The Art of Neuroscience

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The winners of an annual contest capture the brain at its most beautiful

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July 31, 2017 at 08:13AM

Mouse Study Takes Big Step Toward Fast-Acting Antidepressants

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A new study for the first time has described how SSRIs initiate their action by targeting a particular type of nerve cell. The findings, published last week in the journal Neuron, may provide a path to new antidepressants that would not only be safer to use than existing ones, but that would also act more quickly.

For the past 30 years, pills like Prozac or Zoloft — collectively known as selective serotonin reuptake inhibitors, or SSRIs — have offered millions of people a way to shed the heavy cloak of depression.

These medications were designed to increase nerve cells’ access to serotonin, a chemical that helps the brain regulate certain emotions. Yet researchers still don’t know precisely how the drugs work to adjust errant brain chemistry, or how to make them work better.

Dr. Lucian Medrihan, who led the study, explains that while existing SSRIs can produce moderate effects within hours or even minutes, most people don’t really begin to feel better until they’ve been on the drugs for a significant amount of time. Medrihan is a research associate in the lab of neuroscientist and Nobel laureate Dr. Paul Greengard.

The delay in action is a major drawback when it comes to treating clinical depression. The drugs may also cause a wide range of uncomfortable side effects, including nausea, dizziness, weight gain, and sexual dysfunction.

Researchers say the basic idea behind SSRIs is relatively simple. When a neuron releases serotonin to signal another cell, it normally reabsorbs excess amounts of the neurotransmitter, preventing it from lingering in the space where the two nerve cells meet.

The drugs interfere with this mopping-up step, essentially prolonging the signal. What happens next has been a hard nut for neuroscientists to crack, however, because of the intrinsic complexity of the brain.

At least 1000 types of neurons could potentially be affected by a surge in serotonin, and they don’t all respond in the same way —
some get triggered, for example, while others calm down.

“That’s because there are 14 types of serotonin receptors present in various combinations in different neurons,” said Dr. Yotam Sagi, a senior research associate in Greengard’s lab. How a cell reacts to the neurotransmitter depends on the particular hodgepodge of receptors it carries.

Sagi and Medrihan set out to identify the earliest molecular steps by which SSRIs curb depression. To narrow their search, they honed in on a region of the brain known as the dentate gyrus, and on a particular group of cells called cholecystokinin (CCK)-expressing neurons, which they suspected were affected by SSRI-induced serotonin changes.

Using a technique called translating ribosome affinity purification, developed at Rockefeller by Nathaniel Heintz and Greengard, Sagi was able to identify the serotonin receptors present on CCK cells.

“We were able to show that one type of receptor, called 5-HT2A, is important for SSRIs’ long-term effect,” he says, “while the other, 5-HT1B, mediates the initiation of their effect.”

Next, Medrihan set up a series of intricate experiments to see if he could mimic an SSRI response by manipulating CCK neurons in living mice.

He suppressed the activity of these cells with chemogenetics, a technique that makes it possible to switch nerve cells on or off at will, and placed panels of tiny electrodes inside mouse brains. He then monitored the firing of other neurons in the dentate gyrus.

“Only five years ago, this research would not have been feasible,” he said of the methods involved.

The results were unmistakable: when a mouse’s CCK neurons were inhibited, the same neural pathways that mediate responses to SSRIs lit up. In targeting these cells, the scientists had seemingly recreated a quickened, Prozac-like response without the drug itself.

They also performed behavioral experiments by placing the mice in a pool and monitoring their swimming patterns.

After the CCK neurons had been briefly silenced, the behavior of these animals, which had not received any drugs, was similar to that seen in other mice after Prozac treatment: They swam with prolonged zest.

Greengard says the research resolves an important question in the field. “Many different types of synapses throughout the brain use serotonin as their neurotransmitter,” he said.

“An issue of major importance has been to identify where in the myriad of neurons the antidepressants initiate their pharmacological action.”

The findings, which identify CCK neurons in the dentate gyrus as the site of interest, will advance scientists’ understanding of how SSRI antidepressants work, and “should also facilitate development of new classes of potent and selective drugs,” Greengard said.

Such future therapies would presumably act faster than existing SSRIs, and might also produce fewer side effects.

Source: Rockefeller University

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July 31, 2017 at 08:13AM

Elite female tennis players less prone to choking under pressure than elite male players

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By Christian Jarrett

While biological differences between the sexes might give men a physical advantage in many sports, it’s possible that they come at a mental cost. Men typically show a greater spike in the stress hormone cortisol when under pressure than women, and, given that high cortisol levels can interfere with mental processing, it’s feasible this could mean men’s performance is more adversely affected in high-stakes contexts than women’s.

A new analysis of elite tennis performance in the Journal of Economic Psychology is consistent with this account. Based on the outcome of thousands of games played across the four tennis grand slams in 2010, the researchers led by Danny Cohen-Zada at Ben-Gurion University of the Negev, found that men were adversely affected by high pressure by about twice as much as women. Extrapolating to the world of work, Cohen-Zada and his colleagues said this casts doubt on the argument that the gender pay gap is due to women’s inability to compete under pressure, though they acknowledged there are caveats to this conclusion.

The researchers accessed data on scores and players for over 1000 men’s and women’s matches played at Wimbledon, The French Open, The Australian Open and the US Open in 2010. They focused on grand slams because they offer the same prize money to men and women competitors ruling out differences in stakes as an explanation for any observed sex differences in performance under pressure.

