Reinforcing Effects of Electrical Brain Stimulation
Introduction
In 1954, Olds and Milner reported an observation that arguably represents
the most intriguing and enigmatic phenomenon biopsychologists have yet
encountered. They noted that a rat preferred the region of the test
apparatus where it received electrical brain stimulation, and inferred
that it might find the experience pleasurable. When the experimenters
restructured their experimental paradigm to test this possibility, it
was determined that the rat would learn and execute novel behaviors
in order to obtain brief pulses of brain stimulation. Olds and Milner
plausibly concluded that they had discovered brain mechanisms responsible
for "reward."
It is difficult to exaggerate the implications of this observation.
Complex biological organisms could not have survived on earth had they
not developed the ability to learn from experience - i.e., to repeat
behaviors that have positive consequences such as finding food, water,
or a mate, and to eliminate behaviors that have negative consequences
such as exposure to predators, or extremes of heat or cold. Learning
implies a fundamental reorganization of the relationship between the
organism and its environment. Olds and Milner's discovery promised insights
into the basic neural mechanisms that are responsible for our capacity
to achieve that reorganization.
Before we can meaningfully ask what has become of this promise, we
must take a small detour into the domain of the philosopher. If we agree
that the behavior of complex organisms is the result of learning, it
follows that the conditions that promote learning are at the very heart
of psychology. Philosophers have recognized this imperative by debating
whether all behavior should be considered to be determined by a desire
to maximize pleasure and minimize pain. A good many of them are uncomfortable
with the implication of this dictum that humans might not exercise voluntary,
discretionary control over their behavior. For some, this concern can
be assuaged by definitions of reward and punishment that are expanded
to include such acquired elements as satisfaction with one's accomplishments
and disappointment at one's failures. Others will insist that humans
are endowed with rational capabilities that can supersede the basic
relationship between behavior and its consequences however broadly defined.
Scientific psychology must insist on a strict definition of cause-and-effect
relationships. This was formally recognized by Thorndike's statement
of the law of effect around the turn of the Century which stated,
in essence that rewarded behavior is "stamped in" (i.e. learned) whereas
punished behavior is eliminated from the organism's repertoire of responses
(Thorndike, 1898). This idea provides the cornerstone of many subsequent
theories of behavior that attribute a pivotal role to reward and punishment.
B.F. Skinner stated the principle most succinctly in his influential
book:"The Behavior of Organisms" as the now famous dictum that:
"behavior is controlled by its consequences" (Skinner, 1938).
Few contemporary biopsychologists would quarrel with Skinner's conclusion,
particularly if some of its bite is removed by amending it to state
that behavior is controlled by anticipation of its consequences. However,
Skinner's insistence that the intimate relationship between behavior
and its consequences can be understood without recourse to intervening
variables (such as the notions of pleasure and pain that were intrinsic
in the original formulations) has been the subject of much debate. Because
the issue has obscured some of the fundamental implications of the research
that originated with Olds and Milner's historic observation, we need
to bring it to the forefront of our discussion before proceeding.
Skinner postulated that behavior is strengthened by reinforcers. Food,
water, or a desirable mate are positive reinforcers. Painful electric
shock is a negative reinforcer. Whether a particular stimulus is neutral,
a positive reinforcer, or a negative reinforcers in a particular situation
can only be determined by experimental analysis. The data that are thus
collected permit a listing of environmental conditions that predict
the status of a stimulus. For instances, food maybe neutral when the
animal is well-fed; a positive reinforcer after prolonged food deprivation,
and a negative reinforcer after repeated association of a particular
food with illness. There are no ambiguities in this definition, and
this is its appeal of Skinner's argument if one can put up with its
circularity.
Contemporary alternative explanations require recourse to intervening
variables (Hebb, 1955; Stellar, 1954). They postulate that stimuli are
positive reinforcers if they elicit physiological responses (i.e., brain
activity) that gives rise to subjective sensations that humans experience
as rewarding. We refer to that state as "pleasure" or positive affect.
The status of a particular stimulus at any point in time is defined,
not by features of the external environment, but by the prevailing condition
of the organism. When the body has ample energy reserves, there is no
perception of hunger, and food is a neutral stimulus. Depletion of the
body's energy stores gives rise to hunger sensations that motivate the
search for, and ingestion of food which thus is a positive reinforcer.
After a particular food has been associated repeatedly with illness,
a conditioned aversion has been learned that gives rise to negative
affect. This motivates avoidance of the food which thus is a negative
reinforcer.
It is easy to dismiss this distinction as a largely semantic quarrel
between behavioral scientists. It is often suggested that one can reconcile
the two positions by agreeing to the following: "A positive reinforcer,
such as food, (a) strengthens the behavior that produces it and (b)
results in positive affect. A negative reinforcer, such as painful electrical
shock, (a) strengthens the behavior that avoids or terminates it and
(b) results in negative affect." It is not necessary (although convenient
for some purposes) to assume that "a" and "b" are causally related."
Unfortunately, this not only misses the theoretical point of the issue
but also runs afoul of reality. Although positive reinforcers are generally
associated with positive affect, the connection may be quite indirect.
You may study the material in this chapter in the hope of someday obtain
a good grade (or avoiding a bad one) but the actual payoff is uncertain
and the grade has itself only a tenuous relationship to positive affect.
We might learn to live with this ambiguity for the sake of harmony but
matters are even more complex when we consider negative reinforcements.
It is well established that animals as well as humans learn and perform
behaviors that produce consequences associated with neutral or even
negative affect. Rats, for instance, can be trained to press a lever
to receive brief bursts of sound or light that have no obvious hedonic
quality, and may even work to obtain painful electric shocks under some
circumstances. Humans similarly engage in "titillating" risk-taking
behaviors that expose them to the threat of physical or psychological
harm, scuba diving, mountain climbing, and experimenting with psychotropic
drugs (discussed below) being some rather obvious examples.
It is not surprising that the problems we have just touched on should
be an issue in the area of research we are about to discuss. What is
rarely appreciated, however, is how pervasive their influence has been.
Milner has recently reviewed the progress of the field he co-founded
more than 40 years ago and commented that: "During most of the first
half of this century psychologists knew what they wanted to do but had
no idea how to do it, and during the second half they have, for the
most part, been so preoccupied with how to do it that they have forgotten
what they wanted to do." (Milner, 1991). It is, indeed, sad to see that
the initial enthusiasm that greeted Olds and Milner's discovery has
gradually given way to resigned acceptance of our inability to agree
on its implications. The topic is not currently "fashionable" but an
appreciation of the progress that has, in fact, been made in the past
40 years will assist us in our search for an understanding of the intricate
relationship of behavior and its consequences.
