No abstract

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.

Animal studies suggested that acamprosate modulates neuronal hyperexcitability of acute alcohol withdrawal, acting through the glutamatergic neurotransmission. In the present study, we further investigated whether treatment with acamprosate could attenuate the post-alcohol withdrawal hyperexcitability or hyperarousal in humans using brain magnetoencephalography mapping of spontaneous fields. A double-blind, randomised, placebo-controlled study with a parallel group design comparing 2,000 mg/day of acamprosate versus placebo was conducted in alcohol-dependent subjects meeting DSM-IV criteria for alcohol dependence. Treatments were initiated 8 days before alcohol withdrawal and prolonged during the 15 following (abstinence) days. The study demonstrated that during alcohol withdrawal, acamprosate decreased the arousal level as reflected by alpha slow-wave index (ASI) measurement. This effect was mostly evidenced in left parietotemporal regions and, to a lesser extent, in the contiguous anterior, posterior and right-sided regions. In the placebo group, on the contrary, ASI measures increased between day 2 (acute withdrawal) and day 14 (prolonged withdrawal). The present results suggest a sustained effect of acamprosate on the hyperexcitability state due to alcohol withdrawal in alcohol-dependent patients and that acamprosate may have a protective effect when administered 8 days before alcohol withdrawal.

The cognitive potential, P300, is a phenomenon frequently studied in relation to template matching of the brain. To understand the neurochemical mechanisms of its generation, we compared the effects of three antidepressants, fluoxetine, tianeptine and clomipramine after single and repeated application as well as after 1 week of withdrawal on the P300 and N200 waves in an auditory ‘odd-ball’ paradigm in three parallel groups of 10 healthy volunteers. Following single administration, both fluoxetine and clomipramine reduced (–39 ± 14%, p < 0.01) the peak amplitude of P300 at the Pz electrode. For fluoxetine and tianeptine, reduced amplitudes of 19 ± 7% and 24 ± 11%, respectively, were found following 8 days of treatment, 2 h after administration. However, for clomipramine no additional diminution was found on day 8 with respect to day 1. Topographic distributions tended to be significantly modified at the frontal scalp area 1 h after the tianeptine administration on day 8, whereas the postdosing changes induced by fluoxetine were localised in the midline and right centrotemporal scalp regions. Only minor reductions in peak latencies have been observed. It can be concluded that serotonin selective drugs have a slower onset of P300 amplitude decrease than clomipramine, which has additional effects on monoaminergic and on cholinergic systems. These results suggest that serotonin has a regulatory function in the neurotransmission of cerebral structures which are involved in the evaluation of stimulus relevance.

Distributed linear solutions are widely used in source localization to solve the ill-posed EEG/MEG inverse problem. In the classical approach based on dipole sources, these methods estimate the current densities at a great number of brain sites, typically at the nodes of a 3-D grid which discretizes the chosen solution space. The estimated current density distributions are displayed as brain electromagnetic tomography (BET) images. We have tested well known minimum norm solutions (MN, WMN, LORETA) and other linear inverse solutions [WROP, sLORETA, interference uniform, gain uniform, weight vector normalized (WVN), and a new solution named SLF (Standardized Lead Field)], using a MEG configuration (BTi Magnes 2500 WH with 148 axial magnetometers) and a realistic head model using BEM (Boundary Element Method). The solutions were compared in a noise-free condition and in the presence of noise using the classical dipole localization errors (DLE) together with a new figure of merit that we called max gain uniformity, which measures the capability of an inverse linear solution to show spots of activity with similar amplitudes on the brain electromagnetic tomographies when multiple dipole sources with similar moments are simultaneously active. Whereas some solutions (sLORETA, interference uniform and SLF) were capable of zero dipole localization errors in the noise-free case, none of them reached 100% of correct dipole localizations in the presence of a high level of Gaussian noise. The SLF solution, which has the advantage to be independent from any regularization parameter, presented the best results with the lowest max gain uniformities, with almost 100% of correct dipole localizations with 10% of noise and more than 90% of correct localizations with 30% of noise added to the data. Nevertheless, no solution was able to combine at the same time a correct localization of single sources and the capability to visualize multiple sources with comparable amplitudes on the brain electromagnetic tomographies.