Extreme fear experienced without the amygdala

There’s a female patient, known in the research literature as S.M., who’s been dubbed the “woman with no fear”. She has severely damaged amygdala on either side of her brain and consequently is left unmoved by snakes, spiders, horror films, haunted houses and real-life knife attacks. She doesn’t even have a sense of personal space. But when S.M. inhaled carbon dioxide for a new study, she was far from calm. Within seconds, she groped desperately for the air mask and cried for help. After researchers removed the mask, S.M.’s entire body went rigid, her toes and fingers flexed taut, toward the ceiling. Her skin was flushed, her eyes wide like a scared animal. Thirty-seconds after the ordeal, she began to calm, finally releasing the experimenter’s hand. Later, she recalled the experience she’d had was of panic – “the number one, worst” feeling ever.

The amygdala is an almond-shaped structure found deep on either side of the brain. So many studies have shown it to be involved in learning and experiencing fear, it’s become shorthand to refer to it as the brain’s “fear centre”, even though it’s also involved in positive emotional processing. The apparent fearlessness of S.M., who lost her amygdala to Urbach-Wiethe disease (a rare genetic disorder), had previously supported this caricature. But now things have gotten a lot more complicated*. Carbon dioxide inhalation causes unpleasant suffocating feelings and it triggers panic in those susceptible to it. But if S.M. has no “fear centre”, how and why did she get so scared and panicky after inhaling?

To check this was no anomaly, Justin Feinstein at the University of Iowa and his colleagues also tested two other patients with bilateral amygdala damage (a pair of identical twins, A.M. and B.G.). These patients also had panic attacks and experienced fear when they inhaled carbon dioxide. They and S.M. said these fearful feelings were entirely novel to them. It’s notable too that this wasn’t a one off. The patients’ panic reaction occurred all over again during a repeat of the carbon dioxide procedure.

And yet, when the researchers performed the carbon dioxide inhalation with 12 healthy controls, 9 of them exhibited no panic and they reported far less fear than the patients. Three of the controls did panic. The amount of subjective fear and panic reported by these panicky controls and the patients was equivalent, and their physiological signs were similar, such as raised heart-rate. The only difference between the patients and the panicky controls was that the former didn’t show any signs of anticipatory anxiety when they saw the apparatus being prepared.

So we have a situation where three out of three patients with bilateral amygdala damage (who are usually fearless) panicked and experienced more fear than nine of the twelve amygdala-intact controls. What’s going on? Feinstein and his team think that CO2 inhalation acts on “interoceptive” receptors that project directly to the brainstem and other sites that “underlie fear and panic”, whereas other fear-stimuli, like scary films or dangerous animals, are “exteroceptive in nature, mainly processed through visual and auditory pathways that project to the amygdala”. The patients were completely unfazed when the procedure was repeated with normal air, supporting the idea that the carbon dioxide played a specific role in provoking fear.

This still leaves the mystery of why the amygdala-damaged patients were more disturbed by the carbon dioxide inhalation than most of the controls. Here the researchers’ interpretation is bold. They suggest that an intact amygdala might normally serve to inhibit panic. This isn’t as revolutionary as it seems. Feinstein’s team point to a study from ten years ago that found patients with panic disorder had amygdala atrophy. So, if we consider this brain structure as the “centre” of anything, perhaps it should be as the centre of calm!

This new study also raises some deep, almost philosophical questions. If the amgydala-damaged patients usually live a life that’s entirely fear-free, how did they know to describe their feelings during the inhalation as extreme fear or panic? Can we be sure they really felt fear the way that the rest of us do? The researchers have previously reported that S.M. references fear and anxiety appropriately in conversation, and she can recognise fear in others, so perhaps she does have a solid understanding of the concept. Finally, what do these findings say about the neural correlates of the subjective sense of fear and panic? At the very least it seems the amygdala is not necessary for the conscious experience of fear.

ResearchBlogging.org Justin S. Feinstein, Colin Buzza, Rene Hurlemann, Robin L. Follmer, Nader S. Dahdaleh, William H. Coryell, Michael J. Welsh, Daniel Tranel, and John A. Wemmie. (2013). Fear and panic in humans with bilateral amygdala damage. Nature Neuroscience, DOI: 10.1038/nn.3323

*Please note, this isn’t the first documented case of fear in a patient with bilateral amygdala damage. In a 2002 diary study (pdf), one such patient reported normal daily experience of anxiety and fear, but impaired recognition of other people’s fearful expressions. S.M. (in the current study) is impaired at recognising fear in static images of faces but she can recognise fear in people’s voices and from dynamic displays of fearful faces. One obvious question mark over the 2002 study is the reliance on self-report of fear. 

Post written by Christian Jarrett (@psych_writer) for the BPS Research Digest.

14 thoughts on “Extreme fear experienced without the amygdala”

  1. Several Nature papers have shown that SM has a profound deficit in recognizing fear in faces. The last paragraph didn't quite characterize this correctly.

  2. Good post. This is a surprising result because there's animal work showing that the amygdala detects CO2 (specifically, acidity caused by it) via a chemosensory protein ASIC1a.

    Maybe ASIC1a elsewhere in the brain is actually to blame?

  3. hi Neuroskeptic – thanks, that work on ASIC1a is very interesting. I wonder if that protein is found in the brainstem and other areas that Fustein et al believe the C02 must have had its fear-inducing effects in the patients?

  4. This study, even with the Supplementary Information, is not convincing at all. It has an n=3 (two of them being monozygotic twins!!!), and, as mentioned above, reports of feeling fear from someone who never felt it before.
    How did this end up on Nature Neuroscience?

  5. I take it that when the amygdala is destroyed, sensory neurons which affects perception are destroyed, hence one does not perceive the fear and panic from that centre. Other sensory neurons would produce reactions to fear, depending on the intensity of the stimulus.

  6. I wondered if this is a survival aspect of our heredity? For instance limnic eruptions in North-West Camaroon caused massive CO2 rising up through the lakes of Monoun and Nyos which spilt through the surrounding valleys causing massive animal deaths. See link http://www.cou2.com/Carbon-dioxide.html I wonder if the brain stem, being our 'evolutionary brain' alerts us of snakes and spiders and maybe CO2 concentrations that may cause us ill health (above 5,000 ppm according to the link given above) or death (above 50,000 ppm) and thus our amygdala is not required in these instances, as it seems to focus on more visual and auditory perceptions?

  7. I fully agree with the researchers hypothesis. Most of the projections from the amygdala to the brainstem contain GABA, and are tonically active. Interestingly, the amygdala sends GABAergic projections to orexin neurons, which are considered to be of major importance in hypercapnic panic.

    Orexin neurons in panic response to CO2: See Johnson et al 2010: 10.1038/nm.2075
    GABAergic amygdala projections to orexin neurons: Nakamura et al: 10.1016/j.brainres.2009.04.049

  8. You have a point, but bilateral amygdala damage is extremely rare so it's not really possible to increase n. It's important to also note the variance – all 3 responded the same way. It's just enough to make the conclusion that “At the very least it seems the amygdala is not necessary for the conscious experience of fear”

  9. My apologies for commentating on an old post but I have had trouble locating the paper mentioned here showing how SM can recognise fear in dynamic faces. Would you be able to provide a reference or name or something? Thank you.

  10. Does anyone else wonder how they managed to get ethics for this type of study?

  11. Where did you get this quote from S.M. describing her experience with the episode as “'the number one, worst' feeling ever”? All searches seem to come back to the author of this blog, rather than any interview or solid citation.

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