Pupil dilation as an implicit measure of appetitive Pavlovian learning

Appetitive Pavlovian conditioning is a learning mechanism of fundamental biological and pathophysiological significance. Nonetheless, its exploration in humans remains sparse, which is partly attributed to the lack of an established psychophysiological parameter that aptly represents conditioned responding. This study evaluated pupil diameter and other ocular response measures (gaze dwelling time, blink duration and count) as indices of conditioning. Additionally, a learning model was used to infer participants' learning progress on the basis of their pupil dilation. Twenty-nine healthy volunteers completed an appetitive differential delay conditioning paradigm with a primary reward, while the ocular response measures along with other psychophysiological (heart rate, electrodermal activity, postauricular and eyeblink reflex) and behavioral (ratings, contingency awareness) parameters were obtained to examine the relation among different measures. A significantly stronger increase in pupil diameter, longer gaze duration and shorter eyeblink duration was observed in response to the reward-predicting cue compared to the control cue. The Pearce-Hall attention model best predicted the trial-by-trial pupil diameter. This conditioned response was corroborated by a pronounced heart rate deceleration to the reward-predicting cue, while no conditioning effect was observed in the electrodermal activity or startle responses. There was no discernible correlation between the psychophysiological response measures. These results highlight the potential value of ocular response measures as sensitive indices for representing appetitive conditioning

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem?s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes

Abnormal social reward processing in autism as indexed by pupillary responses to happy faces

Background: Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding. Methods: We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects. Results: Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group. Conclusions: We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets

It's the intention that matters : neural representations of learning from intentional harm in social interactions

As a social species, humans are not only driven by the pursuit of necessities such as food and shelter, but also complex processes such as social interactions. To navigate our everyday life, we use information gathered throughout a lifetime of social interactions in which we learn from others and their actions but also, and not less importantly, about others. To create a complete picture of a social interaction, we assess the individual we interact with, make judgements about them and their actions, and integrate what we know with the consequences of their actions. This way, we learn the relationship between events (e.g. others’ actions) and environmental stimuli, such as other individuals that predict the actions. As we encounter more people and go through more interactions, we continuously update information stored in memory from previous experiences. A common task, for example, going through the busy corridor in our workplace in a hurry does not only include avoiding physical harm caused by bumping into the coffee machine with a sharp corner, but also avoiding a co-worker we are in a feud with, and whom we believed knowingly spilled hot coffee on another co-worker the week before. How social information is processed is key in understanding rarer but more impactful events that can have lifelong impact on an individual’s life. Interpersonal trauma, a type of trauma that is acquired from harm received from another individual, leads more often to post-traumatic stress disorder (PTSD) than non-socially related trauma, for example, a car crash (Kleim, Ehlers, & Glucksman, 2007). To understand why a specific social harm affect us negatively, it is crucial to study how the brain integrates social, as well as nonsocial (physical) information during the harmful event. In Study I, II, and III we investigated how different streams of information (social and physical) are integrated during a social interaction. We were interested in how intentionality of an action that has direct aversive consequences on an individual can change the individuals’ judgements of the action and the person performing it. Using a time-based neuroimaging approach, we investigated how the value of an action is integrated with that of the intention behind it. Study I revealed evidence that suggests that intentionality of a directly experienced aversive action is represented throughout the cortex in neural activity patterns that form over time. Study II highlighted the importance of timing and sample size in similar paradigms, and that neural pattern formation in response to aversive actions regardless of the intentions behind them are robustly replicated. In Study III we asked questions about how these learned action outcomes and knowledge about the people performing the harmful action change neural connectivity, and how this translates into changes in perception and memory 24-hours later. We found an increased connectivity between the hippocampus and the amygdala, which correlated with generalized memory responses to images associated with shocks from an intentional harm do-er, and increased connectivity between the FFA and the insula, as well as the FFA and the dorsomedial prefrontal cortex (dmPFC) correlated with facilitated recognition of the intentional harm do-er’s face

