The state of dissociation is commonly described as feeling detached from reality or having an ‘out of body’ experience. This altered state of consciousness is often reported by people who have psychiatric disorders arising from devastating trauma or abuse. It is also evoked by a class of anaesthetic drug, and can occur in epilepsy. The neurological basis of dissociation has been a mystery, but writing in Nature, Vesuna et al.1 describe a localized brain rhythm that underlies this state. Their findings will have far-reaching implications for neuroscience.

The authors first recorded brain-wide neuronal activity in mice using a technique called widefield calcium imaging. They studied changes in these brain rhythms in response to a range of drugs that have sedative, anaesthetic or hallucinogenic properties, including three that induce dissociation — ketamine, phencyclidine (PCP) and dizocilpine (MK801).

Only the dissociative drugs produced robust oscillations in neuronal activity in a brain region called the retrosplenial cortex. This region is essential for various cognitive functions, including episodic memory and navigation2. The oscillations occurred at a low frequency, of about 1–3 hertz. By contrast, non-dissociative drugs such as the anaesthetic propofol and the hallucinogen lysergic acid diethylamide (LSD) did not trigger this rhythmic retrosplenial activity.

Vesuna et al. examined the active cells in more detail using a high-resolution approach called two-photon imaging. This analysis revealed that the oscillations were restricted to cells in layer 5 of the retrosplenial cortex. The authors then recorded neuronal activity across multiple brain regions. Normally, other parts of the cortex and subcortex are functionally connected to neuronal activity in the retrosplenial cortex; however, ketamine caused a disconnect, such that many of these brain regions no longer communicated with the retrosplenial cortex.

The researchers next asked whether inducing the retrosplenial rhythm could cause dissociation. They made use of mice in which layer-5 cells were modified to simultaneously express two ion-channel proteins that are sensitive to light. The first, channelrhodopsin-2, elicits neuronal excitation in response to blue light. The second, eNpHR3.0, silences neurons in response to yellow light. Illuminating the cells with alternating blue and yellow light to induce an artificial 2-Hz rhythm produced behaviours indicative of a dissociated state, analogous to those caused by ketamine (Fig. 1a). For example, the animals did not jump or rear away from threats and did not try to escape when suspended by their tails, but responded normally to pain induced by a hotplate. Although sensation remained intact, the blunted responses to threats suggest dissociation from the surrounding environment.

The authors then deleted two genes that encode ion-channel proteins in the retrosplenial cortex. The first gene encodes a channel activated by the neurotransmitter molecule glutamate. The second encodes hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1), a channel activated by cations that is sometimes called a pacemaker, because of its ability to produce rhythmic activity in the heart and neurons. Vesuna et al. found that the ketamine-induced rhythm was reduced in mice lacking either gene. However, only the HCN1 channel was needed for ketamine to elicit dissociation-like behaviours.

Do these findings translate to humans? Vesuna and colleagues recorded electrical activity from several brain regions in a person with epilepsy, who had previously had electrodes implanted in their cranium to locate seizure activity. The individual experienced dissociation before the onset of seizures. The authors found that this dissociation correlated with a 3-Hz rhythm in the deep posteromedial cortex — a human brain region analogous to the mouse retrosplenial cortex. When the team electrically stimulated the deep posteromedial cortex during a brain-mapping procedure, the person again experienced dissociation (Fig. 1b).

It is premature to draw definitive conclusions from a single individual. However, Vesuna and colleagues’ work provides compelling evidence that a low-frequency rhythm in the deep posteromedial cortex is an evolutionarily conserved mechanism that underlies dissociation across species.

Much of the success of Vesuna and colleagues’ study relies on the reversible dissociative effects of ketamine. At subanaesthetic doses, this fascinating drug elicits dissociation and pain relief (analgesia), and has antidepressant and anti-suicidal properties. At these doses, electroencephalograms (EEGs, which detect neuronal activity at the surface of the brain) show that ketamine broadly dampens 8–12-Hz oscillations3. At higher doses that induce unconsciousness, EEGs reveal a rhythm in the brain’s frontal lobe in humans that alternates between low (1–4 Hz) and high (27–40 Hz) frequencies4. Given that these changes occur over large areas of the brain’s surface, it is striking that a small layer of deep cells is specifically responsible for dissociation. To our knowledge, the oscillations described by Vesuna et al. have not been reported previously for ketamine. This is probably because surface EEG recordings cannot detect localized rhythms generated deep in the cortex.

Rapid technological advances are producing increasingly sophisticated techniques to manipulate neural circuits with precision and high temporal resolution. Vesuna and colleagues’ work exemplifies how these advances are enabling investigators to probe the nature of consciousness itself. They are also revolutionizing the science of anaesthesiology5 — allowing investigators to better understand how anaesthetics produce unconsciousness6, how these mechanisms overlap with natural sleep7, and how people recover consciousness after anaesthesia8. Research into consciousness and anaesthesia overlaps, too, because anaesthetics provide a powerful, reliable means of eliciting reversible states of altered consciousness. Understanding the neural mechanisms of these altered states might lead to fresh approaches to modulate consciousness and control pain without the undesirable side effects of currently available drugs, which include changes in heart rate and blood pressure, cessation of breathing, delirium and nausea.

The complex state of dissociation can be fully described only by humans, who can report their experience. For example, a study in humans was needed to prove that the dissociative and analgesic properties of ketamine are independent9. Going forward, studies that use dissociative drugs in people will continue to be of great interest — for instance, to reveal the connection (if any) between the brain rhythm reported by Vesuna et al. and the various desirable properties of ketamine. Such studies should also include medicines, such as benzodiazepines and lamotrigine, that attenuate ketamine-induced dissociation. An improved understanding of how ketamine alters brain rhythms and associated behavioural states could eventually lead to therapeutics for people experiencing chronic pain, depression and perhaps dissociative disorders.

These analyses will be highly challenging to perform, because studying deep cortical rhythms requires people in whom intracranial electrodes have been implanted. For ethical reasons, only individuals who require electrodes for therapeutic purposes can participate in such studies. We owe them a debt of gratitude for allowing us to better understand the inner workings of the human brain.

Link : https://www.nature.com/articles/d41586-020-02505-z