Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology

Abstract

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

Interleaved Propofol‐Ketamine Maintains DBS Physiology and Hemodynamic Stability: A Double‐Blind Randomized Controlled Trial

“…In addition, patients under ketamine did not experience cognitive decline after surgery and did not report amnesia for this part of the surgery. These findings are similar to previous results reported in the literature 44 …”

“…Ketamine acts via NMDA receptors and HCN1 channels, resulting in enhanced neural activity and specific brain oscillations. Human intracranial recordings revealed that ketamine produces γ oscillations in the prefrontal cortex and hippocampus, along with Δ oscillations in the posteromedial cortex, which contribute to its dissociative effect 44 . Our study demonstrates an increase in low γ and a decrease in Δ/θ oscillatory cortical activity in prefrontal EEG recordings during ketamine administration, consistent with previous research 14,45 .…”

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

“…Ketamine can also alter hyperpolarization-activated nucleotide-gated (HCN) channels [18] for slowdelta oscillatory contributions. In fact, low doses of ketamine have been found to produce 3 Hz oscillations in posteromedial cortex [3, 12]. These 3 Hz oscillations have been found to rely on HCN channels [3].…”

“…In particular, ketamine has been proposed to preferentially antagonize NMDA receptors of inhibitory neurons to drive a surge in excitation [6, 9–11]. It is in this disinhibited brain state that the oscillatory dynamics have been characterized [1, 3, 12]. However, taking into account this disinhibition, it remains unknown how the action of ketamine at the subcellular level can give rise to the oscillatory dynamics at the network level.…”

A mean-field model of gamma-frequency oscillations in networks of excitatory and inhibitory neurons

“…Another interesting feature of Type 2 networks is that they may be relevant to the kind of gamma oscillation induced by drugs like Ketamine. Ketamine is known to induce profound changes in brain oscillatory dynamics that appear to be correlated with its antidepressant and sensory dissociative activity (Tian et al 2023). The electrophysiological profile of sub-anesthetic doses of Ketamine generally includes an increase in gamma oscillation power and a decrease in delta, alpha, and beta oscillation power ( instead of those on excitatory neurons, therefore reducing interneuron activity and leading to a disinhibition effect on the overall network activity.…”