Neurons in the brainstem promote REM sleep and trigger brainwaves that might cause dreaming

Dr. Amanda (Mandy) Schott was the lead author on this study. As a researcher, Mandy is most interested in defining neural circuits, and how specific populations of cells communicate to generate essential human behaviors such as sleep.

or technically,

A medullary hub for controlling REM sleep and pontine waves

[See Original Abstract on Pubmed]

Authors of the study: Amanda Schott, Justin Baik, Shinjae Chung & Franz Weber

Rapid eye movement (REM) sleep is the sleep state that most people associate with dreaming, however REM sleep has many other essential functions. While REM makes up only about 20-25% of our nightly sleep, it is vitally important for memory, emotional processing, and other functions we have yet to understand. This is true not just for humans, but all mammals and maybe even birds and reptiles! To facilitate all these functions of REM, the brain is highly active during this sleep state. In fact, during REM sleep, brain signals look more similar to wake than non-REM sleep. Because of this, REM sleep is sometimes called paradoxical sleep because paradoxically, the brain is so active during rest. 

Surprisingly, we still know very little about how the brain switches from low-activity non-REM sleep to high-activity REM sleep. Moreover, during REM sleep there are sometimes sporadic brain waves that seem to be important for normal brain function but whose precise role is still not totally clear. P-waves are one such waveform that is caused by lots of synchronous neuronal activity in the back of the brain, in a brainstem region called the pons. From the pons, P-waves travel forwards in the brain to brain regions important for forming and storing memories, and also areas involved in visual processing. These P-waves are interesting because they occur only during REM sleep, and are proposed to be involved in dreaming and the memory functions of REM sleep. A paper by recent NGG graduate Dr. Amanda Schott investigated two major unknowns in REM sleep research: 1) What neurons and brain regions are involved in generating REM sleep, and 2) What neurons and brain regions are involved in generating P-waves. Is it possible that one set of neurons could do both? 

While we know of several brain regions in the brainstem that regulate REM sleep, most of them consist of inhibitory neurons, meaning they “turn off’ other brain regions to promote REM sleep. Dr. Schott, however, found a highly unusual group of excitatory neurons in part of the brainstem called the dorsal medial medulla (dmM). These excitatory neurons can “turn-on” other neurons they make connections with. These dmM excitatory neurons were only active during REM sleep, suggesting they may be involved in  promoting REMs sleep. In addition, dmM neurons project their axons and send signals to the part of the pons that is known to generate p-waves. In fact, the dmM neurons were active at the same time the p-waves occurred suggesting that the dmM excitatory neurons could be involved in the generation of p-waves too! Dr. Schott next wanted to directly manipulate the activity of these neurons to see if they could cause transitions to REM sleep or cause generate p-waves. 

Using a modern neuroscience technique called optogenetics, Dr. Schott was able to cause the neurons in the dmM to fire when a laser light was shined over them through an optic fiber. She simultaneously determined if the mouse was awake, asleep, or in REM sleep by measuring the mouse’s brain waves using electroencephalography, or EEG. She found that stimulating these neurons caused the mouse to enter REM sleep, and also increased the length of REM sleep episodes. Shining the laser light also caused a p-wave to be generated when the light was shined about 60-100% of the time when the mouse was sleeping. Experimentally reducing the activity of the dmM neurons also decreased the amount of REM sleep, as well as the amount of p-waves. Dr. Schott interpreted these findings as evidence that dmM excitatory neurons are critical for normal amounts of REM sleep to occur, and for triggering p-waves. 

Overall, Dr. Shott’s work adds an important piece to the puzzle to our understanding of which brain regions can promote REM sleep. Her findings are an important first step in understanding which neurons generate p-waves which is ultimately necessary to understand p-wave function. This work will provide a foundation on which others (including the author of this piece!) can study the role of p-waves in REM sleep, and move closer to finally understanding how and why we dream.

About the brief writer: Emily Pickup

Emily is a 4th year PhD candidate in Dr. Franz Weber’s lab. She is interested in the biological functions of sleep. Specifically, she is interested in understanding the function of REM-specific p-waves. The large pontine waveform implicated in memory consolidation discussed in the brief above.

Interested in learning more about REM sleep and p-waves? See the original paper here.

Can we use maps of how brain regions are connected to better target brain stimulation?

Valerie Sydnor was the lead author on this study. Valerie is a PhD candidate in Ted Satterthwaite’s lab studying how brain plasticity changes throughout neurodevelopment. Valerie aims to uncover how developmental programs contribute to the emergence of youth psychiatric disorders.

or technically,

Cortical-subcortical structural connections support transcranial magnetic stimulation engagement of the amygdala

[See Original Abstract on Pubmed]

Authors of the study: Valerie J. Sydnor, Matthew Cieslack, Romain Duprat, Joseph Delusi, Matthew W. Flounders, Hannah Long, Morgan Scully, Nicholas L. Balderson, Yvette Sheline, Dani S. Bassett, Theodore D. Satterthwaite, and Desmond J. Oathes

In 2019, the World Health Organization estimated that 1 in every 8 people (that’s 970 million people around the world) were living with a mental health disorder. Over the course of the COVID-19 pandemic, as we experienced tremendous uncertainty, isolation, and loss, the prevalence of disorders like anxiety and depression increased by more than 25%. Although effective treatments for mental health conditions are available, for a substantial percentage of people with debilitating mental health symptoms, they don’t provide adequate relief. In a recent collaboration between the Oathes and Satherthwaite labs, Neuroscience Graduate Group student Valerie Sydnor explores how brain stimulation might offer a promising alternative treatment. 

