Prefrontal Mechanisms of Fear Reduction After Threat Offset

Klumpers, Floris; Raemaekers, Mathijs; Ruigrok, Amber N. V.; Hermans, Erno J.; Kenemans, J. Leon; Baas, Johanna M.P.

doi:10.1016/j.biopsych.2010.09.006

Cited by 58 publications

(60 citation statements)

References 61 publications

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“…Additionally, this is the first clinical study to provide physiological evidence to localize emotional word Stroop interference in clinically anxious participants to discrete sensory and cognitive stages. The current results support and extend conceptualizations of threat-related biases and interference as involving dissociable sensory and cognitive components (Cisler & Koster, 2010;Klumpers et al, 2010;, which may be disorder specific (van den Heuvel, et al, 2005). While heightened sensory attention to threat appears to be a characteristic of both PD and OCD, emotional Stroop interference involves additional, cognitive, elaboration of threat.…”

Section: Caveats and Future Directionssupporting

confidence: 85%

Neural time course of threat-related attentional bias and interference in panic and obsessive–compulsive disorders

Thomas

Gonsalvez

Johnstone

2013

Biological Psychology

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Attentional biases to threat are considered central to anxiety disorders, however physiological evidence of their nature and time course is lacking. Event-related potentials (ERPs) characterized sensory and cognitive changes while 20 outpatients with panic disorder (PD), 20 with obsessive-compulsive disorder (OCD), and 20 healthy controls (HCs) responded to the color (emotional Stroop task) or meaning of threatening and neutral stimuli. ERPs indicated larger P1 amplitude and longer N1 latency in OCD, and shorter P1 latency in PD, to threatening (versus neutral) stimuli, across instructions to attend to, or ignore, threat content. Emotional Stroop interference correlated with phobic anxiety and was significant in PD. Participants with emotional Stroop interference had augmented P1 and P3 amplitudes to threat (versus neutral) stimuli when color-naming. The results suggest early attentional biases to threat in both disorders, with disorder-specific characteristics. ERPs supported preferential early attentional capture and cognitive elaboration hypotheses of emotional Stroop interference.

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Section: Caveats and Future Directionssupporting

confidence: 85%

Neural time course of threat-related attentional bias and interference in panic and obsessive–compulsive disorders

Thomas

Gonsalvez

Johnstone

2013

Biological Psychology

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“…Evidence supporting this view is derived primarily from lesion and inactivation studies, but is consistent with the results of unit recording and imaging studies in rats (Quirk et al, 1995) and human beings (Phelps et al, 2001), which have indicated only a transient activation of the amygdala by threat stimuli, but perhaps a more sustained activation of the BNST, the latter which may be exaggerated in subjects with high trait anxiety (Somerville et al, 2010). Perhaps, also relevant are recent results from Klumpers et al (2010), who reported a significant timedependent correlation between amygdala activation and startle potentiation in healthy human beings.…”

Section: Discussionsupporting

confidence: 57%

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Miles

Davis

Walker

2011

Neuropsychopharmacol

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Previous findings suggest differences in the neuroanatomical substrates of short-(seconds) vs longer-duration (minutes) fear responses. We now report that phasic and sustained fear can also be differentiated pharmacologically, based on their response to several treatments that either are or are not clinically effective anxiolytics. For these experiments, short-or long-duration clicker stimuli were paired with footshock. Acoustic startle amplitude was later measured in the absence of the clicker, or within seconds (phasic fear) or minutes (sustained fear) of its onset. Before testing, rats received a single injection of vehicle, the benzodiazepine chlordiazepoxide, the 5HT 1A agonist and dopamine D2 antagonist buspirone, the selective serotonin reuptake inhibitor fluoxetine, or a 3-week treatment with either vehicle or fluoxetine. Chlordiazepoxide blocked sustained, but not phasic startle increases. Acute buspirone, which is not anxiolytic in human beings, did not affect sustained startle increases, but did disrupt phasic increases. Chronic fluoxetine blocked sustained startle increases and unreliably reduced phasic increases; acute fluoxetine affected neither. The results indicate that phasic and sustained fear responses can be pharmacologically dissociated, further validating this distinction, and suggest that sustained startle increases may be especially useful as anxiety models and anxiolytic screens.