Kognitive Interpretationen mehrdeutiger visueller Reize

Unser Gehirn muss zu jeder Zeit relevante Signale von irrelevanten Informationen trennen. Dazu müssen diese als spezifische Einheiten erkannt und klassifiziert werden. Mehrdeutigkeit ist ein wesentlicher Aspekt dieses Verarbeitungsprozesses und kann durch verrauschte Eingangssignale und durch den Aufbau unserer sensorischer Systeme entstehen. Beispielsweise können Reize mehrdeutig sein, wenn sie verrauscht oder unvollständig sind oder nur kurzzeitig wahrgenommen werden. Unter solchen Bedingungen werden Wahrnehmung und Klassifikation eines Reizes deutlich erschwert. Bereits vorhandene kognitive Repräsentationen werden somit möglicherweise nicht aktiviert. Folglich müssen Rückschlüsse über die Reize aufgrund von Kontext und Erfahrung gezogen werden. Ein und derselbe Reiz kann jedoch unterschiedlich repräsentiert und im sensorischen System kodiert werden. Da nur eine Repräsentation die Basis zukünftigen Handelns bilden kann, entsteht eine Art Konkurrenz innerhalb der Wahrnehmung. Derartige Wahrnehmungsphänomene, die mit der Mehrdeutigkeit von Reizen in Verbindung stehen, bilden den Mittelpunkt der vorliegenden Dissertation. Wenn einem physikalisch konstanten Reiz mehrere Interpretationen zugeordnet werden, entsteht ein Wechsel zwischen diesen Einordnungen, den man wahrnimmt und Rivalität ("rivalry") nennt. In dieser Dissertation werden diverse neue Erkenntnisse zu diesem grundlegenden Phänomen der sensorischen Verarbeitung beschrieben. So wird gezeigt, dass Übergänge zwischen drei wahrgenommenen Interpretationen – ein vergleichsweise selten untersuchtes Phänomen, da Rivalität meist mit zweideutigen Reizen untersucht wird – vorhersehbaren Mustern folgen (Kapitel 2). Darüber hinaus zeigt sich, dass derartige Übergänge spezifische Eigenschaften aufweisen, welche die Geschwindigkeit und die Richtung ihrer räumlichen Ausbreitung im visuellen Feld bestimmen (Kapitel 3). Diese Eigenschaften der Mehrdeutigkeit werden weiterhin stark von Aufmerksamkeit und anderen, introspektiven Prozessen beeinflusst. Um die der Rivalität in der Wahrnehmung tatsächlich zugrundeliegenden Prozesse und die damit verbundenen Änderungen des Bewusstseins von derartigen subjektiven Prozessen abzugrenzen, müssen letztere kontrolliert oder sogar vollständig umgangen werden. Ein objektives Maß der Rivalität in der Wahrnehmung wird zur Lösung dieser Aufgabe vorgeschlagen und bietet eine wertvolle Alternative zu introspektivem Berichten über den Wahrnehmungszustand (Kapitel 4). Übergänge in der Wahrnehmung entstehen entlang einer bestimmten Merkmalsdimension des Reizes, wie beispielsweise der Orientierung des berühmten Neckerwürfels. Zudem kann auch eine Änderung in der Merkmalsdimension der Luminanz eine unterschiedliche Interpretation des Reizes hervorrufen. Es wird gezeigt, dass die Pupille kleiner wird, wenn eine Interpretation mit hoher Luminanz die Wahrnehmung übernimmt, und umgekehrt, dass die Pupille größer wird, wenn eine Interpretation mit niedriger Luminanz die Wahrnehmung übernimmt. Folglich kann die Pupille als ein zuverlässiges und objektives Maß für Änderungen in der Wahrnehmung verwendet werden. Durch die Verwendung solcher objektiven Maße konnten neue Eigenschaften der Übergänge in der Wahrnehmung aufgezeigt werden, welche die Theorie unterstützen, dass Introspektion die der Verarbeitung mehrdeutiger Situationen zugrundeliegenden Prozesse merklich beeinflussen kann. Als Nächstes wurden mehrdeutiger Reize im Zusammenhang mit der Wahrnehmung von Objekten eingesetzt (Kapitel 5). Am Beispiel der Kippfigur des "bewegten Diamanten" wird dabei die Bedeutung von mehrdeutigen Reizen veranschaulicht. Beim bewegten Diamanten werden zwei Interpretationen wahrgenommen, die sich entlang der Dimension der Objektkohärenz abwechseln. Das bedeutet, dass die Wahrnehmung zwischen einem einzelnen zusammenhängenden Objekt (Diamant) und mehreren unzusammenhängenden Komponenten kippt. Es wird gezeigt, dass die Interpretation des Reizes als ein einziges kohärentes Objekt, verglichen mit der Interpretation als mehrere Komponenten, zu einer Erhöhung der visuellen Empfindlichkeit innerhalb des Objektes führt. Diese Ergebnisse sind ein Beleg dafür, wie die Aktivierung einer Interpretation eines Reizes als Einzelobjekt (im Vergleich zur Komponentenwahrnehmung) dazu führt, dass die Aufmerksamkeit top-down zu den relevanten Bereichen des Gesichtsfeldes gelenkt wird. Es wird weiter untersucht, welche Eigenschaften des Reizes zu einer bottom-up Aktivierung der Interpretation solcher Objekte beitragen (Kapitel 6). Die Mehrdeutigkeit von Objekten kann erfolgreich aufgehoben werden, indem man einen starken Kontrast in Luminanz oder Farbe zwischen dem Objekt und dem Hintergrund erzeugt. Auch die Größe und die Form haben einen großen Einfluss auf die Detektion und Identifikation von Objekten. Des Weiteren sind die Eigenschaften eines Objektes nicht nur bestimmend für die Erfolgsquote bei der Objekterkennung, sondern ebenso bedeutend für die Speicherung der Repräsentation im Gedächtnis, beispielsweise von neu wahrgenommenen Objekten. Das Klassifizieren von Objekten durch die Versuchsperson wird ebenfalls durch Mehrdeutigkeit beeinflusst. So kann ein Objekt der Versuchsperson einerseits als neu erscheinen, obwohl es bereits bekannt war, weil es beispielsweise der Versuchsperson schon einmal gezeigt worden ist. Andererseits kann auch ein eigentlich unbekanntes Objekt der Versuchsperson dennoch vertraut vorkommen. In dieser Arbeit wird gezeigt, dass solche subjektiven Effekte einen Einfluss auf die Pupillengröße haben (Kapitel 7). Außerdem verkleinert sich die Pupille der Versuchspersonen beim Betrachten neuer Bilder stärker als bei bekannten. Ein ähnlicher Effekt wird gefunden, wenn das Bild vorher erfolgreich im Gedächtnis gespeichert wurde. Daher ist es wahrscheinlich, dass die Pupille die Verfestigung von neuen Objekten im Gedächtnis widerspiegelt. Abschließend wird untersucht, ob sich kognitive Prozesse, wie Entscheidungsfindung – ein wichtiger Prozess, falls mehreren Optionen zur Verfügung stehen und Mehrdeutigkeit aufgehoben werden soll – auch in der Pupille widerspiegeln (Kapitel 8). Es wird zunächst bestätigt, dass die Pupillen sich erweitern, nachdem man eine Entscheidung getroffen hat. Neu wird gezeigt, dass diese Pupillenausdehnungen erfolgreich von anderen Personen erkannt und verwendet werden können, um ein interaktives Spiel gegen die erste Person (den "Gegner") zu gewinnen. Insgesamt wird in dieser Dissertation untersucht, wie mehrdeutige Reize die Wahrnehmung beeinflussen und wie Mehrdeutigkeit verwendet werden kann, um Prozesse des Gehirns zu studieren. Es hat sich gezeigt, dass Mehrdeutigkeit vorhersehbaren Mustern folgt, sie objektiv mit Reflexen gemessen werden kann, und Einblicke in neuronale Prozesse wie