Assessing hypo-arousal during reward anticipation with pupillometry in patients with major depressive disorder: replication and correlations with anhedonia.

Major depressive disorder (MDD) is a devastating and heterogenous disorder for which there are no approved biomarkers in clinical practice. We recently identified anticipatory hypo-arousal indexed by pupil responses as a candidate mechanism subserving depression symptomatology. Here, we conducted a replication and extension study of these findings. We analyzed a replication sample of 40 unmedicated patients with a diagnosis of depression and 30 healthy control participants, who performed a reward anticipation task while pupil responses were measured. Using a Bayesian modelling approach taking measurement uncertainty into account, we could show that the negative correlation between pupil dilation and symptom load during reward anticipation is replicable within MDD patients, albeit with a lower effect size. Furthermore, with the combined sample of 136 participants (81 unmedicated depressed and 55 healthy control participants), we further showed that reduced pupil dilation in anticipation of reward is inversely associated with anhedonia items of the Beck Depression Inventory in particular. Moreover, using simultaneous fMRI, particularly the right anterior insula as part of the salience network was negatively correlated with depressive symptom load in general and anhedonia items specifically. The present study supports the utility of pupillometry in assessing noradrenergically mediated hypo-arousal during reward anticipation in MDD, a physiological process that appears to subserve anhedonia.

Free-viewing gaze patterns reveal a mood-congruency bias in MDD during an affective fMRI/eye-tracking task.

Major depressive disorder (MDD) has been related to abnormal amygdala activity during emotional face processing. However, a recent large-scale study (n = 28,638) found no such correlation, which is probably due to the low precision of fMRI measurements. To address this issue, we used simultaneous fMRI and eye-tracking measurements during a commonly employed emotional face recognition task. Eye-tracking provide high-precision data, which can be used to enrich and potentially stabilize fMRI readouts. With the behavioral response, we additionally divided the active task period into a task-related and a free-viewing phase to explore the gaze patterns of MDD patients and healthy controls (HC) and compare their respective neural correlates. Our analysis showed that a mood-congruency attentional bias could be detected in MDD compared to healthy controls during the free-viewing phase but without parallel amygdala disruption. Moreover, the neural correlates of gaze patterns reflected more prefrontal fMRI activity in the free-viewing than the task-related phase. Taken together, spontaneous emotional processing in free viewing might lead to a more pronounced mood-congruency bias in MDD, which indicates that combined fMRI with eye-tracking measurement could be beneficial for our understanding of the underlying psychopathology of MDD in different emotional processing phases.Trial Registration: The BeCOME study is registered on ClinicalTrials (gov: NCT03984084) by the Max Planck Institute of Psychiatry in Munich, Germany.

The utility of wearable headband electroencephalography and pulse photoplethysmography to assess cortical and physiological arousal in individuals with stress-related mental disorders.

Several stress-related mental disorders are characterised by disturbed sleep, but objective sleep biomarkers are not routinely examined in psychiatric patients. We examined the use of wearable-based sleep biomarkers in a psychiatric sample with headband electroencephalography (EEG) including pulse photoplethysmography (PPG), with an additional focus on microstructural elements as especially the shift from low to high frequencies appears relevant for several stress-related mental disorders. We analysed 371 nights of sufficient quality from 83 healthy participants and those with a confirmed stress-related mental disorder (anxiety-affective spectrum). The median value of macrostructural, microstructural (spectral slope fitting), and heart rate variables was calculated across nights and analysed at the individual level (N = 83). The headbands were accepted well by patients and the data quality was sufficient for most nights. The macrostructural analyses revealed trends for significance regarding sleep continuity but not sleep depth variables. The spectral analyses yielded no between-group differences except for a group × age interaction, with the normal age-related decline in the low versus high frequency power ratio flattening in the patient group. The PPG analyses showed that the mean heart rate was higher in the patient group in pre-sleep epochs, a difference that reduced during sleep and dissipated at wakefulness. Wearable devices that record EEG and/or PPG could be used over multiple nights to assess sleep fragmentation, spectral balance, and sympathetic drive throughout the sleep-wake cycle in patients with stress-related mental disorders and healthy controls, although macrostructural and spectral markers did not differ between the two groups.

Data-Driven Pupil Response Profiles as Transdiagnostic Readouts for the Detection of Neurocognitive Functioning in Affective and Anxiety Disorders.

BACKGROUND: Neurocognitive functioning is a relevant transdiagnostic dimension in psychiatry. As pupil size dynamics track cognitive load during a working memory task, we aimed to explore if this parameter allows identification of psychophysiological subtypes in healthy participants and patients with affective and anxiety disorders. METHODS: Our sample consisted of 226 participants who completed the n-back task during simultaneous functional magnetic resonance imaging and pupillometry measurements. We used latent class growth modeling to identify clusters based on pupil size in response to cognitive load. In a second step, these clusters were compared on affective and anxiety symptom levels, performance in neurocognitive tests, and functional magnetic resonance imaging activity. RESULTS: The clustering analysis resulted in two distinct pupil response profiles: one with a stepwise increasing pupil size with increasing cognitive load (reactive group) and one with a constant pupil size across conditions (nonreactive group). A larger increase in pupil size was significantly associated with better performance in neurocognitive tests in executive functioning and sustained attention. Statistical maps of parametric modulation of pupil size during the n-back task showed the frontoparietal network in the positive contrast and the default mode network in the negative contrast. The pupil response profile of the reactive group was associated with more thalamic activity, likely reflecting better arousal upregulation and less deactivation of the limbic system. CONCLUSIONS: Pupil measurements have the potential to serve as a highly sensitive psychophysiological readout for detection of neurocognitive deficits in the core domain of executive functioning, adding to the development of valid transdiagnostic constructs in psychiatry.

Startle Latency as a Potential Marker for Amygdala-Mediated Hyperarousal.

BACKGROUND: Fear-related disorders are characterized by hyperexcitability in reflexive circuits and maladaptive associative learning mechanisms. The startle reflex is suited to investigate both processes, either by probing it under baseline conditions or by deriving it in fear conditioning studies. In anxiety research, the amplitude of the fear-potentiated startle has been shown to be influenced by amygdalar circuits and has typically been the readout of interest. In schizophrenia research, prolonged startle peak latency under neutral conditions is an established readout, thought to reflect impaired processing speed. We therefore explored whether startle latency is an informative readout for human anxiety research. METHODS: We investigated potential similarities and differences of startle peak latency and amplitude derived from a classical fear conditioning task in a sample of 206 participants with varying severity levels of anxiety disorders and healthy control subjects. We first reduced startle response to stable components and regressed individual amygdala gray matter volumes onto the resulting startle measures. We then probed time, stimulus, and group effects of startle latency. RESULTS: We showed that startle latency and startle amplitude were 2 largely uncorrelated measures; startle latency, but not amplitude, showed a sex-specific association with gray matter volume of the amygdala; startle latencies showed a fear-dependent task modulation; and patients with fear-related disorders displayed shorter startle latencies throughout the fear learning task. CONCLUSIONS: These data provide support for the notion that probing startle latencies under threat may engage amygdala-modulated threat processing, making them a complementary marker for human anxiety research.

Facing Your Fear in Immersive Virtual Reality: Avoidance Behavior in Specific Phobia.

Specific phobias are the most common anxiety disorder and are characterized by avoidance behavior. Avoidance behavior impacts daily function and is proposed to impair extinction learning. However, despite its prevalence, its objective assessment remains a challenge. To this end, we developed a fully automated experimental procedure using immersive virtual reality. The procedure contained a behavioral search, forced-choice, and an approach task with varying degrees of freedom and task relevance of the stimuli. In this study, we examined the sensitivity and feasibility of these tasks to assess avoidance behavior in patients with specific phobia. We adapted the tasks by replacing the originally conditioned stimuli with a spider and a neutral animal and investigated 31 female participants composed of 15 spider-phobic and 16 non-phobic participants. As the non-phobics were quite heterogeneous in terms of their Fear of Spiders Questionnaire (FSQ) scores, we subdivided them into six "fearfuls" that had elevated FSQ scores, and 10 "non-fearfuls" that had no fear of spiders. The phobics successfully managed to complete the procedure and showed consistent avoidance behavior across all behavioral tasks. Compared to the non-fearfuls, which did not show any avoidance behavior at all, the phobics looked at the spider much more often and clearly directed their body toward it in the search task. In the approach task, they hesitated most when they were close to the spider, and their difficulty to touch the spider was reflected in a strong increase in right hand acceleration changes. The fearfuls showed avoidance behavior depending on the tasks: strongest in the search task and weakest in the approach task. Additionally, we identified subjective valence ratings of the spider as the main influence on both objective avoidance behavior and subjective well-being after exposure, mediating the effect of the FSQ. In summary, the behavioral tasks are well suited to assess avoidance behavior in phobic participants and provide detailed insights into the process of avoidance.

Pupillometry tracks cognitive load and salience network activity in a working memory functional magnetic resonance imaging task.

The diameter of the human pupil tracks working memory processing and is associated with activity in the frontoparietal network. At the same time, recent neuroimaging research has linked human pupil fluctuations to activity in the salience network. In this combined functional magnetic resonance imaging (fMRI)/pupillometry study, we recorded the pupil size of healthy human participants while they performed a blockwise organized working memory task (N-back) inside an MRI scanner in order to monitor the pupil fluctuations associated neural activity during working memory processing. We first confirmed that mean pupil size closely followed working memory load. Combining this with fMRI data, we focused on blood oxygen level dependent (BOLD) correlates of mean pupil size modeled onto the task blocks as a parametric modulation. Interrogating this modulated task regressor, we were able to retrieve the frontoparietal network. Next, to fully exploit the within-block dynamics, we divided the blocks into 1 s time bins and filled these with corresponding pupil change values (first-order derivative of pupil size). We found that pupil change within N-back blocks was positively correlated with BOLD amplitudes in the areas of the salience network (namely bilateral insula, and anterior cingulate cortex). Taken together, fMRI with simultaneous measurement of pupil parameters constitutes a valuable tool to dissect working memory subprocesses related to both working memory load and salience of the presented stimuli.

Examining Differences in Fear Learning in Patients With Obsessive-Compulsive Disorder With Pupillometry, Startle Electromyography and Skin Conductance Responses.

Obsessive-compulsive disorder (OCD) is characterized by recurrent, persistent thoughts and repetitive behaviors causing stress and anxiety. In the associative learning model of OCD, mechanisms of fear extinction are supposed to partly underlie symptom development, maintenance and treatment of OCD, proposing that OCD patients suffer from rigid memory associations and inhibitory learning deficits. To test these assumptions, previous studies have used skin conductance and subjective ratings as readouts in fear conditioning paradigms, finding impaired fear extinction learning, impaired fear extinction recall or no differences between individuals with OCD and healthy controls. Against this heterogeneous background, we tested fear acquisition and extinction in 37 OCD patients and 56 healthy controls, employing skin conductance as well as pupillometry and startle electromyography. Extinction recall was also included in a subsample. We did not observe differences between groups in any of the task phases, except a trend toward higher startle amplitudes during extinction for OCD. Overall, sensitive readouts such as pupillometry and startle responses did not provide evidence for moderate-to-large inhibitory learning deficits using classical fear conditioning, challenging the assumption of generically impaired extinction learning and memory in OCD.

Pupil Dilation during Reward Anticipation Is Correlated to Depressive Symptom Load in Patients with Major Depressive Disorder.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

Quantifying Human Avoidance Behavior in Immersive Virtual Reality.

