Stress Reaction and its Pathophysiology

Pathophysiology of Stress Reaction
Stress may be defined as the physiological reaction of the human body which acts as the mediation mechanism, connecting a particular stressor with its associated target- organ effect. In this paper, the physiological and anatomical bases of our body’s stress response will be described, within the bounds of historical bases and analyses, theories and latest research outcomes, through (1) tracing psychophysiological effector processes actually representing the above- defined stress response, and (2) dealing with fundamental neuroanatomical structures (Everly & Lating, 2012).
Neurological Foundations
A grasp of the concept of stress response necessitates a discussion of its bases, residing in the nervous system’s function and structure. The nervous system’s fundamental functional units are called neurons (see Fig.1).
Neurons, which conduct motor, regulatory and sensory signals all through the body, possess the following basic units: (1) dendrites and postsynaptic dendritic membranes; (2) axon presynaptic membranes (end points of the telodendria) and telodendria (the axon’s branching projections); and (3) the neuron’s cell body that contains the cell’s nucleus (Everly & Lating, 2012).
Fig 1. A typical neuron
Neural transmission
Incoming signals first reach postsynaptic dendritic membranes. When these membranes are stimulated, ionotropic (electrical) and metabotropic (chemical) processes commence, with the neuron conducting incoming signals via the cell’s body and the dendrites. Lastly, an impulse is transmitted to presynaptic membranes via the axon and telodendria. From here, the signal is conducted to the next neuron’s postsynaptic membrane, which is a complex task as neurons aren’t in actual physical contact with each other (Everly & Lating, 2012).
Neurons are separated by a synaptic cleft, which may be traversed through the help of neurotransmitters. These chemicals that reside in the telodendria’s storage vesicles wait for the right cue before moving towards presynaptic membranes. After reaching there, they eventually discharge into synaptic clefts for inhibiting or stimulating the succeeding neuron’s postsynaptic membrane.
The subsequent step in this study will be to analyze human stress reaction’s basic anatomical structures. The human body has two basic nervous systems, peripheral and central, which are functional structures that house several million neurons (see fig 2) (Everly & Lating, 2012).
Fig 2. Nervous systems
The central nervous system comprises of a ‘triune’ brain (with 3 functional levels) and spinal cord. The neo- cortex constitutes the brain’s highest and most complex level. Besides communication, interpreting and decoding sensory signals, and controlling overall musculoskeletal or motor behavior, the neo- cortex (especially its frontal lobe) controls imagination, memory, logic, planning, apprehension, decision making, and problem solving (Everly & Lating, 2012).
The next functional level’s key element is the limbic brain, whose discussion is vital to the subject of stress, owing to its being the brain’s affective/ emotional control center. This system comprises several neural structures, including the hippocampus, hypothalamus, septum, amygdala, and cingulate gyrus. The pituitary (endocrine) gland has a key role in the limbic system (Everly & Lating, 2012).
The peripheral nervous system (PNS) comprises all neurons excluding the central nervous system (CNS) and has two networks), namely autonomic and somatic nervous systems. The latter transfers motor and sensory signals between the PNS and CNS, innervating both the skeletal/ striate musculature and sensory organs. The PNS can, anatomically, be considered a CNS extension as the former’s functional control bases reside in the latter (Everly & Lating, 2012).
Human stress reaction may be best understood by analyzing its dynamic “process”, which can be defined from a “system” standpoint, i.e., from the perspective of interlinked multidimensionality. Fig. 3 depicts the systems perspective that has undergone significant evolution of late and which bears upon the human stress reaction phenomenology. The model serves as the uniting theme, facilitating the attainment of better insights into human stress phenomenology as well as its treatment and measurement. Fig.3 indicates that human stress reaction’s epiphenomenology is that of complex interactive processes that possess numerous major elements:
