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Rewiring the Brain to Eliminate Fear

Using a pulse of medication to augment a behavioral therapy

One of the most exciting and clinically relevant areas of neuropsychiatric research involves "neuroplasticity." What is neuroplasticity? Neuroplasticity refers to the processes by which the brain modifies its function in response to changes in internal and external environments. It underlies the incredible flexibility that nerve cells have for forming and eliminating connections with each other and for altering the strengths of their existing connections. Cells and brain regions that are highly connected are in a position to strongly influence each other. Networks of interconnected cells, and the modification of these connections, form the basis of learning and memory, i.e., how we store new information and retrieve older information.

Certain experiences can be more effective in influencing cellular connections than other experiences. For example, a dramatic emotional event can be extremely effective at causing the formation of strong and lasting connections. Such strong connections can be difficult to "disconnect." As most of us know from our own experiences, there are highly emotional events from decades ago that we remember easily and vividly. An overwhelming trauma, for example, often can lead to the development of emotionally-laden, strong cellular connections. Post traumatic stress disorder (PTSD) likely reflects the ability of major stressors to produce powerful circuitry changes in the brain, resulting in persistent and recurring symptoms. On the other hand, routine life events typically involve weaker changes in cellular connections that are more easily disrupted. Thus, in contrast to highly emotional situations, many of us have trouble remembering the exact events of a routine day at work, particularly after a delay of several weeks. Such weaker changes in connectivity are prone to fade over time.

Since neuroplasticity is involved in how we process memories, it seems logical that if we could influence neuroplasticity while we are trying to learn, we may be able to modulate learning. Could this be applied to “unlearning” something? For example, some individuals are handicapped by specific fears that fall outside of what most would consider normal. Some people are profoundly afraid of heights, for instance. It is likely that the nerve cells in these persons’ brains are wired in such a manner that exposure to heights provokes a dramatic fear response.

One common treatment for fear of heights involves a process known as “desensitization.” This behavioral approach involves a therapist systematically exposing a person to varying degrees of heights under controlled conditions in which fear and anxiety are dampened by relaxation or other techniques. This exposure may involve actual heights - such as looking out from windows on higher and higher floors of a building - or may involve virtual scenarios, i.e., using computer programs to simulate frightening situations. Repeated exposure to increasingly fearful situations may eventually allow a person to become less bothered by the feared stimuli. This process results from the brain being trained to diminish the effectiveness of the feared stimulus to generate emotional responses. In other words, the brain’s wiring is being modified by a controlled form of learning.

Might behavioral desensitization therapy be more effective if it is accompanied by a medicine that leads to an increased "rewiring response?"

Recent research suggests that this may be possible. An antibiotic called cycloserine has been shown to influence neuroplasticity by interacting with a neuroreceptor system known as the NMDA glutamate receptor. This receptor system plays a key role in learning, memory, and behavior. The glutamate receptor complex is more responsive to the neurotransmitter glutamate when cycloserine is present, and work in animals suggests that this helps certain types of learning. Key questions under current study involve whether cycloserine can enhance learning in humans and whether this has therapeutic benefits in certain psychiatric illnesses.

A recent study by Jasper Smits and colleagues reported that cycloserine can lead to a substantially greater response to desensitization therapy for fear of heights. Interestingly, the drug was only beneficial when an individual desensitization session led to significant improvement (diminished fear) during the session. When the behavioral treatment session was not helpful, however, cycloserine did not lead to improvement and might even have made symptoms somewhat worse. This result could be interpreted to mean that cycloserine enhanced the learning (positive or negative) that occurred during a therapy session. If the session backfired and was unhelpful, cycloserine augmented the negative outcome. If the session was helpful, cycloserine enhanced the benefit. In this study, cycloserine was administered immediately after the training session. This raises the possibility that the drug can be administered selectively depending on the perceived outcome of a particular therapy session. As is true of many potentially important research findings, the data in this paper are preliminary and must be replicated before being adapted for clinical practice.

This work illustrates the principle that human learning can be modulated pharmacologically and that a pulsed (non-continuous) dose of a medicine during a behavioral treatment may be an effective way to help alleviate anxiety disorders associated with inappropriate learning. If this type of paired approach (behavioral therapy with a pulse of medication) proves to be effective, this has substantial implications for future treatment strategies. If one can treat certain conditions in a manner that does not require chronic use of medications, it is likely that such treatment will be safer than chronic medication exposure. As is true with all new medical approaches, there are potential benefits but also unknown risks. Careful and responsible research is necessary before this area of science is ready for clinical use. At the minimum, the preliminary results highlight the ability of basic neuroscience research - in this case, studies of the glutamate transmitter system and its role in neuroplasticity and in learning and memory - to inform clinical studies and potentially clinical practice.

This column was written by Eugene Rubin MD, PhD, and Charles Zorumski MD