14. Anxiety

12 01neurLecture 14; October 24, 2013Anxiety (and fear)

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Anxiety and fear Fear is an immediate alarm reaction to

present danger, characterized largely by a strong motivation to escape.

The fear response activates the sympathetic nervous system and the sympatho-adrenomedullary (SAM) axis (see the stress lecture for a reminder). This brings about the fight or flight

response that helps prepare our bodies to deal with an immediate threat.

Anxiety and fear are not the same thing, but they are inter-related in some interesting ways.

Anxiety is about looking into the future.

Fear is about dealing with the present.


Anxiety and fear The symptoms of anxiety and fear can overlap to varying

degrees, and in practice they are very dicult to tell apart.

Apprehension/worry about real or

perceived future threats.

Emotional and physiological

reaction to real or perceived

immediate threats.

Anxiety! Fear!


Anxiety and fear Disorders such as generalized anxiety disorder (GAD) consist

mostly of anxiety.





immediate threats.

Anxiety! Fear!GAD


Anxiety and fear On the other hand, panic disorder consists mostly of the fear

response.





immediate threats.

Anxiety! Fear!Panic disorder


Anxiety and fear And to make things more dicult, disorders such as post-

traumatic stress disorder (PTSD) involve a mixture of both anxiety and fear-related symptoms.





immediate threats.

Anxiety! Fear!PTSD


The study of fear Animals (and humans) have an escape

distance. When potential threats cross into the escape distance, the animal will try to escape.

It turns out that in both humans and animals the fear response is graded depending on the perceived proximity of the threat. Distant threats activate different behaviors

and brain regions that immediate threats.

Shorter escape distances typically mean that an animal is more tame, more willing to take risks, or perhaps just stupid.


Studying fear in humans The behavioral eects of the fear response

can be measured by looking at how people try to escape the red circle.

The neurobiological eects of the fear response can be measured with functional MRI imaging (fMRI). fMRI is a brain scanning technology that can

measure neural activation in the human brain. This technique is non-invasive, and works while the person is alive and conscious.

The physiological eects of the fear response can be measured with a polygraph machine. Polygraph machines (aka lie detectors) measure

sympathetic nervous system activity by looking at skin perspiration, breathing rate, heart rate etc.,

Functional MRI machine

Polygraph machine


Fear and the amygdala Recall that the amygdala is a part of the limbic system

found within the temporal lobes.

The amygdala has direct access to fresh sensory information coming from the thalamus and sensory cortex. This allows it to quickly react to dangerous stimuli often

before the individual realizes what theyre looking at!

The amygdala is linked to the recognition, expression, and experience of fear in both humans and animals. The amygdala is active during situations of anxiety and

phobia.

The amygdala has connections with the prefrontal cortex, periaqueductal gray, and hypothalamus. These connections are bi-directional, meaning structures can

mutually influence each other.

However, the amygdala is also activated by positive stimuli such as music and sex. This suggests that the amygdala may be specialized for

processing emotional arousal.

Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014


Physiological eects of fear

Through its connections to the hypothalamus, the amygdala can activate the sympathetic nervous system. Accordingly, the body undertakes a number of adaptations that help is escape or otherwise deal with a threat of some kind.

Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014


Studying fear in humans

Its impractical and unethical to place humans into truly threatening situations. How do we find out whats happening in their brains when theyre afraid? A video game is an acceptable substitute.



In this game, you are a blue triangle stuck in a maze. After a while, a red circle appears and starts chasing you. If it catches your triangle, you receive a real-life mild electric shock.



The game can be varied by increasing the shock, and increasing the diculty of the enemy circle. This changes how people react behaviorally and neurobiologically.


Levels of the fear response

Distant, yet visible threats activate the prefrontal cortex. This seems to reflect planning (possibly

of an escape strategy).

Close, immediate threats perceived as highly dangerous tended to shut down the prefrontal cortex, but activate a region in the midbrain called the periaqueductal gray.


