Publications (28)200.24 Total impact
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Article: Estrogen and the male hippocampus: Genetic variation in the aromatase gene predicting serum estrogen is associated with hippocampal gray matter volume in men.
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ABSTRACT: The neurosteroid 17-beta estradiol (E2) plays an important role in neuronal plasticity, neurogenesis and neuroprotection of hippocampal neurons in slice cultures and the female brain. While some effects of E2 on hippocampal neurons observed in females were also seen in the male hippocampus, others seem to be specific to females. The current study aimed to further explore the effect of E2 on the male hippocampus by investigating the relationship between genetic variations in E2 synthesis and hippocampal gray matter (GM) volume. We chose a single nucleotide polymorphism (rs700158, SNP) in the gene CYP19A1 coding for the final enzyme (aromatase) in E2 synthesis. Men homozygous for the A allele of rs700518 have repeatedly been shown to have higher E2 serum levels than male carriers of the G allele. Two independent cohorts of healthy young men were genotyped for rs700518 and voxel-based morphometry (VBM) was performed on structural magnetic resonance images to determine genotype dependent group differences. Men homozygous for the A allele of rs700518 had greater bilateral posterior hippocampal GM volumes in both cohorts. Thus, the genotype associated with higher E2 serum levels was also associated with greater hippocampal gray matter. © 2012 Wiley Periodicals, Inc.Hippocampus 08/2012; · 5.18 Impact Factor -
Article: Ventral striatal signal changes represent missed opportunities and predict future choice.
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ABSTRACT: Realizing one has missed an opportunity can influence decision behavior in the future, such that a large missed opportunity leads to more risk taking in the next round. To investigate the neuronal mechanism of this phenomenon we used functional magnetic resonance imaging (fMRI) in combination with a sequential decision task in which the magnitude of possible gains linearly increased, but at the same time the gain probability decreased. After subjects decided to stop a trial and to collect the gains, not only the chosen option (actual outcome), but also the alternative option (maximum possible gain in this round) was revealed. Our data show that a missed chance influenced volunteers' decision behavior: volunteers took more risk after rounds in which they had missed a large opportunity. This was paralleled by signal changes in a lateral area of the ventral striatum that scaled with the difference between what could have been gained and what was actually gained in this round. In addition, after gains signal changes in dopaminoceptive structures including the midbrain and ventral striatum together with the insula predicted individual choice behavior in the subsequent round. Thus, our data provide a neural mechanism for how missed opportunities influence future decisions.NeuroImage 05/2011; 57(3):1124-30. · 5.89 Impact Factor -
Article: Processing of facial expressions and their significance for the observer in subregions of the human amygdala.
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ABSTRACT: Amygdala responses to emotional faces can be influenced by concomitant gaze direction. As an explanation it has been suggested that the observer uses eye gaze as a cue to decipher the source of a potential threat in order to evaluate the significance of the situation. To test this assumption, we kept gaze direction ambiguous and replaced the information possibly provided by gaze direction with explicit, contextual information about intentions of angry and fearful faces. Using fMRI we show that this manipulation evokes a similar pattern of amygdala activation as prior gaze-related accounts: angry faces targeting at the observer elicited stronger amygdala responses than angry faces targeting at another person, whereas the opposite pattern was observed for fearful faces. We further combined our paradigm with high-resolution fMRI which enabled us to localize clusters of activation in amygdala subregions: purely facial-expression evoked signal changes were observed in the accessory basal nucleus, whereas our data suggest a critical role of the corticomedial amygdala in linking contextual information to emotional faces and in deciphering the significance of the faces for the observer.NeuroImage 02/2011; 56(1):299-306. · 5.89 Impact Factor -
Article: Emotional processing in anterior cingulate and medial prefrontal cortex.
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ABSTRACT: Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.Trends in Cognitive Sciences 02/2011; 15(2):85-93. · 12.59 Impact Factor -
Article: A test for the implementation-maintenance model of reappraisal.
