Panic Anxiety in Humans with Bilateral Amygdala Lesions: Pharmacological Induction via Cardiorespiratory Interoceptive Pathways

Abstract

We previously demonstrated that carbon dioxide inhalation could induce panic anxiety in a group of rare lesion patients with focal bilateral amygdala damage. To further elucidate the amygdala-independent mechanisms leading to aversive emotional experiences, we retested two of these patients (B.G. and A.M.) to examine whether triggering palpitations and dyspnea via stimulation of nonchemosensory interoceptive channels would be sufficient to elicit panic anxiety. Participants rated their affective and sensory experiences following bolus infusions of either isoproterenol, a rapidly acting peripheral ␤-adrenergic agonist akin to adrenaline, or saline. Infusions were administered during two separate conditions: a panic induction and an assessment of cardiorespiratory interoception. Isoproterenol infusions induced anxiety in both patients, and full-blown panic in one (patient B.G.). Although both patients demonstrated signs of diminished awareness for cardiac sensation, patient A.M., who did not panic, reported a complete lack of awareness for dyspnea, suggestive of impaired respiratory interoception. These findings indicate that the amygdala may play a role in dynamically detecting changes in cardiorespiratory sensation. The induction of panic anxiety provides further evidence that the amygdala is not required for the conscious experience of fear induced via interoceptive sensory channels.

Cardiorespiratory concerns shape brain responses during automatic panic-related scene processing in patients with panic disorder

“…57 Remarkably, findings of greater amygdala activation in patients with panic disorder than in healthy controls are inconsistent, 9,58 and panic attacks have even been observed in patients with amygdala lesions. [59][60][61] Thus, the amygdala seems to be associated with relevance detection and salience processing, 62,63 initiating a cascade of panic-related activations without being necessarily involved in (all) full-blown panic attacks. 60 The thalamus, as a sensory relay station, is important for the fast processing of incoming visual input and weighing its relevance.…”

“…[59][60][61] Thus, the amygdala seems to be associated with relevance detection and salience processing, 62,63 initiating a cascade of panic-related activations without being necessarily involved in (all) full-blown panic attacks. 60 The thalamus, as a sensory relay station, is important for the fast processing of incoming visual input and weighing its relevance. Its activation is modulated by selective attention, which gains special significance in the present study owing to the task-irrelevance of panic-related stimuli.…”

Cardiorespiratory noise correction improves the ASL signal

“…During each task scan, participants received a single bolus intravenous infusion at 60 seconds while lying in the scanner: either saline or isoproterenol hydrochloride (Valeant Pharmaceuticals, Laval, Quebec, Canada), at a dose of 1 microgram (μg) or 2 μg. We selected these bolus doses because (i) they produced sizeable and reliable changes in cardiorespiratory parameters in our previous studies (Khalsa, et al, 2016; Khalsa, et al, 2009a; Khalsa, et al, 2009b), (ii) we have found them to be well tolerated in the fMRI environment (Hassanpour, et al, 2016), and (iii) they induce transient changes lasting <100 seconds, so that we can expect their effects do not extend to subsequent scans. Each dose was repeated twice for a total of six infusion scans, and the infusion order was randomized and double-blinded (Figure 1).…”

“…Isoproterenol is a rapidly acting beta-adrenergic medication that is similar to adrenaline. It acts by peripherally stimulating cardiorespiratory output (Khalsa, et al, 2016; Khalsa, et al, 2009a; Khalsa, et al, 2009b). It does not cross the blood brain barrier (Murphy and Johanson, 1985; Olesen, et al, 1978), and we have recently demonstrated that this medication is amenable to identifying neurocognitive functions in the fMRI environment (Hassanpour, et al, 2016).…”

An active inference theory of allostasis and interoception in depression

“…This may be one mechanism by which vagal nerve stimulation has its effects [233]. Additional novel approaches to increasing the SNR on interoceptive signals are also under development, including pharmacological interventions such as infusion regimens with the b-adrenoreceptor agonist isoproterenol that have been tested in other psychiatric illnesses [234,235] and therapy within sensory-attenuated environments that increase the salience of interoceptive signals [236].…”