Several selective serotonin reuptake inhibitors (SSRIs) like fluoxetine can raise brain concentrations of allopregnanolone, a metabolite of the hormone progesterone.

“[I]t is becoming clear that the name SSRI is in some sense a misnomer, since evidence is now accumulating to indicate that these compounds are far from selective exclusively for serotonin reuptake,” Lovick remarked in her article, published May 23 in the Journal of Psychopharmacology.

The rapid decrease of allopregnanolone in the brain during the luteal phase of the menstrual cycle has been linked to premenstrual syndrome and other disorders.

This could explain why SSRIs are frequently used to treat severe PMS and premenstrual dysphoric disorder (PMDD) symptoms. Research has found the drugs are “highly effective in treating the premenstrual symptoms.”

“Given the undisputed steroid-enhancing properties of fluoxetine, it is perhaps surprising that this aspect of its therapeutic potential has been realized only slowly,” Lovick wrote in her article.

The antidepressant drugs potentially offset the drop of allopregnanolone levels, preventing rapid withdrawal from the hormone, she explained. The dose of SSRIs needed to produce this effect is less than the dose needed for the drugs to produce their antidepressant effects.

“This action of fluoxetine can be achieved at doses far below the threshold for interaction with 5-HT [serotonin] systems, which are the target in antidepressant therapy,” Lovick said. “When translated into the clinical context, these findings suggest that current prescribing practice on SSRIs for PMS in women may not be optimal.”

These results, presented by addiction expert Francesco Leri, Associate Professor of Neuroscience and Applied Cognitive Science at the University of Guelph, suggest food addiction could explain, at least partly, the current global obesity epidemic. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience – Association Canadienne des Neurosciences (CAN-ACN).

The “Food Addiction” hypothesis suggests one could be addicted to food just as one is addicted to drugs of abuse. To test this hypothesis, Dr. Leri studies the response of rats to foods containing unnaturally high concentrations of sugar, fats and taste enhancers, such as high-fructose corn syrup and foods like oreo cookies.

Increased availability of such highly-palatable foods could partly explain the high incidence of obesity around the world, but simple availability does not explain why some people are obese and others are not, given the same amount of available food. Dr. Leri, and others, suggest one important factor could be individual differences in vulnerability to addiction. Surveys of consumption of cocaine show that though many individuals try these drugs, only a small percentage of them become addicted. Dr. Leri wanted to know if the same could be true of “addictive foods”. “We have evidence in laboratory animals of a shared vulnerability to develop preferences for sweet foods and for cocaine” says Leri.

Dr. Leri investigated the behavioural, chemical and neurobiological changes induced by consumption of “addictive foods” in the bodies and brains of rats. “We are not rats, but our children do not think too much about the impact of sweets on their brain and behaviour. There is now convincing neurobiological and behavioural evidence indicating that addiction to food is possible. Our primary objective is to discover biological predictors of vulnerability to develop excessive consumption of high fructose corn syrup ,” says Leri.

Dr. Leri’s findings could lead to novel pharmacological interventions for obese individuals that could help them selectively reduce intake of unhealthy foods. This knowledge could also help increase the public’s understanding of the effects of unhealthy food choices. An effective strategy to combat obesity is to educate people about the causes and consequences of their choices.

The small molecule, called natriuretic polypeptide b (Nppb), streams ahead and selectively plugs into a specific nerve cell in the spinal cord, which sends the signal onward through the central nervous system. When Nppb or its nerve cell was removed, mice stopped scratching at a broad array of itch-inducing substances. The signal wasn’t going through.

Because the nervous systems of mice and humans are similar, the scientists say a comparable biocircuit for itch likely is present in people. If correct, this start switch would provide a natural place to look for unique molecules that can be targeted with drugs to turn off the sensation more efficiently in the millions of people with chronic itch conditions, such eczema and psoriasis.

The paper, published online in the journal Science, also helps to solve a lingering scientific issue. “Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated land line to the brain,” said Mark Hoon, Ph.D., the senior author on the paper and a scientist at the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health.

