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REVIEW
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts
Submitted 20 July 2004; accepted in final form 7 September 2004
ABSTRACT
The purpose of this review is to critically examine phosphene induction and saccadic eye movement generation by electrical microstimulation of striate cortex (area V1) in humans and monkeys. The following issues are addressed: 1) Properties of electrical stimulation as they pertain to the activation of V1 elements; 2) the induction of phosphenes in sighted and blind human subjects elicited by electrical stimulation using various stimulation parameters and electrode types; 3) the induction of phosphenes with electrical microstimulation of V1 in monkeys; 4) the generation of saccadic eye movements with electrical microstimulation of V1 in monkeys; and 5) the tasks involved for the development of a cortical visual prosthesis for the blind. In this review it is concluded that electrical microstimulation of area V1 in trained monkeys can be used to accelerate the development of an effective prosthetic device for the blind.
INTRODUCTION
As early as 1931, Foerster discovered that electrical stimulation delivered to striate cortex (V1) of humans elicits a visual percept of light in the lower part of the visual field when stimulation is delivered above the calcarine fissure, and elicits a visual percept of light in the upper part of the visual field when stimulation is delivered below the calcarine fissure. Years later, using an array of implanted electrodes, Brindley and Lewin (1968a)
reported that electrical stimulation delivered to V1 of a blind patient evokes a phosphene, a percept depicted as a distant star that is stationary as long as the eyes are immobile. Such phosphenes have been evoked from patients blind for years and in some cases blind for decades (Brindley 1972; Brindley and Lewin 1968a, b; Dobelle and Mladejovsky 1974; Schmidt et al. 1996). Typically, a phosphene has been described as a circular spot of white light (but sometimes black) varying in size 
3° of visual angle and persisting for the duration of stimulation (Brindley 1972; Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Dobelle et al. 1974; Lee et al. 2000; Schmidt et al. 1996). As stimulation is delivered to portions of V1 representing a more peripheral part of the visual field, the size of a phosphene increases (Brindley and Lewin 1968a). Phosphenes exhibiting colors of red, green, or blue have also been evoked (Dobelle and Mladejovsky 1974; Schmidt et al. 1996). Phosphenes can be induced in both sighted and blind subjects (Brindley 1972; Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Dobelle et al. 1974; Lee et al. 2000; Maynard 2001; Schmidt et al. 1996).
For the most part, the above results concur with the receptive field properties of V1 cells of nonhuman primates (Dagnelie et al. 1989; Daniel and Whitterridge 1961; Dow et al. 1981; Gawne and Martin 2002; Hubel and Wiesel 1968, 1974b, 1977; Livingston and Hubel 1984; Michael 1981; Schiller 1976a; van Essen et al. 1984): that is, that the receptive field of V1 neurons is roughly circular and stationary (when the eyes are immobile), that the size of a field increases for more peripheral representations of the visual field, and that the maximal receptive field size is within 3° of visual angle. Also, in accordance with the topographic layout of V1, cells above the calcarine fissure respond to visual stimuli presented in the lower visual field and cells below the calcarine fissure respond to visual stimuli presented in the upper visual field (Daniel and Whitterridge 1961; Hubel and Wiesel 1968). Finally, many V1 cells respond to colored stimuli (Dow 1974; Gouras 1974; Hubel and Livingston 1990; Hubel and Wiesel 1968; Michael 1981; Ts'o and Gilbert 1988), which concurs with the observation that phosphenes can exhibit chromatic properties.
By studying etherized monkeys, Schäfer (1888) was the first to suggest a topographic organization for V1 in primates. He found that electrical stimulation of V1 evokes contraversive eye movements and that stimulation above the calcarine fissure produces downward eye movements, whereas stimulation below the calcarine fissure generates upward movements. Over the years others have replicated this basic result in a variety of primates from apes to monkeys (Doty 1965; Grünbaum and Sherrington 1901, 1903; Keating and Gooley 1988; Keating et al. 1983; Schiller 1972, 1977; Wagman 1964; Wagman et al. 1958; Walker and Weaver 1940). In fact, electrical stimulation of V1 evokes saccadic eye movements that terminate in the center of the visual receptive field of the stimulated cells, and long trains of stimulation produce a sequence of multiple saccades until the eyes reach the oculomotor limit (Keating and Gooley 1988; Keating et al. 1983; Schiller 1972, 1977; Tehovnik et al. 2003a). Each saccade within this sequence exhibits a similar size and direction. Thus the retinotopic coding scheme of V1 as described with electrical stimulation is in register with the scheme deduced using single cell recording.
