit hypothesis. In the case of the nongenetically selected Wistar rats, the mismatch hypothesis is supported since the outcome of early-life stress often negatively interacted with the pre-puberty social context. In agreement with the three-hit hypothesis of schizophrenia, we conclude from the current experiments that early-life stress experience in interaction with highly reactive dopaminergic alleles, leads to amygdala priming that, together with additional stressors, precipitate schizophrenia. Show less
The studies of this thesis provide empirical evidence that creativity is not a homogeneous concept; rather it reflects the interplay of separate, dissociable processes such as convergent and... Show moreThe studies of this thesis provide empirical evidence that creativity is not a homogeneous concept; rather it reflects the interplay of separate, dissociable processes such as convergent and divergent thinking (e.g., Guilford, 1967). The cognitive mechanism of these two processes is different, but not opposite as assumed by Eysenck (1993). The results suggest that divergent and convergent thinking are both related to dopamine, but to different degrees and in different ways. It was observed that eye-blink rate was predicting creative performance, which provides strong support for approaches that relate creativity to dopamine (Ashby et al., 1999). However, the obtained dissociation calls for a more differentiated approach that distinguishes between convergent and divergent processes and allows for tapping different creativity-dopamine functions. The findings of this thesis also suggest that convergent thinking induces a control state that emphasizes the top-down biasing of creative solutions and/or local competition between them, whereas divergent thinking is associated with reduced top-down control and/or local competition. Taken together, results of four studies presented in this thesis show that convergent and divergent thinking are not necessarily opposite but they are not the same either, and optimal performance in different types of creativity tasks requires different conditions. Show less
In this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common... Show moreIn this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common psychiatric disorders. We found evidence of the involvement of serotonin, dopamine, and noradrenaline/the autonomic nervous system, but not the hypothalamic-pituitary-adrenal-axis, in the neurobiology of gSAD. As a result of our studies, we hypothesize that serotonin and dopamine function is decreased in gSAD, that there is hyperfunctioning of the autonomic nervous system, and that the other part of the stress system, the hypothalamic-pituitary-adrenal-axis function is not concordant with autonomic nervous system activation, as we saw in basal conditions, and in stress conditions following manipulation of the serotonergic system. We also think that there are indications that the female gonadal hormones also have a modulatory role in gSAD in a subgroup of women. This exploration of the neurobiology of gSAD leads to the conclusion that a variety of brain systems are involved in gSAD in a complex way.involvement of several neurotransmitter and hormonal systems in gSAD. Show less
Top-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions... Show moreTop-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions consistent with externally set rules or internally maintained intentions. Orthogonal to this goal-driven guidance, decisions may be biased also by stimulus-driven factors, such as the automatic reactivation of episodic associations that accompanied the current stimulus in a previous instance. We investigated whether top-down and bottom-up processes account for variation in context based decision making as measured by the AX-CPT in a behavioral [1] and fMRI study [2]. Moreover, several behavioural studies have indicated that transiently induced positive affect modulates control processes in context-based decision making, generally leading to enhanced flexibility. Using ERPs in a classic AX-CPT, we studied the temporal dynamics of a positive affect induction on control processes in context-based decision making [3]. Additionally, we studied learning the associations between a situation, the response to it, and the outcome of that decision and the effect of basal ganglia modulations on this learning process by means of a Parkinson’s patient study. Studies [1] and [2] pointed out that in decisions with rapidly changing environmental demands, goal-driven preparation is often beneficial but may also hamper performance which can be overcome by applying increased control. Moreover, this top-down bias is regulated more efficiently when the specific stimulus is presented in the same context it was previously associated with, compared to when it is presented in a new and unusual context. Additionally, fMRI study shed light on the way these stimulus-driven performance changes may be represented in the brain. Study [3] showed that a positive affect induction influenced reactive and evaluative components of control (indexed by the N2 elicited by the target, and by the Error-Related Negativity elicited after incorrect responses) in an AX-CPT task, whereas cue-induced preparation and maintenance processes remained largely unaffected (as reflected in the P3b and the Contingent Negative Variation components of the ERP). The patient studies suggest that moderate dopaminergic medication and STN stimulation in Parkinson’s patients [chapter 5,6] both improve learning functions relying on caudate and putamen. However, the improvement induced by dopaminergic medication largely depended on individual patient characteristics. Show less
Not everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have... Show moreNot everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse life events (stress) as risk factors. The objective of this thesis is to investigate the contribution of the adrenal stress hormones glucocorticoids and epinephrine to the psychostimulant effects of cocaine in the inbred DBA/2 and C57BL/6 mouse strains. Behavioural sensitisation, measured as an enhanced locomotor response to repeated cocaine exposure, was used as a model for the long-term neural adaptations underlying aspects of drug addiction. The results demonstrate that adrenal hormones play a critical role in cocaine sensitivity, which depends on genetic background because surgical removal of the adrenals (__adrenalectomy__) prevented cocaine sensitisation in DBA/2, but not C57BL/6 mice. The impact of genetic background was further emphasised by strain-specific changes in the midbrain dopamine system that mediates the rewarding effects of drugs. The effects of adrenalectomy could only be fully reversed by co-administration of glucocorticoids and epinephrine. These findings show that, depending on genetic background, adrenal stress hormones are important risk factors for vulnerability to cocaine, suggesting that pharmacological intervention in stress hormone action has therapeutic potential in drug addiction. Show less