Andreas Frick

Fear and brain maturation

Fear is a response to perceived threat, present already in infants and changes over the course of development from concrete threats such as the dark and animals in childhood to abstract threats such as social failure and worry about the future in adolescents and adults. To study learning and memory mechanisms underlying fears, fear conditioning is often used. In this context, fear acquisition is the pairing of an initially neutral stimulus with an aversive response. During fear extinction, repeated exposure of a feared stimulus leads to a gradual attenuation of the fear response. Fear acquisition has been demonstrated in children as young as 2 years old, with a stronger pairing between the neutral stimulus and the fear response with increasing age, whereas fear extinction is impaired in adolescents as compared to children and adults. However, it is unknown how these developmental changes in fear conditioning are related to brain maturation and the surge in sex hormones in adolescence. In this project, we will examine how changes in fear acquisition and extinction from childhood to adulthood relate to changes in the brain and hormonal exposure. Children, adolescents, and adults will undergo fear acquisition and extinction as well as advanced neuroimaging. The project will increase our understanding of how basic mechanisms underlying acquisition and persistence of fears are related to the brain and sex hormones, and if these relations change over the course of development.
Final report
Project purpose and development
Learning which environmental cues that predict danger has great adaptive value to avoid unnecessary threats. This can be accomplished through Pavlovian fear conditioning where a previously neutral stimulus is paired with an aversive event. Equally important is learning when previous threats no longer pose a danger, which can be studied in the lab with fear extinction through repeated presentation of the fear-inducing stimulus and leads to a gradually attenuated fear response. However, the fear response may return with time, change of environment, or under stress. Almost all studies on fear conditioning are in adults, and knowledge of these processes in children, adolescents and adults is scarce. Fear learning has been demonstrated in children as young as two years old, but becomes stronger with age, whereas fear extinction has been found to be impaired in adolescents as compared to children and adults. Also, adolescence has been associated with impaired fear extinction and recurrence of the fear response to a greater extent than in children and adults. The aim of the project was therefore initially to investigate differences in fear learning and extinction between children, adolescents and adults and how these relate to brain maturation and the surge in sex hormones in adolescence.

During the implementation of the project, we sought to strengthen the developmental psychology aspects and therefore initiated a collaboration with Professor Karin Brocki, Department of Psychology, Uppsala University. In consultation with Professor Brocki and our international collaborator Dr Daniel S Pine at the National Institute of Mental Health, USA, and after further literature review, we added reward processing, which also potentially distinguishes adolescents from children and adults and additional concepts of interest for the development of fear and reward processing. Finally, we had an expanded aim of the project to study how learning and extinction of fears and reward processing changes from childhood to adulthood and how these processes relate to brain maturation, hormonal changes, adverse life events and development of self-regulation skills and socio-emotional functioning.

Implementation of the project
The project was severely delayed due to the Covid-19 pandemic and data collection has just been completed. Children, adolescents, and adults were assessed over two days for learning (session 1), extinction (session 1), and long-term memory (session 2, >24 hours after session 1) of fears by classical conditioning; brain function (fMRI), morphology, white matter integrity (diffusion tensor imaging; DTI), and GABA and glutamate concentrations (magnetic resonance spectroscopy; MRS) by magnetic resonance imaging (MRI; session 2); and sex hormone analysis in blood samples at both sessions. Participants also completed cognitive and emotional tasks to measure self-regulation and reward processing and answered questionnaires on emotions and emotion regulation, mental health, reward processing, pubertal development and life events.

Three main results of the project
Data collection has recently been completed and many of the project's questions have yet to be analyzed. We describe here three preliminary results regarding age-related changes in fear extinction, the development of the GABA and glutamate systems and their relation to emotion regulation, and age-related changes in reward processing and functional connectivity in the brain. The project has collected a large amount of data and will provide many more results in the coming years.

In preliminary analyses, we see comparable fear learning between the three age groups, and that, as expected, the adolescents show impaired extinction of the fear response. This is important because it replicates previous findings and shows that age-related changes in fear extinction are robust. No analyses have yet been done on the relationship between fear conditioning and brain maturity or sex hormone levels, which will contribute to a better understanding of the mechanisms behind changes in fear extinction.

Analysis of magnetic resonance spectroscopy data shows that children and adolescents have higher glutamate concentrations in the dorsal anterior cingulate cortex than adults and that children have higher concentration of GABA than adolescents and adults in the same brain region. Hence, it seems like the GABA system develops earlier than the glutamate system. This leads to an altered glutamate/GABA balance that can be understood as age differences in excitatory-inhibitory balance in favor of more excitation in adolescents. The changes in glutamate concentration may also be related to synaptic pruning occurring during adolescence, as glutamate concentration has previously been linked to synaptic density in adults. Further analysis is needed to clarify whether changes in glutamate concentration and/or the balance between glutamate and GABA can explain the preliminary extinction impairment in adolescents.

Preliminary analyses reported at an international scientific conference and currently being written up in a manuscript for publication also showed an association between glutamate and emotion regulation, with adolescents with lower glutamate concentration having better emotion regulation, while in adults it was the other way around, with higher glutamate concentration being associated with better emotion regulation. Adolescents with increased brain maturation (i.e., lower glutamate concentration, more synaptic pruning) thus had better emotion regulation ability.

Reward processing has been studied in the project using a reward learning task where participants play a game with a series of choices between two different figures. If they choose one figure, they receive a reward (in the form of points) and the other figure is associated with an aversive event (minus points). The rewarding/punishing figure changes over the course of the game, i.e. the contingencies change. The choices are then used in computational models to estimate parameters reflecting how quickly participants learn and how much they exploit previous learning or explore the environment. In this study, we were interested in how these parameters relate to resting-state fMRI and for this we implemented a new analysis approach, hierarchical Bayesian modeling with latent variables for parameters and relations. Preliminary analyses suggest that adolescents explore more than adults and that both the rate of learning and exploration are associated with the strength of connectivity between brain areas involved in reward processing at rest, e.g., the nucleus accumbens, orbitofrontal cortex, and ventral tegmental area. We were also able to show that this novel way of analyzing the data provided more robust estimates of parameters and relationships than more traditional variants. This framework constitutes a powerful way to combine multimodal data that, by being hierarchical, can utilize both intra- and inter-individual variation to estimate parameters with greater precision and thus more efficiently utilize the data. As we move forward and analyze the remaining data from the project, this analysis model will be an important cornerstone.

New research questions
We believe that the results from the project will generate many new research questions, but since so little of the material has been analyzed, it is too early to answer this question in a complete way. The preliminary results indicating that the GABA system develops earlier than the glutamate system would need to be tested and replicated in a longitudinal follow-up from childhood to adulthood to ensure that there are actual changes in the systems.

Dissemination of research and collaboration
The research has been and will continue to be disseminated through the publication of peer-reviewed articles in open access scientific journals, presentations at international scientific conferences, invited presentations and seminars at our own and other universities, and in contact with the surrounding community. We work continuously to inform about our activities both in the academic environment and towards the public. In the former case, we have on several occasions lectured on the project's planned approach and status in various research environments at Uppsala University and internationally. Preliminary results have been reported at scientific conferences. To reach out to the public, we have held open lectures and collaborated with science journalists on Swedish national radio (e.g., SR P1 Vetenskapsradion).
Grant administrator
Uppsala University
Reference number
SEK 3,177,000
RJ Projects
Psychology (excluding Applied Psychology)