So what? Well it seems we have yet another situation

where the prefrontal cortex must do battle with lower brain regions (in this case the periaqueductal gray and limbic system).

The extent to which either of these two sets of systems is in control seems to determine our behaviors and emotional states with respect to whatever we are afraid of. Lots of PFC activity suggests thinking, planning

and ruminating on threats (anxiety). More PAG and limbic activity suggests a more

emotional, autonomic driven state (fear).

The fear response is, therefore a combination of the physiological eects of SNS activation, and the psychological/neurobiological eects of the PFC shutting down and the limbic system and brainstem taking control.

This seems like it would be scary.


Introduction to anxiety Anxiety is a complex phenomenon.

On the one hand, anxiety is an emotional state that is a fundamental component of nearly every mental illness in the DSM

On the other hand, anxiety can be its own disorder, neatly separated from the others.

In general, anxiety is a negative mood state characterized by bodily symptoms of physical tension, and psychological symptoms of apprehension about the future.

Each state of anxiety is unique, because one can worry about all sorts of dierent things.


Characteristics of anxiety disorders

Generalized anxiety disorder (GAD) and

panic disorder are both classified by the DSM as anxiety disorders. The various phobias are also classified as anxiety

disorders.

Post-traumatic stress disorder was classified as an anxiety disorder until the DSM5, but it is now classified as a trauma- and stress-related disorder.

Similarly, obsessive-compulsive disorder (OCD) was once categorized as an anxiety disorder, but as of the DSM5, it has its own section.

Other DSM5 anxiety disorders include things like: Separation anxiety disorder, Selective mutism, Phobias, Social anxiety, etc.,


Characteristics of anxiety disorders

Anxiety disorders are often comorbid with depression

and other mental illnesses. Comorbidity is when an individual suffers from two or

more conditions at the same time. They often share biological/psychological links.

Anxiety disorders are often comorbid with other anxiety disorders. Many people have more than just one. Approximately 50% of individuals with one anxiety

disorder also have a second disorder.

Suicide is a surprisingly common risk with anxiety disorders. One study found that 20% of patients with panic disorder had attempted suicide at least once. Depression with comorbid anxiety significantly increases

the risk of suicide as compared to depression alone.


Panic disorder Panic disorder is characterized by recurrent and sudden debilitating

panic attacks that come on unexpectedly. When panic attacks are reliably triggered by a specific stimulus, a

specific phobia is a better diagnosis.

According to the DSM5, panic attacks are abrupt surges of intense fear or discomfort that reach a peak within minutes.

Panic disorder is very prevalent, aecting 3.4-4.7% of the US population at some time in their lives .

Because panic attacks are debilitating and unpredictable, people who experience them often withdraw from society, fearing the consequences of experiencing a panic attack in a public place.


Symptoms of a panic attack


Neurobiology of a panic attack In many ways, panic attacks resemble the normal fear response.

The dierence is that panic attacks are generally unprovoked and undirected. That means that the individual isnt afraid of anything in particular.

Because of this, the fear response is very difficult to escape from.

Brain imaging studies of individuals with panic disorder show amygdala activation in response to anxiogenic stimuli. The amygdala is often, but not always, hyper-sensitive in people with

panic disorder. However, the amygdala has also been shown to be hypo-sensitive

under certain conditions in panic disorder patients.

Twin studies show that panic disorder is highly heritable (48%), but so far the only gene that is clearly linked to the disorder is COMT, which codes for the enzyme Catechol-O-methyltransferase, an enzyme that degrades catecholamine neurotransmitters. Possession of one or two low-activity alleles (versions of the gene) is

associated with increased amygdala reactivity to negative stimuli.


Inducing panic attacks Panic disorder is associated with increased CO2 sensitivity.

Panic attacks can be provoked by exposing patients to higher than normal concentrations of CO2.

This has lead to the suffocation false alarm theory, which posits abnormalities in respiratory control areas of the brainstem.

Other substances can provoke panic attacks in individuals with panic disorder. Administering these compounds to healthy individuals does not generally produce panic attacks. Yohimbine: An agonist at a certain subset of adrenaline receptor.

