LAXPATI, NEALEN G.; GROSS, ROBERT E.
Electrical stimulation (ES) of the nervous system, including deep brain stimulation (DBS), has become a mainstay of treatment for patients with movement disorders and pain, and its indications are being expanded to include other neurological disorders such as epilepsy and psychiatric disorders. In fact, ES has played a seminal role in much of our current understanding of the nervous system, ever since the identification of the motor cortex in the 19th century by Fritsch and Hitzig.
Ranck observed 35 years ago that “despite the extensive use of electrical stimulation of the central nervous system, both clinically and experimentally, there has been little concern with what cells or parts of cells are stimulated.”1 He further observed that “it is a subject which we can come close to solving with currently available methods,” and yet it is remarkable how little progress has been made, as the mechanism of action of ES on the nervous system remains poorly understood. What has become clear is that many stimulation parameters are critical in determining the effects of ES, such as electrode configuration, pulse width, and frequency, to name but a few. Ranck reviewed the relative thresholds of neural elements to ES—axons being most sensitive (myelinated more so than in gray matter), then cell bodies, and dendrites being least sensitive. How these thresholds ultimately influence the output from a stimulated region depends greatly on the cytoarchitecture of that region and orientations/locations with respect to the stimulating electrode. A laminar structure, such as the cortex, will clearly respond differently depending on the layer stimulated. This cortical response might also vary, although not necessarily, with the results of stimulating a nuclear structure such as the subthalamic nucleus, where afferent axons, soma, and efferent axons commingle.
A relationship called the ‘activation function’ describes how threshold current (Ith) varies as a square of the distance (r2) from the stimulating electrode to the activated neuron, governed by the current-distance constant (K) [Ith = Kr2] (reviewed in Gross and Rolston2). The activation function has been explored over the years in animals, oftentimes via recordings from activated cells with microelectrodes.3 However, only single neurons can be examined in this fashion, and it is noteworthy that the current-distance constant (K) varies from neuron to neuron. Moreover, the activation function remains empirical and does not address how the neuron becomes activated (eg, dendritic vs. axonal activation; antidromic vs. orthodromic effects). In recent years, a concept referred to as the volume of tissue activated (VTA) has developed, and has been further estimated in computer modeling experiments in relation to DBS electrodes.4 VTA assumes, however, that (1) increasing the current increases the distance from the electrode that cells are activated, ie, that the activation function pertains, and (2) that all neurons respond similarly (ie, that K is constant (reviewed in Gross and Rolston2).
These assumptions, namely the effects of increasing stimulation intensity in the cortex, and the mechanism by which it increases its effects on nervous tissue, were elegantly examined by Histed et al (Histed MH, Bonin V, Reid RC. Direct Activation of Sparse, Distributed Populations of Cortical Neurons by Electrical Microstimulation. Neuron 2009;63(4):508–522). The researchers utilized simultaneous electrical microstimulation and 2-photon calcium imaging in the visual cortex of mice and cats, which enabled their examination of a large number of cells (Figure A) free of the artifacts of stimulation that appear on electrode recordings. This approach revealed a sparse, distributed population of electrically activated neurons, rather than a homogeneously dense ‘volume of tissue activated’ (Figure B). Surprisingly, cells up to 4 mm from the microelectrode tip were activated by 10 μA stimulation, while many cells close to the tip were not (Ranck1 noted that cells up to 450 μm away may be activated by 100 μA). Furthermore, and most surprisingly, increasing the current activated a greater number of neurons within this volume, rather than neurons within an increasing radius from the electrode (Figure D, E, H). One possible explanation considered was that the sparse, distributed population of activated neurons was the result of varying cell body thresholds (ie, different K values), such that weak currents only activated those neurons with the lowest thresholds, and increasing the current density activated neurons within the same volume that possessed higher thresholds. However, even a slight movement of the electrode tip (15 μm, Figure C), which would have little impact on the current density at distant cell bodies, resulted in significant changes in the cells activated. Furthermore, moving the tip more than 30 μm resulted in an almost entirely novel population of activated neurons.
