September 2019 – Scientists Talk Funny

Will antidepressants work? Brain activity can help predict

You, or someone you care about, probably take an antidepressant — given that one in eight Americans do. Despite this widespread use, many experts question whether these drugs even work. Studies have shown that antidepressants are only slightly more effective than a placebo for treating depression.

“The interpretation of these studies is that antidepressants don’t work well as medications,” said Stanford psychiatrist and neurobiologist Amit Etkin, MD, PhD. “An alternative explanation is that the drugs work well for a small portion of people, but we’re giving them to too broad of a population and diminishing overall efficacy. Right now, we prescribe antidepressants based on patients’ clinical symptoms rather than an understanding of their biology.”

In a new study, Etkin and his collaborators sought a biologically-based method for predicting whether antidepressants will work for an individual patient.

The researchers analyzed data from the EMBARC study, the first randomized clinical trial for depression with both neuroimaging and a placebo control group. EMBARC included over 300 medication-free depressed outpatients who were randomized to receive either the antidepressant sertraline (brand name Zoloft) or a placebo for eight weeks.

Etkin’s team analyzed functional magnetic resonance imaging (fMRI) data — taken before treatment started — to view the patients’ brain activity while they performed an established emotional-conflict task. The researchers were interested in the brain circuitry that responds to emotion because depression is known to cause various changes in how emotions are processed and regulated.

During the task, the patients were shown pictures of faces and asked to categorize whether each facial expression depicted fear or happiness, while trying to ignore a word written across the face. The distracting word either matched or mismatched the facial expression. For example, the fearful face either had “happy” or “fear” written across it, as shown below.

Participants were asked to decide if this expression was happy or fearful.
(Image courtesy of Amit Etkins)

As expected, having a word that was incongruent with the facial expression slowed down the participants’ response time, but their brains were able to automatically adapt when a mismatch trial was followed by another mismatch trial.

“You experience the mismatched word as less interfering, causing less of a slowdown in your behavior, because your brain has gotten ready for it,” explained Etkin.

However, the participants varied in their ability to adapt. The study found that the people who could adapt well to the mismatched emotional stimuli had increased activity in certain brain regions, but they also had massively decreased activity in other brain regions — particularly in places important for emotional response and attention. In essence, these patients were better able to dampen the distracting effects of the stimuli.

Using machine learning, the researchers determined that they could use this fMRI brain activation signature to successfully predict which individual patients responded well to the antidepressant compared to the placebo.

“The better you’re able to dampen the effects of emotional stimuli on emotional and cognitive centers, the better you respond to an antidepressant medication compared to a placebo,” Etkin said. “This means that we’ve established a neurobiological signature reflective of the kind of person who is responsive to antidepressant treatment.”

This brain activation signature could be used to separate the people for whom a regular antidepressant works well from those who might need something new and more tailored. But it could also be used to assess potential interventions — such as medications, brain stimulation, cognitive training or mindfulness training — to help individuals become treatment responsive to antidepressants, he said.

“I think the most important result is that it turns out that antidepressants are not ineffective. In fact, they are quite effective compared to placebo if you give them to the right people. And we’ve identified who those people are using objective biological measures of brain activity.”

The team is currently investigating in clinics around the country whether they can replace the costly fMRI neuroimaging with electroencephalography, a less expensive and more widely available way to measure brain activity.

Etkin concluded with a hopeful message for all patients suffering from depression: “Our data echoes the experience that antidepressants really help some people. It’s just a question of who those people are. And our new understanding will hopefully accelerate the development of new medications for the people who don’t respond to an antidepressant compared to placebo because we also understand their biology.”

Feature image by inspiredImages

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

Looking beyond drug treatments for parasitic disease

A Stanford study investigates the barriers to controlling parasitic disease and possible interventions beyond mass drug and education campaigns.

Just two doses of praziquantel can effectively treat adults and children for schistosomiasis — a disease caused by parasitic worms that develop and multiply inside infected freshwater snails, and then enter the water and penetrate the skin of people who are bathing or fishing.

So why are 200 million people worldwide, mostly in sub-Saharan Africa, still suffering from schistosomiasis despite widespread administration of this antiparasitic drug? Why are people in some “hot spot” regions re-infected over and over?

A new study explored these questions by surveying 74 residents from four rural villages along the Senegal River, a region with very high rates of schistosomiasis despite mass drug administration campaigns. In each village, the field team conducted focused discussion groups separately for adult men, adult women and mixed-gender youth to facilitate open conversation among peers. These different groups are known to have varied activities involving contact with the parasite-infested water

The study made three key findings. First, the researchers learned that many residents have a fairly sophisticated understanding of schistosomiasis risk, including knowing where and when infections occur, even though they don’t understand the underlying biological details. For example, the villagers realize infection risk increases midday — an observation supported by studies, which show snails tend to shed parasites in daily cycles that peak around noon.

Second, the scientists determined that residents use their knowledge to develop strategies to reduce their exposure to the parasite, such as avoiding the river at certain times or forbidding urination and defecation near the river or lake. In addition to personal strategies, some villages adopt written village-wide rules for water use that are enforced with fines.

