< Fundamental Science & Promising Technologies >
2011-21133 Choi Karam
Courtesy by http://targetedindividualscanada.wordpress.com/2010/06/28/blog-reading-your-mind/ Contents
1. Introduction (ES, CNS, ES&CNS)
2. Generation of Potentials in CNS Tissue 3. Response of Neurons to Imposed Extracellular Potentials 4. From Cell to Circuit 5. Sites of Action Potential Initiation in CNS Neuron 6. Excitation Properties of CNS Stimulation
7. Summery
2 Introduction (1/4) : Electirical Stimulation
Electrical Stimulation (ES) Widespread method to study the form & function of the nervous system Used to determine the structure of axonal branching Examine the strength of connection btw neuron Determine the projection patterns of neurons
A technique to restore function following disease or injury Examples of the application of CNS stimulation in treatment of neurological disorders The treatment of pain by stimulation of the brain & spinal cord Treatment of tremor and the other symptoms of Parkinson’s disease As an experimental treatment for epilepsy Host of other neurological disorders Being developed for restoration of hearing by electrical stimulation of the cochlear nucleus & for restoration of vision
3 Nervous System
Brain
Central Nervous System (CNS)
Spinal Cord
Nervous System somatic nervous system Peripheral Sympathetic Nervous System (PNS) Nervous System autonomic nervous system Parsympathetic Nervous System
4 Introduction (2/4) : Central Nervous System
Central Nervous System (CNS) Components : brain, spinal cord Function : integration & coordination of incoming and outgoing neural signals & carrying our higher learning functions (thinking & learning) Structure : gray matter & white matter
B. C. < Brain & Spinal Cord > A.
D. < Structure of Neuron >
5 Introduction (3/4) : ES of CNS
< CNS synapse > A. Part of postsynaptic B. Various size C. Membrane differentiation
Difficulty of understanding the effects of stimulation of CNS (vs. peripheral nervous system) Diversity of neuronal elements the complexity of the volume conductor
6 Introduction (4/4) : Objective
Objective To present the biophysical basis for electrical stimulation of neurons in the CNS Fundamental understanding of both the electric field & its effects on neurons Determine the site of neuronal excitation or modulation in the CNS where electrodes are placed among heterogeneous populations of neuronal elements (cells, axons, and dendrites) electrode
7 20.2. Generation of Potentials in CNS Tissue (1/4)
Passage of current through tissue generate potentials in the tissue (Ohm’s law:V=IR) signal propagation artificial stimulation (by depolarization of the cell’s membrane) generation of action potential propagation (presynaptic neuron) synaptic transmission (in synaps terminal) propagation (in postsynaptic neuron)
signal propagation
aistudy.co.kr
8 20.2. Generation of Potentials in CNS Tissue (2/4)
extracellular potentials Cause : Passage of current through extracellular electrodes positioned near neuron Result : transmembrane current & depolarization Function : modulate or block ongoing neuronal firing Influencing factors 1. Electrode geometry 2. the stimulus parameters (current magnitude) 3. Electrical properties of the extracellular tissue
< Potential generated by a monopolar point source > TABLE 20.1 Electrical Conductivity of CNS Tissues Tissue Type Electrical Conductivity (S/m) Dura 0.030 Ve(r) = I/4πσr Cerebrospinal fluid 1.5; 1.8 I : the stimulating current Gray matter 0.20 σ : the conductivity of the tissue medium White matter (Table) Transverse 0.6,1,1 r : the distance btw the electrode & the Longitudinal 0.083, 0.13 9 measurement point Encapsulation tissue 0.16 20.2. Generation of Potentials in CNS Tissue (3/4)
Types of Electrodes for CNS
(A) Single iridium microwire electrode (Huntington Medical Research Institutes) : used for extracellular recording from single units or extracellular microstimulation of small populations of neurons (B) Multisite silicon microprobe ( University of Michigan) : higher magnification view (b) of two electrode sites near the tip. (C) Three-dimensional assembly of multisite silicon microprobes : four probes, 256 sites on 400-μm centers in three Dimensions, There are 16 parallel stimulating channels (16 sites active at any time) with off-chip current generation The array is fed by a 7-lead ribbon cable at a data rate of up to 10 Mbps. It operates from ±5V supplies (D) Arrays of up to 128 microwires : enable simultaneous extracellular recording from multiple single neurons. Each wire is 50-μm diameter stainless steel, insulated with Teflon (E) Multielectrode silicon array ( University of Utah ) (F) Subdural grid and strip electrode arrays : used for cortical stimulation and recording (PMT Corporation, Chanhassen,Minnesota) (G) Quadrapolar electrode used for deep brain stimulation (Medtronic Inc., Minneapolis, Minnesota). 10 20.2. Generation of Potentials in CNS Tissue (4/4)
Effects of electrode size Larger electrodes : typically used for chronic stimulation of the CNS Different spatial distribution of the potentials in the tissue
to calculate accurately the extracellular potentials generated by extracellular stimulation a numerical solution using a discretized model (with the finite element method) 11 Example of finite element method
12 20.3 Response of Neurons to Imposed Extracellular Potentials (1/2)
CNS : heterogeneous population of neuronal element 1. local cells projecting locally around the electrode 2. neurons projecting away from the region of stimulation 3. axons passing by the electrode 4. presynaptic terminals projecting onto neurons in the region of the electrode Mediating factors in the effects of stimulation Direct effects of stimulation of postsynaptic elements Indirect effects mediated by electrical stimulation of presynaptic terminals electrode
13 20.3 Response of Neurons to Imposed Extracellular Potentials (2/2)
Complexity of ES in CNS (1) what neuronal elements are activated by extracellular stimulation? (2) how can targeted elements be stimulated selectively?
