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Bringing Out the Best in Us During the Pandemic

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Pablo Vidal-Ribas Belil at the grocery store
Caption: Pablo Vidal-Ribas visiting a supermarket to pick up groceries for four neighbors. Credit: Pablo Vidal-Ribas

Sheltering at home for more than two months has made many of us acutely aware of just how much we miss getting out and interacting with other human beings. For some, the coronavirus disease 2019 (COVID-19) pandemic has also triggered a more selfless need: to be a good neighbor to the most vulnerable among us and help them stay well, both mentally and physically, during this trying time.

The term “good neighbor” definitely applies to Pablo Vidal-Ribas Belil, a postdoctoral fellow at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Though Vidal-Ribas has his hands full caring for his 4-year-old son in their condo, which is located near NIH’s main campus in Bethesda, MD, he wasn’t too busy to notice that some of his neighbors were in need of help.

Vidal-Ribas extended a helping hand to pick up groceries and prescriptions for the older woman downstairs, as well as several more of his elderly neighbors. He and other concerned neighbors also began enlisting more volunteers to join a neighborhood coronavirus task force. There are now up to 30 volunteers and sometimes hold virtual meetings.

To try to reach everyone in the more than 950-unit Parkside Condominium community, the group coordinated its activities with the help of the management office. They also issued flyers and email messages via the neighborhood list serv, offering to assist people at greatest risk for COVID-19, including seniors and those with compromised immune systems or other serious conditions, by shopping for essential items and dropping the items off at their doors.

The personal interest and care of Vidal-Ribas also comes with medical expertise: he’s a clinical psychologist by training. Vidal-Ribas, who is originally from Barcelona, Spain, came to the United States four years ago to work with an NIH lab that specializes in the study of depression and related conditions in young people. Last year, Vidal-Ribas moved to NICHD as a Social and Behavioral Sciences Branch Fellow, where he now works with Stephen Gilman. There, he explores prenatal and early developmental factors that contribute to attempts at suicide later in life.

His expertise as a psychologist has come in handy. Vidal-Ribas has found that many of the individuals requesting help with grocery items or prescriptions also want to talk. So, the team’s efforts go a long way toward providing not only basic necessities, but also much-needed social and emotional support.

In recognition of this need, the group has expanded to offer virtual chats and other community activities, such as physically distanced games, conversations, or story times. One talented young volunteer has even offered to give music concerts remotely by request. Folks know they can call on Vidal-Ribas and some of the most active task force volunteers at any time.

Vidal-Ribas reports that they’ve taken great care to follow the latest guidelines from the Centers for Disease Control and Prevention on how to protect yourself and others from COVID-19 to ensure that those volunteering their time do so safely. He and other volunteers typically buy for multiple neighbors at once while they do their own personal shopping to reduce the number of outings. They then leave the bags with groceries or prescriptions at their neighbors’ doors with no direct contact. As far as he knows, none of his vulnerable neighbors have come down with COVID-19.

Vidal-Ribas says he’s prepared to continue his volunteer outreach for as long as it takes. And, even when the threat of COVID-19 subsides, he’ll keep on lending a hand to his neighbors. It’s one of the ways he stays connected to his community and grounded within himself during this difficult time. By sharing his story, he hopes it will inspire others to do what they can to help others in need to stay safe and well.

Links:

Coronavirus (COVID-19) (NIH)

Social and Behavioral Sciences Branch Fellows (National Institute of Child Health and Human Development/NIH)

Stephen Gilman ((National Institute of Child Health and Human Development/NIH)


Dealing with Stress, Anxiety, and Grief during COVID-19

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Zoom conversation between Joshua Gordon and Francis Collins

If somebody had told you last year that that our country, along with the whole world, would soon be facing a major health challenge like the coronavirus disease 2019 (COVID-19) pandemic, you’d have thought it almost unimaginable. Yet here we are.

To help flatten the pandemic’s deadly curve, a great many of us have been asked to remain at home. I have been faithfully adhering to that recommendation—I haven’t been to my office or lab at NIH in almost three weeks, though I can’t remember a time where I have worked harder. While helping to protect ourselves and others, this physical distancing can affect our mental well-being.

Recently, I had an opportunity to discuss these aspects of COVID-19 with Dr. Joshua Gordon, Director of NIH’s National Institute of Mental Health. Our conversation took place via videoconferencing, with him linking in from his home in the New York area and me from my home in Maryland. Here’s a condensed transcript of our chat:

Collins: So, Josh, tell me how you’re doing there. How’s everybody coping?