A variety of investigations, from single-cell recording (e.g., Schiller et al. 1976a, b, c) to functional imaging experiments (e.g., Tootell et al. 1988a, b, c), have been used to study the visual functions of primate V1. These techniques have basically corroborated the original observations of Hubel and Wiesel (Hubel and Freeman 1977; Hubel and Wiesel 1968, 1972, 1974a, b, 1977; LeVay et al. 1975): that is, that V1 is organized according to ocular dominance and orientation columns. By the start of the twentieth century and well into the 1960s, electrical stimulation techniques played a central role in investigating the relationship of V1 function to the execution of ocular behavior (Doty 1965, 1969; Grünbaum and Sherrington 1901, 1903; Schäfer 1888; Wagman 1964; Wagman et al. 1958; Walker and Weaver 1940; Ward and Weiskrantz 1969). This line of work, however, was largely eclipsed by the seminal single-unit recording experiments of Hubel and Wiesel.
Nevertheless, a number of investigators have continued to use electrical stimulation techniques to ascertain V1 function as it pertains to ocular and visual responses in primates (Bartlett and Doty 1980; DeYoe 1983; Doty 1970; Keating and Gooley 1988; Keating et al. 1983; Schiller 1972, 1977). Anatomical studies have shown that the deepest layers of V1 (i.e., lamina V) innervate the superior colliculus (Fries 1984; Graham 1982; Lund et al. 1975; Spatz et al. 1970; Vogt-Weisenhorn et al. 1995). The superior colliculus mediates oculomotor responses (Schiller 1984; Wurtz et al. 2001). Schiller (1977) showed that lesions of the superior colliculus abolished all saccadic eye movements evoked electrically from V1 even when currents as high as 3,000 µA were used. Before any lesion, currents as low as 200 µA had been effective. These results have since been replicated (Keating and Gooley 1988; Keating et al. 1983). Accordingly, it appears that V1 can gain access to the brain stem saccade generator by the superior colliculus.
Using the method of Doty (1965), it has been found that monkeys can be conditioned to respond to electrical stimulation delivered to various layers within V1 (Bartlett and Doty 1980; DeYoe 1983). Monkeys were trained to release a lever for reward after the delivery of electrical stimulation. Doty assumed in these types of experiments that monkeys experience a punctate and unitary visual percept when electricity is delivered to any region within V1 because the conditioning effect attributed to stimulation of V1 is immediately generalized to any ipsilateral or contralateral location within the V1 map (Doty 1965, 1970) and because the conditioning response can be obtained using currents as low as 2 µA (Bartlett and Doty 1980; DeYoe 1983). Such low currents can activate V1 neurons confined to the extent of an ocular dominance column (Tehovnik et al. 2002), which is roughly 0.5 mm wide (Blasdel and Salama 1986; LeVay et al. 1975, 1985; Wiesel et al. 1974). The excitability properties of V1 elements mediating the conditioning response are restrictive (chronaxies ranging from 0.1 to 0.5 ms; a chronaxie, a measure of neuronal excitability, is the shortest duration of an effective electrical stimulation pulse having a strength equal to twice the minimum strength required for neuronal excitation), suggesting that a limited population of neurons mediates this response (DeYoe 1983). Furthermore, the excitabilities of these neuronal elements are similar to those that mediate stimulation-evoked phosphenes in human V1 (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Rushton and Brindley 1978). Thus every time electrical stimulation is delivered to monkey V1 to elicit a conditioning response a visual phosphene is likely produced as well.
Over the past 10 yr many new advances have been made in the study of phosphenes and saccadic eye movements evoked by electrical microstimulation of primate V1. This review summarizes these advances with the purpose of providing a foundation for the development of a cortical visual prosthesis for the blind. Issues discussed are as follows: 1) properties of electrical stimulation with an emphasis on effective current spread in V1 ascertained by single-unit recording and behavioral methods; 2) properties of phosphene induction in relation to stimulation parameters, macrostimulation versus microstimulation, and phosphenes elicited in sighted and blind subjects; 3) monkey psychophysics and the study of phosphenes; 4) the generation of saccadic eye movements elicited by microstimulation of V1; and 5) the development of an effective cortical visual prosthesis for the blind.
PROPERTIES OF ELECTRICAL STIMULATION
Effective current spread in V1 based on single-cell data
The effective range of current spread from an electrode tip is proportional to the square root of the current divided by the square root of a constant (Tehovnik 1996). The constant, called the current–distance constant, can range from 300 to 3,000 µA/mm2 for large pyramidal tract cells with an average of about 1,000 µA/mm2 (Stoney et al. 1968). These values were computed with a single cathodal-current pulse having a duration of 0.2 ms. The constant reflects the excitability of a neural element 1 mm away from the electrode tip such that an element having a constant of 1,000 µA/mm2 would require a 1,000-µA current to be activated 1 mm away 50% of the time. The greater the current–distance constant, the less the conduction velocity of an axonal element (Hentall et al. 1984; Jankowska and Roberts 1972; Roberts and Smith 1973). Therefore the size of a neuron's axon and whether it is myelinated affects the current–distance constant.