Lastly, despite having translated knowledge into strategies to reduce disease risk, the researchers found that the residents are still consistently exposed to the parasite because their rural livelihoods depend on the river and lakes — even in villages with limited piped water. They use surface water to cultivate crops. They wade in the water to fish and do laundry. They harvest the cattail reeds to use for roofs, fences or floor mats. And children play in the water.

“There is a feeling of inevitability around schistosomiasis infection, given the constraints of poverty,” said Susanne Sokolow, PhD, a Stanford disease ecologist and study author with the Woods Institute for the Environment, in a recent Stanford news release. “That jibes with the experience of the many years of efforts to distribute pills and carry out educational campaigns in the regions without a huge drop in schisto transmission or infection.”

Instead of focusing exclusively on mass praziquantel distribution, the researchers also recommend using local community input to develop diverse environmental strategies for reducing infection risk. Possible interventions include chemical or biological snail control, provision of sanitation facilities and laundry platforms, removal of vegetation to reduce snail habitats and behavioral change interventions.

According to the study authors, the key is to work with the local communities to select interventions that take into account their specific social and environmental factors.

Photo by eutrophication&hypoxia / Fundraising | Wikimedia Commons

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

SLAC summer programs encourage students to explore STEM careers

Proving that science can be fun, middle school students at the lab’s CORE Science Institute made giant soap bubbles to learn about thin film interference, which happens when light reflects off the two thin layers of soap film that form a bubble. (Jacqueline Orrell/SLAC National Accelerator Laboratory)

The Department of Energy’s SLAC National Accelerator Laboratory welcomed more than 300 science enthusiasts this summer – from middle schoolers to physics graduate students – for camps, institutes and internships aimed at encouraging them to become part of the science, technology, engineering and mathematics (STEM) community.

The youngest group – 18 students from Ile Omode, an African-centered middle school in Oakland – attended a week-long summer camp hosted by the Committee for Outreach, Recruitment & Engagement (CORE) Science Institute. The students learned about thin film interference from bubbles, coding and electronics from programming Arduino kits, electricity from a Van de Graaf generator and Newton’s laws of motion from playing basketball. They also learned the difference between science and engineering by taking apart old cell phones, and enjoyed the tasty results of a chemistry demonstration on how to make ice cream with liquid nitrogen.

CORE Science Institute students also worked in pairs to prepare and present a poster on one of these activities to a large cross section of SLAC employees. Camp organizer Margaux Lopez said she considers this poster session and the presentation skills it hones the most valuable part of the week.

The second annual SLAC Accelerating Girl’s Engagement in STEM (SAGE-S) summer program introduced high school girls to the work and lifestyles of scientists and engineers at SLAC. The 40 participants came from 30 public high schools, traveling from as far away as Santa Rosa, Sacramento and Gilroy.

Over the course of a week, the students heard talks by scientists and engineers, worked on team science projects and shadowed SLAC professionals as they went about their work. The girls also attended a professional growth program to develop critical skills like effective communication, under the guidance of organizers Diana Gamzina and Giulia Lanza. This year, the SAGE-S executive committee added a “leadership styles” exercise that emphasized the need for diverse approaches to leadership.

But the SAGE-S camp wasn’t all work. The students also enjoyed evening activities like building spaghetti-marshmallow towers and duct tape wallets at their Stanford dorms and stargazing at the Stanford and Foothill observatories. These relaxed activities allowed participants to make friends with other students and with the SLAC scientists and engineers who joined in.

More than 120 undergraduate students got a deeper immersion in the SLAC research community as summer interns through five internship programs. They were guided by organizers Enrique Cuellar and Alan Fry and mentored by SLAC scientists, engineers and other professionals. Interns participating in the two programs that were funded by DOE also wrote papers and gave presentations on their research at the end of the summer. This year, about a third of all the interns were women.

Many of these undergraduates participated in the Science Undergraduate Laboratory Internship (SULI) program, a DOE Office of Science-funded program that provides STEM research opportunities for students from both four-year and community colleges at 17 participating DOE laboratories and facilities. SLAC’s SULI interns also experienced life at Stanford by living in the dorms.

Another popular summer program, the Linac Coherent Light Source (LCLS) Internship program for undergraduates and graduate students, is funded by the LCLS Directorate at SLAC. These interns focused on hands-on laboratory, programming and data analysis projects for the LCLS and LCLS-II programs. They came from 26 colleges and universities, and many were from historically black colleges.

For community college students, the DOE Office of Science-funded Community College Internship (CCI) program provided housing on the Stanford campus and real-world technology experience at SLAC. Meanwhile, the STEM Core Community College program offered students from two local community colleges valuable experience as technicians and technologists at SLAC; the program was funded by Alameda County Workforce Development Corporation and facilitated by Growth Sector.

But what about those who dream of becoming STEM teachers rather than researchers? SLAC had that covered, too, with the STEM Teacher and Researcher (STAR) program, which is funded by Cal Poly, San Luis Obispo for students and alumni of California state universities and the National Science Foundation’s Robert Noyce Teacher Scholarship Program.

