Modeling and Simulation of Deep Brain Stimulation in Parkinson’s Disease

Modeling and Simulation of Deep Brain Stimulation in Parkinson’s Disease

T. Heida, R. Moroney, E. Marani
DOI: 10.4018/978-1-60566-280-0.ch003
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Deep Brain Stimulation (DBS) is effective in the Parkinsonian state, while it seems to produce rather non-selective stimulation over an unknown volume of tissue. Despite a huge amount of anatomical and physiological data regarding the structure of the basal ganglia (BG) and their connections, the computational processes performed by the basal ganglia in health and disease still remain unclear. Its hypothesized roles are discussed in this chapter as well as the changes that are observed under pathophysiological conditions. Several hypotheses exist in explaining the mechanism by which DBS provides its beneficial effects. Computational models of the BG span a range of structural levels, from low-level membrane conductance-based models of single neurons to high level system models of the complete BG circuit. A selection of models is presented in this chapter. This chapter aims at explaining how models of neurons and connected brain nuclei contribute to the understanding of DBS.
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Introduction: Parkinson’S Disease (Pd)

Detection of MPTP

In 1982 in northern California, a young male, age 29, used a new synthetic heroin, injecting approximately 20 g of the drug intravenously during a 1-week period. “He had a long history of drug abuse beginning at age 22, including heroin, cocaine, marijuana, lysergic acid diethylamide (LSD) and amphetamine. Toward the end of the binge he experienced increasing slowness and rigidity. This culminated in admission to a local hospital where profound and unremitting Parkinsonism was observed” (Langston et al. 1999). His brother, who had injected approximately the same drug in the same amounts, developed an identical clinical condition. Treatment with carbidopa/L-dopa resulted in marked improvement. In 1982, a group of approximately 300 young addicts in northern California may have been exposed to this substance; several of them developed severe Parkinsonism after intravenous injection of this new synthetic heroin that was being sold on the streets at the time.

A missing textbook on organic synthesis from the university library of San Francisco University led to a student engaged in the synthesis of designer drugs.The chemical modification of existent, often naturally occurring psychoactive drugs, i.e., “everything a kitchen chemist can engineer”, are exempt from legal control because of their unique chemical structure. In this case Meperidine (Demerol, Pethidine) was used. Normally Meperidine relieves moderate to severe pain and belongs to the narcotic analgetics, a group of pain medications similar to morphine (see Langston et al. 1983). From this analgetic substance a new synthetic heroine was produced from Meperidine (ethyl ester of 1-methyl-4-phenyl-piperidine-carboxylic acid) into MPPP, the “designer heroin” (1-methyl-4-phenyl-4-propionoxypiperidine). Based on the samples obtained from his supplier the drug contained not only MPPP but also 2.5 to 2.9% of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by weight, a byproduct in the synthesis of MPPP. Biotransformation produces from MPTP the 1-methyl-4-phenylpyridinium ion (MPP+), which is taken up by the dopamine (DA) transporter of the substantia nigra neurons, where it blocks the mitochondrial respiratory chain (see Langston et al. 1999 and references herein).

An experimental monkey model was developed. MPTP was quickly shown experimentally to selectively destroy nerve cells in the substantia nigra after systemic administration. The resulting striatal dopamine depletion explained most, if not all of the clinical features of Parkinson's disease (PD) (for an extensive overview see: Langston et al. 1983, Langston et al. 1999, and an earlier report by Davis et al. 1979).

Although an experimental animal model is present and enormous efforts have been carried out to detect the cause of Parkinsonism, what initiates the disease still remains unknown. Moreover, human studies have an ethical drawback and a case as described above is seldom found in literature. Therefore, experimental results from animals, often not possible to translate to the human situation, especially rat and mouse results, is what scientists have to relay on. Consequently, model studies based on systems theory and neuroanatomical and neurophysiological data are of the utmost importance in the study of Parkinson’s disease and are significant in their contribution to the understanding of Parkinson’s disease and the mechanism(s) of Deep Brain Stimulation (DBS), nowadays mainly carried out in the subthalamic nucleus (Benabid et al. 2000).

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