Overview of the limbic system: Research on the amygdala, limbic structures implicated in emotion, what we appear to know about these structures, and how we know it. What is their role in fear and anxiety?
The amygdala, a cluster of neurons, is pertinent to fear and anxiety as we know it and damage to the amygdaloid nucleus makes this abundantly clear. Fear is in response to an immediate threat while anxiety is not the result of an immediate threat. In individuals with PTSD the amygdala is often larger, presumably because dendritic branching is wider or more prominent—sometimes, inversely, the hippocampus (responsible for learning and memory, among other important functions) will get smaller in individuals who suffer from long-term depression and/or PTSD. Research has shown that it can basically shrink; further, having a smaller hippocampus to begin with is also associated with predisposition to being affected by PTSD and related disorders. While the amygdala is central to fear, anxiety, and our stress-response, communication between the amygdala and other brain regions is key in understanding expression of the stress-response. The hippocampus (which is in front of the amygdala) means seahorse–despite looking nothing like a seahorse–but amygdala means “almond” and it actually does look like an almond (one deep within each temporal hemisphere). I could be said that the key role of the amygdala is integration of sensory stimuli that induces fear response. Damage to the amygdala disrupts emotional behavior and has been used in the past to treat severe psychiatric cases that didn’t respond to first-line interventions. Research in laboratory animals has shown that separate amygdaloid paths are responsible for fear painful stimuli, fear of predators, and for fear of aggressive members of one’s own species. Also, separate areas control changes in breathing, avoidance of potentially unsafe environments, and learning which particular environments or areas are optimally safe. Moreover, the path responsible for freezing is separate from the path that influences heart rate. Stimuli that signals a threat is relayed to the amygdala from the thalamus. the central nucleus of the amygdala controls our emotional responses to fear-response-activating stimuli—effects to posture, facial expressions, hormones, heart rate, blood pressure, and respiration all depend on activity in the amygdala. In humans, the prefrontal cortex projects to the amygdala releasing inhibitory neurotransmitters; it can influence the intensity of fear-response/anxiety-response in those who don’t have a significant anxiety disorder. Anxiolytics such as benzodiazepines (valium, Xanax, lorazepam) increase inhibitory GABA activity; there are many GABA receptors in the central amygdaloid nucleus. Barbiturates were common before benzodiazepines were available and had some pretty scary side-effects (Kalat, 2019; Ettinger, 2017).
Originally the limbic system was known as the rhinencephalon because we began studying it in rats and animals that have a proportionally large olfactory bulb, that has a strong association with that animal’s “emotional life”. The olfactory bulb in rats projects to the “nose-brain”, or rhinencephalon. In humans another school of thought emerged because of the complex emotional aspect, thereafter in humans it was referred to as the limbic system. The limbic system is what we consider to be responsible for emotions; patterns of physiology, including hormonal changes brought on by hypothalamic and pituitary activation, neurotransmission, postural and facial expressions from tension–or lack-there–of, which results from influence of pons activity. Feelings are sensory representation emotion. There are several ways to study function, one way we study these structures in humans is by way of damage that has happened naturally through accidents or war injuries. Lesions studies have helped us as well, though sometimes researchers have misinterpreted information because they were lesioning pathways, rather than structures, without knowing it. The inverse of lesioning studies would be stimulation experiments, in which case a structure is activated rather than suppressed. Voracious feeding behavior has been confused with aggression in the past, before researchers learned a bit more about ethology and how animal behavior relates to human behavior. It is difficult in animal studies, to attribute animal actions to human brain areas; this highlights the importance in ethology. We have also learned a lot about brain function from frontal lobotomy’s; they destroyed limbic structures, using extremely primitive tools like ice axes. fMRI studies also provide information in human limbic regions.
