Disrupting neuronal transmission: mechanism of DBS?

Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca(2+)]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases of synaptic enhancement, as well as the interpretation of statistical changes in transmitter release and roles played by other factors such as alterations in presynaptic Ca(2+) influx or postsynaptic levels of [Ca(2+)]i. Synaptic depression dominates enhancement at many synapses. Depression is usually attributed to depletion of some pool of readily releasable vesicles, and various forms of the depletion model are discussed. Depression can also arise from feedback activation of presynaptic receptors and from postsynaptic processes such as receptor desensitization. In addition, glial-neuronal interactions can contribute to short-term synaptic plasticity. Finally, we summarize the recent literature on putative molecular players in synaptic plasticity and the effects of genetic manipulations and other modulatory influences.

How the motor-related cortical areas modulate the activity of the output nuclei of the basal ganglia is an important issue for understanding the mechanisms of motor control by the basal ganglia. The cortico-subthalamo-pallidal 'hyperdirect' pathway conveys powerful excitatory effects from the motor-related cortical areas to the globus pallidus, bypassing the striatum, with shorter conduction time than effects conveyed through the striatum. We emphasize the functional significance of the 'hyperdirect' pathway and propose a dynamic 'center-surround model' of basal ganglia function in the control of voluntary limb movements. When a voluntary movement is about to be initiated by cortical mechanisms, a corollary signal conveyed through the cortico-subthalamo-pallidal 'hyperdirect' pathway first inhibits large areas of the thalamus and cerebral cortex that are related to both the selected motor program and other competing programs. Then, another corollary signal through the cortico-striato-pallidal 'direct' pathway disinhibits their targets and releases only the selected motor program. Finally, the third corollary signal possibly through the cortico-striato-external pallido-subthalamo-internal pallidal 'indirect' pathway inhibits their targets extensively. Through this sequential information processing, only the selected motor program is initiated, executed and terminated at the selected timing, whereas other competing programs are canceled.

(1) There are data on the amount of current necessary to stimulate a myelinated fiber or cell body and/or its axon a given distance away from a monopolar electrode over the entire range of practical interest for intracranial stimulation. Data do not exist for other electrode configurations. (2) Currents from a monopolar cathode of more than 8 times threshold may block action potentials in axons. Therefore, only axons lying in a shell around the electrode are stimulated. Elements very close to the electrode may not be stimulated. Close to an electrode small diameter axons may be stimulated and larger ones may not be. (3) Most, and perhaps all, CNS myelinated fibers have chronaxies of 50-100 musec. When gray matter is stimulated, the chronaxie is often 200-700 musec. It is not clear what is being stimulated in this case. Current-duration relations should be determined for many more responses. (4) There are no current-distance or current-duration data for central finely myelinated or unmyelinated fibers. (5) It takes less cathodal current than anodal to stimulate a myelinated fiber passing by a monopolar electrode. When a monopolar electrode is near a cell body, on the opposite side from the axon, often the lowest threshold is anodal, but sometimes cathodal. Stimulation of a neuron near its cell body is not well understood, but in many cases the axon is probably stimulated. (6) Orientation of cell body and axons with respect to current flow is important. For an axon it is the component of the voltage gradient parallel to the fiber that is important. (7) The pia has a significant resistance and capacitance. Gray matter, white matter, and cerebrospinal fluid have different resistivities, which affect patterns of current flow. (8) More is known about stimulation of mammalian CNS than most workers are aware of. Much of what is unknown seems solvable with current methods.