Neuroscience - the pleasures of the brain / Morten L. Kringlebach and Kent C. Bridge

New insights into how the brain produces a sense of pleasure could lead to better treatment of addiction and depression, and even new information about happiness

In the 50s, Tulane University psychiatrist Robert Heath initiated a controversial program that involved surgeries to implant electrodes into the brains of patients hospitalized for epilepsy, schizophrenia, depression, and other serious neurological conditions. His initial goal was to locate the biological location of these disorders, and try to cure people with them through artificial stimulation of these areas.

According to Heath, the results were impressive. Patients who were deeply depressed could be made to smile, talk and even giggle. However, the relief was only temporary. When the stimulus stopped, the symptoms returned.

To increase the potential therapeutic benefit, Heath fitted some patients with buttons that they could push themselves when they felt the urge to do so. Some patients felt the urge quite often. One patient, a 24-year-old gay man whom Heath was trying to cure from depression (and his attraction to other men), felt the need to stimulate his electrodes about 1,500 times during a single three-hour session. According to Heath, this compulsive self-stimulation gave the patient, known as 19-B, "sensations of pleasure, alertness, and warmth (good will)." The end of the meeting with the patient was accompanied by a vigorous protest on his part.

The experiments helped to define a system of structures that would come to be called the "pleasure center" of the brain. They have also spawned a movement, both in science and popular culture, that aims to better understand the biological basis of pleasure. Over the next 30 years, neuroscientists identified the substances that the brain regions described by Heath and others send and receive to convey information related to pleasure. People began to imagine brave new worlds where activating these pleasure centers could cause supreme happiness.

However, the discovery of the brain's apparent pleasure center did not lead to a breakthrough in the treatment of mental illness. It may even have fooled scientists into thinking they understand how pleasure is encoded and produced within the brain. Recent studies in rodents and humans suggest that activating these structures with electrodes or chemicals actually does not cause pleasure at all. It is possible that it only accelerates desire, and therefore the uncontrollable urge to self-stimulation.

Using advanced techniques in molecular biology, combined with improved methods of deep brain stimulation, our labs and others are redefining the neural circuitry of pleasure in the brain. We are discovering that the systems in the brain that cause pleasure are much more limited and complex than previously thought. By identifying the neural underpinnings of pleasure, we hope to pave the way for more targeted and effective treatments for depression, addiction, and other disorders, and perhaps also offer new insights into the sources of human happiness.

 

misleading electrodes

Whether you experience it as a vibration of pleasure or a warm rush of satisfaction, pleasure is more than a temporary addition, that is, something that someone desires only after their more basic needs have been met. Feeling is actually necessary for life. Pleasure nourishes and preserves the interest animals have in the things they need to survive. Food, sex and in some cases social closeness create positive emotions and serve as a natural reward for all animals, including humans.

The first insights into the biological basis of these sensations were discovered about 60 years ago by the first to discover what are known as pleasure electrodes. James Olds and Peter Milner of McGill University were looking for areas of the brain that can influence the behavior of animals. In earlier studies conducted at Yale University, in which electrodes were inserted into the brains of rats, they identified an area whose stimulation caused the animal to stop any activity it was engaged in at the same time as the stimulation. In trying to replicate these findings, Olds and Milner came across a region of the brain that the rodents actively take steps to stimulate, similar to the way animals repeat any task or behavior that yields an appropriate reward.

When they placed the electrodes in different areas, and sometimes not in the intended location, the pair of researchers were surprised to discover an area of ​​the brain that the animals seemed to enjoy when stimulated with a weak electric current. Rats placed in a large box repeatedly returned to the corner where the researchers gave them a mild electric shock. Using this approach, Olds and Milner found that they could target the rodents almost anywhere. In some cases the animals even preferred the stimulation over food. If the researchers pressed the button when the rats were in the middle of a maze that promised a tasty mash at the end, the animals stayed where they were and did not bother to continue towards the prize.

And amazingly, Olds and Milner found that when the electrodes were attached so that the rats could self-stimulate their brains by pressing a pedal, they self-stimulated almost compulsively, some more than 1,000 times an hour. When they stopped the electric current, the animals pressed the rod a few more times and then fell asleep.

The results encouraged Olds and Milner to state: "We have probably located a system in the brain whose unique function is to create a rewarding effect on behavior." The areas identified by the researchers have been established as the basis of the operation of the brain's reward circuit. These areas include the nucleus accumbens located at the base of the forebrain, and the cingulate cortex that forms a belt around the fiber group that bridges the left and right hemispheres of the brain.