The limbic system sits on top of the “reptilian brain” (the part of the brain responsible for many primitive regulatory processes). The reason it is referred to as the “reptilian brain” is because it is evolutionarily stable and even exists in lizards. For a long time, researchers thought that the prefrontal cortex was relatively unassociated with the limbic system–but we now know that is not true. The anterior cingulate, which is part of the frontal cortex, communicates with the limbic system and helps regulate emotions through higher order thought processes. While executive thought processes can regulate emotion, it does go both ways; strong emotion affects aspects of executive function, such as impulsivity vs. planning. When we think about something sad or devastating to us CRH (corticotropin-releasing hormone) is released. The limbic system consists of many sub areas—it is also highly integrated, sending projections to many other areas within the system and elsewhere in the brain. When I say highly integrated, I’m talking about connections/projections/axonal pathways/circuitry and the like. Robert Sapolsky explains, a simple way to describe what is happening, is that every sub-region wants to tell the hypothalamus what to do (the hypothalamus is responsible for regulatory processes associated with the autonomic nervous system, which includes the sympathetic and parasympathetic nervous system (and much more). The sympathetic system is “fight-or-flight” and the parasympathetic system can be summed up with the phrase “rest and digest”; when one is highly stimulated the other one is suppressed. The hypothalamus is central to neuroendocrinology. Not only does the limbic system want to influence the hypothalamus but it also inhibits other influences—meaning proximity and influence important concepts (one synapse away or several). Most limbic regions have a number of ways to get info down to the hypothalamus, and they differ in the number of synapses. Interestingly, the olfactory system is only one synapse away from the limbic region. Some of the major structures of the system include: The amygdala of course, the Septum (midline structure), and the mammillary bodies, just behind the hippocampus, are also important areas. More key areas; The thalamus, the ventral tegmental (VTA) region, which projects to the nucleus accumbens—one in each hemisphere. Also, the anterior cingulate in the prefrontal cortex that projects bilaterally to limbic system. The circuitry of the limbic system interacts with the amygdala and provides information regarding the function of the amygdala. The prefrontal cortex is the last brain region to evolve and is associated with size of social groups. It is not entirely myelinated until mid to late 20’s, it is the area regulates impulse control, among other things (it makes sense if you think about behavioral changes over lifespan development). An interesting fact, the percentage of the brain devoted to the prefrontal cortex is indicative of social group size (in over 100 species, the best predictor of how big the PFC would be was average size of social group of the species). Circuitry of the PFC, dorsolateral prefrontal cortex, and ventral striatum are indicated in impulse control and have been associated with impulsivity in bipolar disorder, marked by mood disturbance, erratic shifts in energy levels and impulsive behavior.
Some of the main pathways associated with emotion and the limbic system include: The amygdalofugal pathway which sends projections from the amygdala to the hippocampus. It is important for the hippocampus to communicate with the amygdala; it is important to remember what to do to get out of a stressful situation or to remember what you have just done; even if it didn’t work it’s important to remember! The septum also connects bidirectionally to the hippocampus via the fimbria fornix. The septum projects to the hypothalamus and back to the mammillary bodies as well; a major limbic pathway called the medial forebrain bundle. The stria terminalis is a pathway that goes from the amygdala around the hippocampus to the hypothalamus. The mesolimbic pathway is circuitry of the VTA and nucleus accumbens which is important to our understanding of reward-driven, appetitive, behaviors such as addiction. The ventromedial prefrontal cortex and the orbitofrontal cortex have been indicated as important structures as they receive projections from the VTA, thalamus and amygdala and project that information to the cingulate cortex, hypothalamus, and even send inhibitory signals to the amygdala. They are important aspects of behavioral guidance and organization (Ettinger, 2017). We learned last week about the significance of the bed nucleus of the stria terminalis in transexuals and the sex-related volumetric dimorphism. The amygdala is right next to the hypothalamus; We can learn from the fact that this pathway takes such a long detour. This complicated pathway is indicative of neural development. As the brain developed the pathway most likely began to wrap around the hippocampus, suggesting that early in development those two areas were in different positions before flipping over creating what seems like an inefficient pathway. Mammillary bodies connect to the thalamus (the major relay-station of the brain) via the mammillothalamic pathway. The thalamus communicates bidirectionally with the PFC. There are other pathways, these are just some of the major ones. The behavioral activation system (BAS) and the behavioral inhibition system (BIS), are important for understanding situational reactions. When BAS is activated we are more likely to approach, surveys given by counselors and psychologists often address these areas with questions directed at behavioral tendencies. BAS is associated with positivity and healthy reaction, while BIS is associated with anxiety and tendency to avoid a situation based on fear or general uncertainty, and can be further implicated in heightened states of arousal, emphasized fear response and subsequent inhibition.
