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You don’t need to be a therapist to know common clinical terms like anxiety and depression. But terms like derealization and depersonalization remain strangely esoteric, evading popular discussions of mental health. So, what are they?
Depersonalization is a persistent feeling of observing oneself as a stranger, as if detached from one’s body and thoughts. Derealization is a persistent detachment from one’s surroundings, as if living in a dream or watching a movie. Both symptoms are associated with trauma and anxiety and may occur together in depersonalization-derealization disorder or DPD, which occurs in 1-2% of the population. DPD is known as a dissociation disorder: it belongs to a family of mental disorders that feature dissociation, a psychological state of detachment.
Dissociation, in and of itself, is actually an everyday psychological phenomenon. After long car drives, many people find they have little to no memory of driving their car, despite the considerable level of coordination, navigation, and reactivity needed to drive. This is a common occurrence of dissociation. But many people experience persistent dissociation as a result of trauma, epilepsy, or abusing drugs such as cannabis or ketamine. What’s happening in the brain that creates such profound detachment from one’s self or surroundings?
Recently, Karl Deisseroth’s lab at Stanford University set out to answer this question. First, his lab gave ketamine to mice, a drug that induces dissociation, not to mention sedation and a lessening of pain (analgesia). Obviously, no one can ask the mice how they feel, but mice given ketamine do behave differently. If put on a plate warmed to 55 Celsius (131 Fahrenheit, comparable to the temperature of concrete or asphalt on a hot day), “sober” mice will not just reflexively flick their paws away from the hot surface, but also lick their paws to soothe themselves, as if to say, “ouch, my paws hurt!” But, dissociated mice on ketamine don’t show the emotional licking response, only the reflexive paw flick. So, what’s different about the brain on ketamine?
Using electrical brain recordings, Deisseroth’s team found mice on ketamine display a pattern of slowly oscillating activity in a brain region called the retrosplenial cortex. This area sits behind the corpus callosum, the nerve fibers that connect the two hemispheres of the cerebral cortex. Ketamine caused neurons in the retrosplenial cortex to wax and wane in voltage slowly and rhythmically at one to three cycles per second.
But of course, just because two things (dissociation and the slow rhythm) change together doesn’t mean that one of those two things causes the other. Maybe ketamine causes the slow rhythm and dissociation independently, just as your car engine causes your car to accelerate and make loud noises, independently.
To find out if this was the case, the scientists used blue light to excite neurons in the retrosplenial cortex of mice at two cycles per second (the same frequency observed under ketamine). This technique, known as optogenetics (which Deisseroth himself helped to pioneer), induced the rhythm originally observed in ketamine mice and showed that it caused dissociation!
The scientists didn’t stop there—they also wanted to know what proteins the rhythm depended on. For this, they genetically disrupted a potassium channel called HCN1 from the retrosplenial cortex of mice. This channel, which influences the rhythmic firing activity of neurons, also appears to mediate ketamine’s dissociative effects. Mice without HCN1 channels in the retrosplenial cortex didn’t dissociate under ketamine—they still showed the emotional paw licking response.
Finally, to confirm that these findings hold not just in mice but also in humans, the scientists studied a patient with dissociation resulting from epilepsy. This patient routinely felt dissociated before a seizure occurred, as part of the seizure’s aura or preceding sensations. Describing the depersonalization that occurs as part of the aura, the patient is quoted saying, “I took a blanket … I threw it over my body, just to see because I knew that when I don’t feel it, I don’t consider it me and immediately my legs were no longer a part of me.”
Because the patient already had electrodes surgically implanted in the brain to monitor seizures, the scientists were able to observe deep electrical brain activity that occurred during the dissociative aura. Looking at a broad area called the posteromedial cortex that contains the retrosplenial cortex and other regions, the team observed in this patient just what they had seen in the ketamine mice: 3.4 cycles per second of rhythmic activity. Still more interestingly, the scientists could artificially induce a dissociative aura by electrically stimulating this area, but not when the patient was given “sham” or placebo stimulations.
“The whole project was really a series of more and more dramatic surprises,” Isaac Kauvar, one of the paper’s two lead authors (along with Sam Vesuna), told me over Linkedin. “First, observing the ketamine-induced oscillation in mice stirred simple curiosity, over half a decade ago — it was weird and felt potentially important, but it was unclear exactly what it meant. The optogenetic result was very exciting, and then with the HCN1 knockout experiment, we felt like we really had a discovery. Connecting this to humans, however, was astonishing.”
But what do the findings mean for patients with dissociation disorders? I asked Kauvar if he and his colleagues had considered using their results to engineer deep brain stimulation for dissociation disorders—electrical stimulation that could be delivered by surgically implanted electrodes to “correct” for the deep rhythm in posteromedial cortex that appears to cause dissociation, thus helping patients to feel connected again. “Yes, that is one direction we are exploring,” confirmed Kauvar, “although a molecular targeting approach may be even better long term.”
Another fascinating implication of this work could be for patients being treated with ketamine for depression. Ketamine has recently shown promise as a fast-acting antidepressant, spurring many ketamine clinics to open across the country. Could giving ketamine together with another drug that modulates HCN1 channels help to preserve ketamine’s desirable antidepressant effects while avoiding a “bad trip” that leaves the patient feeling dissociated? “Yes, I think that is a very real possibility and a very interesting route to keep investigating,” said Kauvar. “Of course, one question I still have is whether dissociative aspects of ketamine actually play any role in the anti-depressive effects.” Indeed, at least one study has suggested that ketamine’s dissociative effects are associated with its antidepressant effects.
Whatever the clinical implications of the team’s work are, there is still more basic science to be done uncovering the neural basis of dissociation. “We are exploring the details of the brainwide neural state associated with retrosplenial rhythmic activity,” said Kauvar, teasing the team’s next study, “and of how that might disconnect the stimulus detection from affective response.” The team’s current work was published in the journal Nature in October.
References
Vesuna, S., Kauvar, I.V., Richman, E. et al. Deep posteromedial cortical rhythm in dissociation. Nature 586, 87–94 (2020). https://doi.org/10.1038/s41586-020-2731-9