Avoidance behavior is a key symptom of most anxiety disorders and a central readout in animal research. However, the quantification of real-life avoidance behavior in humans is typically restricted to clinical populations, who show actual avoidance of phobic objects. In experimental approaches for healthy participants, many avoidance tasks utilize button responses or a joystick navigation on the screen as indicators of avoidance behavior. To allow the ecologically valid assessment of avoidance behavior in healthy participants, we developed a new automated immersive Virtual Reality paradigm, where participants could freely navigate in virtual 3-dimensional, 360-degrees scenes by real naturalistic body movements. A differential fear conditioning procedure was followed by three newly developed behavioral tasks to assess participants' avoidance behavior of the conditioned stimuli: an approach, a forced-choice, and a search task. They varied in instructions, degrees of freedom, and high or low task-related relevance of the stimuli. We initially examined the tasks in a quasi-experiment (N = 55), with four consecutive runs and various experimental adaptations. Here, although we observed avoidance behavior in all three tasks after additional reinforcement, we only detected fear-conditioned avoidance behavior in the behavioral forced-choice and search tasks. These findings were largely replicated in a confirmatory experiment (N = 72) with randomized group allocation, except that fear-conditioned avoidance behavior was only manifest in the behavioral search task. This supports the notion that the behavioral search task is sensitive to detect avoidance behavior after fear conditioning only, whereas the behavioral approach and forced-choice tasks are still able to detect "strong" avoidance behavior after fear conditioning and additional reinforcement.

The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes.

BACKGROUND: A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications. METHODS: BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques. DISCUSSION: The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses. TRIAL REGISTRATION: Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

No robust differences in fear conditioning between patients with fear-related disorders and healthy controls.

Fear conditioning and extinction serve as a dominant model for the development and maintenance of pathological anxiety, particularly for phasic fear to specific stimuli or situations. The validity of this model would be supported by differences in the physiological or subjective fear response between patients with fear-related disorders and healthy controls, whereas the model's validity would be questioned by a lack of such differences. We derived pupillometry, skin conductance response and startle electromyography as well as unconditioned stimulus expectancy in a two-day fear acquisition, immediate extinction and recall task and compared an unmedicated group of patients (n = 73) with phobias or panic disorder and a group of patients with posttraumatic stress disorder (PTSD, n = 21) to a group of carefully screened healthy controls (n = 35). Bayesian statistics showed no convincing evidence for a difference in physiological and subjective responses between the groups during fear acquisition, extinction learning or recall. Only the PTSD subgroup had altered startle reactions during extinction learning. Our data do not provide evidence for general differences in associative fear or extinction learning in fear-related pathologies and thereby question the diagnostic validity of the associative fear learning model of these disorders.

Neural Processing During Fear Extinction Predicts Intrusive Memories.

BACKGROUND: Deficient extinction learning has been suggested as an important mechanism involved in the etiology of posttraumatic stress disorder. A key feature of posttraumatic stress disorder, reexperiencing the trauma in form of intrusions, may be linked to deficient extinction learning. This link is investigated in a novel, functional magnetic resonance imaging-compatible fear conditioning procedure that uses trauma films. Based on previous results, we expected deficient fear extinction indexed by exaggerated responding in the anterior insula and dorsal anterior cingulate cortex to predict subsequent intrusions. METHODS: A total of 58 healthy participants underwent acquisition and extinction learning with faces as conditioned stimuli (CS) and highly aversive 16-second films depicting interpersonal violence as unconditioned stimuli. During the subsequent 3 days, participants reported intrusive memories on their smartphone. RESULTS: Successful fear acquisition was evidenced by differential (CS+ > CS-) activity (threat cues associated with trauma films > cues paired only with neutral films) of a widespread network, including the anterior insula and dorsal anterior cingulate cortex, whereas extinction was characterized exclusively by differential anterior insula activity. Differential conditioned responding during late extinction in the anterior insula and dorsal anterior cingulate cortex was positively related to intrusive memory frequency independent of unconditioned stimuli responding. Exploratory analysis also revealed intrusion sensitivity of the hippocampus, rostral anterior cingulate cortex, and ventromedial prefrontal cortex, among others. CONCLUSIONS: Results support the role of extinction learning in intrusive memory formation; a failure to uncouple conditioned emotional responding from external threat cues was associated with subsequent intrusive memories, representing a potential risk marker for developing posttraumatic stress disorder symptomatology after trauma.

Cortical hyperarousal in NREM sleep normalizes from pre- to post- REM periods in individuals with frequent nightmares.

