Higher-order comparative reward processing is affected by noninvasive stimulation of the ventromedial prefrontal cortex.

A crucial skill, especially in rapidly changing environments, is to be able to learn efficiently from prior rewards or losses and apply this acquired knowledge in upcoming situations. Often, we must weigh the risks of different options and decide whether an option is worth the risk or whether we should choose a safer option. The ventromedial prefrontal cortex (vmPFC) is suggested as a major hub for basic but also higher-order reward processing. Dysfunction in this region has been linked to cognitive risk factors for depression and behavioral addictions, including reduced optimism and feedback learning. Here, we test whether modulations of vmPFC excitability via noninvasive transcranial direct current stimulation (tDCS) can alter reward anticipation and reward processing. In a financial gambling task, participants chose between a higher and a lower monetary risk option and eventually received feedback whether they won or lost. Simultaneously feedback on the unchosen option was presented as well. Behavioral and magnetoencephalographic correlates of reward processing were evaluated in direct succession of either excitatory or inhibitory tDCS of the vmPFC. We were able to show modulated reward approach behavior (expectancy of greater reward magnitudes) as well as altered reevaluation of received feedback by vmPFC tDCS as indicated by modified choice behavior following the feedback. Thereby, tDCS not only influenced early, rather basic reward processing, but it also modulated higher-order comparative feedback evaluation of gains and losses relative to alternative outcomes. The neural results underline this idea, as stimulation-driven modulations of the basic reward-related effect occurred at rather early time intervals and were followed by stimulation effects related to comparative reward processing. Importantly, behavioral ratings were correlated with neural activity in left frontal areas. Our results imply a dual function of the vmPFC consisting of approaching reward (as indicated by more risky choices) and elaborately evaluating outcomes. In addition, our data suggest that vmPFC activity is associated with adaptive decision-making in the future via modulated behavioral adaptation or reinforcement learning.

Determinants of cognition in autoimmune limbic encephalitis-A retrospective cohort study.

Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood-cerebrospinal fluid (CSF)-barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer- and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2-/fluid attenuated inversion recovery (FLAIR)-signal-weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.

Semantic transparency effects in German compounds: A large dataset and multiple-task investigation.

In the present study, we provide a comprehensive analysis and a multi-dimensional dataset of semantic transparency measures for 1810 German compound words. Compound words are considered semantically transparent when the contribution of the constituents' meaning to the compound meaning is clear (as in airport), but the degree of semantic transparency varies between compounds (compare strawberry or sandman). Our dataset includes both compositional and relatedness-based semantic transparency measures, also differentiated by constituents. The measures are obtained from a computational and fully implemented semantic model based on distributional semantics. We validate the measures using data from four behavioral experiments: Explicit transparency ratings, two different lexical decision tasks using different nonwords, and an eye-tracking study. We demonstrate that different semantic effects emerge in different behavioral tasks, which can only be captured using a multi-dimensional approach to semantic transparency. We further provide the semantic transparency measures derived from the model for a dataset of 40,475 additional German compounds, as well as for 2061 novel German compounds.

From Five to Seven: Ring Expansion of Monoazadiene Titanium Complexes by Insertion of Aldehydes, Ketones and Nitriles.

The ring enlargement reactions at ambient temperatures of non C-terminus substituted monoazabutadiene (η4 -RN=CHCH=CH2 ) titanium complexes 2 are investigated. The insertion of aldehydes/ketones (five examples) and nitriles (four examples) into the Ti-C bonds result in expansion of the five-membered rings to uncommon seven-membered titanacycles 3 and 4 in good yields. These new compounds are fully characterized by NMR spectroscopy and single-crystal X-ray diffraction. In subsequent reactions, the seven-membered ring systems are protolyzed and the released organic fragments are isolated. Whereas the aldehyde/ketone insertion products 3 form substituted δ-amino alcohols 5 after reduction with NaBH3 CN, the nitrile insertion products 4 form substituted pyrroles 6 via cyclization.

Interference and facilitation in spoken word production: effects of morphologically and semantically related context stimuli on picture naming.

We report two picture-word interference experiments investigating conceptual and lexical activation, and response selection, in speaking. We varied stimulus onset asynchrony to investigate potential fine-grained activation and competition effects. Morphologically related existing and pseudoword adjectives, as well as associatively related adjectives, served as context stimuli in Experiment 1. In Experiment 2, we focused on semantic interference by using morphologically related and unrelated subordinates of the target concept as context stimuli. Morphologically complex pseudowords were also included as context stimuli. Pseudowords should not interfere, given that they have no lexical or conceptual representation. We consistently obtained facilitation with all morphologically related context stimuli, irrespective of their lexical status. We argue that effects originate at the word-form level, and discuss how our results may help decide among the many explanations of semantic interference in picture naming.

