Brain’s serotonin system includes multiple, sometimes conflicting, pathways

Photo by Pablo García Saldaña

Although the serotonin system — which helps regulate mood and social behavior, appetite and digestion, sleep, memory and motor skills — is critical to so many functions in the human body, its underlying organization and properties are not well understood. Past studies have even reported divergent results.

New research may help clear up this confusion, as recently reported in Cell. Stanford biologist Liqun Luo, PhD, discovered the serotonin system is actually composed of multiple parallel subsystems that function differently, at times in opposing ways.

“The field’s understanding of the serotonin system was like the story of the blind men touching the elephant,” Luo said in a recent Stanford news release. “Scientists were discovering distinct functions of serotonin in the brain and attributing them to a monolithic serotonin system, which at least partly accounts for the controversy about what serotonin actually does. This study allows us to see different parts of the elephant at the same time.”

Luo’s team studied the dorsal raphe, a region of the brainstem containing a high concentration of serotonin-producing neurons, in mice. They injected this region’s nerve fibers with a modified virus engineered to exhibit bright green fluorescence — allowing them to image and trace how the dorsal raphe’s neurons are connected to other regions in the brain. They observed two distinct groups of neurons in the dorsal raphe.

Using behavioral tests, they then determined that these two neuron groups sometimes responded differently to stimuli. For instance, in response to a mild punishment, neurons from the two groups showed opposite responses.

The researchers also found these neurons released the chemical glutamate in addition to serotonin, raising the question of whether they should even be called serotonin neurons.

These research findings have the potential for wide-ranging clinical applications, including the development of better drugs to treat depression and anxiety. Currently, the most commonly prescribed type of antidepressant are selective serotonin reuptake inhibitors (SSRIs), which target the serotonin system. However, some people can’t tolerate the side effects from SSRI antidepressants. A better understanding of the serotonin system may help.

“If we can target the relevant pathways of the serotonin system individually, then we may be able to eliminate the unwanted side effects and treat only the disorder,” said study first author Jing Ren, PhD, a postdoctoral fellow in Luo’s lab.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Airline crew don’t have significantly elevated risk of thyroid cancer, new study finds

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Commercial airline crew typically spend 1,000 hours per year working at cruising altitudes — above the atmosphere that protects them from cosmic ionizing radiation. In fact, aircrew receive the largest annual radiation dose of all U.S. workers.

Studies have shown that pilots and flight attendants have higher rates of certain cancers than the general population, including breast cancer and melanoma. But less was understood about the link between air travel and thyroid cancer, which is known to be associated with childhood radiation exposure.

Stanford researchers addressed this question with a meta-analysis of published data on thyroid cancer rates in airline crew, as recently reported in Cancers of the Head and Neck. They analyzed eight studies with a total of almost 250,000 crew members from 11 countries. They found no evidence of increased thyroid cancer risk in airline crew.

“None of the eight studies showed a statistically significant increase in risk of thyroid cancer,” wrote first author George Liu, MD, a Stanford medical student, in a recent blog post. “Aggregating the results, using a statistical method called random-effects model, also did not change our conclusion.”

The key phrase in Liu’s statement may be “statistically significant.”

On the surface, the new Stanford results seem to contradict recent findings from the Harvard Flight Attendant Study that stated, “Compared to … [controls] with a similar socioeconomic status, flight attendants had a higher prevalence of every cancer we examined.” And the study included thyroid cancer.

However, the higher prevalence of cancers observed by the Harvard study was statistically significant for only three of the cancers examined: breast cancer, melanoma and non-melanoma skin cancer, Liu argued. In fact, both studies found very similar results for thyroid cancer. In the blog, Liu called for the paper’s authors and media to correct their statements to avoid “undue alarm.”

Based on their own study, the Stanford authors also called for further research that better captures variables such as gender, age and primary and secondary smoking data for airline crew, as well as larger studies with longer follow-up periods.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Busting myths about milk

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Milk used to be simple. Your local dairy, say Berkeley Farms, delivered it to your doorstep.

But now we are faced with an unfathomable array: nonfat, low-fat or whole milk? Almond, soy, rice, hemp or oat milk? From goats or cows? With or without lactase? Raw or pasteurized? Plain or flavored? There’s even an ongoing controversy over which of these drinks can be called milk.

To sort through the confusion, I spoke with Stanford nutrition scientist Christopher Gardner, PhD. He is working to clear up some of the biggest misconceptions we have about milk.

Most of us grew up believing that milk is important for children to build strong bones and for the elderly to prevent osteoporosis. But milk, a good source of calcium, isn’t necessarily the most critical factor for bone health, Gardner said.