Based on past experience, you may meet some of these interns as long-term SLAC employees in the future.

Finally, as the summer nears its end, 120 physics graduate students and early-career scientists from all over the world just attended the SLAC Summer Institute (SSI). This year’s theme was the flavor physics associated with quarks, charged leptons and neutrinos. SSI participants attended lectures, topical conference talks and discussion sessions, did group projects and took tours. According to organizer Thomas Rizzo, the most requested team project used machine learning algorithms to identify electron and muon neutrino events in a liquid argon time projection chamber.

Participants also competed in a “wittiest answer to the question” contest, a highly competitive and long-standing tradition of SSI. This year the question was, “A discovery in the area of the Physics of Flavor could lead to the first clear signal of Beyond the Stanford Model physics. What will it be and how will it impact future developments in HEP?” The winning answer by Innes Bigaran predicted a detection of neutrinoless double beta decay that confirms the Majorana nature of neutrino mass and causes Ettore Majorana, who disappeared under mysterious circumstances in 1938, to reappear to accept a Nobel Prize.

You can find more information about SLAC’s educational and internship programs at https://careers.slac.stanford.edu/node/128

For questions or comments, contact the SLAC Office of Communications at communications@slac.stanford.edu.

This is a reposting of my news feature, courtesy of Department of Energy’s SLAC National Accelerator Center.

What type of concussion is it? The answer could affect treatment

Joe felt irritable and overwhelmed. Carla had blurry vision and didn’t feel safe to drive. Meg had a pounding headache. But all three of them received the same diagnosis: concussion.

Concussion symptoms vary for different people depending on their medical history, age, degree of injury and other factors. To develop the most effective, personalized treatments, concussion experts across the country are working to learn more about how these variables impact concussion symptoms and recovery.

The researchers — including pediatric emergency medicine physician Angela Lumba-Brown, MD, and neurosurgeon Jamshid Ghajar, MD, PhD, from Stanford’s Brain Performance Center — identified five categories of concussions, which have different symptoms and require different initial treatments:

Vestibular — Symptoms include dizziness, fogginess, lightheadedness, nausea, vertigo and disequilibrium. Initially treated with balance and vestibular-ocular training with a physical therapist.
Ocular-motor — Symptoms include difficulties with reading and driving, eye strain, problems changing focus between near and far, blurred or double vision, eye pain, vision-derived nausea and photophobia. Initially treated with dynamic vision training with an optometrist.
Headache — Symptoms include different types of headaches, including migraines. Initially treated with headache management.
Cognitive — Symptoms include problems with attention, reaction time, working memory, new learning, memory retrieval, organization of thoughts and behavior. Initially treated with neuropsychological assessment and treatments.
Anxiety-Mood — Symptoms include nervousness, hypervigilance, ruminative thoughts, depressed mood, anger, irritability, loss of energy, fatigue and feeling more emotional, overwhelmed or hopeless. Initially treated with counseling, including cognitive-behavioral therapies.

The findings appear in Neurosurgery.

However, diagnosing concussions and selecting the correct treatments is a bit more complicated than this list may indicate, Ghajar and Lumba-Brown explained. “These subtypes are not mutually exclusive and they frequently cluster together,” Ghajar said.

This interdependence isn’t all bad news though, because the headache, cognitive and anxiety-mood concussion subtypes often resolve after treating for vestibular and ocular-motor concussion symptoms. Also, early cardiovascular exercise is recommended for all subtypes.

In addition, the experts determined the prevalence of these concussion subtypes in adults and children based on a meta-analysis of previous studies. The most common subtype depends on when a patient is seen, as well as their medical history and age.

“Early on, the headache subtype is the most prevalent for both adult and pediatric populations, and it usually co-exists with the vestibular and ocular-motor subtypes,” said Ghajar. “Weeks to months after injury, the mood subtype with symptoms of anxiety and depression predominates, usually because of inadequate interventions. The prevalence of the vestibular subtype was also very high for pediatric patients.”

The working group also found that sleep disturbance and cervical strain were commonly associated with all five concussion categories. Sleep disturbance symptoms include difficulty falling asleep, frequent awakenings and fatigue, whereas cervical strain symptoms include neck pain, neck stiffness and upper extremity weakness.

According to Lumba-Brown, this work is particularly important because it addresses subtypes in children, a vulnerable subset of patients with unique needs. “Children are expected to go to school daily. They often play sports or engage in risk-taking behaviors. And they often have difficulty expressing their symptoms,” said Lumba-Brown, who recently helped develop clinical guidelines for children with mild traumatic brain injury.

The experts said they hope that a better understanding of the different kinds of concussions and their prevalence will ultimately translate into improved treatment and faster recovery for patients of all ages. The team is now investigating the recovery trajectories for the different subtypes — from the acute period through three months following injury.

They offered clinicians guidance in light of the findings: “Clinicians should assess each subtype of impairment in the acute setting following injury, encourage early cardio exercise and provide prognostic counseling for mood and sleep disturbances.”

Photo by Staff Sgt. Jonathon Fowler/U.S. Air Force

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