To estimate the spread of a current pulse in V1, we use a current–distance constant of 1,000 µA/mm2. This is a very conservative estimate for V1, given that the neuronal elements in V1 of primates tend to be smaller than those in other parts of the cerebral cortex (Cragg 1967; Fries 1984; O'Kusky and Colonnier 1982; Peters 1987; Rockel et al. 1980) and that the conduction velocity distributions of pyramidal tract neurons exiting V1 tend to be significantly lower than those of large pyramidal neurons (Finlay et al. 1976; Macpherson et al. 1982). Using the equation, r = (I/K)1/2, where r is the distance of effective current spread from the electrode tip in mm, I is the current used in µA, and K is the current–distance constant in µA/mm2, a 1-, 10-, and 100-µA current pulse delivered to V1 is estimated to activate elements within 0.03, 0.10, and 0.32 mm, respectively, from the electrode tip. Thus a current pulse at or below 100 µA delivered to V1 can directly activate elements confined to a hypercolumn, which is about 1.0 mm wide (Hubel and Wiesel 1977; LeVay et al. 1985).
Cell counts have shown that V1 of macaque monkeys contains about 120,000 neurons per mm3 of cortical tissue (Cragg 1967; O'Kusky and Colonnier 1982; Peters 1987; Rockel et al. 1980); therefore a 1-, 10-, and 100-µA current pulse should activate about 14, 500, and 16,400 neurons, respectively (calculated using 4/3
r3). This calculation assumes a uniform cell density across all V1 layers.
Effective current spread in V1 based on behavioral data
We have found that if electrical stimulation is delivered to V1 before a monkey generates a saccadic eye movement to a visual target, the execution of the saccade is delayed progressively more the closer the visual target is to the receptive-field center of the stimulated neurons (Tehovnik et al. 2004). This method has been used to deduce the effective spread of trains of pulses delivered to V1. The visual target used in this experiment was a bright circular spot of light 0.2° in diameter, which is comparable to the smallest diameter of V1 receptive fields (Dagnelie et al. 1989). The maximum increase in saccadic latency arising from stimulation with a 100-ms train of 100-µA pulses (0.2-ms pulse duration) delivered at 200 Hz occurred when the target was positioned at the center of the receptive field of the stimulated neurons (Fig. 1A). The magnitude of the latency increase decreased systematically as the distance between the target and receptive-field center was increased. For target eccentricities beyond 0.5° from the receptive-field center, the stimulation became ineffective (Fig. 1A). This delay effect was studied at 3 levels of current. The latency difference for stimulation trials compared with nonstimulation trials was computed for 25-, 50-, and 100-µA currents while the target position was varied. The greatest latency difference was observed for all current conditions when the target was situated at the receptive-field center of the stimulated neurons (Fig. 1B). The magnitude of this effect varied positively with current intensity.
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), which represent 800 µm of V1 tissue (Blasdel and Salama 1986; LeVay et al. 1975, 1985; Wiesel et al. 1974). Therefore 25-, 50-, and 100-µA currents affect V1 tissue within 248, 312, and 464 µm from the electrode tip. These estimates are somewhat greater than those obtained by using the current–distance equation in the preceding section (25-, 50-, and 100-µA currents affect V1 tissue within 158, 224, and 316 µm from the electrode tip). This difference is likely related to the fact that the current–distance equation is based on the delivery of a single pulse, whereas the experiments described here are based on the delivery of a train of 20 pulses. This greater spread is probably related to transynaptic effects (Jankowska et al. 1975; McIlwain 1982).
In conclusion, when a train of stimulation using microampere currents is delivered to the cortex, a relatively punctate region of cortex is activated. This conclusion is consistent with other reports for cortical microstimulation (Nichols and Newsome 2002; Salzman et al. 1990).
Does electrode tip size matter?
It is well known that the larger the surface area of an electrode tip, the greater the current that is required to activate neuronal tissue (Bagshaw and Evans 1976; DeYoe 1983; Keating and Gooley 1988; Milner and Laferriere 1986; West and Wolsencroft 1983; Yeomans et al. 1985). It is for this reason that milliampere currents are required to evoke neuronal responses when macroelectrodes are used (i.e., tip sizes of 0.5 mm2 or more), whereas microampere currents are sufficient when delivered through microelectrodes (i.e., tip sizes of 0.01 mm2 or less). The larger the electrode tip, the less the current density generated at the tip for a given amount of total current. It is current density that determines whether neuronal elements are activated, and it is the current density at the tip that determines whether the stimulation produces tissue damage (Tehovnik 1996). A cathodal pulse with a charge density as high as 438 nC/mm2 per phase is required to activate relatively unexcitable neurons (as derived from Nowak and Bullier 1996: 27,500 µA/mm2 x 0.2 ms pulses/4 per phase), whereas charge densities exceeding 16,000 nC/mm2 per phase produce histological damage after delivering pulses through a microelectrode (tip size = 0.007 mm2) continuously for many hours (McCreery et al. 1990). Because most studies use different parameters of stimulation, no one criterion is suitable for setting a damage threshold. Usable stimulation parameters are those that yield stable responses over time (McCreery et al. 2002; Yeomans 1990). Pulse durations, however, should be routinely set to the chronaxies of the directly stimulated elements (Tehovnik 1996). Durations that surpass the chronaxies do not contribute significantly to the evoked response. Charge-balanced biphasic pulses should be used to reduce damage resulting from electrode polarization (Tehovnik 1996).