“There are countries like Japan and India where the population is predominantly lactose intolerant, where milk intake is low and hip fracture rates are also low. But many of those cultures do more weight-bearing activities than Americans,” he said. “It’s better to be physically active than drink milk as a way to strengthen your bones.”

Studies have shown that drinking milk can improve your bone density, but whether it helps prevent bone fractures is debatable, he added.

But don’t young kids need milk? According to Gardner, it depends on what kind of milk. Breast milk is incredibly important, but cow’s milk isn’t, he said.

“This myth goes way back to before the food pyramid when the National Dairy Council offered to provide nutrition material to schools for free. And in all those materials, they said that you need multiple servings of dairy every day for a healthy diet,” Gardner said. “That was never agreed on. A lot of people are lactose intolerant, and you don’t need it.”

Milk can be healthier than other options like soda. He recommended checking the nutrition panel to make sure the milk isn’t just as sugary as soda though, particularly with plant-based milks. “The popular vanilla and chocolate versions of the plant-based milks are often loaded with added sugar. Even the plain is typically sweetened, but you can get unsweetened. The lactose in milk isn’t so bad so there is no need to water it down, just avoid milks with added sugars.”

The nutrition label also allows you to compare the amount of fats, protein, carbs and vitamins in each type of milk. “For example, the plant-based milks generally don’t have saturated fat like cow’s milk so they don’t raise LDL-cholesterol as much as dairy milk, but they do have about the same amount of calcium,” he said. “And soy milk has the same amount of protein as dairy milk, but almond milk has much less protein.”

Another common misunderstanding is that 2 percent milk means that two percent of the calories are from fat — it’s really 2 percent of the weight (which is mostly water) and 35 percent of the calories, he said. “Whole milk has close to 50 percent of its calories as fat, and 1 percent milk has about 20 percent.”

However, your milk’s fat content may not affect your weight. The old belief was that drinking whole fat milk will make you fat and skim milk will help you lose weight. But this was refuted by Harvard’s Nurses’ Health Study that followed the diets of over 100,000 nurses for over 30 years, including how their diets changed.

“The Harvard study found that switching back and forth from whole fat to 2 percent to 1 percent was not associated with changes in weight,” explained Gardner.

But does drinking more milk help? Some small, short-term studies showed that people lost weight if they drank more milk. According to Gardner, this raises the always present nutrition research challenge: Was it drinking more milk or was it consuming less of something else that caused the weight loss?

And what about raw milk? Raw milk proponents argue that pasteurization kills off important healthy bacteria along with the bad listeria bacteria, but Gardner says that it’s difficult to prove any health benefits from these bacteria. Some raw milk producers also claim that it is easier to digest. However, Gardner’s study found that lactose intolerant participants had the same symptoms with raw and pasteurized milk.

And what does Gardner himself drink? He said he gave up cow’s milk for ethical reasons.

“Now, I drink unsweetened soy milk,” he admitted. ‘In our household, my wife doesn’t digest dairy milk very well, so we don’t even have it around. My four boys all drink unsweetened soy milk.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Deep brain stimulation might benefit those with severe alcoholism, preliminary studies show

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Alcoholics struggling to stay sober are faced with countless triggers that can lead to relapse — driving past a bar, getting together with former drinking buddies or even just feeling down. 

And this is a big problem. Alcoholism is a growing epidemic responsible for at least a quarter trillion dollars in US health care costs per year, as well as inestimable anguish. Current medical therapies suffer from high rates of noncompliance and variable effectiveness.

In the future, severe alcoholics with multiple failed attempts at intensive medical therapies and in-patient rehabilitation may have a different treatment option for their addiction — deep brain stimulation (DBS) — as recently reported in a review article by Stanford researchers in Neurosurgical Focus.

Currently, deep brain stimulation therapy for alcohol use disorders is not approved by the U.S. Food and Drug Administration, but it is widely used to treat Parkinson’s disease and obsessive-compulsive disorder.

“DBS is a minimally-invasive brain surgery,” explained senior author Casey Halpern, MD, an assistant professor of neurosurgery at Stanford. “For Parkinson’s, we place deep brain stimulators to restore normal function of the region in the brain known to be dysfunctional. Patients improve immediately when a small dose of current is delivered to this area. We anticipate a similar treatment will be possible for alcoholism. At the moment, we’re performing animal studies to optimize this potential therapy and to learn its underlying mechanism of action.”

For alcohol use disorders,  researchers are targeting the nucleus accumbens, which plays a central role in the brain’s reward circuitry. They previously found that brain stimulation of this region could reduce impulsive behavior.

