Summary: Researchers have identified a key neural circuit that plays a role in dissociation, a phenomenon in which people can feel disconnected from their bodies and reality.
It’s neither uncommon nor especially worrisome for people to lose themselves in a great book or a daydream. But it’s disconcerting when feeling transported becomes so intense as to seem that one is literally separated from one’s mind or body.
Between 2% and 10% of the population will experience the mysterious phenomenon known as dissociation during their lifetimes, said Karl Deisseroth, MD, PhD, professor of bioengineering and of psychiatry and behavioral sciences, as well as a Howard Hughes Medical Institute investigator.
“This state often manifests as the perception of being on the outside looking in at the cockpit of the plane that’s your body or mind — and what you’re seeing you just don’t consider to be yourself,” Deisseroth said.
Nearly three of every four individuals who have experienced a traumatic event will enter a dissociative state during the event or in the hours, days and weeks that follow, Deisseroth said. For most people, these dissociative experiences subside on their own within a few weeks of the trauma. But dissociation can become chronic and highly disruptive — for example, in post-traumatic stress disorder and other neuropsychiatric conditions.
Because no one knows what’s going on inside the brain to trigger or sustain dissociation, it’s hard to know how to stop it.
“In order to develop treatments, and to understand the biology, we needed to know more,” Deisseroth said.
Now, in a study published online Sept. 16 in Nature, Deisseroth and his colleagues at Stanford University have revealed molecular underpinnings and brain-circuit dynamics underlying dissociation.
“This study has identified brain circuitry that plays a role in a well-defined subjective experience,” Deisseroth said. “Beyond its potential medical implications, it gets at the question, ‘What is the self?’ That’s a big one in law and literature, and important even for our own introspections.”
Deisseroth, the D. H. Chen Professor and a practicing psychiatrist, is the study’s senior author. Former graduate students Sam Vesuna, PhD, and Isaac Kauvar, PhD, share lead authorship of the study.
The findings, which implicate a particular protein in a particular set of cells as crucial to the feeling of dissociation, could lead to better-targeted therapies for conditions such as PTSD and other disorders in which dissociation can happen, such as borderline personality disorder and epilepsy.
A patient’s feeling of dissociation
The researchers mapped out this brain-mind connection not only by observing the brains and behavior of mice but also in the course of treating a patient with chronic seizures at the Stanford Comprehensive Epilepsy Program. The patient had reported experiencing a feeling of dissociation immediately before each seizure. (Such a pre-seizure sensation is called an aura.) The patient described this aura as feeling like being “outside the pilot’s chair, looking at, but not controlling, the gauges,” Deisseroth said.
The researchers recorded electrical signals from the patient’s cerebral cortex and stimulated it electrically to try to determine the point of origin of the seizures. Whenever the patient was about to have a seizure, the study’s authors discovered, it was preceded not only by the dissociative aura but also by a particular pattern of electrical activity localized within the patient’s posteromedial cortex. This activity was characterized by an oscillating signal generated by nerve cells firing in coordination at 3 hertz, or three cycles per second. And when this region was stimulated electrically, the patient experienced the dissociative aura without having a seizure.
The scientists probed the effects of ketamine in mice. The drug is known to induce dissociative states in humans. Mice can’t describe their feelings. But at the right ketamine dose, they behaved in a way that suggested they were experiencing a kind of dissociation — a disconnect between perception of incoming sensations and a more complex emotional response to those sensations. When placed on an uncomfortably warm surface, the mice indicated they could feel the heat; they responded reflexively to it, flicking their paws. But they acted as if they didn’t care enough to do what they would ordinarily do voluntarily in such situations: lick their paws to cool them off.
Inducing dissociative behavior with optogenetics
The researchers used optogenetics, a technology enabling scientists to stimulate or inhibit neuronal activity using light, to stimulate neurons in mice’s equivalent of a posteromedial cortex. Doing so at rhythms of 3 hertz could induce dissociative behavior in drug-free animals, the researchers found. Further experiments showed that a particular type of protein, an ion channel, was essential to the generation of the 3 hertz signal and to the dissociative behavior in mice. This protein could be a potential treatment target.
Deisseroth is a member of Stanford Bio-X and of the Stanford Wu Tsai Neurosciences Institute.
Other Stanford authors are graduate student Ethan Richman; postdoctoral scholar Felicity Gore, PhD; research scientist Tomiko Oskotsky, MD; research assistant Clara Sava-Segal; Liqun Luo, PhD, professor of biology; Robert Malenka, MD, PhD, professor of psychiatry and behavioral sciences; Jaimie Henderson, MD, professor of neurosurgery; Paul Nuyukian, MD, PhD, assistant professor of bioengineering and of neurosurgery; and Joesf Parvizi, MD, PhD, professor of neurology.
Funding: The work was funded by the National Institute on Drug Abuse (grant P50DA042012), the National Institute of Mental Health (grant R01MH086373), the federal Defense Advanced Research Projects Agency, the Tarlton Foundation, the AE Foundation Borderline Research Fund, the NOMIS Foundation, the Else Kroner Fresenius Foundation, the National Science Foundation, the Berry Foundation, the Brain & Behavior Research Foundation, Stanford BioX, and the Stanford Wu Tsai Neurosciences Institute.
Stanford’s department of Bioengineering and of Psychiatry and Behavioral Sciences also supported the work.
About this neuroscience research article
Source: Stanford Contacts: Bruce Goldman – Stanford Image Source: The image is credited to Stanford.
Original Research: Closed access “Deep posteromedial cortical rhythm in dissociation” by Sam Vesuna, Isaac V. Kauvar, Ethan Richman, Felicity Gore, Tomiko Oskotsky, Clara Sava-Segal, Liqun Luo, Robert C. Malenka, Jaimie M. Henderson, Paul Nuyujukian, Josef Parvizi & Karl Deisseroth. Nature.
Deep posteromedial cortical rhythm in dissociation
Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1–3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed—including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.