High Sugar Intake Linked to Low Dopamine Release in Insulin Resistant Patients

PET study led by Stony Brook Professor indicates that overeating and weight gain contributing to onset of diabetes could be related to a deficit in reward circuits in the brain

Using positron emission tomography (PET) imaging of the brain, researchers have identified a sweet spot that operates in a disorderly way when simple sugars are introduced to people with insulin resistance, a precursor to type 2 diabetes. For those who have the metabolic syndrome, a sugar drink resulted in a lower-than-normal release of the chemical dopamine in a major pleasure center of the brain. This chemical response may be indicative of a deficient reward system, which could potentially be setting the stage for insulin resistance. This research could revolutionize the medical community’s understanding of how food-reward signaling contributes to obesity, according to a study presented at the Society of Nuclear Medicine and Molecular Imaging’s 2013 Annual Meeting.

"Insulin resistance is a significant contributor to obesity and diabetes," said Gene-Jack Wang, MD, lead author of the study and Professor of Radiology at Stony Brook University and researcher at the U.S. Department of Energy’s Brookhaven National Laboratory in Upton, N.Y. "A better understanding of the cerebral mechanisms underlying abnormal eating behaviors with insulin resistance would help in the development of interventions to counteract the deterioration caused by overeating and subsequent obesity. We suggest that insulin resistance and its association with less dopamine release in a central brain reward region might promote overeating to compensate for this deficit."

An estimated one-third of Americans are obese, according to the U.S. Centers for Disease Control and Prevention. The American Diabetes Association estimates that about 26 million Americans are living with diabetes and another 79 million are thought to be prediabetic, including those with insulin resistance.

The tendency to overeat may be caused by a complex biochemical relationship, as evidenced by preliminary research with rodents. Dr. Wang’s research marks the first clinical study of its kind with human subjects.

"Animal studies indicated that increased insulin resistance precedes the lack of control associated with pathological overeating," said Wang. "They also showed that sugar ingestion releases dopamine in brain regions associated with reward. However, the central mechanism that contributes to insulin resistance, pathological eating and weight gain is unknown."

He continued, “In this study we were able to confirm an abnormal dopamine response to glucose ingestion in the nucleus accumbens, where much of the brain’s reward circuitry is located. This may be the link we have been looking for between insulin resistance and obesity. To test this, we gave a glucose drink to an insulin-sensitive control group and an insulin-resistant group of individuals and we compared the release of dopamine in the brain reward center using PET.”

In this study, a total of 19 participants-including 11 healthy controls and eight insulin-resistant subjects-consumed a glucose drink and, on a separate day, an artificially sweetened drink containing sucralose. After each drink, PET imaging with C-11 raclopride-which binds to dopamine receptors-was performed. Researchers mapped lit-up areas of the brain and then gauged striatal dopamine receptor availability (which is inversely related to the amount of natural dopamine present in the brain). These results were matched with an evaluation in which patients were asked to document their eating behavior to assess any abnormal patterns in their day-to-day lives. Results showed agreement in receptor availability between insulin-resistant and healthy controls after ingestion of sucralose. However, after patients drank the sugary glucose, those who were insulin-resistant and had signs of disorderly eating were found to have remarkably lower natural dopamine release in response to glucose ingestion when compared with the insulin-sensitive control subjects.

"This study could help develop interventions, i.e., medication and lifestyle modification, for early-stage insulin-resistant subjects to counteract the deterioration that leads to obesity and/or diabetes," said Wang. "The findings set a path for future clinical studies using molecular imaging methods to assess the link of peripheral hormones with brain neurotransmitter systems and their association with eating behaviors."

Why Music Makes Our Brain Sing

MUSIC is not tangible. You can’t eat it, drink it or mate with it. It doesn’t protect against the rain, wind or cold. It doesn’t vanquish predators or mend broken bones. And yet humans have always prized music — or well beyond prized, loved it.

In the modern age we spend great sums of money to attend concerts, download music files, play instruments and listen to our favorite artists whether we’re in a subway or salon. But even in Paleolithic times, people invested significant time and effort to create music, as the discovery of flutes carved from animal bones would suggest.

So why does this thingless “thing” — at its core, a mere sequence of sounds — hold such potentially enormous intrinsic value?

