Beyond Amygdala: Rethinking How the Brain Responds to Threat

Sagittal MRI slice with highlighting indicating location of the anterior cingulate cortex (ACC).

Source: Geoff B. Hall/CCO 1.0 Public Domain

New research sheds light on how an often overlooked area of the subgenual anterior cingulate cortex called sgACC/25 plays a significant role in how the primate brain responds to different threat types. This study suggests that targeting the sgACC may be a way to improve outcomes for patients with clinical depression or anxiety disorders. These findings (Alexander et al., 2020) were published on October 26 in Nature Communications.

For this University of Cambridge study, UK-based neuroscientists utilized positron emission tomography (PET) to investigate how over-activity of the sgACC/25 in response to different threats affected the amygdala, hypothalamus, and prefrontal cortex in seven marmoset monkeys. The tree-dwelling marmoset is a non-human primate with a squirrel-sized body and neural architecture that mirrors the human brain.

First author Laith Alexander and colleagues found that over-activation of area 25 within the sgACC shifts the sympathetic-to-parasympathetic balance as indexed by faster heart rate (BPM), reduced vagus nerve tone, and lower heart rate variability (HRV); these markers reflect increased sympathetic nervous system response and less robust parasympathetic functioning.

"We found that over-activity in sgACC promotes the body's 'fight-or-flight' rather than 'rest-and-digest' response, by activating the cardiovascular system and elevating threat responses," Alexander said in a news release.

Over-activity of sgACC/25 in the marmoset brain also heightened the degree of reactivity to both proximal and distal threats. Proximal threats were triggered using a Pavlovian conditioning paradigm involving a rubber snake. Distal threats were elicited by having an unfamiliar "human intruder" enter the lab, which triggered anxiety-like responses in marmosets with over-activity in their sgACC/25.

"By over-activating sgACC, marmosets stayed fearful for longer as measured by both their behavior and blood pressure, showing that in stressful situations their emotion regulation was disrupted," Alexander noted.

Over-activation of sgACC/25 was also associated with an uptick of activity in the amygdala and hypothalamus, two well-established players within the brain's stress-response network. On the flip side, over-activity in the sgACC/25 region reduced activity within the ventromedial prefrontal cortex (vmPFC) and blunted higher-order reward processing.

"The brain regions we identified as being affected during threat processing differed from those affected during reward processing," senior author Angela Roberts said in the news release. "This is key because the distinct brain networks might explain the differential sensitivity of threat-related and reward-related symptoms to treatment."

As another part of this experiment, marmosets were injected with 0.5 mg/kg ketamine and tested 24 hours later using the "human intruder" threat paradigm following sgACC/25 over-activation.

Interestingly, administering ketamine to marmosets failed to reverse the 'fight-or-flight' stress responses associated with increased activity in the amygdala and hypothalamus. Conversely, previous research by this team (Alexander et al., 2019) identified "ketamine as an efficacious treatment for over-activation-induced blunted reward processing," which involves different brain networks.

"We have definitive evidence for the differential sensitivity of different symptom clusters to treatment—on the one hand, anhedonia-like behavior was reversed by ketamine; on the other, anxiety-like behaviors were not," Roberts concluded. "Our research shows that the sgACC may sit at the head and the heart of the matter when it comes to symptoms and treatment of depression and anxiety."