Estimates of effective current spread from the tip of stimulating electrodes have been made using paired stimulation and recording, behavioral methods, and most recently paired microstimulation and functional magnetic resonance imaging (fMRI) or optical imaging (reviewed in Tehovnik et al., 2006). Recording evoked potentials while stimulating at varying distances from the neuron demonstrates that to activate a neuron 1 mm from the electrode tip requires between 300 and 2700 uA of current (depending on the excitability of the particular neuron), and similar estimates of effective current spread have been obtained via behavioral measures (Tehovnik et al., 2006). A recent study using two-photon calcium imaging to visualize neuronal firing during microstimulation at low currents revealed a sparse pattern of activation greatly altered by small movements of the electrode, implying activation mainly via axons in a small volume around the electrode tip (Histed et al., 2009), consistent with previous findings of the relatively greater excitability of axons compared to cell bodies (Ranck, 1975). Supplementary Figure 1A illustrates how the physical proximity of neural elements to the electrode tip, intrinsic excitability of these elements, and current amplitude combine to determine the pattern of neural activity produced by microstimulation.
Tolias and colleagues (2005) combined microstimulation with fMRI imaging to examine the activation of neurons throughout the brain. Microstimulating V1, they observed that the spatial extent of microstimulation-induced increased BOLD activity in that region exceeded that expected from passive spread of the current, suggesting synaptic propagation of activity via horizontal connections. A positive BOLD response was also observed in areas V2, V3, V4, and MT/V5, all of which are monosynaptically connected to V1 (supplementary Figure 1B). Because these extrastriate areas are reciprocally connected to V1, it is impossible to determine from the fMRI whether the observed extrastriate activity was driven orthodromically via V1’s input to these regions, or by direct antidromic activation of their projections to V1. Consistent with these observations, microstimulation of the SC was found to evoke BOLD activity in many regions of the brain to which is has known anatomical connections, including both the thalamus and the FEF (Field et al., 2008).
Recent work by Logothetis and colleagues (2010) paints a more complex picture. Microstimulation of the LGN increased the BOLD signal in V1, as expected based on previous observations, but reduced the BOLD response in extrastriate areas (supplementary Figure 1C). Injections of GABA antagonists into V1 reversed this suppressive effect, suggesting that it results from synaptic inhibition. Microstimulation of the pulvinar, which is monosynaptically connected to the extrastriate areas, produced activation rather than suppression of these regions. They also examined the effect of microstimulation frequency on neural activity, and found that at low frequencies (<60Hz) both mono- and polysynaptically connected areas showed reduced activity, whereas at higher frequencies they observed the pattern of monosynaptic activation, polysynaptic suppression previously described. If these results generalize to cortical stimulation sites, it will have important implications for interpreting the results and inferring the likely neural substrate of microstimulation’s behavioral effects in numerous previous experiments.
Supplementary references:
Field CB, Johnston K, Gati JS, Menon RS, Everling S (2008) Connectivity of the primate superior colliculus mapped by concurrent microstimulation and event-related FMRI. PLoS One 3:e3928.
Logothetis NK, Augath M, Murayama Y, Rauch A, Sultan F, Goense J, Oeltermann A, Merkle H. (2010) The effects of electrical microstimulation on cortical signal propagation. Nat Neurosci 13:1283-1291.
Ranck JB, Jr. (1975) Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res 98:417-440.
Tehovnik EJ, Tolias AS, Sultan F, Slocum WM, Logothetis NK (2006) Direct and indirect activation of cortical neurons by electrical microstimulation. J Neurophysiol 96:512-521.
Tolias AS, Sultan F, Augath M, Oeltermann A, Tehovnik EJ, Schiller PH, Logothetis NK. (2005) Mapping cortical activity elicited with electrical microstimulation using FMRI in the macaque. Neuron 48:901-911.
Supplemental Figure 1. Activation of neural tissue with microstimulation. A.Illustration of the effects of current amplitude, position relative to the microelectrode, and intrinsic excitability in determining the activation of a neural element with microstimulation. Axons (red) are more excitable (lower threshold) than cell bodies and dendrites (blue). Red and blue circles indicate the spatial extent of activation of neural elements with low versus high excitability, respectively. Action potential icons within a cell body indicate whether a given neuron is activated at the current level illustrated (left side, lower current amplitude; right side, higher current amplitude). B. Effect of V1 microstimulation on BOLD activity in visual cortex. Microstimulation parameters: current amplitude of 1400 μA, frequency of 100 Hz, pulse duration of 200 μs, and train duration of 4 s. Areas of statistically significant increase in BOLD, superimposed on structural image: the operculum of area V1, the posterior bank of the lunate sulcus of area V2/V3, and the posterior bank of the superior temporal sulcus of area MT/V5. C. Effects of LGN microstimulation on BOLD in mono- and polysynaptically connected areas. Red: significant increase in BOLD, observed in LGN and V1. Blue: significant decrease in BOLD observed in extrastriate regions (XC).