Panic disorder

Panic Attack Pathway Mapping Reveals Potential Off Ramp

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People with panic disorder may frequently and unexpectedly experience symptoms that include overwhelming fear, sweaty palms, shortness of breath, and rapid heart rate. Creating a map of the regions, neurons, and connections in the brain that mediate these panic attacks could provide guidance for developing more effective panic disorder therapeutics.

Illustration demonstrating how the neuropeptide PACAP mediates panic disorder and the overwhelming symptoms of a panic attack.
Illustration demonstrating how the neuropeptide PACAP mediates panic disorder and the overwhelming symptoms of a panic attack. [Salk Institute]

Salk researchers have started to construct such a map, with the discovery of a brain circuit that appears to mediate panic disorder. This circuit consists of specialized neurons that send and receive a neuropeptide called pituitary adenylate cyclase-activating polypeptide (PACAP). The results of their study in mice suggest that PACAP and the neurons that produce its receptor could feasibly represent druggable targets for future panic disorder treatments.

“We’ve been exploring different areas of the brain to understand where panic attacks start,” said Sung Han, PhD, associate professor at Salk. “Previously, we thought the amygdala, known as the brain’s fear center, was mainly responsible—but even people who have damage to their amygdala can still experience panic attacks, so we knew we needed to look elsewhere. Now, we’ve found a specific brain circuit outside of the amygdala that is linked to panic attacks and could inspire new panic disorder treatments that differ from current available panic disorder medications that typically target the brain’s serotonin system.”

Han is the senior author of the team’s published paper in Nature Neuroscience, titled, “A pontomesencephalic PACAPergic pathway underlying panic-like behavioral and somatic symptoms in mice,” in which the team concluded that their findings “… delineate a new  neural mechanism underlying panic-specific behavioral and somatic symptoms, which may facilitate the identification of therapeutic targets for the treatment of panic disorder.”

Anxiety disorders constitute the most common class of psychiatric diseases, and encompass post-traumatic stress disorder, generalized anxiety disorder, phobic disorders and panic disorder, the authors explained.

From left: Sukjae Kang and Sung Han.
From left: Sukjae Kang and Sung Han. [Salk Institute]

According to Han, despite panic disorders’ categorization as an anxiety disorder, there are many ways that anxiety and panic are different—like how panic induces many physical symptoms, like shortness of breath, pounding heart rate, sweating, and nausea, but anxiety does not induce those symptoms. Or how panic attacks are uncontrollable and often spontaneous, while other anxiety disorders, like post-traumatic stress disorder (PTSD), are more memory-based and have predictable triggers. These differences, says Han, are why it is critical to construct this panic disorder brain map, so that researchers can create therapeutics specially tailored to panic disorder. As the authors pointed out, “People with panic disorder experience recurrent, spontaneous panic attacks, which begin with feelings of uncontrollable fear and/or distress and rapidly progress to severe autonomic symptoms (for example, palpitation, hypertension, dizziness, nausea, vomiting, abdominal discomfort. This combination of unconditioned fear and somatic symptoms distinguishes panic disorder from other anxiety disorders.”

However, the team continued, “Neural mechanisms underlying these unique symptoms are not completely understood.” To begin sketching out a panic disorder brain map, the researchers looked at a part of the brain called the lateral parabrachial nucleus (PBL) in the pons (part of the brain stem), which is known as the brain’s alarm center. Interestingly, this small brainstem area also controls breathing, heart rate, and body temperature.

“The PBL regulates autonomic functions (for example, cardiorespiratory activity, body temperature), relays multimodal aversive sensory signals to the amygdala and, compellingly, coordinates breathing rate with anxiety,” the authors pointed out. Furthermore, they noted. the PBL is activated by panicogenic conditions in rodents, and possibly in humans. “The PBL is therefore a promising candidate for a neural substrate of panicogenesis.”

PAC1R-expressing dorsal raphe neurons in the mouse brain (red) serve as the projection targets for PACAP parabrachial neurons to mediate panic-like behavioral and physical symptoms.
PAC1R-expressing dorsal raphe neurons in the mouse brain (red) serve as the projection targets for PACAP parabrachial neurons to mediate panic-like behavioral and physical symptoms. [Salk Institute]

This brain area produces the neuropeptide, PACAP, which is known as the master regulator of stress responses. IPACAP is expressed abundantly in the PBL, and human studies have shown that changes to the PACAP gene, Adcyap1, and to the gene ADCYAPIRI encoding the PACAP type 1 receptor (PAC1R), are associated with panic disorder. “Therefore, we hypothesized that PBL PACAP neurons are crucial for panic-specific behavioral and somatic symptoms in mice,” the investigators stated.

As part of their study the team turned to a mouse model of panic attacks to confirm and expand their proposed map. Their investigations, including cell-type and projection-specific circuit monitoring, manipulation and mapping techniques, implicated the PBL in generating panic and bringing about emotional and physical changes.