STUDY OBJECTIVES: Frequent nightmares have a high prevalence and constitute a risk factor for psychiatric conditions, but their pathophysiology is poorly understood. Our aim was to examine sleep architecture and electroencephalographic markers-with a specific focus on state transitions-related to sleep regulation and hyperarousal in participants with frequent nightmares (NM participants) versus healthy controls. METHODS: Healthy controls and NM participants spent two consecutive nights in the sleep laboratory. Second night spectral power during NREM to REM sleep (pre-REM) and REM to NREM (post-REM) transitions as well as during NREM and REM periods were evaluated for 22 NM participants compared to 22 healthy controls with a similar distribution of age, gender, and dream recall frequency. RESULTS: We found significant differences between the groups in the pre-REM to post-REM changes in low- and high-frequency domains. NM participants experienced a lower amount of slow-wave sleep and showed increased beta and gamma power during NREM and pre-REM periods. No difference was present during REM and post-REM phases. Furthermore, while increased pre-REM high-frequency power seems to be mainly driven by post-traumatic stress disorder (PTSD) symptom intensity, decreased low-frequency activity occurred regardless of PTSD symptom severity. CONCLUSION: Our findings indicate that NM participants had increased high-frequency spectral power during NREM and pre-REM periods, as well as relatively reduced slow frequency and increased fast frequency spectral power across pre-and post-REM periods. This combination of reduced sleep-protective activity and increased hyperarousal suggests an imbalance between sleep regulatory and wake-promoting systems in NM participants.

Hyperarousal captured in increased number of arousal events during pre-REM periods in individuals with frequent nightmares.

The aim of this study was to investigate hyperarousal in individuals with frequent nightmares (NM participants) by calculating arousal events during nocturnal sleep. We hypothesized an increased number of arousals in NM participants compared with controls, especially during those periods where the probability of spontaneous arousal occurrence is already high, such as non-rapid eye movement to rapid eye movement transitions (pre-rapid eye movement periods). Twenty-two NM participants and 23 control participants spent two consecutive nights in our sleep laboratory, monitored by polysomnography. Arousal number and arousal length were calculated only for the second night, for 10 min before rapid eye movement (pre-rapid eye movement) and 10 min after rapid eye movement (post-rapid eye movement) periods, as well as non-rapid eye movement and rapid eye movement phases separately. Repeated-measures ANOVA model testing revealed significant Group (NM participants, controls) × Phase (pre-rapid eye movement, post-rapid eye movement) interaction in case of the number of arousals. Furthermore, post hoc analysis showed a significantly increased number of arousals during pre-rapid eye movement periods in NM participants, compared with controls, a difference that disappeared in post-rapid eye movement periods. We propose that focusing the analyses of arousals specifically on state transitory periods offers a unique perspective into the fragile balance between the sleep-promoting and arousal systems. This outlook revealed an increased number of arousals in NM participants, reflecting hyperarousal during pre-rapid eye movement periods.

Human Memories Can Be Linked by Temporal Proximity.

Real-world memories involve the integration of multiple events across time, yet the mechanisms underlying this integration is unknown. Recent rodent studies show that distinct memories encoded within a few hours, but not several days, share a common neural ensemble, and a common fate whereby later fear conditioning can transfer from one memory to the other. Here, we tested if distinct memories could be linked by temporal proximity in humans. 74 young adults encoded two memories (A and B) close (3-h) or far apart (7-day) in time. One day after encoding the second memory (B), Memory A was updated by pairing it with electric shock (i.e., fear conditioning). We tested whether the memory and fear associated with Memory B would be stronger in the 3-h, compared with the 7-day condition. Results were generally consistent with rodent studies, where we found heightened Memory B fear expression when the two memories were encoded close, but not far apart, in time. Furthermore, there was less forgetting of Memory B in the 3-h compared to 7-day condition. Our results suggest that temporally proximal memories may be linked, such that updating one experience updates the other.

Symptoms are not the solution but the problem: Why psychiatric research should focus on processes rather than symptoms.