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ABSTRACT: Reappraisal has been defined as a conscious, deliberate change in the way an emotional stimulus is interpreted, initiated in order to change its emotion-eliciting character (Gross, 2002). Reappraisal can be used to down-regulate negative emotions, including anxiety (reviewed in Kalisch, 2009). There is currently a strong interest in identifying the cognitive processes and neural substrates that mediate reappraisal. We have recently proposed a model (termed implementation-maintenance model or IMMO) that conceptualizes reappraisal as a temporally extended, dynamic, and multi-componential process (Kalisch, 2009). A key tenet of IMMO is that reappraisal episodes are marked by an early phase of implementation that may comprise strategy selection and retrieval of reappraisal material into working memory, and a later phase of maintenance that may comprise working memory and performance monitoring processes. These should be supported by dissociable neural networks. We here show, using a detachment-from-threat paradigm and concurrent functional magnetic resonance imaging, that reappraisal-related brain activity shifts from left posterior to right anterior parts of the lateral frontal cortex during the course of a reappraisal episode. Our data provide first empirical evidence for the existence of two separable reappraisal stages. Implications for further model development are discussed.Frontiers in psychology. 01/2011; 2:216. -
Article: A meta-analysis of instructed fear studies: implications for conscious appraisal of threat.
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ABSTRACT: In classical Pavlovian fear conditioning, a neutral stimulus (conditioned stimulus, CS) comes to be evaluated as threatening due to its association with an aversive stimulus (unconditioned stimulus, UCS), and elicits fear. In a subtype of fear conditioning paradigms, called instructed fear or anticipatory anxiety, subjects are made aware of the CS-UCS association prior to actually experiencing it. Initial fear elicitation during this type of conditioning results from the negative evaluation of the CS as a consequence of CS-UCS contingency awareness. Prior reports have suggested that this conscious appraisal process is mediated by a variety of brain regions, including rostral dorsomedial prefrontal/dorsal anterior cingulate cortex (dmPFC/dACC), lateral prefrontal cortex (lPFC), posterior cingulate, hippocampus/parahippocampus, and nucleus accumbens, but there is little overlap between results. We reasoned that a formal meta-analysis of existing instructed fear studies should help narrow down the search for conscious appraisal areas in fear conditioning to those consistently activated across studies. We found consistent activation in rostral dmPFC but not in the other candidate areas. These results allow for maintaining the theory that the rostral dmPFC is involved in conscious threat appraisal. We also report a meta-analysis of uninstructed (classical) fear conditioning studies in which we found notable activation in more posterior parts of the dmPFC/dACC that overlapped with some of the instructed fear activations. These data suggest that mid regions of the dmPFC/dACC are part of a "core" fear network that is activated irrespective of how fear was learnt.NeuroImage 09/2009; 49(2):1760-8. · 5.89 Impact Factor -
Article: The functional neuroanatomy of reappraisal: time matters.
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ABSTRACT: Humans can regulate their emotional states through a number of effortful cognitive strategies, a type of adaptive behavior not found in animals. The best studied strategy is reappraisal which consists in deliberately changing the emotional interpretation of a stimulus. Reappraisal modulates both subjective and physiological emotional response components and has long-term effects on well-being and mental health. Over the past few years, a rapidly growing neuroimaging literature has attempted to characterize the neural mechanisms that mediate reappraisal, but results have so far been relatively inconsistent. This article provides an overview of the current state of the field and presents a first formal quantitative meta-analysis of neuroimaging findings. It introduces a new model of the cognitive processes underlying reappraisal which builds on a conceptualization of reappraisal as a temporally extended, dynamic process and partitions reappraisal episodes into an early implementation and a later maintenance stage. In agreement with the model, preliminary evidence from parametric meta-analysis suggests the two stages are supported by distinct frontal networks. Hypotheses for further research are presented.Neuroscience & Biobehavioral Reviews 07/2009; 33(8):1215-26. · 8.65 Impact Factor -
Article: Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning.