“The nucleus accumbens is triggered when patients anticipate a reward or prior to completing a rewarding behavior. It’s been shown to be perturbed in both addictive disorders and OCD,” said Allen Ho, MD, a Stanford neurosurgery resident working with Halpern. “By targeting this brain structure with stimulation, we hope to modulate the reward circuit in the brain to help patients resist the temptation to indulge in a binge and other addictive behaviors.”

The review article outlines extensive animal studies and pilot human subject studies have shown promising reductions in alcohol consumption and, in some cases, long-term abstinence.

According to Ho, this success is in part due to the fact that DBS doesn’t rely on patient compliance with therapy sessions, in-patient rehab, medications and abstinence. “Once the patient makes a decision to undergo treatment and the stimulator is implanted and turned on, they don’t have to make a conscious decision to pursue treatment — it is ‘on’ all the time,” said Ho.

Brain surgery may sound scary, but Ho explained that DBS is one of the safest and least invasive operations that they do as neurosurgeons. He believes alcoholics will consider the treatment since the addiction can devastate their lives, he said.

The Stanford team also hopes to apply deep brain stimulation to other addictions. “Should DBS prove effective for alcoholism, we anticipate a similar therapy could be very helpful for all addictions and even obesity,” said Halpern.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Improving domestic violence screening at Stanford: A Q&A

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As part of the Clinical Observation and Medical Transcription fellowship at Stanford, Laurel Sharpless wanted to pursue a project that was personally important to her: intimate partner violence.

Her own experience with intimate personal violence during high school temporarily derailed her career plans of attending a four-year college and then medical school. So she knows how important it is to identify victims early and connect them with help.

During the fellowship — a one-year program that trains prospective health professionals to work as certified medical scribes alongside faculty physicians — Sharpless also looked at how to improve screening for intimate partner violence at Stanford clinics.

Now a San Francisco 49ers cheerleader, a clinical trials coordinator for Stanford immunology and rheumatology and a chief scribe for the COMET fellowship, Sharpless’ own dream is back on track.

I spoke with her recently about her work:

Why is it important for health care workers to screen for domestic violence?

“Intimate partner violence (IPV) is a silent epidemic affecting 1 in 3 women during their lifetime. It leads to injuries and death from physical and sexual assault, sexually transmitted infections, post-traumatic stress disorder, depression, substance abuse, suicide and many other health issues.

We need to promote intervention. This is a public health issue, and primary care and ob/gyn are the best portals for sharing that information. Otherwise, victims might not be aware of the resources they have.”

What are the barriers?

“Although the U.S. Preventive Services Task Force recommends physicians screen women of childbearing age for IPV, rates of screening in primary care settings are low. Physicians have limited time with the patient in the exam room and they have a lot to juggle when coordinating patients’ care. There is also a stigma around the topic with many patients and physicians feeling uncomfortable with the subject.”

What did you study and what did you find?

“I conducted a retrospective chart review at the five Stanford primary care clinics to understand how we were screening patients for intimate partner violence. Some clinics had medical assistants screen and others relied on the physicians alone, and I found a wide variation in screening rates.

Our study supports the national trend that medical staff should do the initial screening, and then physicians should counsel patients who screen positive and then refer them to a social worker and local victims resources.

I presented these results to the medical directors of primary care, which led to an initiative to standardize the way Stanford primary care and ob/gyn screen patients for IPV. I even got to choose the screening question we use. We now ask, ‘Because difficult relationships can cause health problems, we are asking all of our patients the following question: Does a partner, or anyone at home, hurt, hit, or threaten you?'”

What ‘s next?

 “My study results have just been accepted for publication.

I’m currently applying to medical school in hopes of becoming a physician. The COMET fellowship has really peaked my interest in primary care, but I’m going in with an open mind.

As a physician, I wish to become a champion of women’s health care, conducting research and seeing patients. I’ve seen the difference I can make in the quality of care provided to patients. I also aspire to teach the next generation of health care workers and the community at large through advocacy and education from the perspective of an academic physician.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Wearable device designed to measure cortisol in sweat

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Scientists are sweating over how to measure perspiration. That’s because sweat provides a lot of information about a person’s health status, since it contains important electrolytes, proteins, hormones and other factors.

Now, Stanford researchers have developed a wearable device to measure how much cortisol people produce in their sweat.

Cortisol is a hormone critical for many processes in the body, including blood pressure, metabolism, inflammation, memory formation and emotional stress. Too much cortisol over a prolonged period of time can lead to chronic diseases, such as Cushing syndrome.

“We are particularly interested in sweat sensing, because it offers noninvasive and continuous monitoring of various biomarkers for a range of physiological conditions,” said Onur Parlak, PhD, a Stanford postdoctoral research fellow in materials science and engineering, in a recent news release. “This offers a novel approach for the early detection of various diseases and evaluation of sports performance.”