Non-invasive stimulation reveals ventromedial prefrontal cortex function in reward prediction and reward processing.

Introduction: Studies suggest an involvement of the ventromedial prefrontal cortex (vmPFC) in reward prediction and processing, with reward-based learning relying on neural activity in response to unpredicted rewards or non-rewards (reward prediction error, RPE). Here, we investigated the causal role of the vmPFC in reward prediction, processing, and RPE signaling by transiently modulating vmPFC excitability using transcranial Direct Current Stimulation (tDCS). Methods: Participants received excitatory or inhibitory tDCS of the vmPFC before completing a gambling task, in which cues signaled varying reward probabilities and symbols provided feedback on monetary gain or loss. We collected self-reported and evaluative data on reward prediction and processing. In addition, cue-locked and feedback-locked neural activity via magnetoencephalography (MEG) and pupil diameter using eye-tracking were recorded. Results: Regarding reward prediction (cue-locked analysis), vmPFC excitation (versus inhibition) resulted in increased prefrontal activation preceding loss predictions, increased pupil dilations, and tentatively more optimistic reward predictions. Regarding reward processing (feedback-locked analysis), vmPFC excitation (versus inhibition) resulted in increased pleasantness, increased vmPFC activation, especially for unpredicted gains (i.e., gain RPEs), decreased perseveration in choice behavior after negative feedback, and increased pupil dilations. Discussion: Our results support the pivotal role of the vmPFC in reward prediction and processing. Furthermore, they suggest that transient vmPFC excitation via tDCS induces a positive bias into the reward system that leads to enhanced anticipation and appraisal of positive outcomes and improves reward-based learning, as indicated by greater behavioral flexibility after losses and unpredicted outcomes, which can be seen as an improved reaction to the received feedback.

Excitatory stimulation of the ventromedial prefrontal cortex reduces cognitive gambling biases via improved feedback learning.

Humans are subject to a variety of cognitive biases, such as the framing-effect or the gambler's fallacy, that lead to decisions unfitting of a purely rational agent. Previous studies have shown that the ventromedial prefrontal cortex (vmPFC) plays a key role in making rational decisions and that stronger vmPFC activity is associated with attenuated cognitive biases. Accordingly, dysfunctions of the vmPFC are associated with impulsive decisions and pathological gambling. By applying a gambling paradigm in a between-subjects design with 33 healthy adults, we demonstrate that vmPFC excitation via transcranial direct current stimulation (tDCS) reduces the framing-effect and the gambler's fallacy compared to sham stimulation. Corresponding magnetoencephalographic data suggest improved inhibition of maladaptive options after excitatory vmPFC-tDCS. Our analyses suggest that the underlying mechanism might be improved reinforcement learning, as effects only emerge over time. These findings encourage further investigations of whether excitatory vmPFC-tDCS has clinical utility in treating pathological gambling or other behavioral addictions.

Review and meta-analysis of neuropsychological findings in autoimmune limbic encephalitis with autoantibodies against LGI1, CASPR2, and GAD65 and their response to immunotherapy.

OBJECTIVES: It is assumed that autoimmune limbic encephalitis (ALE) demonstrates distinct neuropsychological manifestations with differential responses to immunotherapy according to which associated autoantibody (AAB), if any, is identified. Towards investigating whether this is the case, this study aims to summarize respective findings from the primary literature on ALE with AABs binding to cell surface neural antigens and ALE with AABs against intracellular neural antigens. METHODS: We chose ALE with AABs against leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as the most frequent cell surface membrane antigens, and ALE with AABs to Embryonic Lethal, Abnormal Vision, Like 1 (ELAVL) proteins (anti-Hu) and glutamic acid decarboxylase 65 (GAD65) as the most frequent intracellular neural antigens. The PubMed and Scopus databases were searched on March 1st, 2021 for neuropsychological test and -screening data from patients with ALE of these AAB-types. Findings were reviewed according to AAB-type and immunotherapy status and are presented in a review section and are further statistically evaluated and presented in a meta-analysis section in this publication. RESULTS: Of the 1304 initial hits, 32 studies on ALE with AABs against LGI1, CASPR2, and GAD65 reporting cognitive screening data could be included in a review. In ALE with AABs against LGI1, CASPR2 and GAD65, memory deficits are the most frequently reported deficits. However, deficits in attention and executive functions including working memory, fluency, and psychological function have also been reported. This review shows that ALE patients with AABs against both LGI1 and CASPR2 show higher percentages of neuropsychological deficits compared to ALE patients with AABs against GAD65 before and after initiation of immunotherapy. However, the methodologies used in these studies were heterogenous, and longitudinal studies were not comparable. Moreover, 21 studies including ALE patients with AABs against LGI1 and GAD65 were also suitable for meta-analysis. No suitable study on ALE with AABs against ELAVL proteins could be identified. Meta-Analyses could be executed for cognitive screening data and only partially, due to the small number of studies. However, in statistical analysis no consistent effect of AAB or immunotherapy on performance in cognitive screening tests could be found. CONCLUSION: Currently, there is no definite evidence supporting the notion that different AAB-types of ALE exhibit distinct neuropsychological manifestations and respond differently to immunotherapy. Overall, we could not identify evidence for any effect of immunotherapy on cognition in ALE. More systematic, in-depth and longitudinal neuropsychological assessments of patients with different AAB-types of ALE are required in the future to investigate these aspects.

