Panic Anxiety in Humans with Bilateral Amygdala Lesions: Pharmacological Induction via Cardiorespiratory Interoceptive Pathways
Open accessAbstract
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 non-chemosensory 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 β-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. SIGNIFICANCE STATEMENT We found that monozygotic twins with focal bilateral amygdala lesions report panic anxiety in response to intravenous infusions of isoproterenol, a β-adrenergic agonist similar to adrenaline. Heightened anxiety was evident in both twins, with one twin experiencing a panic attack. The twin who did not panic displayed signs of impaired cardiorespiratory interoception, including a complete absence of dyspnea sensation. These findings highlight that the amygdala is not strictly required for the experience of panic anxiety, and suggest that neural systems beyond the amygdala are also involved. Determining these additional systems could provide key neural modulation targets for future anxiolytic treatments.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Different emotional and cognitive states alter the depth and frequency of breathing, which impacts emotional state in part by regulation of carbon dioxide levels.
“It is also clear that different emotional and cognitive states alter the depth and frequency of breathing,8,9,10,11,12 which likewise impacts emotional state, in part by regulation of carbon dioxide levels.13,14,15,16,17”
From Brief structured respiration practices enhance mood and reduce physiological arousal (2023) · cites this paper as [13]
Cites
Etkin, A., & Wager, T. D. (2007) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07030504 · Cited by 3,391 · cited 2× · see citing works
“amygdala activation in response to exteroceptive threat, with a pronounced hyperactivity observed in patients with anxiety (Büchel et al., 1999; Etkin and Wager, 2007; Davis et al., 2010; Mobbs et al., 2010).”
BackgroundThe amygdala: vigilance and emotion
Davis, M., & Whalen, P. J. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000812 · Cited by 2,882 · see citing works
Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety
Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.109 · Cited by 1,488 · see citing works
A mechanism for impaired fear recognition after amygdala damage
Adolphs, R., Gosselin, F., Buchanan, T. W., Tranel, D., Schyns, P., & Damasio, A. R. (2005) · Nature · doi:10.1038/nature03086 · Cited by 1,331 · cited 1× · see citing works
“Converging evidence in humans with amygdala damage found that these patients often exhibit exteroceptive deficits in fear processing along with a reduced propensity to experience fear and post-traumatic stress (Hamann et al., 1996; Adolphs et al., 2005; Koenigs et al., 2008; Feinstein et al., 2011).”
BackgroundThe Human Amygdala and the Induction and Experience of Fear
Feinstein, J. S., Adolphs, R., Damasio, A., & Tranel, D. (2011) · Current Biology · doi:10.1016/j.cub.2010.11.042 · Cited by 497 · see citing works
Self-citationFear and panic in humans with bilateral amygdala damage
Feinstein, J. S., Buzza, C., Hurlemann, R., Follmer, R. L., Dahdaleh, N. S., Coryell, W. H., Welsh, M. J., Tranel, D., & Wemmie, J. A. (2013) · Nature Neuroscience · doi:10.1038/nn.3323 · Cited by 350 · see citing works
Self-citationFear from the heart: sensitivity to fear stimuli depends on individual heartbeats
Garfinkel, S. N., Minati, L., Gray, M. A., Seth, A. K., Dolan, R. J., & Critchley, H. D. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3507-13.2014 · Cited by 338 · see citing works
Phasic and sustained fear in humans elicits distinct patterns of brain activity
Alvarez, R. P., Chen, G., Bodurka, J., Kaplan, R., & Grillon, C. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2010.11.057 · Cited by 299 · see citing works
Amygdalar and hippocampal substrates of anxious temperament differ in their heritability
Oler, J. A., Fox, A. S., Shelton, S. E., Rogers, J., Dyer, T. D., Davidson, R. J., Shelledy, W., Oakes, T. R., Blangero, J., & Kalin, N. H. (2010) · Nature · doi:10.1038/nature09282 · Cited by 208 · see citing works
Khalsa, S. S., Craske, M. G., Li, W., Vangala, S., Strober, M., & Feusner, J. D. (2015) · International Journal of Eating Disorders · doi:10.1002/eat.22387 · Cited by 191 · see citing works
Self-citationEmotional effects produced by the injection of adrenalin
Cantril, H., & Hunt, W. A. (1932) · The American Journal of Psychology · doi:10.2307/1414829 · Cited by 119 · cited 1× · see citing works
“Likewise, classic experimental findings by Schachter and Singer (1962) demonstrated that modulation of the periphery via subcutaneous administration of adrenaline could induce emotional changes (but see Maranon, 1924; Cantril and Hunt, 1932).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
An active inference theory of allostasis and interoception in depression
Barrett, L. F., Quigley, K. S., & Hamilton, P. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2016.0011 · Cited by 554 · see citing works
Can interoception improve the pragmatic search for biomarkers in psychiatry?
