Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people, that is, how we learn to be... Show moreHumans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people, that is, how we learn to be prosocial. Yet the neurochemical mechanisms underlying such prosocial computations remain poorly understood. Here, we investigated whether pharmacological manipulation of oxytocin and dopamine influence the neurocomputational mechanisms underlying self-benefitting and prosocial reinforcement learning. Using a double-blind placebo-controlled cross-over design, we administered intranasal oxytocin (24 IU), dopamine precursor l-DOPA (100 mg + 25 mg carbidopa), or placebo over three sessions. Participants performed a probabilistic reinforcement learning task with potential rewards for themselves, another participant, or no one, during functional magnetic resonance imaging. Computational models of reinforcement learning were used to calculate prediction errors (PEs) and learning rates. Participants behavior was best explained by a model with different learning rates for each recipient, but these were unaffected by either drug. On the neural level, however, both drugs blunted PE signaling in the ventral striatum and led to negative signaling of PEs in the anterior mid-cingulate cortex, dorsolateral prefrontal cortex, inferior parietal gyrus, and precentral gyrus, compared to placebo, and regardless of recipient. Oxytocin (versus placebo) administration was additionally associated with opposing tracking of self-benefitting versus prosocial PEs in dorsal anterior cingulate cortex, insula and superior temporal gyrus. These findings suggest that both l-DOPA and oxytocin induce a context-independent shift from positive towards negative tracking of PEs during learning. Moreover, oxytocin may have opposing effects on PE signaling when learning to benefit oneself versus another. Show less
Meulen, M. van der; Dobbelaar, S.; Drunen, L. van; Heunis, J.S.; IJzendoorn, M.H. van; Blankenstein, N.E.; Crone, E.A.M. 2023
A fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently... Show moreA fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined inter-individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.0-26.0 years in 269 participants (149 females) with three time points of data (807 scans), drawn from three longitudinal datasets collected in the Netherlands, Norway, and USA. We further investigated the relationship between overall brain size and developmental changes, as well as how females and males differed in change variability across development. There was considerable inter-individual variability in the magnitude of changes observed for all examined brain measures. The majority of individuals demonstrated decreases in total gray matter volume, cortex volume, mean cortical thickness, and white matter surface area in mid-adolescence, with more variability present during the transition into adolescence and the transition into early adulthood. While most individuals demonstrated increases in white matter volume in early adolescence, this shifted to a majority demonstrating stability starting in mid-to-late adolescence. We observed sex differences in these patterns, and also an association between the size of an individual's brain structure and the overall rate of change for the structure. The present study provides new insight as to the amount of individual variance in changes in structural morphometrics from late childhood to early adulthood in order to obtain a more nuanced picture of brain development. The observed individual-and sex-differences in brain changes also highlight the importance of further studying individual variation in developmental patterns in healthy, at-risk, and clinical populations. Show less
While it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce... Show moreWhile it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce developmental outcomes. Here we test an interactive model of learning and development where certain learning-related changes are constrained by developmental changes in the brain against an alternative development-as-practice model where outcomes are determined primarily by the accumulation of experience regardless of age. Participants (8-29 years) participated in a three-wave, accelerated longitudinal study during which they completed a feedback learning task during an fMRI scan. Adopting a novel longitudinal modeling approach, we probed the unique and moderated effects of learning, experience, and development simultaneously on behavioral performance and network modularity during the task. We found nonlinear patterns of development for both behavior and brain, and that greater experience supported increased learning and network modularity relative to naive subjects. We also found changing brain-behavior relationships across adolescent development, where heightened network modularity predicted improved learning, but only following the transition from adolescence to young adulthood. These results present compelling support for an interactive view of experience and development, where changes in the brain impact behavior in context-specific fashion based on developmental goals. Show less