PHOSPHENE INDUCTION
Stimulation parameters
As mentioned earlier, electrical stimulation of V1 in humans tends to evoke a phosphene that conforms to the receptive-field properties of V1 cells: i.e., a circular spot that is stationary as long as the eyes are immobile. Parameters of stimulation such as current, pulse duration, train duration, pulse frequency, and pulse polarity affect the generation of phosphenes.
A broad range of currents has been used to evoke phosphenes. Currents in the milliampere range are required to elicit phosphenes when stimulation is delivered through a macroelectrode located on the surface of V1 (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Lee et al. 2000; Rushton and Brindley 1978), and currents as low as 2 µA are effective when using a microelectrode positioned in the deepest layers of V1 (Schmidt et al. 1996). When using surface macroelectrodes, increasing current initially increases the brightness of a phosphene, and further increases subsequently increase the size (Dobelle and Mladejovsky 1974; Rushton and Brindley 1978). The effect of increments in current is more complicated when using depth microelectrodes. Although increases in current produced brighter phosphenes, such increases do not have a uniform effect on phosphene size (Schmidt et al. 1996). For some sites an increment in current produces an increase in phosphene size, for other sites it produces a decrease, and still for others it produces an increase followed by a decrease (Schmidt et al. 1996).
Pulse durations used to evoke phosphenes have been as short as 0.01 ms and as long as 1 ms (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Schmidt et al. 1996). The chronaxie of phosphene induction is typically <0.4 ms (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Rushton and Brindley 1978); therefore increases in pulse duration beyond 1 ms do not contribute substantially to phosphene induction. Increasing the pulse duration increases the brightness of a phosphene (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Schmidt et al. 1996).
A train of between 5 and 15 pulses delivered at 50 Hz is needed to produce the sensation of a phosphene (Dobelle and Mladejovsky 1974). The onset and offset of a phosphene is locked to the onset and offset of the stimulation train (Dobelle and Mladejovsky 1974; Schmidt et al. 1996). When using surface macrostimulation, phosphenes extinguish before the termination of stimulation for train lengths >10 to 15 s (Dobelle and Mladejovsky 1974), whereas when using depth microstimulation, they extinguish at train lengths >1 s (Schmidt et al. 1996). The brightness and size of a phosphene are increased with an increase in train duration (Schmidt et al. 1996).
A wide range of pulse frequencies from as low as 25 Hz to as high as 4,000 Hz have been used to generate phosphenes (Bak et al. 1990; Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Schmidt et al. 1996). Frequencies above 30 Hz are the best for producing steady phosphenes with minimal or no flicker (Bak et al. 1990; Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Schmidt et al. 1996). The most effective frequencies range between 100 and 200 Hz (Dobelle and Mladejovsky 1974; Schmidt et al. 1996), which is within the range of firing frequencies of V1 cells activated by a visual stimulus (Gawne and Martin 2002; Nowak et al. 1995). Higher frequencies have been reported to produce brighter phosphenes (Dobelle and Mladejovsky 1974; Schmidt et al. 1996).
Mixed reports have arisen regarding the effects of pulse polarity on phosphene induction. Using surface macrostimulation, no threshold differences were reported between cathodal and anodal pulses for the induction of phosphenes (Dobelle and Mladejovsky 1974). For surface stimulation, it is commonly believed that anodal pulses are superior to cathodal pulses for evoking a response (Ranck 1975). Using depth microstimulation, cathodal pulses were always more effective than anodal pulses for producing phosphenes (Schmidt et al. 1996). This result concurs with what would be expected for depth stimulation (Ranck 1975).
Two visual features that are affected systematically by manipulating the parameters of stimulation are the brightness and size of phosphenes. Increases in current or pulse duration increase the brightness and size of a phosphene, particularly when using surface macrostimulation (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Rushton and Brindley 1978; Schmidt et al. 1996). Increasing current can increase the firing rate of the stimulated elements (Ronner 1982). This agrees with the unit properties of cells in V1. That is, as the brightness (or contrast) of a visual stimulus is increased, the firing rate of cells increases to some asymptotic level (Albrecht and Hamilton 1982; Sclar et al. 1990; Tolhurst 1989; Tolhurst et al. 1981). Also, increments in current or pulse duration increase the number of elements activated because of the higher current densities generated at the electrode tip and because of the greater overall volume of tissue activated (Tehovnik 1996). The higher current densities at the tip would maximally activate more neurons, thereby generating a high-contrast phosphene (Albrecht and Hamilton 1982; Sclar et al. 1990) and the increase in the volume of neurons activated should produce an increase in the size of the phosphene as additional hypercolumns are activated.
Increases in pulse frequency and train duration also increase the brightness and size of phosphenes (Dobelle and Mladejovsky 1974; Schmidt et al. 1996). These parametric increases would drive the directly stimulated cells at a higher rate (Finlay et al. 1976), which would translate into a brighter phosphene (Albrecht and Hamilton 1982; Sclar et al. 1990; Tolhurst 1989; Tolhurst et al. 1981) and produce greater intracortical synaptic spread of the signal (Jankowska et al. 1975; McIlwain 1982), thereby increasing phosphene size.