Almost immediately after, other researchers replicated these effects, discovering similar findings in more advanced primates and humans. Heath was particularly extreme when he insisted that stimulating these areas not only encouraged behavior but also created a sense of euphoria. In the minds of many researchers and the general public, these structures have been recognized as the main pleasure center of the brain.

However, about ten years ago, we both began to wonder if the act of self-electrical stimulation was indeed the best measure of pleasure. How do we know that subjects are stimulating these areas because they like the resulting sensation, and not for any other reason? To examine the cycle of pleasure more precisely, we felt that we needed to design a different way to gauge what the subjects actually enjoy, including animals.

 

A measure of pleasure

In human experiments, it is very easy to assess the degree of pleasure: you only need to ask even if the resulting ratings will not accurately reflect the actual sensations. In contrast, such a test is not possible in laboratory animals, which are the easiest for biologists to study.

A different approach originates from Charles Darwin's book from 1872: "Expression of Emotions in Humans and Animals". Darwin claims in the book that animals change their facial expression in response to environmental situations. In other words, they make faces. We now know that the neural mechanisms underlying these expressions work similarly in most mammalian brains. Because of this, some facial expressions have been preserved in evolutionarily distant animals such as rodents and humans, including the faces expressing "it's delicious", which we make in response to appetizing food.

Food is one of the universal routes to pleasure, besides being an essential need for survival. Food is also one of the most available environmental tools for psychologists and neuroscientists studying animal behavior. In our studies, we discovered that the response to food provides a means by which nonverbal pleasures can be examined.

Anyone who has spent any amount of time around babies knows that even the youngest humans have ways of letting their caregivers know how much they like a meal. Sweet flavors cause satisfied licking of the lips. On the other hand, bitter tastes are accompanied by open mouths, shaking of heads and vigorous wiping of the mouth. The same responses seen in infants are also present in rats, mice and non-human primates. The more the subjects like the taste, the more often they lick their lips. By videotaping subjects' reactions to food, and then counting the number of times their tongues darted out in an attempt to capture each flavor molecule, we can measure how much they liked a taste-related stimulus. We used this information to gauge where pleasure is actually located in the brain.

"wanting" is not "loving"

One of the first things we discovered is that pleasure does not arise in the brain in the place or in the way that we thought and argued in the past. The areas first identified by Olds and Milner and others, located in the forebrain, are activated by the neurotransmitter dopamine released from nerve cells that originate near the brain stem. We hypothesized that if these frontal regions do control pleasure, flooding them with dopamine or completely removing dopamine should alter the animal's responses to the pleasure-inducing stimulus. And that's not what we discovered.

For these experiments, our colleague Xiaoxi Zhuang from the University of Chicago engineered mice that lack a protein that brings dopamine back into the cell after it has been released by a stimulated nerve cell. In animals with such a mutation that causes the absence of protein, dopamine concentrations in the brain are unusually high. However, we discovered that the mice do not derive more pleasure from sweets compared to their cagemates. Compared to normal rodents, the mice with excess dopamine do rush more toward sweet rewards; But they don't lick their lips as often anymore. On the contrary, they lick their lips even less than mice with average amounts of dopamine.

The same was also observed in rats that raised their dopamine levels by other means, such as injecting amphetamine into the nucleus accumbens causing an increase in dopamine in that region. But, again, these rats no longer enjoy sweet rewards after chemically boosting their dopamine, even though their motivation to get the sweets is higher.

On the other hand, rats in which they were made to lack dompin, showed no desire for sweet rewards at all. These animals will actually starve to death if not actively fed. Nevertheless, dopamine-deprived rats that have no interest in food still find any sweets they put in their mouths to be mouth-lickingly delicious.

If so, it seems that the effects of dopamine are less than previously thought. This substance probably contributes to motivation more than it contributes to the feeling of pleasure itself. In humans too, dopamine levels seem to correspond to the extent to which people claim to "crave" a tasty treat, rather than how much they "enjoy" it.

The same can be true in the case of addiction. Drugs flood the brain with dopamine, especially the areas associated with "craving". This rush of dopamine not only creates intense cravings, but also makes the cells in these areas more sensitive to future exposure to the drug. Moreover, research by our colleague Terry Robinson from the University of Michigan suggests that this sensitivity can last for months or years. So even after the drug stops causing pleasure, explains Robinson, a drug addict is still able to feel a strong urge to use it. This is an unfortunate consequence of dopamine action.