While it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce... Show moreWhile it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce developmental outcomes. Here we test an interactive model of learning and development where certain learning-related changes are constrained by developmental changes in the brain against an alternative development-as-practice model where outcomes are determined primarily by the accumulation of experience regardless of age. Participants (8–29 years) participated in a three-wave, accelerated longitudinal study during which they completed a feedback learning task during an fMRI scan. Adopting a novel longitudinal modeling approach, we probed the unique and moderated effects of learning, experience, and development simultaneously on behavioral performance and network modularity during the task. We found nonlinear patterns of development for both behavior and brain, and that greater experience supported increased learning and network modularity relative to naïve subjects. We also found changing brain-behavior relationships across adolescent development, where heightened network modularity predicted improved learning, but only following the transition from adolescence to young adulthood. These results present compelling support for an interactive view of experience and development, where changes in the brain impact behavior in context-specific fashion based on developmental goals. Show less
An increasing number of healthy people use methylphenidate, a psychostimulant that increases dopamine and noradrenaline transmission in the brain, to help them focus over extended periods of time.... Show moreAn increasing number of healthy people use methylphenidate, a psychostimulant that increases dopamine and noradrenaline transmission in the brain, to help them focus over extended periods of time. While methylphenidate has been shown to facilitate some cognitive functions, like focus and distractor-resistance, the same drug might also contribute to cognitive impairment, for example, in creativity. In this study, we investigated whether acute administration of a low oral dose (20 mg) of methylphenidate affected convergent and divergent creative processes in a sample of young healthy participants. Also, we explored whether such effects depended on individual differences in ADHD symptoms and working memory capacity. Contrary to our expectations, methylphenidate did not affect participants’ creative performance on any of the tasks. Also, methylphenidate effects did not depend on individual differences in trait hyperactivity–impulsivity or baseline working memory capacity. Thus, although the effects of methylphenidate on creativity might be underestimated in our study due to several methodological factors, our findings do not suggest that methylphenidate impairs people’s ability to be creative. Show less
The human brain is active during rest and hierarchically organized into intrinsic functional networks. These functional networks are largely established early in development, with reports of a... Show moreThe human brain is active during rest and hierarchically organized into intrinsic functional networks. These functional networks are largely established early in development, with reports of a shift from a local to more distributed organization during childhood and adolescence. It remains unknown to what extent genetic and environmental influences on functional connectivity change throughout adolescent development. We measured functional connectivity within and between eight cortical networks in a longitudinal resting-state fMRI study of adolescent twins and their older siblings on two occasions (mean ages 13 and 18 years). We modelled the reliability for these inherently noisy and head-motion sensitive measurements by analyzing data from split-half sessions. Functional connectivity between resting-state networks decreased with age whereas functional connectivity within resting-state networks generally increased with age, independent of general cognitive functioning. Sex effects were sparse, with stronger functional connectivity in the default mode network for girls compared to boys, and stronger functional connectivity in the salience network for boys compared to girls. Heritability explained up to 53% of the variation in functional connectivity within and between resting-state networks, and common environment explained up to 33%. Genetic influences on functional connectivity remained stable during adolescent development. In conclusion, longitudinal age-related changes in functional connectivity within and between cortical resting-state networks are subtle but wide-spread throughout adolescence. Genes play a considerable role in explaining individual variation in functional connectivity with mostly stable influences throughout adolescence. Show less
Klaassens, B.L.; Van Gerven, J.M.A.; Klaassen, E.S.; Van der Grond, J.; Rombouts, S.A.R.B. 2019
Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness... Show moreDisruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group x treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline. Show less
Klaassens, B.L.; Van Gerven, J.M.A.; Klaassen, E.S.; Van der Grond, J.; Rombouts, S.A.R.B. 2019
Our mistakes often have negative consequences for ourselves, but may also harm the people around us. Continuous monitoring of our performance is therefore crucial for both our own and others’ well... Show moreOur mistakes often have negative consequences for ourselves, but may also harm the people around us. Continuous monitoring of our performance is therefore crucial for both our own and others’ well-being. Here, we investigated how modulations in responsibility for other’s harm affects electrophysiological correlates of performance-monitoring, viz. the error-related negativity (ERN) and error positivity (Pe). Healthy participants (N = 27) performed a novel social performance-monitoring paradigm in two responsibility contexts. Mistakes made in the harmful context resulted in a negative consequence for a co-actor, i.e., hearing a loud aversive sound, while errors in the non-harmful context were followed by a soft non-aversive sound. Although participants themselves did not receive auditory feedback in either context, they did experience harmful mistakes as more distressing and reported higher effort to perform well in the harmful context. ERN amplitudes were enhanced for harmful compared to non-harmful mistakes. Pe amplitudes were unaffected. The present study shows that performing in a potentially harmful social context amplifies early automatic performance-monitoring processes and increases the impact of the resulting harmful mistakes. These outcomes not only further our theoretical knowledge of social performance monitoring, but also demonstrate a novel and useful paradigm to investigate aberrant responsibility attitudes in various clinical populations. Show less