The quick and easy explanation is that music brings a unique pleasure to humans. Of course, that still leaves the question of why. But for that, neuroscience is starting to provide some answers.

More than a decade ago, our research team used brain imaging to show that music that people described as highly emotional engaged the reward system deep in their brains — activating subcortical nuclei known to be important in reward, motivation and emotion. Subsequently we found that listening to what might be called “peak emotional moments” in music — that moment when you feel a “chill” of pleasure to a musical passage — causes the release of the neurotransmitter dopamine, an essential signaling molecule in the brain.

When pleasurable music is heard, dopamine is released in the striatum — an ancient part of the brain found in other vertebrates as well — which is known to respond to naturally rewarding stimuli like food and sex and which is artificially targeted by drugs like cocaine and amphetamine.

But what may be most interesting here is when this neurotransmitter is released: not only when the music rises to a peak emotional moment, but also several seconds before, during what we might call the anticipation phase.

The idea that reward is partly related to anticipation (or the prediction of a desired outcome) has a long history in neuroscience. Making good predictions about the outcome of one’s actions would seem to be essential in the context of survival, after all. And dopamine neurons, both in humans and other animals, play a role in recording which of our predictions turn out to be correct.

To dig deeper into how music engages the brain’s reward system, we designed a study to mimic online music purchasing. Our goal was to determine what goes on in the brain when someone hears a new piece of music and decides he likes it enough to buy it.

We used music-recommendation programs to customize the selections to our listeners’ preferences, which turned out to be indie and electronic music, matching Montreal’s hip music scene. And we found that neural activity within the striatum — the reward-related structure — was directly proportional to the amount of money people were willing to spend.

But more interesting still was the cross talk between this structure and the auditory cortex, which also increased for songs that were ultimately purchased compared with those that were not.

Why the auditory cortex? Some 50 years ago, Wilder Penfield, the famed neurosurgeon and the founder of the Montreal Neurological Institute, reported that when neurosurgical patients received electrical stimulation to the auditory cortex while they were awake, they would sometimes report hearing music. Dr. Penfield’s observations, along with those of many others, suggest that musical information is likely to be represented in these brain regions.

The auditory cortex is also active when we imagine a tune: think of the first four notes of Beethoven’s Fifth Symphony — your cortex is abuzz! This ability allows us not only to experience music even when it’s physically absent, but also to invent new compositions and to reimagine how a piece might sound with a different tempo or instrumentation.

We also know that these areas of the brain encode the abstract relationships between sounds — for instance, the particular sound pattern that makes a major chord major, regardless of the key or instrument. Other studies show distinctive neural responses from similar regions when there is an unexpected break in a repetitive pattern of sounds, or in a chord progression. This is akin to what happens if you hear someone play a wrong note — easily noticeable even in an unfamiliar piece of music.

These cortical circuits allow us to make predictions about coming events on the basis of past events. They are thought to accumulate musical information over our lifetime, creating templates of the statistical regularities that are present in the music of our culture and enabling us to understand the music we hear in relation to our stored mental representations of the music we’ve heard.

So each act of listening to music may be thought of as both recapitulating the past and predicting the future. When we listen to music, these brain networks actively create expectations based on our stored knowledge.

Composers and performers intuitively understand this: they manipulate these prediction mechanisms to give us what we want — or to surprise us, perhaps even with something better.

In the cross talk between our cortical systems, which analyze patterns and yield expectations, and our ancient reward and motivational systems, may lie the answer to the question: does a particular piece of music move us?

When that answer is yes, there is little — in those moments of listening, at least — that we value more.

Suzanne Dickson: Brain mechanisms of food reward

Studying what makes us want to eat, could help devise approaches to prevent obesity, which is becoming widespread in Europe.

Suzanne Dickson is a Professor of physiology and neuroendocrinology at the Institute of Neuroscience and Physiology, based at the Sahlgrenska Academy at the University of Gothenburg, Sweden. She tells youris.com about her involvement in the EU funded NeuroFAST project. Her focus is on the impact of appetite-regulating gut hormones on parts of the brain that influence food preference and food reward.

This research is also driven by the huge unmet need of treating the growing group of obese patients.

