Journal of Comparative and Physiological Psychology 1977, Vol. 91, No. 4, 858-874

Neural Substrate for Brain Stimulation Reward in the Rat: Cathodal and Anodal Strength-Duration Properties Gary Matthews

University of Pennsylvania The trade-off between current strength and duration of a stimulating pulse was studied for the rewarding and priming effects of brain stimulation reward (BSR). With cathodal pulses, strength-duration functions for BSR had chronaxies of .8-3 msec. No differences were observed between the results for rewarding and priming effects. With anodal pulses, strengthduration curves were parallel to the cathodal curves at pulse durations of. 1-5 msec, but at pulse durations greater than 5 msec the anodal curves showed a greater drop in required current intensity than did the cathodal curves. The parallel portion of the anodal curves was interpreted as due to anode-make excitation, and the drop at longer pulse durations was interpreted as due to anode-break excitation. Cathodal strength-duration functions for the motor effect elicited through the BSR electrodes had chronaxies of .15-.48 msec. Measurements of the latency of the muscle twitch confirmed that anode-make and anode-break excitation occurred, the latter becoming evident at pulse durations as brief as .3-.4 msec. The results provide quantitative characterization of cathodal and anodal strength-duration properties of the neural substrate for BSR and are discussed in terms of their value in guiding electrophysiological investigation of that substrate.

Electrical stimulation of certain brain regions can act as a powerful reinforcer, a phenomenon referred to as brain stimulation reward (BSR). The stimulating electrode can be viewed as a probe providing direct access to neural systems capable of supporting operant learning and thus allowing electrophysiological identification of neural populations involved in reward. However, since it is likely that the stimulation excites many neurons irrelevant to the reinforcement phenomenon, criteria are required for selecting among the many neural elements activated by the stimulaI thank C. R. Gallistel for advice throughout these experiments. I thank C. R. Gallistel, Warren O. Wickelgren, Peter Shizgal, and Anne Bekoff for suggestions on the manuscript. This research was supported by U. S. Public Health Service Training Grant 5-T01-GM-01036 (Paul Rozin, Program Director) and by National Science Foundation Grant BMS-75-16339 to C. R. Gallistel. W. O. Wickelgren kindly provided funds to cover manuscript expenses. Requests for reprints should be sent to Gary Matthews, who is now at the Department of Physiology C-240, School of Medicine, University of Colorado Medical Center, 4200 E. Ninth Avenue, Denver, Colorado 80220.

tion. Quantitative measurement of the properties of the neural substrate for BSR may provide such criteria. One approach is to vary systematically the parameters of the brain stimulation and obtain quantitative information relating these to measures of the behavioral response. Similar experiments may then be done, with the response of single neurons activated by the electrode as the dependent variable. A close match between the behavioral and neural responses to parametric variation of the stimulus increases the likelihood that the neurons are part of the neural substrate of the behavior. In addition to guiding electrophysiological investigations, inferences about the characteristics of the neural substrate for BSR have other uses; for example, such information may prove useful in distinguishing between components of the substrate. Deutsch (1964) argued that the rewarding and motivational (priming) effects generally found in hypothalamic BSR (Reid, Hunsicker, Kent, Lindsay, & Gallistel, 1973) exist because the stimulating current directly activates two different

858

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD

neural populations. If this is true, it may be possible to distinguish between those populations on the basis of their responsiveness to manipulation of stimulation parameters. The experiments reported here were undertaken to measure the cathodal and anodal strength-duration properties of the neural substrate for BSR. Since the greatest amount of information is provided when the reward and priming effects are analyzed separately, the behavioral experiments reported here make use of the straight-alley runway paradigm developed by Gallistel and his co-workers (Edmonds, Stellar, & Gallistel, 1974; Gallistel, 1966, 1967; Gallistel, Stellar, & Bubis, 1974). This paradigm separates the reward and priming effects of BSR and provides the stability of behavior necessary for the kind of quantitative analysis presented here (Edmonds & Gallistel, 1974). Cathodal strength-duration functions have been measured previously (Barry, Walter, & Gallistel, 1974; Ward, 1959). However, only Barry et al. used a procedure that allowed separation of the rewarding and priming effects of BSR, and they measured only one priming function. Anodal strength-duration functions provide a measure that is apparently independent of cathodal strength-duration characteristics (Hill, 1936; Katz, 1939). The time constant of the anodal strengthduration function is longer than its cathodal counterpart and has been identified with different properties of the neural elements involved (Hill, 1936; Hodgkin & Huxley, 1952). Experiment 1 Method

859

wire. The .31-mm-diam. wire was insulated with Formvar and sharpened to a conical tip with an uninsulated length of approximately .5 mm. Current return was through four stainless steel screws placed in the skull during surgery. The level-skull coordinates for the electrode tips were AP 2.0 mm posterior to bregma, ± 1.8 mm lateral to the sagittal suture, 8.5 mm below the surface of the skull; and AP 4.0 mm posterior to bregma, ± 1.4 mm lateral to the sagittal suture, 9.0 mm below the surface of the skull. Because of the strict stability criterion (see Stabilization below) and loss due to dislodging of the electrode assembly, only 6 of the original 15 rats completed the experiment. Histology. After completion of the experiment, rats were anesthetized with Equi-Thesin and perfused through the heart with saline followed by 10% formalin. The brains were removed, mounted in Parlodion, and sectioned at 40 /xm.

Apparatus The apparatus was a plywood runway 1.8m x 18 cm x 18 cm. At one end was a 30 x 30 x 18 cm start box, separated from the runway by a Plexiglas door which dropped beneath the floor at the start of each trial. Beside the runway was a 20 x 20 x 20 cm box in which rats were kept between trials. There was one retractable lever at the goal and another retractable lever in the start box. Parameters of the brain stimulation and the time intervals for operation of the runway were controlled by solid-state circuitry. Stimulating current was provided by a constant-current stimulator, and all stimulation consisted of rectangular, monophasic current pulses. The shape of the voltage change, measured across the stimulating electrode and the brain, produced by such rectangular current pulses can be seen in Figures 9 and 10. For the purpose of preventing build-up of polarization at the electrode, an electronic switching circuit connected the electrode to ground at all times except when a stimulation pulse was present. Current was monitored on a Tektronix 502A oscilloscope by reading the voltage drop across a 1%, 100-ft resistor in series with the rat. The voltage drop across the rat was monitored simultaneously. Running speed was recorded by electronically transforming the latency between the door drop and the rats' depression of the goal lever to its reciprocal. A voltage proportional to this reciprocal was led to the pen of a Heath chart recorder.

Subjects

Procedure

Surgery. Fifteen male albino rats from the Charles River Company were anesthetized with Equi-Thesin (2.5 ml/kg), and an array of four monopolar stimulating electrodes was implanted in each. Rats weighed 340-550 g at surgery and were maintained on a 12:12 hr reverse night/day cycle. Electrodes were made from 90% platinum - 10% iridium

Pretraining. Rats were trained to self-stimulate at the goal lever of the runway. The electrode that yielded the highest rate of self-stimulation but little or no motor effect was selected for use in the experiment. After rats had learned to self-stimulate, they were shaped to run the runway (see Gallistel et al., 1974) in order to press the goal lever and receive a

860

GARY MATTHEWS

single train of stimulation pulses (50 - 63 pulses, 80 pulses/sec, .1-msec pulse duration, current intensity as appropriate for each rat). Pretraining established stable behavior in the following situation: (a) The rat was placed in the waiting box; (b) 10 trains of noncontingent priming stimulation were delivered over an 18-sec period; (c) the rat was placed in the start box behind the raised Plexiglas door; (d) 6 sec after the end of the last priming train, the door dropped beneath the floor and the rat could run to the goal lever; (e) following the rat's press of the goal lever, it was returned to the waiting box for a 30-sec intertrial interval. During pretraining, the priming stimulation parameters were 63 monopolar, cathodal pulses/train, 80 pulses/sec, and .1-msec pulse duration. Current intensity was set to produce a supermaximal priming effect. Parameters of the single stimulation train received for pressing the reward lever (reward stimulation) were the same except that the number of pulses/train ranged from 50 to 63. The current level was set as appropriate for each rat. Reward training. After running behavior was stable, rats underwent repeated exposure to extinction and reacquisition until they reliably ceased running within 30 sec of the door drop for four consecutive trials within the first seven or eight trials following onset of extinction and consistently resumed running within four trials after the start of reacquisition. After this training, a block of trials was introduced at a reward level intermediate between the high and the zero level to which the rats were accustomed. At this point, the interpulse interval of the reward stimulation was increased to 30 msec, and the current was increased to offset the decline in stimulus efficacy produced by increasing the interval between pulses. The 10 trains of priming stimulation remained the same. Each daily session began with 11 trials of high current reward stimulation followed by extinction to the criterion of failing to run within 30 sec after the door drop for four consecutive trials. An ascending series of current intensities was then presented with 11 trials at each intensity. The current was increased in .3-log-unit steps from a low, to an intermediate, to a high value. As reward training progressed, the size of the steps was reduced to .1 log unit. In such a procedure, the current range over which a rat's running speed rises from zero to an asymptotic value is approximately .2 - .6 log unit (Edmonds et al., 1974). In other words, as the current intensity of reward stimulation increases, the rise of running speed is rather abrupt. This allows the choice of a single criterial current representative of the locus of rise of the whole curve. The criterial current used in the present studies was the current intensity that produced a running speed half as fast as the asymptotic speed. Edmonds and Gallistel (1974) showed that the estimate of the reward value of stimulation provided by parametric criteria like the criterial current is stable and independent of variation in performance factors such as the amount of priming stimulation, state of health, and task difficulty. Stabilization. For all rats that progressed to

