Ketamine effects on CNS responses assessed with MEG/EEG in a passive auditory sensory-gating paradigm: an attempt for modelling some symptoms of psychosis in man.
Disturbances in integrative function have been consistentLy described in psychotic disorder; for instance, prepulse inhibition of the startle reflex (startle-PPI) which is a marker of sensory gating, is deficient in persons with schizophrenia. The N-methyl-D-aspartate antagonist ketamine produces in control subjects a spectrum of neurobehavioural symptoms like encountered in schizophrenia, and disrupts startle-PPI in animals. In the present study, we investigated in 12 healthy subjects whether ketamine would reduce sensory-gating in auditory responses at doses which produce psychotic symptoms. In a double-blind, crossover design loading doses of 0.024, 0.081 and 0.27 mg/kg or saline were employed, followed by maintenance infusion for 120 min. A passive paradigm has been developed which consisted in tone bursts, preceded or not by a (near-threshold) click at intervals of 100 ms or 500 ms. Brain electromagnetic activity imaging of the responses to sound stimuli has been carried out by way of a 148-channel magnetoencephalography-system. Actual evoked response amplitudes and underlying equivalent current dipole strengths have been compared to multi-electrode evoked potentials from the scalp. A click stimulus is capable to inhibit test responses under placebo at the 100 ms interval. During maintenance infusion of ketamine at steady-state (for >30 min) after 0.27 mg/kg, no such amplitude changes were observed anymore (p <0.05) and under these circumstances significant increases in Brief Psychiatric Rating scale and Scale for the Assessment of Negative Symptoms scores were evidenced (p < 0.001). Intermediate effects have been observed when the dose was lowered to 0.081 mg/kg. The present results have shown that ketamine may induce a psychotic-like clinical state associated with gating deficits in healthy subjects.
Boeijinga
Peter H
PH
FORENAP - FRP - Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France. Peter.Boeijinga@forenap.com [corrected]
Soufflet
L
L
Santoro
F
F
Luthringer
R
R
D000161:Acoustic Stimulation; D000328:Adult; D001307:Auditory Perception / Q000187:drug effects*; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D015225:Magnetoencephalography / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011605:Psychoses, Substance-Induced / Q000523:psychology*
D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine