Posts Tagged Frontal Cortex

How Drugs for Schizophrenia Sow Seeds of Resistance


How Drugs for Schizophrenia Sow Seeds of ResistanceA new study has identified why certain drugs have mixed success in treating schizophrenia; effective at first, but with chronic administration becoming less and less so.

In the study, reported online in the journal Nature Neuroscience, scientists investigated the external genetic reasons (called epigenetic factors) that cause treatment-resistance to atypical antipsychotic drugs.

Use of antipsychotic drugs is the standard of care for schizophrenia. Researchers at Mount Sinai School of Medicine report that 30 percent of individuals with schizophrenia do not respond to currently available treatments.

Researchers discovered that, over time, an enzyme in the brains of schizophrenic patients, analyzed at autopsy, begins to compensate for the prolonged chemical changes caused by antipsychotics, resulting in reduced efficacy of the drugs.

“These results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically,” said Javier Gonzalez-Maeso, Ph.D., lead investigator on the study.

Researchers found that an enzyme called HDAC2 was highly expressed in the brain of mice chronically treated with antipsychotic drugs, resulting in lower expression of the receptor called mGlu2 and a recurrence of psychotic symptoms. A similar finding was observed in the postmortem brains of schizophrenic patients.

In response, the research team administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. This treatment prevented the detrimental effect of the antipsychotic called clozapine on mGlu2 expression, and also improved the therapeutic effects of atypical antipsychotics in mouse models.

Previous research conducted by the team showed that chronic treatment with the antipsychotic clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception.

The researchers hypothesized that this effect of clozapine on mGlu2 may play a crucial role in restraining the therapeutic effects of antipsychotic drugs.

“We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs,”said Gonzalez-Maeso. “We wanted to identify the molecular mechanism responsible for this biochemical change, and explore it as a new target for new drugs that enhance the therapeutic efficacy of antipsychotic drugs.”

Mitsumasa Kurita, Ph.D., a postdoctoral fellow at Mount Sinai and the lead author of the study, said, “We found that atypical antipsychotic drugs trigger an increase of HDAC2 in the frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs.”

As a result of these findings, Gonzalez-Maeso’s team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics.

Source:The Mount Sinai Hospital/Mount Sinai School of Medicine

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Why We Can’t Live in the Moment


Why We Can't Live in the MomentThe sought-after ideal of “living in the moment” may be impossible, according to research conducted at the University of Pittsburgh, which pinpoints an area of the brain responsible for using past decisions and outcomes to guide future behavior.

The study analyzes signals associated with metacognition, which is a person’s ability to monitor and control cognition — a term described by the researchers as “thinking about thinking.”

“The brain has to keep track of decisions and the outcomes they produce,” said Marc Sommer, Ph.D., who did his research for the study as a University of Pittsburgh neuroscience faculty member and is now on the faculty at Duke University. “You need that continuity of thought. We are constantly keeping decisions in mind as we move through life, thinking about other things.”

Sommer said the researchers “guessed it was analogous to working memory,” which led them to predict that neuronal correlates of metacognition resided in the same brain areas responsible for cognition, including the frontal cortex, a part of the brain linked with personality expression, decision making, and social behavior.

The research team studied single neurons in three frontal cortical regions of the brain: The frontal eye field, associated with visual attention and eye movements; the dorsolateral prefrontal cortex, which is responsible for motor planning, organization, and regulation; and the supplementary eye field (SEF), which is involved in the planning and control of saccadic eye movements, which are the extremely fast movements of the eye that allow it to continually refocus on an object.

Study participants were asked to perform a visual decision-making task that involved random flashing lights and a dominant light on a cardboard square. They were asked to remember and pinpoint where the dominant light appeared, guessing whether they were correct. The researchers found that while neural activity correlated with decisions and guesses in all three brain areas, the metacognitive activity that linked decisions to bets resided exclusively in the SEF.

