Gamma Oscillations in the Mouse Primary Visual Cortex as an Endophenotype of Schizophrenia

Gamma oscillations (20-50 Hz) are a robust component of brain activity associated with information processing, but are also part of the background spontaneous activity during various brain states including sleep and anesthesia. Our goal was to examine the changes in gamma oscillations that result from pharmacological and genetic manipulations of glutamatergic transmission which produce endophenotypes of schizophrenia. We recorded local field potentials (LFP) and single units through the depth of the mouse primary visual cortex in vivo and examined the alterations in gamma frequency activity under both normal and pathological conditions. Our results indicate that both in awake and anesthetized animals, baseline gamma frequency power in the LFP is increased throughout the cortical lamina, and the signal-to-noise ratio of gamma oscillations produced by a visual stimulus is diminished, most notably in the superficial layers. In addition, the entrainment of single units to the local oscillations in the LFP is reduced in the supragranular (L2/3) and infragranular (L5/6) layers. This work supports the hypothesis that alterations in glutamatergic transmission result in changes to gamma oscillations in primary sensory areas and is consistent with the hypothesis that these changes are associated with disrupted sensory perception

Pharmacokinetic parameters of clobazam.

<p>The table reports the parameters in all volunteers and in the subgroup that included the subjects with peak plasma levels of clobazam below 180 minutes and plasma concentrations of at least 200 µg/ml during the same period (n = 8). Data are expressed as mean values (SD).</p

Results of the pain tests performed.

<p>The data are expressed as mean (SD). Statistical significance is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043896#pone-0043896-t003" target="_blank">table 3</a>.</p><p>n/a: not applicable. AUC: area under the curve. VAS: visual analog scale for pain (range 0–10).</p

Experimental pain tests employed.

<p>Experimental pain tests employed.</p

Results of the ANOVA analyses on all the tests.

<p>The table shows the results for the main, the peak value and the subgroup analysis. The main analysis was performed on all subjects for all data. The peak value analysis included only the basal values and the maximal effect before administration of flumazenil. The subgroup analysis included the subjects with peak plasma levels of clobazam before administration of flumazenil and plasma concentrations of at least 200 µg/ml during the same period (n = 8). The table shows the p values for the interaction of drug with time and for the factors drug and time. For analyses with a significant interaction, the results of the effects of the factors drug and time are not interpretable and are therefore not presented (marked as n/p).</p>*<p>: P-Values <0.05. VAS: pain intensity as assessed by the visual analog scale (0  =  no pain, 10  =  worst pain imaginable). AUC: area under the curve. DSST: digit symbol substitution test (measure of psychomotor performance). n/a: not applicable. n/p: not presented.</p

Time plan of the experiment.

<p>Horizontal arrow: Testing time; ZZ: Resting time; EX: Medical examination, installation of the testing equipment and training measures; CT: Measures on the area of capsaicin hyperalgesia; ET: Cutaneous electrical stimulation; ED: Intramuscular electrical stimulation, pressure stimulation, cold pressor test, conditioned pain modulation and cuff algometry; BT: Psychomotor performance test; b: Blood sample.</p

Flowchart of the study.

<p>Flowchart of the study.</p

Static pinprick hyperalgesia after capsaicin.

<p>The area of static hyperalgesia significantly increased with the active placebo tolterodine (p<0.001), but not with clobazam and clonazepam.</p

Overview of the results.

<p>The table synthetizes the findings of the the main, peak value and subgroup analysis. The statistical significance for “factors” drug and interaction of drug with time is presented. Significance for “factor” time alone is omitted.</p

Effect of single-dose imipramine on chronic low-back and experimental pain. A randomized controlled trial

<div><p>Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed. A single oral dose of imipramine 75 mg was compared to active placebo (tolterodine 1 mg) in 50 patients (32 females) with chronic non-specific low-back pain. Intensity of low-back pain was assessed on a 0–10 numeric rating scale at baseline and every 30 minutes after drug intake. Multimodal QST were performed at baseline and in hourly intervals for 2 hours. Pharmacogenetic influences of cytochrome P450 were addressed by CYP2D6 genotyping. No significant analgesic effect was detected neither on low-back pain nor on any of the sensory tests in the overall analyses. However, evidence for an interaction of the imipramine effect and CYP2D6 genotype was found for electrical and for pressure pain detection thresholds. Intermediate but not extensive metabolizers had a 1.20 times greater electrical pain threshold (95%-CI 1.10 to 1.31) and a 1.10 times greater pressure pain threshold (95%-CI 1.01 to 1.21) 60 minutes after imipramine than after placebo (p<0.001 and p = 0.034, respectively). The present study failed to demonstrate an immediate analgesic effect of imipramine on low-back pain. Anti-nociceptive effects as assessed by quantitative sensory tests may depend on CYP2D6 genotype, indicating that metabolizer status should be accounted for when future studies with tricyclic antidepressants are undertaken.</p></div