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.

A medication for opioid addiction may also help people suffering from depression.

or technically,

A role for the mu opioid receptor in the antidepressant effects of buprenorphine.

[See Original Abstract on Pubmed]

Authors of the study: Shivon A. Robinson, Rebecca L. Erickson, Caroline A. Browne, Irwin Lucki

Do you know someone frustrated by ineffective antidepressant treatment? Nearly one-third of patients with depression will not find relief with current antidepressant medication¹. Creating new medications for depression is tricky, because we still do not completely understand what is happening in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Furthermore, even if we developed a new antidepressant today, it would take over a decade for that medicine to become available to patients due to FDA regulations. To get around this issue, researchers are interested in finding new applications for drugs that have already been FDA approved for other illnesses. Repurposing an already-approved medication can greatly reduce the amount of time it takes for patients to receive effective treatment! Buprenorphine is a medication currently approved for the treatment of opioid addiction. Shivon Robinson, a neuroscience graduate student in Irwin Lucki’s lab, investigated whether buprenorphine could also be used to fight depression.

In her paper, Shivon demonstrated that buprenorphine reduced measures of depression in mice and she wanted to know how buprenorphine was having these effects. To assess depression-like symptoms in mice, she used what is called the “novelty-induced hypophagia” test, or NIH. NIH involves placing yummy treats (in this case, peanut butter chips) in the middle of an open, brightly lit chamber. Mice are generally wary of bright, open spaces so they will take some time to investigate the rest of the chamber before going to snack on the peanut butter chips. Conventional antidepressant medications will reduce the amount of time it takes for the mouse to approach the peanut butter chips, so other medications that do the same thing are thought to have similar effects as traditional antidepressants. She found that giving buprenorphine to mice before the test reduced the amount of time it took for the mice to approach the treats – just like current antidepressants!

After establishing that buprenorphine mimics traditional antidepressants in this task, Shivon wanted to know what buprenorphine was doing in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to help reduce depression-like symptoms in mice. Drugs interact with the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. by binding to receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., which convey chemical messages to neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and other cells. There are many different types of receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. produced by cells, and they only respond to specific drugs and molecules. When buprenorphine reaches the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., it binds to several types of receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., two of which are kappa opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. Shivon wondered if buprenorphine binding to one of these receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. types was important for the antidepressant effects they observed. She found that buprenorphine reduced depression-like behaviors in mice by binding to the mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., not the kappa opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. She further validated this finding by using a different drug, cyprodime, that binds exclusively to mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. Cyprodime also reduced the amount of time it takes for mice to approach the peanut butter chips, supporting the idea that activation of mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. by buprenorphine is important for antidepressant effects on this task.

This study represents an important step towards finding a potential new treatment for depression, an illness that affects nearly 7 million Americans annually. Depression is a disease that affects many different parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Shivon’s work demonstrates that mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. may play an important role in depression. Uncovering new ways that depression affects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can help us find effective treatments for patients that fail to respond to current antidepressants.

Meet the brief writer: Lexi Ellis

Citations:

1. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17(2):111–126.

If you are interested, check out this cited paper here.

Are teens uniquely susceptible to long-term effects of stress?

or technically,

Adolescent Chronic Unpredictable Stress Exposure Is a Sensitive Window for Long-Term Changes in Adult Behavior in Mice.

[See Original Abstract on Pubmed]

Authors of the study: Nicole L Yohn & Julie A Blendy

Stress happens. Whether it’s a dead car battery or a looming work deadline, stress is a fact of life. However, the types of stressors we experience and how they might affect us are constantly changing. Adolescence is one stage of life where these changes are particularly apparent. Most of us can appreciate how the nature of stressors change during adolescence (school pressures, dating and friendships, availability of drugs/sex/alcohol, huge physical and emotional developments, etc.), but less appreciated are the ways in which teens may be uniquely susceptible to the long-term and detrimental effects of these stressors.

This question of if and why adolescents are especially sensitive to stress shaped Nicole Yohn’s research at the University of Pennsylvania in the laboratory of Dr. Julie Blendy. Previous research has shown that human brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development is not fully completed until about the age of 25. In this sense, our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are still undergoing tremendous remodeling during our teenage years. Nicole wondered if exposure to stress during this period of continuing brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development may contribute to the increase in mental disorders, like anxiety, depression, and drug abuse, which often emerge during these years. This was an important question-- even though there’s plenty of research linking stress to mental disorders, there are very few studies looking at how the two are connected. Nicole set out to bridge that gap.

One of the most important (and most frustrating) aspects of stress is that it’s both chronic and unpredictable. In order to best model these aspects of stress in the lab, Nicole created a mouse model and designed her experiment such that each mouse was exposed to three different types of stressors a day for twelve consecutive days. These stressors consisted of things like food restriction, exposure to cold temperatures, isolation, and other unpleasant situations. To ask whether exposure to stress during adolescence is more damaging than exposure to stress during adulthood, Nicole compared two groups of mice-- one that faced these chronic and unpredictable stressors during puberty and one that experienced the stressors during adulthood. Both groups of mice were tested for behaviors associated with anxiety and depression, the most prevalent stress-related disorders.