In cognitive neuroscience there is a growing interest in individual differences. We propose the Multiple Indicators Multiple Causes (MIMIC) model of combined behavioral and fMRI data to determine... Show moreIn cognitive neuroscience there is a growing interest in individual differences. We propose the Multiple Indicators Multiple Causes (MIMIC) model of combined behavioral and fMRI data to determine whether such differences are quantitative or qualitative in nature. A simulation study revealed the MIMIC model to have adequate power for this goal, and parameter recovery to be satisfactory. The MIMIC model was illustrated with a re-analysis of Van Duijvenvoorde et al. (2016) and Blankenstein et al. (2018) decision making data. This showed individual differences in Van Duijvenvoorde et al. (2016) to originate in qualitative differences in decision strategies. Parameters indicated some individuals to use an expected value decision strategy, while others used a loss minimizing strategy, distinguished by individual differences in vmPFC activity. Individual differences in Blankenstein et al. (2018) were explained by quantitative differences in risk aversion. Parameters showed that more risk averse individuals preferred safe over risky choices, as predicted by heightened vmPFC activity. We advocate using the MIMIC model to empirically determine, rather than assume, the nature of individual differences in combined behavioral and fMRI datasets. Show less
Karch, J.D.; Fivelich, E.; Wenger, E.; Lisofski, N.; Becker, M.; Butler, O.; ... ; Kühn, S. 2019
Adequate reliability of measurement is a precondition for investigating individual differences and age-related changes in brain structure. One approach to improve reliability is to identify and... Show moreAdequate reliability of measurement is a precondition for investigating individual differences and age-related changes in brain structure. One approach to improve reliability is to identify and control for variables that are predictive of within-person variance. To this end, we applied both classical statistical methods and machine-learning-inspired approaches to structural magnetic resonance imaging (sMRI) data of six participants aged 24–31 years gathered at 40–50 occasions distributed over 6–8 months from the Day2day study. We explored the within-person associations between 21 variables covering physiological, affective, social, and environmental factors and global measures of brain volume estimated by VBM8 and FreeSurfer. Time since the first scan was reliably associated with Freesurfer estimates of grey matter volume and total cortex volume, in line with a rate of annual brain volume shrinkage of about 1 percent. For the same two structural measures, time of day also emerged as a reliable predictor with an estimated diurnal volume decrease of, again, about 1 percent. Furthermore, we found weak predictive evidence for the number of steps taken on the previous day and testosterone levels. The results suggest a need to control for time-of-day effects in sMRI research. In particular, we recommend that researchers interested in assessing longitudinal change in the context of intervention studies or longitudinal panels make sure that, at each measurement occasion, (a) a given participant is measured at the same time of day; (b) all participants are measured at about the same time of day. Furthermore, the potential effects of physical activity, including moderate amounts of aerobic exercise, and testosterone levels on MRI-based measures of brain structure deserve further investigation. Show less
Klapwijk, E.T.; Van de Kamp, F.; Meulen, M. van der; Peters, S.; Wierenga, L.M. 2019
Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are... Show moreStructural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease. Show less
The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are assumed to play a key role in dopamine-related functions such as reward-related behaviour, motivation, addiction and... Show moreThe ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are assumed to play a key role in dopamine-related functions such as reward-related behaviour, motivation, addiction and motor functioning. Although dopamine-producing midbrain structures are bordering, they show significant differences in structure and function that argue for a distinction when studying the functions of the dopaminergic midbrain, especially by means of neuroimaging. First, unlike the SNc, the VTA is not a nucleus, which makes it difficult to delineate the structure due to lack of clear anatomical borders. Second, there is no consensus in the literature about the anatomical nomenclature to describe the VTA. Third, these factors in combination with limitations in magnetic resonance imaging (MRI) complicate VTA visualization. We suggest that developing an MRI-compatible probabilistic atlas of the VTA will help to overcome these issues. Such an atlas can be used to identify the individual VTA and serve as region-of-interest for functional MRI. Show less