Brain Stimulation Reinforcement in Animals
Literally tens of thousands of research papers were published on the
topic of brain stimulation reinforcement in the first two decades after
Olds and Milner's seminal observations (Wauquier&Rolls, 1976). Brain
stimulation reinforcement has been demonstrated in all species examined,
including humans (Sem-Jacobsen, 1976) ; monkeys (Lilly, 1958) ; cats
(Roberts, 1958) ; teleosts (Boyd&Gardner, 1962) , and snails (Balaban&Maksimova,
1993). Even the activity of single brain cells has been shown to be
modifiable by electrical brain stimulation (EBS) (Olds, 1965). One can
safely conclude that the generality of the phenomenon is not in question.
Relationship to Natural Rewards
Much of the early research was aimed at demonstrating similarities
and/or differences between EBS and natural rewards such as food. A consistent
finding is that the reinforcing effects of brain stimulation can be
far more powerful than those produced by food or water. In one experiment,
rats pressed a lever for brain stimulation reinforcement almost without
pause for 20 days, averaging 29.2 responses per minute (Valenstein&Beer,
1964) ! When the reinforcing effects of brain stimulation are pitted
against those of natural rewards, hungry rats (Routtenberg&Lindy,
1965) as well as humans (Bishop et al., 1963) disregard palatable foods
in order to work for brain stimulation reinforcement. Yet, the reinforcing
effects of brain stimulation are not, in every way like those of natural
rewards. In many instances, animals do not work for intermittent brain
stimulation reinforcements on low density reward schedules (e.g., when
many responses are required to obtain a single reinforcement) (Gallistel,
1964; Sidman et al., 1955). This may be related to the fact that behavior
maintained by brain stimulation reinforcement is subject to rapid
extinction when the behavior is no longer reinforced (extinction
refers to the usually gradual disappearance of learned behavior that
is no longer reinforced). Indeed, in many cases well-trained animals
will not resume EBS reinforced behavior even when there is no opportunity
to emit non-reinforced responses during an enforced pause. The apparently
extinguished behavior can be quickly reinstated by one or more free
"priming" stimulation (Howarth&Deutsch, 1962)
The need for priming has been a hotly debated and much researched subject
because it implies that brain stimulation may not only reinforce the
behavior that produced it but also provides the motivation to emit the
behavior again (Gallistel, 1969; Wise, 1982). Sated rats, that are trained
to work for large and very palatable natural rewards (such as a goodly
amount of chocolate milk) behave quite similarly (Panksepp&Trowill,
1967). This has led to the suggestion (Trowill et al., 1969) that animals
may not work for brain stimulation reinforcements because they are "driven,"
but because the incentive value of the reinforcement is very
high. (Just as we might eat potato chips or nuts at a party even although
we are not hungry.) It is also possible that the "anomalous" effects
of brain stimulation reinforcement may reflect ambivalent reactions
to an undoubtedly unnatural activation of brain pathways. Such an interpretation
suggests that EBS may elicit both positive and negative affect and thus
creates an approach-avoidance conflict. If the reinforcing effects
are initially more potent than the aversive consequences (as they presumably
must be in order to support self-stimulation), but decay more rapidly
(as the effects of positive natural reinforces tend to do), one would
predict rapid extinction and a need for priming. A number of investigators
have, in fact, reported that animals can be trained to press one lever
to obtain brain stimulation and press another to turn it off (Bower&Miller,
1958; Valenstein&Valenstein, 1964). Moreover, in one study, some
animals that did not require priming stimulation in order to initiate
EBS-reinforced behavior, did so when each lever press that resulted
in reinforcing brain stimulation also produced painful tail shock (Kent&Grossman,
1969) In spite of much research on the subject, it is not entirely clear
whether the need for priming is, indeed, a defining characteristic of
all EBS reinforcement
Relationship to Natural Drives
Neither humans nor animals have an innate desire to have their brains
stimulated. Why, then, do we do it and what brain functions are activated
by reinforcing EBS? Does it stimulate neural pathways specifically related
to positive affect (or the processes of positive reinforcement), or
should one search for a direct connection with naturally occurring motivational
states? At some electrode sites, the rate of self-stimulation increases
dramatically as a result of food deprivation and decreases promptly
after a meal or after intragastric or intravenous injections of nutrients
(Hoebel, 1968; Hoebel&Teitelbaum, 1962; Olds, 1958a). At other sites
(which may be in the same animal), the rate of self-stimulation varies
as a function of water deprivation (Brady, 1961), castration (Olds,
1958b), sex hormone replacement therapy (Caggiula, 1970), or changes
in ambient temperature (Bloomfield&Mrosovsky, 1974).
The interaction between hunger and the reinforcing properties of lateral
hypothalamic stimulation has been examined in great detail. We now know
that at some electrode sites, any experimental treatment that modifies
hunger also affects the reinforcing effects of EBS, and does so in a
lawful manner. Self-stimulation increases after ventromedial hypothalamic
(VMH) lesions (Hoebel&Teitelbaum, 1962) or insulin injections (Hoebel,
1968) (both increase food intake), and decreases after vagotomy (which
reduces food intake) (Ball, 1972), and after injections of the satiety-related
hormone glucagon (Balagura&Hoebel, 1967) or appetite depressant
drugs such as amphetamine (Mogenson et al., 1969). We have less complete
data on the relationship of brain stimulation reinforcement to other
basic motivational states. However, the available evidence leaves little
doubt that the extensive and close relationship between brain stimulation
reinforcement and hunger is a good model for other basic drives as well.
This conclusion is supported by another set of intriguing experimental
observatons: Reinforcing brain stimulation often elicits behaviors
such as eating (Margules&Olds, 1962)., drinking (Mendelson,
1967), or copulation (Caggiula&Hoebel, 1966). Stimulation at such
electrode sites is more reinforcing when an appropriate natural reward
is available and consumatory behavior is permitted (Coons&Cruce,
1968; Mendelson, 1967). On closer analysis, it can be demonstrated that
the intensity threshold for eliciting consumatory behaviors at a given
electrode site is often different from the threshold for brain stimulation
reinforcement, suggesting that different types of neurons may be activated
(Coons&Cruce, 1968; Cruce&Coons, 1974). Other changes in the
physical properties of reinforcing electrical stimulation (e.g., the
frequency or duration of pulses) also produce major changes in the apparent
magnitude of its reinforcing properties. This provides additional evidence
that more than one type of neural pathway may be stimulated because
larger and/or more heavily myelinated neurons can respond to higher
stimulation frequencies than smaller cells (Gallistel, 1983; Mark&Gallistel,
1993; Yeomans, 1975).