As neuroscience and its technologies advance, it is becoming possible to more precisely design mental health treatments that target specific brain regions strongly linked to symptoms. For anxiety and depression, one key region is the amygdala, a place where the brain processes things like threats and negative experiences and controls how we respond (both emotionally and behaviorally). In people with anxiety and depression, the amygdala is often extra active. This means that the brain and the body can respond very strongly to scary, upsetting, or stressful situations and remain on high alert even after things have calmed down. We can think of the amygdala like a knob on the stove. If we crank up the heat for a prolonged period, symptoms of anxiety and depression begin to bubble up and boil over. If we were able to reach into the brain and turn the knob back down, perhaps we could provide some relief. 

New technologies, like brain stimulation, allow clinicians to do just that -- toggle brain activity in particular areas using magnetic fields, electrical currents, or even ultrasonic waves. Stimulation can be done even without reaching inside the brain. Techniques like transcranial magnetic stimulation (TMS) are non-invasive, meaning that the treatment (in this case a magnetic field designed to change brain activity) is safely applied using a device placed on the scalp. However, the skull and the brain are so dense that this non-invasive brain stimulation technology only works for targeting regions on the brain’s surface. The amygdala, buried deep within the brain, sits out of reach. 

In an attempt to extend the reach of non-invasive brain stimulation technology, Valerie, Dr. Desmond Oathes, and colleagues wondered if they could make use of the connections between brain regions. You see, the brain isn’t a collection of separate, independent parts. Rather, each brain region is connected to many other regions, forming a sprawling series of pathways that allow activity in one place to easily travel somewhere else. Conveniently, one of these neural pathways directly connects an area on the brain’s surface -- the ventrolateral prefrontal cortex (vlPFC), located on the side of your forehead -- to the amygdala. Just as you might pass through a city or two in order to get to your final destination, Valerie and Desmond figured that if they stimulated vlPFC, some of the activity evoked by the stimulation might pass through, continuing along the connecting pathway and ultimately affecting the amygdala.

There was some solid evidence that this amygdala-targeting strategy would work. Studies show that stimulating the vlPFC increases emotional regulation, reduces negative emotions, and improves mood. Valerie and Desmond speculated that these beneficial effects of brain stimulation applied to  vlPFC may actually stem from engagement of the pathway connecting vlPFC to amygdala and from subsequent reductions in amygdala activity. In other words, the vlPFC functions like our stove operator, using its connection to the amygdala to turn down activity when it’s getting too hot and emotionally charged.

To test this theory, Valerie, Desmond, and colleagues designed a clever (and difficult) experiment that allowed them to both non-invasively stimulate the brain and measure how its activity changed in specific regions. While 45 healthy individuals laid in a functional MRI (fMRI) scanner, the research team applied transcranial magnetic stimulation (TMS) to the vlPFC by placing a magnetic coil against the scalp above the brain region. After each pulse of brain stimulation was applied, they used the fMRI machine to take a quick snapshot of brain activity. This allowed them to examine how activity in the amygdala changed as a result of vlPFC stimulation, and to directly test whether stimulation effects traveled along the connecting neural pathway. 

Excitingly, the team found that stimulation applied to the scalp above vlPFC was able to decrease activity in the amygdala in 30 out of 45 participants. Given that the amygdala’s position deep within the brain was thought to be unreachable by non-invasive brain stimulation, this was a huge feat. Interestingly, amygdala activity tended to decrease by different amounts in different individuals. Wondering why, Valerie used an additional neuroimaging approach to create a map of the structural fibers (a more technical term for a neural pathway), connecting vlPFC and the amygdala for each person. Just as a highway with more lanes allows more traffic to pass through, could a denser connection (a thicker bundle of fibers) allow more stimulation to travel between regions? As it turns out, this was exactly the case! For a given individual, the extent to which neurostimulation was able to spread beyond the brain’s surface and affect amygdala activity depended on the density of their vlPFC-amygdala structural connection. Put simply, the stronger the connection between the vlPFC and the amygdala, the more easily the knob on the stove can be adjusted. 

Even though these results came from an experiment conducted with healthy participants, the ability of non-invasive brain stimulation to both target and decrease amygdala activity has clear implications for mental health treatment. Given the close link between amygdala activity and symptoms of anxiety and depression, brain stimulation represents an exciting new opportunity for people failing to find relief from existing medications and conventional talk therapy. More broadly, this work by Valerie, Desmond, and colleagues demonstrates -- for the first time -- that we can use the brain’s web of connections as a map to target specific brain regions for treatment purposes. Now, not only can we stimulate the amygdala in patients with anxiety and depression, but we can likely reach additional target regions throughout the brain with links to other mental health disorders.

