Model response to simulated medication effects.

<p>Breakdown, by mechanism of action, of top 24 most effective simulated drugs (those scoring 0.9 or higher). Y axis indicates fraction of top 24 drugs having the quantitative alteration shown for the given mechanism (e.g., slightly greater than 60% of the top drugs had an AMPA τ₂ value of 1 ms). Titles correspond to mechanisms of action described in text. Baseline value for AMPA τ₂ is 3 ms. b/l  =  baseline.</p

Brain oscillatory activity from clinical magnetoencephalographic (MEG) and EEG studies, and output of computational model.

<p>(A) Control subjects (left three histograms) and schizophrenic patients (right three histograms) were exposed to auditory click trains at 20, 30, and 40 Hz. Resultant MEG power spectra are shown (from Vierling-Claassen et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-VierlingClaassen1" target="_blank">[54]</a>). (B) The same experimental conditions as (A) above were used, but EEG activity was recorded (from Kwon et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Kwon1" target="_blank">[41]</a>). (C) Simulated EEG power spectra from model when driven at 20, 30, and 40 Hz. Note correspondence with clinical data of panels (A) and (B). (This is the “primary point model”, as defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone-0058607-g002" target="_blank">Fig 2</a>.) (D) Graph of power spectrum peaks from index schizophrenic patient of panel (C) plus 20 simulated patients (in red), and index control patient of panel (C) plus 20 simulated control subjects (blue). In all cases, index patient is indicated by a star; simulated patient averages are indicated by dot, and one and two standard deviations are shown by tick marks on error bar. Although computational model outcomes are not strictly analogous to data from clinical studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Berk1" target="_blank">[59]</a>-<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Easterling1" target="_blank">[61]</a>, we have calculated p-values, by convention (* p < 0.01, ** p < 0.001). Note that <i>Group</i> x <i>Frequency</i> interaction was highly significant, due to the fact that group differences were largest at 40 Hz; please see text for additional details of statistical analysis.</p

Parameter ranges used for simulated medications.

1<p>Resultant increase in intracellular Ca⁺⁺ also induces LTP; the quantitative manner in which this is implemented is described in the text, and is in addition to the effect shown here.</p><p>Using the schizophrenic model, simulated medication trials were run, systematically varying model parameters through the ranges shown. A total of 3×5× 5×5×4  =  1,500 simulated trials were conducted. Incr  =  number of increments.</p

Model output showing unique combinations of abnormalities that may give rise to the schizophrenic phenotype.

<p>Degree of GABA system dysregulation, extent of NMDA hypofunction, and spine density decrease are shown on the axes, respectively. Origin (0, 0, 0) represents the control (unaffected) condition. The degree to which model outputs match experimental findings (illness metric) is indicated via color scale. All model outcomes with illness metric > 0.65 are shown.</p

Simulated effects of nifedipine on control and schizophrenic models.

<p>This agent acts by blocking calcium channels. Electrophysiological studies have indicated that nifedipine can, depending on concentration, effectively decrease the slow inward Ca⁺⁺ current by 50% or more. For illustrative purposes, we decreased calcium channel conductance by a maximum of 80%, in increments of 5%. Above, x axis indicates percent reduction in conductance of Ca⁺ channel, and y axis indicates oscillatory behavior (power in given frequency band) of model when driven at 20, 30 and 40 Hz. Colored tick marks on right border of graphs indicate oscillatory behavior characteristic of control subjects. <b>(A)</b> Schizophrenic model. When applied to the schizophrenic model, it did not show corrective effects, as expected. <b>(B)</b> Control model. For the 20 Hz range, clinical studies have shown no change under treatment with Ca⁺⁺ channel blocker nimodipine <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Deutz1" target="_blank">[69]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Denolle1" target="_blank">[70]</a>, or modest decreases in the relative power of this band <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Sannita1" target="_blank">[71]</a>. For other frequency bands, general increases in resting EEG power <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Sannita1" target="_blank">[71]</a> with treatment have been seen. Thus, simulation results are consistent with the clinical EEG literature.</p

Response of system with respect to change in single parameters.

<p>Oscillatory activity (power) at 20, 30, and 40 Hz with respect to (A) decreased NMDA activity, (B) decreased pyramidal cell spine density, and (C) increasing GABA defect is shown. Colored tick marks on right border of graphs indicate oscillatory behavior characteristic of schizophrenic patients. Solid lines represent model response at that frequency to drive at the given frequency (e.g., solid blue line represents power of 20 Hz activity when model is driven at 20 Hz). Dashed red line represents 20 Hz response to 40 Hz drive. Resp  =  response.</p

Response of schizophrenic model to 40 Hz drive.

<p>Simulated EEG traces in response to 40 Hz drive for primary schizophrenic point (left panels), and secondary schizophrenic point (right panels), as defined in text. (A, B) Power spectra of primary and secondary schizophrenic points, respectively. (C, D) Model produced EEG traces. (E, F) EEG, averaged over two consecutive cycles. (G, H) Spiking histogram and firing rates for individual neuron subtypes. Averages over sets of two consecutive cycles are shown. X-axis label applies to all three histograms. Potent  =  potential; spks  =  spikes; CR  =  calretinin positive cells; PV  =  parvalbumin positive cells; PYR  =  pyramidal cells.</p

Simulated effects of phenytoin on control and schizophrenic models.

<p>The therapeutic dose range for phenytoin is 10–20 mg/L, (40–80 µmol/L <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Kilpatrick1" target="_blank">[62]</a>). Lampl et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Lampl1" target="_blank">[63]</a> and others <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Fink1" target="_blank">[64]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Chao1" target="_blank">[65]</a> have shown that phenytoin concentrations in this range produce a decrease in Na⁺ channel conductance of between 34% and 50%. Above, x axis indicates percent reduction in conductance of Na⁺ channel, and y axis indicates the power in given frequency band of the model when driven at 20, 30 and 40 Hz. Colored tick marks on right border of graphs indicate oscillatory behavior characteristic of control subjects (A) Schizophrenic model. When we implement virtual medication doses, by gradually decreasing g_max of the Na⁺ channel, no ameliorative effect (i.e., specific increase in 40 Hz activity) was seen. (B) Control model. There are no known clinical studies that are precisely comparable to the experimental paradigm we have used—that is, studies of control subjects receiving phenytoin at various doses, who receive auditory click train stimulation at 20, 30, and 40 Hz. However, studies that have looked at resting EEG activity at therapeutically relevant doses have shown that it tends to increase 20 Hz activity <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Fink1" target="_blank">[64]</a>, and have inconsistent effects on frequencies in the 30 Hz range <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Herkes1" target="_blank">[66]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-VanWieringen1" target="_blank">[67]</a>; it was not seen to have a significant gamma band effect. Also, laboratory experiments using kainite-induced gamma oscillations in hippocampal slice preparations showed that therapeutic levels of phenytoin (50 μM) had no effect on gamma oscillations (p  =  0.05) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058607#pone.0058607-Cunningham1" target="_blank">[68]</a>. When applied to our control model at the above doses, we achieve similar effects.</p