We should note, at this point, that rate of responding (e.g., lever-pressing)
is not a good measure of the reinforcing effects of brain stimulation
(Gallistel, 1983). We tend to think that "better" stimulation might
make an animal work harder but it is just as plausible that at some
point, the stimulation becomes so very good that a little bit goes a
long way - rate of responding would then drop off even though each stimulation
produces more reward. Although the notion that more may not always be
better is intuitively appealing, this point has been difficult to demonstrate
experimentally. We now have many complex psychophysical procedures capable
of demonstrating that the correlation between rate and reinforcement
is, in fact low (Shizgal&Murray, 1989; Yeomans et al., 1979; Yeomans,
1975). Most contemporary investigators therefore rely on rate-free
measures. Some use simple tests, such as the place-preference procedure
employed in the first experiment by Olds and Milner - the rat is simply
rewarded for going into or staying in a particular part of the test
apparatus. Others have developed sophisticated analyses of lever pressing
behavior that permit a critical assessment of the relationship between
the reinforcing properties of EBS and the physical properties of the
affected neurons (such as their refractory periods, axon diameter, etc.)
From such an analysis, one can predict, with some success whether increased
stimulation intensity does, in fact, increase its reinforcing properties
(Forgie&Shizgal, 1993; Gallistel&Leon, 1991a; Gallistel et al.,
1991b).
The results of these experiments indicate that reinforcing brain
stimulation may have two distinct effects: (a) it activates pathways
related to natural drives, and (b) it stimulates reinforcement pathways
normally activated by natural rewards. The empirical observations seem
to contradict classic "drive-reduction" theories of reinforcement (reinforcement
appears to be associated with increased drive in the EBS paradigm).
However, it is not difficult to construct a plausible alternate hypothesis:
Animals may self-stimulate because the stimulation provides the experience
of an intense drive that is instantly reduced due to the concurrent
activation of related reward neurons. This interpretation accounts neatly
for many of the apparent paradoxes we have already encountered. Priming
is necessary, according to this interpretation, because EBS reinforcement
not only activates reward pathways but also provides the reason why
that should be pleasurable (Deutsch, 1976). (This also accounts for
rapid extinction, as well as the decreased efficacy of intermittent
reinforcement.) The hypothesis assumes that the reinforcing properties
of EBS are determined by the degree of activation of related motivational
systems. It therefore accounts readily for the observed interactions
between the reinforcing properties of a stimulus and various experimental
conditions that affect related primary drives such as hunger. When there
is little endogenous activity, for instance immediately after a meal,
the stimulation elicits only a small amount of drive-related activity.
Concurrent activation of related reward circuits therefore can produce
only a small reinforcement effect. When hunger-related neural pathways
are already active because of deprivation, the same stimulation elicits
more drive and hence more reinforcement. Indeed, it may arouse the drive
system sufficiently to elicit consumatory behavior that further potentiates
the reinforcing effects of the electrical stimulation.
It is important to emphasize, at this point, that most of what we have
said about the relationship between brain stimulation reinforcement
and natural rewards and drives applies only to electrode sites in the
hypothalamus and adjacent areas of the brainstem and forebrain. This
region has been the target of most investigations because these placements
are far more effective than electrode sites in other regions of the
brain (See our discussion of neuroanatomical observations, below). Animals
and humans work to obtain stimulation of many other areas of the brain
but the acquisition of EBS-reinforced behavior is usually slow and rates
of responding typically low. There is little or no evidence that stimulation
rates (or more sophisticated measures of the reinforcing properties
of the stimulation) covary with endogenously generated drive states.
This raises interesting questions about the possible relationship of
brain stimulation reinforcement and motivational states that may be
less readily identified and manipulated than hunger or thirst. There
are, as yet, few answers because such questions are difficult to translate
into animal experiments. (If one predicts that EBS may be reinforcing
because it satisfies a need to be loved or appreciated, how does one
design an animal experiment to test the hypothesis?) Since primary drive
states are not represented in many of the cerebral and cerebellar regions
that sustain EBS reinforced behavior, it must be assumed that the simple
model we have just described may not pertain to other brain regions.
Indeed, the limited data we have on human responses to brain stimulation
(below) indicate that EBS may owe its reinforcing properties to a wide
variety of reasons - a not altogether surprising conclusion in view
of the multitude of motivations humans can cite for their behavior.
Conclusions
The reinforcing effects of electrical brain stimulation are (a) ubiquitous
(they have been reported in every species tested to date); (b) powerful
(humans, as well as animals, may voluntarily starve when given the option
to eat or work for EBS); and (c) effervescent (often there is no indication
of satiation but also no persisting desire to obtain EBS). The reinforcing
properties of EBS are often related to natural drives and rewards -
at least in the most extensively studied regions of the brain. Stimulation
is often more reinforcing when a natural drive, such as hunger, and
a natural reward, such as food, are present. Indeed, reinforcing EBS
often elicits consummatory behavior such as eating or mating.
Brain Stimulation Reinforcement in Humans
When psychiatrists and neurologists learned of the reinforcing effects
of brain stimulation in animals, they immediately saw a potential application
of the technique in psychotic patients that were unresponsive to psychiatric
treatment, at least in part because they failed to respond to normal
social rewards such as praise or disapproval. At a time when the frontal
lobotomies that Moniz had introduced in the 1930s began to loose favor,
a new neurological miracle seemed to become available. In the United
States and many European countries, the enthusiasm for clinical applications
of rewarding brain stimulation lasted barely two decades. We nonetheless
have published data on several thousand patients that were trained to
push a button to obtain electrical brain stimulation and often worked
avidly for hours on end to receive it. (Delgado, 1976; Sem-Jacobsen,
1968). Could we not simply ask them how it feels or why they work for
it? The questions have obviously been asked many times but the answers
are ambiguous and complex. (That should, of course, not be surprising.
Could one expect to elicit coherent affective experiences that can be
communicated in terms of their similarity to normal emotions, by a procedure
that causes grossly unphysiological activation of some brain region
and is not, in any meaningful way related to ongoing mental activity?
It is, indeed, remarkable is the fact that EBS does, in fact, produce
sufficiently positive reactions in humans to sustain effortful behavior.)
Due to obvious ethical concerns, electrodes are not implanted
into the brains of humans unless they are afflicted with a severe and
debilitating illness. Indeed, we currently have a moratorium on most
kinds of "psycho-surgery" (brain surgery not related to life-threatening
physical conditions such as tumor growth or stroke) in the United States.
