Colin Weber, used with permissio
Source: Colin Weber, used with permissio

If you have a fear or anxiety disorder, or know someone who does, you have probably asked yourself, why aren’t the treatment options better? My previous post, “What’s Wrong with Antianxiety Drugs,” addressed how issues in the conception and design of antianxiety drug research has hampered the discovery of more effective psychopharmacological treatments. In the present post, I discuss how psychotherapeutic treatment of fear and anxiety problems might be improved by following clues from the neuroscience of learning and memory.

A psychotherapy session is a learning experience, one in which memories formed during the session help the person cope with personal challenges in their life. The memories may be the result of insights from verbal exchanges with the therapist, free association about one’s past or dreams, re-evaluation of beliefs and attitudes, or exposure procedures that weaken the impact of trigger stimuli, among others. Laboratory findings showing ways to enhance memory might therefore also be useful in enhancing memories formed during a therapy session and improving therapeutic outcomes. This is at least worth considering, given the enormous progress that has been made in understanding the neuroscience of learning and memory.

In Anxious: Using the Brain to Understand and Treat Fear and Anxiety (Viking, 2015), I discussed how information from psychological and neuroscience research might be useful in improving therapeutic outcomes. Below, I summarize some of these, emphasizing finding from neuroscience.

Defining Terms. Understanding the principles below will be easier if I define how I will use certain terms.

Learning is the process of information acquisition by way of plasticity (change) in brain circuits.

Memory is the process by which information acquired during learning is stored and made to persist.

Short-term memory is an initial, temporary state that results from a leaning experience. It dissipates unless it is converted into a long-term memory

Memory consolidation is the process by which short-term memory is converted into a persistent long-term memory. Consolidation involves protein synthesis by the neurons in circuits that are forming the memory.

Retrieval refers to the reactivation of long-term memories, often by trigger stimuli that were part of the initial learning.

Some long-term memories are consolidated in systems that operate non-consciously (implicit memory systems) while other systems form memories that can be consciously accessed (explicit memory systems). In a given learning situation, both conscious and non-conscious memories are typically formed, albeit separately.

Exposure Therapy as Test Case. The most widely used psychotherapeutic approach today for dealing with problems related to fear and anxiety involves variants of cognitive therapy. A key tool used in cognitive approaches, especially in cognitive behavioral therapy, is exposure, which was originally based on principles of extinction derived from studies of Pavlovian and operant conditioning in non-human animals.  The basic idea is that repetition of threat-related stimuli in a safe context weakens the ability of the stimuli to elicit the unwanted outcomes, including behavioral and physiological responses that function as symptoms in fear and anxiety disorders. As a result, a new memory is formed indicating that stimulus is not harmful. The new memory  (the stimulus is safe) dominates over and suppresses expression of the old memory (the stimulus is harmful). Exposure can involve presentation of pictures of specific stimuli or situations, use of virtual reality techniques, asking the client to imagine relevant stimuli or situations, or having the person engage with real world stimuli or situations.

Extinction in the laboratory and exposure therapy in a clinical setting are both fairly effective in reducing responses to learned threats.  But in both cases, the effects tend to be temporary and can be undone by the passage of time or by certain kinds of experiences, such as reencountering cues that were part of the original experience. When this happens, the old memory reappears and overrides the suppressive effects of the new memory.  This is not ideal for producing long-term therapeutic benefits.  Because research on the neuroscience of learning and memory, including extinction learning and memory, has made tremendous progress, it might be possible to use these discoveries to improve extinction, and hence exposure therapy. While exposure is not the only tool used in cognitive therapies, and cognitive therapies are not the only kinds of therapy in use today, because of its connection to extinction, exposure is perhaps the ideal test case for exploring whether findings about the neuroscience of learning and memory might improve therapy.

1. Pharmaceutical enhancement of glutamate neurotransmission facilitates extinction learning and memory consolidation. As noted above, a major limit of extinction-based procedures is that the original threat memory often pops back up, suppressing the new memory that the stimulus is safe. Research in animals has shown that a drug, d-cycloserine, that facilitates glutamate neurotransmission at a particular receptor (the NMDA receptor) enhances the effects of extinction. Facilitation of glutamate transmission has consequences that ramify, ultimately facilitating protein synthesis consolidation processes and producing stronger extinction memory.  The net result is that the extinction memory is better protected from being overridden by the original threat memory.  Based on this finding, studies in humans by Michael Davis, Kerry Ressler, Barbara Rothbaum and colleagues tested the effect of d-cycloserine on exposure therapy and found that the therapeutic outcome improved. This is not “drug therapy,” as the client is not “on” the drug.  The drug is just used during the exposure session to strengthen the extinction memory.