The researchers used various statistical techniques to weight the amount of pressure in any given game (including assessing how important the game was for increasing the odds of winning the match) and they looked to see how this affected the server’s performance compared with how often the server typically wins a game (the server has a big advantage in tennis). The researchers also adjusted the numbers to account for the fact that women play best of three games at Grand Slams whereas man play best of five, meaning that early games are more consequential for women than men.

There was ample evidence of high pressure adversely affecting male players’ performance. With a given unit increase in pressure (one standard deviation in statistical terms), men’s likelihood of losing a game in which they were serving increased by 4.9 per cent. For women, the same increase in pressure was associated with an increased likelihood of losing their service game of just 2.8  per cent. This apparent sex difference in the effect of pressure held even after factoring out other influences such as fatigue and differences in ranking between competing players.

In an another analysis, the researchers focused on the effect of high pressure when both players had so far won an equal number of games (to help rule out strategic issues such as one player deciding to give up when they were too far behind). The detrimental effects of pressure were little changed for men in this context, but for women there was now no evidence of choking at all.

“Our robust evidence that women can respond better than men to competitive pressure is compelling,” the researchers said. “Our results do not seem to support the claim that gender differences in wages in the labor market can be attributed to the fact that women respond more poorly to competitive pressure.”

Among the caveats to this conclusion are the fact that in normal work situations men and women may be competing against each other (for sales targets, for instance), whereas the current results are based on men and women competing separately. In fact, there is past research to suggest that women’s performance under pressure may particularly suffer in mixed-sex competition. Of course, it’s also not clear how far the current findings pertain specifically to elite tennis or whether they reveal something about men and women’s performance more generally.

—Choking under pressure and gender: Evidence from professional tennis

Image: Serena Williams during the China Open on September 21, 2005 (Photo by Cancan Chu/Getty Images).

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July 31, 2017 at 07:57AM

12-Step Programs Plus Evidence-Based Care Show Promise for Young Adults

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Combining the practices and philosophies of 12-step treatment programs, such as Alcoholics Anonymous (AA), with the motivational/cognitive-behavioral therapies currently being used to treat substance use disorders appears to produce better results in young people than the traditional program alone, according to a new study published in the journal Addiction.

It is common for drug treatment programs in the U.S. to link young patients to mutual-help organizations like AA, Narcotics Anonymous (NA) or Marijuana Anonymous (MA). But there has been no well-defined treatment protocol combining 12-step approaches with motivational enhancement/cognitive-behavioral therapies — and no evidence evaluating the effectiveness of such a pairing.

“In countries like the U.S., the greatest health risks for young people by far are from alcohol or other drug use,” said study leader John Kelly, Ph.D., director of the Recovery Research Institute in the Massachusetts General Hospital (MGH) Department of Psychiatry.

“Cognitive-behavioral and motivational programs are evidence-based, popular approaches for addressing youth substance-use disorder, and now these data suggest that integrating these approaches with 12-step philosophy and practices can further help reduce the impact of substance use in their lives and potentially facilitate higher rates of abstinence.”

The new intervention is based on motivational/cognitive-behavioral approaches but incorporates information from the kinds of discussions featured in 12-step program meetings.

“While all adolescents can improve when they receive well-articulated substance-use disorder treatment, we showed that adding a 12-step component to standard cognitive-behavioral and motivational strategies produced significantly greater reductions in substance-related consequences during and in the months following treatment,” said Kelly.

“It also produced higher rates of 12-step meeting participation, which was associated with longer periods of continuous abstinence.”

“Given the prevalence of substance-use disorders among young people, having treatments that are both effective and cost-effective — linking patients to free and ubiquitous community resources — is needed and welcome.”

The study involved 59 participants aged 14 to 21 who met substance-use disorder criteria and had been actively using within the past 90 days. Participants were randomly assigned to either a standard motivational enhancement/cognitive behavioral program or the Integrated Twelve-Step Facilitation (iTSF) program.

Both programs featured 10 consecutive weekly sessions; two individual sessions with a therapist and eight group sessions. The motivational enhancement/cognitive-behavioral approach was designed to enhance adolescents’ motivation for change towards remission and recovery. Sessions focused on teaching and practicing cognitive-behavioral relapse prevention and coping skills and included setting and reporting on weekly treatment goals.

Group sessions for the iTSF group included discussions of topics such as changing social networks and reducing relapse risk. Two of the sessions featured young members of NA or MA who shared their own experiences with addiction and recovery.

“That peer-to-peer aspect was probably the most powerful in disabusing young people of the negative stereotypes they often hold about 12-step members and about recovery more broadly,” says Kelly. “Similar-aged peers who are in recovery seemed much better able to capture the attention of participants than clinic staff.”

Along with the weekly reports at their sessions, the young people were formally evaluated at the onset of the study and then three, six and nine months later. By the end of the study, both groups showed similar improvements in the primary outcome, percent days abstinent.

However, participants in the iTSF group had greater attendance at 12-step meetings during the three months that included the intervention. This group also reported significantly fewer substance-related consequences, things like feeling unhappy, guilty or ashamed because of their substance use; neglecting responsibilities; taking risks; having money problems; damaging relationships with family and friends, and having under-the-influence accidents.

The fact that the higher rate of 12-step attendance among the iTSF participants was not maintained after the intervention program may indicate the need for a longer treatment program or regular, follow-up visits.

“We want to replicate and extend the testing of this treatment even further to determine the benefits of longer term care,” Kelly said.

“We know that the transition to adulthood is fraught with relapse risks for young people recovering from a substance-use disorder, so some kind of regular but brief ‘clinical recovery check-up,’ like what is common for other chronic conditions like diabetes or hypertension, could improve outcomes.”

Source: Massachusetts General Hospital

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July 31, 2017 at 07:23AM

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