“Emotional and stress-related behaviors have been associated with PACAP-expressing neurons in the past,” says co-first author Sukjae Kang, PhD, senior research associate in Han’s lab. “By mimicking panic attacks in the mice, we were able to watch those neurons’ activity and discover a unique connection between the PACAP brain circuit and panic disorder.”

They found that during a panic attack, PACAP-expressing neurons became activated. Once activated, they release PACAP neuropeptide messenger to another part of the brain called the dorsal raphe (DR), where neurons expressing PACAP receptors reside. The released PACAP messengers activate those receptor neurons, thereby producing panic-associated behavioral and physical symptoms in the mice. This connection between panic disorder and the PACAP brain circuit is an important step forward for mapping panic disorder in the brain, Han says.

The team also found that by inhibiting PACAP signaling, they could disrupt the flow of PACAP neuropeptides and reduce panic symptoms—a promising finding for the future development of panic disorder-specific therapeutics. “Chemogenetic or pharmacological inhibition of downstream PACAP receptor-expressing dorsal raphe neurons abolished the panic-like symptoms,” they wrote. Taken together, these findings demonstrate that the PACAPPBL→DR signaling pathway mediates panic disorder-specific behavioral and somatic symptoms … Therefore, the PACAPPBL → PAC1RDR signaling pathway is an ideal target for new therapeutic interventions for panic disorder.”

The team will look to explore PACAP-expressing neurons and PACAP neuropeptides as novel druggable targets for panic disorder. Additionally, they are hoping to further build out their map of panic disorder in the brain to see where the PACAP receptor-producing neurons in the dorsal raphe send their signals, and how other anxiety-related brain areas interact with the PACAP panic system. “

We found that the activity of PACAP-producing neurons in the brain’s parabrachial nucleus is inhibited during anxiety conditions and traumatic memory events—the mouse’s amygdala actually directly inhibits those neurons,” noted Han, who is also the Pioneer Fund Developmental Chair at Salk. “Because anxiety seems to be operating conversely to the panic brain circuit, it would be interesting to look at the interaction between anxiety and panic, since we need to explain now how people with anxiety disorder have a higher tendency to experience panic attack.”

Brain breakthrough opens door to cure for panic attacks

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A significant breakthrough could lead to the development of new medications that prevent panic attacks, researchers from the Salk Institute in California explain. The team identified a specific brain circuit composed of specialized neurons in mice. They believe this circuit can be manipulated to manage panic disorder effectively.

The team pinpointed a brain region responsible for initiating panic, which triggers both emotional and physical responses. Furthermore, the scientists discovered that inhibiting certain neural signals could diminish panic symptoms. This finding offers hope for creating drugs that could relieve panic disorder.

The Salk researchers charted the brain’s regions and connections involved in panic attacks. Their goal was to facilitate the creation of effective treatments in the future. Individuals with panic disorder frequently experience sudden, unexpected attacks. These episodes cause intense fear, sweaty palms, shortness of breath, and rapid heart rate.

To start mapping these brain regions, the researchers focused on the lateral parabrachial nucleus (PBL) within the brain stem. This area, known as the alarm center, is part of the pons and regulates breathing, heart rate, and body temperature.

Study authors found that the PBL plays a role in initiating panic and inducing emotional and physical changes. Additionally, this brain region produces the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide), a critical regulator of stress responses.

However, the exact relationship between these elements remained unclear. Therefore, the researchers conducted experiments on mice to confirm and refine their proposed brain map.

“Emotional and stress-related behaviors have been associated with PACAP-expressing neurons in the past,” says co-first author Sukjae Kang in a media release. “By mimicking panic attacks in the mice, we were able to watch those neurons’ activity and discover a unique connection between the PACAP brain circuit and panic disorder.”

Woman screaming from bad dream or nightmare
(© Prostock-studio – stock.adobe.com)

While studying the brains of mice during panic attacks, researchers discovered that neurons expressing the neuropeptide PACAP become activated. Upon activation, these neurons release the PACAP messenger to another brain region called the dorsal raphe, where neurons with PACAP receptors are located.

The released PACAP messengers then activate these receptor neurons, resulting in the mice exhibiting panic-associated behavioral and physical symptoms. This newly identified link between panic disorder and the PACAP brain circuit marks a significant advancement in understanding how panic disorder operates within the brain.

Furthermore, the team found that inhibiting PACAP signaling disrupted the flow of PACAP neuropeptides, leading to a reduction in panic symptoms. This discovery holds promise for the future development of targeted treatments for panic disorder.

Dr. Sung Han, the study’s senior author and an associate professor at the Salk Institute, notes that while panic disorder is classified as an anxiety disorder, it differs from anxiety in several ways. For instance, panic can trigger physical symptoms such as shortness of breath, rapid heart rate, sweating, and nausea, which are not typically induced by anxiety.