Enhancing precision in human neuroscience.

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

Neuropsychological Performance in Autoimmune Limbic Encephalitis: Evidence from an Immunotherapy-Naïve Cohort.

OBJECTIVE: Autoimmune limbic encephalitis (ALE) is characterized by memory impairment, psychiatric symptoms, and epileptic seizures. Though, the neuropsychological profile of ALE is not yet well defined. However, there is some evidence that neuropsychological impairments might exceed those related to the limbic system and that different autoantibodies (AABs) are associated with distinguishable pattern of neuropsychological impairments. We provide a comprehensive presentation of neuropsychological performance of ALE in an immune therapy-naïve sample. METHODS: We retrospectively analyzed 69 immunotherapy-naïve ALE-patients (26 seropositive-[8 LGI1-, 4 CASPR2-, 2 GABAB-R-, 3 Hu-, 4 GAD65-, 2 Ma2-, 2 unknown antigen, and 1 Yo-AABs] and 43 seronegative patients, mean age 56.0 years [21.9-78.2], mean disease duration 88 weeks [0-572]). Neuropsychological evaluations comprised of the domains memory, attention, praxis, executive functions, language, social cognition, and psychological symptoms. We compared these functions between seronegative -, seropositive patients with AABs against intracellular neural antigens and seropositive patients with AABs against surface membrane neural antigens. RESULTS: No effect of AAB group on neuropsychological performance could be detected. Overall, ALE predominantly presents with deficits in long-term memory and memory recognition, autobiographical-episodic memory loss, impairment of emotion recognition, and depressed mood. Furthermore, deficits in praxis of pantomimes and imitations, visuo-construction, and flexibility may occur. CONCLUSION: ALE shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between AAB groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression.

Conceptual representation of actions in sign language.

The idea that knowledge of events entails a universal spatial component, that is conceiving agents left of patients, was put to test by investigating native users of German sign language and native users of spoken German. Participants heard or saw event descriptions and had to illustrate the meaning of these events by means of drawing or arranging toys. Two types of verbs were tested, differing in the way they are signed. Verbs with a horizontal transient are typically signed with a left-to-right directionality, from the addressee's point of view. In contrast, verbs with sagittal transients display transitions moving toward or away from speaker. Signers showed a direct mapping preference for verbs with horizontal transients, by putting agents at the same position in space as in the signed message (i.e., mirroring signing space). No such effect was found for verbs with sagittal transients. In all, the data fit with the idea that interpretations of signed or spoken languages are modulated by task and culture as well as language-related factors and constraints.

The Agony of Choice? Preserved Affective Decision Making in Early Multiple Sclerosis.

Background: Cognitive impairment (CI) is an early and frequent symptom of multiple sclerosis (MS). Likewise, affective symptoms (e.g., depression and anxiety) and alterations in the processing of emotional stimuli have been frequently reported. Thus, abilities that integrate affective and cognitive processes such as decision making (DM) based on affective feedback are potentially valuable early diagnostic markers for MS. The available research on this topic, however, is still inconclusive and suffers from methodological issues. Methods: We compared DM ability in a clinically homogeneous cohort of 24 patients with early relapsing-remitting MS (RRMS) and 59 age-matched healthy controls (HCs). A modified version of the Iowa gambling task (IGT) allowed us to control for individual differences in search strategies during the risk exploration phase. Besides standard IGT measures (netscore, obtained play money, and learning index), we also examined reaction times and post-error slowing (PES) patterns as a proxy for abnormalities in the processing of affective feedback. Results: The performance of patients did not significantly deviate from HCs in any standard parameter of the modified IGT. Furthermore, although RRMS patients reacted significantly slower than HCs overall, we found similar patterns of PES in both groups, suggesting similarly efficient processing of affective feedback. Conclusion: We conclude that there is no specific deficit in affective feedback processing in early RRMS. Previous findings of IGT impairments in this patient group may thus not represent a genuine deficit in affective DM but rather be related to sample characteristics, general CI, and/or differences in individual search strategies. Future research should explore the potential influence of lesion volumes and locations on DM ability by employing brain imaging techniques.