Permanent electrode implantations are permitted only for the control
of intractable pain (e.g., in terminal cancer patients). Electrical
brain stimulation can be applied briefly to verify the placement of
electrodes that are used to make lesions for the control of epilepsy
or other severe neurological disorders but this rarely provides information
that would be helpful in the context of our discussion. This effectively
restricts our data base to early clinical trials of rewarding electrical
brain stimulation in humans, conducted mostly before many of our contemporary
questions about the phenomenon had taken shape. The usefulness of these
data is further limited by practical considerations. Neurosurgeons did
not want to incur unnecessary risk of vascular damage, particularly
in deep brain structures known to control basic biological functions.
Yet, they wanted to optimize their chances for success by implanting
as many electrodes as possible for future study (some implanted arrays
of 50 electrodes). Combined with a lingering predilection for assigning
complex affective reactions to the cerebral hemispheres, these considerations
dictated predominantly cortical electrode placements. Only few were
directed at such limbic system structures as the septal area and amygdala,
and almost none at the hypothalamus which provides more than 90 % of
the data from animal laboratories (Heath, 1963; Sem-Jacobsen, 1968).
Some patients respond to electrical brain stimulation by spontaneous
and often abrupt expressions of general pleasure, well-being,
fondness of the interviewer, and general approval of their present situation
(Higgins et al., 1956). Others report "pleasant" sensations in various
parts of their body that are not amenable to definition in terms of
normal human experience (Heath, 1963). Although casual reports of sexual
arousal during brain stimulation abound in the clinical literature,
one careful examination of human responses to stimulation of over 2000
electrode sites revealed only 2 that had unambiguous sexual content
(Sem-Jacobsen&Styri, 1972). Most common among clearly positive behavioral
reactions to brain stimulation in human patients is what psychiatrists
call a positive change in mood. This may include frequent laughter
and expressions of positive feelings towards the treatment in general.
The effect often includes an increase in the patients' willingness to
discuss his problems with the interviewer and to be friendly and cooperative
(Sem-Jacobsen, 1968). This can be viewed as a very positive outcome
in many mental patients but provides little insight into the nature
of their experiential reaction to the stimulation. Patients typically
cannot identify the reasons for their apparent well-being. One of the
pioneers in this field has suggested that: "curiosity about the strange
sensations that are aroused by brain stimulation, rather than pleasure
per se, may be the dominant cause of human self-stimulation" (Sem-Jacobsen&Styri,
1972)
It is interesting to note that while the animal literature suggests
that brain stimulation has positive, reinforcing effects, the human
literature indicates that relief of anxiety, depression and other
unpleasant affective conditions may be the most common "reward" of electrical
brain stimulation in humans. Patients with electrodes in the septum,
thalamus, and periventricular gray of the midbrain often express euphoria
because the stimulation seems to reduce existing negative affective
reactions (even intractable pain appears to loose its affective impact).
However, many psychiatrists caution that this may not reflect an activation
of a basic reward mechanism (Delgado, 1976; Heath et al., 1968). Relief
from chronic anxiety has been reported during and even long after stimulation
of frontal cortex. Again, the experiential response appears to be relief
rather than reward per se (Crow&Cooper, 1972).
We might briefly note that psychiatrists have reported apparently pleasurable
affective reactions to reinforcing brain stimulation in primates other
than humans. Lilly, for instance, conduced a detailed analysis of hundreds
of electrode sites in monkeys and concluded that his subjects showed
clear evidence of "contentment, increased interest, reduction of anxiety,
improved cooperation with the observer, improved appetitive, etc." His
animals initially worked for EBS reinforcements until exhausted (emitting
as many as 200,000 responses before stopping) before eventually settling
down to a regular rhythm of about 16 hours of "work" and 8 hours of
sleep (Lilly, 1958).
Anatomical Distribution of Brain Stimulation Reinforcement
Lateral Hypothalamus
The highest rates of responding for brain stimulation reinforcement
have consistently been found in the lateral hypothalamus (Olds et al.,
1960; Olds&Olds, 1963). The region is traversed by the medial forebrain
bundle (MFB), a major fiber system that interconnects the brainstem
with most areas of the cerebrum that have also been implicated in EBS
reinforcement. It is thus tempting to agree with Olds, who conducted
many of the seminal mapping experiments in this field and concluded
that the efficacy of lateral hypothalamic stimulation might be due to
an activation of the densely concentrated fibers of the MFB (Olds et
al., 1960).
The lateral hypothalamus does contain so-called pathneurons that are
in contact with many fibers of passage and are thus in a position to
monitor the ascending and descending information flow in the MFB (Millhouse,
1969). Olds has argued that this arrangement provides an ideal anatomical
substrate for the complex interactions between basic biological drive
states (e.g., hunger and thirst) and reinforcing brain stimulation that
we have discussed above. (Olds, 1977). The possible contribution
of lateral hypothalamic cell bodies to the reinforcing effect of
electrical stimulation in the region has been the subject of debate,
although evidence of dendritic sprouting after reinforcing stimulation
in the region indicates significant persisting local effects (Bindu&Desiraju,
1990). Neurotoxin lesions in the area of the stimulating electrode (which
destroy nerve cell bodies but not fibers of passage) have been reported
to produce significant impairments (Velley et al., 1983) but it has
been suggested that this might be due to axonal damage in the immediate
vicinity of the neurotoxin injection (Stellar et al., 1991).
The most consistent body of evidence for a lateral hypothalamic focus
for the reinforcing effects of EBS comes from electrophysiological
studies. In the rat and monkey, neurons in the lateral hypothalamus
respond to reinforcing stimulation of electrode sites in the posterior
LH as well as other regions of the brain (Olds, 1974; Rolls, 1974b).
Some of the hypothalamic cells that respond to reinforcing brain stimulation
also respond to the taste or sight of food or water and the effect can
be remarkably specific. For instance, a cell has been isolated that
responded to the taste of glucose (but not other foods or fluids) and
did so only when the animal was food deprived. Other hypothalamic cells
responded to the sight of a peanut when food deprived but not to other
foods or other visual stimuli (Rolls, 1976). Stimuli that do not affect
neural activity in the LH may come to do so after they have been repeatedly
associated with food-reward (Olds, 1973). The convergence of signals
for unconditioned as well as conditioned natural reinforcers, such as
food and reinforcing electrical brain stimulation, has been interpreted
as strong evidence that the lateral hypothalamus may play a major role
in the mediation of reward (Rolls, 1976). It is only fair, however,
to point out that the direction of information flow is not unidirectional.
Reinforcing stimulation of the lateral hypothalamus also modulates the
electrical activity of neurons in other regions of the brain (e.g.,
the ventral tegmental area and frontal cortex) that are also EBS reinforcement
sites (Rolls, 1971a; Rolls, 1971b; Rolls&Cooper, 1974c). Moreover,
neurons in other regions of the brain (e.g., the nucleus accumbens)
are activated, apparently selectively, by reinforcing brain stimulation
(Wolske et al., 1993).
Medial Forebrain Bundle
Many of the pioneering studies in this field were essentially mapping
studies, designed to describe the anatomical substrate of EBS reinforcement
in detail. A large data base accumulated rapidly indicating that the
reinforcing effect was most pronounced in brain regions that received
afferents from, or contributed efferents to the medial forebrain bundle
(German&Bowden, 1974; Olds et al., 1960; Wauquier&Rolls, 1976).(Fig.
XXX) More recent studies, using autoradiographic labeling to
detect neuronal activation, have supported this conclusion. In these
experiments radioactive 2-deoxy-D-glucose (2-DG) was systemically
administered to rats before permitting them to self-administer EBS at
electrodes in the medial forebrain bundle. (2-DG is incorporated into
active neurons just like glucose but cannot be metabolized. It thus
remains concentrated in active neurons and its radioactive label can
later be detected by a variety of quantitative techniques.) These autoradiographic
studies demonstrated that reinforcing stimulation at many different
MFB sites produced a common, widespread pattern of neural activation,
whereas stimulation at electrodes in prefrontal cortex (which may not
be part of the MFB circuit) resulted in a quite different pattern. (Gallistel
et al., 1985; Porrino et al., 1990; Yadin et al., 1983).(Fig. XXX) Most
contemporary investigators have accepted the view that components of
the medial forebrain bundle are responsible for the reinforcing effects
of electrical stimulation in many areas of the brain (Milner, 1991;
Mora&Cobo, 1990; Phillips&Fibiger, 1989a).
That the MFB is probably not the sole anatomical substrate of reinforcing
brain stimulation is indicated by the fact that EBS reinforcement can
be obtained from regions of the brain that have no direct projections
to or from the MFB (discussed below). Some investigators have, in fact,
suggested that the MFB might not play a very important role in EBS reinforcement
at all. This minority opinion is based mainly on the disappointingly
small and transient effects of MFB lesions. Many investigators
have reported transient impairments after large MFB lesions. However
most also find significant, and often complete recovery. In a few investigations,
MFB lesions produced little or no effects at all. Valenstein's review
of this extensive literature (Valenstein, 1966) concluded that the reinforcing
effects of EBS at two of the most positive reinforcement sites (the
lateral hypothalamus and septal area) does not depend on the integrity
of the MFB. This conclusion receives support from a series of studies
on thalamic rats whose cortex and forebrain had been removed.
Although incapable of lever-pressing, these animals learn simple operant
responses such as head turning or tail-lifting to obtain hypothalamic
stimulation even though most ascending and descending components of
the MFB are undoubtedly transected and their target tissues missing
(Huston&Borbely, 1973).
The negative results of the lesion studies are almost certainly influenced
by the fact that some MFB components course through portions of the
diencephalon (e.g., the cerebral peduncle and the medial hypothalamus)
that are not affected by MFB lesions. (The thalamic rat also has intact
interconnections between the hypothalamus and midbrain.) The fact remains,
however, that EBS reinforcement can survive massive damage to the MFB.
This leaves us with a choice of unpalatable conclusions: either the
MFB is, indeed, not as important to EBS reinforcement as is generally
believed, or the system is so redundant that a small percentage of its
components can support its role in EBS reinforcement. We shall return
to this conundrum in our discussion of neurochemical mechanisms where
similar problems have been raised (below).
Before we briefly turn to other regions of the brain that appear to
be related to EBS reinforcement, it is interesting to consider the direction
of information flow in the MFB. Two different lines of evidence
supported the initial conclusion that reinforcement related information
ascends to the forebrain in the MFB: (a) The reinforcing effects of
EBS were discovered at about the time that the attention of neuroscientists
was drawn to small groups of brainstem neurons that project axons into
the forebrain which use catecholamines (i.e., dopamine and norepinephrine)
as neurotransmitters. These pathways were soon implicated in sleep and
arousal as well as the mood-altering effects of many drugs and EBS reinforcement
itself (discussed below). (b) Lesions caudal to an EBS reinforcement
site in the hypothalamus typically produce much more severe and persisting
effects of EBS reinforced responding than comparable lesions rostral
to the stimulation site (Valenstein, 1966).
Contemporary neuropharmacological studies, (discussed below) have strongly
implicated catecholaminergic pathways in EBS reinforcement. However,
the results of psychophysical studies consistently indicate that the
reinforcing effects of hypothalamic stimulation are mediated by descending
components of the MFB. The details of these studies are very complex
but their rationale is simple: An analysis of changes in the reinforcing
properties of distinct pulses of electricity provides data for estimating
the duration of the refractory periods of the neurons that are activated.
This, in turn, permits inferences about the physical properties of the
affected axons as well as the direction and velocity of the action potentials
they propagate.
Refractory period estimates provide consistent evidence that
the reinforcing effects of electrical stimulation in the lateral hypothalamus
and adjacent ventral tegmental area are related to one or perhaps two
populations of neurons that have common physical properties (Bielajew
et al., 1982; Gratton&Wise, 1988a; Yeomans et al., 1979). The results
of so-called "directionality" studies indicate that reinforcing
EBS produces action potentials that always travel from the lateral hypothalamus
to the ventral tegmentum. (Directionality studies involve an analysis
of the interactions of orthodromically and antidromically conducted
action potentials. Electrical stimulation of an axon causes action potentials
that travel not only orthodromically - i.e., towards the axon terminal
- but also antidromically - i.e., towards the cell body.) (Bielajew&Shizgal,
1986; Durivage&Miliaressis, 1987; Gratton&Wise, 1988b).(Fig.
XXX) Related experiments have provided evidence of a similar relationship
between the ventral tegmentum and EBS reinforcement sites in the midbrain
and pons (Boyce&Rompré, 1987). These studies do not indicate a direct
interaction between the lateral hypothalamus and the midbrain and pons
(Bielajew et al., 1981). This suggests that the VTA may be a focal point
in the EBS reinforcement system that collects both descending influences
from the hypothalamus and ascending influences from the lower brainstem.
Other Areas of the Brain
Many of the pioneering studies in this field concentrated on electrode
sites in the hypothalamus and adjacent forebrain regions, including
the septal area, because animals rapidly learned to self-administer
stimulation in this region and worked very hard to obtain it afterwards
(Brady, 1961). Early clinical studies of the phenomenon also focused
on the septal area and adjacent forebrain regions because tumor
growth in the area had been related to psychiatric disturbances (Heath,
1963). Most investigators paid little attention to the region after
Olds concluded that even higher responses rates (and presumably stronger
reinforcing effects) could be obtained from the lateral hypothalamus
(Olds et al., 1960). The forebrain region just anterior to the hypothalamus
and preoptic region reappeared prominently in the EBS reinforcement
literature when it was demonstrated that the nucleus accumbens,
adjacent to the septal area, was a major target for dopaminergic projections
from the brainstem that have been strongly implicated in EBS reinforcement
(see below).
Other brain regions that support high rates of responding for EBS reinforcements
include: the prefrontal cortex (Rolls&Cooper, 1974a; Rolls&Cooper,
1974c; Routtenberg&Sloan, 1972), amygdala, cingulate gyrus, entorhinal
cortex, and hippocampus (Kane et al., 1991; Rolls, 1974b), and ventral
tegmental area of the midbrain (Rompré&Miliaressis, 1985). Regions
that support lower rates of EBS reinforced behavior include: lower portions
of the brainstem (pons and medulla), the cerebellum, thalamus and striatum
(Olds, 1977; Sem-Jacobsen, 1976; Wauquier&Rolls, 1976). Many of
the structures that support EBS reinforced behavior have been implicated
in positive or negative affect on the basis of lesion studies and/or
clinical observations but some (e.g., the pons, medulla, cerebellum
and striatum) have not. Even some primary sensory pathways, including
the olfactory bulb (Phillips&Mogenson, 1969), pontine trigeminal
nuclei (Corbett&Wise, 1979; Van der Kooy&Phillips, 1979) and
pontine taste nuclei (Carter&Phillips, 1975) support EBS reinforcement.
The major "silent" component of the brain appears to the neocortex (Olds
et al., 1960) although experimental as well as clinical studies have
reported a few positive sites in frontal and temporal lobe neocortex
(Bishop et al., 1963; Rolls, 1974b; Sem-Jacobsen, 1968).
Psychophysical studies indicate that the physical properties
of the neurons that mediate the reinforcing effects of frontal cortex
stimulation are quite different from those observed in the ventral tegmentum
and lateral hypothalamus (Schenk&Shizgal, 1982). Investigations
of the basal forebrain (preoptic area and nucleus accumbens) have obtain
refractory period estimates that were intermediate between those obtained
from LH electrodes and those recorded from cortical sites. The data
from these studies are compatible with the hypothesis that two different
neural reinforcement systems may overlap in this transitional area of
the brain (Bielajew et al., 1987; Fouriezos et al., 1987).
Summary
The complex data we have just reviewed show that EBS reinforcement
can be obtained from most major regions of the brain except for the
neocortex. The diversity of the EBS reinforcement sites suggests that
the subjective sensations associated with EBS reinforcement are also
probably diverse. Human instrospection supports that conclusion. Stimuli
of all sensory modalities are capable of eliciting positive as well
as negative affect. In some (relatively rare) instances, the associations
are innate (humans, at least, have little difficulty identifying pleasant
or unpleasant odors, tastes, sights and sounds, and respond positively
to light touch and negatively to deep pressure.) More typically, the
associations between specific stimuli and their affective consequences
are learned.
Most recent reviews of the literature that describes the anatomical
basis of EBS reinforcement conclude that there are probably several
anatomically distinct and perhaps functionally independent circuits:
The most prominent MFB system may itself encompass two or more distinct
pathways, including separate mesolimbic and mesocortical dopamine pathways
(discussed below). There is also evidence for a separate cortical reinforcement
system that originates in the prefrontal cortex (where it interfaces
with dopaminergic pathways) and projects to limbic cortex in the cingulate
gyrus and in the entorhinal region of the temporal lobe. In addition,
some investigators have proposed a distinct hind brain reinforcement
system that may be specifically related to taste- and gustatory sensations
that play a major role in survival, as well as mating and maternal behavior,
in many mammalian species.
Neurochemistry of Brain stimulation Reinforcement
Shortly after the brain stimulation reinforcement phenomenon was discovered,
neuroanatomist learned to stain catecholamine neurotransmitters in the
brain. This led to the discovery that several major noradrenergic and
dopaminergic pathways originated the midbrain and lower brainstem and
projected diffusely to the hypothalamus, medial forebrain, and limbic
system. Their trajectory followed the medial forebrain bundle and overlapped
extensively with maps of brain stimulation reinforcement sites. Biopsychologists
therefore initiated a concerted effort to determine whether noradrenergic
or dopaminergic pathways provide the anatomical substrate of brain stimulation
reinforcement.
We now know that there are two principal noradrenergic pathways.
The ventral tegmental tract arises from several nuclei in the
lower brainstem and projects preferentially to the hypothalamus. The
dorsal tegmental tract arises mainly from the nucleus locus coeruleus
in the midbrain and projects diffusely to the medial forebrain and limbic
system components of the cerebrum, as well as the cerebellum. There
are three major dopamine pathways. The nigro-striatal bundle
arises from the substantia nigra (SN) in the ventrolateral midbrain
and projects exclusively to the striatum. The mesolimbic pathway originates
in the ventral tegmental area (VTA) just medial to the substantia nigra.
It projects mainly to the medial forebrain (nucleus accumbens, lateral
septum) and amygdala. The mesocortical pathway also originates in the
VTA and projects diffusely to limbic system cortex (Fallon, 1988; Moore&Bloom,
1979).
Noradrenergic Reinforcement Pathways
By the early 1960s, we knew that drugs that increase the release, or
block the re-uptake or metabolic destruction of catecholamines, increase
the rate of EBS reinforced behavior. Drugs that reduce the availability
of catecholamines in the brain, or block their postsynaptic receptors,
decrease EBS reinforced behavior (Olds, 1959; Stein, 1962; Stein, 1968).
The drugs that were available for this pioneering research affected
both noradrenergic and dopaminergic transmitter mechanisms. Stein nonetheless
proposed a norepinephrine "theory of reward" that played a major
role in shaping subsequent research in this field (Stein, 1968; Stein
et al., 1976). He selected norepinephrine (NE) rather than dopamine
(DA) as the critical "reinforcement transmitter" mainly because of two
sets of empirical findings. Firstly, there were the results of numerous
mapping studies indicating that there were many good EBS reinforcement
sites in the brainstem below the level of the substantia nigra and ventral
tegmental area, that received no dopaminergic innervation. The positive
sites were most prominent in regions (such as the locus coeruleus)
that were known to give rise to the major noradrenergic projections
to the forebrain (Ritter&Stein, 1973). Secondly, psychopharmacological
studies showed that drugs that block the conversion of dopamine
into norepinephrine in the brain (the only way NE can be synthesized
in noradrenergic neurons), reduced or abolished self-stimulation and
this effect was blocked by NE but not DA injections into the ventricles
(Stein et al., 1976). Since these NE synthesis blockers did not affect
dopaminergic neurons in the brain, Stein's conclusion seemed well founded.