Khalsa, S. S., & Lapidus, R. C. (2016) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2016.00121 · Cited by 366 · see citing works
Self-citationBrief structured respiration practices enhance mood and reduce physiological arousal
Balban, M. Y., Neri, E., Kogon, M. M., Weed, L., Nouriani, B., Jo, B., Holl, G., Zeitzer, J. M., Spiegel, D., & Huberman, A. D. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100895 · Cited by 284 · see citing works
Park, H.-D., Bernasconi, F., Salomon, R., Tallon-Baudry, C., Spinelli, L., Seeck, M., Schaller, K., & Blanke, O. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhx136 · Cited by 190 · see citing works
The insular cortex dynamically maps changes in cardiorespiratory interoception
Hassanpour, M. S., Simmons, W. K., Feinstein, J. S., Luo, Q., Lapidus, R. C., Bodurka, J., Paulus, M. P., & Khalsa, S. S. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.154 · Cited by 130 · see citing works
Self-citationTeed, A. R., Feinstein, J. S., Puhl, M., Lapidus, R. C., Upshaw, V., Kuplicki, R. T., Bodurka, J., Ajijola, O. A., Kaye, W. H., Thompson, W. K., et al. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2021.4225 · Cited by 79 · see citing works
Self-citationThe practice of meditation is not associated with improved interoceptive awareness of the heartbeat
Khalsa, S. S., Rudrauf, D., Hassanpour, M. S., Davidson, R. J., & Tranel, D. (2020) · Psychophysiology · doi:10.1111/psyp.13479 · Cited by 71 · see citing works
“…accuracy (i.e. cross-correlations between dial ratings and heart rate) in previous studies, all of which used the same randomized, double-blinded, and placebo controlled approach (Khalsa et al., 2015; Khalsa et al., 2016; Khalsa, Hassanpour, et al., 2018; Khalsa, Rudrauf, Sandesara, et al., 2009).”
BackgroundMethodResultInfluentialSelf-citationHassanpour, M. S., Yan, L., Wang, D. J. J., Lapidus, R. C., Arevian, A. C., Simmons, W. K., Feusner, J. D., & Khalsa, S. S. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2016.0017 · Cited by 70 · see citing works
Self-citation
- Authors
- Khalsa, S. S., Feinstein, J. S., Li, W., Feusner, J. D., Adolphs, R., & Hurlemann, R.
- Affiliations
- University of California, Los Angeles (US)
- California Institute of Technology (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-03-23
- Volume
- 36
- Issue
- 12
- Pages
- 3559-3566
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4804013
- OpenAlex
- W2310499978
- Cited by
- 86
- References
- 11
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 16 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 9 · 2018: 14 · 2017: 5 · 2016: 7
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- William K. Warren Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (UL1TR000124, CTSI UL1TR000124)
- U.S. Public Health Service (NIMH 3R01MH093535-02S2)
- National Institute of Mental Health (R01MH105662, R01MH093535, P50MH094258)
- National Center for Advancing Translational Sciences (UCLA CTSI UL1TR 000124)
- Clinical and Translational Science Institute, University of California, Los Angeles (UL1TR000124)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- panic anxiety, isoproterenol, beta-adrenergic agonists, panic attacks, monozygotic twins
- MeSH terms
- Adrenergic beta-Agonists, Adult, Afferent Pathways, Amygdala, Female, Heart, Humans, Isoproterenol, Lung, Male, Panic Disorder, Interoception
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