Dissociating predictability, plausibility and possibility of sentence continuations in reading: evidence from late-positivity ERPs.

Late positive event-related potential (ERP) components occurring after the N400, traditionally linked to reanalysis due to syntactic incongruence, are increasingly considered to also reflect reanalysis and repair due to semantic difficulty. Semantic problems can have different origins, such as a mismatch of specific predictions based on the context, low plausibility, or even semantic impossibility of a word in the given context. DeLong, Quante & Kutas (2014) provided the first direct evidence for topographically different late positivities for prediction mismatch (left frontal late positivity for plausible but unexpected words) and plausibility violation (posterior-parietal late positivity for implausible, incongruent words). The aim of the current study is twofold: (1) to replicate this dissociation of ERP effects for plausibility violations and prediction mismatch in a different language, and (2) to test an additional contrast within implausible words, comparing impossible and possible sentence continuations. Our results replicate DeLong, Quante & Kutas (2014) with different materials in a different language, showing graded effects for predictability and plausibility at the level of the N400, a dissociation of plausible and implausible, anomalous continuations in posterior late positivities and an effect of prediction mismatch on late positivities at left-frontal sites. In addition, we found some evidence for a dissociation, at these left-frontal sites, between implausible words that were fully incompatible with the preceding discourse and those for which an interpretation is possible.

When a Social Experimenter Overwrites Effects of Salient Objects in an Individual Go/No-Go Simon Task - An ERP Study.

When two persons share a Simon task, a joint Simon effect occurs. The task co-representation account assumes that the joint Simon effect is the product of a vicarious representation of the co-actor's task. In contrast, recent studies show that even (non-human) event-producing objects could elicit a Simon effect in an individual go/no-go Simon task arguing in favor of the referential coding account. For the human-induced Simon effect, a modulation of the P300 component in Electroencephalography (EEG) is typically considered as a neural indicator of the joint Simon effect and task co-representation. Showing that the object-induced Simon effects also modulates the P300 would lead to a re-evaluation of the interpretation of the P300 in individual go/no-go and joint Simon task contexts. To do so, the present study conceptually replicated Experiment 1 from Dolk et al. (2013a) adding EEG recordings and an experimenter controlling the EEG computer to test whether a modulation of the P300 can also be elicited by adding a Japanese waving cat to the task context. Subjects performed an individual go/no-go Simon task with or without a cat placed next to them. Results show an overall Simon effect regardless of the cat's presence and no modulatory influence of the cat on the P300 (Experiment 1), even when conceivably interfering context factors are diminished (Experiment 2). These findings may suggest that the presence of a spatially aligned experimenter in the laboratory may produce an overall Simon effect overwriting a possible modulation of the Japanese waving cat.

Seeing for speaking: Semantic and lexical information provided by briefly presented, naturalistic action scenes.

At the interface between scene perception and speech production, we investigated how rapidly action scenes can activate semantic and lexical information. Experiment 1 examined how complex action-scene primes, presented for 150 ms, 100 ms, or 50 ms and subsequently masked, influenced the speed with which immediately following action-picture targets are named. Prime and target actions were either identical, showed the same action with different actors and environments, or were unrelated. Relative to unrelated primes, identical and same-action primes facilitated naming the target action, even when presented for 50 ms. In Experiment 2, neutral primes assessed the direction of effects. Identical and same-action scenes induced facilitation but unrelated actions induced interference. In Experiment 3, written verbs were used as targets for naming, preceded by action primes. When target verbs denoted the prime action, clear facilitation was obtained. In contrast, interference was observed when target verbs were phonologically similar, but otherwise unrelated, to the names of prime actions. This is clear evidence for word-form activation by masked action scenes. Masked action pictures thus provide conceptual information that is detailed enough to facilitate apprehension and naming of immediately following scenes. Masked actions even activate their word-form information-as is evident when targets are words. We thus show how language production can be primed with briefly flashed masked action scenes, in answer to long-standing questions in scene processing.

Prosopagnosia without apparent cause: overview and diagnosis of six cases.