Hoon said his group’s findings began with searching for the signaling components on a class of nerve cells, or neurons, that contain a molecule called TRPV1. These neurons, with their long nerve fibers extending into the skin, muscle, and other tissues, help to monitor a range of external conditions, from extreme temperature changes to detecting pain.

Yet little is known about how these neurons recognize the various sensory inputs and, like sorting mail, know how to route them correctly to the appropriate pathway to the brain.

To fill in more of the details, Hoon said his laboratory identified in mice some of the main neurotransmitters that TRPV1 neurons produce. A neurotransmitter is a small molecule that neurons selectively release when stimulated, like a quick pulse of water from a faucet, to communicate sensory signals to other nerve cells.

The scientists screened the various neurotransmitters, including Nppb, to see which ones corresponded with transmitting sensation.

“We tested Nppb for its possible role in various sensations without success,” said Santosh Mishra, lead author on the study and a researcher in the Hoon laboratory. “When we exposed the Nppb-deficient mice to several itch-inducing substances, it was amazing to watch. Nothing happened. The mice wouldn’t scratch.”

Further experiments established that Nppb was essential to initiate the sensation of itch, known clinically as pruritus. Equally significant, the molecule was necessary to respond to a broad spectrum of pruritic substances. Previous research had suggested that a common start switch for itch would be unlikely, given the myriad proteins and cell types that seemed to be involved in processing the sensation.

Hoon and Mishra turned to the dorsal horn, a junction point in the spine where sensory signals from the body’s periphery are routed onward to the brain. Within this nexus of nerve connections, they looked for cells that expressed the receptor to receive the incoming Nppb molecules.

“The receptors were exactly in the right place in the dorsal horn,” said Hoon, the receptor being the long-recognized protein Npra. “We went further and removed the Npra neurons from the spinal cord. We wanted to see if their removal would short-circuit the itch, and it did.”

Hoon said this experiment added another key piece of information. Removing the receptor neurons had no impact on other sensory sensations, such as temperature, pain, and touch. This told them that the connection forms a dedicated biocircuit to the brain that conveys the sensation of itch.

But the scientists had stepped into a conundrum. Previous reports had suggested that another neurotransmitter called GRP might initiate itch. If that wasn’t the case, where did GRP fit into the process?

They tested the receptor neurons that express GRP, finding the previous reports were correct about this molecule relaying the signal to the central nervous system. GRP just enters the picture after Nppb already has set the sensation in motion.

Based on these findings, Nppb would seem to be an obvious first target to control itch. But that’s not necessarily the case. Nppb also is used in the heart, kidneys, and other parts of the body, so attempts to control the neurotransmitter in the spine has the potential to cause unwanted side effects.

“The larger scientific point remains,” said Hoon. “We have defined in the mouse the primary itch-initiating neurons and figured out the first three steps in the pruritic pathway. Now the challenge is to find similar biocircuitry in people, evaluate what’s there, and identify unique molecules that can be targeted to turn off chronic itch without causing unwanted side effects. So, this is a start, not a finish.”

Those results, presented online Feb. 9, 2012, suggested that the drug bexarotene (marketed as Targretin®) could rapidly reverse the buildup of beta amyloid plaques (Aβ) — a pathological hallmark of Alzheimer’s disease — in the brains of mice. According to the authors of the 2012 report, drug treatment quickly removed most of the plaques and brought rapid reversal of the pathological, cognitive and memory deficits related to the onset of Alzheimer’s.

However, the new reports from extensive and carefully controlled studies did not show any reduction in the number of plaques or total area occupied by the plaques during or after treatment. These results are described in three “technical comments” — one of which comes from researchers at the University of Chicago, Northwestern University, Massachusetts General Hospital, Washington University in St Louis and University of Tubingen in Germany — to be published in the May 24, 2013, issue of Science.