this point in the training, the criterial current for reward stimulation could be defined with three current intensities: One intensity produced a running speed less than 50% of the asymptotic speed; another intensity, . 1 log unit greater than the first, produced a running speed greater than 50% of the asymptotic speed; and a third current intensity, .3 log unit greater than the second, produced a running speed taken as asymptote. This estimate of asymptote is reasonable because of the abruptness with which running speed rises as reward current is increased. In this manner, repeated determinations of criterial current were made until it fell within the same .1-log-unit interval of reward current intensity for four consecutive days. To establish this stringent stability criterion required from 3 to 6 wk of daily reward training, depending on the rat, and this criterion ensured that the rats would be stable across the experimental sessions. Six rats met this criterion and thus entered the experiment proper. Priming stabilization. In collecting data on the priming effect, the frequency of reward stimulation was fixed at 80 pulses/sec and the pulse duration at .1 msec. The number of pulses and the current were set for each animal so as to be just high enough to produce rapid running when the priming stimulation was at a high level. The just sufficient reward obtained by this procedure has little priming effect (Gallistel, 1969; Gallistel et al., 1974). During the intertrial interval the small priming effect of the reward decays to essentially zero. Thus, with a just sufficient reward, the strength of priming on a trial reflects only the priming delivered just before the trial. The interpulse interval of the stimulation that the rat received before running (priming stimulation) was 30 msec, and the pulse duration was .1 msec. There were 10 trains of priming stimulation, evenly spaced throughout a 30-sec interval. The intertrial interval was 30 sec, and the door-drop delay was 6 sec; therefore, the total time from pressing the goal lever to the next door drop was 66 sec. Sessions consisted of an ascending series of priming intensity, with blocks of seven trials at each intensity. Since Gallistel et al. (1974) showed that the adjustment of running speed following a change in priming is immediate, all seven trials of a block were counted, the median being taken as the running speed for that block. A current step of .1 log unit was used to bracket the criterial current for priming, and a current .4 log unit above the criterial current was used to estimate asymptotic running speed. The criterial current for priming was defined as the current intensity that produced a running speed halfway between that produced by zero priming and that produced by maximal priming. This definition was necessitated by the fact that with no priming, most rats still run to the goal lever, albeit more slowly than when primed. Training was continued until the criterial current for priming was stable within .1 log unit for three consecutive days. To achieve stability of the priming effect required virtually no training and was complete in less than 1 wk for all rats but one. Experimental sessions. Once stability was

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD reached, rats were run in daily sessions. A particular pulse duration was used in each session. At each pulse duration I attempted to estimate what intensity values would be required to bracket the criterion. Sessions for which this estimate proved accurate consisted of five blocks of trials (for reward curves) or four blocks of trials (for priming curves). A block consisted of 11 trials for reward curves. The running speed for each block was taken as the median of the last seven trials, the first four trials being required for adjustment of the rat's running speed following a change in reward magnitude. A block consisted of seven trials for priming curves, the running speed being taken as the median of all seven trials. To the extent that the estimate of criterial current proved inaccurate, extra intensity values, and thus extra blocks of trials, were required to estimate the criterial current for a particular pulse duration. Pulse durations tested ranged from . 1 to 15 msec, with at least six durations used to describe a strength-duration curve. Five animals began the experimental sessions with reward manipulations; the sixth, Rat Pt-10, began with priming manipulations but lost its electrode assembly before completing the cathodal strength-duration function for reward. In all cases a cathodal strength-duration function was completed first, followed by an anodal function. During reward manipulation, the order of presentation of the currents used to define the criterial current varied across rats. For three rats, current intensity was progressively increased following extinction; for one rat, current was set at an asymptotic level following extinction and then progressively decreased; for another, the order was mixed. In this manner a series of curves showing running speed as a function of current intensity was obtained for each rat; each curve in the series was obtained at a different pulse duration. From such a series I derived the trade-offs between pulse strength and pulse duration in reward and priming stimulation for both cathodal and anodal pulses.

861

curves showing running speed as a function of current intensity at a variety of pulse durations. On each curve the running speed halfway between zero and the asymptotic speed is indicated by an arrow. The criterial current for each curve is determined by dropping a vertical line to the abscissa (current axis) from the point of the arrow. The lower part of Figure 2 presents the strength-duration curve obtained by plotting the criterial currents against the corresponding pulse durations. The solid line through the data points in the lower part of Figure 2 was derived from the equation/ = Ir(l + C/D), where/ is the current required at a given pulse duration, D; Ir is the current for infinitely long pulses (the rheobase); and C is the chronaxie. In this case/r = 50 juA and C =

Pt-14

;-02-H Pt-02-E

Results Histology In Figure 1, locations of electrode tips in the six animals that completed the experiment are marked on tracings from Konig and Klippel's (1963) atlas of the rat brain. All electrode tips were in the medial forebrain bundle at the lateral to posterior hypothalamus. Data Format Figure 2 shows the derivation of a strength-duration function from runningspeed data of one rat. The set of curves in the upper part of Figure 2 is composed of

PI-09 Pt-10 W-1

Pt-12

Figure 1. Locations of the stimulating electrodes used in Experiments 1 and 2. (Filled squares indicate sites used in Experiments 1 and 2; X indicates an additional electrode site used in Experiment 2 only. The letter-number combinations identify the rats and serve to indicate from which electrode site individually reported data were collected. The number in the upper left of each tracing indicates the plate number in Konig and Klippel's, 1963, atlas of the rat brain from which the tracings were made.)

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Figure 2. Illustration of the derivation of a strength-duration curve from behavioral data. (Data are the reward data of Rat Pt-02. The upper curves are a set of running-speed-vs.-current-intensity functions. The arrow on each curve indicates the running speed used to define the criterial current in each case. The numbers above each curve indicate the pulse duration [in milliseconds] for that curve. The criterial currents are defined by dropping vertical lines to the abscissa from the points where the arrows touch the running-speed curves. The criterial currents are plotted against the appropriate pulse duration to yield the behavioral strength-duration function shown in the lower graph.)