So, does stress during particular stages of development alter susceptibility to mental illness? Nicole found that it seems to depend on exactly which mental illness we’re talking about. For example, Nicole observed depression-like behaviors in all mice exposed to stress, regardless of whether they experienced that stress during puberty or adulthood. In contrast, anxiety behaviors only appeared if stress occurred during adolescence, not adulthood. The sex of the mice also seemed to be an important factor in effects of stress on behavior. In one behavioral assessment, female mice showed more anxiety than males. This might mean that how we respond to stress may have something to do with sex-specific hormonesA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act..

Speaking of hormonesA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. and chemicals, Nicole wanted to look for a chemical that might underlie the different effects stress has on adolescents versus adults. One chemical she chose to investigate was corticotropin releasing factor (Crf) -- a hormoneA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. that’s released in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. when we feel stressed. Crf is responsible for the extra alertness or the feeling of butterflies in our stomachs we might notice before doing something important, like giving a presentation. While a short-term boost of Crf might be helpful in focusing our attention on the task at hand, too much Crf can be a bad thing. When looking at Crf levels in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of her mice, Nicole found increases only in mice that were exposed to stress during adolescence. Interesting, right? It seems like this increase in Crf could be what’s causing the development of anxiety in adolescent but not adult animals.

What do we know for sure? Nicole’s work suggests that mice are especially susceptible to stress during adolescence. She also showed that being female might make you even more susceptible to the long-lasting effects of stress. While more research is needed to determine whether these findings hold true for humans, Nicole has established a good model for future studies to look into how stress affects us throughout our lives, and how we might be able to prevent or lessen the damage it causes.

About the brief writer: Kara McGaughey

Fascinated by the long-standing linguistic connection between the gut and the brain ("gutsy," "gut feeling," "gut instinct," etc.), Kara is using her second year in NGG to examine the interplay between microbiota and brain development.

Controlling serotonin circuits in the brain with light manipulates mice into approaching or avoiding rodent bullies

or, technically, 
Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat. [See the original abstract on PubMed]

Authors: Collin Challis, Sheryl G. Beck, Olivier Berton

Brief prepared by: Collin Challis
Brief approved by: Isaac Perron and Yin Li
Section Chief: Shivon Robinson
Date posted: May 3, 2016 

Brief in Brief (TL;DR)

What do we know: Serotonin—a 'happiness' molecule in the brain—is important for making social decisions. The ventromedial prefrontal cortex is important for deciding what emotion we attach to things or people. 

What don’t we know: The specific way the brain is wired to control serotonin when we are deciding to approach or avoid a stranger. 

What this study shows: We can control whether a mouse approaches or avoids a new social partner by changing the activity of prefrontal cortical neurons that communicate with cells that inhibit serotonin neurons. 

What we can do in the future because of this study: We could find out if dysfunction in this brain wiring contributes to social symptoms of mood disorders and whether changing activity of this circuit can improve behavior. Future findings could also determine how changing the activity of this brain pathway affects serotonin actions in other brain regions, both long- and short-term. 

Why you should care: Current antidepressants, which broadly target serotonin in the brain, do not work well for many people. Instead of affecting all serotonin in the brain, new treatments that target specific parts of the brain (like the regions described here) may be more effective at treating patients with mood disorders.

Brief for Non-Neuroscientists

When we meet strangers, we make social decisions, including whether we want to approach or avoid them. These are based on social judgments made immediately and often unconsciously. People that are diagnosed with mood disorders, such as depression and anxiety disorders, often excessively avoid other people. Therefore, understanding how these social decisions are made can help us design new therapies to treat disorders involving skewed social decisions. Researchers have shown that altering levels of serotonin—a molecule in the brain thought to contribute to 'happiness'—can influence these decisions; however, scientists do not know which parts of the brain communicate to control this. In our study, we investigated how communication between a brain area important for processing social information (the prefrontal cortex) and a brain area that provides serotonin to the rest of the brain (the dorsal raphe) can affect social approach or avoidance decisions in mice. With a technique called optogenetics, which uses light from a laser to either increase or decrease communication between the prefrontal cortex and the dorsal raphe, we were able to change the social decisions made by mice. Understanding how brain wiring affects social behavior will improve our comprehension of mood disorders, such as depression, which may allow development of better therapies to treat those people affected.

Brief for Neuroscientists

Though it has long been known that serotonin can alter social perception, the underlying neural circuits that control serotonergic output during social interaction are complex. Previous mapping studies have shown that the ventromedial prefrontal cortex (vmPFC), an area of the brain believed to be important for encoding emotional value, sends excitatory projections to the serotonergic dorsal raphe nucleus (DRN). In this study, we first show that these vmPFC afferents actually synapse directly on GABA neurons in the DRN that then locally inhibit serotonin neurons. We then used optogenetics to manipulate this specific and direct pathway from the vmPFC to the DRN during social defeat, a paradigm that exposes mice to physical and sensory contact with a larger, more aggressive strain of mice and induces a long lasting form of social avoidance. We found that blocking vmPFC inputs to the DRN, thus disinhibiting serotonin neurons, prevented the social avoidance typically observed after defeat. Conversely, when we optogenetically activated the vmPFC terminals, these mice displayed strong social avoidance and a considerable delay in their decision to approach a social partner. Dissecting the role of the vmPFC-DRN in social decisions has implications for the social symptoms observed in mood disorders as well as the development of novel therapeutic treatments for these behaviors.