“The drug has no impact on plaque burden in three strains that exhibit Aβ amyloidosis,” according to that group’s comment. “We have failed to support earlier findings by Cramer et al that Targretin is efficacious in reducing plaque burden in transgenic mouse models of cerebral Aβ deposition.”

Comment co-author Sangram Sisodia, PhD, professor of neurosciences at the University of Chicago, said he and his colleagues were curious about the initial report in 2012.

“We were surprised and excited, even stunned, when we first saw these results presented at a small conference,” said Sisodia. “The mechanism of action made some sense, but the assertion that they could reduce the areas of plaque by 50 percent within three days, and by 75 percent in two weeks, seemed too good to be true.”

“We all went back to our labs and tried to confirm these promising findings,” Sisodia added. “We repeated the initial experiments — a standard process in science. Combined results are really important in this field. None of us found anything like what they described in the 2012 paper.”

The researchers found no effects on plaque burden in three different strains of mice that were treated with bexarotene.

The discrepancy, besides being disappointing, also raises concerns about patient safety. The Food and Drug Administration approved bexarotene in December 1999 for a very specific use: treatment of refractory cutaneous T-cell lymphoma, a type of skin cancer. Once approved, the drug became legally available by prescription for “off-label” uses as well.

“Anecdotally, we have all heard that physicians are treating their Alzheimer’s patients with bexarotene, a cancer drug with severe side effects,” said co-author Robert Vassar, PhD, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine. “This practice should be ended immediately, given the failure of three independent research groups to replicate the plaque-lowering effects of bexarotene.”

Bexarotene has never been tested as a treatment for Alzheimer’s disease in humans, not even to determine the optimal dose or duration of treatment. This drug has significant side effects, including major blood-lipid abnormalities, pancreatitis, liver function test abnormalities, thyroid axis alterations, leucopenia, headaches, fatigue, weight gain, depression, nausea, vomiting, constipation and rash.

The two other technical comments came from research teams led by Kevin Felsenstein, Todd Golde, David Borchelt and colleagues at the University of Florida and by Bart DeStrooper and colleagues at the University of Leuven, Belgium.

There is no cure or effective treatment for Alzheimer’s disease, which is a progressive type of dementia that occurs when nerve cells in the brain die. When Alzheimer’s was first identified in 1906, it was considered a rare disorder. Today, Alzheimer’s is the most common cause of dementia. An estimated 5.3 million Americans have the disease.

Researchers from the University of North Carolina School of Medicine have uncovered some surprising insights about the process of axon amputation, or “pruning,” in a study published May 21 in the journal Nature Communications. Axon pruning has mystified scientists curious to know how a neuron can unleash a self -destruct mechanism within its axon, but keep it from spreading to the rest of the cell. The researchers’ findings could offer clues about the processes underlying some neurological disorders.

“Aberrant axon pruning is thought to underlie some of the causes for neurodevelopmental disorders, such as schizophrenia and autism,” said Mohanish Deshmukh, PhD, professor of cell biology and physiology at UNC and the study’s senior author. “This study sheds light on some of the mechanisms by which neurons are able to regulate axon pruning.”

Axon pruning is part of normal development and plays a key role in learning and memory. Another important process, apoptosis — the purposeful death of an entire cell — is also crucial because it allows the body to cull broken or incorrectly placed neurons. But both processes have been linked with disease when improperly regulated.

The research team placed mouse neurons in special devices called microfluidic chambers that allowed the researchers to independently manipulate the environments surrounding the axon and cell body to induce axon pruning or apoptosis.

They found that although the nerve cell uses the same poison — a group of molecules known as Caspases — whether it intends to kill the whole cell or just the axon, it deploys the Caspases in a different way depending on the context.

“People had assumed that the mechanism was the same regardless of whether the context was axon pruning or apoptosis, but we found that it’s actually quite distinct,” said Deshmukh. “The neuron essentially uses the same components for both cases, but tweaks them in a very elegant way so the neuron knows whether it needs to undergo apoptosis or axon pruning.”

