Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

Abstract

Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear. Hum Brain

Structural evidence for involvement of a left amygdala-orbitofrontal network in subclinical anxiety

“…Our finding of increased cortical thickness in OFC corresponds with healthy volunteer functional activation studies that show increased responsivity in OFC during fear conditioning (Morris and Dolan, 2004; Mechias et al, 2010) and during anxiety symptom provocation (Benkelfat et al, 1995; Servan-Schreiber et al, 1998; Javanmard et al, 1999; Eser et al, 2009). Our lack of findings in the vmPFC might be explained by our choice of measures, which capture the subjective experience of anxiety rather than the active modulation of it.…”

Neurologic bases for comorbidity of balance disorders, anxiety disorders and migraine: neurotherapeutic implications

“…The anterior insula also overlaps with a region of reduced GABA A -benzodiazepine receptor binding in individuals with panic disorder [135]. The posterior cingulate field that has been identified in vestibular stimulation experiments overlaps with a region that is both activated by anticipatory anxiety in CCK-4-induced panic attacks [136] and has reduced 5-HT 1A receptor binding activity in panic disorder patients [137]. Finally, the anterior aspect of the parahippocampal gyrus also shows increased GABA A -benzodiazepine binding in panic disorder patients [138].…”

“…The cerebellar posterior lobe is another potential site where benzodiazepines could have a simultaneous effect on the vestibular system and activity engaged in panic attacks. There is a significant enhancement of blood oxygenation level-dependent signals from the cerebellar posterior lobe and culmen during precipitation of a panic attack with CCK-4 [136]. The Purkinje cells from these cerebellar sites project to both vestibulo-ocular and vestibulo-spinal pathways [145], and could contribute to postural instability.…”

The role of the amygdala in the pathophysiology of panic disorder: evidence from neuroimaging studies

“…When challenged with cholecystokinin tetrapeptide (CCK-4) or procaine, healthy volunteers showed increased amygdalar activation [82] or increased regional cerebral blood flow [83-85]. In patients with PD, CCK-4 or doxapram intravenous injection did not elicit significantly greater amygdalar activation [86,87].…”