“The SEF is a complex area linked with motivational aspects of behavior,” said Sommer. “If we think we’re going to receive something good, neuronal activity tends to be high in SEF. People want good things in life, and to keep getting those good things, they have to compare what’s going on now versus the decisions made in the past.”

Sommer said he sees his research as one step in a systematic process of working toward a better understanding of consciousness. By studying metacognition, he says, he reduces the big problem of studying a “train of thought” into a simpler component: Examining how one cognitive process influences another.

“Why aren’t our thoughts independent of each other? Why don’t we just live in the moment? For a healthy person, it’s impossible to live in the moment. It’s a nice thing to say in terms of seizing the day and enjoying life, but our inner lives and experiences are much richer than that.”

The scientist said that patients with mental disorders have not been tested on these tasks, but added he is interested to see how SEF and other brain areas might be disrupted in people with these disorders.

“With schizophrenia and Alzheimer’s disease, there is a fracturing of the thought process,” he said. “It is constantly disrupted, and despite trying to keep a thought going, one is distracted very easily. Patients with these disorders have trouble sustaining a memory of past decisions to guide later behavior, suggesting a problem with metacognition.”

The study was published in the  journal Neuron.

Source: University of Pittsburgh

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Increased Dopamine Can Reduce Impulsivity


Increased Dopamine Can Reduce ImpulsivityResearchers have discovered that elevating the level of the neurotransmitter dopamine in the frontal lobe of the brain can significantly decrease impulsivity in healthy adults.

The finding is important as impulsiveness is a risk factor for substance abuse.

“Impulsivity is a risk factor for addiction to many substances, and it has been suggested that people with lower dopamine levels in the frontal cortex tend to be more impulsive,” said lead author Andrew Kayser, Ph.D.

Researchers from the Ernest Gallo Clinic and Research Center at the University of California, San Francisco performed a double-blinded placebo study. The study has been published in the Journal of Neuroscience.

In the research, 23 adult research participants were given either tolcapone, a medication approved by the Food and Drug Administration (FDA) that inhibits a dopamine-degrading enzyme, or a placebo.

Investigators then gave the participants a task that measured impulsivity, asking them to make a hypothetical choice between receiving a smaller amount of money immediately (“smaller sooner”) or a larger amount at a later time (“larger later”).

Each participant was tested twice, once with tolcapone and once with placebo.

More impulse (at baseline) participants were more likely to choose the less impulsive “larger later” option after taking tolcapone than they were after taking the placebo.

Magnetic resonance imaging conducted while the participants were taking the test confirmed that regions of the frontal cortex associated with decision-making were more active in the presence of tolcapone than in the presence of placebo.

“To our knowledge, this is the first study to use tolcapone to look for an effect on impulsivity,” said Kayser.

The study is a proof-in-concept investigation and was not designed to investigate the reasons that reduced dopamine is linked with impulsivity.

However, explained Kayser, scientists believe that impulsivity is associated with an imbalance in dopamine between the frontal cortex, which governs executive functions such as cognitive control and self-regulation, and the striatum, which is thought to be involved in the planning and modification of more habitual behaviors.

“Most, if not all, drugs of abuse, such as cocaine and amphetamine, directly or indirectly involve the dopamine system,” said Kayser.

“They tend to increase dopamine in the striatum, which in turn may reward impulsive behavior. In a very simplistic fashion, the striatum is saying ‘go,’ and the frontal cortex is saying ‘stop.’ If you take cocaine, you’re increasing the ‘go’ signal, and the ‘stop’ signal is not adequate to counteract it.”

Kayser and his research team plan a follow-up study of the effects of tolcapone on drinking behavior.

“Once we determine whether drinkers can safely tolerate this medication, we will see if it has any effect on how much they drink while they’re taking it,” said Kayser.

Currently, Tolcapone is approved as a medication for Parkinson’s disease — a disease in which a chronic deficit of dopamine inhibits movement.

Source: University of California – San Francisco

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