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“…However, we indeed observed that vmPFC (subgenual anterior cingulate) was involved in the development of blocking, but its responseswhich were characterized by a significant deactivation-were limited to the comparison of CSAX versus CSA. This selective response is especially interesting given this region's involvement in the control of conditioned fear in animals (Rosenkranz et al, 2003;Vidal-Gonzalez et al, 2006) and in both automatic and voluntary forms of fear regulation in humans (Phelps et al, 2004;Delgado et al, 2008a;Klumpers et al, 2010;Nili et al, 2010), but obviously it leaves open the question via which pathway the dlPFC-mediated upregulation of amygdala responses-as observed on BY trials-is realized.…”

Section: Discussionmentioning

confidence: 99%

“…Correction for multiple comparisons using Gaussian random field theory was based on probabilistic maps of our target regions (obtained from the Harvard-Oxford atlas and thresholded at 50%): amygdala, dlPFC (approximated by the middle frontal gyrus mask), and ventromedial PFC (vmPFC)/subgenual anterior cingulate cortex (sgACC) (approximated by the subcallosal cortex mask, which is somewhat overly conservative as it also includes more lateral parts). While the terminology used to describe this latter region is rather inconsistent across studies, note that we were specifically interested in the subgenual anterior cingulate cortex, as it shows a very prominent involvement in various processes of human fear control (Phelps et al, 2004;Delgado et al, 2008a;Klumpers et al, 2010;Nili et al, 2010). No probabilistic maps exist for dACC and AI, which we therefore approximated by spheres (10 mm radius) centered on coordinates from a recent meta-analysis of fear conditioning (Mechias et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Neurobiological Mechanisms Underlying the Blocking Effect in Aversive Learning

2012

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Current theories of classical conditioning assume that learning depends on the predictive relationship between events, not just on their temporal contiguity. Here we employ the classic experiment substantiating this reasoning-the blocking paradigm-in combination with functional magnetic resonance imaging (fMRI) to investigate whether human amygdala responses in aversive learning conform to these assumptions. In accordance with blocking, we demonstrate that significantly stronger behavioral and amygdala responses are evoked by conditioned stimuli that are predictive of the unconditioned stimulus than by conditioned stimuli that have received the same pairing with the unconditioned stimulus, yet have no predictive value. When studying the development of this effect, we not only observed that it was related to the strength of previous conditioned responses, but also that predictive compared with nonpredictive conditioned stimuli received more overt attention, as measured by fMRI-concurrent eye tracking, and that this went along with enhanced amygdala responses. We furthermore observed that prefrontal regions play a role in the development of the blocking effect: ventromedial prefrontal cortex (subgenual anterior cingulate) only exhibited responses when conditioned stimuli had to be established as nonpredictive for an outcome, whereas dorsolateral prefrontal cortex also showed responses when conditioned stimuli had to be established as predictive. Most importantly, dorsolateral prefrontal cortex connectivity to amygdala flexibly switched between positive and negative coupling, depending on the requirements posed by predictive relationships. Together, our findings highlight the role of predictive value in explaining amygdala responses and identify mechanisms that shape these responses in human fear conditioning.

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Prefrontal Mechanisms of Fear Reduction After Threat Offset

Cited by 58 publications

References 61 publications

Neural time course of threat-related attentional bias and interference in panic and obsessive–compulsive disorders

Neural time course of threat-related attentional bias and interference in panic and obsessive–compulsive disorders

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Neurobiological Mechanisms Underlying the Blocking Effect in Aversive Learning

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