The Neuroscience of Anxiety Disorders
Anxiety is a native language to all humans.
Let’s imagine anxiety as a 100-floor skyscraper with a metaphorical elevator capable of containing the entire world’s population (sorry if you’re claustrophobic or afraid of heights). Each floor of Anxiety Estates represents a different baseline level of anxiety. As the elevator makes its long journey to the top, some low-anxiety folks get off at the 5th floor, slightly more step off onto the 25th floor, but the majority (50%) get off at the 50th floor. Spoiler alert: I am describing a normal distribution for those familiar with Gaussian functions.
Unfortunately for those of us with anxiety disorders, the elevator doesn’t stop at the 50th floor. The exact level of anxiety that characterizes a “disorder” is entirely dependent on the individual experiencing the anxiety. “Normal” anxiety crosses the threshold into a disorder when it causes significant distress and impairment in social, occupational, or other important areas of functioning (1).
Some of us may tolerate the 65th floor of Anxiety Estates while others will be paralyzed and unable to function.
The point of this thought experiment is to impress upon the reader that mental illness is a matter of normative psychological extremes rather than novel pathology.
This means that the underlying mechanism of any mental illness is adaptive and present throughout the human population. A mental disorder is not a new and aberrant development of the human mind but an under- or over-representation of a native mechanism. Even schizophrenia, an extremely disabling disease, involves genes that have been selected for by evolutionary pressures because of their adaptive nature in healthy individuals (11).
We will maintain this concept throughout our ensuing discussion of anxiety. First let’s examine nonclinical anxiety so that we can better understand clinical anxiety disorders.
“Anxiety” and “fear” are often used interchangeably but are considered separate entities in the neuroscientific community. Fear is the physiological reaction to something in our external or internal environment. Fear causes our heart to race when we see a snake in our path.
Anxiety on the other hand is the psychological and emotional reaction to the aforementioned environmental stimulus. Anxiety is the conscious worry and sense of subconscious unease that we experience when we observe the slithering serpent before us.
If fear were jumping into an ice-cold body of water, anxiety would be wading slowly in.
Anxiety and fear share an intimate relationship. In fact, anxiety has been conceptualized as a syndrome of abnormal fear response and avoidance (2). Fear is much easier to study as compared to anxiety because it produces biological outputs that we can measure: increased blood pressure, pulse, respiration rate, etc. For the aforementioned reason, many of the studies I will discuss have utilized insights into fear circuits to extrapolate anxiety circuits.
I feel it necessary to include the disclaimer that the anxiety circuits we will discuss are based on decades of study but are still hypotheses nonetheless. Establishing causation is a very complex matter, and as scientists we often have to settle for well-supported correlation.
I would highly recommend reviewing my previous article The Neuroscience of Mindfulness & Anxiety to review the role of the various components of the limbic system in the fear response. And I would recommend reviewing Default Mode Network, Meditation, & Mindfulness for information about higher cortical processing involved in our conscious experience of the world. That being said, I will attempt to repeat myself whenever I can to allow the reader to use this article as a standalone work.
To begin, allow me to introduce the cast of characters that we will consider in our discussion of anxiety.
The lead role will be played by the amygdala.
The amygdala acts as an emotional radar gun for internal and external experiences. The amygdala colors our direct experience and memories depending on the emotional “speed” of an event. It is most often associated with fear because this is an easy emotion to study and a great deal has been written about it. But the amygdala is involved in a wide array of emotions.
The amygdala has direct inputs and outputs to a large number of structures in the brain and as such exerts enormous conscious, subconscious, and unconscious control over our lives. One of the most important outputs from the amygdala leads to the brainstem and hypothalamus, both of which influence our heart rate, breathing, and blood pressure.
We will refer to the amygdala as the Emoter because it produces the raw emotional and physiological content that we experience as conscious anxiety.
The insula is the next structure that we must consider in our quest to explain anxiety. The insula processes our internal states such as our heartbeat, breath, gurgling stomach, or full bladder. I have previously named the insula the Internal Sensor because of this role.
The medial prefrontal cortex (mPFC) functions as the Emotional Sensor. The mPFC/Emotional Sensor is activated when we consciously or subconsciously experience emotion, negative mood, or self-referential thought (3).
The anterior cingulate cortex (ACC) facilitates our attentional focus, allowing us to attend to our emotional, cognitive, and sensory experience. The ACC monitors and signals the need to exert conscious control over our emotional, cognitive, or sensory experience (4). For the aforementioned reasons I have nicknamed the ACC the Attender.
The final member of our cast is the lateral prefrontal cortex (lPFC). The lPFC is responsible for attentional direction, conscious decision-making, and working memory. Working memory is the etch-a-sketch of our mind. It allows us to remember a phone number long enough to dial or to follow a complicated set of directions.
Because of the supervisory role of the lPFC we will refer to it as the Director.
Let me run the credits before we begin the show.
We have the amygdala/Emoter, mPFC/Emotional Sensor, insula/Internal Sensor, ACC/Attender, and lPFC/Director (for a neuroanatomical cheat sheet click here).
The following discussion will be simplified and intermediate neurological structures will sometimes be omitted for the sake of clarity.
Let’s use the scenario of giving a presentation in front of a large audience in order to observe our anxiety circuit in action. This is a very common source of “normal” anxiety and most of us can identify with this experience.
Imagine you are standing backstage and hear the rumble of your audience or see them taking their seats. This sensory information is relayed to your amygdala/Emoter, which triggers your heart to race courtesy of the brainstem. The sensory feedback from your now racing heart is then sent to your insula/Internal Sensor.
The amygdala/Emoter and insula/Internal Sensor merge into an anxious harmony, projecting their information forward to your mPFC/Emotional Sensor and ACC/Attender.
Your mPFC/Emotional Sensory and ACC/Attender act as a gate to conscious awareness, determining whether the information about your anxious state makes its way from your subconscious to your conscious mind.
The combined signals from the amygdala/Emoter and insula/Internal Sensor coupled with the severity of your anxiety force their way past the gate into your conscious awareness. If we were to look at an fMRI (imaging technique that shows active parts of the brain) at this point in our discussion we would see your mPFC/Emotional Sensor and ACC/Attender light up like a Christmas tree.
Now you have the full anxious experience. You are entertaining conscious thoughts of forgetting your speech, embarrassing yourself, or being unable to speak. Your mind spins itself into an incoherent storm of worry as your heart thunders within your chest.
But wait! Maybe instead of getting lost in your swirling thoughts, you are able to step back and view them more objectively. You may even take a couple deep mindful breaths and engage your Task-Positive Network. As your heart slows, you are able to challenge your maladaptive thoughts with evidence from past events.
“I have given successful presentations in the past and there is no reason to think this one will be different.”
“So what if I forget part of my presentation. I’ll just look at my notes and get back on track.”
The thoughts and supervisory control over your runaway anxious brain are made possibly by the lPFC/Director. The lPFC/Director uses detached cognitive appraisal to reassess the emotional brain’s anxious state. And once the situation is reframed in a more logical formulation, the lPFC/Director sends signals to the mPFC/Emotional Sensor and ACC/Attender to quiet the circuit.
The mPFC/Emotional Sensor and ACC/Attender acknowledge this order from the lPFC/Director and utilize their inhibitory connections to the amygdala/Emoter to decrease its activation. In essence the mPFC/Emotional Sensor and ACC/Attender tell the amygdala/Emoter that the higher brain structures have deemed the situation nonthreatening despite the primary signals the amygdala is receiving. And luckily for you, the amygdala/Emoter generally listens to the mPFC/Emotional Sensor and ACC/Attender. (2)
Your heart slows, your worry subsides, and you step out onto the stage and give an excellent presentation.
This sequence of events had a happy ending, but what happens in the case of someone suffering from an anxiety disorder?
Patients suffering from a wide array of anxiety disorders demonstrate increased grey matter in the amygdala/Emoter (6). Grey matter refers to the neuronal cells that are responsible for electrical and chemical informational transmission in the brain. And if we remember from previous discussions the brain is like a muscle; the regions that are more frequently used tend to grow stronger aided by increased synaptic connections. The brain-muscle analogy is not quite perfect because the association between strength of connections and activity is relational and not necessarily causal. This means that a strong amygdala/Emoter is not necessarily the result of bench-pressing anxiety in a stressful environment. It is more likely that certain individuals may just be predisposed to developing a stronger and thus overactive amygdala/Emoter.
Interestingly, amygdala/Emoter size in childhood has been demonstrated to predict trait anxiety levels (7). And childhood anxiety has a demonstrable link to adult anxiety and mood disorders.
Another important insight for the purposes of our discussion is the fact that patients with anxiety disorders also show a consistent hyperactivation of the insula/Internal Sensor (2).
And finally, patients with anxiety disorders have decreased grey matter in the mPFC/Emotional Sensor and ACC/Attender (12).
So what does this all mean?
In your hypothetical presentation you were able to overcome your anxiety by engaging the lPFC/Director and using some basic mindfulness skills. However, in a patient with an anxiety disorder this may not be possible for a variety of reasons.
First, the anxiety alarm is quite a bit louder in patients with anxiety disorders. The amygdala/Emoter and insula/Internal Sensor are hyper-reactive to the sights and sounds of the audience, so our mPFC/Emotional Sensor and ACC/Attender get a much larger anxious jolt.
This increased dose of anxious substrate is delivered to a smaller than average mPFC/Emotional Sensor and ACC/Attender. And if we recall the inhibitory role of the mPFC/Emotional Sensor and ACC/Attender in tamping down amygdala/Emoter hyperactivation, we will realize the perfect storm that results from the neuroanatomy of patients with anxiety disorders. Not only is there more oomph to the anxiety, but also our neuroanatomy is less capable of getting the proverbial genie back in the bottle.