2. The timing of events during learning can influence the effectiveness of memory storage. My lab discovered that extinction memory could be made more persistent and dominant (more successful in preventing the original memory from returning) without drugs—this was achieved by altering the timing of the exposures.  In typical laboratory studies of extinction in animals, stimuli are repeated at regular, short intervals (one every minute or two). We found that inserting a 10-minute pause between the first and second exposure, and then using the standard 1-2 minute interval for the remaining exposures, prevented reversal of extinction by the passage of time or by cues related to the original experience.  Daniela Schiller and Liz Phelps then showed the same thing in healthy humans (people without an anxiety disorder). The power of this approach was later demonstrated by researchers who extinguished drug-related cues in addicts and found that the addicts relapsed in the presence of such cues when extinction was done the usual way, but not when it was done with the spacing trick we discovered in our rat studies.  Mechanistically, this process, like the d-cycolserine studies above, involves enhanced glutamate neurotransmission.  However, the change in glutamate transmission is effected behaviorally rather than by way of drug enhancement.  In either case, the net result is a facilitation of protein synthesis and thus an enhancement of consolidation.

3. Cramming depletes enzymes necessary for memory formation. It’s common knowledge that students who cram for an exam generally don’t do as well as those who study at a more leisurely pace.  In psychological parlance, this is known as the difference between massed vs. spaced learning.  Research in animals has shown why spaced learning is more efficient. With massed training (cramming), an enzyme called CREB, which controls protein synthesis during memory formation gets depleted and memory consolidation is disrupted.  With spaced training, CREB is used more efficiently and memory formation proceeds more effectively. Studies by Michelle Craske show that exposure therapy is more effective when done over several spaced sessions that involve a few trials each rather than in a single session of massed exposure. This creates a stronger exposure memory that persists in suppressing the old unwanted memory more effectively outside the therapist’s office.

4.  Memory formation is greatly impacted by experiences that occur shortly after learning. Memory is susceptible to either disruption or facilitation for several hours after learning. The timing roughly corresponds with the window during which protein synthesis consolidation processes are stabilizing memory. For example, if one has had an exposure therapy session to ameliorate discomfort when in crowded public places, walking out in to a crowded city street after the session may lead to the reactivation and revival of the original memory.  But even completely irrelevant stressors, say being mugged, can interfere with memory storage.  This is called retroactive interference.   Since the memory of extinction has not been fully consolidated by the lengthy process of protein synthesis stabilization, it is not well protected from interference. On the other hand, sleep facilitates memory consolidation, including extinction memory consolidation, in animals and humans, and taking a nap after therapy improves therapeutic outcomes.  To prevent interference effects, a post-therapy sequestration session might be used in which the client participates in structured activities that promote rather than interfere with memory formation. And for added benefit, this might be followed by a sleep session. These additions would require that therapy sessions be extended beyond the typical 50-min hour, but may result in a memory that is more effectively consolidated and better-protected from interference. 

5.  Consolidated memories are destabilized by retrieval and must be re-stabilized (reconsolidated) in order to persist.  So far, my emphasis has ben on how therapy might be improved by enhancing the learning and storage of extinction memories, and preventing interference while the memory is being consolidated.  But suppose the memory of some trauma is now fully consolidated.  Are there ways to dampen its effects? In rat studies we found that blockade of protein synthesis, or molecular steps on the path to protein synthesis, after retrieval of a fully consolidated memory dampened its effects.  This led to the idea that retrieval can, under some conditions, destabilize the memory (basically un-consolidate it) and in order for the memory to then persist, it has to be reconsolidated through new protein synthesis. In a clinical setting, reconsolidation blockade might therefore be a way to reduce the impact of long-standing troubling memories: expose the person to cues that retrieve aspects of a memory, and then prevent the re-storage (reconsolidation) of these memory components.  The evidence for reconsolidation is strongest for implicit memory of threats.  If reconsolidation of implicit threat memory can indeed be selectively targeted, it would be possible to reduce arousal and other nonconsciously controlled symptoms while preserving one’s conscious memory of the trauma, a condition that some trauma therapists feel is important. Like the d-cycloserine approach above, using a drug to block reconsolidation is not drug therapy, as the drug is given once or at most a few times and only during the reconsolidation session.  At this point, reconsolidation works really well in animal studies of implicit memory, but many of the drugs that are effective in animals are not safe for use in humans—the search for useful drugs continues.  Reconsolidation is thought to underlie the effects, discussed above, of inserting a break between the first and second trial of extinction—the first trial is retrieval trial that destabilizes the original memory, and later trails reconsolidate the stimulus as being safe rather than dangerous since there are no negative outcomes.

6.  Pure extinction might be more effective than the typical exposure approach that combines extinction with cognitive support. Extinction in the laboratory is largely a process of stimulus repetition.  But early on, exposure therapy became much more than extinction; it also came to include verbal instruction, relaxation training, and learning of cognitive coping and emotion regulation skills to manage the adverse consequences of threat exposure,.  While these additions were thought to make extinction during exposure therapy more effective, recent work by the cognitive behavioral therapist Stefan Hofmann and others has suggested that exposure alone or the cognitive approaches alone are equally effective; outcomes do not improve when combined.  However, the “exposure alone” condition was not simply the stimulus repetition procedure typical of extinction studies in the lab. The instructions and other verbal exchanges involved engage “top-down” cognitive control processes that may compete with and interfere with the beneficial effects pure stimulus repetition. It would be of interest to compare pure stimulus repetition with more traditional exposure techniques that include top-down cognition. My idea here is that “less may be more;” that pure extinction, by minimizing engagement of top-down processes, may be more effective. One reason to suspect that this might be the case is that overlapping brain areas in the prefrontal cortex are involved in extinction and top-down cognition. Top-down cognition and extinction both involve extensive circuits in the medial prefrontal cortex (top-down cognition engages a broader prefrontal network. Although the extinction and the cognitive control circuits may, in effect, function independently, if they share overlapping neural elements (cells and synapses) in medial prefrontal cortex, top-down processes may compete for resources with extinction processes and reduce its efficiency.