Progress in psychiatric research has been hindered by the use of artificial disease categories to map distinct biological substrates. Efforts to overcome this obstacle have led to the misconception that relevant psychiatric dimensions are not biologically reducible. Consequently, the return to phenomenology is once again advocated. We propose a process-centered paradigm of biological reduction compatible with non-reductive materialism.

Peritraumatic Neural Processing and Intrusive Memories: The Role of Lifetime Adversity.

BACKGROUND: Pathological peritraumatic encoding is proposed as a proximal risk factor for the development of posttraumatic stress disorder (PTSD), with trauma-analog studies linking increased neural processing of trauma films to intrusive trauma recollections, a core symptom of PTSD. Cumulative lifetime adversity is proposed as a more distal risk factor, with research indicating a tipping point at about five events with regard to PTSD development following re-exposure to trauma. Thus, within a diathesis × stress framework, increased peritraumatic neural processing may constitute a specific risk factor for PTSD, particularly in individuals with several lifetime adversities. METHODS: Fifty-three healthy women watched highly aversive films depicting severe interpersonal violence versus neutral films during functional magnetic resonance imaging, and they reported involuntary recollections during subsequent days. Moderation analyses tested the interactive relationship between peritraumatic neural processing and lifetime adversity in predicting intrusion load, i.e., the total number of intrusions weighted for their average distress. RESULTS: Increased processing of aversive versus neutral films in the amygdala, anterior insula, dorsal and rostral anterior cingulate cortices, and hippocampus predicted increased intrusion load only in participants reporting above five lifetime adversities; for participants reporting few to none, no such relationship was found. This interactive relationship explained ≤59% of variance. Conditioned stimuli preceding film viewing mirrored this pattern. CONCLUSIONS: Peritraumatic neural processing in multiple salience network regions and cumulative lifetime adversity interactively predicted PTSD-like symptomatology, representing a diathesis × stress framework that might guide identification of at-risk individuals and potential targets for symptom prevention after traumatic incidents.

Aetiology and treatment of nightmare disorder: State of the art and future perspectives.

This consensus paper provides an overview of the state of the art in research on the aetiology and treatment of nightmare disorder and outlines further perspectives on these issues. It presents a definition of nightmares and nightmare disorder followed by epidemiological findings, and then explains existing models of nightmare aetiology in traumatized and non-traumatized individuals. Chronic nightmares develop through the interaction of elevated hyperarousal and impaired fear extinction. This interplay is assumed to be facilitated by trait affect distress elicited by traumatic experiences, early childhood adversity and trait susceptibility, as well as by elevated thought suppression and potentially sleep-disordered breathing. Accordingly, different treatment options for nightmares focus on their meaning, on the chronic repetition of the nightmare or on maladaptive beliefs. Clinically, knowledge of healthcare providers about nightmare disorder and the delivery of evidence-based interventions in the healthcare system is discussed. Based on these findings, we highlight some future perspectives and potential further developments of nightmare treatments and research into nightmare aetiology.

Measuring the conditioned response: A comparison of pupillometry, skin conductance, and startle electromyography.

In human fear conditioning studies, different physiological readouts can be used to track conditioned responding during fear learning. Commonly employed readouts such as skin conductance responses (SCR) or startle responses have in recent years been complemented by pupillary readouts, but to date it is unknown how pupillary readouts relate to other measures of the conditioned response. To examine differences and communalities among pupil responses, SCR, and startle responses, we simultaneously recorded pupil diameter, skin conductance, and startle electromyography in 47 healthy subjects during fear acquisition, extinction, and a recall test on 2 consecutive days. The different measures correlated only weakly, displaying most prominent differences in their response patterns during fear acquisition. Whereas SCR and startle responses habituated, pupillary measures did not. Instead, they increased in response to fear conditioned stimuli and most closely followed ratings of unconditioned stimulus (US) expectancy. Moreover, we observed that startle-induced pupil responses showed stimulus discrimination during fear acquisition, suggesting a fear potentiation of the auditory pupil reflex. We conclude that different physiological outcome measures of the conditioned response inform about different cognitive-affective processes during fear learning, with pupil responses being least affected by physiological habituation and most closely following US expectancy.