About the brief writer: Kara McGaughey

Kara is a PhD candidate in Josh Gold’s lab studying how we make decisions in the face of uncertainty and instability. Combining electrophysiology and computational modeling, she’s investigating the neural mechanisms that may underlie this adaptive behavior.

Want to learn more about the potential for treating mental health conditions with brain stimulation? You can find Valerie’s full paper here! A list of nationally available resources for mental health and mental illness can also be found below.

Resources for Mental Health and Mental Illness:

National Institute of Mental Health: Information on Mental Disorders

https://www.nimh.nih.gov/health/topics/  

This web link will bring you to a page where you can learn more information about individual psychiatric disorders. Information on disorder symptoms, risk factors, available treatments/therapies, and relevant research is provided. Access this information for anxiety disorders, ADHD, autism spectrum disorder, bipolar disorder, depression, eating disorders, obsessive-compulsive disorder, PTSD, schizophrenia, substance use disorders, and others by clicking on the relevant link under “Mental Disorders and Related Topics”. 

National Suicide Prevention Lifeline

Call 1-800-273-TALK (8255); En español 1-888-628-9454

The Suicide Prevention Lifeline provides free, confidential emotional support to people in suicidal crisis or emotional distress. You can call above or use the chat below.

Use Lifeline Chat on the web (https://suicidepreventionlifeline.org/chat/)

The Lifeline is a free, confidential crisis service that is available to everyone 24 hours a day, seven days a week. The Lifeline connects people to the nearest crisis center. These centers provide crisis counseling and mental health referrals.

Crisis Text Line

Text “HELLO” to 741741 for free, 24/7 crisis counseling

The Crisis Text hotline is available 24 hours a day, seven days a week throughout the U.S. The Crisis Text Line serves anyone, in any type of crisis, connecting them with a crisis counselor who can provide support and information. The Crisis text line is available for any crisis, painful emotional experience, or time when you need support. When you text the line, a live crisis counselor receives the text and responds from a secure, online platform, typically within 5 minutes.

Substance Abuse and Mental Health Services Administration (SAMHSA)

For general information on mental health and to locate treatment services in your area, call the SAMHSA Treatment Referral Helpline at 1-800-662-HELP (4357). SAMHSA also has a Behavioral Health Treatment Locator on its website that can be searched by location. Navigate to the website and click the “Find Treatment” tab. The “Public Messages” tab also has useful information.

Health Resources and Services Administration (HRSA):

HRSA works to improve access to health care. The HRSA website has information on finding affordable healthcare.

Anxiety and Depression Association of America (https://adaa.org/)

Depression and Bipolar Support Alliance (https://www.dbsalliance.org/)

Apps for Therapy

Talkspace: Assessment and therapy provided online or via app. Provides online therapy, teen therapy, couples therapy, and medication management for psychiatric disorders.

BetterHelp: This app offers professional help from licensed therapists. You can message your therapist any time and schedule live sessions. The app is free to download, but therapy sessions cost money.

Apps for Coping with Stress, Anxiety, and Depression

Sanvello: Clinically validated techniques for reducing stress and treating anxiety and depression (free premium access during COVID-19 pandemic).

Depression CBT Self-Help Guide: Free app for helping to understand depression, factors that contribute to depression symptoms, and how to manage symptoms using cognitive-behavioral therapy.

Shine: Personalized self-care toolkit and community support, developed specifically for individuals of color.

WhatsUp: A free app that uses cognitive behavioral therapy and acceptance and commitment therapy methods to help with depression, anxiety, and stress. Includes a positive and negative habit tracker and helps identify thinking patterns.

Happify: Some free content; stress reduction and cognitive techniques for anxiety.

MindShift CBT: Free content, including cognitive behavioral therapy strategies to address general worry, social anxiety, and panic. Designed for teens and young adults.

COVID Coach: Created for everyone, including veterans and service members, to support self-care and overall mental health during the coronavirus pandemic.

Apps for Eating Disorder Support

Recovery Road: Free app for helping with eating disorder recovery and body positivity.

Apps for OCD Support

nOCD: Uses exposure response prevention treatment and mindfulness-based treatments to help with symptoms of OCD.

Apps for LGBTQ+ Mental Health

Pride Counseling: This app offers 1-on-1 sessions with a licensed counselor as well as group therapy and webinars for LGBTQ+ individuals. You can message your counselor any time and schedule phone, video, or chat sessions. You pay monthly.

Apps for Meditation and Relaxation

Headspace: Two-week free trial for the general public.

Calm: Seven-day free trial. A meditation, sleep, and relaxation app that also provides resources specifically for coping with COVID-19 anxiety.

Stop, Breathe & Think: Always free, and for kids too.

Insight Timer: Always free. This is not a daily app, but rather a great library where you can search for various types of meditations and lengths by excellent teachers.