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.

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.

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.

The brain's hemodynamic response function rapidly changes under acute psychosocial stress in association with genetic and endocrine stress response markers.

Ample evidence links dysregulation of the stress response to the risk for psychiatric disorders. However, we lack an integrated understanding of mechanisms that are adaptive during the acute stress response but potentially pathogenic when dysregulated. One mechanistic link emerging from rodent studies is the interaction between stress effectors and neurovascular coupling, a process that adjusts cerebral blood flow according to local metabolic demands. Here, using task-related fMRI, we show that acute psychosocial stress rapidly impacts the peak latency of the hemodynamic response function (HRF-PL) in temporal, insular, and prefrontal regions in two independent cohorts of healthy humans. These latency effects occurred in the absence of amplitude effects and were moderated by regulatory genetic variants of KCNJ2, a known mediator of the effect of stress on vascular responsivity. Further, hippocampal HRF-PL correlated with both cortisol response and genetic variants that influence the transcriptional response to stress hormones and are associated with risk for major depression. We conclude that acute stress modulates hemodynamic response properties as part of the physiological stress response and suggest that HRF indices could serve as endophenotype of stress-related disorders.

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.

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).

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.

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.

Disentangling reward anticipation with simultaneous pupillometry / fMRI.

The reward system may provide an interesting intermediate phenotype for anhedonia in affective disorders. Reward anticipation is characterized by an increase in arousal, and previous studies have linked the anterior cingulate cortex (ACC) to arousal responses such as dilation of the pupil. Here, we examined pupil dynamics during a reward anticipation task in forty-six healthy human subjects and evaluated its neural correlates using functional magnetic resonance imaging (fMRI). Pupil size showed a strong increase during monetary reward anticipation, a moderate increase during verbal reward anticipation and a decrease during control trials. For fMRI analyses, average pupil size and pupil change were computed in 1-s time bins during the anticipation phase. Activity in the ventral striatum was inversely related to the pupil size time course, indicating an early onset of activation and a role in reward prediction processing. Pupil dilations were linked to increased activity in the salience network (dorsal ACC and bilateral insula), which likely triggers an increase in arousal to enhance task performance. Finally, increased pupil size preceding the required motor response was associated with activity in the ventral attention network. In sum, pupillometry provides an effective tool for disentangling different phases of reward anticipation, with relevance for affective symptomatology.

Neural correlates of pupil dilation during human fear learning.

BACKGROUND: Fear conditioning and extinction are prevailing experimental and etiological models for normal and pathological anxiety. Pupil dilations in response to conditioned stimuli are increasingly used as a robust psychophysiological readout of fear learning, but their neural correlates remain unknown. We aimed at identifying the neural correlates of pupil responses to threat and safety cues during a fear learning task. METHODS: Thirty-four healthy subjects underwent a fear conditioning and extinction paradigm with simultaneous functional magnetic resonance imaging (fMRI) and pupillometry. After a stringent preprocessing and artifact rejection procedure, trial-wise pupil responses to threat and safety cues were entered as parametric modulations to the fMRI general linear models. RESULTS: Trial-wise magnitude of pupil responses to both conditioned and safety stimuli correlated positively with activity in dorsal anterior cingulate cortex (dACC), thalamus, supramarginal gyrus and insula for the entire fear learning task, and with activity in the dACC during the fear conditioning phase in particular. Phasic pupil responses did not show habituation, but were negatively correlated with tonic baseline pupil diameter, which decreased during the task. Correcting phasic pupil responses for the tonic baseline pupil diameter revealed thalamic activity, which was also observed in an analysis employing a linear (declining) time modulation. CONCLUSION: Pupil dilations during fear conditioning and extinction provide useful readouts to track fear learning on a trial-by-trial level, particularly with simultaneous fMRI. Whereas phasic pupil responses reflect activity in brain regions involved in fear learning and threat appraisal, most prominently in dACC, tonic changes in pupil diameter may reflect changes in general arousal.

Multi-echo EPI of human fear conditioning reveals improved BOLD detection in ventromedial prefrontal cortex.

