Neural Circuit Underlying Long-Lasting Treatment for PTSD

Post by Deborah Joye

What's the science?

Post-traumatic stress disorder (PTSD) is a condition in which individuals experience persistent anxiety, flashbacks, and intense fear after a traumatic event. PTSD treatments vary and can include everything from exposure therapy and cognitive processing therapy to medications such as antidepressants. One current treatment for PTSD uses a process called Eye Movement Desensitization and Reprocessing (EMDR), which has patients recall a traumatic memory while they track a flashing light switching from left to right (called Alternating Bilateral Sensory Stimulation or ABS). This treatment effectively directs visual stimulation and eye movements, resulting in reduced fear responses. This method has successfully been used to treat PTSD, but how it might result in long-lasting weakening of fear responses remains a mystery. The role of eye movements and orientation in the technique suggests involvement of the superior colliculus, a region of the midbrain involved in eye movements, head orientation, and distractibility. This week in Nature, Baek and colleagues investigate the neural circuitry underlying long-lasting reduction in fear when fear extinction is paired with ABS in mice.

How did they do it?

To test the effects of visual stimulation in fear conditioned mice, the authors trained mice to associate a sound with a mild foot shock. The authors then put those mice in a cylinder with a line of LEDs installed around the wall and played the sound without the additional foot shock (fear extinction). Mice undergoing fear extinction were simultaneously exposed to one of three lighting conditions: 1) LEDs were continuously lit, 2) all LEDs flashed on and off at the same time or 3) LEDs were sequentially lit, then turned off in alternating directions (mimicking ABS). The authors then measured activity using single-unit recordings in the superior colliculus and the mediodorsal thalamus, a brain region which receives information from the superior colliculus and is also tightly linked to the prefrontal cortex and the amygdala (main regions involved in fear extinction). To test how the ABS lighting condition might be associated with reduced fear responses, the authors performed single-unit recordings in the basolateral amygdala, which has at least two distinct cell populations, one that is active during the fear state, and another that is active when fear is being extinguished. Finally, to assess whether the superior colliculus to mediodorsal thalamus (SC-MD) projection and/or the mediodorsal thalamus to basolateral amygdala (MD-BLA) projection play a causal role in the fear-attenuating effect of ABS, the authors used optogenetics. They then either inhibited or excited the two different projections (SC-MD or MD-BLA) to determine the effect on fear responses.

What did they find?

First, the authors found that pairing ABS with fear extinction resulted in an overall reduced fear response compared to all other groups. This finding was specific to the pairing of ABS with fear extinction as mice who experienced ABS when the sound wasn’t played did not show the same reduction in fear. The authors also found that the ABS fear extinction increased the number of activated cells within the superior colliculus. The magnitude of superior colliculus activation for each mouse was negatively correlated with fear response (more activation resulted in lower fear response). When the authors used optogenetics to specifically excite or inhibit the SC-MD pathway, they found that inhibition of the SC-MD pathway resulted in increased fear and stimulation of this pathway resulted in decreased fear. Single-unit recordings in the amygdala revealed that ABS paired with fear extinction increased the number of inhibited neurons in that region. The authors that inhibited cells in the amygdala were neurons that encode the fear state (versus other cells that encode the fear extinction state). They also found that the inhibitory effects of ABS paired extinction in the basolateral amygdala persisted for at least a week after extinction training. Finally, using optogenetics, the authors found that inhibition of the MD-BLA pathway completely blocked the fear-attenuating effect of ABS, suggesting that this pathway is required for fear attenuation.

What's the impact?

This study is the first to describe the neural circuitry that may underlie the therapeutic effects of eye movement desensitization and reprocessing (EMDR). Understanding the biological basis for how therapeutic treatments work can provide new ways to strengthen treatment plans resulting in better patient outcomes and efficient, targeted therapies. The findings of this study present a neural pathway consisting of the superior colliculus, mediodorsal thalamus, and the basolateral amygdala which could be a central target for the effective treatment of PTSD.

Baek et al., Neural circuits underlying a psychotherapeutic regimen for fear disorders, Nature (2019), Access the original scientific publication here.