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ABSTRACT: Lesion studies in animals have identified a critical role of the hippocampus in context fear conditioning. To extend these findings to human volunteers, we used functional magnetic resonance imaging to investigate neural responses associated with context fear conditioning in humans. Our novel conditioning paradigm consisted of aversive electrical shocks (unconditioned stimulus) that were delivered either cue or context related. Differential evoked responses, related to the conditioned stimulus (CS), were found in the anterior cingulate cortex and the bilateral insular cortices, regions that have been implicated in anticipatory anxiety. In case of context conditioning, a similar pattern was observed during the presentation of the entire context. In line with previous conditioning studies, differential responses in the amygdala showed a time by stimulus interaction, suggesting rapid adaptation of CS-specific responses. More importantly, a similar differential decay of activation was observed during context conditioning in the hippocampus, in agreement with a role of the hippocampus in the acquisition phase of human context fear conditioning.Journal of Neuroscience 10/2008; 28(36):9030-6. · 7.11 Impact Factor -
Article: Learning affective values for faces is expressed in amygdala and fusiform gyrus.
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ABSTRACT: To monitor the environment for social threat humans must build affective evaluations of others. These evaluations are malleable and to a high degree shaped by responses engendered by specific social encounters. The precise neuronal mechanism by which these evaluations are constructed is poorly understood. We tested a hypothesis that conjoint activity in amygdala and fusiform gyrus would correlate with acquisition of social stimulus value. We tested this using a reinforcement learning algorithm, Q-learning, that assigned values to faces as a function of a history of pairing, or not pairing, with aversive shocks. Behaviourally, we observed a correlation between conditioning induced changes in skin conductance response (SCR) and subjective ratings for likeability of faces. Activity in both amygdala and fusiform gyrus (FG) correlated with the output of the reinforcement learning algorithm parameterized by these ratings. In amygdala, this effect was greater for averted than direct gaze faces. Furthermore, learning-related activity change in these regions correlated with SCR and subjective ratings. We conclude that amygdala and fusiform encode affective value in a manner that closely approximates a standard computational solution to learning.Social Cognitive and Affective Neuroscience 07/2008; 3(2):109-18. · 6.13 Impact Factor -
Article: Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity.
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ABSTRACT: Social relations between humans critically depend on our affective experiences of others. Oxytocin enhances prosocial behavior, but its effect on humans' affective experience of others is not known. We tested whether oxytocin influences affective ratings, and underlying brain activity, of faces that have been aversively conditioned. Using a standard conditioning procedure, we induced differential negative affective ratings in faces exposed to an aversive conditioning compared with nonconditioning manipulation. This differential negative evaluative effect was abolished by treatment with oxytocin, an effect associated with an attenuation of activity in anterior medial temporal and anterior cingulate cortices. In amygdala and fusiform gyrus, this modulation was stronger for faces with direct gaze, relative to averted gaze, consistent with a relative specificity for socially relevant cues. The data suggest that oxytocin modulates the expression of evaluative conditioning for socially relevant faces via influences on amygdala and fusiform gyrus, an effect that may explain its prosocial effects.Journal of Neuroscience 07/2008; 28(26):6607-15. · 7.11 Impact Factor -
Article: Enhanced processing of threat stimuli under limited attentional resources.
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ABSTRACT: The ability to process stimuli that convey potential threat, under conditions of limited attentional resources, confers adaptive advantages. This study examined the neurobiology underpinnings of this capacity. Employing an attentional blink paradigm, in conjunction with functional magnetic resonance imaging, we manipulated the salience of the second of 2 face target stimuli (T2), by varying emotionality. Behaviorally, fearful T2 faces were identified significantly more than neutral faces. Activity in fusiform face area increased with correct identification of T2 faces. Enhanced activity in rostral anterior cingulate cortex (rACC) accounted for the benefit in detection of fearful stimuli reflected in a significant interaction between target valence and correct identification. Thus, under conditions of limited attention resources activation in rACC correlated with enhanced processing of emotional stimuli. We suggest that these data support a model in which a prefrontal "gate" mechanism controls conscious access of emotional information under conditions of limited attentional resources.Cerebral Cortex 06/2008; 19(1):127-33. · 6.54 Impact Factor -
Article: The NMDA agonist D-cycloserine facilitates fear memory consolidation in humans.