James-lang theory was widely discredited and the argument hasn’t necessarily been settled, but there is much research in favor of the theory. There was a study conducted where people were injected with epinephrine without knowing it. The real experiment took place in the in the waiting room, unbeknownst to the participants. A confederate would either act stressed and negative or happy, outgoing, and not generally stressed. The study showed that epinephrine is modulatory–it stimulated/strengthened whatever emotion the social situation encouraged (Sapolsky, 2011).
Where in the brain are postural and facial expressions represented? What is their role in emotion?
The pons receives input from the amygdala and sends projections that affect muscle rigidity, postural and facial expressions. One of the most important areas that the pons affects is the neck muscles; not only is the neck a vulnerable place but if damaged consequences can be dire. The central nucleus of the amygdala projects to the hypothalamus and to the pons and medulla (among other areas). The pons and medulla control fear and stress-response related facial freezing, expression, respiratory, startle-response, and heart rate. Botox, a procedure meant to reduce wrinkles and laugh-lines, has been indicated in lessening intensity of emotions. Posture has also been indicated in aggressive vs. passive behaviors and even how we react to praise. Slouching or laying down causes a more passive response and is associated with reacting with less pride when hearing good news about a performance (like a good grade). There is an interesting and noteworthy procedure, where someone is forced to smile intermittently (over and over) for a certain amount of time and eventually reports better mood through means of mechanical stimulation. This has been done in response to depression and has been shown to work. The startle reflex is a very common response to a loud noise or surprising stimuli. The auditory cortex projects to the cochlear nucleus of the medulla and then to the pons, causing this response (Ettinger; 2017; Kalat, 2019; Sapolsky, 2011).
The location and function of the cingulate cortex (cingulate): Does it have connections to the frontal cortex? What is the function of cortical influence on the cingulate?
The cingulate cortex is located in the central fissure anterior to the corpus callosum. The cingulate cortex can be divided into the cingulate sulcus and the cingulate gyrus. The region is also referred to as the limbic cortex due to high level of integration and influence associated with the limbic system. The anterior cingulate projects directly to the prefrontal cortex and is considered part of it, while the posterior cingulate connects to the more central limbic area. The cingulate receives projections or sensory information about our behavioral and physiological responses to stress and fear. As I mentioned previously, heart rate will increase, respirations increase, muscle rigidity, blood flow, posture and facial expression are all notable changes, processed by this area. The cingulate cortex essentially integrates and maps these changes contributing to our perception of these changes and the feelings that represent them. Damage to the cingulate cortex does not prohibit understanding of fear but it does inhibit our subjective perception of related feelings. When we are not in immediate danger, and it is wise to ignore these adaptive responses, it is the job of the prefrontal cortices to inhibit amygdaloid activity. Unfortunately, this does not always happen.
What is the main difference between fear and anxiety?
Fear is an evolutionary adaptive mechanism. Fear can be associated with an immediate threat to our safety while anxiety is a primarily psychological stressor. When we are stressed several mechanisms are activated and we call this the “stress response”. One of the primary issues is that this stress response evolved for short term use and if used to much it can cause many health issues. The stress-response essentially shuts down the “long-term projects” in order to mobilize energy and increase cardiovascular activity to push that energy. In short term this response can sharpen cognition, responsiveness and alertness. If we consider what is happening in the body, we can understand why this mechanism is meant as a short-term solution. Digestion, growth, and reproductive systems are all suppressed in order to focus the bodies energy and attention on an immediate threat. For instance, if you have the bacteria known for causing stomach ulcers, and you are stressed your body isn’t going to effectively protect and repair your stomach lining. Long-term efforts to mobilize energy cause stress-related disorders such as myopathy and increase the severity of adult onset diabetes. Increased cardiovascular tone is associated with cardiac stress, and hypertension, among other serious and sometimes life threatening issues. Not only does suppression of the digestive system impair the ability to repair an ulcer but it also increases deposition of fat. In extreme cases of psychogenic distress, children have been known to actually stop grown. Stress impairs the release of hormones and when a child is severely stressed, they can be affected by what is called Psychogenic Dwarfism. When they are taken out of the severely stressful situation they generally start growing again. Suppression of the reproductive system can cause irregularity in menstrual cycles and other serious stress-related health issues—essential if we cannot use androgen to synthesize estradiol, we will suffer the consequences. In men similar issues are caused by decreased testosterone. Erectile dysfunction is a possible stress-related issue that will cause even more stress! There is a clear-cut relationship between fear, the adaptive stress response, stress-related disorders, muscle rigidity and suppression of many important long-term bodily functions. To further elaborate the difference between fear and anxiety I will give an example; Fear could be associated with being held at gun-point or having to escape a threatening situation rapidly whereas anxiety can be worrying about the next panic attack you will have—worrying about a test—worrying that you will give yourself an ulcer because you worry so much (Ettinger, 2017; Sapolsky, 2017).