In apoptosis, the neuron deploys the deadly Caspases using an activator known as Apaf-1. In the case of axon pruning, Apaf-1 was simply not involved, despite the presence of Caspases. “This is really going to take the field by surprise,” said Deshmukh. “There’s very little precedent of Caspases being activated without Apaf-1. We just didn’t know they could be activated through a different mechanism.”

In addition, the team discovered that neurons employ other molecules as safety brakes to keep the “kill” signal contained to the axon alone. “Having this brake keeps that signal from spreading to the rest of the body,” said Deshmukh. “Remarkably, just removing one brake makes the neurons more vulnerable.”

Deshmukh said the findings offer a glimpse into how nerve cells reconfigure themselves during development and beyond. Enhancing our understanding of these basic processes could help illuminate what has gone wrong in the case of some neurological disorders.

“Pulse wave velocity from the aortic arch provides functional information about vessel compliance that may help determine a patient’s risk for cerebrovascular disease down the road,” said Kevin S. King, M.D., assistant professor of radiology at UT Southwestern Medical Center in Dallas.

Recent studies have shown an association between aortic stiffness and cerebrovascular disease. Dr. King and colleagues set out to evaluate the relationship between aortic arch pulse wave velocity and subsequent cerebral microvascular disease, independent of other cardiovascular risk factors, among 1,270 participants in the multiethnic Dallas Heart Study.

Aortic arch pulse wave velocity was measured with phase-contrast magnetic resonance imaging (MRI). Seven years later, the volume of white matter hyperintensities was determined using brain MRI. White matter hyperintensities, which appear as bright spots on brain MR images, are associated with accelerated motor and cognitive decline, Alzheimer’s disease, stroke and death.

The researchers also analyzed 15 other cardiovascular risk factors, as well as age, gender and ethnicity, as predictors of white matter hyperintensities.

The results showed that aortic arch pulse wave velocity helped predict white matter hyperintensity volume, independent of the other demographic and cardiovascular risk factors. The researchers estimated that a one percent increase in aortic arch pulse wave velocity (in meters per second) is related to a 0.3 percent increase in subsequent white matter hyperintensity volume (in milliliters) when all other variables are constant.

“Our results demonstrate that aortic arch pulse wave velocity is a highly significant independent predictor of subsequent white matter hyperintensity volume and provides a distinct contribution—along with systolic blood pressure, hypertension treatment, congestive heart failure and age—in predicting risk for cerebrovascular disease,” Dr. King said.

Drs. Paul Frankland and Sheena Josselyn, both from the Hospital for Sick Children in Toronto, argue this reorganization could have the positive effect of clearing old memories, reducing interference and thereby increasing capacity for new learning. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience – Association Canadienne des Neurosciences (CAN-ACN).

Researchers have long known of the phenomenon of infantile amnesia: This refers to the absence of long-term memory of events occurring within the first 2-3 years of life, and little long-term memories for events occurring until about 7 years of age. Studies have shown that though young children can remember events in the short term, these memories do not persist. This new study by Frankland and Josselyn shows that this amnesia is associated with high levels of new neuron production – a process called neurogenesis – in the hippocampus, and that more permanent memory formation is associated with a reduction in neurogenesis.

Dr. Frankland and Dr. Josselyn’s approach was to look at retention of memories in young mice in which they suppressed the usual high levels of neurogenesis in the hippocampus (thereby replicating the circuit stability normally observed in adult mice), but also in older mice in which they stimulated increased neurogenesis (thereby replicating the conditions normally seen in younger mice). Dr. Frankland was able to show a causal relationship between a reduction in neurogenesis and increased remembering, and the converse, decreased remembering when neurogenesis increased.

Dr. Frankland concludes: ” Why infantile amnesia exists has long been a mystery. We think our new studies begin to explain why we have no memories from our earliest years.”

The results suggest a monthly window of opportunity that could potentially be targeted in efforts to prevent common mental health problems developing in women. The research is the first to show a potential link between psychological vulnerability and the timing of a biological cycle, in this case ovulation.

