A Look at Anxiety: More than the Amygdala

I’m not a fan of horror movies, but with Halloween approaching, my roommates and I decided to treat ourselves to a night of spooky flicks. As we all curled up on the couch and began to watch “The Ring,” I increasingly felt what is the topic for my blog post this week: anxiety. As it turns out, fear and anxiety go hand in hand. Normally, sensory information is sent to the thalamus, where it is then relayed to cortical structures for processing. But when learned or hardwired fear-provoking stimuli are encountered, such as a spider, sensory information is instead rerouted to the amygdala, which in turn sends activating signals to the muscles, hypothalamus, and sympathetic nervous system, causing me to leap and spill my popcorn on my roommates (Higgins & George, 2013). Although the fight or flight system served our evolutionary predecessors well, abnormalities in this circuitry are often implicated in anxiety disorders.

The role of the amygdala must be understood in the context of the neural circuitry in which it is situated. For instance, it is connected within a larger network of subcortical and prefrontal regions, often involved in reward and emotion (Haber & Knutson, 2008). In particular, the amygdala connects to the orbitofrontal cortex (OFC), a structure that may relate to stable patterns of anxiety. In studying this neural relationship, researchers have hypothesized that some personality trait-like tendencies may protect against the development of pathological levels of anxiety.

In a 2015 study, Dolcos, Hu, Iordan, Moore, and Dolcos (2015) asked whether persistent positive expectations about the future, or optimism, might attenuate the relationship between the OFC and anxiety. They collected structural neuroimaging data, as well as baseline measures of optimism and anxiety, on 61 non-psychiatric subjects ages 18 to 34. Individual positive and negative affect traits were also assessed at baseline to determine if results were specific to anxiety, or negative affect broadly. A negative correlation was found between OFC volume and optimism. The relationship was also mediated by optimism, such that the greater the OFC volume, the more optimistic, and less anxious the subject was found to be at the group level. This research suggests that the size of the orbitofrontal cortex may be a protective factor within healthy individuals, perhaps related to tendencies towards optimism. Conversely, a smaller orbitofrontal cortex may contribute to a predisposition to the development of anxiety disorders.

Although the previous study examined both men and women, worldwide incidences of anxiety disorders (including generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia and specific phobias) are higher in females (American Psychiatric Association, 2013). Specific neuroanatomical differences in the male and female brain have been considered in anxiety disorders, and research has indicated the OFC and the adjacent ventromedial prefrontal cortex (vmPFC) to be among these differences.

Wellborn et al. (2009) examined whether OFC volume mediated the relationship between emotion regulation and gender. For their study, 117 non-psychiatric men and women completed behavioral measures at baseline, examining emotion regulation, expression and experience in addition to brain imaging. Women were found to have increased ventromedial prefrontal cortex volume, right lateral OFC volume within the orbital cortex, and higher levels of anxiety overall. Interestingly, researchers also found that greater volumes of the ventromedial PFC were selectively associated with the use of reappraisal as an emotional regulation strategy. Could reappraisal related to ventromedial volume be protective for women specifically against anxiety disorders?

The convergence of findings by Dolcos et al. (2015) and Wellborn et al. (2009) lends credibility to the potential relationship between anxiety and orbital prefrontal volumes. It should be noted, however, that the orbital cortex is located adjacent to the sinus cavity, and is often susceptible to signal dropout and head motion artifacts during MRI. A recent paper by Reuter et al. (2014) demonstrates that head motion influences measurements of cortical volume and thickness, and trait levels of anxiety likely correlate with movement and unrest during MRI scans. To validate these findings, future cortical thickness studies should employ larger sample sizes and explicitly account for confounding variables like head motion.

Although differences in brain hardware are likely important for anxiety, measures of neuroanatomy alone do not reflect function of this system. Given the known role of the hypothalamic-pituitary-axis in physiological stress, hormones may also help to explain why women experience more anxiety than men, especially during times of hormone fluctuations such as puberty and menopause. In a series of experiments on rats and humans, Zeidan et al. (2011) investigated how estrogen affects how a fear response is unlearned. On day one of the experiment on rodents, a neutral stimulus was paired with a negative outcome (i.e., a foot shock). On day two, after the stimulus-shock association had been developed, the rats were each administered an alpha-estrogen receptor agonist, beta-estrogen receptor agonist, or sesame oil (control), and the formerly neutral tone was reintroduced continuously, without the shock, for unlearning to occur. On the final day of testing, the extent to which the stimulus-shock association was unlearned was measured by freezing behavior. Compared to the other groups, the rats that received the beta-estrogen receptor agonist became unconditioned to fear the stimulus the most. A similar process conducted with human female subjects showed that women with higher endogenous estradiol had greater fear extinction, which also reflected increased activity of the ventromedial PFC and amygdala.

In summary, areas of the orbitofrontal cortex may relate to anxiety, perhaps mediated by protective personality factors such as optimism and reappraisal. In addition, gender may help elucidate the mechanisms of the disorder, as men and women differ in brain size and hormone levels. Undoubtedly, a key piece of anxiety is an overgeneralized or accentuated fear or anxiety response to contexts and cues within the environment. Ideally, people adaptively disassemble fear provoking connections given time and repeated new experiences, which is also the goal of many therapies (e.g., desensitization therapy). Perhaps future treatments should emphasize optimism, anxiety reappraisal therapies (perhaps especially for women via cognitive behavioral therapy), and pharmacological aids such as estrogen to combat clinical anxiety.


American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association.

Dolcos, S., Hu, Y., Iordan, A.D., Moore, M., & Dolcos, F. (2015). Optimism and the brain: Trait optimism mediates the protective role of the orbitofrontal cortex gray matter volume against anxiety. Social Cognitive and Affective Neuroscience, 10(10), 1-9. doi: 10.1093/scan/nsv106

Haber, S. N., & Knutson, B. (2010). The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology, 35(1), 4–26. http://doi.org/10.1038/npp.2009.129

Higgins, E. S., & George, M. S. (2013). The neuroscience of clinical psychology: The pathophysiology of behavior and mental illness (2nd ed.). Philadelphia, PA: Lippincott William & Wilkins.

Wellborn, B. L., Papademetris, X., Reis, D. L., Rajeevan, N., Bloise, S. M. & Gray, J. R. (2009). Variation in orbitofrontal cortex volume: Relation to sex, emotion regulation, and affect. Social Cognitive and Affective Neuroscience, 4(4), 328 – 339. doi:10.1093/scan/nsp028

Zeidan, M. A., Igoe, S. A., Linnman, C., Vitalo, A., Levine, J. B., Klibanski, A., … Milad, M. R. (2011). Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biological Psychiatry, 70(10), 920–927. http://doi.org/10.1016/j.biopsych.2011.05.016





2 thoughts on “A Look at Anxiety: More than the Amygdala

  1. It’s fascinating that women with higher endogenous estradiol have higher levels of fear extinction. I wonder if this has implications for how to treat women with anxiety. Additionally, I wonder if studies have looked at women on birth control (particularly long acting types) and their relation to mood and anxiety.

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