Aufmerksamkeit, Objektwahrnehmung und Entscheidungsmechanismen liefern kann. Diese Ergebnisse zeigen, dass Mehrdeutigkeit eine zentrale Eigenschaft sensorischer Systeme ist, und Lebewesen in die Lage versetzt, mit ihrer Umwelt flexibel zu interagieren. Mehrdeutigkeit macht das Verhalten vielfältiger, ermöglicht es dem Gehirn, mit der Welt auf verschiedenen Wegen zu interagieren, und ist die Basis der Dynamik von Wahrnehmung, Interpretation und Entscheidung.Brains can sense and distinguish signals from background noise in physical environments, and recognize and classify them as distinct entities. Ambiguity is an inherent part of this process. It is a cognitive property that is generated by the noisy character of the signals, and by the design of the sensory systems that process them. Stimuli can be ambiguous if they are noisy, incomplete, or only briefly sensed. Such conditions may make stimuli indistinguishable from others and thereby difficult to classify as single entities by our sensory systems. In these cases, stimuli fail to activate a representation that may have been previously stored in the system. Deduction, through context and experience, is consequently needed to reach a decision on what is exactly sensed. Deduction can, however, also be subject to ambiguity as stimuli and their properties may receive multiple representations in the sensory system. In such cases, these multiple representations compete for perceptual dominance, that is, for becoming the single entity taken by the system as a reference point for subsequent behavior. These types of ambiguity and several phenomena that relate to them are at the center of this dissertation. Perceptual rivalry, the phenomenal experience of alternating percepts over time, is an example of how the brain may give multiple interpretations to a stimulus that is physically constant. Rivalry is a very typical and general sensory process and this thesis demonstrates some newly discovered properties of its dynamics. It was found that alternations between three perceptual interpretations – a relatively rare condition as rivalry generally occurs between two percepts – follow predictable courses (Chapter 2). Furthermore, such alternations had several properties that determine their speed and direction of spatial spread (suppression waves) in the visual field (Chapter 3). These properties of ambiguity were further strongly affected by attention and other introspective processes. To demarcate the true underlying process of perceptual rivalry and the accompanied changes in awareness, these subjective processes need to be either circumvented or controlled for. An objective measure of perceptual rivalry was proposed that resolved this issue and provided a good alternative for introspective report of ambiguous states (Chapter 4). Changes in percepts occur along a specific feature domain such as depth orientation for the famous Necker cube. Alternatively, luminance may also be a rivalry feature and one percept may appear brighter as the other rivaling percept. It was demonstrated that the pupil gets smaller when a percept with high luminance becomes dominant, and vice versa, gets bigger when a percept with low luminance gets dominant during perceptual rivalry. As such, the pupil can serve as a reliable objective indicator of changes in visual awareness. By using such reflexes during rivalry, several new properties of alternations were discovered and it was again confirmed that introspection can confound the true processes involved in ambiguity. Next, the usefulness of ambiguous stimuli was explored in the context of objects as entities (Chapter 5). Some ambiguous stimuli can induce two percepts that alternate along the feature domain of object coherency, that is, whether a single coherent object or multiple incoherent objects are seen. In other words, an ambiguous stimulus can induce two cognitive interpretations of either seeing an entity or not. It was reported that being aware of a single coherent object results in the increase in visual sensitivity for the areas that constitute the object. These results are evidence of how the activation of a representation of a single and unique object can guide and allocate attentional resources to relevant areas in the visual field in a top-down way. It was further explored which features help to bottom-up access such object representations (Chapter 6). Ambiguity of objects can be successfully resolved by adding strong contrasts between the object and its background in luminance and color. The size and variability of the object's shape was also found to be an important factor for its successful detection and identification. Furthermore, the characteristics of objects do not only determine the rate of success in a recognition task, but are equally important for the storage of their representations in memory if, for instance, the object is novel to the observer. The subjective experience of a novel object is also subject to ambiguity and objects may appear novel to the observer although they are familiar (i.e., previously shown to the observer), or vice versa, they appear familiar to the observer although they are actually novel. It was here shown that such subjective effects are reflected in the pupil (Chapter 7). In addition, if novel images were presented to observers, their pupils constricted stronger as compared to if familiar images were presented. Similarly, if novel stimuli were shown to observers, pupillary constrictions were stronger if these stimuli were successfully stored in memory as compared to those later forgotten. As such, the pupil reflected the cognitive process of novelty encoding. Finally, it was tested whether other cognitive processes, such as decision-making – an important process when multiple options are available and ambiguity has to be resolved with a conscious decision – were also reflected in changes of pupil size (Chapter 8). It was confirmed that the pupil tends to dilate after an observer has made a decision. These dilations can successfully be detected between individuals and further used to gain the upper hand during an interactive game. In sum, this thesis has explored how ambiguous signals affect perception and how ambiguity inside perceptual systems can be used to study processes of the brain. It is found that ambiguity follows predictable courses, can be objectively assessed with reflexes, and can provide insights into other neuronal mechanisms such as attention, object representations, and decision-making. These findings demonstrate that ambiguity is a core property of the sensory systems that enable living beings to interact with their surroundings. Ambiguity adds variation to behavior, allows the brain to flexibly interact with the world, and lies at the bottom of the dynamics of sense, interpretations, and behavioral decisions