Computational modeling of the effects of extracellular stimulation on neurons a powerful tool to study extracellular excitation of CNS neurons enable examination of parameters under controlled conditions The volume of tissue stimulated, both for fibers and cells how this changes with electrode geometry stimulus parameters the geometry of the neuronal elements enable simultaneous determination of the effects of stimulation on all the different neural elements around the electrode two-step approach to calculate the electric potentials generated in the tissue by passage of current through the electrode to determine the effect (or effects) of those potentials on the surrounding neurons
14 20.4 From Cell to Circuit: Construction of Models of CNS Neurons (1/2)
Electrical circuits (cable models) used to model the electrical behavior of neurons < Construction of models of CNS neurons >
15 Construction of models of CNS neurons
compartment model of the membrane
• Several nonlinear ionic conductances (gi, gj) • gL : a linear ionic conductance (various ionic channels in the Membrane McIntyre, C.C. and Grill, W.M. (2002) • batteries (Ei, Ej, EL) : Nernst potential arising from the difference in concentration of ions on the inside and outside of the membrane
• capacitor (Cm) : the capacitance arising from the lipid bilayer of the cell 16 20.4 From Cell to Circuit: Construction of Models of CNS Neurons (2/2)
membrane resistance (Rm ) = Specific membrane resistance / Area of segment
= rm/ π∙ d ∙ l
typical values for the specific membrane resistance range d l :1000 ~ 5000Ω -cm2 l The membrane resistance Nonlinear, its value depending on the voltage across the membrane (transmembrane potential) d∙π rm
membrane capacitance (Cm) = Specific membrane capacitance ∙ Area of segment
= cm ∙ π∙ d ∙ l typical values for the specific membrane capacitance range :and 1~2μF/cm2
Intracellular resistance (Ri) = Intracellular resistivity∙ Segment length / Cross-sectional area of segment 2 = ρi ∙l /(π∙ (d/2) ) typical values of the intracellular resistivity range from 50 to 400Ω-cm
17 20.5 Sites of Action Potential Initiation in CNS Neurons
< Action Potential >
18 20.5 Sites of Action Potential Initiation in CNS Neurons
B(-) C(+)
A(-)
19 Image snagged from http://www.steve.gb.com 20 20.6. Excitation Properties of CNS Stimulation
AP initiation occurs in the axon has several important implication for CNS stimulation 1. Excitation occurs in the axon, there is little difference in the extracellular chronaxie times for excitation of local cells and excitation of passing axons chronaxie time is not a sensitive indicator of the neuronal element that is activated by extracellular stimulation. 2. Action potential initiation occurs at some distnace from the site of integration of synaptic inputs, the effects of coactivation of presynaptic fibers may be less than expected, and the axon may still fire even when the cell body is hyperpolarized Extracellular unit recordings of cell body firing may not accurately reflect the output of the neuron 3. the difference in the mode of activation of local cells by cathodic stimuli and anodic stimuli is the basis for the difference in threshold btw cathodic & anodic stimuli
21 20.6.1. Strength-Duration Relationship
Ith=Irh [1+Tch /PW]
Ith= stimulus amplitude necessary for exitation
Irh = rheobase current, current amplitude necessary to excite the neuron with a pulse of infinite duration
Tch= chronaxie, the pulse duration necessary to excite the neuron with a pulse amplitude equal to twice the rheobase current
22 20.6.2. Current-Distance Relationship
2 Ith = IR + k∙r
Ith : threshold
IR (offset) : determine absolte threshold slope (k) : determine the threshold difference btw neurons at different distances from the electrode
23 20.6.3. Effect for Stimulus Polarity & Stimulus Waveform on CNS Stimulation
Results of a computational study to determine During excitation of axons in which neuronal elements are activated by ES the CNS in the CNS different stimulus polarities produce changes in the threshold & in the site of action potential initiation similar but more pronounced effects than peripheral nervous system A model Includeing populations of local cells & axons of passage randomly positioned around a point source stimulating electrode used to compare the activation of local cells to the activation of passing fibers with different stimulation waveforms
24 20.6.3. Effect of Stimulus Polarity & Stimulus Waveform on CNS Stimulation