Gordon: Right now, my family and I are doing fine. My daughter and I are ensconced here at home, both working from home. She’s finishing up high school online and my wife works for New York City. She’s an essential employee, so she’s still going into work but, fortunately, she’s able to make sure that her workspace is very sparse and she’s able to commute by herself.

Collins: I’m glad you’re okay. Exactly how do you name this kind of stress that everybody’s feeling right now? Is it fear? Is it anxiety about being put in such an area of uncertainty? Is it just grief, the sense that something really profound has happened here and we are losing things in terms of our ability to move around freely? Certainly, we also grieve deeply about the suffering and the death that we see.

Gordon: For different people, it’s different combinations. I know that I feel anxiety for myself and my family in terms of our health. But it’s not just anxiety about contracting the coronavirus, it’s also fear and anxiety about what’s happening to society, what’s happening to our economy, what’s happening to our friends and relatives.

And then there is tremendous grief. We’ve acknowledged that we’ve all lost something already. Right? We’ve lost our normal day-to-day interactions. We’ve lost our ability to physically connect with people and it makes it more challenging to socially connect with people. And we’ve lost that sense of certainty and self-power.

Collins: Talking to my wife Diane about this, I think the grief part of it was something we were both feeling, but hadn’t quite named. Somehow being able to talk about it, experience it, and not try to run away from it turned out to be helpful.

Gordon: Yes, it’s important to talk about it. For most people, it’s a matter of being able to talk about your feelings, get it out into the open, and hear from others that are going through the same thing. They’re your friends that you’re Zooming with, they’re your parents or grandparents that you’re talking to on the phone.

Collins: I hope everybody will feel a little more free to be honest about what they are going through. Maybe sometimes we try to just be tough and keep it all to ourselves and don’t want others around us to be influenced, if we’re talking about our own emotions. But we need to share those things. Besides that, what other things, can be helpful to people who are trying to cope with the current circumstances?

Gordon: One important thing is to focus on the facts. There’s a lot of rumor, there’s a lot of hyperbole out there, and there’s a lot of, frankly, uncertainty. But to the extent that you can, learn and share the facts about the virus. If you know what’s happening, it reduces the uncertainty.

At the same time, one can get so taken up with reading the daily news, listening to the various news conferences that are going on, checking the websites, etc., that it becomes all-consuming. So, it’s really important to set aside periods of each day where you turn off social media, you turn off the TV, turn off the news, and do something that you enjoy. It could be art, it could be exercise, it could be picking up the phone and talking to someone about something other than COVID.

The other thing that’s really important is to take care of your body in addition to your mind. Taking care of your body can help your mind do better. So, yoga, exercise, resting, naps, regular meals, all these things can be helpful. Alcohol is often used as an escape mechanism when you’re feeling stressed. That can be a little tricky or dangerous, so try to avoid drinking excessively.

Connecting with others is really important in this day of physical distancing. I like to call it physical distancing, rather than social distancing, because I think we can be socially intimate and physically distant. So, connect with others, reach out to people, use digital tools, use telephones, use email and text, write a letter.

Collins: A letter?

Gordon: Yes, why not? I haven’t gotten mail for three days. Just saying. So, write a letter, connect with people that you can unwind with, that you can get joy from.

Collins: My wife Diane just stepped in and I want to have her to come over for a minute and say something about this, because I think part of the grief we were feeling was this disconnection from face-to-face interactions with people. Diane’s a very sociable person and this is particularly hard when you’re so isolated in one place. But she came up with something yesterday that seemed to be a help.

Diane Baker: Yes. I’ve got to say, the shelter in place order here in Maryland just surprised me. It took me down a couple of notches and I can’t say it was warranted, I was like I can’t take this. Even though it’s what we’ve been doing, it just emotionally really got to me. And so a friend came up with this idea. She went for a walk in her neighborhood, I went for a walk in my neighborhood, we pulled our phones out and we had a conversation. Even though it was cold rainy day, we didn’t mind it because we were talking to each other. So, we’re going to try and do that on a regular basis.

Gordon: You’re right, your social connectedness really helps. Like I can reach out to my parents in North Carolina, I can reach out to my brother in Philadelphia. We’ve had almost nightly Zoom get-togethers and I actually feel like I’m seeing my relatives more these last couple of weeks than I have in months.

