Renée M. Visser

Neural substrates of individual differences in human fear learning: Evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data

To provide insight into individual differences in fear learning, we examined the emotional and cognitive expressions of discriminative fear conditioning in direct relation to its neural substrates. Contrary to previous behavioral–neural (fMRI) research on fear learning—in which the emotional expression of fear was generally indexed by skin conductance—we used fear-potentiated startle, a more reliable and specific index of fear. While we obtained concurrent fear-potentiated startle, neuroimaging (fMRI), and US-expectancy data, healthy participants underwent a fear-conditioning paradigm in which one of two conditioned stimuli (CS+ but not CS–) was paired with a shock (unconditioned stimulus [US]). Fear learning was evident from the differential expressions of fear (CS+ > CS–) at both the behavioral level (startle potentiation and US expectancy) and the neural level (in amygdala, anterior cingulate cortex, hippocampus, and insula). We examined individual differences in discriminative fear conditioning by classifying participants (as conditionable vs. unconditionable) according to whether they showed successful differential startle potentiation. This revealed that the individual differences in the emotional expression of discriminative fear learning (startle potentiation) were reflected in differential amygdala activation, regardless of the cognitive expression of fear learning (CS–US contingency or hippocampal activation). Our study provides the first evidence for the potential of examining startle potentiation in concurrent fMRI research on fear learning.

Neural pattern similarity predicts long-term fear memory

Although certain changes in the brain may reflect fear learning, there are no known markers that indicate whether an aversive experience will develop into fear memory. We examined the moment-to-moment dynamics of human fear learning by applying multi-voxel pattern analysis to single-trial blood oxygen level–dependent magnetic resonance imaging data. We found that the long-term behavioral expression of fear memory could be predicted from neural patterns at the time of learning.

The trauma film paradigm as an experimental psychopathology model of psychological trauma: intrusive memories and beyond.

A better understanding of psychological trauma is fundamental to clinical psychology. Following traumatic event(s), a clinically significant number of people develop symptoms, including those of Acute Stress Disorder and/or Post Traumatic Stress Disorder. The trauma film paradigm offers an experimental psychopathology model to study both exposure and reactions to psychological trauma, including the hallmark symptom of intrusive memories. We reviewed 74 articles that have used this paradigm since the earliest review (Holmes & Bourne, 2008) until July 2014. Highlighting the different stages of trauma processing, i.e. pre-, peri- and post-trauma, the studies are divided according to manipulations before, during and after film viewing, for experimental as well as correlational designs. While the majority of studies focussed on the frequency of intrusive memories, other reactions to trauma were also modelled. We discuss the strengths and weaknesses of the trauma film paradigm as an experimental psychopathology model of trauma, consider ethical issues, and suggest future directions. By understanding the basic mechanisms underlying trauma symptom development, we can begin to translate findings from the laboratory to the clinic, test innovative science-driven interventions, and in the future reduce the debilitating effects of psychopathology following stressful and/or traumatic events.

Associative Learning Increases Trial-by-Trial Similarity of BOLD-MRI Patterns

Associative learning is a dynamic process that allows us to incorporate new knowledge within existing semantic networks. Even after years, a seemingly stable association can be altered by a single significant experience. Here, we investigate whether the acquisition of new associations affects the neural representation of stimuli and how the brain categorizes stimuli according to preexisting and emerging associations. Functional MRI data were collected during a differential fear conditioning procedure and at test (4–5 weeks later). Two pictures of faces and two pictures of houses served as stimuli. One of each pair coterminated with a shock in half of the trials (partial reinforcement). Applying Multivoxel Pattern Analysis (MVPA) in a trial-by-trial manner, we quantified changes in the similarity of neural representations of stimuli over the course of conditioning. Our findings show an increase in similarity of neural patterns throughout the cortex on consecutive trials of the reinforced stimuli. Furthermore, neural pattern similarity reveals a shift from original categories (faces/houses) toward new categories (reinforced/unreinforced) over the course of conditioning. This effect was differentially represented in the cortex, with visual areas primarily reflecting similarity of low-level stimulus properties (original categories) and frontal areas reflecting similarity of stimulus significance (new categories). Effects were not dependent on overall response amplitude and were still present during follow-up. We conclude that trial-by-trial MVPA is a useful tool for examining how the human brain encodes relevant associations and forms new associative networks.

Representational similarity analysis offers a preview of the noradrenergic modulation of long-term fear memory at the time of encoding