A common symptom of mood and anxiety problems is the tendency to experience repetitive and unwanted thoughts. These ‘intrusive thoughts’ often occur in the days and weeks after a stressful experience.

In this study, the researchers examined whether the effects of a stressful event are linked to different stages of the menstrual cycle. The participants were 41 women aged between 18 and 35 who had regular menstrual cycles and were not using the pill as a form of contraception. Each woman watched a 14-minute stressful film containing death or injury and provided a saliva sample so that hormone levels could be assessed. They were then asked to record instances of unwanted thoughts about the video over the following days.

“We found that women in the ‘early luteal’ phase, which falls roughly 16 to 20 days after the start of their period, had more than three times as many intrusive thoughts as those who watched the video in other phases of their menstrual cycle,” explains author Dr Sunjeev Kamboj, Lecturer in UCL’s Department of Clinical, Educational and Health Psychology. “This indicates that there is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event.”

The findings could have important implications for mental health problems and their treatment in women who have suffered trauma.

“Asking women who have experienced a traumatic event about the time since their last period might help identify those at greatest risk of developing recurring symptoms similar to those seen in psychological disorders such as depression and post-traumatic stress disorder (PTSD),” said Dr Kamboj.

“This work might have identified a useful line of enquiry for doctors, helping them to identify potentially vulnerable women who could be offered preventative therapies,” continued Dr Kamboj.

“However, this is only a first step. Although we found large effects in healthy women after they experienced a relatively mild stressful event, we now need to see if the same pattern is found in women who have experienced a real traumatic event. We also need further research to investigate how using the contraceptive pill affects this whole process.”

Female gamers playing Halo 3 receive roughly three times as many negative comments compared to a male player, research published in the June issue of New Media & Society found.

“In summary, this study has established that gamers react differently to a female voice than to a male voice or no voice,” Jeffrey H. Kuznekoff and Lindsey M. Rose of Ohio University explained in the study. “Specifically, gamers reacted more negatively to a female voice than a male voice, even when both voices were communicating the same message.”

For their observational study, the researchers played Halo 3 on the Xbox 360 against 1,660 unique gamers and broadcasted pre-recorded audio clips of either a man or a woman speaking. The audio clips said innocuous things like, “Hi everybody,” “I like this map,” “Nice job so far”, and “I think I just saw a couple of them heading this way.”

In 163 multiplayer games in which verbal communication occurred, the female voice received roughly three times as many negative comments as the male voice and no voice. In addition, the female voice received more private messages and friend requests from other players.

Kuznekoff and Rose controlled for skill level and win percentage. This ensured that the players were not simply reacting with negative comments because they were frustrated with losing the game. Overall, there was no link between skill level and negative comments.

“On several occasions the female condition was exposed to derogatory gendered language,” the researchers noted in the study. The presumably female player was called a “whore,” “stupid slut,” “hooker,” and “bitch” for simply for saying “hi” or “good game.”

Gender and video games has become a hot topic. While researchers have examined the stereotypical portrayal and objectification of women in video games, the online gaming environment has received relatively little attention.

“The next logical step is to determine exactly what causes this reaction and why gamers feel inclined to communicate in this way,” Kuznekoff and Rose concluded. “It could be, as others have hypothesized, that characteristics of the communication channel may allow this negative behavior to flourish. It may also be that, within video games, people feel more freedom to express themselves without fearing the consequences of their actions.”

Significant numbers felt unprepared to diagnose or treat such disorders, results similar to surveys of practicing physicians. In response to the findings, recently published online in the journal Substance Abuse, the MGH has increased residents’ training in addiction medicine.

“Our residents estimated that one in four hospital inpatients has a substance use disorder, which matches what other studies have found and represents a disease prevalence similar to that of diabetes,” says Sarah Wakeman, MD, chief medical resident at MGH and lead author of the report. “Finding that the majority of residents feel unprepared to treat addiction and rate the quality of their education so low represents a tremendous disparity between the burden of disease and the success of our current model of training.”