Interestingly, there has never been any evidence for decreased activity in the lPFC/Director in patients with anxiety disorders (2). This fact reminds us that even though the magnitude of our anxiety may be definitively larger, there is still hope of developing control over it.
I imagine the lPFC/Director as the levee that protects the rest of the brain from the storm surge of emotional content. The lPFC/Director is able to direct the wash of emotion downstream and avoid a breach that would flood our consciousness with panic. This analogy reveals that no matter how well constructed our lPFC/Director-levee is, a storm of a large enough magnitude is still capable of overrunning its embankment. It’s all a matter of magnitude.
Thus, an anxiety disorder can be conceptualized as a hyper-reactivity to the normal stresses inherent to our world. It is not a personal weakness or defect but more accurately resembles an overrun levee.
Cognitive behavioral therapy (CBT), mindfulness, medications, and many other treatments can help build up our emotional levee and allow us to deal with the inevitable surges of life.
CBT has been demonstrated to increase the ability of the lPFC/Director, mPFC/Emotional Sensor, and ACC/Attender to exert feedback inhibition on the hyperactive amygdala/Emoter and insula/Internal Sensor circuit (8).
Selective serotonin reuptake inhibitors (SSRIs) are a first line treatment in anxiety disorders. Their use has been shown to decrease activation of the amygdala/Emoter during anxiety producing situations (9).
And finally, mindfulness meditation activates the Task-Positive Network (TPN). The TPN includes the ACC/Attender and lPFC/Director and is engaged during present-moment awareness tasks. The positive effects of mindfulness meditation are hypothesized to be a result of increased control over amygdala/Emoter and insula/Internal Sensor hyper-reactivity. The cognitive control over these anxiety-generating regions of the brain is believed to be from an increased collaboration between the lPFC/Director, mPFC/Emotional Sensor, and ACC/Attender. (3)
Just 8 weeks of mindfulness-based stress reduction (MBSR) training can decrease the physical volume of the amygdala/Emoter (10).
Thus, mindfulness seems to work both at the source and at the control centers for anxiety processing.
So the next time you are feeling especially anxious, remember the lessons of the anxiety circuit. Take three deep breaths and engage your lPFC/Director to reassess the situation. Do not look away from the worst-case scenarios. Instead, look deeply into them and examine your survival in spite of each one. Communicate this knowledge of resilience to your mPFC/Emotional Sensor and ACC/Attender and allow them to quiet the churning waters of your insula/Internal Sensor and amygdala/Emoter.
1. American Psychiatric Association. (2013). The Diagnostic and Statistical Manual of Mental Disorders: DSM 5.
2. Etkin, A. (2010). Functional neuroanatomy of anxiety: a neural circuit perspective. In Behavioral neurobiology of anxiety and its treatment (pp. 251-277). Springer Berlin Heidelberg.
3. Farb, N. A., Anderson, A. K., & Segal, Z. V. (2012). The mindful brain and emotion regulation in mood disorders. Canadian journal of psychiatry. 57(2), 70.
4. Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in cognitive sciences, 4(6), 215-222.
5. Hofmann, S. G. (2011). An introduction to modern CBT: Psychological solutions to mental health problems. John Wiley & Sons.
6. Baur, V., Hänggi, J., Langer, N., & Jäncke, L. (2013). Resting-state functional and structural connectivity within an insula–amygdala route specifically index state and trait anxiety. Biological psychiatry, 73(1), 85-92.
7. Qin, S., Young, C. B., Duan, X., Chen, T., Supekar, K., & Menon, V. (2014). Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood. Biological psychiatry, 75(11), 892-900.
8. Carvalho, M. R. D., Rozenthal, M., & Nardi, A. E. (2010). The fear circuitry in panic disorder and its modulation by cognitive-behaviour therapy interventions. World Journal of Biological Psychiatry, 11(2_2), 188-198.
9. Arce, E., Simmons, A. N., Lovero, K. L., Stein, M. B., & Paulus, M. P. (2008). Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology, 196(4), 661-672.
10. Hölzel, B. K., Carmody, J., Evans, K. C., Hoge, E. A., Dusek, J. A., Morgan, L., … & Lazar, S. W. (2009). Stress reduction correlates with structural changes in the amygdala. Social cognitive and affective neuroscience.
11. Crespi, B., Summers, K., & Dorus, S. (2007). Adaptive evolution of genes underlying schizophrenia. Proceedings of the Royal Society B: Biological Sciences, 274(1627), 2801-2810.
12. Radua, J., van den Heuvel, O. A., Surguladze, S., & Mataix-Cols, D. (2010). Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders. Archives of General Psychiatry, 67(7), 701-711.