Although contemporary interest is focused on precisely those dopaminergic
pathways (below), there is some contemporary research suggesting that
noradrenergic pathways may, indeed, play a role in EBS reinforcement.
For instance, microdialysis studies have shown that reinforcing brain
stimulation at some electrode sites releases NE, but not DA, from the
nucleus accumbens and medial frontal cortex (Cenci et al., 1992). Electrophysiological
studies have demonstrated that stimulation of the locus coeruleus stimulates
alpha-1 noradrenergic receptors on neurons in the ventral tegmentum
and thus increases their activity (Grenhoff et al., 1993).
A conceptual problem has plagued Stein's noradrenergic theory
from the start: The brainstem NE pathways are strongly implicated in
cortical as well as behavioral arousal (Jones, 1990). If one finds that
drugs or lesions that interfere with the functions of NE pathways, inhibit
EBS reinforced behavior, could this not be explained, most parsimoniously,
in terms of a general decrease in reactivity to all stimuli? Stein,
and other advocates of a noradrenergic basis of EBS reinforcement, tried
to circumvent this problem by demonstrating preferential effects on
EBS reinforced behavior, but that has proven to be an extremely difficult
task. One might, in fact, argue that we would expect a general inhibition
of most, if not all behavior, when reinforcement-related pathways are
blocked (if, as is generally accepted, reinforcement is an integral
part of all learned behavior and nearly all behavior is learned). As
we shall see shortly, similar problems plague contemporary dopamine
theories of reinforcement.
In the 1970s, more evidence for dopaminergic involvement in EBS reinforcement
became available. At first, this led to the hypothesis that whereas
"reward" itself might be a product of noradrenergic pathways, the "incentive
motivation" for brain stimulation might be due to an activation of dopaminergic
neurons (Crow, 1972). More recently, the prevailing opinion has favored
explanations that propose a central role for dopaminergic pathways in
EBS reinforcement itself (Self&Stein, 1992; Wise et al., 1992).
This does not, of course, exclude a significant role of noradrenergic
pathways in EBS reinforcement, and some models of interacting NE-DA
reinforcement systems have been proposed (Stellar&Rice, 1989).
Dopaminergic Reinforcement Pathways
Systemic injections of dopamine antagonists (e.g., receptor
blockers) reduce the reinforcing effects of EBS in the ventral tegmentum
and hypothalamus (Gallistel et al., 1982; Stellar et al., 1983; Stellar&Rice,
1989) as well as medial frontal cortex (Corbett, 1990.; Duvauchelle&Ettenberg,
1991). Dopamine antagonists also block the effects of natural reinforcers,
such as food or water, as one might expect if the EBS reinforcement
phenomenon is as fundamental to behavior as many biopsychologists assume
(Rolls et al., 1974d; Spyraki et al., 1982). Dopamine antagonists inhibit
the reinforcing effects of EBS not only in portions of the brain that
are innervated by DA pathways but also in lower brainstem regions that
have no dopaminergic innervation. This suggests that dopaminergic neurons
may be "in series" with other (possibly noradrenergic) pathways. (Rompré&Boyce,
1989a; Rompré&Wise, 1989b).
Dopamine, like many other neurotransmitters, acts on several different
receptor sites that interact differently with various dopamine agonists
and antagonists. Some early studies demonstrated inhibitory effects
on EBS reinforcement of dopamine D2 receptor blockers (Gallistel&Davis,
1983), but more recent reports have specifically implicated D1 receptors
(Miller et al., 1990; Nakajima, 1986; Sabater et al., 1993). (D 2 receptors
may exert facilitatory effects on EBS reinforcement that can only be
expressed after D1 receptors have been activated) (Nakajima et al.,
1993; Nakajima&OŐRegan, 1991).
Systemic injections of dopamine agonists, (mainly drugs that
release dopamine or inhibit its reuptake) such as cocaine or
amphetamine, enhance the reinforcing effect of EBS in the ventral
tegmental area (Frank et al., 1992), medial forebrain bundle (Gallistel&Karras,
1984; Kornetsky&Esposito, 1981), and frontal cortex (Corbett, 1991;
McGregor et al., 1992). (Fig. XXX) In some cases, the effect is only
small, possibly because the drugs themselves produce reinforcing effects
that are independent of the animals' behavior in these studies (discussed
below). Dopamine agonists increase locomotor activity and there have
been many attempts to dissociate their general stimulant effects from
a more specific facilitation of EBS reinforcement. For instance, one
such study demonstrated that the locomotor effects of amphetamine become
more prominent with repeated administration, whereas the drug's facilitating
effect on EBS reinforced behavior is largest the first time the drug
is administered (Wise&Munn, 1993).
The nucleus accumbens, as well as the prefrontal cortex,
have been implicated in the effects of dopamine agonists. Rats avidly
self-administer amphetamine into either of these regions (Hoebel et
al., 1983; Stein&Belluzzi, 1989). Experimenter-controlled microinjections
of dopamine and amphetamine into both regions also modulate EBS reinforcement
elsewhere, but the pattern of the behavioral effects is quite different
in nucleus accumbens than in prefrontal cortex, suggesting that the
two regions may exert different dopaminergic influences on EBS reinforcement
(Olds, 1990). Drug discrimination experiments have shown that reinforcing
electrical stimulation of the VTA has subjective effects similar to
those of systemic amphetamine (Druhan et al., 1990).
Microdialysis studies consistently show that reinforcing electrical
stimulation of the ventral tegmental area (Fiorino et al., 1993; Phillips
et al., 1989b) or medial forebrain bundle (Nakahara et al., 1989) releases
dopamine from the nucleus accumbens. Systemic injections of dopamine
agonists, such as amphetamine or cocaine, have similar effects. (Hernandez&Hoebel,
1988; Moghaddam&Bunney, 1989). Consumatory behaviors such as eating,
drinking, or mating, have also been shown to release dopamine from the
nucleus accumbens and prefrontal cortex (Damsma et al., 1992; Hernandez&Hoebel,
1988; Hernandez&Hoebel, 1990; Mark et al., 1989).