Currently, cortisol levels are usually measured with a blood test that takes several days to analyze in the lab. So Stanford material scientists developed a wearable sensor — a stretchy patch placed on the skin. After the patch soaks up sweat, the user attaches it to a device for analysis and gets the cortisol level measurements in seconds.

As recently reported in Science Advances, the new wearable sensor is composed of four layers of materials. The bottom layer next to the skin passively wicks in sweat through an array of channels, and then the sweat collects in the reservoir layer. Sitting on top of the reservoir is the critical component, a specialized membrane that specifically binds to cortisol. Charged ions in the sweat, like sodium or potassium, pass through the membrane unless the bound cortisol blocks them — and those charged ions are detected by the analysis device, rather than directly measuring the cortisol. Finally, the top waterproof layer protects the sensor from contamination.

The Stanford researchers did a series of validation tests in the lab, and then they strapped the device onto the forearms of two volunteers after they went for a 20-minute outdoor run. Their device’s lab and real-world results were comparable to the corresponding cortisol measurements made with a standard analytic biochemistry assay.

Before this prototype becomes available, however, more research is needed. The research team plans to integrate the wearable patch with the analysis device, while also making it more robust when saturated with sweat so it’s reusable. They also hope to generalize the design to measure several biomarkers at once, not just cortisol.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Inaccurate direct-to-consumer raw genetic data can harm patients, new research suggests

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Whether or not you’ve ever had genetic testing, you probably know someone that has. Millions of people each year have their DNA analyzed by companies like 23andMe and Ancestry.com, seeking out personalized information about their heritage, health and other traits.

“The general public is excited about genetics because it can tell us a lot about our past ancestry and, if the right technology is used, about our future­­ ­— such as the likelihood of developing certain health problems,” said Tia Moscarello, a genetic counselor with Stanford’s Center for Inherited Cardiovascular Disease. “These tests are popular for good reason: many people want to be proactive about their health without spending a lot of money or making a trip to the doctor’s office to do it.”

Typically, these direct-to-consumer (DTC) genetic tests are less expensive than more comprehensive, clinical-grade genetic tests obtained through a health care provider.

However, the Food and Drug Administration limits what these companies can say about a consumer’s health. So many people download their raw genetic data obtained from the company, and then upload it to another company’s website for additional interpretation. But their raw data come with a disclaimer stating the information is not validated for accuracy nor intended for medical use.

“To our understanding, raw genetic data doesn’t go through quality control. We and the DTC labs know that raw data may not be accurate,” Moscarello said. For instance, a small study recently showed that 40 percent of genetic variants identified in direct-to-consumer raw data and sent for clinical confirmation were false positives — meaning that the genetic variants weren’t really present.

Moscarello has personally witnessed the impact of these false positives on patients and their families. In a recent commentary in Genetics in Medicine, she and her colleagues describe two cases of false positives seen at Stanford and two more seen at other institutions. These patients received raw data with genetic variants known to be associated with inherited heart conditions that would predispose them to sudden death, she said. Fortunately, a clinical lab determined that the results were incorrect.

Moscarello said she and her co-authors wrote the commentary to call attention to the potential harms of direct-to-consumer raw data interpretation, which extend beyond the potential for inaccurate results. She explained:

“Finding out that you or a family member are at risk for an inherited heart condition can be a very emotional, life-changing event. To go through that without an expert to talk to, or perhaps without support systems nearby, was challenging for our patients. They had to wait for an appointment with a genetic counselor who could explain the test and its limitations, and to provide support. That is usually provided prior to genetic testing, so patients can decide if they would like to proceed.”

The commentary also discussed the impact that DTC testing is having on the health care system.  For the four cases, this burden included the time and expense of four clinical-grade genetic tests, several echocardiograms and electrocardiograms for each patient, multiple visits with physician specialists, an MRI, and the implant and subsequent explant of an implantable cardioverter defibrillator, Moscarello said.

So what can be done?  The authors call for more research to determine the frequency and impact of people being affected by false positives in their raw genetic data interpretations. When a result with potential clinical significance is found, they recommend that it be sent for confirmation to a clinical-grade lab. This should occur before the consumer has to undergo costly clinical evaluations and tests, she said, concluding:

“It is clear that DTC genetic testing is here to stay, and for good reason. So it’s important to focus on maximizing the benefits of such large-scale, clinician-free testing, while minimizing the harms to consumers.

Collaboration between clinicians, consumers and the DTC genetic testing companies is a priority. I hope that DTC genetic testing companies will work with clinical genetics experts to create educational resources — so that consumers and non-specialist physicians know the data may be inaccurate, and what to do next if something is found.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.