Study Shows Working Memory Is Driven By Prefrontal Cortex And Dopamine

One of the unique features of the human mind is its ability re-prioritize its goals and priorities as situations change and new information arises. This happens when you cancel a planned cruise because you need the money to repair your broke-down car, or when you interrupt your morning jog because your cell phone is ringing in your pocket.

In a new study published in the Proceedings of the National Academy of Sciences (PNAS), researchers from Princeton University say that they have discovered the mechanisms that control how our brains use new information to modify our existing priorities.

The team of researchers at Princeton’s Neuroscience Institute (PNI) used functional magnetic resonance imaging (fMRI) to scan subjects and find out where and how the human brain reprioritizes goals. Unsurprisingly, they found that the shifting of goals takes place in the prefrontal cortex, a region of the brain which is known to be associated with a variety of higher-level behaviors. They also observed that the powerful neurotransmitter dopamine – also known as the “pleasure chemical” – appears to play a critical role in this process.

Using a harmless magnetic pulse, the scientists interrupted activity in the prefrontal cortex of the participants while they were playing games and found they were unable to switch to a different task in the game.

“We have found a fundamental mechanism that contributes to the brain’s ability to concentrate on one task and then flexibly switch to another task,” explained Jonathan Cohen, co-director of PNI and the university’s Robert Bendheim and Lynn Bendheim Thoman Professor in Neuroscience.

“Impairments in this system are central to many critical disorders of cognitive function such as those observed in schizophrenia and obsessive-compulsive disorder.”

Previous research had already demonstrated that when the brain uses new information to modify its goals or behaviors, this information is temporarily filed away into the brain’s working memory, a type of short-term memory storage. Until now, however, scientists have not understood the mechanisms controlling how this information is updated.

Placebo and the Brain: How Does it Work?

Placebo, the positive effect of a drug that lacks any beneficial ingredients, has been researched for centuries but remain a mystery for psychologists and neuroscientists alike. Although there is now a considerable amount of amassed knowledge of how placebo can be induced, through which mechanisms it works, and which individuals are susceptible to the effect, the explicit answer to why and how our brains have the ability to ‘cure’ themselves under certain circumstances is yet to be found. Having dived into the literature on the phenomenon, a picture has emerged in which one of the brain’s greatest tricks can be better understood and the fascinating implications it has for how we look at the body-mind distinction.

What is termed a placebo is usually defined in research trying to pin down its nature as the treatment that results in a change in symptom or condition that differs from the natural course of the specific disease. Placebo effects have been shown for mainly relief of pain, but also in studies of depression, parkinson’s, and anxiety. While the sugar pill is still in use, we now know that there are a two factors that are crucial for a placebo effect to occur. These are the level of expectancy and desire to get better/not get worse that the patient feels and both are in turn sensitive to a host of psychosocial variables such as their faith in medical staff, the emotional tone of the physician-patient interaction (whether it is optimistic or pessimistic for example), memories of past experiences with the effects of medicine, and so on.

While some individuals show reliable placebo effects, others do not and the underlying causes have recently been suggested to be tied to our individual genetic makeup. Researchers from the Harvard Program for Placebo Studies found that the magnitude of the placebo effect was tied to genes coding for an anzyme that regulates the levels of dopamine in various regions of the brain. Dopamine plays a key role in processing of reward, pain, memory, and learning, all areas in which the placebo effect has been demonstrated. The study, led by Kathryn Hall, concluded that persons whose genes promote an upregulation of the levels of dopamine in the brain also exhibit the greatest placebo effects. In other studies examining release of another group of transmitters called opioids, which regulate the activity in areas that code for pain, higher amounts of opioids were matched to the size of the placebo effect found.

As for where the effect originates, research using brain imaging have found that when a real drug is compared to the effects of a placebo very similar areas show activation but some areas, such as the lateral and central prefrontal cortex, show a greater response in the placebo condition. This part of the brain is often described as overseeing and exerting control over other processing in the brain and act as a connecting point for different streams of information that build up our expectations and desires.

