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Humans are social animals that naturally seek secure, trusting and stable partnerships, forming companionate affiliations and relationships as a part of social wellbeing, as previously brought to light by Aristotle (van Honk, Bos, Terburg, Heany, & Stein, 2015). While such companionate relations may be rewarding, given the centrality of affiliative and social concerns, negative affects such as anxiety can gain association from social situations and hierarchies. Social anxiety disorder (SAD), formerly termed social phobia, is a distressing and functionally disabling psychological disorder characterized by evident fears of social and performance based situations, resulting in phobic avoidance or endurance with intense distress despite the sociocultural context (Shlik, Maron, Tõru, Aluoja & Vasar, 2004; Cremers & Roelofs, 2016).
Amongst the most common mental disorders are anxiety disorders whereby SAD is highly prevalent, typically onsetting around mid-adolescence. Although likely underestimated, SAD has an approximated 12-month prevalence of 7.1% and a lifetime estimate of 12.1%(Ruscio et al., 2007). Despite the eminent prevalence, whilst prevailing the third highest endured psychiatric disorder, SAD is an under-recognized and under-treated condition despite being predated by childhood histories of shyness and social inhibition (Li, Chokka, & Tibbo, 2001). Anxiety disorders are highly prevalent but, the study is still in its infancy. In an attempt to understand the rising prevalence SAD in the global population, there has been increased interest by researchers determining the differences in the neurophysiology, neuroendocrinology and neurochemistry of patients with SAD in comparison to healthy controls (Bandelow et al., 2016).
In 1984, Lazarus was the first to link stress with cognitive appraisals, based on the relationship of the perceived social environment (Faravelli et al., 2012b). A self-evaluation can be positive, irrelevant or stressful and in the case of stressful appraisals they can be broken down into a threat, challenge or harm/loss depending on the available coping options as self-efficacy and the costs and benefits to wellbeing (Mulder, 2011). When inadequate coping options are perceived in the social environment along with the perception of scrutiny by others, stress in the form of social anxiety will endure (Bystritsky, Khalsa, Cameron, & Schiffman, 2013).
Social Anxiety Disorder
Diagnostic Criteria of SAD
According to the diagnostic criteria for SAD, one must endure unreasonable or excessive fear or anxiety about at least one social activity, specifically the fear of being engaged in a social activity, being observed or performing, in which one is exposed to possible scrutiny by others symptoms lasting at least 6 months (Klumbies, Braeuer, Hoyer & Kirschbaum, 2014). Such avoidance or endurance should cause intense distress or functional impairment during social, academic, occupational or other significant areas of functioning and not be attributable to direct physiological effects of substances or be better explained by the symptoms of another mental disorder or medical condition (Spence & Rapee, 2016).
Etiology and Course of SAD
In line with existing biopsychosocial diathesis-stress model of etiological onset and maintenance for SAD, a predisposition to a disorder known as the diathesis and the environmental disturbances known as the stress may lead to a clinical diagnosis of SAD (Faravelli et al., 2012b). Genetic or biological predispositions have been established for many psychopathological disorders, in the case of SAD having a hyperactive amygdala, increased CRH and cortisol levels are risk and maintenance factors (Cremers & Roelofs, 2016). Other anxiety disorders appear to be rooted more in the occurrence psychological factors such as life history, personality and stressful life experiences that eventually result in neuroendocrine alterations (Faravelli et al., 2012a). In addition to a 20-25 year course, SAD often occurs as a secondary disorder, not a short-lived process that can last a lifetime if not treated (Bystritsky et al., 2013). As long as the social aspect causes significant impairment atop the existing disorder, both disorders are labeled (Bystritsky et al., 2013). Anxiety often presents as nervousness, inhibition and other internalizing behaviours, but can also demonstrate as externalizing or oppositional behaviours in younger persons. Moreover, higher rates of functional impairment, increased likelihood of comorbid behavioural and mood disorders, and more complex profiles follow (Ruscio et al., 2007). Negative self-evaluations in social affairs and successive negative reinforcements are vital both in the development and maintenance of SAD, associated with generalized or specific approach-avoidance conflicts (Myllyneva, Ranta & Hietanen, 2015).
Neuroendocrinology, Neurochemistry and Neurophysiology of SAD
As suggested by McEwen in his model of allostatic load, prolonged and chronic or repeated hits of stress-induced exaggerations of HPA activity and sympathetic-adrenal-medullary (SAM) reaction increases the risk of vulnerability to SAD across the lifespan altering the neurogenesis and programming, thereby affecting behaviour by way of modified neuroendocrinology (Lai & Huang, 2011; McEwen, 2000). Treatments of anxiety disorders typically only brings about partial remission of symptoms or manifests elevated relapse rates, bringing to surface the need for more specific and individually tailored treatment options. As of lately, neuropeptides have emerged as viable candidates (Neumann & Slattery, 2016).
HPA axis cascade. SAD together with other anxiety disorders represent stress-related conditions whereby hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis is the joining factor between stressful life events and disorder onset (Faravelli et al., 2012a; Faravelli et al., 2012b). Centrally involved in mediating the HPA axis is, the hypothalamus (Herman & Tasker, 2016). In response to stress, after secretion of corticotropin-releasing hormone (CRH) by the parvocellular neurosecretory neurons in the paraventricular nucleus (PVN) of the hypothalamus to the anterior pituitary, adrenocorticotropic hormone (ACTH) is released into the bloodstream, eventually causing the glucocorticoid, cortisol to be released from the adrenal cortex, atop the kidneys (Herman et al., 2016).
HPA axis regulation. The CRH neurons of the hypothalamus are regulated by the amygdala, and the hippocampus of the limbic system (Faravelli et al., 2012b). After sensory information enters the basolateral amygdala, it is relayed to the central nucleus where the stress response begins to develop, where anxiety can lead to inappropriate activation, stimulating excessive CRH release (Herman et al., 2016). On the other hand, the hippocampus suppresses CRH release rather than stimulating it. With glucocorticoid receptors, the hippocampus responds to cortisol released from the adrenal gland after systemic HPA activation, participating in negative feedback regulation. Prolonged cortisol exposure during periods of chronic stress and increased glucocorticoids, results in neuronal atrophy that gives rise to a cycle of more pronounced stress responses, leading to greater hippocampal damage and reduced hippocampal volume (Faravelli et al., 2012b; Marečková et al., 2018).
HPA axis in response to stressors.Reports indicate that when tested for urinary free cortisol levels, basal cortisol levels and responses after pharmacological or psychosocial challenges are similar between SAD patients and healthy controls, (Bandelow et al., 2016). Human neuroimaging studies have shown decreased volumes of grey matter in both left and right hippocampi of individuals with maternal-prenatal stress, post-natal psychosocial stress in those suffering from SAD where a genetic predisposition may be established for anxiety disorders (Marečková et al., 2018).
HPA axis in response to treatment. Two studies in 2016 found that lesions within the paracellular PVN, as well as knocking out receptors for CRH in mice or pharmacological antagonism of CRH in humans minimized anxiety-like behaviours in a novel conditions, as opposed to ever expression of CRH which heightened anxiety-like behaviours which led to the proposal of its role in emotional regulation (Herman & Tasker, 2016; Zhang et al., 2016). CRH receptors are a promising drug target, not only because of the role in hypothalamic neurons of the HPA axis but also when used as a neurotransmitter itself in central circuits involved in the stress response such as the central nucleus of the amygdala. Therefore, injections of CRH within this region can produce the complete stress responses and signs of anxiety. On the contrary, increased glucocorticoid levels through cortisone administration may be able to prevent retrieval of fear-related memories at the level of the amygdala resulting in reduced social and phobic fear during the anticipation, exposure and recovery phase of the stressor, although not general anxiety (Bandelow et al., 2016).
SAM cascade. The emotional response to stress or threat whether it be perceived or actual, causes the hypothalamus to immediately activate the sympathetic nervous system which in turn activates the adrenal medulla through the reticular formation nerve paths of the brainstem thus secreting epinephrine and norepinephrine catecholamines. As proposed by Walter Cannon, epinephrine (E) prepares for the ‘fight or flight’ response whilst norepinephrine (NE) activates the internal body organs for physiological readiness, a short-lived process (Faravelli et al., 2012b).
HPA and SAM axes with the Stress Response
Elevated amygdala and reduced prefrontal cortex activity lead to HPA and SAM axis activation during a stressful event although through the measurement of plasma neuropeptides; Y, S, oxytocin (OXT) and plasma noradrenaline (indicators of peripheral sympathetic activity), did not reveal any differences during resting conditions or after hand immersion in ice water, a physiological stressful task, among persons with SAD (Klumbies et al., 2014; Li et al., 2001).
That being said, compared to E and NE released by the SAM system, cortisol is able to cross the blood-brain barrier, exerting direct effects on the brain (Essex et al., 2011). Despite previous thoughts that cortisol being able to cross this barrier would produce longer lasting neurologic effects, as found by Shlik and colleagues (2004), cortisol responses increased in patients with SAD but results were not statistically different from responses in healthy controls. Basal or pre-test cortisol levels were negatively correlated with social stress from the Trier Social Stress Test (TSST) suggesting that patients with chronically high levels of cortisol may actually have blunted HPA and SAM responses to experimental social stress because of the already saturated neuroendocrine reactivity. Subjects with higher basal cortisol reported higher perceived but not physiological stress during the TSST, resulting in the enhancement of subjective emotional reactivity (Takahashi et al., 2005).
Hippocampal neural activity was tracked using electroencephalograms (EEGs) and event-related potentials (ERPs) during an alternate form of the TSST, a social stressor in a study done by Faravelli and colleagues (2012b). Peer evaluations and thoughts of negative social evaluations took place, finding that females had increased neural activity even if reporting the same level of anxiety as boys, supporting the notion that SAD is more frequently reported in women, as compared to men at about a 2:1 ratio (Faravelli et al., 2012b). Although biological reactivity based on the perception of appraisals and how its physiologically manifested could be due to expectations and self-fulfilling prophecies.
Pharmacologic Treatments and Medications for SAD
Anxiolytic drugs are medications that reduce anxiety by altering synaptic neurochemical transmission in the brain (Neumann & Slattery, 2016). These medications are widely used in the treatment and reduction of anxiety, as in the case of SAD.
Serotonin. Serotonin-selective reuptake inhibitors (SSRIs); fluoxetine, paroxetine, sertraline and citalopram, are frequently used by patients with SAD, at 24% function by prolonging the actions of the serotonin, a key neurotransmitter of the emotion network, in the synapse by inhibiting their reuptake, as their name implies (Bandelow et al., 2016; Lang & McTeague, 2009). In the early 2000s, it was found by Sclik et al. (2004) owing to the high efficacy of SSRIs for the treatment of SAD, the function of serotonin was involved in its neurobiology. Such effects remain supported today; patients with SAD show exaggerated cortisol responses to SSRIs, indicating sensitivity of the post-synaptic serotonin receptors (Faravelli et al., 2012b). In a recent study, the presence of a rare mutation in the serotonin transporter gene was associated with a high incidence of SAD, further implicating serotonin in its origins (Forstner et al., 2017). Effects of SSRIs are not immediate, and therapeutic benefits develop chronically after elevated brain serotonin accumulates over weeks in response to sustained daily dosing, the structural or functional change is not yet understood (Goel, Plyler, Daniels & Bale, 2011). While SSRIs are highly efficacious, they result in weaker neuroendocrine responses than direct post-synaptic agonists and serotonin releasers, being said, immediate rises of extracellular serotonin caused by SSRIs is not responsible for an anxiolytic effects (Shlik et al., 2004). Conversely, an adaptive response to SSRIs, is the increase in glucocorticoid receptors in the hippocampal region of the brain corticosterone production independent of stress, dampening anxiety by increasing the negative feedback of the hypothalamic CRH neurons (Goel et al., 2011). According to Bandelow et al. (2016), in an assessment of salivary amylase, a marker of autonomic nervous system response and HPA axis response, measured by salivary cortisol tryptophan depleted persons showed significantly higher stress responses to a public speaking tasks than healthy controls. Tryptophan depletion represents a reduction in serotonin, as it acts as a precursor and enhancer, shown by Li et al. (2001), administration of tryptophan promotes social dominance in animal models.