1.5 msec. This equation is Weiss' (1901) hyperbolic function for describing strength-duration functions of peripheral nerve. In all cases the Lapicque-Hill exponential function, 7 = Ir/(l - exp(-Dlk)), did not approach a close fit to the data. No single value of time constant, k, existed which could account for the rate of change of criterial current at both long and brief pulse durations. Strength-Duration Data To facilitate comparison of strengthduration curves and to make clear the

changes and differences occurring at extremely long and extremely short pulse durations, I plotted all strength-duration functions after Figure 2 on log-log coordinates. In Figure 3A the data of Figure 2 are replotted on log-log coordinates. Figure 3 presents strength-duration functions for cathodal and anodal reward stimulation from the five animals that completed this part of the experiment. Figure 4 presents the same functions for priming stimulation from the six animals that completed the priming experiments. The anodal curves are parallel to the cathodal curves over most of the range of pulse duration tested and lie at higher current intensities than the cathodal curves. In all cases the anodal curve shows a dip between 5 and 15 msec, falling to or below the level of the cathodal curves. The solid lines in Figures 3 and 4 were drawn by using the hyperbolic functions given in Table 1. Hyperbolic functions were chosen to give the smallest average percentage of deviation from the empirically determined data. Also presented in Table 1 is the estimate of chronaxie obtained by inspection of each of the cathodal functions. Since chronaxie is defined as the pulse duration at which the required current is twice the rheobase, the chronaxie and the time factor C in the hyperbolic function should be identical. For comparison of the results of priming and reward manipulations, the data of Figures 3 and 4 are replotted in Figures 5 and 6. In Figure 5, cathodal strength-duration functions are compared for priming and reward stimulation, and in Figure 6 is the comparison for the anodal curves. Note that the strength-duration curves for priming and reward are approximately parallel in all cases. With two rats I obtained more complete data concerning the drop in the anodal reward curves at longer pulse durations. The interpulse interval was increased to 60 msec in one case and 80 msec in the other, which allowed the use of pulse durations longer than 15 msec. These data are presented in Figure 7, where it is apparent that for the two placements tested, the drop in the required anodal current began

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Figure 3. Cathodal (open squares) and anodal (filled squares) strength-duration functions from reward data of five rats. (The functions are plotted on log-log coordinates. The letter-number combinations on the face of each graph refer to the rat [see Figure 1 for location of each electrode]. The solid lines drawn through the cathodal data represent the hyperbolic functions given in Table 1.)

somewhere around 10 msec and continued to the longest duration tested (36 msec). Discussion The strength-duration relation represents a constant-output function in which a decrease in BSR current intensity is used to compensate for an increase in pulse duration in order to keep behavioral output constant. Thus, the strength-duration curves of Figures 3 and 4 can be taken as

the strength-duration functions of the directly excited neural substrate for BSR. Even though running speed in a runway is a multiply transformed index of direct excitation in that neural substrate, the use of a constant-output behavioral criterion ensures that it is direct excitation that is measured, provided one makes the reasonable assumption that all subsequent transformations of that excitation are monotonic (Gallistel, 1974).

864

GARY MATTHEWS Log Duration

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Figure 4. Cathodal (open squares) and anodal (filled squares) strength-duration functions for the priming effect in six rats. (The letter-number combinations refer to the electrode locations shown in Figure 1. Rat Pt12 lost its electrode assembly before completing the anodal curve. The solid lines drawn through the cathodal data represent the best fitting hyperbolic functions [see Table 1].)

Cathodal Strength-Duration Functions The chronaxies of the cathodal strength-duration data are rather long (see Table 1). Most chronaxies summarized from the neurophysiological literature by Ranck (1975) are in the range of .04-.09 msec for single myelinated axons, although values over 1 msec are sometimes reported for somata. It is interesting to note, however, that Li and Bak (1976)

recently reported chronaxie of 1.5 msec for unmyelinated C-fibers of the cat saphenous nerve. Thus, it seems that the chronaxies for BSR observed here, although long, do not exceed the known range for somata and fine fibers. The cathodal strength-duration curves of Figure 3 (reward) are in accord with those reported by Barry et al. (1974), who used the same behavioral procedure as that in the present experiments. They

865

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD

Table 1 Chronaxies ofCathodal Strength-Duration Functions for Reward and Priming Effects of Brain Stimulation and Values of Constants in the Best Fitting Hyperbolic Function, I = I,. (1 + C/D) Priming

Reward

Rat

Pt-02 Pt-09 Pt-10 Pt-12 Pt-14 W-l

Ir (in fj,A)

C (in msec)

Chronaxie (in msec)

7r (in /xA)

C (in msec)

Chronaxie (in msec)

50 37 _

1.5 1.8 __

1.9 1.7

40

1.5 1.0

2.0 .9 3.0

60 52 51 55 45 60

2.0 2.5 2.3 2.0 1.2 .7

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1.4

found values of chronaxie ranging from .8 to 2.5 msec, according to my estimates from the published data. This is the same range as that shown in Table 1. Also consistent with the study by Barry et al. is the fact that the hyperbolic function fits the cathodal strength-duration data better than does Hill's (1936) exponential equation. An exponential equation that fits the BSR data at brief pulse durations levels off much too rapidly as pulse duration is increased, reaching rheobase long before the empirical strength-duration functions reach rheobase. One possible reason that the hyperbolic function provides a better fit is that the strengthduration functions of the individual neural elements in the underlying substrate could also be hyperbolic. According to Ranck (1975), the hyperbolic function frequently fits single-unit data. Another possibility is that there is a range of time constant present in the substrate, and the hyperbolic function represents the weighted sum of a population of exponential time constants. In this case the weight that a particular time constant receives will vary as the pulse duration changes. At short pulse durations, neural elements with short time constants should make up a greater proportion of the total number of elements being stimulated than at longer pulse durations. As pulse duration is increased, long time constant elements have more time to charge during each pulse, and more of them will be fired by a pulse of a given intensity. Thus, at longer pulse durations fewer of the short time constant elements are needed in order to reach a particular level of activity in the substrate as a whole.