So, how can this knowledge about the placebo effect influence the way doctors discuss, promote, and administer their own treatments? Surely, if we know that an encouraging prognosis given together with a sugar pill can be as effective in some cases as a pharmacological product but without the side- effects, we should be using that. However, having doctors treat their patients through deception leads to obvious problems such as public mistrust in the profession. A finding from the scientists at the very same Harvard program for placebo studies might have the answer. They namely demonstrated that the placebo effect remained when participants were told explicitly that the treatment they were given was in effect useless.

Stress-Resilience/Susceptibility Traced to Neurons in Reward Circuit

A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking – they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient.

“For the first time, we have shown that split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light,” explained Ming-Hu Han, Ph.D., of the Mount Sinai School of Medicine, New York City, a grantee of NIH’s National Institute of Mental Health (NIMH). “These results add to mounting clues about the mechanism of fast-acting antidepressant responses.” Han, Eric Nestler, M.D., Ph.D., of Mount Sinai, and colleagues, report on their study online, Dec. 12, 2012, in the journal Nature.

In a companion article, NIMH grantees Kay Tye, Ph.D., of the Massachusetts Institute of Technology, Cambridge, Mass., and Karl Deisseroth, M.D., Ph.D., of Stanford University, Stanford, Calif., used the same cutting-edge technique to control mouse brain activity in real time. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by daily presentations of chronic, unpredictable mild physical stressors, instead of by shorter-term exposure to severe social stress.

Prior to the new studies, Han’s team suspected that a telltale pattern – rapid firing of neurons that secrete the chemical messenger dopamine in a key circuit hub – makes an animal vulnerable to the depression-like effects of acute severe stress, and that slower firing supports resilience. But they lacked direct, real-time evidence.

To pinpoint cause-and-effect, they turned to a research technology pioneered by Deisseroth, called optogenetics. It melds fiber optics and genetic engineering to precisely control the activity of a specific brain circuit in a living, behaving animal. Genetically modified viruses are used to inject light-reactive proteins, borrowed from primitive organisms like algae, to make the circuitry similarly light-responsive.

Researchers both induce, relieve depression symptoms in mice by stimulating single brain region with light

Researchers at Stanford University have successfully induced and relieved depression-like deficiencies in both pleasure and motivation in mice by controlling just a single area of the brain known as the ventral tegmental area. It is the first time that well-defined types of neurons within a specific brain region have been directly tied to the control of myriad symptoms of major depressive illness.

In the paper published in Nature on Dec. 12, Stanford bioengineer Karl Deisseroth, MD, PhD, and a team including postdoctoral scholars Kay Tye, PhD, and Melissa Warden, PhD, and research assistant Julie Mirzabekov have used a technique known as optogenetics to pinpoint a specific brain location that produces multiple depression-like symptoms. The region in question is the ventral tegmental area, or VTA, a source of dopamine and a central player in the brain’s internal motivation and reward systems.

“We have for the first time directly tied dopamine neurons in the VTA to controlling and relieving these very different and diverse symptoms,” said Deisseroth, the study’s senior author and a professor of bioengineering and of psychiatry and behavioral sciences. “While depression is a complex disease with still many unknowns, this knowledge may help launch new kinds of investigation into the pathways of depression in the brain, and develop concepts to help people suffering from depression.”

Deisseroth’s team was able to both induce and relieve multiple depression-like symptoms in laboratory mice by genetically modifying the dopamine neurons in the VTA to be sensitive to light. Using fiber optic cables inserted in rodents’ brains, they could then instantaneously produce and inhibit the depression-like symptoms by turning the light on and off. This research technique, developed by Deisseroth at Stanford in 2005, is known as optogenetics.

Dopamine Not About Pleasure (Anymore)

To John Salamone, professor of psychology and longtime researcher of the brain chemical dopamine, scientific research can be very slow-moving.

“It takes a long time for things to change in science,” he says. “It’s like pulling on the steering wheel of an ocean liner, then waiting for the huge ship to slowly turn.”

