Didier Pinault | Searcharxiv

arXiv2020

Transcranial Bipolar Direct Current Stimulation of the Frontoparietal Cortex Reduces Ketamine-Induced Oscillopathies: A Pilot Study in the Sedated Rat

Running title: Frontoparietal anodal tDCS reduces ketamine-induced oscillopathies.Abstract: During the prodromal phase of schizophrenia with its complex and insidious clinical picture, electroencephalographic recordings detect widespread oscillation disturbances (or oscillopathies). Neural oscillations are electro-biomarkers of the connectivity state within systems. A single systemic administration of ketamine, a non-competitive NMDA glutamate receptor antagonist, transiently reproduces the oscillopathies with a clinical picture reminiscent of the psychosis prodrome. This acute pharmacological model may help the research and development of innovative treatments against the psychotic transition. Transcranial electrical stimulation is recognized as an appropriate non-invasive therapeutic modality since it can increase cognitive performance and modulate neural oscillations with little or no side effects. Therefore, our objective was to set up, in the sedated adult rat, a stimulation method able to normalize the ketamine-induced oscillopathies. Unilateral transcranial frontoparietal anodal stimulation by direct current (<+1 mA) was applied in ketamine-treated rats. A concomitant electroencephalographic recording of the parietal cortex measured the stimulation effects on its spontaneously-occurring oscillations. A 5-min bipolar anodal tDCS immediately and quickly reduced, significantly with an intensity-effect relationship, the ketamine-induced oscillopathies at least in the bilateral parietal cortex. A duration effect was also recorded. These preliminary neurophysiological findings are promising for developing a therapeutic proof-of-concept against neuropsychiatric disorders.

q-bio.NC↗

arXiv2020

A single psychotomimetic dose of ketamine decreases thalamocortical spindles and delta oscillations in the sedated rat

Background: In patients with psychotic disorders, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the spindle deficit observed in schizophrenia. Methods: An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine in the sensorimotor and associative/cognitive thalamocortical (TC) systems. Results: Under the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations. Conclusion: The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.

q-bio.NC↗