Neuroimaging research on emotional memory has greatly advanced our understanding of the pathogenesis of anxiety disorders. While the behavioral expression of fear at the time of encoding does not predict whether an aversive experience will evolve into long-term fear memory, the application of multi-voxel pattern analysis (MVPA) for the analysis of BOLD-MRI data has recently provided a unique marker for memory formation. Here, we aimed to further investigate the utility of this marker by modulating the strength of fear memory with an α2-adrenoceptor antagonist (yohimbine HCl). Fifty-two healthy participants were randomly assigned to two conditions - either receiving 20mg yohimbine or a placebo pill (double-blind) - prior to differential fear conditioning and MRI-scanning. We examined the strength of fear associations during acquisition and retention of fear (48 h later) by assessing the similarity of BOLD-MRI patterns and pupil dilation responses. Additionally, participants returned for a follow-up test outside the scanner (2-4 weeks), during which we assessed fear-potentiated startle responses. Replicating our previous findings, neural pattern similarity reflected the development of fear associations over time, and unlike average activation or pupil dilation, predicted the later expression of fear memory (pupil dilation 48 h later). While no effect of yohimbine was observed on markers of autonomic arousal, including salivary α-amylase (sAA), we obtained indirect evidence for the noradrenergic enhancement of fear memory consolidation: sAA levels showed a strong increase prior to fMRI scanning, irrespective of whether participants had received yohimbine, and this increase correlated with the subsequent expression of fear (48 h later). Remarkably, this noradrenergic enhancement of fear was associated with changes in neural response patterns at the time of learning. These findings provide further evidence that representational similarity analysis is a sensitive tool for studying (enhanced) memory formation.

Quantifying learning-dependent changes in the brain: Single-trial multivoxel pattern analysis requires slow event-related fMRI.

Single-trial analysis is particularly useful for assessing cognitive processes that are intrinsically dynamic, such as learning. Studying these processes with fMRI is problematic, as the low signal-to-noise ratio of fMRI requires the averaging over multiple trials, obscuring trial-by-trial changes in neural activation. The superior sensitivity of multivoxel pattern analysis over univariate analyses has opened up new possibilities for single-trial analysis, but this may require different fMRI designs. Here, we measured fMRI and pupil dilation responses during discriminant aversive conditioning, to assess associative learning in a trial-by-trial manner. The impact of design choices was examined by varying trial spacing and trial order in a series of five experiments (total n = 66), while keeping stimulus duration constant (4.5 s). Our outcome measure was the change in similarity between neural response patterns related to two consecutive presentations of the same stimulus (within-stimulus) and between patterns related to pairs of different stimuli (between-stimulus) that shared a specific outcome (electric stimulation vs. no consequence). This trial-by-trial similarity analysis revealed clear single-trial learning curves in conditions with intermediate (8.1-12.6 s) and long (16.5-18.4 s) intervals, with effects being strongest in designs with long intervals and counterbalanced stimulus presentation. No learning curves were observed in designs with shorter intervals (1.6-6.1 s), indicating that rapid event-related designs-at present, the most common designs in fMRI research-are not suited for single-trial pattern analysis. These findings emphasize the importance of deciding on the type of analysis prior to data collection.

Quantifying learning‐dependent changes in the brain

Single-trial analysis is particularly useful for assessing cognitive processes that are intrinsically dynamic, such as learning. Studying these processes with fMRI is problematic, as the low signal-to-noise ratio of fMRI requires the averaging over multiple trials, obscuring trial-by-trial changes in neural activation. The superior sensitivity of multivoxel pattern analysis over univariate analyses has opened up new possibilities for single-trial analysis, but this may require different fMRI designs. Here, we measured fMRI and pupil dilation responses during discriminant aversive conditioning, to assess associative learning in a trial-by-trial manner. The impact of design choices was examined by varying trial spacing and trial order in a series of five experiments (total n = 66), while keeping stimulus duration constant (4.5 s). Our outcome measure was the change in similarity between neural response patterns related to two consecutive presentations of the same stimulus (within-stimulus) and between patterns related to pairs of different stimuli (between-stimulus) that shared a specific outcome (electric stimulation vs. no consequence). This trial-by-trial similarity analysis revealed clear single-trial learning curves in conditions with intermediate (8.1-12.6 s) and long (16.5-18.4 s) intervals, with effects being strongest in designs with long intervals and counterbalanced stimulus presentation. No learning curves were observed in designs with shorter intervals (1.6-6.1 s), indicating that rapid event-related designs-at present, the most common designs in fMRI research-are not suited for single-trial pattern analysis. These findings emphasize the importance of deciding on the type of analysis prior to data collection.

‘I Can't Concentrate’: A Feasibility Study with Young Refugees in Sweden on Developing Science-Driven Interventions for Intrusive Memories Related to Trauma

Background The number of refugees is the highest ever worldwide. Many have experienced trauma in home countries or on their escape which has mental health sequelae. Intrusive memories comprise distressing scenes of trauma which spring to mind unbidden. Development of novel scalable psychological interventions is needed urgently. Aims We propose that brief cognitive science-driven interventions should be developed which pinpoint a focal symptom alongside a means to monitor it using behavioural techniques. The aim of the current study was to assess the feasibility and acceptability of the methodology required to develop such an intervention. Method In this study we recruited 22 refugees (16–25 years), predominantly from Syria and residing in Sweden. Participants were asked to monitor the frequency of intrusive memories of trauma using a daily diary; rate intrusions and concentration; and complete a 1-session behavioural intervention involving Tetris game-play via smartphone. Results Frequency of intrusive memories was high, and associated with high levels of distress and impaired concentration. Levels of engagement with study procedures were highly promising. Conclusions The current work opens the way for developing novel cognitive behavioural approaches for traumatized refugees that are mechanistically derived, freely available and internationally scalable.

A translational perspective on neural circuits of fear extinction: Current promises and challenges

&NA; Fear extinction is the well‐known process of fear reduction through repeated re‐exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state‐of‐the‐art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub‐cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed.

From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France

This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP.