The Immune System, Mental Health and Emotions
The immune system refers to how the body responds to pathogens and removing cancer cells. It is now recognised that inflammation has a critical role in psychosis. Likewise, inflammation is pertinent for depressed and anxious behaviour. Targeting the immune system can modify mood, behaviour, and inclination for auditory deliria.
Overview of the Immune System
Leukocytes (white blood cells) are the main cells of the immune system. Inflammation ensues when white blood cells are activated to migrate and fight against a pathogen. With inflammation, the local blood vessels dilate, and the skin turns red and may appear swollen.
This vasculature dilation happens when the white blood cells migrate to the specific site. Some of the activated white blood cells may discharge damaging molecules that alter molecules (oxidizing) of either the pathogen or components of our body. These particles can eradicate pathogens, but the unrestricted discharge of harmful molecules is detrimental to the individual. The immune system can make various types of responses to fight specific threats.
Two Major Divisions: Innate and Adaptive Immunity
The Innate System
Two key leukocytes of the innate system are macrophages and neutrophils. These cells react to foreign substances located in the body. Receptors for foreign-appearing molecules are situated on the exterior or inside the leukocytes. These receptors can react to more than one specific molecule. When countering an abnormal molecule, the innate system responds quickly. Activated macrophages and neutrophils discharge hormones called cytokines. Some of the cytokines (hormones from white blood cells or infected cells) include interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha. These cytokines cause the cells lining the blood vessels to express intercellular adhesion molecules (surface molecules) that let the white blood cells transfer more quickly to the intruder. Interleukin-6 stimulates the liver to release proteins, (i.e., C-reactive protein), which assist the attack on the invader (Murphy, 2012). Macrophages and neutrophils can both engulf pathogens and are the white blood cells that first respond to the site of inflammation. The macrophages and neutrophils release harmful molecules once at the site of inflammation. Unfortunately, the innate immune system cells are not specific, and the inflammation can negatively impact the health of the individual.
The innate immune system is a major player in many chronic diseases (i.e., chronic obstructive pulmonary disease, arthritis, cardiovascular disease, and cancer). For instance, neutrophils (first responders to a site of infection) can discharge superoxide and nitric oxide (noxious chemicals) that can harm tissue. The superoxide can oxidise fats in the bloodstream. In a blood vessel, the oxidised fat molecule can appear like a foreign intruder to a macrophage. The macrophage attacks the transformed fat element adheres to the wall of the blood vessel and results in plaque on the vasculature wall (i.e., cardiovascular disease)
Moreover, cancer also appears to be advanced by an activated innate immune system (Caielli, Banchereau, & Pascual, 2012; Mantovani, 2010; Slavich & Irwin, 2014). The existing academic evidence suggests that inflammation is also the main cause of depression, anxiety, and psychosis. It is important to remember that if you cut your hand, the fast-responding macrophages and neutrophils are your first line of defence and sometimes inflammation is a good thing. However, the control of inflammation is critical (Murphy, 2012).
The Adaptive Immune System
The other key division for the immune system is adaptive immunity. The T cells and B cells (adaptive responders) are very specific and only react to one protein. After a preliminary encounter with a pathogen, the T and B cells need approximately five days to proliferate and launch a response. The B cells generate antibodies that bind to foreign elements, so they get attacked by other cells. Antibodies can also inhibit the foreign pathogen or elements from infecting other cells. The role of T cells is multidimensional with some T cells communicating to the B cells to construct antibodies and other T cells attack the tumour cells or cells infected with a virus.
Vaccination is an approach for manipulating the adaptive immune system. Following a preliminary encounter with a foreign protein in the vaccine, the T and B cells activate, separate, and proliferate with some T and B cells becoming memory cells. Memory cells can mount a rapid response when the same pathogen is seen on a subsequent occasion.
Psychoneuroimmunology
Psychoneuroimmunology is an area of research that studies how our emotions affect the immune system. Original research by Ader found that the immune system can be classically conditioned. Ader paired an immune system–dampening drug with needle injection. After the classic conditioning, Ader indicated that the needle only was enough to suppress immune system activity in patients with autoimmune disease. Ader’s work was highly appropriate for individuals with inflammatory conditions such as systemic lupus erythematosus (lupus) (Ader and Cohen, 2001).
Subsequently, contemporary studies have shown that individuals in distress have greater activation of the immune system in terms of inflammation, but less of an ability to mount an adaptive immune response. Stressed individuals may also have a depressed capacity for producing antiviral cytokines (O’Connor et al., 2014). As previously discussed, individuals who are stressed fail to respond to vaccinations. Consequently, distressed people are more disposed to innate immune system activation diseases (e.g., cardiovascular disease), and are also more predisposed to diseases associated with failure to activate the adaptive system (e.g., cancer, viral infections of cells).
The Glial Cells
Most of the cells in our brain are glial cells or support cells. (Glial descends from the Greek word for glue.) There are three types of glial cells: microglia, astrocytes, and oligodendrocytes and all have essential functions. Microglia are the brain’s resident macrophages and are a form of white blood cell that can phagocytise (eat) debris. The microglia play an essential role in removing old synapses and remodelling the brain. They also have a critical part in brain inflammation, which may be problematic in those individuals with depression. When the microglia are not initiated to fight infection, they have a role in maintaining brain health (Kettenmann, Kirchhoff, and Verkhratsky, 2013; Littrell, 2012; Parkhurst et al., 2013).
Astrocytes are the second type of glial cell in our brain and have receptors for glutamate (the main excitatory neurotransmitter). By detecting glutamate release, they can discharge elements that will affect blood vessels, resulting in a redistribution of blood flow to more active brain regions (Nolte, 2009). Astrocyctes also [in part] have a role in depositing glucose and attaining this fuel (in the form of lactic acid) to highly active neurons. One belief regarding the cause of ADHD is that the astrocytes are slow in their functioning (Killeen et al., 2013). Oligodendrocytes are support cells that bind around the axons of neurons and allow for quicker movement of neurotransmitter bundles down an axon.
Regions in the Brain and Emotions
Emotion is a term used in our collective dialect. Emotion has been suggested to be multifaceted in our behaviour. Explicit actions are often a part of an emotional reaction. The autonomic nervous system prepares the body for a response (Lang and Bradley, 2010). This action is reinforced by alterations in heart rate and blood flow and output from several glands. Individuals are normally aware of the experience of emotional changes and can describe their feelings. Subsequently, emotions involve three channels: explicit behaviour, subjective experience measured by self-reporting, and the involuntary nervous system responding.
How individuals become cognisant of their feelings so that they can self-report was an area of great debate between James and Cannon and Bard, who proposed the Cannon-Bard concept. James hypothesised that individuals decided what they experienced by observing their own physical responses. The Cannon-Bard notion proposed that internal events founded the core for self-report (Friedman, 2010). Both concepts have been supported to some degree. Backing for James’s concept is found in trials in which research subjects have their facial expressions manipulated by the investigators and are then subjects self-report their thoughts. Corresponding facial positions can increase subjective feeling while being required to maintain a neutral expression can diminish self-report of feeling (Duclos et al., 1989). Therefore, when individuals define their subjective experience some of their self-reports will be established on what is occurring in their brains without communication with other structures, feedback from their overt behaviour may also add to their self-assessment.
A large body of research has focussed on brain structures connected with changes in emotional behaviour. The amygdala is involved when assigning emotional significance to an environmental stimulus. Though the circuitry in the amygdala is articulated for fearful reacting to conditioned and unconditioned stimuli, the amygdala is also concerned in responding to positive stimuli (Berridge and Kringelbach, 2013; Lane et al., 2009b). The amygdala receives input from a structure central in the brain that receives incoming information from all sensory modalities called the thalamus. The amygdala sends output to the hypothalamus. The hypothalamus regulates the autonomic nervous system and the pituitary gland (master gland) of the body. Consequently, output from the amygdala controls the autonomic nervous system affects several of the body’s major glands (Lane et al., 2009b).