1. Perceived or actual stressor events.
2. Activation of target organ.
3. Affective integration and cognitive evaluation.
4. Coping behavior
5. Neurological stimulating mechanisms (for instance, locus ceruleus, hypothalamic nuclei and limbic nuclei).
6. Stress reaction (a physiological mediation mechanism) (Everly & Lating, 2012).
Fig. 3 A systems model of the human stress response
Stressor Events
Stressor events may be categorized into: (1) biogenic and (2) psychosocial stressors (Girdano, Dusek, & Everly, 2009). The latter represent perceived or actual environmental events which set the scene for stress reaction production. They aren’t able to cause stress reactions directly; rather, they need cognitive evaluation mechanics. In fact, a majority of stressors are psychosocial stressors. On the other hand, biogenic stressors are the actual causative elements of stress reaction production. These stimuli get around higher cognitive evaluation processes, working directly on the neurological and affective stimulating nuclei. Therefore, owing to their biochemical facets, they trigger stress reaction directly without the customary required affective-cognitive processing (Everly & Lating, 2012). Biogenic stimuli include:
· Nicotine
· Ginseng
· Caffeine and
· Extreme cold or heat, pain- causing stimuli and other such physical factors
Cognitive–Affective Domain
Realistically, “reality” doesn’t exist if one fails to consider the human perception which potentially bears upon it. This model outlines the affective- cognitive domain for capturing this concept. Cognitive evaluation denotes the cognitive interpretation process (or, in other words, the meanings assigned to the universe unfolding before us). Further, affective integration denotes the coloring and mixing of experienced emotions into cognitive interpretation, which leads to an affective- cognitive complex which reflects the way stressors are eventually felt. Basically, this crucial integrated view implies an ascertainment of whether or not the psychosocial stimuli get converted into stressors. But this perceptual process is personalized uniquely, and susceptible to personality trends, biological dispositions, available coping resources and learning history. While Fig.3 depicts a mutuality between affective and cognitive mechanisms, one point to bear in mind is: considerable evidence exists in support of the cognitive primacy theory, which claims that cognition governs perceived emotion or affect, thereby assuming a superordinate part when restructuring human behavioral trends (Everly & Lating, 2012).
As previously observed, appraisal represents a function of all extant coping resources on hand, biological dispositions, personality trends, and learning history. After evaluation is carried out, efferent impulse projects to the following, for potentiating stimulation of key effector systems:
1. The limbic system’s extremely sensitive affective anatomy, particularly the hippocampus region, for experiencing stimulus- specific sensed emotion, in addition to the ability of triggering visceral effector processes.
2. Neo- cortex regions related to neuromuscular behavior; here, tension or muscle tone increased via extrapyramidal and pyramidal systems, with the intent to act being translated, potentially, to real evident motor activity (Everly & Lating, 2012).
Up until now, one may have understood that after being perceived, psychosocial stimuli stimulate general arousal and cognitive evaluation mechanisms. Stimuli that are evaluated as being of a threatening, challenging or abhorrent nature will probably lead to emotional arousal. In a majority of persons, limbic center activation for emotional stimulation results in the expression of sensed emotions as neuromuscular and visceral activity. This neuromuscular and visceral activation denotes the multi- axial physiological mediation mechanisms known as “stress response”. Prior to discussing this nature of stress reaction, there is a need to, firstly, take a look at the mechanism prefacing stress reaction axes activation. Prior studies have called for specific considerations of mechanisms, labelled ‘neurological triggering mechanisms’ (NTM) which trigger multi- axial stress reaction production (Everly & Lating, 2012).
Neurological Triggering Mechanisms
NTMs comprise of locus ceruleus, hypothalamic efferent stimulating complex, and the limbic system. Connected via both serotonergic and dorsal and ventral adrenergic projections, the complex seems to include the hippocampus, locus ceruleus, posterior and anterior hypothalamic nuclei, and septal– amygdaloid –hippocampal complexes. The structures are, apparently, the functional epicenters for somatic and visceral efferent secretions as a reaction to emotional stimulation. In other words, the structures apparently result in multi- axial stress reaction. In fact, the aforementioned centers are also apparently able to establish a possibly-self-perpetuating, endogenously- governed neurological tone. Fig. 3 initially portrays this positive feedback loop concept using ‘I’ (dotted line). The dotted lines that follow are marked using Roman numerals for showing other feedback processes which maintain the state defined as “ego-tropic tuning,” “charged arousal” or “limbic hypersensitivity”. All terms indicate a tendency for physiological stimulation.
To be more specific, the above terms express a preferential SNS pattern (and relevant arousal mechanism) reactiveness. This chronic tonic standing might, with time, constitute the foundation for multiple psychophysiological and psychiatric disorders. The processes whereby this neurological tone might impact a specific target organ forms the focus of the system’s model’s subsequent phase: the stress reaction— a physiological mediation mechanism (Everly & Lating, 2012).
The Stress Response
What pathogenic mediation mechanisms potentially cause stressors and their subsequent evaluations to eventually impact target organs to the extent that they lead to disease and dysfunction? While an all-inclusive conclusive answer hasn’t been discovered as yet, applied physiological studies offer significant insights into pathogenesis mechanisms whereby stressors lead to disease. In this section of the paper, three physiological pathways recognized for demonstrating extraordinary reactiveness with regard to psychosocial stimuli will be explained: (1) neural axes, (2) endocrine axes, and (3) neuroendocrine axis (see Fig.4) (Everly & Lating, 2012; Tort & Teles, 2011).
Fig. 4 The stress response
The stress reaction process’s temporal sequencing is the amalgamating thread all through the course of stress response. Research reveals that a stressful stimulus’s most direct reaction takes place through end organs’ neural innervations, directly. Intermediate stress impacts are on account of the neuroendocrine “fight- or- flight” axis. This axis’s response time is decreased through its use of systemic movement as a mechanism of transport. But its impacts vary in duration from intermediary to chronic, potentially overlapping with the final stress reaction system for responding to endocrine axes (stimulus). These axes represent the final stress reaction pathways, largely on account of their nearly total dependency on the human circulatory system for transport, and of the need for a more intense stimulus for activating the axis.