In light of these new insights, we believe that the "pleasure" electrodes that cause the accumulation of dopamine in the brains of rats and humans, did not cause pleasure as previously thought. In support of this view, we find that activating electrodes that cause an increase in dopamine in the nucleus accumbens will motivate a rat to eat and drink, but the same stimulation does not make that food more enjoyable - quite the opposite. Rats that are made to eat sweets by electrical stimulation wipe their mouths and shake their heads. These are signs of disgust, as if the current made them feel the sweetness as bitter or disgusting. The fact that the electrodes forced rats to consume large amounts of food that did not give them pleasure is evidence that desires and pleasures are controlled through different mechanisms in the brain.

We believe that the differential control is also found in humans. Passing current through the classic pleasure electrodes caused at least one patient to have a strong desire to drink. In other patients, including 19-B, electrical stimulation evoked sexual drive. At the time, sexual urges such as these were considered evidence of pleasure. But in our extensive review of the literature, we have never come across any evidence that a patient implanted with such electrodes felt that they gave him any particular pleasure. 19-B never cried out: "Ah, I like it!" Instead, stimulation of the electrodes made him and others want more stimulation, probably not because they liked the sensation but because they were made to want it.

 

Areas associated with hedonism

Both passions and pleasures can make the experiencer feel that it is rewarding. If so, it makes sense that the real pleasure centers in the brain, which are directly responsible for causing pleasurable sensations, are found in some of the structures previously identified as part of the reward circuit. One of these areas known to be associated with hedonism is located in a sub-region of the nucleus accumbens called the "medial shell". A second area is found within the ventral pallidum, a structure located deep in the brain, near the base of the forebrain, and receives most of its signals from the nucleus accumbens.

To locate these areas, we looked for brain areas whose stimulation increases the feeling of pleasure. For example, making sweet things even more enjoyable. Chemically stimulating these areas with enkephalin, a morphine-like substance produced in the brain, makes the rat like sweets more. Onandamide, the brain version of the active ingredient in marijuana, causes the same effect. Another hormone called orexin, which the brain releases during hunger, is also able to stimulate areas associated with hedonism, thus helping to increase the delicious taste of food.

Each of these areas is a particle of a larger structure within which it resides, only about a cubic millimeter in a rat brain and probably no more than a cubic centimeter in humans. But like islands of an archipelago, these areas are connected to each other and to other brain areas that process signals of pleasure. Together they create an integrated and dominant circle of pleasure.

This circuit is relatively flexible. In our experience, neutralizing individual components of the pleasure circuit does not reduce the typical response to normal sweet talk, except in one exceptional case. Damage to the ventral pallidum seems to reduce the animal's ability to enjoy food, turning the aftertaste on the palate into a repulsive one.

On the other hand, it is more difficult to reach an intense euphoria than to reach everyday pleasures. The reason for this may be that a strong increase in pleasure, such as the increase in pleasure we have produced in laboratory animals using chemicals, probably requires the whole network to be activated at once. A defect in a single component impairs the increase in pleasure.

It is not known if the pleasure circuit, and especially the ventral pallidum, works in a similar way in humans. Few people come to the clinic with damage to these structures only, without damage to the surrounding areas. It is therefore difficult to assess whether the ventral pallidum and other components of the circuit are necessary for the sensation of pleasure in humans. We know of one patient whose ventral pallidum was damaged by a drug overdose. Afterwards, he reported feeling depressed, helpless, guilty, and unable to feel pleasure. This case supports that this structure has a central role that has not been appreciated until now.

 

Enough and enough

The pleasure circuit does not act alone in regulating feelings of pleasure. Additional areas are added to add the warmth of pleasure to the feeling or experience. Higher functioning areas of the brain help determine how enjoyable the experience is based on the conditions. For example, if someone is hungry or full or just having some pleasure. For example, after someone has eaten an entire pan of brownies, even someone who admits to being a chocolate addict tends to see candy as much less appealing.

In the case of food, such a sense of selective satiety probably evolved in part because it encourages animals to obtain a wide variety of nutrients as opposed to fixating on one preferred meal. It is probably encoded in the part of the brain called the orbitofrontal cortex. This area, located in the lower part of the prefrontal cortex that is found in humans just above the eyes, receives information from the nucleus accumbens and the ventral pallidum. It probably regulates the form in which pleasure is consciously represented, by intensifying the feeling of satisfaction, which we associate with contentment, and refining our sensations when we are full to the neck.

With the help of sophisticated brain imaging methods, we discovered that there is a high correspondence between the activity of a small area within the orbitofrontal cortex, called the midanterior cortex, and the subjective pleasure of a pleasant sensation, such as the taste of chocolate. At the first sip, for example, the site lights up due to activity. But as soon as the subjects consumed enough of the sweet substance, the midenteric site went off and the experience ceased to be pleasurable.