—

If it is assumed that the behavioral data reflect a sum of exponential functions, it is possible to obtain an estimate of what values of time constant are necessary to fit the behavioral data. Hill's (1936) equation for strength-duration functions is/ = Ir/(l - exp(-D/k)), where Ir is the rheobase, D is the duration of the stimulation pulse, and k is the time constant. If one plots log (1 - Ir/I) versus the pulse duration, one obtains a straight line if Hill's equation applies. Since a single exponential equation does not fit the behavorial data, such semilogarithmic plots of the data do not yield straight lines. However, it is possible to fit a straight line to the longer pulse durations on such a plot, subtract this from the data at shorter pulse durations, and fit another line to this remainder. If this is done, one finds that two exponential functions provide a reasonable approximation to the data. The values of time constant obtained for these two functions are presented for each rat and for priming and reward in Table 2. Note that in most cases, the time constant of the first exponential function is quite long: In 9 of 11 cases the time constant is greater than 10 msec (chronaxie = 6.9 msec). There is little information available on the time constant of central nervous system axons and somata stimulated extracellularly. I have measured cathodal strength-duration functions of 27 single units in the rat brain stem that were excited directly or transsynaptically by stimulation of the medial forebrain bundle (Matthews, 1976). None of these strengthduration functions yielded chronaxies longer than .55 msec. Ranck (1975) reported that somatic time constants mea-

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Pulse Duration (msec) Figure 5. Data of Figures 3 and 4 replotted for comparison of reward and priming data. (This figure presents the cathodal functions for both effects. Open circles are reward data from Figure 3; filled circles are priming data from Figure 4.)

sured intracellularly can range up to 10 msec; however, the relation between membrane time constant and the time constant measured by strength-duration curves has not been established (see Jack, Noble, & Tsien, 1975). Both the hyperbolic and exponential models discussed above require that there be long time constant elements in the substrate. However, a different kind of explanation exists for the decline in current intensity at long pulse durations. A main-

tained depolarization may produce not one impulse, but a train of impulses, in a neuron. Thus, it is possible that the decrease in required current at long pulse durations reflects the firing of more than one action potential per pulse. This would be equivalent to an increase in the frequency of stimulation, and as shown by Gallistel et al. (1974), an increase in stimulation frequency allows the same behavioral output to be reached at a lower current intensity. In observations of single units in the rat

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brain stem that were directly (i.e., electrically) excited by stimulation of the medial forebrain bundle, I found two units that fired two or three action potentials during stimulation pulses longer than 2 msec (Matthews, 1976). This adds weight to the possibility that multiple firing may account for the observed long chronaxies. Another possibility is that the changes in required current at long pulse durations are the result of interaction between depolarization produced by the stimulating current and depolarization produced by the release of neurotransmitter substances by neural elements within the stimulation field (Szabo, 1973). Anodal Strength-Duration Curves The anodal strength-duration curves shown in Figures 3 and 4 are parallel to

the cathodal curves at pulse durations from .1 to 5 msec. Between 5 and 15 msec (when the cathodal curves are reaching asymptote) the anodal curves show a sudden drop in required current. In the parallel portion, anodal curves have approximately the same slope as their cathodal counterparts, a fact that indicates they are governed by the same temporal parameter. This suggests that anodal pulses .1-5 msec in duration excite the substrate for BSR by pushing current out through the neural membrane at some point distant from the stimulating electrode. Current will flow inward across the membrane of neural elements in the vicinity of an anode and exit at other regions of these elements. If the outward current density and resulting depolarization at an exit point are sufficiently great, an action potential will be generated. Such excitation remote from

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Hodgkin & Huxley, 1952). Thus, the drop in anodal curves at long pulse durations may represent the occurrence of both anode-make and anode-break excitation. As the data in Figure 7 show, in the two cases tested most of the anode-break effect occurred at pulse durations greater than 10 msec. Priming-Reward Comparison

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the anode will be referred to here as anodemake excitation. Since anode-make stimulation excites in much the say way as cathodal stimulation, the temporal parameters governing the strength-duration curves should be similar, as is the case in the data. The only difference between cathodal strength-duration curves and anodal curves resulting from anode-make stimulation should be that the anodal pulses require more current, since the excitatory effect is produced at a greater distance from the electrode. The drop in required current intensity for anodal pulses 5-15 msec in duration does not appear in the cathodal curves. A reasonable interpretation of this effect at long pulse durations is that it reflects the generation of action potentials at the termination of the anodal pulses. Such anodebreak excitation is due to the removal of resting inactivation of the action potential mechanism during the hyperpolarizing pulse, permitting excitation to occur when the membrane potential returns to normal following the termination of the pulse (see