The GAS (General Adaptation Syndrome) offers another schema for extending the endocrine reaction axis in organism adaptation to a chronic stressor’s presence. Understanding that all the above axes’ activation can potentially overlap is vital. The endocrine and neuroendocrine axes which both possess chronic responsiveness capability are most commonly concurrently active. Meanwhile, clearly, every axis and mechanism outlined will not be able to discharge whenever an individual experiences a stressor. Possibly the clearest fact is: all parasympathetic and sympathetic effects aren’t evident in case of every stressor (Everly & Lating, 2012; Tort & Teles, 2011).
But certain evidences indicate that a psychophysiological tendency exists for certain individuals to experience stress-reaction pattern specificity – the stress reaction axes and multiple mechanisms working within each. These represent the likely reaction patterns resulting whenever human organisms are subject to stressors. The timing and reason for response aren’t clear. The IInd and IIIrd feedback loops denote the physiological stress reaction’s capacity of further stimulating the affective- cognitive domain, in addition to neurological stimulation mechanisms, for further promulgating the stress reaction. This sort of feedback mechanism can offer the potential for self-sustaining psycho-physiological reaction. This represents the human stress physiology as is understood at present (Everly & Lating, 2012).
Target-Organ Activation
The word ‘target- organ activation’ as has been utilized within the current model denotes the phenomenon wherein the neural, endocrine and neuroendocrine components of stress reaction just described in the preceding paragraphs engage in the (1) activation, (2) inhibition, or (3) increase of regular activation, or (4) catabolizing of a specific human organ system. Potential stress reaction target- organ systems include, but aren’t limited to, the skin, cardiovascular system, immune system, gastrointestinal system, and the human brain along with its mental state. Target organs’ activation and the resultant emergence of a number of clinical symptoms and signs typically leads to the deduction that extreme stress stimulation exists. With respect to which target organ/ organs will be most prone to manifesting stress- connected dysfunction or disease, this determination seems to be aided by the following two key biogenic elements: target- organ specificity and reaction mechanism stereotypy. Lastly, in Fig. 3, the feedback loop IV suggests that activation of the target organ and the resultant symptoms and signs of disease might impact the affective- cognitive conduct of the patient, thus potentially impacting further neurological stimulation and ongoing stress reaction activity. In certain instances (for example, hysteria-prone, agoraphobic or obsessive patients), hypersensitive target- organ symptom awareness may lead to the creation of a pathogenic self- sustaining feedback loop (Everly & Lating, 2012).
Coping
The term ‘coping’ may be described as: intra- psychic as well as action- oriented attempts at managing (or, in other words, mastering, reducing, minimizing or tolerating) internal and environmental demands, and the conflicts between them, that either stretch or go beyond the resources of an individual. The coping mechanism/ process may take place both before a stress- giving confrontation (this pre- event coping is known as anticipatory coping), and as a response to an earlier or a current harmful confrontation. From the point of view of the present model (Figure 3), coping might be regarded as cognitive or environmental techniques which aim at attenuating stress reaction. According to the model in question, coping is perceived to be residing after target- organ activation and physiological stress reaction. Therefore, coping may be viewed as a means of reestablishing homeostasis (Everly & Lating, 2012).
Coping approaches may be both maladaptive and adaptive (Girdano et al., 2009). The former effectively decrease stress for the short run; however, they cause long- run health issues (for instance, drug/ alcohol misuse, interpersonal withdrawal, and cigarette smoking), whereas the latter coping approaches decrease stress whilst simultaneously promoting health in the long run (for instance, exercise, a proper diet, and relaxation) (Everly & Lating, 2012).
Figure 3 echoes the view that effective coping leads to the reduction or elimination of extraordinary target organ activation and the re- establishment of homeostasis. In case the coping mechanisms prove unsuccessful, activation of target organ is maintained, with increased likelihood of development of disease associated with the target organ. Again, the feedback loops V & VI indicate the interrelationship between every element that is covered by Fig. 3. The model that Fig. 3 portrays is a reflection of the integration of critical thought and latest studies on the subject of human stress. It has been presented as a pedagogical instrument which is aimed at facilitating clinicians’ understanding of the stress reaction phenomenology (Everly & Lating, 2012).

























References
Everly Jr, G. S., & Lating, J. M. (2012). A clinical guide to the treatment of the human stress response. Springer Science & Business Media.
Girdano, D., Dusek, D., & Everly, G. (2009). Controlling stress and tension. San Francisco, CA: Pearson Benjamin Cummings.
Tort, L., & Teles, M. (2011). The endocrine response to stress-a comparative view. In Basic and Clinical Endocrinology Up-to-Date. InTech.