When we think back on our lives, we generally try to dwell on good times and come to terms with bad. But for those who suffer from anxiety disorders, including post-traumatic stress disorder and phobias, just one intractable and unwelcome memory can influence a lifetime of perceptions, emotions and behavior, despite therapists' best efforts.
But thanks to better imaging technology, neuroscientists and psychologists are able to explore the neural mechanisms by which memories are made and stored. And their research has uncovered several physiological interventions — including electrical currents and well-timed pharmacology — that appear to help destabilize fearful memories, a finding that could lead to more effective, targeted psychotherapy in the future.
While practitioners today rely solely on patient reports, "in years to come, neuroscience will inform clinical practice," says Stefan Hofmann, PhD, who directs the Psychotherapy and Emotion Research Laboratory at Boston University. "We will use both biological and neurological measures to give us clues as to treatment."
How fearful memories are made
Though just beginning to plumb the brain's depths, scientists have formulated some theories on how our brains process fearful memories. First, as we witness a scary event, the thalamus relays sensory information to the amygdala, which stamps the memory as emotionally significant and stores it for future use, to help us avoid related threats. Neural networks in the hippocampus busily begin building a map of the memory's context in the first few hours after an event, and related synaptic connections grow stronger in a process called long-term potentiation, consolidating the memory. It is, however, not set in stone.
"Whenever you're learning something, multiple corners of the brain are talking to each other to represent the sights and sounds and smells that you're learning," says Steve Ramirez, PhD, a neuroscientist at the Massachusetts Institute of Technology (MIT). "Yet the process of actually recalling a memory renders it susceptible to modification. [These memories] feel like a bona fide representation of the past, but memories are constantly modified with new information."
Extinguishing the traumatic aspect of a memory involves creating new, safer mental associations to the same sensory cues. Even long-term memories, when recalled, have plasticity and the potential to be updated, an ability psychologists co-opt during exposure therapy, in which a patient faces his or her fears in a non-threatening environment in the hope of gaining control of them. This requires neural communication among a number of areas in the brain: The hippocampus cues the ventromedial prefrontal cortex of changed conditions, which inhibits neuron activity — and the conditioned fear response — in the amygdala (Annual Review of Psychologyopens in new window, 2012).
In some people, though, the process goes awry, and they're unable to escape intrusive thoughts.
"We really don't know why people respond so differently to traumatic experiences," says Gregory J. Quirk, PhD, who investigates the neuroscience of fear at University of Puerto Rico School of Medicine. "It may be that the prefrontal cortex is less connected to the amygdala, so it can't say, ‘No, you're not in danger right now.'"
Malleable memories
Some scientists are trying to manipulate the reconsolidation process. Ramirez co-authored a 2014 study in which he and a team from RIKEN-MIT Center for Neural Circuit Genetics were able to change bad memories to good in male mice. Using a technique called optogenetics, in which genetically encoded, light-responsive proteins are inserted into cells, the scientists were able to pinpoint where a mouse's negative memory of a shock to the foot was formed, in the neural circuitry that connects the dentate gyrus in the hippocampus to the amygdala. The researchers then manipulated those neurons with lasers. Each time the mice ventured to a certain part of their enclosure, the negative memory was reactivated, and they quickly learned to fear the area.
The male mice were then allowed to frolic with female mice, while the same neurons were tapped, helping to switch their messages from one of pain to one of pleasure. The next time the male mice ventured into the chamber, their fear reactions had vanished (Natureopens in new window, 2014).
Another idea under investigation: Can we enhance relearning with drugs? For more than a decade, psychologists have been studying the effects of the antiobiotic D-cycloserine (DCS) in helping augment extinction in conjunction with cognitive behavioral therapy. The drug binds to N-methyl-D-aspartate (NMDA) receptors, which are important to learning and memory, and boosts activity of glutamate, a neurotransmitter in the amygdala, facilitating memory reconsolidation. In trials with the most positive results to date, researchers administered small doses within hours before each of three to five exposure therapy sessions.
"One of the reasons we got interested in DCS was that it is a drug that can theoretically facilitate learning processes, so if you can use it to facilitate extinction learning, that's got fantastic clinical implications," explains Mark Bouton, PhD, professor of psychology at the University of Vermont.
But results of initial studies on DCS for treatment of anxiety disorders were mixed. In one trial, patients suffering from post-traumatic stress disorder who were given DCS reported even worse symptoms post-treatment (Journal of Psychiatric Researchopens in new window, 2012).
What needs to be studied more carefully are DCS dosage amount and timing, Hofmann says, and its interplay with therapy. As he wrote in the journal Depression and Anxietyopens in new window (2014), if memory extinction therapy is weak compared with the strength of the original conditioning, DCS can actually lead to stronger fear memory reconsolidation. In one study, patients who had successful therapy sessions who received DCS right after showed more improvement than those who received a placebo. However, those whose fear levels were still elevated post-session showed less improvement than the placebo group (Biological Psychiatryopens in new window, 2013).
Eradicating memories
Another line of inquiry examines whether fear memories can be reduced or extinguished completely. Last summer, Edward G. Meloni, PhD, assistant professor of psychiatry at Harvard Medical School, and Marc J. Kaufman, PhD, director of the McLean Hospital Translational Imaging Laboratory, experimented with using xenon gas, an anesthetic already used for humans, to modify memory reconsolidation in mice (PLOS ONEopens in new window, 2014). The gas inhibits NMDA receptor activity. Dosed within an hour after a foot shock, it significantly reduced fear reactions, both to the shock and to its context, compared with controls.
Some labs are exploring whether drugs can remove memories. Richard Huganir, MD, PhD, who co-directs the Brain Science Institute at Johns Hopkins University, observes living mouse brains through small panes of surgically installed plexiglass sealed with dental cement to see artificially fluorescent neurotransmitter receptors at work. He and his team studied whether using a drug that blocks a group of proteins — calcium-permeable AMPA receptors that are increased in the cells of the amygdala after fear exposure — could weaken neural connections on the brain caused by trauma. The team discovered that removing the proteins by chemically manipulating a related neurotransmitter completely removed fear associations induced by a loud, sudden noise (Scienceopens in new window, 2010).
"When receptors are added and taken away from synapses, it changes the strength of synaptic transmission and learning," says Huganir. "The trick is being able to selectively disrupt or enhance these mechanisms in different regions of the brain."
Lifestyle factors
Other researchers are looking at whether lifestyle interventions, such as exercise, might also influence how we process memories. For example, brain-derived neurotrophic factor (BDNF) is a naturally occurring protein that regulates the growth of neurons and synapses. Lower blood levels of BDNF signal that a patient may not respond well to exposure therapy, for reasons as yet unclear. Although BDNF isn't given as a drug, blood plasma levels can be increased through moderate to intense physical exercise, and a recent study showed that aerobic exercise reduced PTSD symptoms, an area that needs more study (Cognitive Behaviour Therapy, 2014).
"I don't believe the effects of exercise — the timing and amount of it, and how it affects mental health and treatment for PTSD — have been adequately researched or manipulated," Quirk says.
Other factors might include how soon a patient should sleep after exposure therapy, as sleep plays a role in memory consolidation.
"Sleep is key for learning, and people with PTSD show reduced or disrupted sleep. Recent data show that extinction of conditioned fear occurs more effectively in the morning versus the evening, suggesting that there may be optimal times of the day for exposure therapy," Quirk says.
Timing exposure therapy to a woman's menstrual cycle could also enhance its benefits. A number of studies suggest hormone levels may influence treatment effectiveness, and there is evidence that estrogen activates parts of the brain responsible for extinguishing conditioned fear. The work of Mohammed Milad, PhD, at Massachusetts General Hospital showed that women with lower estradiol levels had poorer extinction recall than both women with higher levels and than men (Neuroscience,opens in new window 2010). The same group found that female rats with higher levels of estrogen and progesterone were better able to consolidate fear extinction; injecting the hormones also facilitated extinction learning (Neuroscienceopens in new window, 2009).
Still, promising as they are, clinical applications of physiological memory tinkering are likely many years away.
"It's neat that these higher order processes can be manipulated, but we do have to be cognizant of not anthropomorphizing too much in this because there's a lot in humans we can't model in animals," Ramirez says.
As part of President Obama's BRAIN Initiative — Brain Research through Advancing Innovative Neurotechnologies — scientists from various organizations will be further exploring the cellular mechanisms of learning and memory over the next three years.
Greater collaboration between neuroscientists and psychologists in treating anxiety disorders can be expected as well.
"Talk therapies are really triggering neural circuits and manipulating the brain, but if neuroscientists can understand how that's happening, we may be able to facilitate the therapy," Quirk says.