Accommodation to repeated bouts of stimulation
The brightness of an evoked phosphene accommodates after repeated bouts of stimulation. When a 125-ms train of 0.1-ms pulses (with pulse frequency of 200 Hz) was presented every 4 s and repeated 50 times, the relative brightness between the first and last bout of stimulation decreased by 80% (Schmidt et al. 1996). Increasing the train and pulse duration of stimulation to 250 ms and 0.4 ms, respectively, reduced accommodation. Furthermore after repeated bouts of stimulation over a period of many months, V1 tissue became more resistant to accommodation. Accommodation occurs for both surface and depth stimulation and it is observed in both sighted and blind subjects (Dobelle and Mladejovsky 1974; Rushton and Brindley 1978; Schmidt et al. 1996). Brightness accommodation must be understood and controlled to develop an effective V1 prosthesis.
Macro- versus microelectrodes
Most studies that have evoked phosphenes from V1 in humans have used surface macroelectrodes (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Lee et al. 2000). Fewer studies have used intracortical microelectrodes (Bak et al. 1990; Schmidt et al. 1996). With surface macroelectrodes, the electrode spacing must be >2 to 3 mm for subjects to report 2 distinct phosphenes (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974), whereas with intracortical microelectrodes 2 distinct phosphenes can be resolved with an electrode spacing as little as 0.5 mm (Bak et al. 1990; Schmidt et al. 1996). This minimal spacing agrees with that reported for monkeys trained to discriminate between the activation of 2 closely spaced intracortical electrodes (Doty 1965). Also, with the use of intracortical microelectrodes, currents in the microampere range can be used (Schmidt et al. 1996), the current spread of which may be confined to within one hypercolumn (Tehovnik et al. 2002, 2004). Confining current to one hypercolumn is not possible with surface macroelectrodes because currents above 1 mA and as high as 15 mA are routinely needed to evoke phosphenes (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Lee et al. 2000).
Typically, phosphenes generated by surface macroelectrodes fail to exhibit chromatic features (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Lee et al. 2000). This is less true when using intracortical microelectrodes, provided a current of <10 µA is used (Schmidt et al. 1996). Colored phosphenes are more readily evoked with low currents, perhaps because fewer V1 neurons are activated. Activating regions of V1 that are known to contain neurons mediating chromatic vision might increase the chances of evoking colored phosphenes (Livingston and Hubel 1984; Michael 1981). Whether other visual features coded by single cells can be studied at the lowest current levels remains to be seen.
Stimulating through multiple electrodes
Electrical stimulation has been delivered through multiple electrodes in V1 of humans to induce the perception of patterns such as horizontal and vertical lines as well as letters (Dobelle et al. 1974, 1976; Schmidt et al. 1996). With the use of microelectrodes, Schmidt et al. (1996) found that a train duration of over 200 ms is sufficient to evoke a pattern of phosphenes, and as mentioned earlier a pair of electrodes needs to be separated by 0.5 mm or more to evoke 2 separate phosphenes. A major concern in evoking patterns is that each phosphene constituting a pattern must be of comparable brightness; otherwise a human subject judges the collection of phosphenes as separate objects (Schmidt et al. 1996). For one object to be perceived, currents delivered through each electrode have to be adjusted until all phosphenes of a pattern are of comparable brightness.
Phosphene induction in sighted versus blind subjects
When electrical stimulation is delivered to V1 of humans, the evoked phosphene is most often described as a bright spot of light, and only rarely is it described as a dark spot (Brindley and Lewin 1968a, b; Dobelle and Mladejovsky 1974; Schmidt et al. 1996). Based on what we know about the visual system, there is no reason to think that light-on responses should be more common than light-off responses (Schiller 1992). Cells in V1 respond to light and dark edges and spots, as well as to the onset and termination of flashed light and dark stimuli (Hubel and Livingston 1990; Hubel and Wiesel 1968; Schiller et al. 1976a). So why are bright phosphenes overreported by human subjects? Two factors might account for this, one related to blindness and the other to the way subjects are tested. Regarding blindness, most studies of electrically evoked phosphenes have been performed using blind subjects. In the one study that has successfully evoked both bright and dark phosphenes from V1, all of the subjects were sighted (Lee et al. 2000). It is therefore possible that in blind subjects the default phosphene is always bright because the OFF channels have been rendered inoperative by the blindness, which has fixed the background illumination level of the visual system to pitch black, as happens when one closes one's eyes.
The way sighted subjects are tested for phosphene induction should determine whether white or black phosphenes are reported. If the background illumination during testing is set to pitch black then once again the default phosphene should be white. On the other hand, if the background illumination is of intermediate brightness then both white and black phosphenes should be evoked, as found by Lee et al. (2000).