Collins: That’s interesting. We’ve done that too. Every Sunday now we have a Zoom meeting with my daughters and my grandkids.

Diane Baker: The other thing I think it’s done is forced us to be more intentional about our communication. I think that’s something we take for granted. For instance, I have this book club I’ve been a part of for a long time, but we always talk books and politics and topical issues. Now, I’m starting to reach out to them on email and say, “Hey, I’m having a real tough time,” and we’re supporting each other in a way that we haven’t before. It’s been very nice. I’ll let you guys go on..

Gordon: Nice to see you, Diane.

Collins: I think we all feel this urge to do something, to try to contribute in some way. In many ways, we feel a little paralyzed by the fact that we’re stuck indoors and all of the things you might like to do might be risky for yourself or other people. What can we do as far as actions to help other people?

Gordon: Those of you who are working directly on COVID can take a lot of pride in the fact that you’re contributing to that mission. But everyone is contributing to that mission by staying home. I would add a more practical bent to all this, which is that it is important to set goals and priorities for yourself. Finally, there are volunteer opportunities that can be done remotely. There are donations that are being accepted. So, I encourage you, if you feel so moved and have the means to do so, contribute in that way.

Collins: Parents are worried about their kids in terms of how this is affecting them. So, what kind of advice can you give to parents about how to interact with children in this very unusual situation?

Gordon: Kids are, I’m sure, feeling anxious. First, recognize what they’re going through. Talk to them about it, find out what’s concerning them.

Kids always surprise you. They’re not necessarily anxious or worried about the things that you’re anxious or worried about. They might be worried about getting COVID, but they might also just be worried that they’re going to miss their best friend’s birthday next week. So, if you find out what’s bothering them, then you can help them. You can have them Zoom a happy birthday song or connect in some other way.

Reassuring them can help. But, more importantly, it’s just answering their questions as honestly as you can. When you don’t know, admit that you don’t, but say that you’ll be there for them.

Collins: Everybody is facing a certain amount of stress, anxiety, and grief at this time, but it hits some people even harder. What would be the signs that this is getting into a circumstance that might require some additional help?

Gordon: Let’s talk about how we recognize when this might be a thing that we can’t deal with and that is sending us over the edge. I went out grocery shopping last Friday. I managed to find a mask to wear and gloves, but I actually couldn’t take it. I was so anxious. I bought a few things and I had to leave. I felt in me something I’ve really never felt before. My heart started racing, I started breathing fast. I was getting a panic attack. That was something pushing me over the edge in ways that I hadn’t been challenged before.

If that happens to you, recognize it and seek help. So, what are the signs? We’re all feeling anxious, but if you feel so anxious you can’t get your work done, you actually can’t do the thing that you set out to do, reach out for help either from a friend or from a professional. Other signs would be you’re starting to withdraw from people, having trouble sleeping, change in appetite, change in physical energy levels, or starting to become irritable or angry.

For those with pre-existing mental illnesses, it’s really important that they reach out to their providers and find ways of connecting. Every mental health provider that I know of right now is moving to telehealth sessions. Not everyone is used to teleconferences, not everyone knows how to use them. So, plan in advance with your provider how you’re going to contact with them so that you can get the help you need when you need it. Make sure that you have enough medication in-house and work out with your pharmacy how you can get it delivered rather than having to go pick it up, whether that’s from a mail order pharmacy or getting your local pharmacy to deliver to you.

Finally, there are hot lines. For those experiencing distress with the COVID epidemic, the Substance Abuse and Mental Health Service Administration has the Disaster Distress Helpline. That’s 800-985-5990 or text “TalkWithUs” to 66746. For those who are really struggling, and are thinking of hurting or killing themselves, there’s the National Suicide Prevention Lifeline at 800-273-8255 or you can text “HOME” to the Crisis Text Line at 741741.

Collins: Before we close, I’d like to talk about how, despite the stress, the anxiety, and the grief that we’re all feeling, we might somehow learn something pretty significant about ourselves during this pandemic. Can you say something about that?

Gordon: One thing we know is that resilience isn’t necessarily about something you already have. It’s something that you learn, that people who’ve been through challenging times and risen to the occasion, they learn from that. They become resilient. They learn how to get through challenging situations in the future.