Salamone has spent most of his career battling a particular long-held scientific idea: the popular notion that high levels of brain dopamine are related to experiences of pleasure. As increasing numbers of studies show, he says, the famous neurotransmitter is not responsible for pleasure, but has to do with motivation.

He summarizes and comments on the evidence for this shift in thinking in a Nov. 8 review in the Cell Press journal Neuron.

Promising Drug Slows Down Advance of Parkinson’s Disease and Improves Symptoms

Treating Parkinson’s disease patients with the experimental drug GM1 ganglioside improved symptoms and slowed their progression during a two and a half-year trial, Thomas Jefferson University researchers report in a new study published online November 28 in the Journal of the Neurological Sciences.

Although the precise mechanisms of action of this drug are still unclear, the drug may protect patients’ dopamine-producing neurons from dying and at least partially restore their function, thereby increasing levels of dopamine, the key neurochemical missing in the brain of Parkinson’s patients.

The research team, led by senior author Jay S. Schneider, Ph.D., Director of the Parkinson’s Disease Research Unit and Professor in the Department of Pathology, Anatomy and Cell Biology and the Department of Neurology at Jefferson, found that administration of GM1 ganglioside, a substance naturally enriched in the brain that may be diminished in Parkinson’s disease brains, acted as a “neuroprotective” and a “neurorestorative” agent to improve symptoms and over an extended period of time slow the progression of symptoms.

What’s more, once the study participants went off the drug, their disease worsened. The study enrolled 77 subjects and followed them over a 120-week period and also followed 17 subjects who received current standard of care treatment for comparison.

“The drugs currently available for Parkinson’s disease are designed to treat symptoms and to improve function, but at this time there is no drug that has been shown unequivocally to slow disease progression,” said Dr. Schneider. “Our data suggest that GM1 ganglioside has the potential to have symptomatic and disease-modifying effects on Parkinson’s disease. If this is substantiated in a larger clinical study, GM1 could provide significant benefit for Parkinson’s disease patients.”

Study suggests L-DOPA therapy for Angelman syndrome may have both benefits and unanticipated effects

Last year a clinical trial of L-DOPA — a mainstay of Parkinson’s disease therapy — was launched for Angelman syndrome, a rare intellectual disorder that shares similar motor symptoms such as tremors and difficulty with balance. The clinical trial is based on a 10-year-old case report showing benefit with the drug, but few studies since have explored the neurological justification for using L-DOPA to treat parkinsonian features in Angelman syndrome.

New research from the University of North Carolina School of Medicine, conducted in animal models of the disorder, now provides justification for this therapeutic approach. The study, published online ahead of print on Nov. 12 by the Journal of Clinical Investigation, suggests that L-DOPA could compensate for a loss of the neurochemical dopamine in the brain’s motor pathways and improve motor symptoms. However, it also indicates that the drug could add to an already increased amount of dopamine in the brain’s reward pathways and thus have unanticipated consequences on emotion and attention.

“The results were extremely surprising, because we don’t know of any other disorder where dopamine is affected one way in one brain pathway and the opposite way in another,” said Benjamin D. Philpot, PhD, associate professor of cell biology and physiology at UNC.

“If what we see in humans mirrors what we see in mice, then it does provide some optimism that L-DOPA might provide benefit for tremor,” said C.J. Malanga, MD, PhD, associate professor of neurology at UNC. “But it also raises caution that researchers might want to consider assessing other aspects of Angelman syndrome that might be affected by dopamine — not just motor symptoms but also other neuropsychiatric features.”  Malanga and Philpot are senior authors of the study.

ADHD medicine affects the brain’s reward system

A group of scientists from the University of Copenhagen has created a model that shows how some types of ADHD medicine influence the brain’s reward system. The model makes it possible to understand the effect of the medicine and perhaps in the longer term to improve the development of medicine and dose determination. The new research results have been published in the Journal of Neurophysiology.

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