Yohimbine produces sympathetic arousal by mimicking the effects of peripheral norepinephrine and epinephrine.

Cholecystokinin (CCK): A peptide hormone produced in the small intestine. CCK normally mediates digestion and satiety.

These results suggest that panic disorder is associated with increased sensitivity to certain chemical compounds. This is an important finding, because it tells us that panic disorder

is not all in the mind.


Generalized anxiety disorder In contrast to panic disorder and specific

phobias, generalized anxiety does not have a specific focus, nor does it have a specific start or end time. Generalized anxiety is also called free-

floating anxiety.

Generalized anxiety disorder (GAD) is characterized by excessive anxiety, worry, and rumination. People with GAD tend to worry endlessly

about multiple things, frequently switching between worries.

Approximately 2.9% of the US populations meets the criteria for GAD during a given 1-year period. This makes GAD quite a common disorder.

Interestingly, only a minority of individuals with this condition seek treatment.

About 66% of people diagnosed with GAD are female.


Symptoms of GAD


Neurobiology of GAD Relatively little is known about the neurobiology

of GAD.

Unlike panic disorder, GAD is not associated with sympathetic nervous system over-activity. Rather, individuals with GAD are said to be

autonomic restrictors, meaning that their sympathetic nervous system is actually less responsive to stressors.

Individuals with GAD show increased activation of the frontal lobes in response to stressful stimuli. This might be indicative of their frantic, intense

thought processes about whatever is worrying them.

Data on the amygdala in GAD is mixed, but many studies point to reduced amygdala size/function.


A highly simplified synthesis

PD is a disorder thats primary fear-based. People with this condition show (during panic attacks)

decreased PFC activity and increased limbic, PAG, and SNS activity.

PFC! GAD is a disorder thats primarily anxiety-based. People with this condition show increased PFC activity

and reduced limbic and SNS activity.

PFC!

Amygdala!PAG!

Amygdala!

PAG!


Pharmacological treatment of anxiety Many drugs are eective in treating anxiety, and

some of those currently in use today have a history dating back thousands of years.

It turns out that alcohol has been a perennial favorite of the stressed and anxious. This was true even before the disorders had official

names. Hippocrates once wrote Wine drunk with an equal

quantity of water puts away anxiety and terrors implying that even ancient medicine was aware of this phenomenon.

There is a high rate of comorbid anxiety disorders in alcoholic patients. A surprisingly large number of alcoholics meet the

diagnostic criteria for one or another anxiety disorder (GAD, and social anxiety being the most common).


Pharmacological treatment of anxiety Drugs that treat anxiety are called anxiolytics (from

anxietatem anguish (L.) and lytos loosen (G.)).

Anxiolytics can be broadly classified into fast-acting and slow-acting drugs. Fast-acting drugs tend to be given for PD, while slow, longer acting drugs are favored for GAD.

Benzodiazepines are drugs that are agonists at GABA receptors. They increase inhibitory signaling in the brain, leading to sedation and relaxation. Examples: Xanax (alprazolam), Valium (diazepam),

Ativan (lorazepam) Side effects: excessive sedation, cloudy thoughts, risk

of dependence.


Pharmacological treatment of anxiety Antidepressant medications, such as SSRIs are

often quite eective in treating anxiety disorders. These have begun to replace classic anxiolytic

drugs as the first line of treatment for anxiety disorders.

Beta blockers are traditionally prescribed for cardiovascular disease, but can also be useful in treating short-term anxiety. Beta blockers block the -adrenergic receptor in

the sympathetic nervous system. They do not cross the blood brain barrier and enter the CNS.

Because they dont enter the brain, beta blockers only treat the autonomic symptoms of panic/anxiety.

This turns out to be quite useful, because mental processes are unaffected. These are often used by musicians who have performance anxiety.

14. Anxiety

Documents

fear fear

fear response

fear disorders

perceived immediate

symptoms of anxiety

fearrelated symptoms

perceived future threats

study of fear animals