What is the focus of your work relating to food and the brain?
We work on food reward, which involves neurobiological circuits linked to the addiction process. We decided to work on this because increasing evidence linked excessive over-eating to brain pathways involved in reward, including pathways known to be targets for addictive drugs.  Over-eating can be influenced by genetic predisposition traits, psychiatric diseases, cues from the environment that trigger expectation of a food reward. Other factors include socio-economic pressures, stressful lifestyle including stress in the workplace or home.

What is the nature of food reward?
Our specific focus is on the property of the reward value. If animals find food rewarding, they will display altered behaviours that indicate that the reward value of the food is changed. Members of our team are working with sugars, fats and combinations of the above. We have also been working in clinical projects with foods of similar taste but with altered caloric value. By targeting brain mechanisms involved in food reward, we hope to reveal new mechanisms that will help develop new treatment strategies for obesity.

We have studied an area of the brain called ventral tegmental area (VTA) is a key node in the brain’s reward pathway. It is the home of the dopamine cells that are activated by rewards, including food rewards. Its role is very complex. Many believe that these cells are involved in food searching behaviours or food motivation, for example. However, they also can be activated simply by cues associated with foods akin to deciding to consume a chocolate bar by the sight of one at the cashier in a supermarket and novelty of the reward stimulus appears to play a role.

Did you identify the difference between the brain’s pleasure center and hunger center?
The pleasure centres are involved in food intake that is linked to its reward value. Whether we are hungry or fed, by raising the reward value of food the reward system encourages us to eat more, especially rewarding food. This system has been critical during the evolution process to ensure survival from famine. In our modern environment that generates obesity, food reward is no longer our friend as it encourages us to over-indulge in sweet and fatty food, even when we are not hungry.

By contrast, the hunger pathways can be considered more primitive. They detect and respond to nutrient deficit. If we enter negative energy balance, homeostatic pathways become activated informing higher feeding networks to initiate feeding behaviours.

What strategies have studied to try and find ways to limit over-eating?
We have recently learned from the field of bariatric—weight loss—surgery that it is possible to change reward behaviour towards food. This involves unknown mechanisms that are likely linked to the brain’s food reward system. We focus particularly on a hormone called ghrelin whose secretion is altered after bariatric surgery. We hope to reveal new information that is of clinical and therapeutic relevance for future drug strategies for this disease area.

So far, in the laboratory, we have learned a lot about the basic brain mechanisms controlling food reward and the role played by gut hormones in regulating these. We therefore know a lot more about mechanisms—namely about the brain systems and circuits underpinning over-eating—especially for calorie dense foods.

(Image credit: Zorrilla Laboratory, The Scripps Research Institute)

Turning repulsive feelings into desires

Hunger, thirst, stress and drugs can create a change in the brain that transforms a repulsive feeling into a strong positive “wanting,” a new University of Michigan study indicates.

The research used salt appetite to show how powerful natural mechanisms of brain desires can instantly transform a cue that always predicted a repulsive Dead Sea Salt solution into an eagerly wanted beacon or motivational magnet.

Mike Robinson, a research fellow in the U-M Department of Psychology and the study’s lead author, said the findings help explain how related brain activations in people could cause them to avidly want something that has been always disliked.

This instant transformation of motivation, he said, lies in the ability of events to activate particular brain circuitry—a structure called the nucleus accumbens, which sits near the base of the front of the brain and is also activated by addictive drugs.

Cues for rewards often trigger intense motivation. The smell of food can make a person suddenly feel hungry when this wasn’t the case earlier. Drug cues may prompt relapse in addicts trying to quit. In some cases, desires may be triggered even for a relatively unpleasant event.

Researchers studied how rats responded to metal objects that represented either pleasant sugar or disgustingly intense Dead Sea saltiness. The rats quickly learned to jump on and nibble the sweetness cue, but turned away from and avoided the saltiness cue.

But one day the rats suddenly woke up in a new state of sodium appetite induced by drugs given the night before. On their first re-encounter with the saltiness cue in the new appetite state, their brain systems became activated and the rats instantly jumped on and nibbled the saltiness cue as though it were the sugar cue.

"The cue becomes avidly ‘wanted’ despite knowledge the salt always tasted disgusting," Robinson said.