Research on animal models suggests that emotions can be evoked by stimuli without cognitive processing of the meaning of the stimuli. For instance, rats become alarmed at the scent of a cat (LeDoux, 2012). Imaging work with human subjects confirms that subliminal staging of a fearful face can induce activity in the amygdala. Fear can be evoked without any cognitive processing of the stimulus.
The late Lazarus was an authority figure in stress research and maintained that situations or stimuli require appraisals regarding the seriousness of the situation as well as appraisals of our resources for coping with the situation before emotion would be evoked (Schooler and Mauss, 2010). The research on emotional regulation shows that when situations are interpreted in non–emotion-provoking means, activity in the amygdala subsides.
Autonomic Nervous System
Neurons in the hypothalamus and in the brain stem, regulate the autonomic nervous system. The autonomic nervous system may be separated into two distinctive divisions: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). Both systems direct projections to internal organs, however, neither system is under voluntary control.
Structurally, the neurons in each system are easy to identify with the neurons belonging to the PNS occur at the top and bottom regions of the spinal cord. The neurons of the PNS perform independently of each other. The neurons of the SNS project from the middle segments of the spinal cord and at their first synapse transfer projections to each other (sympathetic chain ganglia) so that they perform concurrently. There are two synapses from neurons in the spinal cord to the target organ in both the PNS and the SNS. In physiology literature, the terms preganglionic neuron and postganglionic neuron are used to explain this. The word preganglionic denotes the first neuron in the autonomic nervous system whose cell body is in the spinal cord, which synapses onto the neuron in a collection of neuronal bodies (ganglion). The postganglionic neuron is the second neuron whose cell body is in the ganglion whose axon interacts with the target organ.
Sympathetic Nervous System
Activation of the SNS transpires in preparation for fight or flight. The initial neurotransmitter discharged in this response is acetylcholine and the second is norepinephrine. With the activation of the SNS our pupils dilate, heart rate accelerates, vasculature constricts, respiration increases, and the force of the heart pumping blood is increased. The centre of the adrenal gland (termed the medulla of the adrenal gland) which secretes adrenaline is formed by a postganglionic neuron of the SNS. Adrenaline/epinephrine mainly interacts with cortisol (a stress hormone) ensuring that fat cells release accumulated fuel and the liver releases glucose. To regulate the SNS, the output is measured at various points. Regions in the brain stem monitor blood loss and other bodily conditions. For an emotional response to complex situations, areas in the hypothalamus and the amygdala are more pertinent to regulating the SNS (Critchley et al., 2003).
Parasympathetic Nervous System
The first and second neurotransmitters of the PNS are acetylcholine with activation of the PNS being incorrectly interpreted as opposing the SNS. The PNS and SNS are distinct systems that often affect organs in opposed ways but sometimes work together. However, the PNS normally dominates during phases of relaxation, when the body digests food. The hypothalamus and areas in the brain stem control the PNS.
Hormonal Activity
A hormone is a substance released into the bloodstream, generally by a gland, which affects targets that are further away. There are several hormones in the body that control behaviour. Indeed, more hormones involved in weight and appetite control seem to be discovered each year.