The comparisons of data from the priming and reward effects are of interest, since Deutsch (1964) argued that the priming and reward effects of BSR are due to the direct activation of two distinct neural systems at the electrode tip. If two such systems exist, they may differ in cathodal and anodal strength-duration characteristics. However, it is apparent in Figures 5 and 6 and Table 2 that there are no systematic differences between the functions for priming and reward. This holds true for both cathodal and anodal functions and for the drop in the anodal curves attributed to anode-break excitation. Further, Table 2 shows that there are no consistent differences in the values of time constant of the exponential functions necessary to fit the data for priming and reward. Thus, since two independent neuronal characteristics are quite similar for the priming and reward systems, the present data do not support the existence of distinct, directly excited neural systems underlying the priming and reward effects. Rather, the data are most simply explained by assuming that brain stimulation excites directly Table 2 Values of Time Constant for Exponential Functions Necessary to Fit BSR Data Reward Rat

Pt-02 Pt-09 Pt-10 Pt-12 Pt-14

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Time constant 1

Time constant

Time constant

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.7 .8

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD

only one population of neurons relevant to BSR and that since there are two behaviorally distinct effects of rewarding brain stimulation (reward and priming), activity in this single neural population must somehow have two effects as a consequence of further processing. Deutsch (1964) and Gallistel, Rolls, and Greene (1969) presented behavioral evidence that the neurons underlying the rewarding and priming effects of BSR have different refractory periods, a conclusion in conflict with the single-population hypothesis presented above. However, neither Deutsch nor Gallistel et al. used constant-output behavioral techniques, and thus their measures may have been contaminated by nonaxonal, downstream processing in the two neural systems; for instance, since changes in the effectiveness of the second pulse (T pulse) of a pair due to refractoriness can be thought of as a change in the frequency of stimulation, previously reported refractory-period differences between priming and reward effects of BSR may be due to differences in the frequency sensitivity of the downstream neurons underlying the two effects. This problem was discussed in detail by Yeomans (1975), who also presented a cogent description of the general measurement problems inherent in behavioral inference of neuronal properties. For present purposes, it is sufficient to point out that conclusions concerning the refractory-period estimates of neurons underlying the priming and reward effects of BSR should be deferred until studies with more appropriate measurement techniques are completed. Experiment 2 The validity of using behavioral responses to make inferences concerning the basic neurophysiological properties of the directly stimulated neural elements would be increased if two neural systems could be distinguished on the basis of such inferred characteristics. Thus, in Experiment 1, the similarity of the strength-duration curves for the priming and reward effects

869

of BSR could have resulted from a fundamental insensitivity of the technique. Therefore, in Experiment 2, a different behavioral effect of BSR, namely, the production of brief twitches of somatic musculature at high levels of current (presumably by current spread to fibers in the internal capsule), was examined in the same manner as the running response in Experiment 1 to determine whether different strength-duration curves would result. Method Subjects Four of the six electrodes used in the strengthduration functions of Experiment 1 were used in Experiment 2. Rats Pt-10 and Pt-12 lost their electrode assemblies during Experiment 1 and were therefore unavailable for study. Two electrodes in Rat Pt-02 were used in the present study, making a total of five electrodes in four rats. The histologically determined locations of the five electrodes are given in Figure 1.

Apparatus Current pulses were generated by the same constant-current device used in Experiment 1. The muscle twitch associated with stimulation was measured by placing the subject in a stabilimeter consisting of a cardboard and hardware-cloth cage, fixed to the pan of a top-pan, spring balance. A permanent magnet attached to the pan of the balance moved through a stationary coil whenever the pan moved. Thus, vertical motion of the pan induced electric current in the coil. The output of the coil went to a high-gain, ac electroencephalograph preamplifier, and the amplified signal was displayed on a polygraph and a storage oscilloscope. For Rat Pt02, electrode H, the electromyographic activity (EMG) was also recorded by means of a stainlesssteel suture thread imbedded in the muscles of the neck and one shoulder.

Procedure Because a single stimulation pulse suffices to produce a muscle twitch, stimulation pulses were delivered singly rather than in trains. Pulse durations were presented in ascending order. At each pulse duration, current intensity was first set to a value that produced a readily observable twitch after each pulse. Current intensity was then progressively lowered until there was no detectable coil output for each pulse. The current was then alternately raised and lowered until a threshold, defined as that inten-

GARY MATTHEWS

870

Results Strength-Duration Data Figure 8 presents the cathodal and anodal strength-duration functions for the five electrodes tested. All the cathodal functions drop rapidly from .1 msec to rheobase, completing most of that drop by a pulse duration of 1 msec. The anodal functions show a steady drop from .1 msec to the longest duration used. Note that the anodal curves are not parallel to the cathodal curves over any portion of the tested range of pulse duration; rather, the slope

sity necessary to produce a detectable coil output on 6 of 10 trials, was obtained. Pulse durations of .1-36 msec were used. After completion of the strengthduration curve for cathodal pulses, the curve was repeated for anodal pulses. For Rat Pt-02, electrode H, the cathodal curve was determined first with a just detectable coil output as the criterion and then redetermined with a just detectable EMG response as the criterion. The coil proved as sensitive as EMG and gave the same strength-duration curve. All subsequent data were collected by using the stabilimeter only. The occurrence of a muscle twitch following every stimulation pulse allowed measurement of the latency of the response. The latency of the coil output following pulses greater than 15 msec in duration was determined from the trace on the storage oscilloscope.

W-1

Pt-14

-o—a

•1

5: Pt-09

Pt-02-H

i j

5:

i i i i mil .2 A -6.8.J

i i i i mil i 2 4 68.^ 220

Pt-02-E

'• .....

1

I

I I 1 I Mil

2

•* 6

^

I

2

I I | Mill

4

6

I

I .

