William James, the late 19th- through early 20th-century philosopher, once proposed that people do not fear a bear when they see it but, rather, become frightened when running from it.

One hundred years later, a new brain-imaging study proves James may have been right. Using a Pac-Man–like video game and functional magnetic resonance (fMRI) scans, scientists showed that when a fear-provoking stimulus (say, a bear) is detected in the distance, the human brain switches on circuitry that analyzes the threat level and ways to avoid the animal or harm. Should the bear move closer—increasing the threat—other, more reactive regions of the brain jump into action, triggering an immediate protective response, whether it be to fight, flee or freeze in one's tracks.

"This [duality] is evolutionarily advantageous because a system needs to be in place that evaluates and makes decisions about external stimuli and decides if it is a threat or not," says study co-author Dean Mobbs, a PhD candidate in University College London's imaging neuroscience department. "Fast responses," he adds, "are also important because in early mammals, who were smaller and weaker than the larger reptiles, a quick response in the form of fight, flight or freeze were and still are critical to the survival of the animal." Human abnormalities in these functions, he notes, could lead to anxiety and panic disorders

Mobbs and his colleagues report in Science that they devised a video game that required 14 subjects to move game pieces along a virtual grid to avoid a virtual predator. To increase the fear factor, players snagged by predators could receive a series of three slight electric shocks, a slight shock or no punishment at all.

Researchers discovered by taking fMRIs of participants' brains as they played that when the predator was a distance away, there was increased activity in areas of the brain responsible for the more sophisticated processing, such as the ventromedial prefrontal cortex (vmPFC), a section of the cortex (the brain's main computer) located just behind the eyebrows. As the predator moved closer, the periaqueductal gray (PAG) area of the brain, located near the brain stem, kicked into action; the PAG, which triggers the release of opioid analgesia, the body's internal painkiller, also handles more visceral reactions like the fight-or-flight response.

"With the threat of more shocks, we saw more activity in the (PAG), while the threat of less shocks increased activity in the (vmPFC)," Mobbs says. "This suggests that the more fearful the stimuli is, the more we recruit the PAG, while a threat of low salience is under the control of the vmPFC."

In an editorial accompanying the study, Stephen Maren, an associate professor of psychology and neuroscience at the University of Michigan at Ann Arbor, wrote that the trigger shifts may underlie an individual's subjective appraisal of fear. "Activation of the prefrontal cortex by distal, unpredictable threats might foster anxiety, whereas activation of the periaqueductal gray by proximal threats may fuel panic," he wrote. "Dysfunction in these circuits is, therefore, likely to yield a variety of chronic anxiety disorders."

Mobbs agrees that overactive PAGs (and underactive vmPFCS) may play a role in panic disorders, whereas the reverse—deficient PAGs and hyper vmPFCS—may lead to anxiety. Knowing this, he says, could "help us to understand the systems that are aberrant in such populations…. This is the first step to helping such patients."