Cortisol
Cortisol is considered a stress hormone; however, it is important to remember that it is a glucocorticoid, a name that indicates that cortisol will adjust the availability of blood glucose. All varieties of stress, including distance running or starvation, elevate cortisol levels in the body. The effects of cortisol are extensive. Cortisol can enter cells and bind to receptors in the cytoplasm of a cell. Along with its receptor, it travels to the cell’s nucleus to increase the expression of various proteins and decrease the expression of others. Cortisol regulates the expression of various proteins and one of cortisol’s roles is to prepare the body for fight or flight. In response to cortisol, fatty acids are released from fat cells so that fuel is available for the working skeletal muscles. Numerous immune system functions become suppressed. Long-term cortisol secretion can ultimately catabolise the body, reduce bone strength, alter the location of fat stores throughout the body, and decrease fat deposits under the skin so the skin tears more readily. Continued levels of raised cortisol are also suggested to reduce the hippocampus (area for memory retrieval and memory formation; Chetty et al., 2014; McEwen & Milner, 2007) and may also affect psychological function. In the central amygdala, cortisol increases the production of another stress-enhancing neurotransmitter called corticotropin-releasing factor [CRF] (Davis, Walker, Miles, and Grillon, 2010; Shin and Liberzon, 2010).
Cortisol also sensitises the receptors for norepinephrine and epinephrine (adrenaline), which are spread throughout the vascular system in our body. Individuals who have lost the capacity to produce cortisol (Addison’s disease) because they are unable to respond to norepinephrine and may not have the physical capacity to ascend a flight of stairs. The regulation of cortisol secretion, as with most major hormones, is through the hypothalamus. The amygdala and the dorsal anterior cingulate cortex send projections to the hypothalamus. It is a two-step process to get from the hypothalamus to the release of cortisol. A part of the hypothalamus (the paraventricular nucleus) releases corticotropin-releasing factor to the pituitary gland of the brain. In response to the release of the corticotropin-releasing factor the pituitary gland releases adrenocorticotropic hormone [ACTH]) into the bloodstream. The pituitary glands hormone (ACTH) acts on the adrenal glands (which sit on top of your kidneys) to release cortisol.
There is a short-term cessation in this pathway (termed the hypothalamic-pituitary-adrenal axis or HPA). The ventromedial prefrontal cortex, the structure involved in downregulating anxiety in response to a dopamine signal, can restrict the extent of the cortisol stress response (Sullivan and Dufresne, 2006). For long-term regulation, the body does have a receptor in the hippocampus to “turn off” cortisol release. When there are excessive levels of cortisol in the blood, the hippocampus turns off the region in the hypothalamus which releases CRF, and the rest of the cascade is, therefore, turned off. In extremely stressed individuals, who are elevated on inflammatory markers, the cytokines induce a loss of sensitivity in the cortisol receptor to the cortisol (Pace & Miller, 2009). In those instances, the turnoff mechanism does
not work properly.
The dexamethasone suppression test is a rudimentary measure of depression. Synthetic cortisol is administered, and a blood test is taken to determine whether cortisol levels are inhibited. Individuals with depression are more likely to fail this test as their receptors for cortisol in the hippocampus do not respond and they do not decrease their secretion of cortisol in response to the synthetic cortisol. The dexamethasone suppression test is not specific for depression and individuals with systemic inflammation (alcoholism, autoimmune disease, infection) may also be dexamethasone “non-suppressors” (Pace & Miller, 2009).
Chronic distress can evoke an additional abnormality of the HPA system as well. The loss of a variable pattern of release during the day (called a circadian pattern) is also an indication of stress. In those individuals who are extremely stressed, cortisol is released at a continual rate throughout the day, rather than being at the peak levels in the morning and declining during the day (O’Connor et al., 2012).
Specific Emotions
Distress/Anxiety
The amygdala is a central structure involved in responding to innate and learned fears. The bed nucleus of the stria terminalis (BNST) is involved in maintaining a strong disposition to respond to fearful situations. Segments of the amygdala are also involved in fear conditioning. Higher-order brain structures also contribute to the subjective experience of distress. The dorsal anterior cingulate is involved in processing pain, whether emotional or physical pain and potentiating anxiety. The dorsal anterior cingulate activates in response to social exclusion, and when an individual perceives to be stressed (Eisenberger et al., 2007; Lieberman, 2013). The dorsal anterior cingulate is active in processing physical pain, the pain of a broken heart (Eisenberger, 2012), and the pain of envy (Takahashi et al., 2009). Research-based on brain imaging with humans has noted that the dorsal anterior cingulate has been involved in error detection, conflict monitoring, and processing emotion (Lieberman, 2013). This region receives input from the amygdala, from the locus coeruleus (releasing norepinephrine) and the ventral tegmental region and has reciprocal connections with the prefrontal cortex (Paus, 2001).