7. Nonconscious and conscious exposure might be needed to achieve the most benefit.   Using “pure” extinction (minimal verbal exchanges during the process) may help reduce the impact of top-down cognition on extinction processes. But two more steps might yield an even more effective outcome. 

First, just because the client is not interacting verbally with the therapist does not mean that top-down cognition has been eliminated—rumination is a form of top-down cognition.  A more drastic may provide additional benefits.  Experimental psychologists have several tricks that prevent conscious awareness of visual stimuli (brief stimulus presentations or masking, for example).  Using non-conscious stimulus presentations to conduct stimulus exposure, especially following the temporal spacing approach discussed above) would specifically target non-conscious (implicit) threat processing systems that control behavioral (e.g. freezing) and physiological (arousal) symptoms of anxiety and weaken the ability of the stimulus to trigger these symptoms. Specifically, behavioral and physiological reactions triggered by threat stimuli are controlled by circuits within the amygdala. During extinction learning, the ability of threats to elicit these behavioral and physiological responses by activating amygdala circuits is dampened by plasticity in specific connections between medial prefrontal cortex and the amygdala.  In Anxious I argued that extinction learning by these amygdala-prefrontal interactions is a form of implicit learning and that these processes therefore are best treated by using procedures that target the circuits through non-conscious stimulus presentations.

Second, although extinction is most often thought about in terms of these nonconscious circuits involving medial prefrontal regulation of the amygdala, it is also necessary to separately extinguish the explicit, consciously accessible memories that contribute to thoughts, beliefs and conscious feelings about threats.  These conscious memories are stored by way of connections between hippocampal and cortical areas and are retrieved via prefrontal circuits involved in top-down cognition.  Once the non-conscious responses are dampened by extinction, then conscious extinction can be performed to both gain control over conscious feeling of fear and anxiety, and prevent top-down reactivation of the nonconscious threat processing circuits.  This might then pave the way for other forms of therapy that would then work on beliefs and feelings that also negatively  impact well-being.

Wrapping Up. The key idea in this essay is that therapy is a learning experience, and thus that findings from the neuroscience of learning and memory can suggest ways to improve the storage of memories that are formed during a therapy session.  This should, in turn, improve the therapeutic outcomes that depend on memory.  The subtext in this an other essays that are part of my “I Got A Mind to Tell You” blog is that understanding how different psychological processes are related to different brain systems, especially differences between systems that function nonconsciously vs. those that contribute to conscious content, is key to further progress in understanding the relation of mind and behavior to brain, and the application of this knowledge to improve the quality of our lives.

Blog Music from The Amygdaloids

As always, stream the blog song, “I Got a Mind to Tell You” here.

The theme song of this post is “Once Bitten, Twice Shy”  fromThe Amygdaloids CD, Anxious, a musical companion to Anxious (the book).

Further reading

Bouton ME, Mineka S, Barlow DH (2001) A modern learning theory perspective on the etiology of panic disorder. Psychol Rev 108:4-32.

Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B (2014) Maximizing exposure therapy: an inhibitory learning approach. Behav Res Ther 58:10-23.

Dudai Y (2012) The restless engram: consolidations never end. Annu Rev Neurosci 35:227-247.

Hofmann SG (2008) Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin Psychol Rev 28:199-210.

Kandel ER (1999) Biology and the future of psychoanalysis: a new intellectual framework for psychiatry revisited. The American journal of psychiatry 156:505-524.

Kandel ER (2006) In Search of Memory: The emergence of a new science of mind. New York: W.W. Norton.

LeDoux JE (2015) Anxious: Using the Brain to Understand and Treat Fear and Anxiety (New York, Viking).

McNally RJ (2007) Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin Psychol Rev 27:750-759.

Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129-151.

Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324:951-955.

Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722-726.

Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry 61:1136-1144.

Schiller D, Kanen JW, LeDoux JE, Monfils MH, Phelps EA (2013) Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proceedings of the National Academy of Sciences of the United States of America 110:20040-20045.

Siegel P, Warren R (2013) Less is still more: maintenance of the very brief exposure effect 1 year later. Emotion 13:338-344

About the Author

Joseph LeDoux, Ph.D.

Joseph LeDoux, Ph.D., directs the Emotional Brain Institute at NYU and at the Nathan Kline Institute for Psychiatric Research. He is author of Anxious: Using the Brain to Understand and Treat Fear and Anxiety.

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