Antianxiety medication is effective in reducing severe anxiety. How does this work? There are GABA receptors in the amygdala? Describe them
Studies have found deficiencies in GABA receptor expression, in patients with certain types of anxiety disorders like GAD. GABAergic neurons are distributed throughout the cortex, hippocampus, limbic region, basal ganglia, and other regions as well. GABA exerts inhibitory effects on nuclei of the amygdala and hypothalamus.
Studies have used an elevated maze to test a rodent’s propensity toward avoidance or action in pursuit of food/reward. Drugs that are known to reduce anxiety in humans also reduce anxiety in the rodents which helps in understanding the associated mechanisms. It is thought that GABA activity in the amygdala and anxiety are both regulated by the hypothalamic activity. Dopamine projections from the VTA to the amygdala inhibit the inhibitory projections from the prefrontal cortex to the amygdala, that are meant to dampen anxiety. Therefore, disinhibition causes these anxiety-related symptoms. Dopamine, along with GABA, and serotonin, play a crucial role in modulation of anxiety and stress. Stress influences dopamine activity in the nucleus accumbens and the frontal cortex (among other areas). The function of a medications like Xanax or other GABA agonists rely on presence of GABA. If there is no GABA available, they would not work. Medications like valium have been used to treat muscle spasms as well which highlights the strong relationship between stress and muscle tension. As the amygdala has many GABA receptors in the central nucleus, benzodiazepines readily bind to these sites and increase sensitivity to the GABA. There are GABA A and GABA B receptors. The GABA A receptors are ionotropic and GABA B receptors are metabotropic. The ionotropic GABA A receptor has at least five different binding sites; The primary site is for GABA but there are more sites and they are named after the drugs that bind to them. For example, the benzodiazepines bind specifically to the benzodiazepine site. The GABA A sites are more common and contextually relevant. Benzodiazepines open Cl- ion channels when they bind, hyperpolarizing the postsynaptic neuron. Hyperpolarizing a postsynaptic neuron makes it less likely to fire–essentially it takes more positive input to make it fire. (Ettinger, 2017).
Alcohol’s biphasic (low vs high dose) effects on aggression:
At low doses alcohol simply acts as an anxiolytic, inhibiting anxiety but acting as a system depressant. As a GABA A agonist, alcohol exerts inhibitory signals on the cortex which can lead to poor judgment and impulse control while at the same time inhibiting the central amygdaloid nucleus, reducing stress/anxiety. At high doses other systems are affected substantially through inhibition of dopamine and serotonin-regulating-mechanisms. This causes euphoria and also contributes to aggressive tendencies or other antisocial behaviors. As I mentioned above, the frontal cortex is important for impulse control, judgment, social behavior and our understanding of what kind of social behavior is acceptable—inhibiting this area disinhibits many other areas. Essentially the cortex is no longer monitoring and regulating your behavior which can lead to more drinking and many other poor decisions that one wouldn’t normally make. So, we have inhibited executive function and disinhibited reward-seeking behaviors. As mentioned before, the ventral tegmental area and nucleus accumbens are considered to be the area associated with appetitive behaviors and addictions reliant upon activity of dopamine releasing neurons that promote pursuit of reward; referred to as the mesolimbic system. Alcohol acts upon this system; though it should be mentioned that alcohol acts upon many systems at a cellular level. Apparently, injecting GABA directly into the VTA inhibits the regulatory activity, increasing dopaminergic activity in the nucleus accumbens. Ingesting alcohol in large amounts will also act upon this system and increase dopamine activity. Dopamine neurons in the ventral tegmentum are influenced by GABAergic neurons within that brain region. When alcohol increases GABA activity this inhibits dopamine activity in the VTA and therefore release of dopamine in the nucleus accumbens. GABA Areceptors seige the VTA stimulating increased mesolimbic dopamine activity by lack of regulation. A (2008) study indicates that alcohol causes a biphasic effect on dopamine activity. Initially, in phase one alcohol increases dopamine activity in the mesolimbic system before phase two, GABA mediated inhibition. There are potentially two different and distinct populations of neurons with different levels of sensitivity to GABA inhibition—Or the effects of alcohol on reward-system release of dopamine might be limited by neural inhibition in the VTA (Ettinger, 2017).