The sudden brain changes help explain how an event, such as taking an addictive drug, could become “wanted” despite a person’s knowledge of the negative and unpleasant consequences of the drug.

"Our findings highlight what it means to say that drugs hijack our natural reward system," said Robinson, who authored the new study with Kent Berridge, James Olds Collegiate Professor of Psychology and Neuroscience.

Parkinson’s Treatment Can Trigger Creativity

Parkinson’s experts across the world have been reporting a remarkable phenomenon — many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.

Prof. Rivka Inzelberg of Tel Aviv University’s Sackler Faculty of Medicinefirst noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients — typically chocolates or similar gifts — took a surprising turn. “Instead, patients starting bringing us art they had made themselves,” she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor — all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report published in the journal Behavioral Neuroscience.

Giving in to artistic impulse

Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson’s patients is associated with tremors and a difficulty in coordinating their movements.

But it’s also involved in the brain’s “reward system” — the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It’s possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It’s possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.

Therapeutic value

Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.

The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. “We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative,” says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.

Birdsong study pecks at theory that music is uniquely human

A bird listening to birdsong may experience some of the same emotions as a human listening to music, suggests a new study on white-throated sparrows, published in Frontiers of Evolutionary Neuroscience.

“We found that the same neural reward system is activated in female birds in the breeding state that are listening to male birdsong, and in people listening to music that they like,” says Sarah Earp, who led the research as an undergraduate at Emory University.

For male birds listening to another male’s song, it was a different story: They had an amygdala response that looks similar to that of people when they hear discordant, unpleasant music.

The study, co-authored by Emory neuroscientist Donna Maney, is the first to compare neural responses of listeners in the long-standing debate over whether birdsong is music.

“Scientists since the time of Darwin have wondered whether birdsong and music may serve similar purposes, or have the same evolutionary precursors,” Earp notes. “But most attempts to compare the two have focused on the qualities of the sound themselves, such as melody and rhythm.”

Earp reviewed studies that mapped human neural responses to music through brain imaging.

She also analyzed data from the Maney lab on white-throated sparrows. The lab maps brain responses in the birds by measuring Egr-1, part of a major biochemical pathway activated in cells that are responding to a stimulus.

The study used Egr-1 as a marker to map and quantify neural responses in the mesolimbic reward system in male and female white-throated sparrows listening to a male bird’s song. Some of the listening birds had been treated with hormones, to push them into the breeding state, while the control group had low levels of estradiol and testosterone.

During the non-breeding season, both sexes of sparrows use song to establish and maintain dominance in relationships. During the breeding season, however, a male singing to a female is almost certainly courting her, while a male singing to another male is challenging an interloper.

For the females in the breeding state every region of the mesolimbic reward pathway that has been reported to respond to music in humans, and that has a clear avian counterpart, responded to the male birdsong. Females in the non-breeding state, however, did not show a heightened response.

And the testosterone-treated males listening to another male sing showed an amygdala response, which may correlate to the amygdala response typical of humans listening to the kind of music used in the scary scenes of horror movies.

“The neural response to birdsong appears to depend on social context, which can be the case with humans as well,” Earp says. “Both birdsong and music elicit responses not only in brain regions associated directly with reward, but also in interconnected regions that are thought to regulate emotion. That suggests that they both may activate evolutionarily ancient mechanisms that are necessary for reproduction and survival.”

A major limitation of the study, Earp adds, is that many of the regions that respond to music in humans are cortical, and they do not have clear counterparts in birds. “Perhaps techniques will someday be developed to image neural responses in baleen whales, whose songs are both musical and learned, and whose brain anatomy is more easily compared with humans,” she says.

Decision to give a group effort in the brain

A monkey would probably never agree that it is better to give than to receive, but they do apparently get some reward from giving to another monkey.

During a task in which rhesus macaques had control over whether they or another monkey would receive a squirt of fruit juice, three distinct areas of the brain were found to be involved in weighing benefits to oneself against benefits to the other, according to new research by Duke University researchers.

The team used sensitive electrodes to detect the activity of individual neurons as the animals weighed different scenarios, such as whether to reward themselves, the other monkey or nobody at all. Three areas of the brain were seen to weigh the problem differently depending on the social context of the reward. The research appears Dec. 24 in the journal Nature Neuroscience.

