Gene-Based Neuromodulation

This chapter focuses on the gene-based neuromodulation. Neuromodulation has become a principal tool of functional neurosurgery, finding applications in the treatment of clinical syndromes that result from imbalanced signaling within neural networks. The ability to affect specific cells in a constrained anatomical target region can be achieved with the use of implantable microinfusion pumps that are programmable, rechargeable, refillable, and capable of delivering medications directly to the intrathecal space, neural parenchyma, or adjacent to a peripheral nerve. This approach has been employed predominately for the treatment of pain or spasticity. As the subcellular machinery underlying synaptic transmission is made up of a variety of proteins, gene delivery encoding these proteins can be used to achieve gene-based neuromodulation. As most synaptic proteins are intracellular, gene delivery bypasses the plasma membrane, producing the protein within the target cells. The vectors used for gene delivery can be targeted either through engineering of tropism or the promoters that control gene expression. These features provide potentially improved cellular, and hence functional, specificity. The fact that advanced generation vectors are capable of delivering genes to terminally differentiated cells like neurons creates the ability to alter the machinery of synaptic activity and neuronal excitability without disruption to the connectivity of existing neural networks. Gene-based approaches can also be used to augment the production of endogenous neurotransmitters, generate signaling receptors or components of the intracellular signaling machinery, and to impact specific events required for synaptic vesicle release.