FIGURE. A, 2-photon ...Image Tools
These data are not consistent with the K value determining which neurons became activated. Rather, they support the interpretation that a small volume of neural processes around the electrode tip, rather than the cell bodies themselves, are activated by electrical microstimulation (Figure F, G, I–K). The pattern of activation visualized by voltage-dependent dyes is thus dependent on the composition of local neuronal processes that pass in close proximity to the electrode, rather than the nearest cell bodies. The authors directly demonstrated this in an experiment where they were able to visualize the activation of neuropil around the microelectrode (Figure D-F). Histed et al went on to show that neurons were activated directly rather than post-synaptically: in the presence of pharmacological agents that block excitatory glutamatergic transmission (CNQX and APV) large populations of cells remained strongly activated by electrical microstimulation, but no longer responded to visual stimulation of the visual cortex (the latter serving as a positive control), implying activation through direct depolarization.
The results of Histed et al suggest that electrical microstimulation primarily influences neuronal processes, rather than cell bodies, inducing subsequent activity in a sparse and distributed population of neurons surrounding the electrode tip (Figure G-K). The authors surmised that axons, as opposed to dendrites, played a primary role due to the large distances over which neurons were activated, the low threshold of axonal projections,1 and the regenerative conductive properties of axons that would facilitate stimulation transmission. Increasing stimulation intensity, rather than increasing the “volume of tissue activated,” increases the percentage of cells within a given volume that become activated, by increasing the amount of neuropil that is stimulated.
Are these experiments applicable to the mechanism of action of clinical ES, which utilizes macro-rather than microelectrodes, and often involves nuclear (eg, STN DBS) rather than cortical (eg, for epilepsy) stimulation? First, microelectrode and macrostimulation are fundamentally similar, differing mostly in the current density generated (see Gross et al5). It should be noted, however, that high current densities may inactivate axons closest to the electrode (cathodal currents greater than 8x threshold may inactivate axons1). Second, whether in nuclear or cortical (laminar) ES, neuropil always contains axons as well as cell bodies. (Indeed, some stimulation, such as subgenual cingulate or anterior internal capsule DBS for psychiatric disorders ostensibly targets white matter pathways directly). Yet, while DBS and cortical macrostimulation differ from the microelectrode ES used in this study, the implications of these results remain important in clinical practice. Much of the application and understanding of DBS has revolved around hypothesized activation and inhibition of cell bodies. Evidence has, however, been accumulating to support mechanisms involving axonal activation in DBS.4,6 Indeed, we have found direct evidence for antidromic activation of GPi neurons by STN DBS (unpublished data). The present study elegantly and convincingly demonstrates axonal activation by ES in an experimental model, and it is likely that the DBS exerts its effects similarly. What is important to realize, however, is that the activation, in addition to propagating antidromically, ultimately exerts its effects orthodromically through synaptic downstream connections (not visualized in the Histed et al experiments). Revealed by these experiments is that ‘turning up the juice’ does not necessarily increase the volume of tissue activated, but rather the percentage of axons within the volume that are activated. The implications of this, clinically, are not as yet obvious, but should inform the results of modeling experiments that previously had not considered this possibility.6 However, the implications of the weight of the evidence turning towards a mechanism of action of DBS involving orthodromic activation of axons, rather than direct effects on cell bodies, should have profound implications for techniques and targets in human therapeutic electrical stimulation.
NEALEN G. LAXPATI
ROBERT E. GROSS/
1. Ranck JJB. Which elements are excited in electrical stimulation of mammalian central nervous system: A review. Brain Res
2. Gross RE, Rolston JD. The clinical utility of methods to determine spatial extent and volume of tissue activated by deep brain stimulation. Clin Neurophysiol
3. Tehovnik EJ. Electrical stimulation of neural tissue to evoke behavioral responses. J Neurosci Methods
4. McIntyre CC, Miocinovic S, Butson CR. Computational analysis of deep brain stimulation. Expert Rev of Med Devices
5. Gross RE, Krack P, Rodriguez-Oroz MC, Rezai AR, Benabid AL. Electrophysiological mapping for the implantation of deep brain stimulators for Parkinson's disease and tremor. Mov Disord
6. Miocinovic S, Parent M, Butson CR, et al. Computational Analysis of Subthalamic Nucleus and Lenticular Fasciculus Activation During Therapeutic Deep Brain Stimulation. J Neurophysiol