Standard T2* weighted functional magnetic resonance imaging (fMRI) performed with echo-planar imaging (EPI) suffers from signal loss in the ventromedial prefrontal cortex (vmPFC) due to macroscopic field inhomogeneity. However, this region is of special interest to affective neuroscience and psychiatry. The Multi-echo EPI (MEPI) approach has several advantages over EPI but its performance against EPI in the vmPFC has not yet been examined in a study with sufficient statistical power using a task specifically eliciting activity in this region. We used a fear conditioning task with MEPI to compare the performance of MEPI and EPI in vmPFC and control regions in 32 healthy young subjects. We analyzed activity associated with short (12ms), standard (29ms) and long (46ms) echo times, and a voxel-wise combination of these three echo times. Behavioral data revealed successful differentiation of the conditioned versus safety stimulus; activity in the vmPFC was shown by the contrast "safety stimulus > conditioned stimulus" as in previous research and proved significantly stronger with the combined MEPI than standard single-echo EPI. Then, we aimed to demonstrate that the additional cluster extent (ventral extension) detected in the vmPFC with MEPI reflects activation in a relevant cluster (i.e., not just non-neuronal noise). To do this, we used resting state data from the same subjects to show that the time-course of this region was both connected to bilateral amygdala and the default mode network. Overall, we demonstrate that MEPI (by means of the weighted sum combination approach) outperforms standard EPI in vmPFC; MEPI performs always at least as good as the best echo time for a given brain region but provides all necessary echo times for an optimal BOLD sensitivity for the whole brain. This is relevant for affective neuroscience and psychiatry given the critical role of the vmPFC in emotion regulation.

Spontaneous pupil dilations during the resting state are associated with activation of the salience network.

Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.

One night of partial sleep deprivation affects habituation of hypothalamus and skin conductance responses.

Sleep disturbances are prevalent in clinical anxiety, but it remains unclear whether they are cause and/or consequence of this condition. Fear conditioning constitutes a valid laboratory model for the acquisition of normal and pathological anxiety. To explore the relationship between disturbed sleep and anxiety in more detail, the present study evaluated the effect of partial sleep deprivation (SD) on fear conditioning in healthy individuals. The neural correlates of 1) nonassociative learning and physiological processing and 2) associative learning (differential fear conditioning) were addressed. Measurements entailed simultaneous functional MRI, EEG, skin conductance response (SCR), and pulse recordings. Regarding nonassociative learning, partial SD resulted in a generalized failure to habituate during fear conditioning, as evidenced by reduced habituation of SCR and hypothalamus responses to all stimuli. Furthermore, SCR and hypothalamus activity were correlated, supporting their functional relationship. Regarding associative learning, effects of partial SD on the acquisition of conditioned fear were weaker and did not reach statistical significance. The hypothalamus plays an integral role in the regulation of sleep and autonomic arousal. Thus sleep disturbances may play a causal role in the development of normal and possibly pathological fear by increasing the susceptibility of the sympathetic nervous system to stressful experiences.

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.

Spatiotemporal reconfiguration of large-scale brain functional networks during propofol-induced loss of consciousness.

Applying graph theoretical analysis of spontaneous BOLD fluctuations in functional magnetic resonance imaging (fMRI), we investigated whole-brain functional connectivity of 11 healthy volunteers during wakefulness and propofol-induced loss of consciousness (PI-LOC). After extraction of regional fMRI time series from 110 cortical and subcortical regions, we applied a maximum overlap discrete wavelet transformation and investigated changes in the brain's intrinsic spatiotemporal organization. During PI-LOC, we observed a breakdown of subcortico-cortical and corticocortical connectivity. Decrease of connectivity was pronounced in thalamocortical connections, whereas no changes were found for connectivity within primary sensory cortices. Graph theoretical analyses revealed significant changes in the degree distribution and local organization metrics of brain functional networks during PI-LOC: compared with a random network, normalized clustering was significantly increased, as was small-worldness. Furthermore we observed a profound decline in long-range connections and a reduction in whole-brain spatiotemporal integration, supporting a topological reconfiguration during PI-LOC. Our findings shed light on the functional significance of intrinsic brain activity as measured by spontaneous BOLD signal fluctuations and help to understand propofol-induced loss of consciousness.

Effects of unconditioned stimulus intensity and fear extinction on subsequent sleep architecture in an afternoon nap.