'Q 20 40

Pulse Duration

(msec)

Figure 8. Cathodal (open squares) and anodal (filled circles) strength-duration functions for the motor effect of medial forebrain bundle stimulation. (The letter-number combinations on the face of each graph refer to electrode locations shown in Figure 1.)

871

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD

of each anodal curve is greater than that of its cathodal companion. The cathodal strength-duration functions are fit by hyperbolic functions. However, three of the five curves are fit better by Hill's (1936) exponential function than by the hyperbolic function. The best fitting hyperbolic and exponential functions for each curve are presented in Table 3. Comparison with Table 1 shows that the cathodal motor-effect curves have a shorter time constant than the cathodal BSR curves, usually by an order of magnitude. The chronaxies for the reward-effect curves ranged from .85 to 3.0 msec, and the chronaxies for the motor-effect curves range from .15 to .48 msec. This latter range is approximately the same as the chronaxie of .45 msec reported for AS-fibers of cat saphenous nerve by Li and Bak (1976). The anodal curves for the motor effect also differ from their reward-effect counterparts. Recall that for the reward effect, the anodal and cathodal curves remained parallel out to pulse durations of 5-10 msec, which was taken to indicate that anode-break firing did not become significant until pulse durations greater than 10 msec were used. Figure 8, however, shows that for the motor effect, the anodal and cathodal curves are not parallel at pulse durations longer than .3-.4 msec, which indicates that anode-break effects begin at much shorter pulse durations in the motor-effect substrate than in the BSR substrate. Latency Data Observations of the latency of the mus-

Figure 9. Latencies of the muscle twitch after cathodal and anodal pulses of the same duration. (The upper trace of each pair is the output of the stabilimeter coil; the lower trace of each pair is the stimulation pulse monitored across the rat. The upper pair of traces shows the result of cathodal stimulation; the lower pair shows anodal stimulation. There are four superimposed traces in all cases. The arrow indicates the point taken as the onset of the coil output. The pulse duration was 15 msec, the cathodal current was 1.6 x threshold, and the anodal current was 1.8 x threshold. Calibration marks: 10 msec; 5 V on coil; 2 V on pulse. The later part of the uppermost trace was lost because at the gain employed, the oscillations were off the face of the oscilloscope.)

cle twitch proved a test for the interpretation of the anodal strength-duration curves. If anode-break excitation occurs with long-duration anodal pulses, the latency of the muscle twitch should be longer than the latency following a cathodal pulse of the same duration. One might expect, for example, that the latency of the muscle twitch from the end of a threshold anodal pulse, where excitation

Table 3 Values of Constants of Best Fitting Exponential, I = Irl(l • exp( -D Ik), and Hyperbolic, I = Ir(l + C/D), Functions for Motor-Effect Data Rat

Pt-02-H Pt-02-E Pt-09 Pt-14 W-l

Best fit exponential exponential hyperbolic exponential hyperbolic

Exponential

Hyperbolic

Ir (in juA)

k (in msec)

/r (in juA)

C (in msec)

330 450

.32 .25

175 230

.26 .23

330 440 180 170 220

.33 .17 .49 .17 .15

872

GARY MATTHEWS

would be expected to occur at termination of the pulse, would be the same as the latency of the twitch from the beginning of a higher intensity cathodal pulse, where excitation would be expected to occur at the onset of the pulse. This is illustrated in Figure 9, which presents sample oscilloscope records showing the latency of the muscle twitch following cathodal and anodal pulses of 15-msec duration. The latency of the muscle twitch, measured from pulse onset to onset of the coil output, was 20 msec for the cathodal pulse and 36 msec for the anodal pulse. However, the latency from termination of the anodal pulse to the coil output was 21 msec, about the same as the latency from cathodal pulse onset. This indicates that the excitation responsible for the muscle twitch occurred at the termination of the anodal pulse. Similar results were observed at all five electrode placements tested. Figure 10 shows the effects of increasing the current intensity of cathodal and anodal pulses of 30-msec duration. With anodal pulses, the latency of the muscle twitch decreased as current intensity was increased, which indicates the progressive increase in anode-make firing at higher

stimulation intensities. When current was sufficiently high, the latency from anodal pulse onset was approximately the same as the latency from cathodal pulse onset, which shows that at high current intensities anode-make effects predominate. The latency of the muscle twitch also decreased slightly as cathodal current was increased. This decrease is attributable to the fact that at higher current intensities, less time for current integration is required to reach threshold. Discussion The difference between the chronaxies for the motor effect (.15-.48 msec) and for BSR (.8-3 msec) suggests that the technique is capable of detecting differences in the basic neurophysiological properties of functionally distinct populations of neurons. Since the motor-effect and the BSR data were collected by using stimulation applied through the same electrode, the observed differences cannot be attributed to differences between animals or in the physical properties of the electrodes. Anode-break effects also differ between the substrates for the motor effect and BSR.

Figure 10. Latencies of the muscle twitch after cathodal and anodal stimulation pulses of various intensitities. (The upper trace of each pair is the output of the stabilimeter coil; the lower trace is the stimulation pulse monitored across the rat. There are four superimposed traces in all cases. Upward-going pulses [right] are anodal; downward-going pulses Heft] are cathodal. The numbers in each stimulation pulse refer to the current intensity of that pulse relative to the threshold, and the arrows indicate the points taken as the onset of the coil output. The horizontal calibration mark represents 20 msec in all cases. Only the first deflection of the coil trace carries information; subsequent oscillations are due to the resonance of the stabilimeter. Data are from Rat Pt-14.)