Additionally, panic attacks are often uncontrollable and spontaneous, unlike other anxiety disorders such as post-traumatic stress disorder (PTSD), which are more memory-based and have predictable triggers. According to Dr. Han, these distinctions underscore the importance of mapping the brain circuitry specific to panic disorder. Such mapping is crucial for developing treatments that are specifically tailored to address panic disorder.

“We found that the activity of PACAP-producing neurons in the brain’s parabrachial nucleus is inhibited during anxiety conditions and traumatic memory events—the mouse’s amygdala actually directly inhibits those neurons,” says Han, who is also the Pioneer Fund Developmental Chair at Salk.

“Because anxiety seems to be operating conversely to the panic brain circuit, it would be interesting to look at the interaction between anxiety and panic, since we need to explain now how people with anxiety disorder have a higher tendency to experience panic attack.”

Dr. Han’s team aims to investigate PACAP-expressing neurons and PACAP neuropeptides as potential targets for drugs treating panic disorder. The researchers, whose study is published in the journal Nature Neuroscience, also intend to expand their understanding of panic disorder’s neural map.

They plan to trace the pathways of PACAP receptor-producing neurons in the dorsal raphe to determine where these neurons send their signals. Additionally, they are interested in exploring how other brain areas associated with anxiety interact with the PACAP-related panic system.

You are enough. Always have been and always will be…

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“He who knows that enough is enough will always have enough.” ~ Lao Tzu

For years my life was defined by deep feelings of inadequacy as well as concurrent actions of striving to keep those feelings at bay. Even as a young child, I felt nothing I did was good enough, and I can still recall feelings of intense anxiety, sometimes terror, at simply waking up and knowing I had to go to school. While my parents meant well, I was inculcated with the belief that to be loved meant having to prove your worth each and every day, which meant doing things in a certain way—staying quiet, doing what you were told, getting good grades, taking certain subjects.  In other words, I was given a supposed checklist of success, which would supposedly lead to this elusive state called “happiness.”

I was taught to be competitive, to believe that my self-worth was directly tied to accomplishment.  I could not be of value unless I achieved something. This is a belief system embraced by many, and for me, it only served to deepen the feelings of emptiness and downright devastation that I experienced, especially if I failed at something.  When one lives in a constant state of competition, there is no such thing as ever being good enough.  One lives in a constant fear that you NEVER will be good enough. Even as I continually achieved and collected accolades, I suffered from constant panic attacks, chronic anxiety and depression.  Therapy and anti-depressants would provide short-lived respite.

However, even as I spent most of waking time dedicated to “doing,” part of me was suspicious of what the point exactly was to all this “doing.”  A secret voice was always asking, “Is this all there is?”  Part of me was deeply ashamed that this voice even existed. After all, society was reinforcing that I was doing things the “right way.”  I dutifully checked off the items on my checklist of success, completely believing that once I completed each task, I would be closer and closer to that state called “happiness.”  However, with each accomplishment, I only seemed to be further and further away from where I wanted to be. A part of me resigned myself to believing that perhaps what I really wanted could never be attained, that it was elusive and outside myself.  But even as I tried to give into resignation, that voice and its question “Is this all there is?” continued to plague me.  I had become an adult and done everything that was expected of me.  And I was completely miserable.

“Is this all there is?” became an accusation.  But I busied myself with tasks to which I attached great importance.  I cooked gourmet meals.  I traveled to faraway places.  I did yoga.  I went through the motions of what a good life was supposed to be, never realizing in all those years that what I had longed for resided within myself.  My self-worth still resided in the external— from accomplishments and material possessions, in the need for validation from others.  It never occurred to me that I could give myself validation because I had never been taught that.

I remember back in 2001 discovering a book by Thich Nhat Hanh, in which he spoke about suffering.  It struck a chord with me, but I could not understand it.  For he said to lessen suffering in the world, you had to reduce suffering within yourself.  That concept seemed completely foreign to me. I did not understand how lessening MY suffering could possibly lessen the suffering of others. So even when we are well-meaning in focusing on the suffering of others, it only serves to distract from addressing what needs to change within ourselves.

“We must be willing to let go of the life we planned so as to have the life that is waiting for us.” ~ Joseph Campbell

Fast forward to the present, I now realize that we cannot possibly give or receive love without knowing love within ourselves first.  And how did I finally understand this?  It was when I heard the words, “Who you are is enough.”  I don’t know from whom or exactly when I heard this, but the concept was so revolutionary to me that I shed tears.  And for the first time, I felt free.  I have heard this mantra echoed numerous times from many spiritual teachings and teachers since hearing it the first time, but I finally understood what Thich Nhat Hanh meant.

I have dedicated the past few years to releasing my old belief systems related to worthiness. When the inner voice asked the question “Is there all there is?”, it was really asking, “Are you good enough?”  And the answer has been and always will be, “I am enough.”

You are enough. Always have been and always will be…

Do you think your life would look any different if you knew that you were enough?