Visual adaptation and afterimages
Experiments in which images are stabilized on the retina have shown that after a relatively short time, measured in seconds, the images fade and disappear. Numerous studies have explored this dramatic effect (e.g., Pritchard et al. 1960). In large part this phenomenon is the result of adaptation processes that occur in the retina (Schiller 1996). Thus when a stimulus is presented and maintained, the responses of the retinal ganglion cells gradually decline to their spontaneous activity. Subsequent removal of the image elicits a new set of responses. A persistent bright spot of light elicits an initial vigorous response in ON-center ganglion cells followed by a gradual decline in their activity. When the stimulus is then turned off, a vigorous response is produced in the OFF-center ganglion cells whose receptive fields fall within the region of the spot. This activity elicits the perception of a negative afterimage. The magnitude and duration of the initial responses as well as those of the afterimage is a function of the contrast of the stimulus: the higher the contrast the greater the initial response and the more pronounced and longer lasting the afterimage. The effect works equally with light-incremental and light-decremental stimuli. By contrast, images do not fade with prolonged electrical stimulation of V1. Phosphenes can be generated for over 1 min using a continuous train of stimulation. Once the stimulation is terminated, there is never any report of an afterimage (Brindley 1972).
MONKEY PSYCHOPYSICS AND THE STUDY OF PHOSPHENES
Stimulation-induced interference
It has been known for some time that electrical stimulation of V1 disrupts a monkey's performance of visual tasks (Ward and Weiskrantz 1969). When electrical stimulation is delivered concurrently with the presentation of a visual target placed in the receptive field of the stimulated neurons, saccades generated toward the receptive-field target can be either suppressed or facilitated, depending on the cortical layers activated (Schiller and Tehovnik 2001). In the upper layers of V1 interference is most commonly obtained: the stimulation decreases the probability of saccades and increases the latency of saccades made to the receptive-field target. By contrast, in the lower layers stimulation generally produces facilitation: the probability of saccades being generated to the receptive-field target increases and the latency of saccade initiation decreases.
To illustrate these effects, monkeys were presented with paired targets such that one target of a pair was positioned in the receptive field of the stimulated neurons and the other target of a pair was located in the mirror-position of the opposite hemifield (Fig. 2, A and B). On a fraction of trials a train of electrical stimulation was delivered that began 30 ms after the presentation of the first target (Fig. 2C). Thirty milliseconds is about the minimal time it takes for cells in V1 to discharge after the presentation of a visual stimulus (Miller and Glickstein 1967; Nowak et al. 1995; Vogels and Orban 1994). In the absence of electrical stimulation, monkeys will generate saccades to each target of a pair roughly 50% of the time when the targets are presented simultaneously (Schiller and Tehovnik 2001), although there can be subtle position habits (Tehovnik et al. 2002). If one target of a pair leads the other target, however, monkeys tend to produce saccades to the first target. By varying the temporal offset between the targets, a psychophysical function can be generated showing the probability of saccades being made to the receptive-field target (Fig. 2D, Control). When electrical stimulation of a site produces interference, this function is shifted rightward (Fig. 2D, Interference), whereas when electrical stimulation of a site produces facilitation this function is shifted leftward (Fig. 2D, Facilitation).
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). Several experiments have been conducted to investigate these ideas (Slocum and Tehovnik 2004; Tehovnik and Slocum 2003a, b; Tehovnik et al. 2002).
After testing for interference and/or facilitation at fine depth increments with respect to the cortical surface, it was found that the most pronounced interference occurred at 0.8 mm below the cortical surface and the most pronounced facilitation occurred at 1.7 mm below the cortical surface (Fig. 3). Additionally, it was discovered that anodal pulses were superior to cathodal pulses for inducing interference (Fig. 4). This suggests that cell bodies and axon terminals are being activated disproportionately more than axons to produce the interference effect (Ranck 1975). According to Ranck, effective stimulation of neural tissue induces an outward current at the initial segment and nodes of Ranvier, thereby triggering an action potential. When cathodal current is delivered adjacent to a neural element, an outward current is induced, causing the membrane to depolarize, whereas when an anodal current is delivered the resulting inward current causes the membrane to be hyperpolarized. For this reason cathodal pulses are more effective than anodal pulses at activating axons (Armstrong et al. 1973; McIntyre and Grill 2000; Porter 1963; Rattay 1999; Stoney et al. 1968). When an anodal current is delivered to a cell body or axon terminal an inward current is produced at the cell body or terminal, whereas an outward current occurs at the axon. This outward current activates the neuron. This property makes anodal pulses superior to cathodal pulses when activating cell bodies and terminals (Armstrong et al. 1973; Clendenin et al. 1974; McIntyre and Grill 2000; Porter 1963; Rattay 1999; Stoney et al. 1968).