The study’s authors note that residents provide most direct medical care in teaching hospitals and often find caring for patients with addictions to be troublesome – possibly due to a lack of training and faculty role models – which can lead to a lack of trust between patients and physicians. Several previous studies have pointed out deficiencies in addictions education for primary care and internal medicine residents, with some programs offering none at all. Wakeman explains, “Our findings are in line with previous data from training programs that reported limited addictions training and with studies of medical residents showing low satisfaction in caring for addicted patients. It is unlikely that MGH is unique in this educational deficiency, but rather these findings may demonstrate a critical failure in medical education as a whole.”

Wakeman and her colleagues designed their survey to assess residents’ basic knowledge of substance use disorders, how they evaluated the training they had received and how prepared they felt to diagnose and treat addiction to alcohol or drugs. In May 2012 the survey was e-mailed to all MGH residents in internal medicine, primary care and in a joint medicine/pediatrics residency – a total of 184 recipients. Survey recipients were informed that their participation was voluntary and anonymous, and 101 of them completed and returned the survey. The authors note that while psychiatrists care for many patients with addiction, people with substance use disorders are most likely to seek medical care from internists, often for problems caused by their addictions.

At the time the survey was taken, formal addiction training for most residents was confined to a single noontime conference on alcohol withdrawal and three highly rated lectures on addiction-related topics during ambulatory rotations. The primary care residency, however, included an intensive two-week outpatient rotation in addictions, which was available as an elective to other residents. One quarter of survey respondents indicated feeling unprepared to diagnose addiction, and 62 percent felt unprepared to treat it. Addictions training in the outpatient setting was rated fair to poor by 72 percent of respondents, and 56 percent rated inpatient addictions training as fair to poor. In contrast, 95 percent of participants in the primary care addictions rotation rated it as good or excellent.

Participants were also asked six questions evaluating their knowledge about diagnosing and treating substance abuse, and while their diagnostic answers were more accurate than their knowledge of treatment options – including the available FDA-approved medications – none of them answered all questions correctly, and only 6 percent correctly answered all three questions regarding pharmacologic treatment options for addiction. How many years into residency the respondents were made no significant differences in any of the survey responses.

James Morrill, MD, PhD, an MGH internist and core faculty member of the outpatient addictions elective rotation, says, “It’s time to bring the level of addictions education in elite medical training programs like MGH’s up to the same high level that residents receive in areas such as cardiology. We need to help our residents recognize the great potential of primary care to stem the tide of morbidity and mortality due to addiction and keep addicted patients in treatment and out of the hospital.”

Also on the faculty of the outpatient addictions rotation, Michael Bierer, MD, an MGH internist specializing in addiction treatment, says, “Addictions are highly prevalent; they affect general health and health care, break up families and cause suffering that extends beyond the patients themselves. But they are highly treatable. Ignoring these problems doesn’t make sense from any perspective, and doing the right thing at the right time is not hard. Treating addictions well is certainly no more complex than some of the sophisticated skills our residents typically master.”

In response to the survey’s findings, the MGH has expanded resident education on addictions – adding another ten noontime conferences and including addiction case histories in 25 percent of ambulatory intern reports. Wakeman and her co-authors are now repeating the survey to assess the impact of those changes. They also hope to expand the survey to a national sample of residents to determine whether their findings can be broadly applied to programs nationwide. Wakeman, Morrill, Bierer and several other faculty members have formed a group that meets monthly to discuss additional educational needs in addiction medicine and develop more resources for MGH residents.

“Along with designing new addiction treatment models, the more we can involve patients in our educational programs, the better,” Wakeman says. “Having patients involved in lectures and in small-group teaching settings may help residents develop more empathy for the courageous men and women living with and recovering from addiction. And as we enter an era of patient-centered medical homes, having patients as the central focus point of our care models is crucial.”