As Far as the Eye Can See: Relationship between Psychopathic Traits and Pupil Response to Affective Stimuli

Psychopathic individuals show a range of affective processing deficits, typically associated with the interpersonal/affective component of psychopathy. However, previous research has been inconsistent as to whether psychopathy, within both offender and community populations, is associated with deficient autonomic responses to the simple presentation of affective stimuli. Changes in pupil diameter occur in response to emotionally arousing stimuli and can be used as an objective indicator of physiological reactivity to emotion. This study used pupillometry to explore whether psychopathic traits within a community sample were associated with hypo-responsivity to the affective content of stimuli. Pupil activity was recorded for 102 adult (52 female) community participants in response to affective (both negative and positive affect) and affectively neutral stimuli, that included images of scenes, static facial expressions, dynamic facial expressions and sound-clips. Psychopathic traits were measured using the Triarchic Psychopathy Measure. Pupil diameter was larger in response to negative stimuli, but comparable pupil size was demonstrated across pleasant and neutral stimuli. A linear relationship between subjective arousal and pupil diameter was found in response to sound-clips, but was not evident in response to scenes. Contrary to predictions, psychopathy was unrelated to emotional modulation of pupil diameter across all stimuli. The findings were the same when participant gender was considered. This suggests that psychopathy within a community sample is not associated with autonomic hypo-responsivity to affective stimuli, and this effect is discussed in relation to later defensive/appetitive mobilisation deficits