On balance, these data provide strong empirical support for the general
conclusion that dopaminergic pathways play a very important role in
EBS reinforcement, and a dopamine theory of reward is now widely
accepted. However, we also have numerous observations indicating that
DA pathways may be only one link in a complex system. The psychophysical
experiments we have briefly discussed above show that the reinforcing
effects of EBS are probably rarely due to the direct activation of dopamine
(or norepinephrine) fibers. Refractory period estimates consistently
indicate that reinforcement neurons in the MFB have refractory periods
that are typically shorter than 1 msec. and rarely longer than 1.4 msec.
(Gratton&Wise, 1985; Rompré&Miliaressis, 1987; Yeomans, 1975).
Most catecholamine fibers, one the other hand, have refractory periods
greater than 2.0 msec (Foote et al., 1983; Wang, 1981). Moreover, directionality
studies have shown that reinforcement related signals typically descend
in the MFB (dopaminergic fibers only ascend) (Bielajew&Shizgal,
1986). (There is some evidence that excitatory amino acid receptors
on VTA dopamine neurons may mediate the reinforcing effects of EBS in
the hypothalamus and forebrain (Herberg&Rose, 1990).)
Mapping studies demonstrate that the reinforcement pathways extend
into brain areas that do not contain dopamine cells or their projections
(Rompré&Boyce, 1989a; Rompré&Miliaressis, 1985). Yet, a review
of the pharmacological literature indicates that a blockade of brain
dopamine reduces EBS reinforced behavior at all electrode sites (MacConell
et al., 1992; Simon et al., 1979). On the other hand, near-complete
depletion of brain dopamine has been reported to produce only minor
disturbances in some rate-free measures of EBS reinforcement (Colle&Wise,
1987; Fibiger et al., 1987). There are, moreover, some experimental
findings that indicate that activation of dopaminergic components of
the nucleus accumbens or frontal cortex does not always imply activation
of reinforcement-related functions. For instance, chronic stress, which
reduces the reinforcing effects of EBS, has been shown to release dopamine
from the nucleus accumbens just as positive natural reinforcers, such
as food or water, do (Stamford et al., 1991). Microdialysis studies
have also demonstrated that changes in the physical parameters of VTA
stimulation can produce major changes in the amount of dopamine that
is released from nucleus accumbens even though they do not affect the
reinforcing property of the stimulation as measured by rate-free measures
(Miliaressis et al., 1991).
Proponents of a dopaminergic theory of EBS reinforcement have found
it very difficult to distinguish drug- and lesion- effects on reinforcement
from changes in other functions that are mediated by brain dopamine
pathways. The most obvious problem concerns the well-documented involvement
of DA in motor functions and arousal. Electrolytic as
well as neurotoxin-induced lesions in the ventral tegmentum typically
produce somnolence and severe sensory-motor disturbances due to the
destruction of dopaminergic nigro-striatal projections (see our discussion
of hunger for detail) (Ungerstedt, 1971). Complex, learned behavior
remains severely impaired long after simple voluntary behaviors have
recovered (Kent&Grossman, 1973). This suggests that an interference
with reinforcement-related pathways may also occur (Grossman, 1976).
Lesions restricted to medial portions of the VTA, as well as systemic
injections of DA antagonists, can have less severe sensory-motor dysfunctions,
but a decrease in EBS reinforced behavior is nonetheless difficult to
interpret. Dopamine agonists, such as cocaine and amphetamine, have
well-known psychomotor stimulant effects and there is considerable evidence
that electrical stimulation of DA brain sites can produce similar effects.
Rate-free measures of the reinforcing effects of EBS address this problem
but cannot entirely assuage one's concerns. There is, in fact, no entirely
satisfactory solution to this problem (just as there is none for the
involvement of NE in arousal). If EBS reinforcement is, in fact, related
to natural reward, and reinforcement is, in fact, essential for learned
behavior, one should not expect to be able to separate behavior from
reinforcement (any more than one can separate behavior from the intervening
variable reward).
Conclusions
There is consensus among contemporary specialists in this area that
EBS reinforcement is a far more complex phenomenon than originally believed.
Although connectivity studies have discovered direct interconnections
between some of the key areas, reinforcement-related brain pathways
are undoubtedly multi-synaptic. Since dopamine pathways do not project
to other dopamine pathways, non-dopaminergic components undoubtedly
occur in the reinforcement system(s) of the brain. Some of these may
well be noradrenergic. Most contemporary investigators agree that dopamine
pathways are part of the neural substrate of reinforcement. However,
many reject the stronger hypothesis that reinforcement is uniquely associated
only with dopaminergic pathways. The notion of a single neural pathway
for all types of reinforcement processes seems no longer tenable even
if one modifies the original idea to include a number of non-catecholaminergic
stages connected "in series" with a dopaminergic link.
Section Review
Brain-stimulation reinforcement is, arguably, the most intriguing and
enigmatic phenomenon biopsychologists have yet encountered. The mere
fact that the administration of random electrical pulses that cannot
bear any meaningful relation to ongoing neural processes should be rewarding
seems to defy our basic concepts of how the brain works. The fact that
in most cases some "priming" stimulation must be administered deepens
the mystery. Surely the animal has not forgotten that the stimulation
was rewarding or how it could be obtained? Does prolonged and unnatural
activation of the reinforcement system cause functional changes (such
as decreased transmitter production or release or decreased receptor
sensitivity) that makes it more difficult to be activated by natural
rewards? Is this a sufficiently negative experience to keep the animal
away from brain stimulation reinforced behavior unless it is in some
way "hooked" again by the administration of some free "priming" stimuli?
The relationship between brain stimulation reinforcement and natural
reward also remains a puzzle. Some studies have shown that experimental
treatments that facilitate brain stimulation reinforced behavior also
affect natural rewards. Others fail to find a reliable interaction,
perhaps because different areas of the brain (and different aspects
of the postulated reinforcement system) are involved. Such a conclusion
is supported by the observation that some neurons respond to brain stimulation
as well as natural rewards, but others are responsive only to one or
other.
Lastly, we need to know more about the nature of the experiential response
to reinforcing brain stimulation. Is it so difficult to describe because
there is no "reward" experience per se? Or are there numerous different
experiences depending upon the motivational aspects of the situation?
Can we define a special experience when we receive a natural reward
such as money for running an errand or praise from the boss for a job
well done? If there is no clear-cut experiential component, why do animals
(and humans) avidly press a lever to obtain brain stimulation? If it
were just curiosity about the unusual experiences elicited by the stimulation
(as some have suggested), surely animals would not forgo nourishment
and sleep in order to work furiously for days on end?