For many of us, this is an opportunity to learn more about ourselves and how we can grow as people, as human beings, and as fathers and mothers and daughters and sons. This is an opportunity to prove that we can respond to an emergency like this in a way that is thoughtful, in a way that is caring, and in a way that contributes to improving the situation for all of us

Collins: It does call us, doesn’t it, to focus on things that in our daily rush of business as usual, we neglect to think about. What are we really here for? What’s the meaning of all of this? What is our responsibility to try to make the world a better place?

I’d predict that all of us who are living through this COVID-19 experience will look back on it as a time of special significance in terms of what we learned about ourselves and about the perspective of what really matters in this world. So, yes, it’s stressful, it’s full of grief and sorrow, but maybe it’s a way in which you can gain something to carry forward. Josh, thank you so much.

Resources:

The Disaster Distress Helpline, 1-800-985-5990 (Substance Abuse and Mental Health Services Administration)

National Suicide Prevention Lifeline, 1-800-273-8255

Crisis Text Line, 741741

Coping with Coronavirus: Managing Stress, Fear, and Anxiety, Director’s Messages (National Institute of Mental Health/NIH)

Stress and Coping, Coronavirus (Centers for Disease Control and Prevention)

Coronavirus (COVID-19) (NIH)


Multiplex Rainbow Technology Offers New View of the Brain

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Proteins imaged with this new approach
Caption: Confocal LNA-PRISM imaging of neuronal synapses. Conventional images of cell nuclei and two proteins (top row, three images on the left), along with 11 PRISM images of proteins and one composite, multiplexed image (bottom row, right). Credit: Adapted from Guo SM, Nature Communications, 2019

The NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is revolutionizing our understanding of how the brain works through its creation of new imaging tools. One of the latest advances—used to produce this rainbow of images—makes it possible to view dozens of proteins in rapid succession in a single tissue sample containing thousands of neural connections, or synapses.

Apart from their colors, most of these images look nearly identical at first glance. But, upon closer inspection, you’ll see some subtle differences among them in both intensity and pattern. That’s because the images capture different proteins within the complex network of synapses—and those proteins may be present in that network in different amounts and locations. Such findings may shed light on key differences among synapses, as well as provide new clues into the roles that synaptic proteins may play in schizophrenia and various other neurological disorders.

Synapses contain hundreds of proteins that regulate the release of chemicals called neurotransmitters, which allow neurons to communicate. Each synaptic protein has its own specific job in the process. But there have been longstanding technical difficulties in observing synaptic proteins at work. Conventional fluorescence microscopy can visualize at most four proteins in a synapse.

As described in Nature Communications [1], researchers led by Mark Bathe, Massachusetts Institute of Technology (MIT), Cambridge, and Jeffrey Cottrell, Broad Institute of MIT and Harvard, Cambridge, have just upped this number considerably while delivering high quality images. They did it by adapting an existing imaging method called DNA PAINT [2]. The researchers call their adapted method PRISM. It is short for: Probe-based Imaging for Sequential Multiplexing.

Here’s how it works: First, researchers label proteins or other molecules of interest using antibodies that recognize those proteins. Those antibodies include a unique DNA probe that helps with the next important step: making the proteins visible under a microscope.

To do it, they deliver short snippets of complementary fluorescent DNA, which bind the DNA-antibody probes. While each protein of interest is imaged separately, researchers can easily wash the probes from a sample to allow a series of images to be generated, each capturing a different protein of interest.

In the original DNA PAINT, the DNA strands bind and unbind periodically to create a blinking fluorescence that can be captured using super-resolution microscopy. But that makes the process slow, requiring about half an hour for each protein.

To speed things up with PRISM, Bathe and his colleagues altered the fluorescent DNA probes. They used synthetic DNA that’s specially designed to bind more tightly or “lock” to the DNA-antibody. This gives a much brighter signal without the blinking effect. As a result, the imaging can be done faster, though at slightly lower resolution.

Though the team now captures images of 12 proteins within a sample in about an hour, this is just a start. As more DNA-antibody probes are developed for synaptic proteins, the team can readily ramp up this number to 30 protein targets.

Thanks to the BRAIN Initiative, researchers now possess a powerful new tool to study neurons. PRISM will help them learn more mechanistically about the inner workings of synapses and how they contribute to a range of neurological conditions.