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ABSTRACT: Animal research suggests that the consolidation of fear and extinction memories depends on N-methyl D-aspartate (NMDA)-type glutamate receptors. Using a fear conditioning and extinction paradigm in healthy normal volunteers, we show that postlearning administration of the NMDA partial agonist D-cycloserine (DCS) facilitates fear memory consolidation, evidenced behaviorally by enhanced skin conductance responses, relative to placebo, for presentations of a conditioned stimulus (CS) at a memory test performed 72 h later. DCS also enhanced CS-evoked neural responses in a posterior hippocampus/collateral sulcus region and in the medial prefrontal cortex at test. Our data suggest a role for NMDA receptors in regulating fear memory consolidation in humans.Cerebral Cortex 06/2008; 19(1):187-96. · 6.54 Impact Factor -
Article: Ventromedial prefrontal cortex processing during emotional evaluation in late-life depression: a longitudinal functional magnetic resonance imaging study.
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ABSTRACT: Functional imaging studies using emotional stimuli have suggested a role for the ventromedial prefrontal cortex (vmPFC) in the pathophysiology of midlife depression. In contrast, the neural correlates of late-life depression (LLD), a highly prevalent but under-recognized clinical entity in which age-related brain changes might influence disease mechanisms, have not been studied in great detail. With an emotional evaluation task, we conducted a longitudinal study of vmPFC functioning in a homogeneous sample of elderly antidepressant naive female outpatients with isolated, first diagnosed mild to moderate depressive symptoms. Neural responses of the vmPFC to the emotional evaluation of positive, negative, and neutral words were measured with functional magnetic resonance imaging (fMRI) in LLD (n = 13) and healthy older subjects (n = 13). All patients were rescanned after approximately 7 months. Although there were no performance differences, compared with healthy volunteers, LLD patients showed a decreased response to negative compared with positive stimuli in the vmPFC. This altered pattern was positively correlated with symptom severity. At follow-up, the attenuated neural response in the vmPFC had "normalized," accompanied by a significant improvement in symptoms. These findings indicate vmPFC dysfunction as a biological state marker of geriatric depression. Furthermore, our data underline the pathological significance of mild to moderate LLD and highlight the usefulness of functional neuroimaging for evaluating remission processes in this specific depression subtype.Biological psychiatry 05/2008; 64(4):349-55. · 8.93 Impact Factor -
Article: Effects of altered corticosteroid milieu on rat hippocampal neurochemistry and structure--an in vivo magnetic resonance spectroscopy and imaging study.
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ABSTRACT: Altered corticosteroid milieu induces changes in hippocampal volume, neuronal structure, neurochemistry and cognitive function in humans and rodents. This in vivo magnetic resonance spectroscopy (1H MRS) and imaging (MRI) study investigated whether long-term alterations of the corticosteroid milieu cause: (i) metabolic and/or (ii) structural changes of the rat hippocampus. Therefore, hypocortisolism was induced by adrenalectomy (ADX), normocortisolism by ADX with low-dose corticosterone replacement, and hypercortisolism by ADX and high-dose dexamethasone treatment (for 11 weeks, respectively). All groups including a control group (n=23) were studied by in vivo 1H MRS and MR volumetry. Effects of treatment on normalized hippocampal metabolites and volumes were tested for significance using one-factorial multivariate analysis of variance (MANOVA). Hypercortisolemic rats revealed significantly elevated glutamate. Hypocortisolemic rats showed significantly decreased myo-inositol ratio levels, and were associated with significantly reduced normalized hippocampal volumes. Our findings suggest chronic hypercortisolism to be associated with glutamate-mediated excitotoxicity in the absence of volumetric abnormalities. In contrast, hypocortisolism appears to be associated with neurodegenerative processes, altered astrocytic metabolism but preserved neuronal density.Journal of Psychiatric Research 02/2008; 42(11):902-12. · 4.66 Impact Factor -
Article: Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging.
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ABSTRACT: The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism.Neuropsychopharmacology 10/2007; 32(9):1911-21. · 7.99 Impact Factor -
Article: How the brain translates money into force: a neuroimaging study of subliminal motivation.
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ABSTRACT: Unconscious motivation in humans is often inferred but rarely demonstrated empirically. We imaged motivational processes, implemented in a paradigm that varied the amount and reportability of monetary rewards for which subjects exerted physical effort. We show that, even when subjects cannot report how much money is at stake, they nevertheless deploy more force for higher amounts. Such a motivational effect is underpinned by engagement of a specific basal forebrain region. Our findings thus reveal this region as a key node in brain circuitry that enables expected rewards to energize behavior, without the need for the subjects;awareness.Science 06/2007; 316(5826):904-6. · 31.20 Impact Factor -
Article: Gene-gene interaction associated with neural reward sensitivity.