Poets, musicians, and writers have described for centuries the pain associated with emotional loss. We have all experienced this pain when we lost a loved one or a relationship ended badly. Now science has exposed this pain. Panksepp et al Actions describes the similarities in the experiences of physical pain and emotional pain. They provide great evidence:
I think we have all experienced psychological pain; pain rooted in psychological distress that actually has the ability to affect us physiologically. It is an interesting phenomenon and I enjoyed learning about it from a neurobiological vantage point. According to the Panksepp article, “Feeling the Pain of Social Loss”, there are nine forms of grief. We often associate psychological pain with abstract metaphors rather than accounting for the physiological and neurobiological implications. Functional Magnetic Resonance Imaging has become a powerful tool in discovering which brain mechanisms are at play during emotional stimulation and the subsequent subjective evaluation. The study of reference was done by Eisenberger et al., using fMRI to elucidate brain mechanisms associated with social isolation or “being left-out” or excluded, so to speak. While lying in an fMRI machine, participants were put into two different situations, in one scenario they were able to watch as others participated in a ball-tossing game but they were not actively and intentionally excluded after participating. In the second scenario they were prompted to think they were included for a short amount of time before being purposely secluded by, what they thought, were their peers or other participants. This is where the cingulate gyrus comes in to play. The cingulate gyrus is often referred to in terms of anterior and posterior and different areas activate based on type of stimuli and expression of subjective emotion (feelings). The cingulate is known to bilaterally project to the frontal cortex and the limbic system. Situational differentiation was seen based on subjective feelings of type of exclusion. Both, the cingulate and the ventromedial prefrontal cortex are highly associated with limbic regions due to integration. The anterior cingulate cortex activates in relation to level of subjective psychological distress in relation to feelings of seclusion. The prefrontal cortex is implicated in executive function, regulatory action—rooted in logic—essentially evaluating a distress signal and inhibiting emotional distress when necessary; Meaning both areas activate for different reasons. While the prefrontal cortex wants to inhibit, or at least dampen psychological distress, that doesn’t mean the distress signals don’t have an evolutionary purpose and value. There are many benefits in social support. Of course, there’s the obvious reason that it is important for survival associated with immediate distress (a baby being left alone). But also, much research involving stress-response—even in animals—identifies psychological benefits in social interaction that can have long-term effects on health and stress. Even rats who are put in stressful situations show much less severe health side-effects when they have a “friend” to support them! Empathy for others and emotion based on personal experience is associated with this area in the cingulate cortex. One study showed that this area that is associated with the pain of actually being poked in the finger AND of watching a loved one get poked in the same manner (poked hard enough to cause distress but not enough to do any lasting damage). While the anterior cingulate is associated with distress exaggeration and emphasis, the posterior cingulate is indicated in emphasis or elaboration of positive feelings. Endorphins, endogenous brain opioids, and synthesized opioids sooth pain and antagonists of opioid receptors are known to do the opposite. Other neurotransmitters are involved in regulation, but they are difficult to study. Antidepressants and even placebos can inhibit anterior cingulate activity and promote posterior activity. Brain regions associated with evolutionary drive to be near caregivers are not limited to the anterior cingulate, they also include the dorsomedial thalamus, brain stem, the bed nucleus of the stria terminalis, the ventral septal and dorsal preoptic areas (studies in non-human animals have been particularly helpful in studying this through stimulation of separation cries). This study highlighted the neural circuitry and brain regions associated with exclusion, but there are many associated questions yet to be answered (which is great for researchers).
Rather than simply providing APA style citations I will specifically credit some of my sources. Especially with lectures and books, general citations don’t always do justice. Much of the information I gathered was based on open-course lectures from Robert Sapolsky, Biological Psychology (Kalat, 2019), and R.H. Ettinger PhD (psychopharmacology, 2017). Dr. Ettinger posted very helpful information; Beyond he wrote a great textbook on psychopharmacology that actually addresses many of these questions. Even with this plethora of resources, the neurobiology of emotion is a complicated subject. I found myself continually adding information and attempting to dissect complex concepts.
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