References:

[1] Multiplexed and high-throughput neuronal fluorescence imaging with diffusible probes. Guo SM, Veneziano R, Gordonov S, Li L, Danielson E, Perez de Arce K, Park D, Kulesa AB, Wamhoff EC, Blainey PC, Boyden ES, Cottrell JR, Bathe M. Nat Commun. 2019 Sep 26;10(1):4377.

[2] Super-resolution microscopy with DNA-PAINT. Schnitzbauer J, Strauss MT, Schlichthaerle T, Schueder F, Jungmann R. Nat Protoc. 2017 Jun;12(6):1198-1228.

Links:

Schizophrenia (National Institute of Mental Health)

Mark Bathe (Massachusetts Institute of Technology, Cambridge)

Jeffrey Cottrell (Broad Institute of MIT and Harvard, Cambridge)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Mental Health; National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; National Institute of Environmental Health Sciences


Mood-Altering Messenger Goes Nuclear

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Serotonin

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

These data begged the question: Is serotonylation important in the brain and/or other living tissues that produce serotonin in vivo? After a lot of hard work, the answer now appears to be yes.

These NIH-supported researchers found that serotonylation does indeed occur in the cell nucleus. They also identified a particular enzyme that directly attaches serotonin molecules to histone proteins. With serotonin attached, DNA loosens on its spool, allowing for increased gene expression.

The team found that histone serotonylation takes place in serotonin-producing human neurons derived from induced pluripotent stem cells (iPSCs). They also observed this process occurring in the brains of developing mice.

In fact, the researchers found evidence of those serotonin marks in many parts of the body. They are especially prevalent in the brain and gut, where serotonin also is produced in significant amounts. Those marks consistently correlate with areas of active gene expression.

The serotonin mark often occurs on histones in combination with a second methyl mark. The researchers suggest that this double marking of histones might help to further reinforce an active state of gene expression.

This work demonstrates that serotonin can directly influence gene expression in a manner that’s wholly separate from its previously known role in transmitting chemical messages from one neuron to the next. And, there are likely other surprises in store.

The newly discovered role of serotonin in modifying gene expression may contribute significantly to our understanding of mood disorders and other psychiatric conditions with known links to serotonin signals, suggesting potentially new targets for therapeutic intervention. But for now, this fundamental discovery raises many more intriguing questions than it answers.

Science is full of surprises, and this paper is definitely one of them. Will this kind of histone marking occur with other chemical messengers, such as dopamine and acetylcholine? This unexpected discovery now allows us to track serotonin and perhaps some of the brain’s other chemical messengers to see what they might be doing in the cell nucleus and whether this information might one day help in treating the millions of Americans with mood and behavioral disorders.

Reference:

[1] Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H 3rd, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, Maze I. Nature. 2019 Mar 13. [Epub ahead of print]

Links:

Any Mood Disorder (National Institute of Mental Health/NIH)

Drugs, Brains, and Behavior: The Science of Addiction (National Institute on Drug Abuse/NIH)

Epigenomics (National Human Genome Research Institute/NIH)

Maze Lab (Icahn School of Medicine at Mount Sinai, New York, NY)

NIH Support: National Institute on Drug Abuse; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute


Measuring Brain Chemistry

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Anne Andrews

Anne Andrews
Credit: From the American Chemical Society’s “Personal Stories of Discovery”

Serotonin is one of the chemical messengers that nerve cells in the brain use to communicate. Modifying serotonin levels is one way that antidepressant and anti-anxiety medications are thought to work and help people feel better. But the precise nature of serotonin’s role in the brain is largely unknown.

That’s why Anne Andrews set out in the mid-1990s as a fellow at NIH’s National Institute of Mental Health to explore changes in serotonin levels in the brains of anxious mice. But she quickly realized it wasn’t possible. The tools available for measuring serotonin—and most other neurochemicals in the brain—couldn’t offer the needed precision to conduct her studies.

Instead of giving up, Andrews did something about it. In the late 1990s, she began formulating an idea for a neural probe to make direct and precise measurements of brain chemistry. Her progress was initially slow, partly because the probe she envisioned was technologically ahead of its time. Now at the University of California, Los Angeles (UCLA) more than 15 years later, she’s nearly there. Buoyed by recent scientific breakthroughs, the right team to get the job done, and the support of a 2017 NIH Director’s Transformative Research Award, Andrews expects to have the first fully functional devices ready within the next two years.


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