Using a computer screen to allocate juice rewards, the monkeys preferred to reward themselves first and foremost. But they also chose to reward the other monkey when it was either that or nothing for either of them. They also were more likely to give the reward to a monkey they knew over one they didn’t, preferred to give to lower status than higher status monkeys, and had almost no interest in giving the juice to an inanimate object.

Calculating the social aspects of the reward system seems to be a combination of action by two centers involved in calculating all sorts of rewards and a third center that adds the social dimension, according to lead researcher Michael Platt, director of the Duke Institute for Brain Sciences and the Center for Cognitive Neuroscience.

The orbital frontal cortex, right above the eyes, was activated when calculating rewards to the self. The anterior cingulate sulcus in the middle of the top of the brain seemed to calculate giving up a reward. But both centers appear “divorced from social context,” Platt said. A third area, the anterior cingulate gyrus (ACCg), seemed to “care a lot about what happened to the other monkey,” Platt said.

Based on results of various combinations of the reward-giving scenario the monkeys were put through, it would appear that neurons in the ACCg encode both the giving and receiving of rewards, and do so in a remarkably similar way.

The use of single-neuron electrodes to measure the activity of brain areas gives a much more precise picture than brain imaging, Platt said. Even the best imaging available now is “a six-second snapshot of tens of thousands of neurons,” which are typically operating in milliseconds.

What the team has seen happening is consistent with other studies of damaged ACCg regions in which animals lost their typical hesitation about retrieving food when facing social choices. This same region of the brain is active in people when they empathize with someone else.

"Many neurons in the anterior cingulate gyrus (ACCg) respond both when monkeys choose a drink for themselves and when they choose to give a drink to another monkey," Platt said. "One might view these as sort of mirror neurons for the reward system." The region is active as an animal merely watches another animal receiving a reward without having one themselves.

The research is another piece of the puzzle as neuroscientists search for the roots of charity and social behavior in our species and others. There have been two schools of thought about how the social reward system is set up, Platt said. One holds that there is generic circuitry for rewards that has been adapted to our social behavior because it helped humans and other social animals like monkeys thrive. Another school holds that social behavior is so important to humans and other highly social animals like monkeys that there may be some special circuits for it, Platt said.

This finding, in macaques that have only a very distant common ancestor with us and are “not a particularly prosocial animal,” suggests that “this specialized social circuitry evolved a long time ago presumably to support cooperative behavior,” Platt said.

(Photo: EPA)

Alcohol Drinking Behavior Reduced By Inhibiting Brain Protein in Rodents

Decreasing the level of a key brain protein led to significantly less drinking and alcohol-seeking behavior in rats and mice that had been trained to drink, according to a study by researchers at the Ernest Gallo Clinic and Research Center at UCSF.

The scientists identified the protein, known as H-Ras, as a promising target for development of new medications to treat alcohol abuse disorders in humans.

The study, which was published on Nov. 7 in the Journal of Neuroscience, was recommended as being of special significance in its field by the Faculty of 1000, an online service that identifies great peer-reviewed biomedical research.

The researchers, led by Gallo investigator Dorit Ron, PhD, first demonstrated that alcohol intake significantly increased H-Ras activity in the animals’ nucleus accumbens, a brain region that in both rodents and humans is part of the reward system that affects craving for alcohol and other addictive substances.

They then showed that suppressing H-Ras levels in the nucleus accumbens with a targeted virus reduced alcohol consumption among mice that had been trained to seek out and drink alcohol in an animal model of binge drinking.

The researchers then administered FTI-276, an experimental compound that has been shown to inhibit H-Ras production, to binge-drinking rats. They observed a significant reduction in alcohol consumption after the compound was given.

The scientists also found that H-Ras inhibition reduced alcohol-seeking behavior among rats that had been trained to receive a drink of alcohol when they pressed a lever. When alcohol was withheld, rats that had received FTI-276 discontinued pressing the lever significantly sooner than rats that did not receive the compound.

Importantly, the rodents’ consumption of water, sugar solution, saccharine solution and quinine was not reduced when H-Ras was inhibited, indicating that H-Ras activity is specific to alcohol.