Oxytocin. Neuropeptide OXT is an anxiolytic and anti-stress factor demonstrated to be a moderator of anxiety, fear and social dysfunctions through neuroimaging studies and the reduction of amygdalar responses in the face of perceptually threatening or aversive stressors (Neumann & Slattery, 2016). The dysregulation of OXT underlies social attachment (Bandelow et al., 2016). Marečková et al., (2018) found that OTX treatments protected SAD animal models against hippocampal atrophy after chronic stress exposure. Results from van Honk and colleagues (2015) show that intranasal OXT promotes trust, while reducing the level of anxiety at the level of the amygdala in combination-exposure therapy to treat SAD. This was based off the finding that OXT, as an adjunctive to exposure therapy produced positive self-evaluations of appearance and speech performance in SAD individuals, improving treatment outcome (Guastella, Howard, Dadds, Mitchell & Carson, 2009). Accordingly, because treatment for SAD is rather unspecific, hormonal, pharmacotherapy treatments and psychosocial interventions alone or in combination can be tailored and employed in a personalized way to reduce such anxiety-related tendencies (Neumann & Slattery, 2016).
Conclusions and Future Study
The present synthesis of the neuroendocrinology, neurochemistry and neurophysiology of SAD evidences an association between stress and social anxiety through different brain regions associated with the HPA axis and SAM cascade as well as the subjective perception and appraisal of social stimuli. Further, neurophysiological studies show that social anxiety is coupled with both hyperactivity of the amygdala and hippocampal hyperactivity or atrophy (Marečková et al., 2018). Additionally, it is important to keep in mind that the amygdala and hippocampus both receive highly processed information from the prefrontal region of the neocortex and this should be factored into new treatment approaches.
While research on pharmacological treatments are limited, this review provides insight into one aspect of widespread neural anomalies associated with SAD disorder. Not much was found on the application of stress treatments for anxiety aside from pharmacotherapeutic and its associated neurochemical studies on neuropeptides and neurotransmitters. Further research should look at the interactions between serotonin and oxytocin neurochemicals along with newer behavioural psychotherapies such as exposure and systematic desensitization along with cognitive behavioural therapies to determine optimal interactions for patient specific and tailored treatments to reduce symptom severity. Research should also look beyond pharmaceuticals and determine the roles of neurocogntiion and neurophysiological processes such as EEG and ERP or heart rate variability throughout the effect of psychosocial stressors on SAD.
Additionally, while this review provides support for the causal role of abnormal neural networks predisposing the onset of SAD, longitudinal studies could investigate changes over time in the stress response and the role of demographics or clinical factors play as risk factors of such changes in SAD patients along with therapeutical treatment decisions to tease apart the effects of biological predispositions and life experiences.
Finally, it is important to note that SAD is a complex mental disorder that cannot be reduced to a single neural structure thus no biological, genetic or environmental predictor is of sufficient clinical utility to inform the onset for an individual patient. In a perfect world, it would be possible to diagnose mental disorders simply by taking blood tests and choosing personalized medications or treatments for specific patients, what would be known as precision medicine.
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