Neuronal modeling approaches

To simulate the disease episodes and subthreshold oscillations we again refer to our neuronal modeling approaches (Fig. 7.2b). The algorithms have been implemented with a simple but physiologically plausible approach, i.e. with two nonlinear feedback loops, one positive and one negative. Depending on the parameter setting, such a system can attain stable dynamics but also can develop oscillations. 

Clearly the solitary neuron model is just an abstraction of much larger circuits in the brain. But such reductionism affords not only a conceptual model for approaching epilepsy but also an experimental model for testing certain hypotheses. The one neuron model appears to be the minimal circuit for cortical forms of epilepsy, but for modelhng subcortical absence epilepsy it appears that a two neuron model is the minimal circuit one excitatory neuron with prominent Ca currents connected to one inhibitory neuron with prominent Ca2+ currents (von Krosigk et al 1993). 

The biological relevance and feasibility of the results obtained with this connec-tionist approach are confirmed in a second stage of analysis with computer simulations of realistic, spiking neuron models presented in section 1.3. I will indicate the details of the models when they are introduced and will refer to previously published work where appropriate. 

To study the effect of an increased gene dosage of GR, Reichardt et al. (2000) and van den Brandt et al. (2007) generated rodent models of GR overexpression. These approaches confirmed that GR controls neuronal and immune functions in a dosage-dependent manner. These results highlight the importance of tight control of GR expression in target tissues and may explain... 

Since HC is such a progressive disorder with clear neuronal loss, it is not surprising that NT manipulation has been of little value in therapy and that there is no drug treatment of any significance. More hope rests on a genetic approach and the mutated gene has in fact been identified and cloned but its precise role remains uncertain. For details of its structure, possible actions and appropriate models see Reddy, Williams and Tagle (1999). 

Aqueous solubility is selected to demonstrate the E-state application in QSPR studies. Huuskonen et al. modeled the aqueous solubihty of 734 diverse organic compounds with multiple linear regression (MLR) and artificial neural network (ANN) approaches [27]. The set of structural descriptors comprised 31 E-state atomic indices, and three indicator variables for pyridine, ahphatic hydrocarbons and aromatic hydrocarbons, respectively. The dataset of734 chemicals was divided into a training set ( =675), a vahdation set (n=38) and a test set (n=21). A comparison of the MLR results (training, r =0.94, s=0.58 vahdation r =0.84, s=0.67 test, r =0.80, s=0.87) and the ANN results (training, r =0.96, s=0.51 vahdation r =0.85, s=0.62 tesL r =0.84, s=0.75) indicates a smah improvement for the neural network model with five hidden neurons. These QSPR models may be used for a fast and rehable computahon of the aqueous solubihty for diverse orgarhc compounds. 

This chapter considers the effects of indolealkylamine (LSD-like) and phenyl-alkylamine (mescaline-like) hallucinogens on learned behavior. We concentrate on those approaches that have shed the most light on underlying neuronal mechanisms or that show promise of becoming useful (in vivo) animal models of hallucinogenic drug action. Thus we are selective rather than exhaustive, a luxury made possible in part because several more empirically oriented reviews have been published recently (14,16,34,35). 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

The above project represents a novel approach and a possible new treatment for psychiatric disorder. The possibility that neuronal discharge short of total brain convulsion may have psychiatric effects would be a major advance in understanding the action of ECT. Moreover, a possible substitute treatment for ECT would be a major clinical breakthrough. TMS might allow us to stimulate deep brain regions without convulsions, pain, or known hazards. Before one widens the use of TMS in humans, further evaluation of the effectiveness of TMS in animal models for depression is necessary. Our hypothesis is that ECT exerts its therapeutic effects by stimulation of specific brain regions. We suggest that TMS may exert therapeutic effects without need for total brain convulsion. 

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