We compared six cases of congenital prosopagnosia to unimpaired participants using standardized test batteries, tailor-made experimental paradigms, and clinical questionnaires. Every prosopagnosic participant displayed deficits in recognizing famous faces and retaining novel faces over short periods of time. Other aspects of face perception such as judgment of emotional expression, speech reading and memory for faces and names were impaired to a lesser degree or only in single cases. No evidence was found for general visual deficits or social dysfunctions. Two of our six cases are first order relatives, and a further three report first-order relatives suffering from prosopagnosic symptoms. The results are in line with the idea of a genetic component to congenital prosopagnosia.

Describing scenes hardly seen.

Knowledge about scene categories, the so-called gist, can be extracted very rapidly, while recognition and naming of individual scene objects is a more effortful process. We investigate this phenomenon by presenting action scenes involving two actors for durations varying between 100 and 300 ms. Incoherence was created by mirroring individual scene actors. Upon masked presentation participants had to report content, actors and objects and to indicate whether the scene was meaningful or not. Scene coherence was judged correctly at all presentation durations. Actors were correctly identified in about one-third of the cases even with presentation durations of 100 ms, and identification rate increased up to 80% with longer durations. Identification depended on scene coherence, on the position of agents in the scene, and on the position of actors relative to the fixation cross. These interdependencies of scene and object perception indicate that the visual system seems to be very sensitive to meaningful interactions of living entities. A series of fixations is not necessary to identify actors of a scene.

Electrophysiological correlates of aesthetic processing of webpages: a comparison of experts and laypersons.

We investigated whether design experts or laypersons evaluate webpages differently. Twenty participants, 10 experts and 10 laypersons, judged the aesthetic value of a webpage in an EEG-experiment. Screenshots of 150 webpages, judged as aesthetic or as unaesthetic by another 136 participants, served as stimulus material. Behaviorally, experts and laypersons evaluated unaesthetic webpages similarly, but they differed in their evaluation of aesthetic ones: experts evaluated aesthetic webpages as unaesthetic more often than laypersons did. The ERP-data show main effects of level of expertise and of aesthetic value only. There was no interaction of expertise and aesthetics. In a time-window of 110-130 ms after stimulus onset, aesthetic webpages elicited a more negative EEG-amplitude than unaesthetic webpages. In the same time window, experts had more negative EEG-amplitudes than laypersons. This patterning of results continued until a time window of 600-800 ms in which group and aesthetic differences diminished. An interaction of perceiver characteristics and object properties that several interactionist theories postulate was absent in the EEG-data. Experts seem to process the stimuli in a more thorough manner than laypersons. The early activation differences between aesthetic and unaesthetic webpages is in contrast with some theories of aesthetic processing and has not been reported before.

Differential Abnormal Pattern of Anterior Cingulate Gyrus Activation in Unipolar and Bipolar Depression: an fMRI and Pattern Classification Approach.

Distinguishing bipolar disorder from major depressive disorder is a major challenge in psychiatric treatment. Consequently, there has been growing interest in identifying neuronal biomarkers of disorder-specific pathophysiological processes to differentiate affective disorders. Thirty-six depressed bipolar patients, 36 depressed unipolar patients, and 36 matched healthy controls (HCs) participated in an fMRI experiment. Emotional faces served as stimuli in a matching task. We investigated neural activation towards angry, fearful, and happy faces focusing on prototypical regions related to emotion processing, ie, the amygdala and the anterior cingulate gyrus (ACG). Furthermore, we employed a whole-brain and a multivariate pattern classification analysis. Unipolar patients showed abnormally reduced ACG activation toward happy and fearful faces compared with bipolar patients and HCs respectively. Furthermore, the whole-brain analysis revealed significantly increased activation in bipolar patients compared with unipolar patients in the fearful condition in the right frontal and parietal cortex. Moreover, the multivariate pattern classification analysis yielded significant classification rates of up to 72% based on ACG activation elicited by fearful faces. Our results question the rather 'amygdalocentric' neurobiological models of mood disorders. We observed patterns of abnormally reduced ventral and supragenual ACG activation, potentially indicating impaired bottom-up emotion processing and automatic emotion regulation specifically in unipolar but not in bipolar individuals.

Stability of wave-packet dynamics under perturbations.

We introduce a method to investigate the stability of wave-packet dynamics under perturbations of the Hamiltonian. Our approach relies on semiclassical approximations, but is nonperturbative. Two separate contributions to the quantum fidelity are identified: one factor derives from the dispersion of the wave packets, whereas the other factor is determined by the separation of a trajectory of the perturbed classical system away from a corresponding unperturbed trajectory. We furthermore estimate both contributions in terms of classical Lyapunov exponents and find a decay of fidelity that is, generically, at least exponential, but may also be doubly exponential. The latter case is shown to be realized for inverted harmonic oscillators.