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This next paper is possibly the best ketamine paper I have read to this date (no more k holing sheep).
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 states1,2,3,4,5,6,7,8,9,10,11,12. 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 use13,14, 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.
The tldr by figure:
1: using brain imaging 3 hz oscillations of firing are identified in the retrosplenial cortex during high dose ketamine.
2: these waves are characterized electrophisiologically.
3: these oscillations map strongly to measures of dissociation. They are able to use optogenetics to create these waves of firing with light stimulation and they cause dissociation (3b has some of the strongest evidence I have seen of the "plateau" effect commonly cited with dxm).
4: they identify 2 sets of ion channels that drive the effect.. Nmda receptors (fairly obvious but a good internal positive control) and hcn channels which provide a pacemaker current. They abolish the effects by performing global knockouts of the channels, and then using a cre driven system, restoring the channels solely in the retrosplenial cortex.
5: finally they drop the fucking mic.
They found a patient who had seizures that cause dissociative effects, and was previously implanted with electrodes in their brain for mapping of their seizures . They found the seizures induce rhythmic activity in the retrosplenial cortex.
They briefly stimulated this person's brain and were able to induce dissociative experiences.
This is such a rare thing in neuroscience, and for it to cap off such a methodical and elegant paper is amazing. I have been popping off at my mates for like the last hour after reading this.
Definately read the paper it's a nature paper so pretty clear.
Deep posteromedial cortical rhythm in dissociation
- 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
- -Show fewer authors
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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 states1,2,3,4,5,6,7,8,9,10,11,12. 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 use13,14, 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.
Deep posteromedial cortical rhythm in dissociation - Nature
Dissociative states in mouse and human brains are traced to low-frequency rhythmic neural activity—with distinct molecular, cellular and physiological properties—in the deep retrosplenial cortex and the posteromedial cortex.
www.nature.com
The tldr by figure:
1: using brain imaging 3 hz oscillations of firing are identified in the retrosplenial cortex during high dose ketamine.
2: these waves are characterized electrophisiologically.
3: these oscillations map strongly to measures of dissociation. They are able to use optogenetics to create these waves of firing with light stimulation and they cause dissociation (3b has some of the strongest evidence I have seen of the "plateau" effect commonly cited with dxm).
4: they identify 2 sets of ion channels that drive the effect.. Nmda receptors (fairly obvious but a good internal positive control) and hcn channels which provide a pacemaker current. They abolish the effects by performing global knockouts of the channels, and then using a cre driven system, restoring the channels solely in the retrosplenial cortex.
5: finally they drop the fucking mic.
They found a patient who had seizures that cause dissociative effects, and was previously implanted with electrodes in their brain for mapping of their seizures . They found the seizures induce rhythmic activity in the retrosplenial cortex.
They briefly stimulated this person's brain and were able to induce dissociative experiences.
This is such a rare thing in neuroscience, and for it to cap off such a methodical and elegant paper is amazing. I have been popping off at my mates for like the last hour after reading this.
Definately read the paper it's a nature paper so pretty clear.