Impaired fear extinction and disturbed sleep coincide in post-traumatic stress disorder (PTSD), but the nature of this relationship is unclear. Rapid eye movement (REM) sleep deprivation impairs fear extinction recall in rodents and young healthy subjects, and animal models have demonstrated both disrupted sleep after fear conditioning and normalized sleep after extinction learning. As a correlation between unconditioned stimulus (US) responding and subsequent sleep architecture has been observed in healthy subjects, the goal of this study was to test whether US intensity would causally affect subsequent sleep. Twenty-four young healthy subjects underwent a fear conditioning session with skin conductance response measurements before an afternoon session of polysomnographically recorded sleep (up to 120 min) in the sleep laboratory. Two factors were manipulated experimentally in a 2 × 2 design: US (electrical shock) was set at high or low intensity, and subjects did or did not receive an extinction session after fear conditioning. We observed that neither factor affected REM sleep amount, that high US intensity nominally increased sleep fragmentation (more Stage 1 sleep, stage shifts and wake after sleep onset), and that extinction increased Stage 4 amount. Moreover, reduced Stage 1 and increased Stage 4 and REM sleep were associated with subjective sleep quality of the afternoon nap. These results provide evidence for the notion that US intensity and extinction affect subsequent sleep architecture in young healthy subjects, which may provide a translational bridge from findings in animal studies to correlations observed in PTSD patients.

Baseline depression levels do not affect efficacy of cognitive-behavioral self-help treatment for insomnia.

BACKGROUND: Cognitive-behavioral therapy can effectively treat insomnia (CBT-I). Randomized controlled trials have shown efficacy of self-help CBT-I, but unclear is whether excluding depressive patients boosted treatment effects. METHOD: We administered unsupported self-help CBT-I to insomnia patients with low and high depression levels. Based on the validated Centre of Epidemiological Studies-Depression (CES-D) scale, the internet-recruited sample (N = 479) was divided into three groups: low depression scores (n = 198), mild depression scores (n = 182), and high depression scores (n = 99). Follow-ups were 4 and 18 weeks after completion of the treatment. RESULTS: At 4-week follow-up, all groups had a similar amelioration on the primary sleep measures (d = 0.1-0.7; P < 0.05) and the secondary insomnia ratings (d = 1.2; P < 0.001). The only difference was that the high/mild depression groups had a steeper reduction in depression (d = 1.0-1.1; P < 0.001) and anxiety scores (d = 0.7-0.8; P < 0.001) than the low depression group (depression and anxiety: d = 0.3; P < 0.01), possibly due to floor effects in the latter group. The observed effects were sustained at the 18-week follow-up. CONCLUSIONS: This study showed that CBT-I is effective regardless of baseline depression levels. Treating the combination of insomnia and depression is an extra challenge since it is associated with increased sleep problems. These data may help us understand the relationship between insomnia and depression and indicate that self-help CBT-I may be a promising addition to regular depression treatment.

Translational approaches to anxiety: focus on genetics, fear extinction and brain imaging.

Anxiety disorders are highly prevalent and debilitating psychiatric disorders. Owing to the complex aetiology of anxiety disorders, translational studies involving multiple approaches, including human and animal genetics, molecular, endocrinological and imaging studies, are needed to get a converging picture of function or dysfunction of anxiety-related circuits. An advantage of anxiety disorders is that the neural circuitry of fear is comparatively well understood, with striking analogies between animal and human models, and this article aims to provide a brief overview of current translational approaches to anxiety. Experimental models that involve similar tasks in animals and humans, such as fear conditioning and extinction, seem particularly promising and can be readily integrated with imaging, behavioural and physiological readouts. The cross-validation between animal and human genetics models is essential to examine the relevance of candidate genes, as well as their neural pathways, for anxiety disorders; a recent example of such cross-validation work is provided by preclinical and clinical work on TMEM132D, which has been identified as a candidate gene for panic disorder. Further integration of epigenetic data and gene × environment interaction are promising approaches, as highlighted by FKPB5 and PACAP, early life trauma and stress-related anxiety disorders. Finally, connecting genetic and epigenetic data with functionally relevant imaging readouts will allow a comparison of overlap and differences across species in mechanistic pathways from genes to brain functioning and behaviour.

REM sleep, hippocampus, and memory processing: insights from functional neuroimaging studies.

Neuroimaging studies show that episodic memory encoding is associated with increased activity in hippocampus and lateral prefrontal cortex; however, the latter structure shows decreased activity in rapid eye movement (REM) sleep. Together with few episodic memory traces in REM sleep, and REM sleep deprivation affecting hippocampus-independent emotional processes, this argues for generic information processing in REM sleep rather than linking episodic memory traces.

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.