Target parameter values in the handle condition. As shown in Fig. C and Fig. D, the mode in the network is transited from SW back to spindle at about s as a result of the lower of AMPA mediated excitation. Filly, we show the impact of a combition of GABAA agonists and AMPA antagonists. In this case, the conductances of both GABAA and AMPA receptors are target parameters. Though the conductances of each of the GABAA receptor channels scale up linearly from xGABAA to xGABAA at time s, the conductances of each of the AMPA receptor channels scale down linearly from xAMPA to :xAMPA, exactly where xGABAA and xAMPA represents the correspondingIntegration of Epileptic Mechanism and ImplicationFigure. Percentages of SW activities with a offered sypse strength for every single with the twelve sypses inside the network. Yaxis represents the percentages of SW activities. Xaxis represents the relative strength in the sypse in terms of 5 grade levels: : (:,:x, : (:,:x, : (:,:x, : (:,:x, and : (:,:x, exactly where x represents the corresponding maximum conductances of receptor channels within the handle condition. (A) GABAA(INPY PubMed ID:http://jpet.aspetjournals.org/content/153/3/544 ). (B) GABAB(INPY ). (C) AMPA(PY PY ). (D) AMPA(TCPY ). (E) AMPA(PY IN). (F) AMPA(TCIN). (G) GABAA(RERE). (H) AMPA(PY RE). (I) AMPA(TCRE). (J) GABAA(RETC). (K) GABAB(RETC). (L) AMPA(PY TC)..poneg One one particular.orgIntegration of Epileptic Mechanism and ImplicationCdoseEC E : Emax {EOptimal therapeutic treatments. The toxicity of a drug is dose related. Furthermore, as the tests of toxicity can not be easily performed on humans, dose of the drug is often adopted as a metric for toxicity and it is important to reduce the dose to avoid adverse effects. To quantitatively investigate the optimal therapeutic E133 treatments, we consider an optimization problem as follows. Given a number of N antiepileptic drugs, the optimal treatment Tr is defined as a combition of the drugs with the minimal total dose such that the epilepsy can be controlled. Tr fCdose,,Cdose,,,Cdose,N g is found by solving the following optimization problemN P iFigure. The joint distribution of SW activities in terms of the strength of two critical sypses. Xaxis represents the relative strength of GABAA(INPY ). Yaxis represents the percentage of SW activities. Different colors represent the relative strength of AMPA(PY PY) as specified in the legend. The relative strength of both GABAA(INPY ) and AMPA(PY PY ) are in terms of five grade levels: : (:,:x, : (:,:x, : (:,:x, : (:,:x, and : (:,:x, where x represents the corresponding maximum conductances of receptor channels in the control condition..MK-1439 custom synthesis ponegminimizeCdose,iCdose,i subjecttoCdose,i, i.,N, ! P (Tr )[Sphysiological,parameter values in the control condition. As shown in Fig. E and Fig. F, in this case, the mode of the network is transited from SW back to spindle at about s, which is much earlier than the previous two cases with each drug alone (s and s, respectively). In fact, the efficacy of the drug degrades significantly as the dose increases. Two lowdose drugs with complementary receptors in combition are likely to produce a greater therapeutic effect a larger dose of a single drug, which will be discussed in the following sections. Doseresponse relationship. In general, the concentration of a drug at the site of binding determines its effect. However, the actual dependency can be complex and is often nonlinear. The relationship between the drug dose and the response often empirically follows the shape of a receptor binding curve, which is described by.Target parameter values in the handle condition. As shown in Fig. C and Fig. D, the mode on the network is transited from SW back to spindle at about s as a result of the reduce of AMPA mediated excitation. Filly, we show the impact of a combition of GABAA agonists and AMPA antagonists. Within this case, the conductances of both GABAA and AMPA receptors are target parameters. When the conductances of all the GABAA receptor channels scale up linearly from xGABAA to xGABAA at time s, the conductances of each of the AMPA receptor channels scale down linearly from xAMPA to :xAMPA, where xGABAA and xAMPA represents the correspondingIntegration of Epileptic Mechanism and ImplicationFigure. Percentages of SW activities with a given sypse strength for every on the twelve sypses inside the network. Yaxis represents the percentages of SW activities. Xaxis represents the relative strength of the sypse in terms of five grade levels: : (:,:x, : (:,:x, : (:,:x, : (:,:x, and : (:,:x, exactly where x represents the corresponding maximum conductances of receptor channels within the control condition. (A) GABAA(INPY PubMed ID:http://jpet.aspetjournals.org/content/153/3/544 ). (B) GABAB(INPY ). (C) AMPA(PY PY ). (D) AMPA(TCPY ). (E) AMPA(PY IN). (F) AMPA(TCIN). (G) GABAA(RERE). (H) AMPA(PY RE). (I) AMPA(TCRE). (J) GABAA(RETC). (K) GABAB(RETC). (L) AMPA(PY TC)..poneg One particular one particular.orgIntegration of Epileptic Mechanism and ImplicationCdoseEC E : Emax {EOptimal therapeutic treatments. The toxicity of a drug is dose related. Furthermore, as the tests of toxicity can not be easily performed on humans, dose of the drug is often adopted as a metric for toxicity and it is important to reduce the dose to avoid adverse effects. To quantitatively investigate the optimal therapeutic treatments, we consider an optimization problem as follows. Given a number of N antiepileptic drugs, the optimal treatment Tr is defined as a combition of the drugs with the minimal total dose such that the epilepsy can be controlled. Tr fCdose,,Cdose,,,Cdose,N g is found by solving the following optimization problemN P iFigure. The joint distribution of SW activities in terms of the strength of two critical sypses. Xaxis represents the relative strength of GABAA(INPY ). Yaxis represents the percentage of SW activities. Different colors represent the relative strength of AMPA(PY PY) as specified in the legend. The relative strength of both GABAA(INPY ) and AMPA(PY PY ) are in terms of five grade levels: : (:,:x, : (:,:x, : (:,:x, : (:,:x, and : (:,:x, where x represents the corresponding maximum conductances of receptor channels in the control condition..ponegminimizeCdose,iCdose,i subjecttoCdose,i, i.,N, ! P (Tr )[Sphysiological,parameter values in the control condition. As shown in Fig. E and Fig. F, in this case, the mode of the network is transited from SW back to spindle at about s, which is much earlier than the previous two cases with each drug alone (s and s, respectively). In fact, the efficacy of the drug degrades significantly as the dose increases. Two lowdose drugs with complementary receptors in combition are likely to produce a greater therapeutic effect a larger dose of a single drug, which will be discussed in the following sections. Doseresponse relationship. In general, the concentration of a drug at the site of binding determines its effect. However, the actual dependency can be complex and is often nonlinear. The relationship between the drug dose and the response often empirically follows the shape of a receptor binding curve, which is described by.