STRENGTH-DURATION PROPERTIES OF BRAIN STIMULATION REWARD

Anode-break effects began to be important in the substrate for the motor effect at pulse durations of .3-.4 msec, but comparable effects were observed for BSR at pulse durations of 5-15 msec. The failure to find a difference between the strengthduration data for the priming and reward effects of BSR is made more significant by this demonstration. If there were two substrates underlying the two behavioral effects of BSR, it seems likely that the technique would have detected any substantial difference in cathodal and anodal strength-duration properties. The results of the experiments show that characterization of the strength-duration properties of the substrate for BSR can provide information useful in the investigation of that substrate. The cathodal strength-duration curves indicate that the substrate for BSR has unusually great current-integrating capacity, compared with single neurons (Ranck, 1975) and with the motor effect. The motor-effect data also demonstrate that anode-break excitation is an observable phenomenon with stimulation of the type employed in BSR and establish the validity of anode-break effects as a discriminator between neural systems. Thus, cathodal and anodal strength-duration properties are potentially valuable criteria in the electrophysiological investigation of the substrate for BSR; that is, they establish criteria by which one may distinguish neural systems mediating self-stimulation from neural systems mediating other behavioral effects of the stimulation, such as its direct motor effects. References Barry, F. E., Walter, M. S., & Gallistel, C. R. On the optimal pulse duration in electrical stimulation of the brain. Physiology and Behavior, 1974, 12, 749-754. Deutsch, J. A. Behavioral measurement of the neural refractory period and its application to intracranial self-stimulation. Journal of Comparative and Physiological Psychology, 1964,55, 1-9. Edmonds, D. E., & Gallistel, C. R. Parametric analysis of brain stimulation reward in the rat: III. Effect of performance variables on the reward

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summation function. Journal of Comparative and Physiological Psychology, 1974, 87, 876-883. Edmonds, D. E., Stellar, J. R., & Gallistel, C. R. Parametric analysis of brain stimulation reward in the rat: II. Temporal summation in the reward system. Journal of Comparative and Physiological Psychology, 1974, 87, 860-869. Gallistel, C. R. Motivating effects in self-stimulation. Journal of Comparative and Physiological Psychology, 1966, 62, 95-101. Gallistel, C. R. Intracranial stimulation and natural rewards: Differential effects of trial spacing. Psychonomic Science, 1967, 9, 167-168. Gallistel, C. R. The incentive of brain stimulation reward. Journal of Comparative and Physiological Psychology, 1969, 69, 713-721. Gallistel, C. R. Motivation as central organizing process: The psychophysical approach to its functional and neurophysiological analysis. In J. K. Cole & T. B. Sonderegger (Eds.), Nebraska Symposium on Motivation (Vol. 22). Lincoln: University of Nebraska Press, 1974. Gallistel, C. R., Rolls, E. T., & Greene, D. Neuron function inferred by behavioral and electrophysiological measurement of refractory period. Science, 1969,166, 1028-1030. Gallistel, C. R., Stellar, J. R., & Bubis, E. Parametric analysis of brain stimulation reward in the rat: I. The transient process and the memory-containing process. Journal of Comparative and Physiological Psychology, 1974, 87, 848-859. Hill, A. V. Excitation and accommodation in nerve. Proceedings of the Royal Society of London, Serial B, 1936,779, 305-355. Hodgkin, A. L., & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology, 1952,117, 500-544. Jack, J. J. B., Noble, D., & Tsien, R. W. Electric current flow in excitable cells. London: Oxford University Press, 1975. Katz, B. Electric excitation of nerve. London: Humphrey Milford-Oxford University Press, 1939. Konig, J. F. R. & Klippel, R. A. The rat brain: A stereotaxic atlas. Baltimore: Williams & Wilkins, 1963. Li, C. L., & Bak, A. Excitability characteristics of the A- and C-fibers in a peripheral nerve. Experimental Neurology, 1976, 50, 67-79. Matthews, G. G. Excitation and accommodation in the substrate for self-stimulation: A behavioral approach to neurophysiology (Doctoral dissertation, University of Pennsylvania, 1975). Dissertation Abstracts International, 1976, 36, 4206B. (University Microfilms No. 76-3197) Ranck, J. B., Jr. Which elements are excited in electrical stimulation of mammalian central nervous system: A review. Brain Research, 1975, 98, 417-440. Reid, L. D., Hunsicker, J. P., Kent, E. W., Lindsay, J. L., & Gallistel, C. R. Incidence and magnitude of the "priming effect" in self-stimulating rats. Journal of Comparative and Physiological Psychology, 1973, 82, 286-293.

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Szabo, I. Path neuron system of medial forebrain bundle as possible substrate for hypothalamic self-stimulation. Physiology and Behavior, 1973, 10, 315-328. Ward, H. P. Stimulus factors in septal self-stimulation. American Journal of Physiology, 1959,196, 774-782. Weiss, G. Sur la possibility de rendre comparables

entre eux les servant a Pexcitation electrique. Archives Italiennes deBiologie, 1901,35, 413-446. Yeomans, J. S. Quantitative measurement of neural post-stimulation excitability with behavioral methods. Physiology and Behavior, 1975,15, 593602. Received July 9, 1976 •