Molecular targets for modulation of dissociative and associative states
Inventors
Kauvar, Isaac V. • Vesuna, Sam • Deisseroth, Karl A.
Assignees
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Publication Number
US-12582616-B2
Publication Date
2026-03-24
Expiration Date
Abstract
Methods of treating a subject for a dissociative disorder and methods of screening agents for the ability to modulate dissociative and associative states in a subject are provided. In particular, agents that alter rhythmic neural activity in the posteromedial cortex can be used to modulate dissociative and associative states in a subject.
Core Innovation
The invention provides therapies and screening methods that modulate dissociative versus associative states by using rhythmic neural activity in the deep posteromedial cortex and retrosplenial cortex. Dissociative-state effects are linked to rhythmic neural activity, including a spatially restricted 1-3 Hz rhythm in retrosplenial or deep posteromedial cortex, and the approach uses modulation of posteromedial cortical activity through agents that act on rhythmic mechanisms, including HCN pacemaker channels and NMDAR-associated dissociative agents.
A key aspect of the invention is targeting HCN pacemaker channels to modulate dissociative versus associative states. The document describes treatment compositions and methods using inhibitors of HCN pacemaker channels, including agents listed by name and isoform targeting of HCN1-4 for dissociative disorders. It also describes symptom modulation by administering agents that modulate rhythmic posteromedial cortical activity via HCN, NMDAR, posteromedial cortical activity, or monoamine oxidase.
The document further provides candidate-agent screening by administering a candidate agent and detecting whether it induces or inhibits rhythmic activity in the posteromedial cortex. The screening can optionally include inducing dissociative rhythmic activity using a dissociative inducer such as ketamine or PCP, and then detecting whether the candidate agent inhibits that induced rhythmic activity. The invention is supported by experimental and clinical evidence relating ketamine/PCP-induced retrosplenial rhythm and dissociation-like behavioral phenotypes, along with correlation and causation of dissociative experiences during rhythmic activity and stimulation in humans.
Claims Coverage
The independent claim covers a screening method that determines whether a candidate agent induces or inhibits a dissociative state by administering the candidate agent and detecting its effect on rhythmic neural activity in the posteromedial cortex. The dependent claims refine the independent claim by specifying detection modalities, adding an intermediate dissociative-agent induction step, and narrowing the dissociative agent to ketamine or phencyclidine (three inventive refinements).
Screening by administering candidate agent and detecting posteromedial rhythmic neural activity
Administering the candidate agent to the subject and detecting whether the candidate agent induces or inhibits rhythmic neural activity in the posteromedial cortex of the subject.
Detecting rhythmic neural activity using specified neuroimaging or neurophysiology modalities
Detecting rhythmic neural activity in the posteromedial cortex using electrocorticography (ECoG), electroencephalography (EEG), stereoelectroencephalography (sEEG), magnetoencephalography (MEG), SPECT, fMRI, or PET.
Candidate testing as inhibition of dissociative-agent induced rhythmic activity
Administering a dissociative agent that induces rhythmic neural activity in the posteromedial cortex and detecting whether the candidate agent inhibits the rhythmic activity induced by the dissociative agent.
Limiting the dissociative agent to ketamine or phencyclidine
Specifying that the dissociative agent used is ketamine or phencyclidine.
Overall, the claim set ties dissociative-state determination to effects on posteromedial cortical rhythmic neural activity, with optional use of a dissociative-agent induction step and specified measurement modalities, and with dissociative induction limited to ketamine or phencyclidine in narrower embodiments.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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