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). If interference were a result of activation of the visual inputs originating from the lateral geniculate nucleus, interference should vary according to which eye is presented with the visual stimuli, given that these inputs are organized according to eye dominance (Hubel and Wiesel 1972; LeVay et al. 1975, 1985). After targeting the visual input layers with our stimulating electrode (Tehovnik and Slocum 2003b), we found that stimulation here produced maximal interference when visual stimuli were presented to the eye with the primary (i.e., ocular dominant) input to the stimulated column, and produced less interference when presented to the eye with the lesser (i.e., ocular inferior) input to the stimulated column (Fig. 5). This result was also obtained when an animal generated saccades to a single target located in the receptive field of the stimulated neurons.
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-aminobutyric acid (GABA)ergic interneurons that are concentrated near the input layers of V1 (Fitzpatrick et al. 1987; Hubel and Wiesel 1972; Lund et al. 1975). There is evidence supporting both possibilities. Stimulating V1 with a single pulse renders neurons in the lateral geniculate nucleus, as well as neurons within V1, unresponsive to visual stimuli for tens of milliseconds (Chung and Ferster 1998; Schiller and Malpeli 1977), and injection of GABAergic agents into V1 disrupts both the selection and detection of visual targets (Newsome et al. 1985; Schiller and Tehovnik 2003). Accordingly, interference that is produced while delivering stimulation concurrently with the presentation of visual targets seems to occur by activation of the visual input fibers of V1, whereas facilitation under such conditions is produced by activation of the output fibers. In subsequent sections, we will return to the issue of activating the output fibers of V1.
The relationship of phosphene generation to interference and facilitation is not known. Whether stimulating individual layers within V1 differentially induces phosphenes and whether phosphene induction is related to interference and facilitation needs to be determined in both monkeys and humans.
Stimulation-induced saccadic delays
Saccadic eye movements to a visual target positioned in the receptive field of stimulated V1 neurons are systematically delayed when stimulation is delivered to those neurons while monkeys are actively fixating (Tehovnik et al. 2004). This effect is confined to the receptive-field location of the stimulated neurons (Fig. 1). The greatest delay occurs when a train of stimulation is delivered during the fixation period immediately before the onset of the visual target. The optimal parameters of stimulation for the delay are as follows: 1) anodal pulses (as opposed to cathodal pulses); 2) train durations of >40 ms with frequencies >100 Hz; and 3) pulse durations of <0.4 ms. Delays are evoked with currents as low as 4 µA.
The chronaxies of V1 elements mediating the saccadic delay were determined and compared with those of V1 elements mediating phosphenes in human V1 (Tehovnik et al. 2004). A chronaxie is a measure of neuronal excitability such that axons have shorter chronaxies than cell bodies (axons: 0.03–7 ms; cell bodies: 7–31 ms; Nowak and Bullier 1998; Ranck 1975), and large, myelinated axons have shorter chronaxies than small, nonmyelinated axons (large: 0.03–0.7 ms; small: >1.0 ms; Li and Bak 1976; Ranck 1975; West and Wolstencroft 1983). Chronaxies have been determined for elements mediating a functional MRI signal, neurotransmitter release, classical conditioning, self-stimulation, phosphene induction, and saccadic eye movements (Brindley and Lewin 1968a; DeYoe 1983; Dobelle and Mladejovsky 1974; Farber et al. 1997; Matthews 1977; Tehovnik and Lee 1993; Tehovnik and Sommer 1997; Tehovnik et al. 2003a; Tolias et al. 2003).
To determine the excitability of the directly stimulated elements inducing the saccadic delay, current–duration functions (Fig. 6A) were normalized such that the current threshold to evoke a 20-ms delay was set to unity for a pulse duration of 0.7 ms and all other thresholds were expressed as a multiple of this threshold (Fig. 6B). The average latency difference of 20 ms is greater than 3 SDs of the mean difference observed when comparing nonstimulation and dummy stimulation trials (SD = 4.3, n = 35; Tehovnik et al. 2004). Power functions were fitted for every data set pertaining to a site. The chronaxie value for a site can be determined as the pulse duration at which the power function crosses 2 units of threshold (Fig. 6B, dashed horizontal line). The chronaxie values ranged from 0.13 to 0.24 ms. This range of chronaxies overlaps with those reported for elements that mediate phosphene induction in human V1 (Brindley and Lewin 1968a; Dobelle and Mladejovsky 1974; Rushton and Brindley 1978). Therefore every time electrical stimulation produces a saccadic delay, monkeys probably experience a visual phosphene, as is presumed to occur when conditioning responses are evoked by stimulation of macaque V1 (Bartlett and Doty 1980; DeYoe 1983; Doty 1965).
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; Slocum and Tehovnik 2004; Tehovnik and Slocum 2003a; Tehovnik et al. 2002) we wanted to see whether the current threshold for producing a saccadic delay also varied as a function of cortical depth (Tehovnik et al. 2004). The current threshold to induce a 20-ms saccadic delay was determined as a function of cortical depth (Fig. 7). It was found that the lowest current thresholds for the induction of a saccadic delay occurred in the deepest layers of V1 (from 1.5 to 2.25 mm below the top of V1).