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ABSTRACT: Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.Proceedings of the National Academy of Sciences 06/2007; 104(19):8125-30. · 9.68 Impact Factor -
Article: Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain.
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ABSTRACT: Perceived control attenuates pain and pain-directed anxiety, possibly because it changes the emotional appraisal of pain. We examined whether brain areas associated with voluntary reappraisal of emotional experiences also mediate the analgesic effect of perceived control over pain. Using functional magnetic resonance imaging, we compared self-controlled noxious stimuli with physically identical stimuli that were externally controlled. Self-controlled stimulation was accompanied by less pain and anxiety and higher activation in dorsal anterior cingulate (dACC), right dorsolateral, and bilateral anterolateral prefrontal (alPFC) cortices. Activation in dACC and right alPFC was negatively correlated with pain intensity ratings. For externally controlled pain, activation in right alPFC was inversely correlated with the participants' general belief to have control over their lives. Our results are consistent with a reappraisal view of control and suggest that the analgesic effect of perceived control relies on activation of right alPFC. Failure to activate right alPFC may explain the maladaptive effects of strong general control beliefs during uncontrollable pain.Journal of Neuroscience 12/2006; 26(44):11501-9. · 7.11 Impact Factor -
Article: Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network.
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ABSTRACT: In fear extinction, an animal learns that a conditioned stimulus (CS) no longer predicts a noxious stimulus [unconditioned stimulus (UCS)] to which it had previously been associated, leading to inhibition of the conditioned response (CR). Extinction creates a new CS-noUCS memory trace, competing with the initial fear (CS-UCS) memory. Recall of extinction memory and, hence, CR inhibition at later CS encounters is facilitated by contextual stimuli present during extinction training. In line with theoretical predictions derived from animal studies, we show that, after extinction, a CS-evoked engagement of human ventromedial prefrontal cortex (VMPFC) and hippocampus is context dependent, being expressed in an extinction, but not a conditioning, context. Likewise, a positive correlation between VMPFC and hippocampal activity is extinction context dependent. Thus, a VMPFC-hippocampal network provides for context-dependent recall of human extinction memory, consistent with a view that hippocampus confers context dependence on VMPFC.Journal of Neuroscience 10/2006; 26(37):9503-11. · 7.11 Impact Factor -
Article: Neural correlates of self-distraction from anxiety and a process model of cognitive emotion regulation.
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ABSTRACT: Cognitive strategies used in volitional emotion regulation include self-distraction and reappraisal (reinterpretation). There is debate as to what the psychological and neurobiological mechanisms underlying these strategies are. For example, it is unclear whether self-distraction and reappraisal, although distinct at a phenomenological level, are also mediated by distinct neural processes. This is partly because imaging studies on reappraisal and self-distraction have been performed in different emotional contexts and are difficult to compare. We have therefore investigated the neural correlates of self-distraction, as indexed by a thought suppression task, in an anticipatory anxiety paradigm previously employed by us to study reappraisal. Brain activity was measured by functional magnetic resonance imaging. We show that self-distraction recruits the left lateral prefrontal cortex. Based on a review of the existing data, we develop a process model of cognitive emotion regulation. The model posits that both self-distraction and reappraisal attenuate emotional reactions through replacement of emotional by neutral mental contents but achieve replacement in different ways. This is associated with a dependence of self-distraction on a left prefrontal production function, whereas reappraisal depends on a right prefrontal higher order monitoring process.Journal of Cognitive Neuroscience 09/2006; 18(8):1266-76. · 5.18 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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Stanford University
- Department of Psychiatry and Behavioral Sciences
Stanford, CA, USA
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2007–2011
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Universität Hamburg
- Department of Systems Neuroscience
Hamburg, Hamburg, Germany
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2005–2008
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University College London
- Wellcome Department of Imaging Neuroscience
London, ENG, United Kingdom
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2001–2008
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Max-Planck-Institut für Psychiatrie
München, Bavaria, Germany
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2006
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University of Oxford
Oxford, ENG, United Kingdom
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