comparing action potential initiation in local cells using cathodic & anodic stimuli cathodic pulses anodic pulses the threshold for less than the threshold for activation of local activation of passing neurons axons when 70% of the approximately 10% of activated 25% of the axons were activated the local cells were passing axons activated
biphasic stimulus pulses Objective : To prevent the possible degradation of the stimulating electrode(s) or damage to the tissue Used to chronic stimulation
different neuronal elements have similar thresholds for extracellular stimulation illustrates the need for the design of methods that enable selective stimulation 25 20.6.3. Effect of Stimulus Polarity & Stimulus Waveform on CNS Stimulation
Stimulus waveforms can be designed explicitly to take advantage of the nonlinear conductance properties of neurons thereby increase the selectivity between activation of different neuronal elements. Biphasic asymmetrical stimulus waveforms capable of selectively activating either local cells or axonal elements consist of a long-duration, low-amplitude prepulse followed by a short-duration, high-amplitude stimulation Phase The long-duration prepulse phase of the stimulus is designed to create a subthreshold depolarizing prepulse in the nontarget neurons and a hyperpolarizing prepulse in the target neurons same polarity prepulse will produce opposite polarization at the sites of excitation in local cells and passing axons The effect of this subthreshold polarization is to decrease the excitability of the nontarget population and increase the excitability of the target population via alterations in the degree of sodium channel inactivation when the stimulating phase of the waveform is applied, neuronal population targeted for stimulation will be activated with greater selectivity Asymmetrical chargebalanced, biphasic, cathodic phase first stimulus waveforms result in selective activation of local cells, while asymmetrical charge-balanced, biphasic, anodic phase first stimulus waveforms result in selective activation of fibers of passage. charge balancing is achieved as required to reduce the probability of tissue damage and electrode corrosion 26 20.6.4. Indirect Effects of Extracellular Stimulation (1/2)
Similarity btw indirect effects & direnct effects 1. the thresholds of ①,② & threshold for direct effects ④ (mediated by stimulus current) 2. the chronaxie : ① & ④ ① “indirect” effects of stimulation must be considered when electrodes are placed within the heterogeneous ② environment of the CNS ③
27 20.6.4. Indirect Effects of Extracellular Stimulation (2/2)
Excitatory postsynaptic potential (EPSP) Inhibitory postsynaptic potential (IPSP)
28 20.7 Summary (1/2)
Contents of this chapter : Electrical activation of neurons within CNS Usage of electricial stimulation : to study the form and function of the Nervous System(NS) and as a technique to restore function following disease or injury Need to understand the cellular-level effects of stimulation : Successful application of ES to treat NS disorder as well as interpretation of the results of stimulation require an Importance of accurate quantitative models provide a means to understand the response of neurons to extracellular stimulation powerful design tools that can be used to engineer stimuli that produce a desired response Fundamental properties of the excitation of CNS neurons : presented with a focus on what neural elements During CNS stimulation, AP are initiated in the axons of local cells, even for electrodes positioned over the cell body
29 20.7 Summary (2/2)
Cause of the threshold difference btw cathodic & anodic stimuli arises : differences in the mode of activation Difference btw Anodic stimuli & cathodic stimuli Anodic stimuli cause depolarization of the axon & excitation via a “virtual cathode” Cathodic stimuli cause hyperpolarization at the site of excitation and the action potential is initiated during repolarization The threshold for activation of presynaptic terminals projecting into the region of stimulation often less than or equal to the threshold for direct excitation of local cells Indirect effects mediated by synaptic transmission may alter the direct effects of stimulation on the postsysnapytic cell The fundamental understanding provied by this analysis enables the rational design & interpretation of studies & devices employing ES of the brain or spiral cord
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