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; Slocum and Tehovnik 2004; Tehovnik and Slocum 2003a; Tehovnik et al. 2002). By delivering electrical stimulation during active fixation instead of during saccade execution (i.e., concurrently with the execution of the visual task), the excitability of the cells between the deepest layers of V1 and the saccade generator in the brain stem that mediates saccades is suppressed (Fig. 8); currents as high as 1,500 µA fail to evoke saccades from V1 during active fixation (Tehovnik et al. 2003b). We believe that this suppression of saccades enables the neurons within the deepest layers of V1 to participate in the saccadic delay.
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). The duration of this effect tends to be longer when the pulse is delivered to V1 as compared with the optic tract. Also, the delivery of a single pulse to superficial V1 mainly dampens the responsivity of cells within V1, whereas stimulation of deeper regions of V1 affects cells in V1 plus those in the lateral geniculate nucleus (Chung and Ferster 1998). Chung and Ferster (1998) suggested that the deeper stimulation might be activating the lateral geniculate nucleus antidromically from lamina IV as well as orthodromically by a corticothalamic projection originating from lamina VI (Fig. 8).
The excitability properties of the elements that mediate the saccadic delay are similar to those of pyramidal neurons whose chronaxies vary from 0.1 to 0.4 ms (Asanuma et al. 1976; Stoney et al. 1968). Stimulation of these elements may delay saccades by activating pyramidal fibers intrinsic to V1 and by exciting such fibers that feedback to the lateral geniculate nucleus. The pyramidal elements can then activate GABAergic elements intrinsic to these structures (Fitzpatrick et al. 1987; Montero 1986), thereby interrupting the transmission of visual information. This idea is consistent with the observations of Schiller and Malpeli (1977) and Chung and Ferster (1998) and with known projections between the striate cortex and the lateral geniculate nucleus (Lund et al. 1975). It also concurs with the finding that cortical neurons are hyperpolarized for many tens of milliseconds after the delivery of a single electrical pulse to cortex and that this hyperpolarization is mediated by GABA (Krnjevi
and Schwartz 1967; Krnjevi et al. 1966a, b, c).
Using saccadic eye movements to study phosphenes
To assess phosphene induction using saccadic eye movements, we trained a monkey to generate saccadic eye movements to the receptive field of the stimulated V1 neurons using 6 conditions, all randomized (Fig. 9, right). For all conditions, the monkey had to acquire the fixation spot and remain fixated for 300 ms. After termination of the fixation spot one of the 6 conditions could occur.
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CONDITION B. A visual target was presented in the visual field of the cells under study similar to that of condition a; electrical stimulation was delivered to those cells 30 ms after the onset of the visual target; and the monkey was required to generate a saccade to a target location to get a juice reward.
CONDITION C. No visual target was presented and electrical stimulation was delivered to the cells under study 130 ms after the termination of the fixation spot; a juice reward was provided to the monkey if a saccade was generated to the receptive-field location after the onset of stimulation. We interpret an increase in the probability of evoking saccades under this condition as a monkey responding to a putative phosphene produced by stimulation.
CONDITION D. No visual target was presented, no electrical stimulation was delivered, but a juice reward was provided to the monkey if it generated a saccade to the receptive-field location. This condition matched condition c except for the absence of electrical stimulation.
CONDITION E. The monkey was provided with juice immediately after termination of the fixation spot. Electrical stimulation was delivered 130 ms after the offset of the fixation spot. The time of stimulation with respect to fixation-spot offset was the same as in conditions b and c. Condition e determined whether electrical stimulation could drive the eyes into the receptive-field location after reward delivery.
CONDITION F. A juice reward was delivered immediately after termination of the fixation spot, but no stimulation was delivered. This condition tested whether the monkey spontaneously generated saccades into the receptive-field location after reward delivery.
Electrical stimulation occurred with respect to the onset of the visual target whether real (as for condition b) or virtual (as for conditions c and e). The stimulation commenced 30 ms after target onset. This is roughly the minimum time for a visual signal to be transmitted from the retina to V1 (Miller and Glickstein 1967; Nowak et al. 1995; Vogels and Orban 1994).
The percentage of saccades made to the receptive target across the 6 conditions varied (Fig. 9, left). For conditions a and b the monkey generated saccades to the receptive-field location over 95% of the time as defined by the location of the visual target. For condition c, the monkey generated saccades to the receptive-field location over 60% of the time as defined by the stimulation. This condition was considered the test for phosphene induction. On the various control trials (conditions d, e, and f) the monkey generated saccades to the receptive-field location <20% of the time. Because saccades were rarely evoked into the receptive-field location of the stimulated neurons in condition e, it is highly unlikely that the effect attributed to phosphene induction in condition c is the result of a simple motor response. Also the latencies of saccades generated to the visual target were comparable to those generated during stimulation in condition c. If the phosphene induced were identical to that of the visual target (i.e., monochromatic, bright circular, 0.2° in diameter at 100% contrast) one might expect the performance of the monkey to be closer to 95% than to 65%. On initial inspection, however, these results suggest that the monkey was generating saccades to a stimulation-induced phosphene