The neurotransmitter involved in distress, agonists at acetylcholine receptors in the brain stem (periaqueductal gray) are linked with distress calls (Kroes et al., 2007). The periaqueductal gray, in the midbrain, is an output structure for the amygdala. The areas in the dorsal area of the periaqueductal gray induce fight or flight. The areas in the ventral area of the periaqueductal gray induce freezing.
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Revulsion and Disgust
The insula has an essential role in responding to varied emotions concerning disgust and anxiety. The insula receives input about the condition of the body and the skin (Craig, 2002). This region of the brain is activated by disgust induced by unpleasant flavours and in response to psychologically repulsive images (Calder et al., 2007; Wicker et al., 2003). Some distressing situations involve both the activation of the dorsal anterior cingulate cortex and the anterior insula. Both the dorsal anterior cingulate cortex and the anterior insula are active when managing emotionally distressing and repulsive images, responding to unpleasant tastes, managing the distressing facets of pain, and when thinking about unhappy events (Lieberman, 2013; Shin and Liberzon, 2010). Additionally, the basal ganglia are also activated during disgust or recognition of disgust in others. Including moral disgust.
Pleasure
According to Berridge, pleasure producing nuclei are in the ventral pallidum, part of the nucleus accumbens, and the parabrachial nucleus, which is in the midbrain. The neurotransmitters in these nuclei are cannabinoids, GABA, and opioids. Though dopamine is concerned in signalling to these nuclei, it is not the neurotransmitter used in producing our subjective experience of pleasure but the orbitofrontal cortex. Naturally, pleasure is a complex emotion if it can be termed an emotion. Kringelbach (2010) states that pleasure is the result of a process of valuation, that is, the consequence of reaching a conclusion. For instance, anticipating a reward can be distinguished from appreciating a reward (Der-Avakian and Markou, 2012). Equally, pleasure many come in several forms including relaxed satisfaction, excitement, pleasure from consumption, and pleasure from sex. Pleasure can also originate from the individual accomplishment or from a connection to others. These experiences are likely to include their own circuitry. Describing positive affective experiences involve a variety of qualitative experiences. For those pleasurable conditions that are associated with excitement, activity is frequently registered in the orbitofrontal cortex and the ventral striatum, including the nucleus accumbens (Kringelbach, 2010).
The pleasure of observing an enemy suffering is catalogued in the nucleus accumbens (Takahashi et al., 2009). For aggressive play in animals, the medial prefrontal cortex and the parietal cortex have an essential role (Burgdorf et al., 2010; Burgdorf, Panksepp, and Moshal, 2011) as does endocannabinoids in the amygdala and nucleus accumbens (Trezza et al., 2012). Moreover, Porges (2011) contends that the evolutionarily newer segments of the vagus nerve, when active, are associated with subjective comfort and conceivably a component of specific forms of pleasure.
Anger and Rage
Anger and rage are other emotions that may be evoked by various circuitry systems. For instance, when an animal aggressively bares its teeth (sham rage) can be evoked by stimulating several areas of the hypothalamus or the septal area. Anger can be activated by triggering the circuitry linked with safeguarding the young and staking out reproducing prospects (Young and Alexander, 2014). Carver and Harmon-Jones (2009) propose that kinds of anger are linked with activation of the behavioural activation system, involving dopamine. For predatory aggression targeted at acquisition or activation of appetitive the dopaminergic structures may be involved. Making individuals angry is also linked with the activity of the behavioural activation system (Harmon-Jones and Sigelman, 2001). Though, predatory aggression may not be the same as aggression involved in securing territory or defensive aggression linked with fear.