Further evidence that the midenteric site is important for pleasure in humans comes from deep brain stimulation studies performed for therapeutic purposes. This procedure is designed to treat several conditions, including alleviating the suffering of patients with chronic pain that cannot be treated in any other way. In one of our patients, an amputee who felt pain in his missing limb, stimulation of an area within the brain stem not only relieved the pain but also caused feelings of great pleasure. Brain imaging performed at the same time showed a burst of activity in the mediastinal site as well. To this day, the question of whether it is possible to use such stimulation of certain areas related to the pleasure system to treat depression or other forms of inability to experience pleasure is still being investigated.

Similarly, future research may reveal how the circuits that control pleasure and reward are related. Under normal conditions, hedonic areas are associated with the dopamine-driven reward system. We desire things that make us feel good, and avoid or are indifferent to things that do not make us feel good. In the case of addiction, these systems become disconnected in some way, causing the person to continue to crave things that no longer provide pleasure. Such dissociation may also contribute to other types of compulsive behaviors, such as binge eating and gambling. Understanding the manner and causes of this disconnection can reveal better ways to undo the changes in the brain that cause addiction, thus restoring the natural connection between desires and desires.

According to Aristotle, happiness consists of two main components: hedonia (or pleasure) and eudaimonia (a sense of meaning). Although scientists have made some progress in uncovering the biological basis of donia, we know very little about how the brain induces a more comprehensive sense of the good life. However, we hope that this puzzle too can be solved in time, and that the discoveries will help people to unite pleasure with purpose by turning everyday experiences into something truly satisfying, perhaps even sublime.

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About the authors

Morten L. Kringelbach (Kringelbach) is the director of "Hedoniya": the Trigfunden research group at the University of Oxford and the University of Aarhus in Denmark. He is a member of the advisory board of Scientific American.

Kent C. Berridge is the James Olds Professor of Psychology and Neuroscience at the University of Michigan.

in brief

A new study has discovered sensitive areas in the brain that when stimulated increase feelings of pleasure.

These hedonistic areas are different from the "reward circuit" that was previously considered to be the basis of good feelings. Today it is believed that that route arouses passion and not pleasure.

Higher functioning areas of the brain receive information from these pleasure and reward circuits to consciously represent the sense of satisfaction we associate with pleasure.

The disconnection of the brain systems that cause "desires" and "fear" is probably at the root of the compulsive behavior. This clue may lead to new treatments.

Anatomy of happiness

Paths to pleasure

Pleasure is a complex experience that has everything, from anticipation and desire to excitement to satisfaction. So, it's no wonder that several brain areas work together to create the sense of satisfaction of feeling good.

passions and pleasures

The neural circuit (blue) that originates near the brain stem and reaches the forebrain, was previously considered the only mediator of pleasure. In fact it focuses more on craving. In addition to this pathway, there are several other brain areas associated with hedonism, including two shown in the diagram (red), which work together to cause a feeling of pleasure.

After that, a patchwork of cortical areas (pink) translates information received from the "passions" and "pleasure" circuits into conscious pleasure, and adjusts this sensation based on inputs from other brain areas.

The chemistry of pleasure

Within a hedonic area, a pair of intoxicating neurotransmitters work cooperatively to increase feelings of pleasure. A pleasant stimulus, such as something sweet, causes a nerve cell in the area (upper part) to release enkephalin, a calming drug produced in the brain. Enkephalin binds to receptor proteins in a neighboring neuron (lower part). This triggers the production of onandamide, the brain's version of marijuana. As anandamide diffuses away from its site of production, it can bind to receptors on the first neuron, thereby increasing the sensation of pleasure and possibly stimulating the production of more enkephalin. Together, these ingredients create a cycle that increases pleasure.

And more on the subject

A Common Neurobiology for Pain and Pleasure. Siri Leknes and Irene Tracey in Nature Reviews Neuroscience, Vol. 9, pages 314-320; April 2008.

The Pleasure Center: Trust Your Animal Instincts. Morten L. Kringelbach. Oxford University Press, 2008.

Pleasures of the Brain. Edited by Morten L. Kringelbach and Kent C. Berridge. Oxford University Press, 2010.

Building a Neuroscience of Pleasure and Well-Being. Kent C. Berridge and Morten L. Kringelbach in Psychology of Well-Being: Theory, Research, and Practice, Vol. 1, no. 3; October 2011. www.psywb.com/content/1/ 1 / 3

 

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